Abstract: Nell'ultimo ventennio abbiamo assistito a due grandi rivoluzioni tecnologiche, lo sviluppo delle tecniche del DNA ricombinante e lo sviluppo delle Tecnologie informatiche. I metodi di sequenziamento sempre più avanzati hanno reso disponibili una grande quantità di dati ma la loro utilità è strettamente correlata alla disponibilità di strumenti informatici che ne consentano l'immagazzinamento e la catalogazione razionale allo scopo di consentirne l'analisi. Tutto ciò ha fatto nascere la neccessità di creare banche dati specializzate. MitBASE, AMmtDB e MitoNuc sono tre banche dati specializzate mitocondriali sviluppate dal gruppo di bioinformatica di Bari. MitBASE è una banca dati che raccoglie in maniera integrata sequenze di DNA mitocondriale di differenti organismi. La sua realizzazione è stata possibile grazie alla collaborazione tra sette differenti gruppi di ricerca europei ciascuno dei quali si è occupato della raccolta e della codifica dei dati relativi ad uno specifico gruppo di organismi (uomo, vertebrati, invertebrati, protisti, funghi, piante ed alghe). Le sequenze nucleotidiche e le loro eventuali varianti, raccolte dalle banche dati primarie e dalla letteratura, relative ai diversi organismi sono state poi arricchite con informazioni aggiuntive di carattere specifico per ciascun nodo. Il gruppo di ricerca di Bari si è occupato della strutturazione e della codifica dei dati relativi a varianti del DNA mitocondriale di uomo e di altri vertebrati con particolare attenzione ai dati inerenti a studi di genetica di popolazioni umane e a studi correlati alle patologie mitocondriali. Un nodo supplementare è stato inoltre sviluppato per raccogliere sequenze di geni nucleari del lievito Saccharomyces cerevisiae coinvolti nella biogenesi mitocondriale. Il database è disponibile al seguente indirizzo: http://www3.ebi.ac.uk/Research/Mitbase/mitbase.pl. AMmtDB è invece una banca dati costituita da una collezione di sequenze multiallineate di geni mitocondriali di vertebrati e invertebrati. Le sequenze multiallineate si riferiscono a geni che codificano per proteine e tRNA. Sono presenti inoltre anche multiallineamenti della regione del D-loop dei mammiferi. Tutti i dati sono stati strutturati per essere interrogati mediante il sistema di retrieval SRS all'indirizzo: http://bio-www.ba.cnr.it:8000/BioWWW/#AMMTDB. MitoNuc è una banca dati specializzata di geni nucleari di Metazoi coinvolti nella biogenesi dei mitocondri. Le informazioni relative a ciascun gene riguardanti ad esempio la localizzazione submitocondriale del prodotto, la sua eventuale tessuto specificità, il peptide segnale, le regioni 5' e 3' UTR dell'mRNA, sono strutturate in modo tale da consentire un efficace retrieval. Tale banca dati potrà essere proficuamente utilizzata per lo studio delle proprietà strutturali e funzionali dei geni nucleari codificanti per proteine mitocondriali, dei loro prodotti e delle interazioni tra il sistema genetico nucleare e quello mitocondriale. La banca dati è disponibile all'indirizzo: http://bio-www.ba.cnr.it:8000/srs6/

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Abstract: The explosive growth of the biological data, stimulated by genome projects, has generated a parallel development of efficient computational approaches suitable for several biological research projects. In this area the need of high performance computing is growing, though usually not affordable by computational resources of a single research laboratory. Grid computing addresses this problem by coordinating and unificating several computational resources. To face the problem of searching "Conserved Sequence Tags" (CSTs) between an input DNA sequence, and several whole model genomes a grid framework can provide high performance, high availability and can fairly handle hundreds of concurrent request. Because the size of several whole genomes now exceed the memory capacity of a single machine, it is necessary to spread the search across multiple distributed working hosts to achieve high performance. This also improves the high availability, since the redundancy of the services increases the tolerance to both machine and network failures. This system also guarantees that the same services can be completed by many machines, reaching the ability to perform more requests that a single machine can handle.

