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1. A Gonococcal Vaccine Has the Potential to Rapidly Reduce the Incidence of Neisseria gonorrhoeae Infection Among Urban Men Who Have Sex With Men.

Author

Hui, BB, Padeniya, TN, Rebuli, N, Gray, RT, Wood, JG, Donovan, B, Duan, Q, Guy, R, Hocking, JS, Lahra, MM, Lewis, DA, Whiley, DM, Regan, DG, Seib, KL, Hui, BB, Padeniya, TN, Rebuli, N, Gray, RT, Wood, JG, Donovan, B, Duan, Q, Guy, R, Hocking, JS, Lahra, MM, Lewis, DA, Whiley, DM, Regan, DG, and Seib, KL

Abstract

BACKGROUND: A gonococcal vaccine is urgently needed due to increasing gonorrhea incidence and emerging multidrug-resistant gonococcal strains worldwide. Men who have sex with men (MSM) have among the highest incidences of gonorrhea and may be a key target population for vaccination when available. METHODS: An individual-based, anatomical site-specific mathematical model was used to simulate Neisseria gonorrhoeae transmission in a population of 10 000 MSM. The impact of vaccination on gonorrhea prevalence was assessed. RESULTS: With a gonococcal vaccine of 100% or 50% protective efficacy, gonorrhea prevalence could be reduced by 94% or 62%, respectively, within 2 years if 30% of MSM are vaccinated on presentation for sexually transmitted infection (STI) testing. Elimination of gonorrhea is possible within 8 years with vaccines of ≥ 50% efficacy lasting 2 years, providing a booster vaccination is available every 3 years on average. A vaccine's impact may be reduced if it is not effective at all anatomical sites. CONCLUSIONS: Our study indicates that with a vaccine of modest efficacy and an immunization strategy that targets MSM presenting for STI screening, the prevalence of gonorrhea in this population could be rapidly and substantially reduced.

Published
2022

2. Moraxella catarrhalisphase-variable loci show differences in expression during conditions relevant to disease

Author

Reid, S, Tan, A, Blakeway, LV, Taha, Yang, Y, Zhou, Y, Atack, JM, Peak, IR, Seib, KL, Reid, S, Tan, A, Blakeway, LV, Taha, Yang, Y, Zhou, Y, Atack, JM, Peak, IR, and Seib, KL

Abstract

Moraxella catarrhalis is a human-adapted, opportunistic bacterial pathogen of the respiratory mucosa. Although asymptomatic colonization of the nasopharynx is common, M. catarrhalis can ascend into the middle ear, where it is a prevalent causative agent of otitis media in children, or enter the lower respiratory tract, where it is associated with acute exacerbations of chronic obstructive pulmonary disease in adults. Phase variation is the high frequency, random, reversible switching of gene expression that allows bacteria to adapt to different host microenvironments and evade host defences, and is most commonly mediated by simple DNA sequence repeats. Bioinformatic analysis of five closed M. catarrhalis genomes identified 17 unique simple DNA sequence repeat tracts that were variable between strains, indicating the potential to mediate phase variable expression of the associated genes. Assays designed to assess simple sequence repeat variation under conditions mimicking host infection demonstrated that phase variation of uspA1 (ubiquitous surface protein A1) from high to low expression occurs over 72 hours of biofilm passage, while phase variation of uspA2 (ubiquitous surface protein A2) to high expression variants occurs during repeated exposure to human serum, as measured by mRNA levels. We also identify and confirm the variable expression of two novel phase variable genes encoding a Type III DNA methyltransferase (modO), and a conserved hypothetical permease (MC25239_RS00020). These data reveal the repertoire of phase variable genes mediated by simple sequence repeats in M. catarrhalis and demonstrate that modulation of expression under conditions mimicking human infection is attributed to changes in simple sequence repeat length.

Published
2020

3. Transcriptome RNA Sequencing Data Set of Gene Expression in Moraxella catarrhalis On- and Off-Phase Variants of the Type III DNA Methyltransferase ModM3

Author

Dunning Hotopp, JC, Blakeway, LV, Tan, A, Peak, IR, Atack, JM, Seib, KL, Dunning Hotopp, JC, Blakeway, LV, Tan, A, Peak, IR, Atack, JM, and Seib, KL

Abstract

Moraxella catarrhalis is a leading bacterial cause of otitis media and exacerbations of chronic obstructive pulmonary disease. Here, we announce a transcriptome RNA sequencing data set detailing global gene expression in two M. catarrhalis CCRI-195ME variants with expression of the DNA methyltransferase ModM3 phase varied either on or off.

