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1. Geographic variation of mutagenic exposures in kidney cancer genomes

Author

Senkin, Sergey, Moody, Sarah, Díaz-Gay, Marcos, Abedi-Ardekani, Behnoush, Cattiaux, Thomas, Ferreiro-Iglesias, Aida, Wang, Jingwei, Fitzgerald, Stephen, Kazachkova, Mariya, Vangara, Raviteja, Le, Anh Phuong, Bergstrom, Erik N., Khandekar, Azhar, Otlu, Burçak, Cheema, Saamin, Latimer, Calli, Thomas, Emily, Atkins, Joshua Ronald, Smith-Byrne, Karl, Cortez Cardoso Penha, Ricardo, Carreira, Christine, Chopard, Priscilia, Gaborieau, Valérie, Keski-Rahkonen, Pekka, Jones, David, Teague, Jon W., Ferlicot, Sophie, Asgari, Mojgan, Sangkhathat, Surasak, Attawettayanon, Worapat, Świątkowska, Beata, Jarmalaite, Sonata, Sabaliauskaite, Rasa, Shibata, Tatsuhiro, Fukagawa, Akihiko, Mates, Dana, Jinga, Viorel, Rascu, Stefan, Mijuskovic, Mirjana, Savic, Slavisa, Milosavljevic, Sasa, Bartlett, John M. S., Albert, Monique, Phouthavongsy, Larry, Ashton-Prolla, Patricia, Botton, Mariana R., Silva Neto, Brasil, Bezerra, Stephania Martins, Curado, Maria Paula, Zequi, Stênio de Cássio, Reis, Rui Manuel, Faria, Eliney Ferreira, de Menezes, Nei Soares, Ferrari, Renata Spagnoli, Banks, Rosamonde E., Vasudev, Naveen S., Zaridze, David, Mukeriya, Anush, Shangina, Oxana, Matveev, Vsevolod, Foretova, Lenka, Navratilova, Marie, Holcatova, Ivana, Hornakova, Anna, Janout, Vladimir, Purdue, Mark P., Rothman, Nathaniel, Chanock, Stephen J., Ueland, Per Magne, Johansson, Mattias, McKay, James, Scelo, Ghislaine, Chanudet, Estelle, Humphreys, Laura, de Carvalho, Ana Carolina, Perdomo, Sandra, Alexandrov, Ludmil B., Stratton, Michael R., and Brennan, Paul

Published
2024
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3. The Mutographs biorepository: A unique genomic resource to study cancer around the world

Author

Perdomo, Sandra, Abedi-Ardekani, Behnoush, de Carvalho, Ana Carolina, Ferreiro-Iglesias, Aida, Gaborieau, Valérie, Cattiaux, Thomas, Renard, Hélène, Chopard, Priscilia, Carreira, Christine, Spanu, Andreea, Nikmanesh, Arash, Cardoso Penha, Ricardo Cortez, Antwi, Samuel O., Ashton-Prolla, Patricia, Canova, Cristina, Chitapanarux, Taned, Cox, Riley, Curado, Maria Paula, de Oliveira, José Carlos, Dzamalala, Charles, Fabianova, Elenora, Ferri, Lorenzo, Fitzgerald, Rebecca, Foretova, Lenka, Gallinger, Steven, Goldstein, Alisa M., Holcatova, Ivana, Huertas, Antonio, Janout, Vladimir, Jarmalaite, Sonata, Kaneva, Radka, Kowalski, Luiz Paulo, Kulis, Tomislav, Lagiou, Pagona, Lissowska, Jolanta, Malekzadeh, Reza, Mates, Dana, McCorrmack, Valerie, Menya, Diana, Mhatre, Sharayu, Mmbaga, Blandina Theophil, de Moricz, André, Nyirády, Péter, Ognjanovic, Miodrag, Papadopoulou, Kyriaki, Polesel, Jerry, Purdue, Mark P., Rascu, Stefan, Rebolho Batista, Lidia Maria, Reis, Rui Manuel, Ribeiro Pinto, Luis Felipe, Rodríguez-Urrego, Paula A., Sangkhathat, Surasak, Sangrajrang, Suleeporn, Shibata, Tatsuhiro, Stakhovsky, Eduard, Świątkowska, Beata, Vaccaro, Carlos, Vasconcelos de Podesta, Jose Roberto, Vasudev, Naveen S., Vilensky, Marta, Yeung, Jonathan, Zaridze, David, Zendehdel, Kazem, Scelo, Ghislaine, Chanudet, Estelle, Wang, Jingwei, Fitzgerald, Stephen, Latimer, Calli, Moody, Sarah, Humphreys, Laura, Alexandrov, Ludmil B., Stratton, Michael R., and Brennan, Paul

Published
2024
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4. Observation of an Intermediate to H2 Binding in a Metal-Organic Framework.

