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5. Minimum Information about a Biosynthetic Gene cluster

Author

Medema, M., Kottmann, R., Yilmaz, P., Cummings, M., Biggins, J., Blin, K., de Bruijn, I., Chooi, Y., Claesen, J., Coates, R., Cruz-Morales, P., Duddela, S., Düsterhus, S., Edwards, D., Fewer, D., Garg, N., Geiger, C., Gomez-Escribano, J., Greule, A., Hadjithomas, M., Haines, A., Helfrich, E., Hillwig, M., Ishida, K., Jones, A., Jones, C., Jungmann, K., Kegler, C., Uk Kim, H., Kötter, P., Krug, D., Masschelein, J., Melnik, A., Mantovani, S., Monroe, E., Moore, M., Moss, N., Nützmann, H., Pan, G., Pati, A., Petras, D., Reen, F., Rui, Z., Tian, Z., Tsunematsu, Y., Tobias, N., Wiemann, P., Wyckoff, E., Yan, X., Yim, G., Yu, F., Xie, Y., Aigle, B., Apel, A., Balibar, C., Balskus, E., Barona-Gómez, F., Bechthold, A., Bode, H., Borriss, R., Brady, S., Brakhage, A., Caffrey, P., Cheng, Y., Clardy, J., Cox, R., De Mot, R., Donadio, S., van der Donk, W., Dorrestein, P., Doyle, S., Driessen, A., Ehling-Schulz, M., Entian, K., Fischbach, M., Gerwick, L., Gerwick, W., Gross, H., Gust, B., Hertweck, C., Höfte, M., Jensen, S., Ju, J., Katz, L., Kaysser, L., Klassen, J., Keller, N., Kormanec, J., Kuipers, O., Kuzuyama, T., Kyrpides, N., Kwon, H., Lautru, S., Lavigne, R., Lee, C., Linquan, B., Liu, X., Liu, W., Luzhetskyy, A., Mahmud, T., Mast, Y., Méndez, C., Metsä-Ketelä, M., Micklefield, J., Mitchell, D., Moore, B., Moreira, L., Müller, R., Neilan, B., Nett, M., Nielsen, J., O’Gara, F., Oikawa, H., Osbourn, A., Osburne, M., Ostash, B., Payne, S., Pernode, J., Petricek, M., Piel, J., Ploux, O., Raaijmakers, J., Salas, J., Schmitt, E., Scott, B., Seipke, R., Shen, B., Sherman, D., Sivonen, K., Smanski, M., Sosio, M., Stegmann, E., Süssmuth, R., Tahlan, K., Thomas, C., Tang, Y., Truman, A., Viaud, M., Walton, J., Walsh, C., Weber, T., van Wezel, G., Wilkinson, B., Willey, J., Wohlleben, W., Wright, G., Ziemert, N., Zhang, C., Zotchev, S., Breitling, R., Takano, E., and Glöckner, F.

Abstract

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

Published
2015

6. Insights into the physiology and ecology of the brackish-water-adapted cyanobacterium Nodularia spumigena sp. CCY9414 based on a genome-transcriptome analysis

Author

Voß, B., Bolhuis, H., Fewer, D., Kopf, M., Möke, F., Haas, F., El-Shehawy, R., Hayes, P., Bergman, B., Sivonen, K., Dittmann, E., Scanlan, D.J., Hagemann, M., Stal, L.J., Hess, W.R., and Aquatic Microbiology (IBED, FNWI)

Abstract

Nodularia spumigena is a filamentous diazotrophic cyanobacterium that dominates the annual late summer cyanobacterial blooms in the Baltic Sea. But N. spumigena also is common in brackish water bodies worldwide, suggesting special adaptation allowing it to thrive at moderate salinities. A draft genome analysis of N. spumigena sp. CCY9414 yielded a single scaffold of 5,462,271 nucleotides in length on which genes for 5,294 proteins were annotated. A subsequent strand-specific transcriptome analysis identified more than 6,000 putative transcriptional start sites (TSS). Orphan TSSs located in intergenic regions led us to predict 764 non-coding RNAs, among them 70 copies of a possible retrotransposon and several potential RNA regulators, some of which are also present in other N2-fixing cyanobacteria. Approximately 4% of the total coding capacity is devoted to the production of secondary metabolites, among them the potent hepatotoxin nodularin, the linear spumigin and the cyclic nodulapeptin. The transcriptional complexity associated with genes involved in nitrogen fixation and heterocyst differentiation is considerably smaller compared to other Nostocales. In contrast, sophisticated systems exist for the uptake and assimilation of iron and phosphorus compounds, for the synthesis of compatible solutes, and for the formation of gas vesicles, required for the active control of buoyancy. Hence, the annotation and interpretation of this sequence provides a vast array of clues into the genomic underpinnings of the physiology of this cyanobacterium and indicates in particular a competitive edge of N. spumigena in nutrient-limited brackish water ecosystems.