Published
2020

4. Proteome of a Moraxella catarrhalis Strain under Iron-Restricted Conditions

Author

Newton, ILG, Blakeway, L, Tan, A, Peak, IR, Atack, JM, Seib, KL, Newton, ILG, Blakeway, L, Tan, A, Peak, IR, Atack, JM, and Seib, KL

Abstract

Moraxella catarrhalis is a leading cause of otitis media and exacerbations of chronic obstructive pulmonary disease; however, its response to iron starvation during infection is not completely understood. Here, we announce a sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) data set describing the differential expression of the M. catarrhalis CCRI-195ME proteome under iron-restricted versus iron-replete conditions.

Published
2020

5. An Overview of Neisseria meningitidis

Author

Hollingshead, S, Tang, CM, Seib, KL, and Peak, IR

Abstract

Neisseria meningitidis (the meningococcus) is a member of the normal nasopharyngeal microbiome in healthy individuals, but can cause septicemia and meningitis in susceptible individuals. In this chapter we provide an overview of the disease caused by N. meningitidis and the schemes used to type the meningococcus. We also review the adhesions, virulence factors, and phase variable genes that enable it to successfully colonize the human host. Finally, we outline the history and current status of meningococcal vaccines and highlight the importance of continued molecular investigation of the epidemiology and the structural analysis of the antigens of this pathogen to aid future vaccine development.

Published
2019

6. Neisseria meningitidis: Methods and protocols

Author

Hollingshead, S, Tang, CM, Deghmane, A-E, Maiden, MCJ, Seib, KL, and Peak, IR

Abstract

This volume provides methods to analyze the meningococcus and its interactions with biologically relevant host cells and sites, to interrogate the population structure and biology of the meningococcus that defines its capacity to cause disease, and to aid in vaccine development and surveillance. Many of these methods are applicable to the close relative, Neisseria gonorrhoeae, and several of the methods described can also be used in investigating host-pathogen interactions for a range of other organisms. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Neisseria meningitidis: Methods and Protocols will allow for the use of these methods by more laboratories and foster collaboration and consistency in investigations of this enigmatic and dangerous pathogen.

Published
2019

7. The Moraxella catarrhalis phase-variable DNA methyltransferase ModM3 is an epigenetic regulator that affects bacterial survival in an in vivo model of otitis media

Author

Blakeway, LV, Tan, A, Jurcisek, JA, Bakaletz, LO, Atack, JM, Peak, IR, Seib, KL, Blakeway, LV, Tan, A, Jurcisek, JA, Bakaletz, LO, Atack, JM, Peak, IR, and Seib, KL

Abstract

BACKGROUND: Moraxella catarrhalis is a leading cause of otitis media (OM) and chronic obstructive pulmonary disease (COPD). M. catarrhalis contains a Type III DNA adenine methyltransferase (ModM) that is phase-variably expressed (i.e., its expression is subject to random, reversible ON/OFF switching). ModM has six target recognition domain alleles (modM1-6), and we have previously shown that modM2 is the predominant allele, while modM3 is associated with OM. Phase-variable DNA methyltransferases mediate epigenetic regulation and modulate pathogenesis in several bacteria. ModM2 of M. catarrhalis regulates the expression of a phasevarion containing genes important for colonization and infection. Here we describe the phase-variable expression of modM3, the ModM3 methylation site and the suite of genes regulated within the ModM3 phasevarion. RESULTS: Phase-variable expression of modM3, mediated by variation in length of a 5'-(CAAC)n-3' tetranucleotide repeat tract in the open reading frame was demonstrated in M. catarrhalis strain CCRI-195ME with GeneScan fragment length analysis and western immunoblot. We determined that ModM3 is an active N6-adenine methyltransferase that methylates the sequence 5'-ACm6ATC-3'. Methylation was detected at all 4446 5'-ACATC-3' sites in the genome when ModM3 is expressed. RNASeq analysis identified 31 genes that are differentially expressed between modM3 ON and OFF variants, including five genes that are involved in the response to oxidative and nitrosative stress, with potential roles in biofilm formation and survival in anaerobic environments. An in vivo chinchilla (Chinchilla lanigera) model of otitis media demonstrated that transbullar challenge with the modM3 OFF variant resulted in an increased middle ear bacterial load compared to a modM3 ON variant. In addition, co-infection experiments with NTHi and M. catarrhalis modM3 ON or modM3 OFF variants revealed that phase variation of modM3 altered survival of NTHi in the middle ear dur

Published
2019

8. The Serogroup B Meningococcal Vaccine Bexsero Elicits Antibodies to Neisseria gonorrhoeae

Author

Semchenko, EA, Tan, A, Borrow, R, Seib, KL, Semchenko, EA, Tan, A, Borrow, R, and Seib, KL