Author

Barnett, Brandon R, Evans, Hayden A, Su, Gregory M, Jiang, Henry ZH, Chakraborty, Romit, Banyeretse, Didier, Hartman, Tyler J, Martinez, Madison B, Trump, Benjamin A, Tarver, Jacob D, Dods, Matthew N, Funke, Lena M, Börgel, Jonas, Reimer, Jeffrey A, Drisdell, Walter S, Hurst, Katherine E, Gennett, Thomas, FitzGerald, Stephen A, Brown, Craig M, Head-Gordon, Martin, and Long, Jeffrey R

Subjects
Chemical Sciences, General Chemistry
Abstract

Coordinatively unsaturated metal sites within certain zeolites and metal-organic frameworks can strongly adsorb a wide array of substrates. While many classical examples involve electron-poor metal cations that interact with adsorbates largely through physical interactions, unsaturated electron-rich metal centers housed within porous frameworks can often chemisorb guests amenable to redox activity or covalent bond formation. Despite the promise that materials bearing such sites hold in addressing myriad challenges in gas separations and storage, very few studies have directly interrogated mechanisms of chemisorption at open metal sites within porous frameworks. Here, we show that nondissociative chemisorption of H2 at the trigonal pyramidal Cu+ sites in the metal-organic framework CuI-MFU-4l occurs via the intermediacy of a metastable physisorbed precursor species. In situ powder neutron diffraction experiments enable crystallographic characterization of this intermediate, the first time that this has been accomplished for any material. Evidence for a precursor intermediate is also afforded from temperature-programmed desorption and density functional theory calculations. The activation barrier separating the precursor species from the chemisorbed state is shown to correlate with a change in the Cu+ coordination environment that enhances π-backbonding with H2. Ultimately, these findings demonstrate that adsorption at framework metal sites does not always follow a concerted pathway and underscore the importance of probing kinetics in the design of next-generation adsorbents.

Published
2021

7. The Fire and Tree Mortality Database, for empirical modeling of individual tree mortality after fire.

Author

Cansler, C Alina, Hood, Sharon M, Varner, J Morgan, van Mantgem, Phillip J, Agne, Michelle C, Andrus, Robert A, Ayres, Matthew P, Ayres, Bruce D, Bakker, Jonathan D, Battaglia, Michael A, Bentz, Barbara J, Breece, Carolyn R, Brown, James K, Cluck, Daniel R, Coleman, Tom W, Corace, R Gregory, Covington, W Wallace, Cram, Douglas S, Cronan, James B, Crouse, Joseph E, Das, Adrian J, Davis, Ryan S, Dickinson, Darci M, Fitzgerald, Stephen A, Fulé, Peter Z, Ganio, Lisa M, Grayson, Lindsay M, Halpern, Charles B, Hanula, Jim L, Harvey, Brian J, Kevin Hiers, J, Huffman, David W, Keifer, MaryBeth, Keyser, Tara L, Kobziar, Leda N, Kolb, Thomas E, Kolden, Crystal A, Kopper, Karen E, Kreitler, Jason R, Kreye, Jesse K, Latimer, Andrew M, Lerch, Andrew P, Lombardero, Maria J, McDaniel, Virginia L, McHugh, Charles W, McMillin, Joel D, Moghaddas, Jason J, O'Brien, Joseph J, Perrakis, Daniel DB, Peterson, David W, Prichard, Susan J, Progar, Robert A, Raffa, Kenneth F, Reinhardt, Elizabeth D, Restaino, Joseph C, Roccaforte, John P, Rogers, Brendan M, Ryan, Kevin C, Safford, Hugh D, Santoro, Alyson E, Shearman, Timothy M, Shumate, Alice M, Sieg, Carolyn H, Smith, Sheri L, Smith, Rebecca J, Stephenson, Nathan L, Stuever, Mary, Stevens, Jens T, Stoddard, Michael T, Thies, Walter G, Vaillant, Nicole M, Weiss, Shelby A, Westlind, Douglas J, Woolley, Travis J, and Wright, Micah C

Abstract

Wildland fires have a multitude of ecological effects in forests, woodlands, and savannas across the globe. A major focus of past research has been on tree mortality from fire, as trees provide a vast range of biological services. We assembled a database of individual-tree records from prescribed fires and wildfires in the United States. The Fire and Tree Mortality (FTM) database includes records from 164,293 individual trees with records of fire injury (crown scorch, bole char, etc.), tree diameter, and either mortality or top-kill up to ten years post-fire. Data span 142 species and 62 genera, from 409 fires occurring from 1981-2016. Additional variables such as insect attack are included when available. The FTM database can be used to evaluate individual fire-caused mortality models for pre-fire planning and post-fire decision support, to develop improved models, and to explore general patterns of individual fire-induced tree death. The database can also be used to identify knowledge gaps that could be addressed in future research.

Published
2020

8. SARS-CoV-2 RNA levels in Scotland’s wastewater

Author

Scorza, Livia C. T., Cameron, Graeme J., Murray-Williams, Roisin, Findlay, David, Bolland, Julie, Cerghizan, Brindusa, Campbell, Kirsty, Thomson, David, Corbishley, Alexander, Gally, David, Fitzgerald, Stephen, Low, Alison, McAteer, Sean, Roberts, Adrian M. I., Fang, Zhou, Mayer, Claus-Dieter, Frantsuzova, Anastasia, Baby, Sumy V., Zieliński, Tomasz, and Millar, Andrew J.

Published
2022
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9. Record High Hydrogen Storage Capacity in the Metal–Organic Framework Ni2(m‑dobdc) at Near-Ambient Temperatures

Author

Kapelewski, Matthew T, Runčevski, Tomče, Tarver, Jacob D, Jiang, Henry ZH, Hurst, Katherine E, Parilla, Philip A, Ayala, Anthony, Gennett, Thomas, FitzGerald, Stephen A, Brown, Craig M, and Long, Jeffrey R

Subjects
Macromolecular and Materials Chemistry, Engineering, Chemical Sciences, Affordable and Clean Energy, Materials, Chemical sciences
Abstract