Published
2013

7. Method for detecting toxic and non toxic cyanobacteria

Author

SIVONEN, K, RANTALA, A, Rouhianen, L, Fewer, D, Rajaniemi, P, Wilmotte, A, Boutte, C, Grubisic, S, Balthasart, P, De Bellis, G, Rizzi, E, Frosini, A, Castiglioni, B, Ventura, S, and Mugnai, M

Subjects
NULL, cianobatteri, biotecnologie, cianotossine, microarray
Published
2004

11. Unruptured intracranial aneurysms--risk of rupture and risks of surgical intervention

Author

Wiebers, D., Whisnant, J., Forbes, G., Meissner, I., Brown, R., Piepgras, D., Huston, J., Nichols, D., O Fallon, W., Peacock, J., Jaeger, L., Kassell, N., Kongable-Beckman, G., Torner, J., Rajput, M., Drake, C., Kurtzke, J., Marler, J., Walker, M., Meyer, F., Atkinson, J., Marsh, W., Thielen, K., Ferguson, G., Barr, H., Lownie, S., Hachinski, V., Fox, A., Sahjpaul, R., Parrent, A., Mayer, C., Lindsay, K., Teasdale, E., Bone, I., Fatukasi, J., Lindsay, M., Cail, W., Sagher, O., Davis, M., Sengupta, R., Bates, D., Gholkar, A., Murdy, J., Wilson, S., Praharaj, S., Partridge, G., Reynolds, C., Hind, N., Ogilvy, C., Crowell, R., Gress, D., Schaefer, P., Choi, I., Buckley, D., Sloan, K., King, D., Giannotta, S., Ameriso, S., Teitelbaum, T., Thomson, E., Fishback, D., Vajda, J., Nyary, I., Czirjak, S., Horvath, M., Szikora, I., Pasztor, E., Varady, P., Erdos, A., Edner, G., Wahlgren, N., Lindqvist, M., Antonsson, A., Da Pian, R., Pasqualin, A., Chioffi, F., Beltramello, A., Zampieri, G., Benati, A., Rossi, G., Ronkainen, A., Hernesniemi, J., Vapalahti, M., Rinne, J., Luukkonen, M., Vihavainen, M., Savolainen, S., Koivisto, T., Leivo, S., Helin, K., Steinberg, G., Marks, M., Vanefsky, M., Norbash, A., Thompson, R., Bell, T., Marcellus, M., Meyer, A., Kerr, R., Adams, C., Molyneux, A., Vinden, S., Bacon, F., Shrimpton, J., Parker, S., Day, A., Nadeau, S., Stachniak, J., Friedman, W., Fessler, R., Peters, K., Jacob, R., Roper, S., Smith, A., Lafrentz, P., Howard, M., Loftus, C., Adams, H., Crosby, D., Rogers, M., Broderick, J., Tew, J., Brott, T., Loveren, H., Yeh, H., Zuccarello, M., Tomsick, T., Gaskill-Shipley, M., Minneci, L., Mcmahon, N., Castel, J., Orgogozo, J., Loiseau, H., Bourgeois, P., Berge, J., Dousset, V., Cuny, E., Richard, M., Agbi, C., Hugenholtz, H., Benoit, B., Morrish, W., Wee, R., Grahovac, S., Pratt, L., Mortensen, M., Andreoli, A., Testa, C., Comani, V., Trevisan, C., Limoni, P., Carlucci, F., Leonardi, M., Sturiale, C., Pendl, G., Eder, H., Klein, G., Eder, M., Leber, K., Horner, T., Leipzig, T., Payner, T., Denardo, A., Scott, J., Redelman, K., Fisher, W., Rosner, M., Vitek, G., Hand, M., Flack, Wf, Sichez, J., Pertuiset, B., Fohanno, D., Marsault, C., Casasco, A., Biondi, A., Capelle, L., Duffau, H., Winn, H., Grady, M., Newell, D., Longstreth, W., Thompson, P., Bybee, H., Jones, D., Findlay, J., Petruk, K., Steinke, D., Ashforth, R., Stenerson, P., Schindel, D., Vanderhoven, H., Neves, J., Zager, E., Flamm, E., Raps, E., Hurst, R., Parrott, S., Sellers, M., Torchia, M., Anderson, B., West, M., Fewer, D., Hill, N., Sutherland, G., Ross, I., Mcclarty, B., Brownstone, R., Williams, O., Narotam, P., Christane, L., Mcginn, G., Gladish, D., Kirkpatrick, P., Pickard, J., Antoun, N., Simpson, D., Higgins, N., Turner, C., Tebbs, S., Holness, R., Malloy, D., Phillips, S., Maloney, W., Molina-De-Orozco, V., Baxter, B., Connolly-Campbell, K., Macdougall, A., Gentili, F., Wallace, M., Ter