Abstract

BACKGROUND: Neisseria gonorrhoeae and Neisseria meningitidis are closely-related bacteria that cause a significant global burden of disease. Control of gonorrhoea is becoming increasingly difficult, due to widespread antibiotic resistance. While vaccines are routinely used for N. meningitidis, no vaccine is available for N. gonorrhoeae. Recently, the outer membrane vesicle (OMV) meningococcal B vaccine, MeNZB, was reported to be associated with reduced rates of gonorrhoea following a mass vaccination campaign in New Zealand. To probe the basis for this protection, we assessed the cross-reactivity to N. gonorrhoeae of serum raised to the meningococcal vaccine Bexsero, which contains the MeNZB OMV component plus 3 recombinant antigens (Neisseria adhesin A, factor H binding protein [fHbp]-GNA2091, and Neisserial heparin binding antigen [NHBA]-GNA1030). METHODS: A bioinformatic analysis was performed to assess the similarity of MeNZB OMV and Bexsero antigens to gonococcal proteins. Rabbits were immunized with the OMV component or the 3 recombinant antigens of Bexsero, and Western blots and enzyme-linked immunosorbent assays were used to assess the generation of antibodies recognizing N. gonorrhoeae. Serum from humans immunized with Bexsero was investigated to assess the nature of the anti-gonococcal response. RESULTS: There is a high level of sequence identity between MeNZB OMV and Bexsero OMV antigens, and between the antigens and gonococcal proteins. NHBA is the only Bexsero recombinant antigen that is conserved and surfaced exposed in N. gonorrhoeae. Bexsero induces antibodies in humans that recognize gonococcal proteins. CONCLUSIONS: The anti-gonococcal antibodies induced by MeNZB-like OMV proteins could explain the previously-seen decrease in gonorrhoea following MeNZB vaccination. The high level of human anti-gonococcal NHBA antibodies generated by Bexsero vaccination may provide additional cross-protection against gonorrhoea.