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Abstract: Mitochondria are sub-cellular organelles, present in the majority of eukaryotic organisms, which play a central role in the energy metabolisms of cells. They are also involved in many other cellar processes such as apoptosis, aging and in a number of different human diseases, including Parkinson’s, diabetes mellitus and Alzheimer’s. Despite to their importance in the cell life maintenance, about the 95% of proteins, contributing to mitochondrial biogenesis and functional activities, are nuclear encoded, synthesized in the cytosol and targeted to mitochondria. The expression and assembling of these proteins are strictly dependent by the coordinated activities of the two genomes, mitochondrial and nuclear, but the molecular mechanisms and co-evolutionary processes of the cross-talk between these two genomes are still largely unknown. MitoNuc is a specialized database of nuclear encoded mitochondrial proteins in Metazoa. It provides comprehensive data on genes and proteins consolidating information from external databases. These data include: gene sequence, structure and information from ENSEMBL, protein sequence and information from SWISSPROT, transcript sequence and structure from RefSeq and UTRdb, disease information from OMIM. Each database entry consists of a nuclear gene coding for a mitochondrial protein in a given species, and reports information on: species name and taxonomic classification; gene name, functional product, sub-cellular mitochondrial localization, protein tissue specificity, Enzyme Classification (EC) code for enzyme and disease data related to protein dysfunction. For each gene and gene product the Gene Ontology (GO) classification with regard to molecular function, biological processes and cellular component is reported too. Links to external database resources are also provided. As far as the gene and transcript sequences data are concerned, in the previous MitoNuc releases they were extracted from the EMBL related entries. Due to the high level of sequences redundancy in the primary database, the majority of MitoNuc entries contained more than one transcript and coding gene sequence for the same gene, thus introducing a remarkable redundancy level that affects the effectiveness of the database for sequence analysis aims. In order to remove redundancy we generated a MitoNuc section of gene and transcript sequences derived from those organisms whose genome sequence draft has been completed and annotated in ENSEMBL. These MitoNuc entries are available in the database section called “MitoNuc Genomics” that, at present, include the following species: Homo sapiens, Rattus Norvegicus and Mus Musculus. MitoNuc can be queried using the SRS Retrieval System (http://www.ba.itb.cnr.it/srs/); the present release contains a total of 1344 entries among which 662 are collected in the MitoNuc Genomic section. The total number of species included in MitoNuc is about 64.

Abstract: The incredible explosion of “knowledge production” in Biology in the past two decades has created a critical need for bioinformatic instruments able to manage data and facilitate their retrieval and analysis. Molecular sequences and biological data on nuclear mitochondrial genes and their products are publicly available from a wide variety of mitochondrial specialized databases. Some are species-specific, mainly human dedicated, others contain only few species and for most of them the only sequences data reported concern proteins. We have developed MitoRes database to collect and integrate information on nuclearly encoded proteins and genes targeting the mitochondrion for all metazoan species and to provide a flexible and efficient tool for the export of bio-sequences in support of researchers interested in functional characterization of gene, transcript and amino acid sequences related to biogenesis, metabolism and pathological dysfunctions of mitochondria.

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Abstract: Mitochondrial disorders are clinical phenotypes associated with abnormalities of oxidative phosphorylation (OXPHOS), the primary energy-producing process of all aerobic organisms. Disorders of OXPHOS are recognized as the most common inborn errors of metabolism affecting at least one in 5000 newborn children. Except for complex II, which is composed of proteins all encoded by nuclear genes, the other OXPHOS complexes are built up of both mitochondrial and nuclear DNA encoded proteins; so, assembling the OXPHOS complexes and fine tuning their activity require specialized regulatory mechanisms to optimize the cross-talk between the two genomes and ensure the coordinated expression of their relevant products. In this context, the characterization of nuclear genes encoding for mitochondrial proteins and of functional elements regulating their expression is of crucial importance to clarify real genetic causes of mitochondrial diseases, to assess the correct diagnosis and set up new and effective therapies. Despite the long evolutionary divergent time, many key pathways that control development and cellular physiology are conserved between Drosophila and humans, and about 70% of the genes associated with human diseases have direct counterpart in the Drosophila genome. To investigate on the functional constraints acting on the evolution and on the regulatory mechanism coordinating the expression of OXPHOS genes we have identified and characterized sequence and structure of these genes in three species of diptera, D. melanogaster, D. pseudoobscura and A. gambiae, and compared them with their human counterparts. Data obtained from this study have been annotated in the MitoDrome2 database. The availability of data produced by our study in MitoDrome2 is expected to be particularly useful for biologists and clinicians interested in studies of functional genomics related to mitochondrial biogenesis, metabolism and to their pathological dysfunctions.