Brugge, K., Willinsky, R., Tymianski, M., Rickards, L., Tucker, W., Lambert, C., Montanera, W., Rychlewski, C., Flood, C., Villani, R., Sganzerla, E., Tomei, G., Bettinelli, A., Ceccarelli, G., Righini, A., Bello, L., Marras, C., Nelson, R., Lewis, T., Renowden, C., Clarke, Y., Varian, L., Chyatte, D., Sila, C., Perl, J., Masaryk, T., Porterfield, R., Shaw, M., Foy, P., Nixon, T., Dunn, L., Clitheroe, N., Smith, T., Eldridge, P., Humphrey, P., Wiseman, J., Hawkins, K., Owen, L., Ost, K., Saminaden, S., Mohr, G., Schondorf, R., Carlton, J., Maleki, M., Just, N., Brien, S., Entis, S., Tampieri, D., Simons, N., Mooij, J., Metzemackers, J., Hew, J., Beks, J., Veen, A., Bosma, I., Sprengers, M., Rinkel, G., Gijn, J., Ramos, L., Tulleken, C., Greebe, P., Vliet, F., Borgesen, S., Jespersen, B., Boge-Rasmussen, T., Willumsen, L., Homer, D., Eller, T., Carpenter, J., Meyer, J., Munson, R., Small, B., Nussbaum, E., Heros, R., Latchaw, R., Camarata, P., Lundgren, J., Mattsen, N., Whittle, I., Sellar, R., O Sullivan, M., Steers, A., Statham, P., Malcolm, G., Price, R., Hoffman, B., Yonas, H., Wechsler, L., Thompson-Dobkin, J., Jungreis, C., Kassam, A., Kirby, L., Parent, A., Lewis, A., Azordegan, P., Smith, R., Alexander, L., Gordon, D., Russell, W., Benashvili, G., Perry, R., Scalzo, D., Mandybur, G., Morgan, C., Karanjia, P., Madden, K., Kelman, D., Gallant, T., Vanderspek, H., Choucair, A., Neal, J., Mancl, K., Saveland, H., Brandt, L., Holtas, S., Trulsson, B., Macdonald, R., Weir, B., Mojtahedi, S., Amidei, C., Vermeulen, M., Bosch, D., Hulsmans, F., Albrecht, K., Roos, Y., Vet, A., Gorissen, A., Mechielsen, M., Martin, N., Gobin, Y., Saver, J., Vinuela, F., Duckwiler, G., Kelly, D., Frazee, J., Da Graca, R., Gravori, T., Illingworth, R., Richards, P., Wade, J., Colquhoun, I., Bashir, E., Shortt, S., Weaver, J., Fisher, M., Stone, B., Chaturvedi, S., Davidson, R., Davidson, K., Giombini, S., Solero, C., Boiardi, A., Cimino, C., Valentini, S., Antonio Silvani, Alberts, M., Friedman, A., Gentry, A., Hoffman, K., Hughes, R., Lillihei, K., Earnest, M., Nichols, J., Kindt, G., Anderson, A., Levy, S., Breeze, R., Noonan, V., Dowd, C., Vanwestrop, J., Wilson, C., Berger, M., Hannegan, L., Marcos, J., Ugarte, L., Kitchen, N., Taylor, W., Kumar, M., Grieve, J., Durity, F., Boyd, M., Fairholm, D., Griesdale, D., Honey, C., Redekop, G., Toyota, B., Turnbull, I., Woodhurst, W., Zwimpfer, T., Teal, P., Grabe, D., Brevner, A., Piepgras, A., Schmiedek, P., Schwartz, A., Weber, T., Biller, J., Brem, S., Cybulski, G., Chadwick, L., Bronstein, K., Pietila, T., Brock, M., Krug, D., Krznaric, I., and Kivisaari, R.