Published
2019

9. Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Author

Brown, P, Tan, A-C, El-Esawi, MA, Liehr, T, Blanck, O, Gladue, DP, Almeida, GMF, Cernava, T, Sorzano, CO, Yeung, AWK, Engel, MS, Chandrasekaran, AR, Muth, T, Staege, MS, Daulatabad, SV, Widera, D, Zhang, J, Meule, A, Honjo, K, Pourret, O, Yin, C-C, Zhang, Z, Cascella, M, Flegel, WA, Goodyear, CS, van Raaij, MJ, Bukowy-Bieryllo, Z, Campana, LG, Kurniawan, NA, Lalaouna, D, Huttner, FJ, Ammerman, BA, Ehret, F, Cobine, PA, Tan, E-C, Han, H, Xia, W, McCrum, C, Dings, RPM, Marinello, F, Nilsson, H, Nixon, B, Voskarides, K, Yang, L, Costa, VD, Bengtsson-Palme, J, Bradshaw, W, Grimm, DG, Kumar, N, Martis, E, Prieto, D, Sabnis, SC, Amer, SEDR, Liew, AWC, Perco, P, Rahimi, F, Riva, G, Zhang, C, Devkota, HP, Ogami, K, Basharat, Z, Fierz, W, Siebers, R, Tan, K-H, Boehme, KA, Brenneisen, P, Brown, JAL, Dalrymple, BP, Harvey, DJ, Ng, G, Werten, S, Bleackley, M, Dai, Z, Dhariwal, R, Gelfer, Y, Hartmann, MD, Miotla, P, Tamaian, R, Govender, P, Gurney-Champion, OJ, Kauppila, JH, Zhang, X, Echeverria, N, Subhash, S, Sallmon, H, Tofani, M, Bae, T, Bosch, O, Cuiv, PO, Danchin, A, Diouf, B, Eerola, T, Evangelou, E, Filipp, FV, Klump, H, Kurgan, L, Smith, SS, Terrier, O, Tuttle, N, Ascher, DB, Janga, SC, Schulte, LN, Becker, D, Browngardt, C, Bush, SJ, Gaullier, G, Ide, K, Meseko, C, Werner, GDA, Zaucha, J, Al-Farha, AA, Greenwald, NF, Popoola, SI, Rahman, MS, Xu, J, Yang, SY, Hiroi, N, Alper, OM, Baker, CI, Bitzer, M, Chacko, G, Debrabant, B, Dixon, R, Forano, E, Gilliham, M, Kelly, S, Klempnauer, K-H, Lidbury, BA, Lin, MZ, Lynch, I, Ma, W, Maibach, EW, Mather, DE, Nandakumar, KS, Ohgami, RS, Parchi, P, Tressoldi, P, Xue, Y, Armitage, C, Barraud, P, Chatzitheochari, S, Coelho, LP, Diao, J, Doxey, AC, Gobet, A, Hu, P, Kaiser, S, Mitchell, KM, Salama, MF, Shabalin, IG, Song, H, Stevanovic, D, Yadollahpour, A, Zeng, E, Zinke, K, Alimba, CG, Beyene, TJ, Cao, Z, Chan, SS, Gatchell, M, Kleppe, A, Piotrowski, M, Torga, G, Woldesemayat, AA, Cosacak, MI, Haston, S, Ross, SA, Williams, R, Wong, A, Abramowitz, MK, Effiong, A, Lee, S, Abid, MB, Agarabi, C, Alaux, C, Albrecht, DR, Atkins, GJ, Beck, CR, Bonvin, AMJJ, Bourke, E, Brand, T, Braun, RJ, Bull, JA, Cardoso, P, Carter, D, Delahay, RM, Ducommun, B, Duijf, PHG, Epp, T, Eskelinen, E-L, Fallah, M, Farber, DB, Fernandez-Triana, J, Feyerabend, F, Florio, T, Friebe, M, Furuta, S, Gabrielsen, M, Gruber, J, Grybos, M, Han, Q, Heinrich, M, Helantera, H, Huber, M, Jeltsch, A, Jiang, F, Josse, C, Jurman, G, Kamiya, H, de Keersmaecker, K, Kristiansson, E, de Leeuw, F-E, Li, J, Liang, S, Lopez-Escamez, JA, Lopez-Ruiz, FJ, Marchbank, KJ, Marschalek, R, Martin, CS, Miele, AE, Montagutelli, X, Morcillo, E, Nicoletti, R, Niehof, M, O'Toole, R, Ohtomo, T, Oster, H, Palma, J-A, Paterson, R, Peifer, M, Portilla, M, Portillo, MC, Pritchard, AL, Pusch, S, Raghava, GPS, Roberts, NJ, Ross, K, Schuele, B, Sergeant, K, Shen, J, Stella, A, Sukocheva, O, Uversky, VN, Vanneste, S, Villet, MH, Viveiros, M, Vorholt, JA, Weinstock, C, Yamato, M, Zabetakis, I, Zhao, X, Ziegler, A, Aizat, WM, Atlas, L, Bridges, KM, Chakraborty, S, Deschodt, M, Domingues, HS, Esfahlani, SS, Falk, S, Guisado, JL, Kane, NC, Kueberuwa, G, Lau, CL, Liang, D, Liu, E, Luu, AM, Ma, C, Ma, L, Moyer, R, Norris