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Abstract: The present paper describes AMmtDB a database collecting the multi-aligned sequences of Vertebrate mitochondrial genes coding for proteins and tRNAs, as well as the multiple alignment of the Mammalian mtDNA main regulatory region (D-loop) sequences. The genes coding for proteins are multi-aligned based on the translated sequences and both the nucleotide and aminoacid multialignments are provided. As far as the genes coding for tRNAs are concerned, the multi-alignments based on the primary and the secondary structures are both provided; for the Mammalian D-loop multialignments we report the conserved regions of the entire D-loop (CSB1, CSB2, CSB3, the Central region, ETAS1 and ETAS2) as defined by Sbis? et al. (1). A flatfile format for AMmtDB has been designed allowing its implementation in SRS (2) (http://bio- www.ba.cnr.it:8000/BioWWW/#AMMTDB). Data selected through SRS can be managed using GeneDoc (3) or other programs for the management of multi-aligned data depending on the userís operative system. The multiple alignments have been produced with CLUSTALV (4) and PILEUP (5) programs and then carefully optimized manually.

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Abstract: The detemination of nucleic acids and protein sequences, made ever easier and faster by modern technologies and instruments, has allowed considerable progress in biomedical research. Nowadays exponential growth in the number of amminoacid and protein sequences needs computer-based technologies and tools for their management and analysis. Furthermore, suitable network infrastructures are also instrumental for researchers to access these data from the PC on their desk and analyse them with specific algorithms. To this purpose we have developed a WEB interface (BioWWW) which allows to access different specialised databases and biosequence analysis methods developed within the research activities of the Italian EMBnet node and of other EU funded projects. Products presently available under BioWWW are the following: - MmtDB, a metazoan mitochondrial DNA variant database; - KEYnet, a hierarchically structured database classifying genes and proteins according to their function; - UTRdb, a non-redundant database of untranslated 5' and 3' sequences of mRNA from eukaryotes; - PLMItRNA, a higher plant mitochondrial tRNA genes and molecules database. - WORDUP, an algorithm to determine statistically significant oligonucleotides in isofuctional sequence collections; - CODONTREE, a programme for the analysis of codon usage in protein coding genes; - PATSCAN, a programme to identify complex patterns in nucleotide and amminoacid sequences. The site BioWWW (http://bio-www.ba.cnr.it:8000/BioWWW/#AMMTDB) is constantly updated as new programs and databases are made available by our research group.