Subjects
Adult, Male, medicine.medical_specialty, International Subarachnoid Aneurysm Trial, Adolescent, Rupture rate, Aneurysm, Ruptured, Risk Factors, Intervention (counseling), Unruptured cerebral aneurysm, Medicine, Humans, Prospective Studies, Aged, Probability, Retrospective Studies, Aged, 80 and over, Rupture, Spontaneous, business.industry, Age Factors, Intracranial Aneurysm, General Medicine, Middle Aged, Subarachnoid Hemorrhage, Emergency medicine, Female, business, Vascular Surgical Procedures
Abstract

The management of unruptured intracranial aneurysms requires knowledge of the natural history of these lesions and the risks of repairing them.A total of 2621 patients at 53 participating centers in the United States, Canada, and Europe were enrolled in the study, which had retrospective and prospective components. In the retrospective component, we assessed the natural history of unruptured intracranial aneurysms in 1449 patients with 1937 unruptured intracranial aneurysms; 727 of the patients had no history of subarachnoid hemorrhage from a different aneurysm (group 1), and 722 had a history of subarachnoid hemorrhage from a different aneurysm that had been repaired successfully (group 2). In the prospective component, we assessed treatment-related morbidity and mortality in 1172 patients with newly diagnosed unruptured intracranial aneurysms.In group 1, the cumulative rate of rupture of aneurysms that were less than 10 mm in diameter at diagnosis was less than 0.05 percent per year, and in group 2, the rate was approximately 11 times as high (0.5 percent per year). The rupture rate of aneurysms that were 10 mm or more in diameter was less than 1 percent per year in both groups, but in group 1, the rate was 6 percent the first year for giant aneurysms (or =25 mm in diameter). The size and location of the aneurysm were independent predictors of rupture. The overall rate of surgery-related morbidity and mortality was 17.5 percent in group 1 and 13.6 percent in group 2 at 30 days and was 15.7 percent and 13.1 percent, respectively, at 1 year. Age independently predicted surgical outcome.The likelihood of rupture of unruptured intracranial aneurysms that were less than 10 mm in diameter was exceedingly low among patients in group 1 and was substantially higher among those in group 2. The risk of morbidity and mortality related to surgery greatly exceeded the 7.5-year risk of rupture among patients in group 1 with unruptured intracranial aneurysms smaller than 10 mm in diameter.

Published
1998

18. Galega orientalis is more diverse than Galega officinalis in Caucasus-whole-genome AFLP analysis and phylogenetics of symbiosis-related genes

Author

ÖSTERMAN, J., primary, CHIZHEVSKAJA, E. P., additional, ANDRONOV, E. E., additional, FEWER, D. P., additional, TEREFEWORK, Z., additional, ROUMIANTSEVA, M. L., additional, ONICHTCHOUK, O. P., additional, DRESLER-NURMI, A., additional, SIMAROV, B. V., additional, DZYUBENKO, N. I., additional, and LINDSTRÖM, K., additional

Published
2011
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34. REPORT ON SURFACE STUDIES.

Author

TEXAS INSTRUMENTS INC DALLAS, Fewer, D. R., Carlson, Harold G., TEXAS INSTRUMENTS INC DALLAS, Fewer, D. R., and Carlson, Harold G.

Abstract

Some of the variables of processing are examined for formation of metal-oxide-silicon (MOS) structures stable at 175 C under bias of 1,000,000 v/cm of oxide with the metal positive with respect to the silicon. Sodium distributions found in oxides formed by various techniques are determined using neutron activation analysis. Oxides formed on chemically polished surfaces have a high sodium concentration in a thin outer layer of oxide which originates on the polished silicon surface. A clean system using rf heating of a silicon carbide coated graphite slab and water cooled quartz wall permitted vapor etching in HCl-H2 mixtures to remove native oxides, flushing and then using dry oxygen for oxidation. Sodium and phosphorus distributions are compared in oxides diffused with phosphorus oxide. The kinetics of the phosphorus diffusion are explored. A segregation of sodium into the glassy regions of samples diffused at high temperatures is found. From 600 - 1200 C a low level of phosphorus near to solid solubility in oxide is found distributed throughout the oxide. (Author)

Published
1967

35. RELIABILITY TESTING AND PREDICTION TECHNIQUES FOR HIGH POWER SILICON TRANSISTORS.

Author

TEXAS INSTRUMENTS INC DALLAS, Fewer, D. R., Tomlinson, J. R., TEXAS INSTRUMENTS INC DALLAS, Fewer, D. R., and Tomlinson, J. R.

Abstract

Work performed is divided into two main parts: (1) a test and data analysis program designed to produce a method for reliability screening, and (2) a physics of failure program on fundamental mechanism causing device degradation. Surface studies have been directed toward analysis of techniques for production of MOS systems that are electrically and thermally stable. Process considerations are described. Increases in stability of MOS capacitor structures of more than two orders of magnitude are reported. A model for second breakdown is presented together with results and a comparison with device behavior. Studies on thermal effects are reported with particular reference to methods of measuring thermal impedance. Both carrier and current densities in a transistor and the temperature distribution across the surfaces of a transistor are discussed. The use of thermal studies to understand device operation and interpret the reliability test data is discussed along with more explicit definitions of thermal failure modes involving temperature sensitive mechanisms. Comparison with experimental data shows good agreement with analytical results.

Published
1966

36. INVESTIGATION OF RELIABILITY TESTING AND PREDICTION TECHNIQUES FOR INTEGRATED CIRCUITS.

Author

TEXAS INSTRUMENTS INC DALLAS, Fewer, D. R., Gill, W. L., Musket, S. F., Workman, W. L., TEXAS INSTRUMENTS INC DALLAS, Fewer, D. R., Gill, W. L., Musket, S. F., and Workman, W. L.