, AD, Panthee, S, Parsons, JR, Peng, Y, Pinto, IM, Reschke, CR, Sillanpaa, E, Stewart, CJ, Uhle, F, Yang, H, Zhou, K, Zhu, S, Ashry, M, Bergsland, N, Berthold, M, Chen, C-E, Colella, V, Cuypers, M, Eskew, EA, Fan, X, Gajda, M, Gonzalezlez-Prendes, R, Goodin, A, Graham, EB, Groen, EJN, Gutierrez-Sacristan, A, Habes, M, Heffler, E, Higginbottom, DB, Janzen, T, Jayaraman, J, Jibb, LA, Jongen, S, Kinyanjui, T, Koleva-Kolarova, RG, Li, Z, Liu, Y-P, Lund, BA, Lussier, AA, Mier, P, Moore, MD, Nagler, K, Orme, MW, Pearson, JA, Prajapati, AS, Saito, Y, Troder, SE, Uchendu, F, Verloh, N, Voutchkova, DD, Abu-Zaid, A, Bakkach, J, Baumert, P, Dono, M, Hanson, J, Herbelet, S, Hobbs, E, Kulkarni, A, Liu, S, Loft, ND, Reddan, T, Senghore, T, Vindin, H, Xu, H, Bannon, R, Chen, B, Cheung, JTK, Cooper, J, Esnakul, AK, Feghali, KA, Ghelardi, E, Gnasso, A, Horbar, J, Lai, HM, Ma, R, Pan, Z, Peres, MA, Pranata, R, Seow, E, Sydes, M, Testoni, I, Westermair, AL, Yang, Y, Afnan, M, Albiol, J, Albuquerque, LG, Amiya, E, Amorim, RM, An, Q, Andersen, SU, Aplin, JD, Argyropoulos, C, Asmann, YW, Assaeed, AM, Atanasov, AG, Atchison, DA, Avery, SV, Avillach, P, Baade, PD, Backman, L, Badie, C, Baldi, A, Ball, E, Bardot, O, Barnett, AG, Basner, M, Batra, J, Bazanova, OM, Beale, A, Beddoe, T, Bell, ML, Berezikov, E, Berners-Price, S, Bernhardt, P, Berry, E, Bessa, TB, Billington, C, Birch, J, Blakely, RD, Blaskovich, MAT, Blum, R, Boelaert, M, Bogdanos, D, Bosch, C, Bourgoin, T, Bouvard, D, Boykin, LM, Bradley, G, Braun, D, Brownlie, J, Bruhl, A, Burt, A, Butler, LM, Byrareddy, SN, Byrne, HJ, Cabantous, S, Calatayud, S, Candal, E, Carlson, K, Casillas, S, Castelvetro, V, Caswell, PT, Cavalli, G, Cerovsky, V, Chagoyen, M, Chen, C-S, Chen, DF, Chen, H, Chen, J-T, Chen, Y, Cheng, C, Cheng, J, Chinapaw, M, Chinopoulos, C, Cho, WCS, Chong, L, Chowdhury, D, Chwalibog, A, Ciresi, A, Cockcroft, S, Conesa, A, Cook, PA, Cooper, DN, Coqueret, O, Corea, EM, Costa, E, Coupland, C, Crawford, SY, Cruz, AD, Cui, H, Cui, Q, Culver, DC, D'Angiulli, A, Dahms, TES, Daigle, F, Dalgleish, R, Danielsen, HE, Darras, S, Davidson, SM, Day, DA, Degirmenci, V, Demaison, L, Devriendt, K, Ding, J, Dogan, Y, Dong, XC, Donner, CF, Dressick, W, Drevon, CA, Duan, H, Ducho, C, Dumaz, N, Dwarakanath, BS, Ebell, MH, Eisenhardt, S, Elkum, N, Engel, N, Erickson, TB, Fairhead, M, Faville, MJ, Fejzo, MS, Festa, F, Feteira, A, Flood-Page, P, Forsayeth, J, Fox, SA, Franks, SJ, Frentiu, FD, Frilander, MJ, Fu, X, Fujita, S, Galea, I, Galluzzi, L, Gani, F, Ganpule, AP, Garcia-Alix, A, Gedye, K, Giordano, M, Giunta, C, Gleeson, PA, Goarant, C, Gong, H, Gora, D, Gough, MJ, Goyal, R, Graham, KE, Grande-Perez, A, Graves, PM, Greidanus, H, Grice, D, Grunau, C, Gumulya, Y, Guo, Y, Gurevich, VV, Gusev, O, Hacker, E, Hage, SR, Hagen, G, Hahn, S, Haller, DM, Hammerschmidt, S, Han, J, Han, R, Handfield, M, Hapuarachchi, HC, Harder, T, Hardingham, JE, Heck, M, Heers, M, Hew, KF, Higuchi, Y, St