Abstract: La crescita parallela delle tecnologie Informatiche e delle Telecomunicazioni ha sin dalla seconda metà degli anni ‘80 favorito la crescita delle reti Bioinformatiche. La grande quantità di dati, da una parte, e il gran numero di ricercatori interessati a consultare le banche dati biologiche e a svolgere analisi sui dati in esse contenute, dall’altra, ha indotto i ricercatori coinvolti nella gestione dei dati a strutturare reti informatiche. La prima rete Bioinformatica è stata EMBnet (European Molecular Biology Network) costituita nel 1988 su iniziativa del laboratorio Europeo di Biologia Molecolare di Heidelberg (GE) da parte di dodici centri di differente nazionalità europee afferenti al laboratorio stesso. La rete EMBnet rappresenta il primo modello di 'Laboratorio di Bioinformatica distribuito e senza muri'. La finalità di EMBnet è quella di sostenere e far progredire la ricerca nel settore della biologia molecolare e della biotecnologia, nel senso più ampio del termine, attraverso gli sforzi combinati dei rappresentanti di ciascun nodo EMBnet, i quali offrono le loro specifiche competenze a supporto della comunità scientifica. La rete EMBnet attualmente è costituita da trentacinque nodi europei ed extraeuropei. I nodi sono a loro volta classificati in: Nodi Nazionali e Speciale. I nodi nazionali sono centri di bioinformatica, nominati dall’autorità governativa del proprio paese, i quali hanno il compito di fornire alla comunità scientifica accademica e industriale accesso a banche dati di biosequenze e programmi d’analisi, e organizzare corsi di formazione orientati all’utilizzo degli strumenti Bioinformatici. I nodi speciali sono centri di bioinformatica che possiedono delle forti competenze negli aspetti legati allo sviluppo di banche dati di biosequenze e di programmi d’analisi. Nodo Nazionale Italiano EMBnet Il gruppo di Bioinformatica e Genomica, dell’Area di Ricerca CNR di Bari, è responsabile del nodo nazionale Italiano. Il nodo nazionale mette a disposizione dell’utenza, costituita da numerosi laboratori universitari, centri di ricerca pubblici e privati, banche dati primarie di biosequenze (Acidi Nucleici, Proteine), banche dati specializzate e programmi per l’analisi funzionale. Le analisi che i ricercatori possono condurre utilizzando i pacchetti e i programmi d’analisi disponibili presso il nodo nazionale EMBnet sono: Ricerca di similarità tra sequenze e banche dati; Allineamento e multiallineamento di biosequenze; Individuazione di regioni codificanti proteine; Ricerca di elementi funzionali funzionali quali promotori, siti di splicing ecc. ; Predizione di strutture secondarie in sequenze di acidi nucleici e proteine. Evoluzione Molecolare Parte degli strumenti bioinformatici, banche dati e programmi di analisi, (Tabella I) messi a disposizione dell’utenza è il risultato delle attività di ricerca del gruppo. Tutti i servizi forniti dal nodo nazionale sono accessibili per via telematica mediante delle connessioni di lavoro interattive ed utilizzando la rete Internet. Il nodo italiano EMBnet, nell'ambito dell'attività di formazione, organizza periodicamente corsi di formazione presso la sede dell'Area di Ricerca o su richiesta presso le sedi degli utenti.

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Abstract: The 5’ and 3’ untranslated regions of eukaryotic mRNAs may play a crucial role in the regulation of gene expression controlling mRNA localization, stability and translation efficiency. In order to study the general structural and compositional features of these sequences we have previously developed UTRdb, a specialized database of 5’ and 3’ UTR sequences of eukaryotic mRNAs cleaned from redundancy (Pesole, Liuni et al. 2000) . Utrdb (release 10.0) contains 75,448 entries (26,145,985 nucleotides) which are also annotated for the presence of functional sequence patterns whose biological activity has been experimentally demonstrated. All these patterns have been collected in the UTRsite database where for each functional pattern, corresponding to a specific entry, the consensus structure is reported with a short description of its biological activity and the relevant bibliography. Furthermore, UTRdb entries have been annotated for the presence of repeated elements present in the Repbase database (Jurka 1998) . A total of 5,818 functional elements and 54,975 repetitive elements are annotated in UTRdb. All Web resources we implemented for the retrieval and the analysis of UTR sequences are available at the UTR home page (Pesole and Liuni 1999b) we recently implemented. UTRdb entries can be retrieved through the SRS system where crosslinks to UTRsite as well as to the nucleotide or aminoacid primary database are also established. Through the Web facility UTRscan any input sequence can be searched for the presence of a functional pattern annotated in UTRsite and UTRfasta allows to assess sequence similarity between a query sequence and UTRdb entries. The analysis of complete UTR sequences contained in this database showed that 5’-UTR sequences, on the average 187 nucleotides long, were 1,2 to 4,3 times shorter than the corresponding 3’-UTR sequences in the various taxonomic groups considered. As far as the compositional properties were concerned, on average 5’-UTR sequences resulted in all cases GC richer than 3’-UTR sequences and significant correlation was found between the GC content of 5’ and 3’-UTR sequences and the GC content of the third silent codon positions of the corresponding protein coding genes (Pesole, Liuni et al. 1997) . Some structural features of 5'UTRs were investigated, such as presence of upstream ORFs and context of initiator ATG, which are known to affect the mRNA translation efficiency (Pesole, Bernardi et al. 1999) . In order to assess the level of functional constraint of UTR sequences we have studied their evolutionary dynamics also in comparison with the corresponding coding regions. With suitable evolutionary models we have calculated the nucleotide substitution rate of 5’-UTR, 3’-UTR, synonymous and asynonymous positions by comparing complete human, murid (rat and mouse) and artiodactyl mRNAs, for which a suitable number of orthologous sequences was available.

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