Abstract

The work is divided into four parts: (1) data analysis and preliminary tests to determine failure mechanisms for early direction in the study; (2) a physics of failure program consisting of fundamental oxide studies, metal contact and interconnection evaluations, and circuit analysis; (3) a test program including data and failure analysis and consisting of two major segments; and (4) the development of a reliability screening procedure for integrated circuits. Three computer programs, SERF, LINDA 1 and LINDA 2 were written to assist in the analysis of data. The physics of failure program consisted of fundamental surface studies to produce stable metal-oxide-silicon (MOS) systems, circuit analysis of the SN5420 integrated circuit, and a study of the molybdenum-gold expanded contact system. (Author)

Published
1967

37. RELIABILITY TESTING AND PREDICTION TECHNIQUES FOR HIGH POWER SILICON TRANSISTORS.

Author

TEXAS INSTRUMENTS INC DALLAS, Fewer, D. R., Tomlinson, J. R., TEXAS INSTRUMENTS INC DALLAS, Fewer, D. R., and Tomlinson, J. R.

Abstract

Work performed under this contract is divided into two main parts: (1) a Test and Data Analysis program designed to produce a method for reliability screening; and (2) a Physics of Failure Program on fundamental mechanisms causing device degradation. The test program was divided into three parts, Preliminary, Main and Verification Test Programs. Results of each test program are discussed. Accelerated test results and comparison of fixed stress and step stress results are presented. A non-destructive screening procedure was developed and is contained in this report. Three computer programs, SERF, LINDA 1 and LINDA 2 were developed to assist in the development of the nondestructive screening procedure. The Physics of Failure Program consisted of studies of surfaces and oxides, noise, thermal effects and second breakdown. Extensive analyses of failures were also carried out. Surface studies include the developemnt and analysis of techniques for the production of metal-oxide-silicon (MOS) systems that are electrically and thermally stable. Thermal studies include results of actual temperature measurements of operating transistors using an infrared (IR) microradiometer. Results of electrical and thermal techniques are compared as a tool for measuring thermal resistance. Models to calculate the current and temperature distributions in operating power transistors give results which ar in agreement with experimental data. The second breakdown studies include a discussion of a model for thermal breakdown. (Author)

Published
1967

42. Genome-derived insights into the biology of the hepatotoxic bloom-forming cyanobacterium Anabaena sp. strain 90

Author

Wang Hao, Sivonen Kaarina, Rouhiainen Leo, Fewer David P, Lyra Christina, Rantala-Ylinen Anne, Vestola Johanna, Jokela Jouni, Rantasärkkä Kaisa, Li Zhijie, and Liu Bin

Subjects
Cyanobacteria, Anabaena, Mobile genetic elements, Insertion sequences, Biosynthetic gene clusters, Restriction-modification system, nifH excision element, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Cyanobacteria can form massive toxic blooms in fresh and brackish bodies of water and are frequently responsible for the poisoning of animals and pose a health risk for humans. Anabaena is a genus of filamentous diazotrophic cyanobacteria commonly implicated as a toxin producer in blooms in aquatic ecosystems throughout the world. The biology of bloom-forming cyanobacteria is poorly understood at the genome level. Results Here, we report the complete sequence and comprehensive annotation of the bloom-forming Anabaena sp. strain 90 genome. It comprises two circular chromosomes and three plasmids with a total size of 5.3 Mb, encoding a total of 4,738 genes. The genome is replete with mobile genetic elements. Detailed manual annotation demonstrated that almost 5% of the gene repertoire consists of pseudogenes. A further 5% of the genome is dedicated to the synthesis of small peptides that are the products of both ribosomal and nonribosomal biosynthetic pathways. Inactivation of the hassallidin (an antifungal cyclic peptide) biosynthetic gene cluster through a deletion event and a natural mutation of the buoyancy-permitting gvpG gas vesicle gene were documented. The genome contains a large number of genes encoding restriction-modification systems. Two novel excision elements were found in the nifH gene that is required for nitrogen fixation. Conclusions Genome analysis demonstrated that this strain invests heavily in the production of bioactive compounds and restriction-modification systems. This well-annotated genome provides a platform for future studies on the ecology and biology of these important bloom-forming cyanobacteria.