Hydrogen holds promise as a clean alternative automobile fuel, but its on-board storage presents significant challenges due to the low temperatures and/or high pressures required to achieve a sufficient energy density. The opportunity to significantly reduce the required pressure for high density H2 storage persists for metal-organic frameworks due to their modular structures and large internal surface areas. The measurement of H2 adsorption in such materials under conditions most relevant to on-board storage is crucial to understanding how these materials would perform in actual applications, although such data have to date been lacking. In the present work, the metal-organic frameworks M2(m-dobdc) (M = Co, Ni; m-dobdc4- = 4,6-dioxido-1,3-benzenedicarboxylate) and the isomeric frameworks M2(dobdc) (M = Co, Ni; dobdc4- = 1,4-dioxido-1,3-benzenedicarboxylate), which are known to have open metal cation sites that strongly interact with H2, were evaluated for their usable volumetric H2 storage capacities over a range of near-ambient temperatures relevant to on-board storage. Based upon adsorption isotherm data, Ni2(m-dobdc) was found to be the top-performing physisorptive storage material with a usable volumetric capacity between 100 and 5 bar of 11.0 g/L at 25 °C and 23.0 g/L with a temperature swing between -75 and 25 °C. Additional neutron diffraction and infrared spectroscopy experiments performed with in situ dosing of D2 or H2 were used to probe the hydrogen storage properties of these materials under the relevant conditions. The results provide benchmark characteristics for comparison with future attempts to achieve improved adsorbents for mobile hydrogen storage applications.

Published
2018

11. The Complexity of Tobacco Smoke-Induced Mutagenesis in Head and Neck Cancer

Author

Torrens, Laura, primary, Moody, Sarah, additional, de Carvalho, Ana Carolina, additional, Kazachkova, Mariya, additional, Abedi-Ardekani, Behnoush, additional, Cheema, Saamin, additional, Senkin, Sergey, additional, Cattiaux, Thomas, additional, Cortez Cardoso Penha, Ricardo, additional, Atkins, Joshua R, additional, Gaborieau, Valérie, additional, Chopard, Priscilia, additional, Carreira, Christine, additional, Abbasi, Ammal, additional, Bergstrom, Erik N, additional, Vangara, Raviteja, additional, Wang, Jingwei, additional, Fitzgerald, Stephen, additional, Latimer, Calli, additional, Diaz-Gay, Marcos, additional, Jones, David, additional, Teague, Jon, additional, Ribeiro Pinto, Felipe, additional, Kowalski, Luiz Paulo, additional, Polesel, Jerry, additional, Giudici, Fabiola, additional, de Oliveira, José Carlos, additional, Lagiou, Pagona, additional, Lagiou, Areti, additional, Vilensky, Marta, additional, Mates, Dana, additional, Mates, Ioan N, additional, Arantes, Lidia MRB, additional, Reis, Rui, additional, Podesta, Jose Roberto V, additional, von Zeidler, Sandra V, additional, Holcatova, Ivana, additional, Curado, Maria Paula, additional, Canova, Cristina, additional, Fabianova, Elenora, additional, Rodríguez-Urrego, Paula A, additional, Humphreys, Laura, additional, Alexandrov, Ludmil B, additional, Brennan, Paul, additional, Stratton, Michael R, additional, and Perdomo, Sandra, additional

Published
2024
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13. Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence

Author

Moody, Sarah, Senkin, Sergey, Islam, S. M. Ashiqul, Wang, Jingwei, Nasrollahzadeh, Dariush, Cortez Cardoso Penha, Ricardo, Fitzgerald, Stephen, Bergstrom, Erik N., Atkins, Joshua, He, Yudou, Khandekar, Azhar, Smith-Byrne, Karl, Carreira, Christine, Gaborieau, Valerie, Latimer, Calli, Thomas, Emily, Abnizova, Irina, Bucciarelli, Pauline E., Jones, David, Teague, Jon W., Abedi-Ardekani, Behnoush, Serra, Stefano, Scoazec, Jean-Yves, Saffar, Hiva, Azmoudeh-Ardalan, Farid, Sotoudeh, Masoud, Nikmanesh, Arash, Poustchi, Hossein, Niavarani, Ahmadreza, Gharavi, Samad, Eden, Michael, Richman, Paul, Campos, Lia S., Fitzgerald, Rebecca C., Ribeiro, Luis Felipe, Soares-Lima, Sheila Coelho, Dzamalala, Charles, Mmbaga, Blandina Theophil, Shibata, Tatsuhiro, Menya, Diana, Goldstein, Alisa M., Hu, Nan, Malekzadeh, Reza, Fazel, Abdolreza, McCormack, Valerie, McKay, James, Perdomo, Sandra, Scelo, Ghislaine, Chanudet, Estelle, Humphreys, Laura, Alexandrov, Ludmil B., Brennan, Paul, and Stratton, Michael R.

Published
2021
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15. Alignathon: a competitive assessment of whole-genome alignment methods

Author

Earl, Dent, Nguyen, Ngan, Hickey, Glenn, Harris, Robert S, Fitzgerald, Stephen, Beal, Kathryn, Seledtsov, Igor, Molodtsov, Vladimir, Raney, Brian J, Clawson, Hiram, Kim, Jaebum, Kemena, Carsten, Chang, Jia-Ming, Erb, Ionas, Poliakov, Alexander, Hou, Minmei, Herrero, Javier, Kent, William James, Solovyev, Victor, Darling, Aaron E, Ma, Jian, Notredame, Cedric, Brudno, Michael, Dubchak, Inna, Haussler, David, and Paten, Benedict

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Generic health relevance, Animals, Computational Biology, Computer Simulation, Datasets as Topic, Genome, Genome-Wide Association Study, Genomics, Humans, Mammals, Phylogeny, Reproducibility of Results, Sequence Alignment, Software, Medical and Health Sciences, Bioinformatics
Abstract