Hilaire, C, Hilton, R, Hodzic, E, Hone, A, Hongoh, Y, Hu, G, Huber, HP, Hueso, LE, Huirne, J, Hurt, L, Idborg, H, Ikeo, K, Ingley, E, Jakeman, PM, Jensen, A, Jia, H, Jia, S, Jiang, J, Jiang, X, Jin, Y, Jo, D, Johnson, AM, Johnston, M, Jonscher, KR, Jorens, PG, Jorgensen, JOL, Joubert, JW, Jung, S-H, Junior, AM, Kahan, T, Kamboj, SK, Kang, Y-K, Karamanos, Y, Karp, NA, Kelly, R, Kenna, R, Kennedy, J, Kersten, B, Khalaf, RA, Khalid, JM, Khatlani, T, Khider, T, Kijanka, GS, King, SRB, Kluz, T, Knox, P, Kobayashi, T, Koch, K-W, Kohonen-Corish, MRJ, Kong, X, Konkle-Parker, D, Korpela, KM, Kostrikis, LG, Kraiczy, P, Kratz, H, Krause, G, Krebsbach, PH, Kristensen, SR, Kumari, P, Kunimatsu, A, Kurdak, H, Kwon, YD, Lachat, C, Lagisz, M, Laky, B, Lammerding, J, Lange, M, Larrosa, M, Laslett, AL, LeClair, EE, Lee, K-W, Lee, M-Y, Lee, M-S, Li, G, Lieb, K, Lim, YY, Lindsey, ML, Line, P-D, Liu, D, Liu, F, Liu, H, Lloyd, VK, Lo, T-W, Locci, E, Loidl, J, Lorenzen, J, Lorkowski, S, Lovell, NH, Lu, H, Lu, W, Lu, Z, Luengo, GS, Lundh, L-G, Lysy, PA, Mabb, A, Mack, HG, Mackey, DA, Mahdavi, SR, Maher, P, Maher, T, Maity, SN, Malgrange, B, Mamoulakis, C, Mangoni, AA, Manke, T, Manstead, ASR, Mantalaris, A, Marsal, J, Marschall, H-U, Martin, FL, Martinez-Raga, J, Martinez-Salas, E, Mathieu, D, Matsui, Y, Maza, E, McCutcheon, JE, Mckay, GJ, McMillan, B, McMillan, N, Meads, C, Medina, L, Merrick, BA, Metzger, DW, Meunier, FA, Michaelis, M, Micheau, O, Mihara, H, Mintz, EM, Mizukami, T, Moalic, Y, Mohapatra, DP, Monteiro, A, Montes, M, Moran, JV, Morozov, SY, Mort, M, Murai, N, Murphy, DJ, Murphy, SK, Murray, SA, Naganawa, S, Nammi, S, Nasios, G, Natoli, RM, Nguyen, F, Nicol, C, van Nieuwerburgh, F, Nilsen, EB, Nobile, CJ, O'Mahony, M, Ohlsson, S, Olatunbosun, O, Olofsson, P, Ortiz, A, Ostrikov, K, Otto, S, Outeiro, TF, Ouyang, S, Paganoni, S, Page, A, Palm, C, Paradies, Y, Parsons, MH, Parsons, N, Pascal, P, Paul, E, Peckham, M, Pedemonte, N, Pellizzon, MA, Petrelli, M, Pichugin, A, Pinto, CJC, Plevris, JN, Pollesello, P, Polz, M, Ponti, G, Porcelli, P, Prince, M, Quinn, GP, Quinn, TJ, Ramula, S, Rappsilber, J, Rehfeldt, F, Reiling, JH, Remacle, C, Rezaei, M, Riddick, EW, Ritter, U, Roach, NW, Roberts, DD, Robles, G, Rodrigues, T, Rodriguez, C, Roislien, J, Roobol, MJ, Rowe, JA, Ruepp, A, van Ruitenbeek, J, Rust, P, Saad, S, Sack, GH, Santos, M, Saudemont, A, Sava, G, Schrading, S, Schramm, A, Schreiber, M, Schuler, S, Schymkowitz, J, Sczyrba, A, Seib, KL, Shi, H-P, Shimada, T, Shin, J-S, Shortt, C, Silveyra, P, Skinner, D, Small, I, Smeets, PAM, So, P-W, Solano, F, Sonenshine, DE, Song, J, Southall, T, Speakman, JR, Srinivasan, MV, Stabile, LP, Stasiak, A, Steadman, KJ, Stein, N, Stephens, AW, Stewart, DI, Stine, K, Storlazzi, C, Stoynova, NV, Strzalka, 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Ortiz, A, Ostrikov, K, Otto, S, Outeiro, TF, Ouyang, S, Paganoni, S, Page, A, Palm, C, Paradies, Y, Parsons, MH, Parsons, N, Pascal, P, Paul, E, Peckham, M, Pedemonte, N, Pellizzon, MA, Petrelli, M, Pichugin, A, Pinto, CJC, Plevris, JN, Pollesello, P, Polz, M, Ponti, G, Porcelli, P, Prince, M, Quinn, GP, Quinn, TJ, Ramula, S, Rappsilber, J, Rehfeldt, F, Reiling, JH, Remacle, C, Rezaei, M, Riddick, EW, Ritter, U, Roach, NW, Roberts, DD, Robles, G, Rodrigues, T, Rodriguez, C, Roislien, J, Roobol, MJ, Rowe, JA, Ruepp, A, van