Published
2012
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43. Molecular evidence for a diverse green algal community growing in the hair of sloths and a specific association with Trichophilus welckeri (Chlorophyta, Ulvophyceae)

Author

Chiarello Adriano G, Friedl Thomas, Aiello Annette, Voirin Bryson, Fewer David P, Majaneva Markus, Suutari Milla, and Blomster Jaanika

Subjects
Evolution, QH359-425
Abstract

Abstract Background Sloths are slow-moving arboreal mammals inhabiting tropical rainforests in Central and South America. The six living species of sloths are occasionally reported to display a greenish discoloration of their pelage. Trichophilus welckeri, a green algal species first described more than a century ago, is widely believed to discolor the animals fur and provide the sloth with effective camouflage. However, this phenomenon has not been explored in any detail and there is little evidence to substantiate this widely held opinion. Results Here we investigate the genetic diversity of the eukaryotic community present in fur of all six extant species of sloth. Analysis of 71 sloth hair samples yielding 426 partial 18S rRNA gene sequences demonstrates a diverse eukaryotic microbial assemblage. Phylogenetic analysis reveals that sloth fur hosts a number of green algal species and suggests that acquisition of these organisms from the surrounding rainforest plays an important role in the discoloration of sloth fur. However, an alga corresponding to the morphological description of Trichophilus welckeri was found to be frequent and abundant on sloth fur. Phylogenetic analysis demonstrated the retention of this alga on the fur of sloths independent of geographic location. Conclusions These results demonstrate a unique diverse microbial eukaryotic community in the fur of sloths from Central and South America. Our analysis streghtens the case for symbiosis between sloths and Trichophilus welckeri.

Published
2010
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44. Evidence for positive selection acting on microcystin synthetase adenylation domains in three cyanobacterial genera

Author

Rouhiainen Leo, Jokela Jouni, Rohrlack Thomas, Fewer David P, Tooming-Klunderud Ave, Sivonen Kaarina, Kristensen Tom, and Jakobsen Kjetill S

Subjects
Evolution, QH359-425
Abstract

Abstract Background Cyanobacteria produce a wealth of secondary metabolites, including the group of small cyclic heptapeptide hepatotoxins that constitutes the microcystin family. The enzyme complex that directs the biosynthesis of microcystin is encoded in a single large gene cluster (mcy). mcy genes have a widespread distribution among cyanobacteria and are likely to have an ancient origin. The notable diversity within some of the Mcy modules is generated through various recombination events including horizontal gene transfer. Results A comparative analysis of the adenylation domains from the first module of McyB (McyB1) and McyC in the microcystin synthetase complex was performed on a large number of microcystin-producing strains from the Anabaena, Microcystis and Planktothrix genera. We found no decisive evidence for recombination between strains from different genera. However, we detected frequent recombination events in the mcyB and mcyC genes between strains within the same genus. Frequent interdomain recombination events were also observed between mcyB and mcyC sequences in Anabaena and Microcystis. Recombination and mutation rate ratios suggest that the diversification of mcyB and mcyC genes is driven by recombination events as well as point mutations in all three genera. Sequence analysis suggests that generally the adenylation domains of the first domain of McyB and McyC are under purifying selection. However, we found clear evidence for positive selection acting on a number of amino acid residues within these adenylation domains. These include residues important for active site selectivity of the adenylation domain, strongly suggesting selection for novel microcystin variants. Conclusion We provide the first clear evidence for positive selection acting on amino acid residues involved directly in the recognition and activation of amino acids incorporated into microcystin, indicating that the microcystin complement of a given strain may influence the ability of a particular strain to interact with its environment.

Published
2008
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45. Recurrent adenylation domain replacement in the microcystin synthetase gene cluster

Author

Laakso Kati, Wahlsten Matti, Jokela Jouni, Rouhiainen Leo, Fewer David P, Wang Hao, and Sivonen Kaarina

Subjects
Evolution, QH359-425
Abstract

Abstract Background Microcystins are small cyclic heptapeptide toxins produced by a range of distantly related cyanobacteria. Microcystins are synthesized on large NRPS-PKS enzyme complexes. Many structural variants of microcystins are produced simulatenously. A recombination event between the first module of mcyB (mcyB1) and mcyC in the microcystin synthetase gene cluster is linked to the simultaneous production of microcystin variants in strains of the genus Microcystis. Results Here we undertook a phylogenetic study to investigate the order and timing of recombination between the mcyB1 and mcyC genes in a diverse selection of microcystin producing cyanobacteria. Our results provide support for complex evolutionary processes taking place at the mcyB1 and mcyC adenylation domains which recognize and activate the amino acids found at X and Z positions. We find evidence for recent recombination between mcyB1 and mcyC in strains of the genera Anabaena, Microcystis, and Hapalosiphon. We also find clear evidence for independent adenylation domain conversion of mcyB1 by unrelated peptide synthetase modules in strains of the genera Nostoc and Microcystis. The recombination events replace only the adenylation domain in each case and the condensation domains of mcyB1 and mcyC are not transferred together with the adenylation domain. Our findings demonstrate that the mcyB1 and mcyC adenylation domains are recombination hotspots in the microcystin synthetase gene cluster. Conclusion Recombination is thought to be one of the main mechanisms driving the diversification of NRPSs. However, there is very little information on how recombination takes place in nature. This study demonstrates that functional peptide synthetases are created in nature through transfer of adenylation domains without the concomitant transfer of condensation domains.