Multiple sequence alignments (MSAs) are a prerequisite for a wide variety of evolutionary analyses. Published assessments and benchmark data sets for protein and, to a lesser extent, global nucleotide MSAs are available, but less effort has been made to establish benchmarks in the more general problem of whole-genome alignment (WGA). Using the same model as the successful Assemblathon competitions, we organized a competitive evaluation in which teams submitted their alignments and then assessments were performed collectively after all the submissions were received. Three data sets were used: Two were simulated and based on primate and mammalian phylogenies, and one was comprised of 20 real fly genomes. In total, 35 submissions were assessed, submitted by 10 teams using 12 different alignment pipelines. We found agreement between independent simulation-based and statistical assessments, indicating that there are substantial accuracy differences between contemporary alignment tools. We saw considerable differences in the alignment quality of differently annotated regions and found that few tools aligned the duplications analyzed. We found that many tools worked well at shorter evolutionary distances, but fewer performed competitively at longer distances. We provide all data sets, submissions, and assessment programs for further study and provide, as a resource for future benchmarking, a convenient repository of code and data for reproducing the simulation assessments.

Published
2014

16. M2(m‑dobdc) (M = Mg, Mn, Fe, Co, Ni) Metal–Organic Frameworks Exhibiting Increased Charge Density and Enhanced H2 Binding at the Open Metal Sites

Author

Kapelewski, Matthew T, Geier, Stephen J, Hudson, Matthew R, Stück, David, Mason, Jarad A, Nelson, Jocienne N, Xiao, Dianne J, Hulvey, Zeric, Gilmour, Elizabeth, FitzGerald, Stephen A, Head-Gordon, Martin, Brown, Craig M, and Long, Jeffrey R

Subjects
Adsorption, Binding Sites, Cobalt, Hydrogen, Iron, Magnesium, Manganese, Molecular Structure, Nickel, Organometallic Compounds, Phthalic Acids, Spectrophotometry, Infrared, Thermogravimetry, X-Ray Diffraction, Chemical Sciences, General Chemistry
Abstract

The well-known frameworks of the type M2(dobdc) (dobdc(4-) = 2,5-dioxido-1,4-benzenedicarboxylate) have numerous potential applications in gas storage and separations, owing to their exceptionally high concentration of coordinatively unsaturated metal surface sites, which can interact strongly with small gas molecules such as H2. Employing a related meta-functionalized linker that is readily obtained from resorcinol, we now report a family of structural isomers of this framework, M2(m-dobdc) (M = Mg, Mn, Fe, Co, Ni; m-dobdc(4-) = 4,6-dioxido-1,3-benzenedicarboxylate), featuring exposed M(2+) cation sites with a higher apparent charge density. The regioisomeric linker alters the symmetry of the ligand field at the metal sites, leading to increases of 0.4-1.5 kJ/mol in the H2 binding enthalpies relative to M2(dobdc). A variety of techniques, including powder X-ray and neutron diffraction, inelastic neutron scattering, infrared spectroscopy, and first-principles electronic structure calculations, are applied in elucidating how these subtle structural and electronic differences give rise to such increases. Importantly, similar enhancements can be anticipated for the gas storage and separation properties of this new family of robust and potentially inexpensive metal-organic frameworks.

Published
2014

18. Genome-wide epitope mapping across multiple host species reveals significant diversity in antibody responses to Coxiella burnetii vaccination and infection

Author

Bach, Emil, primary, Fitzgerald, Stephen F., additional, Williams-MacDonald, Sarah E., additional, Mitchell, Mairi, additional, Golde, William T., additional, Longbottom, David, additional, Nisbet, Alasdair J., additional, Dinkla, Annemieke, additional, Sullivan, Eric, additional, Pinapati, Richard S., additional, Tan, John C., additional, Joosten, Leo A. B., additional, Roest, Hendrik-Jan, additional, Østerbye, Thomas, additional, Koets, Ad P., additional, Buus, Søren, additional, and McNeilly, Tom N., additional

Published
2023
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20. Analysis of Escherichia coli O157 strains in cattle and humans between Scotland and England & Wales: implications for human health

Author

Chase-Topping, Margo, primary, Dallman, Timothy J., additional, Allison, Lesley, additional, Lupolova, Nadejda, additional, Matthews, Louise, additional, Mitchell, Sonia, additional, Banks, Christopher J., additional, Prentice, Jamie, additional, Brown, Helen, additional, Tongue, Sue, additional, Henry, Madeleine, additional, Evans, Judith, additional, Gunn, George, additional, Hoyle, Deborah, additional, McNeilly, Tom N., additional, Fitzgerald, Stephen, additional, Smith-Palmer, Alison, additional, Shaaban, Sharif, additional, Holmes, Anne, additional, Hanson, Mary, additional, Woolhouse, Mark, additional, Didelot, Xavier, additional, Jenkins, Claire, additional, and Gally, David L., additional

Published
2023
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22. A high-resolution map of human evolutionary constraint using 29 mammals.