Ruitenbeek, J, Rust, P, Saad, S, Sack, GH, Santos, M, Saudemont, A, Sava, G, Schrading, S, Schramm, A, Schreiber, M, Schuler, S, Schymkowitz, J, Sczyrba, A, Seib, KL, Shi, H-P, Shimada, T, Shin, J-S, Shortt, C, Silveyra, P, Skinner, D, Small, I, Smeets, PAM, So, P-W, Solano, F, Sonenshine, DE, Song, J, Southall, T, Speakman, JR, Srinivasan, MV, Stabile, LP, Stasiak, A, Steadman, KJ, Stein, N, Stephens, AW, Stewart, DI, Stine, K, Storlazzi, C, Stoynova, NV, Strzalka, W, Suarez, OM, Sultana, T, Sumant, AV, Summers, MJ, Sun, G, Tacon, P, Tanaka, K, Tang, H, Tanino, Y, Targett-Adams, P, Tayebi, M, Tayyem, R, Tebbe, CC, Telfer, EE, Tempel, W, Teodorczyk-Injeyan, JA, Thijs, G, Thorne, S, Thrift, AG, Tiffon, C, Tinnefeld, P, Tjahjono, DH, Tolle, F, Toth, E, del Tredici, AL, Tsapas, A, Tsirigotis, K, Turak, A, Tzotzos, G, Udo, EE, Utsumi, T, Vaidyanathan, S, Vaillant, M, Valsesia, A, Vandenbroucke, RE, Veiga, FH, Vendrell, M, Vesk, PA, Vickers, P, Victor, VM, Villemur, R, Vohl, M-C, Voolstra, CR, Vuillemin, A, Wakelin, S, Waldron, L, Walsh, LJ, Wang, AY, Wang, F, Wang, Y, Watanabe, Y, Weigert, A, Wen, J-C, Wham, C, White, EP, Wiener, J, Wilharm, G, Wilkinson, S, Willmann, R, Wilson, C, Wirth, B, Wojan, TR, Wolff, M, Wong, BM, Wu, T-W, Wuerbel, H, Xiao, X, Xu, D, Xu, JW, Xue, B, Yalcin, S, Yan, H, Yang, E-C, Yang, S, Yang, W, Ye, Y, Ye, Z-Q, Yli-Kauhaluoma, J, Yoneyama, H, Yu, Y, Yuan, G-C, Yuh, C-H, Zaccolo, M, Zeng, C, Zevnik, B, Zhang, L, Zhang, Y, Zhang, Z-Y, Zhao, Y, Zhou, M, Zuberbier, T, Aanei, CM, Ahmad, R, Al-Lawama, M, Alanio, A, Allardyce, J, Alonso-Caneiro, D, Atack, JM, Baier, D, Bansal, A, Benezeth, Y, Berbesque, C, Berrevoet, F, Biedermann, PHW, Bijleveld, E, Bittner, F, Blombach, F, Van den Bos, W, Boudreau, SA, Bramoweth, AD, Braubach, O, Cai, Y, Campbell, M, Catry, T, Chen, X, Cheng, S, Chung, H-J, Chavez-Fumagalli, MA, Conway, A, Costa, BM, Cyr, N, Dean, LT, Denzel, MS, Dlamini, SV, Dudley, KJ, Dufies, M, Ecke, T, Eckweiler, D, Eixarch, E, El-Adawy, H, Emmrich, JV, Eustace, AJ, Falter-Wagner, CM, Fuss, J, Gao, J, Gill, MR, Gloyn, L, Goggs, R, Govinden, U, Greene, G, Greiff, V, Grundle, DS, Gruneberg, P, Gumede, N, Haore, G, Harrison, P, Hoenner, X, Hojsgaard, D, Hori, H, Ikonomopoulou, MP, Jeurissen, P, Johnson, DM, Kabra, D, Kamagata, K, Karmakar, C, Kasian, O, Kaye, LK, Khan, MM, Kim, Y-M, Kish, JK, Kobold, S, Kohanbash, G, Kohls, G, Kugler, J-M, Kumar, G, Lacy-Colson, J, Latif, A, Lauschke, VM, Li, B, Lim, CJ, Liu, X, Lu, J-J, Lu, Q, Mahavadi, P, Marzocchi, U, McGarrigle, CA, van Meerten, T, Min, R, Moal, I, Molari, M, Molleman, L, Mondal, SR, Van de Mortel, T, Moss, WN, Moultos, OA, Mukherjee, M, Nakayama, K, Narayan, E, Navaratnarajah, Neumann, P-A, Nie, J, Nie, Y, Niemeyer, F, Fiona, Nwaiwu, O, Oldenmenger, WH, Olumayede, E, Ou, J, Pallebage-Gamarallage, M, Pearce, SP, Pelkonen, T, Pelleri, MC, Pereira, JL, Pheko, M, Pinto, KA, Piovesan, A, Pluess, M, Podolsky, IM, Prescott, J, Qi, D, Qi, X, Raikou, VD, Ranft, A, Rhodes, J, Rotge, J-Y, Rowe, AD, Saggar, M, Schuon, RA, Shahid, S, Shalchyan, V, Shirvalkar, P, Shiryayev, O, Singh, J, Smout, MJ, Soares, A, Song, C, Srivastava, K, Srivastava, RK, Sun, J, Szabo, A, Szymanski, W, Tai, CNP, Takeuchi, H, Tanadini-Lang, S, Tang, F, Tao, W, Theron, G, Tian, CF, Tian, Y-S, Tuttle, LM, Valenti, A, Verlot, P, Walker, M, Wang, J, Welter, D, Winslade, M, Wu, D, Wu, Y-R, Xiao, H, Xu, B, Xu, Z, Yang, D, Yang, M, Yankilevich, P, You, Y, Yu, C, Zhan, J, Zhang, G, Zhang, K, Zhang, T, Zhao, G, Zhao, J, Zhou, X, Zhu, Z, Ajani, PA, Anazodo, UC, Bagloee, SA, Bail, K, Bar, I, Bathelt, J, Benkeser, D, Bernier, ML, Blanchard, AM, Boakye, DW, Bonatsos, V, Boon, MH, Bouboulis, G, Bromfield, E, Brown, J, Bul, KCM, Burton, KJ, Butkowski, EG, Carroll, G, Chao, F, Charrier, EE, Chen, Y-C, Chenguang, Choi, JR, Christoffersen, T, Comel, JC, Cosse, C, Cui, Y, van