Published
2007
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46. Gamma knife for cerebral arteriovenous malformations at a single centre.

Author

Zeiler, F. A., Bigder, M. G., Mcdonald, P. J., Kaufmann, A. M., Fewer, D., Butler, J., Schroeder, G., and West, M.

Subjects
CEREBRAL arteriovenous malformations, CEREBRAL artery surgery, ANGIOGRAPHY, HEADACHE treatment, NEUROLOGICAL emergencies, THERAPEUTICS
Abstract

Background: We report the results of a consecutive series of patients treated with Gamma Knife (GK) Surgery for cerebral arteriovenous malformations (AVMs). Methods: We retrospectively reviewed 69 patients treated with GK for cerebral AVMs between November 2003 and April 2009, recording clinical data, treatment parameters, and AVM obliteration rates in order to assess our effectiveness with GK in treating these lesions. Results: Ten patients were lost to follow-up. Presentations included: seizure (24), hemorrhage (18), persistent headache (12), progressing neurological signs (10), and incidental (9). In 24 patients (34.8%) treatment planning consisted of digital subtraction angiography (DSA), magnetic resonance imaging (MRI), and computed tomogram (CT) angiography (CTA). Currently we rely predominantly on CTA and/or MRI scanning only. Fourty-one patients have been followed for a minimum of 3 years; average age 40.9 yr., 58.5% males. Average dose at the 50% isodose line was 20.3 Gy (range 16 to 26.4 Gy). Obliteration was observed in 87.8% by MRI, CT, or DSA. Not all obliteration was confirmed by DSA. Complications occurred in 12 of 59 (20.3%) patients, and in 11 of 41 (26.8%) with 3 year follow-up. Major (temporary) complications for the 59 included symptomatic cerebral edema (7), seizure (2), and hemorrhage (1). Major permanent complications occurred in one patient suffering a cranial nerve V deafferentation, and in two patients suffering a hemorrhage. Conclusion: GKS for cerebral AVM's offers an effective and safe method of treatment, with low permanent complication rate Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Published
2013

47. Gamma knife stereotactic radiosurgery for large vestibular schwannomas: the Manitoba experience.

Author

Bigder, M. G., Zeiler, F. A., Mcdonald, P. J., Kaufmann, A. M., Fewer, D., Butler, J., Schroeder, G., and West, M.

Subjects
ACOUSTIC neuroma, STEREOTACTIC radiosurgery, NEUROMAS, VESTIBULAR apparatus diseases, FACIAL nerve diseases, THERAPEUTICS
Abstract

Object: To review our institutional experience with Gamma Knife (GK) stereotactic radiosurgery in treating large vestibular schwannomas (VS) of 3 to 4 cm diameter. Methods: We retrospectively reviewed records of all patients treated with GK for VS at our institution between November 2003 and March 2012. Data on age, sex, VS volume, location and maximal diameter, House-Brackmann (HB) facial nerve scores pre and post-GK, Gardner-Robertson (GR) hearing score pre and post-GK, GK treatment parameters, VS response time, complications and clinical outcome was recorded Results: A total of 28 patients during the defined time period were identified. Three patients were lost to follow-up. Mean follow-up was 34.5 months. Tumor control occurred in 92%, and was maintained in 85.7% at 2 years. Facial nerve or hearing preservation occurred in all treated compared to pre-GK status, as per HB and GR grading. Transient complications occurred in 80%. Temporary vestibular dysfunction occurred in 7 patients (28%). One patient (4%) had the permanent complication of worsening pre-GK hemifacial spasm. Four patients (16%) developed hydrocephalus post-GK. Conclusion: GK stereotactic radiosurgery as a primary treatment modality for large VS, can provide acceptable tumor control rates with good facial nerve and hearing preservation, and low complication rates. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Published
2013

49. Fatty Acid Substitutions Modulate the Cytotoxicity of Puwainaphycins/Minutissamides Isolated from the Baltic Sea Cyanobacterium Nodularia harveyana UHCC-0300

Author

Kumar Saurav, Alessia Caso, Petra Urajová, Pavel Hrouzek, Germana Esposito, Kateřina Delawská, Markéta Macho, Jan Hájek, José Cheel, Subhasish Saha, Petra Divoká, Sila Arsin, Kaarina Sivonen, David P. Fewer, Valeria Costantino, University of Helsinki, Department of Microbiology, Helsinki Institute of Sustainability Science (HELSUS), Cyanobacteria research, Department of Food and Nutrition, Microbial Natural Products, Saurav, K., Caso, A., Urajova, P., Hrouzek, P., Esposito, G., Delawska, K., Macho, M., Hajek, J., Cheel, J., Saha, S., Divoka, P., Arsin, S., Sivonen, K., Fewer, D. P., and Costantino, V.