Author

Lindblad-Toh, Kerstin, Garber, Manuel, Zuk, Or, Lin, Michael F, Parker, Brian J, Washietl, Stefan, Kheradpour, Pouya, Ernst, Jason, Jordan, Gregory, Mauceli, Evan, Ward, Lucas D, Lowe, Craig B, Holloway, Alisha K, Clamp, Michele, Gnerre, Sante, Alföldi, Jessica, Beal, Kathryn, Chang, Jean, Clawson, Hiram, Cuff, James, Di Palma, Federica, Fitzgerald, Stephen, Flicek, Paul, Guttman, Mitchell, Hubisz, Melissa J, Jaffe, David B, Jungreis, Irwin, Kent, W James, Kostka, Dennis, Lara, Marcia, Martins, Andre L, Massingham, Tim, Moltke, Ida, Raney, Brian J, Rasmussen, Matthew D, Robinson, Jim, Stark, Alexander, Vilella, Albert J, Wen, Jiayu, Xie, Xiaohui, Zody, Michael C, Broad Institute Sequencing Platform and Whole Genome Assembly Team, Baldwin, Jen, Bloom, Toby, Chin, Chee Whye, Heiman, Dave, Nicol, Robert, Nusbaum, Chad, Young, Sarah, Wilkinson, Jane, Worley, Kim C, Kovar, Christie L, Muzny, Donna M, Gibbs, Richard A, Baylor College of Medicine Human Genome Sequencing Center Sequencing Team, Cree, Andrew, Dihn, Huyen H, Fowler, Gerald, Jhangiani, Shalili, Joshi, Vandita, Lee, Sandra, Lewis, Lora R, Nazareth, Lynne V, Okwuonu, Geoffrey, Santibanez, Jireh, Warren, Wesley C, Mardis, Elaine R, Weinstock, George M, Wilson, Richard K, Genome Institute at Washington University, Delehaunty, Kim, Dooling, David, Fronik, Catrina, Fulton, Lucinda, Fulton, Bob, Graves, Tina, Minx, Patrick, Sodergren, Erica, Birney, Ewan, Margulies, Elliott H, Herrero, Javier, Green, Eric D, Haussler, David, Siepel, Adam, Goldman, Nick, Pollard, Katherine S, Pedersen, Jakob S, Lander, Eric S, and Kellis, Manolis

Subjects
Broad Institute Sequencing Platform and Whole Genome Assembly Team, Baylor College of Medicine Human Genome Sequencing Center Sequencing Team, Genome Institute at Washington University, Animals, Mammals, Humans, Disease, RNA, Sequence Alignment, Sequence Analysis, DNA, Genomics, Evolution, Molecular, Phylogeny, Genome, Genome, Human, Exons, Health, Selection, Genetic, Molecular Sequence Annotation, Sequence Analysis, DNA, Evolution, Molecular, Human, Selection, Genetic, General Science & Technology
Abstract

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.

Published
2011

24. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

Author

Steward, Charles A., Roovers, Jolien, Suner, Marie-Marthe, Gonzalez, Jose M., Uszczynska-Ratajczak, Barbara, Pervouchine, Dmitri, Fitzgerald, Stephen, Viola, Margarida, Stamberger, Hannah, Hamdan, Fadi F., Ceulemans, Berten, Leroy, Patricia, Nava, Caroline, Lepine, Anne, Tapanari, Electra, Keiller, Don, Abbs, Stephen, Sanchis-Juan, Alba, Grozeva, Detelina, Rogers, Anthony S., Diekhans, Mark, Guigó, Roderic, Petryszak, Robert, Minassian, Berge A., Cavalleri, Gianpiero, Vitsios, Dimitrios, Petrovski, Slavé, Harrow, Jennifer, Flicek, Paul, Lucy Raymond, F., Lench, Nicholas J., Jonghe, Peter De, Mudge, Jonathan M., Weckhuysen, Sarah, Sisodiya, Sanjay M., and Frankish, Adam

Published
2019
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26. Analysis of Escherichia coli O157 strains in cattle and humans between Scotland and England & Wales: implications for human health.

Author

Chase-Topping, Margo, Dallman, Timothy J, Allison, Lesley, Lupolova, Nadejda, Matthews, Louise, Mitchell, Sonia, Banks, Christopher J, Prentice, Jamie, Brown, Helen, Tongue, Sue, Henry, Madeleine, Evans, Judith, Gunn, George, Hoyle, Deborah, McNeilly, Tom N, Fitzgerald, Stephen, Smith-Palmer, Alison, Shaaban, Sharif, Holmes, Anne, Hanson, Mary, Woolhouse, Mark, Didelot, Xavier, Jenkins, Claire, Gally, David L, Chase-Topping, Margo, Dallman, Timothy J, Allison, Lesley, Lupolova, Nadejda, Matthews, Louise, Mitchell, Sonia, Banks, Christopher J, Prentice, Jamie, Brown, Helen, Tongue, Sue, Henry, Madeleine, Evans, Judith, Gunn, George, Hoyle, Deborah, McNeilly, Tom N, Fitzgerald, Stephen, Smith-Palmer, Alison, Shaaban, Sharif, Holmes, Anne, Hanson, Mary, Woolhouse, Mark, Didelot, Xavier, Jenkins, Claire, and Gally, David L

Abstract

For the last two decades, the human infection frequency of Escherichia coli O157 (O157) in Scotland has been 2.5-fold higher than in England and Wales. Results from national cattle surveys conducted in Scotland and England and Wales in 2014/2015 were combined with data on reported human clinical cases from the same time frame to determine if strain differences in national populations of O157 in cattle could be associated with higher human infection rates in Scotland. Shiga toxin subtype (Stx) and phage type (PT) were examined within and between host (cattle vs human) and nation (Scotland vs England and Wales). For a subset of the strains, whole genome sequencing (WGS) provided further insights into geographical and host association. All three major O157 lineages (I, II, I/II) and most sub-lineages (Ia, Ib, Ic, IIa, IIb, IIc) were represented in cattle and humans in both nations. While the relative contribution of different reservoir hosts to human infection is unknown, WGS analysis indicated that the majority of O157 diversity in human cases was captured by isolates from cattle. Despite comparable cattle O157 prevalence between nations, strain types were localized. PT21/28 (sub-lineage Ic, Stx2a+) was significantly more prevalent in Scottish cattle [odds ratio (OR) 8.7 (2.3-33.7; P<0.001] and humans [OR 2.2 (1.5-3.2); P<0.001]. In England and Wales, cattle had a significantly higher association with sub-lineage IIa strains [PT54, Stx2c; OR 5.6 (1.27-33.3); P=0.011] while humans were significantly more closely associated with sub-lineage IIb [PT8, Stx1 and Stx2c; OR 29 (4.9-1161); P<0.001]. Therefore, cattle farms in Scotland were more likely to harbour Stx2a+O157 strains compared to farms in E and W ( P<0.001). There was evidence of limited cattle strain migration between nations and clinical isolates from one nation were more similar to cattle isolates from the same nation, with sub-lineage Ic (mainly PT21/28) exhibiting clear national association an

Published
2023

27. Efficacy of Phase I and Phase II Coxiella burnetii Bacterin Vaccines in a Pregnant Ewe Challenge Model

Author

Williams-Macdonald, Sarah E., Mitchell, Mairi, Frew, David, Palarea-Albaladejo, Javier, Ewing, David, Golde, William T., Longbottom, David, Nisbet, Alasdair J., Livingstone, Morag, Hamilton, Clare M., Fitzgerald, Stephen F., Buus, Søren, Bach, Emil, Dinkla, Annemieke, Roest, Hendrik-Jan, Koets, Ad P., McNeilly, Tom N., Williams-Macdonald, Sarah E., Mitchell, Mairi, Frew, David, Palarea-Albaladejo, Javier, Ewing, David, Golde, William T., Longbottom, David, Nisbet, Alasdair J., Livingstone, Morag, Hamilton, Clare M., Fitzgerald, Stephen F., Buus, Søren, Bach, Emil, Dinkla, Annemieke, Roest, Hendrik-Jan, Koets, Ad P., and McNeilly, Tom N.

Abstract

The bacterium Coxiella burnetii can cause the disease Q-fever in a wide range of animal hosts. Ruminants, including sheep, are thought to play a pivotal role in the transmission of C. burnetii to humans; however, the only existing livestock vaccine, namely, Coxevac® (Ceva Animal Health Ltd., Libourne, France), a killed bacterin vaccine based on phase I C. burnetii strain Nine-Mile, is only approved for use in goats and cattle. In this study, a pregnant ewe challenge model was used to determine the protective effects of Coxevac® and an experimental bacterin vaccine based on phase II C. burnetii against C. burnetii challenge. Prior to mating, ewes (n = 20 per group) were vaccinated subcutaneously with either Coxevac®, the phase II vaccine, or were unvaccinated. A subset of pregnant ewes (n = 6) from each group was then challenged 151 days later (~100 days of gestation) with 106 infectious mouse doses of C. burnetii, Nine-Mile strain RSA493. Both vaccines provided protection against C. burnetii challenge as measured by reductions in bacterial shedding in faeces, milk and vaginal mucus, and reduced abnormal pregnancies, compared to unvaccinated controls. This work highlights that the phase I vaccine Coxevac® can protect ewes against C. burnetii infection. Furthermore, the phase II vaccine provided comparable levels of protection and may offer a safer and cost-effective alternative to the currently licensed vaccine.

Published
2023

28. Genome-wide epitope mapping across multiple host species reveals significant diversity in antibody responses to Coxiella burnetii vaccination and infection

Author

Bach, Emil, Fitzgerald, Stephen F., Williams-MacDonald, Sarah E., Mitchell, Mairi, Golde, William T., Longbottom, David, Nisbet, Alasdair J., Dinkla, Annemieke, Sullivan, Eric, Pinapati, Richard S., Tan, John C., Joosten, Leo A.B., Roest, Hendrik Jan, Østerbye, Thomas, Koets, Ad P., Buus, Søren, McNeilly, Tom N., Bach, Emil, Fitzgerald, Stephen F., Williams-MacDonald, Sarah E., Mitchell, Mairi, Golde, William T., Longbottom, David, Nisbet, Alasdair J., Dinkla, Annemieke, Sullivan, Eric, Pinapati, Richard S., Tan, John C., Joosten, Leo A.B., Roest, Hendrik Jan, Østerbye, Thomas, Koets, Ad P., Buus, Søren, and McNeilly, Tom N.

Abstract

Coxiella burnetii is an important zoonotic bacterial pathogen of global importance, causing the disease Q fever in a wide range of animal hosts. Ruminant livestock, in particular sheep and goats, are considered the main reservoir of human infection. Vaccination is a key control measure, and two commercial vaccines based on formalin-inactivated C. burnetii bacterins are currently available for use in livestock and humans. However, their deployment is limited due to significant reactogenicity in individuals previously sensitized to C. burnetii antigens. Furthermore, these vaccines interfere with available serodiagnostic tests which are also based on C. burnetii bacterin antigens. Defined subunit antigen vaccines offer significant advantages, as they can be engineered to reduce reactogenicity and co-designed with serodiagnostic tests to allow discrimination between vaccinated and infected individuals. This study aimed to investigate the diversity of antibody responses to C. burnetii vaccination and/or infection in cattle, goats, humans, and sheep through genome-wide linear epitope mapping to identify candidate vaccine and diagnostic antigens within the predicted bacterial proteome. Using high-density peptide microarrays, we analyzed the seroreactivity in 156 serum samples from vaccinated and infected individuals to peptides derived from 2,092 open-reading frames in the C. burnetii genome. We found significant diversity in the antibody responses within and between species and across different types of C. burnetii exposure. Through the implementation of three different vaccine candidate selection methods, we identified 493 candidate protein antigens for protein subunit vaccine design or serodiagnostic evaluation, of which 65 have been previously described. This is the first study to investigate multi-species seroreactivity against the entire C. burnetii proteome presented as overlapping linear peptides and provides the basis for the selection of antigen targets for next