Subjects
11832 Microbiology and virology, General Chemical Engineering, General Chemistry, CYCLIC LIPOPEPTIDES
Abstract

Puwainaphycins (PUW) and minutissamides (MIN) are structurally homologous cyclic lipopeptides that exhibit high structural variability and possess antifungal and cytotoxic activities. While only a minor variation can be found in the amino acid composition of the peptide cycle, the fatty acid (FA) moiety varies largely. The effect of FA functionalization on the bioactivity of PUW/MIN chemical variants is poorly understood. A rapid and selective liquid chromatography-mass spectrometry-based method led us to identify 13 PUW/MIN (1-13) chemical variants from the benthic cyanobacterium Nodularia harveyana strain UHCC-0300 from the Baltic Sea. Five new variants identified were designated as PUW H (1), PUW I (2), PUW J (4), PUW K (10), and PUW L (13) and varied slightly in the peptidic core composition, but a larger variation was observed in the oxo-, chloro-, and hydroxy-substitutions on the FA moiety. To address the effect of FA substitution on the cytotoxic effect, the major variants (3 and 5-11) together with four other PUW/MIN variants (14-17) previously isolated were included in the study. The data obtained showed that hydroxylation of the FA moiety abolishes the cytotoxicity or significantly reduces it when compared with the oxo-substituted C-18-FA (compounds 5-8). The oxo-substitution had only a minor effect on the cytotoxicity of the compound when compared to variants bearing no substitution. The activity of PUW/ MIN variants with chlorinated FA moieties varied depending on the position of the chlorine atom on the FA chain. This study also shows that variation in the amino acids distant from the FA moiety (position 4-8 of the peptide cycle) does not play an important role in determining the cytotoxicity of the compound. These findings confirmed that the lipophilicity of FA is essential to maintain the cytotoxicity of PUW/MIN lipopeptides. Further, a 63 kb puwainaphycin biosynthetic gene cluster from a draft genome of the N. harveyana strain UHCC-0300 was identified. This pathway encoded two specific lipoinitiation mechanisms as well as enzymes needed for the modification of the FA moiety. Examination on biosynthetic gene clusters and the structural variability of the produced PUW/MIN suggested different mechanisms of fatty-aryl-AMP ligase cooperation with accessory enzymes leading to a new set of PUW/MIN variants bearing differently substituted FA.

Published
2022
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50. A refactored biosynthetic pathway for the production of glycosylated microbial sunscreens.

Author

Arsın S, Pollari M, Delbaje E, Jokela J, Wahlsten M, Permi P, and Fewer D

Abstract

Mycosporine-like amino acids (MAAs) are a family of water-soluble and colorless secondary metabolites, with high extinction coefficients, that function as microbial sunscreens. MAAs share a cyclohexinimine chromophore that is diversified through amino acid substitutions and attachment of sugar moieties. The genetic and enzymatic bases for the chemical diversity of MAAs remain largely unexplored. Here we report a series of structurally distinct MAAs and evidence for an unusual branched biosynthetic pathway from a cyanobacterium isolated from lake sediment. We used a combination of high-resolution liquid chromatography-mass spectrometry (HR-LCMS) analysis and nuclear magnetic resonance (NMR) spectroscopy to identify diglycosylated-palythine-Ser (C 22 H 36 N 2 O 15 ) as the dominant chemical variant in a series of MAAs from Nostoc sp. UHCC 0302 that contained either Ser or Thr. We obtained a complete 9.9 Mb genome sequence to gain insights into the genetic basis for the biosynthesis of these structurally distinct MAAs. We identified MAA biosynthetic genes encoded at two locations on the circular chromosome. Surprisingly, direct pathway cloning and heterologous expression of the complete mysABCJ 1 D 1 G 1 H biosynthetic gene cluster in Escherichia coli ( E. coli ) led to the production of 450 Da monoglycosylated-palythine-Thr (C 18 H 30 N 2 O 11 ). We reconstructed combinations of the two distant biosynthetic gene clusters in refactored synthetic pathways and expressed them in the heterologous host. These results demonstrated that the MysD 1 and MysD 2 enzymes displayed a preference for Thr and Ser, respectively. Furthermore, one of the four glycosyltransferases identified, MysG 1 , was active in E. coli and catalysed the attachment of a hexose moiety to the palythine-Thr intermediate. Together these results provide the first insights into the enzymatic basis for glycosylation of MAAs and demonstrates how paralogous copies of the MysD enzymes allow the simultaneous biosynthesis of specific chemical variants to increase the structural variation in this family of microbial sunscreens., Competing Interests: There are no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Published
2024
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