Published
2023

29. Data from: Genome-wide epitope mapping reveals significant diversity in antibody responses to Coxiella burnetii vaccination and infection

Author

Bach, Emil, Fitzgerald, Stephen F., Williams-MacDonald, Sarah E., Mitchell, Mairi, Golde, William T., Longbottom, David, Nisbet, Alasdair J., Dinkla, Annemieke, Sullivan, Eric, Pinapati, Richard S., Tan, John C., Koets, Ad, Roest, Hendrik-Jan, Buus, Søren, Østerbye, Thomas, McNeilly, Tom N., Bach, Emil, Fitzgerald, Stephen F., Williams-MacDonald, Sarah E., Mitchell, Mairi, Golde, William T., Longbottom, David, Nisbet, Alasdair J., Dinkla, Annemieke, Sullivan, Eric, Pinapati, Richard S., Tan, John C., Koets, Ad, Roest, Hendrik-Jan, Buus, Søren, Østerbye, Thomas, and McNeilly, Tom N.

Abstract

Coxiella burnetii is an important zoonotic bacterial pathogen of global importance, causing the disease Q fever in a wide range of animal hosts. Ruminant livestock, in particular sheep and goats, are considered the main reservoir of infection. Vaccination is a key control measure and two commercial vaccines based on formalin-inactivated C. burnetii bacterins are currently available. However, their deployment is limited due to significant reactogenicity in individuals previously sensitized to C. burnetii antigens. Furthermore, these vaccines interfere with available serodiagnostic tests which are also based on C. burnetii bacterin preparations. Subunit vaccines based on recombinant proteins offer significant advantages, as they can be designed to reduce reactogenicity and can be co-designed with defined antigen serodiagnostic tests to allow discrimination between vaccinated and infected individuals. This study aimed to investigate the diversity of antibody responses to C. burnetii vaccination and/or infection in cattle, goats, humans, and sheep through genome-wide linear epitope mapping to identify candidate vaccine and diagnostic antigens within the predicted bacterial proteome. Using high-density peptide microarrays, we analyzed the seroreactivity in 156 serum samples from vaccinated and infected individuals to peptides derived from 2,092 ORFs in the C. burnetii genome. We found significant diversity in the antibody responses within and between species and across different C. burnetii exposure statuses. However, C. burnetii exposure did result in more uniform seroreactivity across species. Through the implementation of three different vaccine candidate methods, we identified 493 candidate protein antigens for protein subunit vaccine design or serodiagnostic, out of which 65 have been previously described. This is the first study to investigate seroreactivity against the entire C. burnetii genome presented as overlapping linear peptides and provides the basis for se

Published
2023

30. Analysis of Escherichia coli O157 strains in cattle and humans between Scotland and England & Wales: implications for human health.

Author

IRAS OH Epidemiology Microbial Agents, IRAS – One Health Microbial, Chase-Topping, Margo, Dallman, Timothy J, Allison, Lesley, Lupolova, Nadejda, Matthews, Louise, Mitchell, Sonia, Banks, Christopher J, Prentice, Jamie, Brown, Helen, Tongue, Sue, Henry, Madeleine, Evans, Judith, Gunn, George, Hoyle, Deborah, McNeilly, Tom N, Fitzgerald, Stephen, Smith-Palmer, Alison, Shaaban, Sharif, Holmes, Anne, Hanson, Mary, Woolhouse, Mark, Didelot, Xavier, Jenkins, Claire, Gally, David L, IRAS OH Epidemiology Microbial Agents, IRAS – One Health Microbial, Chase-Topping, Margo, Dallman, Timothy J, Allison, Lesley, Lupolova, Nadejda, Matthews, Louise, Mitchell, Sonia, Banks, Christopher J, Prentice, Jamie, Brown, Helen, Tongue, Sue, Henry, Madeleine, Evans, Judith, Gunn, George, Hoyle, Deborah, McNeilly, Tom N, Fitzgerald, Stephen, Smith-Palmer, Alison, Shaaban, Sharif, Holmes, Anne, Hanson, Mary, Woolhouse, Mark, Didelot, Xavier, Jenkins, Claire, and Gally, David L

Published
2023

33. Efficacy of Phase I and Phase II Coxiella burnetii Bacterin Vaccines in a Pregnant Ewe Challenge Model

Author

Williams-Macdonald, Sarah E., primary, Mitchell, Mairi, additional, Frew, David, additional, Palarea-Albaladejo, Javier, additional, Ewing, David, additional, Golde, William T., additional, Longbottom, David, additional, Nisbet, Alasdair J., additional, Livingstone, Morag, additional, Hamilton, Clare M., additional, Fitzgerald, Stephen F., additional, Buus, Søren, additional, Bach, Emil, additional, Dinkla, Annemieke, additional, Roest, Hendrik-Jan, additional, Koets, Ad P., additional, and McNeilly, Tom N., additional

Published
2023
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40. Inhibition of IRE1α RNase activity sensitizes patient‐derived acute myeloid leukaemia cells to proteasome inhibitors

Author

Creedican, Stuart, primary, Robinson, Claire M., additional, Mnich, Katarzyna, additional, Islam, Md Nahidul, additional, Szegezdi, Eva, additional, Clifford, Ruth, additional, Krawczyk, Janusz, additional, Patterson, John B., additional, FitzGerald, Stephen P., additional, Summers, Mark, additional, Richardson, Ciaran, additional, Martin, Kenneth, additional, Gorman, Adrienne M., additional, and Samali, Afshin, additional

Published
2022
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42. SARS-CoV-2 RNA levels in Scotland’s wastewater

Author

Scorza, Livia C. T., primary, Cameron, Graeme J., additional, Murray-Williams, Roisin, additional, Findlay, David, additional, Bolland, Julie, additional, Cerghizan, Brindusa, additional, Campbell, Kirsty, additional, Thomson, David, additional, Corbishley, Alexander, additional, Gally, David, additional, Fitzgerald, Stephen, additional, Low, Alison, additional, McAteer, Sean, additional, Roberts, Adrian M. I., additional, Fang, Zhou, additional, Mayer, Claus-Dieter, additional, Frantsuzova, Anastasia, additional, Baby, Sumy V., additional, Zieliński, Tomasz, additional, and Millar, Andrew J., additional

Published
2022
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45. Clinical features and predictive biomarkers for bladder cancer in patients with type 2 diabetes presenting with haematuria

Author

Tonry, Claire L., primary, Evans, Raymond M., additional, Ruddock, Mark W., additional, Duggan, Brian, additional, McCloskey, Oonagh, additional, Maxwell, Alexander P., additional, O’Rourke, Declan, additional, Boyd, Ruth E., additional, Watt, Joanne, additional, Reid, Cherith N., additional, Curry, David J., additional, Stevenson, Michael, additional, Young, Margaret K., additional, Jamison, Catherine S., additional, Gallagher, Joe, additional, Fitzgerald, Stephen P., additional, Lamont, John, additional, and Watson, Chris J., additional

Published
2022
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47. Simultaneous detection of colorectal cancer mutations in stool samples with biochip arrays

Author

Murray Helena A., Latten Mark J., Cartwright Andrew, Mcaleer Damien, and Fitzgerald Stephen P.

Subjects
biochip array technology, colorectal cancer, mutation, non-invasive, stool, Biochemistry, QD415-436
Abstract

Colorectal cancer (CRC) is the second main cause of cancer-related death in the Western world and like many other tumors is curable if detected at an early stage. Current detection options include faecal occult blood testing and invasive direct visualization techniques such as flexible sigmoidoscopy, colonoscopy and barium enema. The availability of a more simple, non-invasive test that detects tumor specific products with optimal analytical performance might overcome barriers among patients who are not willing to undergo more sensitive but invasive tests. One such emerging technology, which has shown promise in recent years, is the analysis of DNA alterations exfoliated from tumor cells into stool. Here we report an analytical platform for non-invasive detection of 28 common mutations within CRC-related genes APC, TP53, K-ras and BRAF in stool samples based on biochip array technology and applied to the semi-automated Evidence Investigator analyzer. Mutation detection was possible in 1000-fold excess of wild type DNA and analysis of 10 CRC-positive patient samples showed presence of targeted mutations with equivalent mutations also identified by an alternative method. This application represents an excellent tool for the multiplex detection of CRC-specific mutations using a single platform.

Published
2009

48. Genome structural variation in Escherichia coli O157:H7

Author

Fitzgerald, Stephen F, Lupolova, Nadejda, Shaaban, Sharif, Dallman, Timothy J, Greig, David, Allison, Lesley, Tongue, Sue C, Evans, Judith, Henry, Madeleine K, McNeilly, Tom N, Bono, James L, Gally, David L, IRAS OH Epidemiology Microbial Agents, and IRAS OH Epidemiology Microbial Agents

Subjects
Optical mapping, Duplication, Epidemiology, Virulence, Biology, medicine.disease_cause, Genome, Microbiology, Structural variation, Type 3 secretion, Genome structure, Gene duplication, medicine, Genetics, O157:H7, Gene, Escherichia coli, Molecular Biology, Prophage, E. coli, Inversion, Shiga toxin, General Medicine, PFGE, H7 [O157], biology.protein, Cattle
Abstract

The human zoonotic pathogen Escherichia coli O157:H7 is defined by its extensive prophage repertoire including those that encode Shiga toxin, the factor responsible for inducing life-threatening pathology in humans. As well as introducing genes that can contribute to the virulence of a strain, prophage can enable the generation of large-chromosomal rearrangements (LCRs) by homologous recombination. This work examines the types and frequencies of LCRs across the major lineages of the O157:H7 serotype. We demonstrate that LCRs are a major source of genomic variation across all lineages of E. coli O157:H7 and by using both optical mapping and Oxford Nanopore long-read sequencing prove that LCRs are generated in laboratory cultures started from a single colony and that these variants can be recovered from colonized cattle. LCRs are biased towards the terminus region of the genome and are bounded by specific prophages that share large regions of sequence homology associated with the recombinational activity. RNA transcriptional profiling and phenotyping of specific structural variants indicated that important virulence phenotypes such as Shiga-toxin production, type-3 secretion and motility can be affected by LCRs. In summary, E. coli O157:H7 has acquired multiple prophage regions over time that act to continually produce structural variants of the genome. These findings raise important questions about the significance of this prophage-mediated genome contingency to enhance adaptability between environments.

Published
2021

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