Dessel, P, Dhaval, Diodato, D, Duffey, M, Dutt, A, Egea, LG, El-Said, M, Faye, M, Fernandez-Fernandez, B, Foley, KG, Founou, LL, Fu, F, Gadelkareem, RA, Galimov, E, Garip, G, Gemmill, A, Gouil, Q, Grey, J, Gridneva, Z, Grothe, MJ, Grebert, T, Guerrero, F, Guignard, L, Haenssgen, MJ, Hasler, D, Holgate, JY, Huang, A, Hulse-Kemp, AM, Jean-Quartier, C, Jeon, S-M, Jia, Y, Jutzeler, C, Kalatzis, P, Karim, M, Karsay, K, Keitel, A, Kempe, A, Keown, JR, Khoo, CM, Khwaja, N, Kievit, RA, Kosanic, A, Koutoukidis, DA, Kramer, P, Kumar, D, Kirag, N, Lanza, G, Le, TD, Leem, JW, Leightley, D, Leite, A, Lercher, L, Li, Y, Lim, R, Lima, LRA, Lin, L, Ling, T, Liu, Y, Liu, Z, Lu, Y, Lum, FM, Luo, H, Machhi, J, Macleod, A, Macwan, I, Madala, HR, Madani, N, de Maio, N, Makowiecki, K, Mallinson, DJ, Margelyte, R, Maria, C, Markonis, Y, Marsili, L, Mavoa, S, McWilliams, L, Megersa, M, Mendes, CSM, Menichetti, J, Mercieca-Bebber, R, Miller, JJ, Minde, D-PM, Minges, A, Mishra, E, Mishra, VR, Moores, C, Morrice, N, Moskalensky, AE, Navarin, N, Negera, E, Nolet, P, Nordberg, A, Norden, R, Nowicki, JP, Olova, N, Olszewski, P, Onzima, R, Pan, C-L, Park, C, Park, DI, Park, S, Patil, CD, Pedro, SA, Perry, SR, Peter, J, Peterson, BM, Pezzuolo, A, Pozdnyakov, I, Qian, S, Qin, L, Rafe, A, Raote, I, Raza, A, Rebl, H, Refai, O, Regan, T, Richa, T, Richardson, MF, Robinson, KR, Rossoni, L, Rouet, R, Safaei, S, Schneeberger, PHH, Schwotzer, D, Sebastian, A, Selinski, J, Seltmann, S, Sha, F, Shalev, N, Shang, J-L, Singer, J, Singh, M, Smith, T, Solomon-Moore, E, Song, L, Soraggi, S, Stanley, R, Steckhan, N, Strobl, F, Subissi, L, Supriyanto, I, Surve, CR, Suzuki, T, Syme, C, Sorelius, K, Tang, Y, Tantawy, M, Tennakoon, S, Teseo, S, Toelzer, C, Tomov, N, Tovar, M, Tran, L, Tripathi, S, Tuladhar, AM, Ukubuiwe, AC, Ung, COL, Valgepea, K, Vatanparast, H, Vidal, A, Wang, Q, Watari, R, Webster, R, Wei, J, Wibowo, D, Wingenbach, TSH, Xavier, RM, Xiao, S, Xiong, P, Xu, S, Yao, R, Yao, W, Yin, Q, Zaitsu, M, Zeineb, Z, Zhan, X-Y, Zhang, R, Zhang, W, Zheng, S, Zhou, B, Ahmad, H, Akinwumi, SA, Albery, GF, Alhowimel, A, Ali, J, Alshehri, M, Alsuhaibani, M, Anikin, A, Azubuike, SO, Bach-Mortensen, A, Baltiansky, L, Bartas, M, Belachew, KY, Bhardwaj, V, Binder, K, Bland, NS, Boah, M, Bullen, B, Calabro, GE, Callahan, TJ, Cao, B, Chalmers, K, Chang, W, Che, Z, Chen, ATY, Chen, Z, Choi, Y, Chowdhury, MAK, Christensen, MR, Cooke, RSC, Cottini, M, Covington, NV, Cunningham, C, Delarocque, J, Devos, L, Dhar, AR, Ding, K-F, Dong, K, Dong, Z, Dreyer, N, Ekstrand, C, Fardet, T, Feleke, BE, Feurer, T, Freitas, A, Gao, T, Asefa, NG, Giganti, F, Grabowski, P, Guerra-Mora, JR, Guo, C, Guo, X, Gupta, H, He, S, Heijne, M, Heinemann, S, Hogrebe, A, Huang, Z, Iskander-Rizk, S, Iyer, LM, Jahan, Y, James, AS, Joel, E, Joffroy, B, Jegousse, C, Kambondo, G, Karnati, P, Kaya, C, Ke, A, Kelly, D, Kickert, R, Kidibule, PE, Kieselmann, JP, Kim, HJ, Kitazawa, T, Lamberts, A, Liang, H, Linn, SN, Litfin, T, Liusuo, W, Lygirou, V, Mahato, AK, Mai, Z-M, Major, RW, Mali, S, Mallis, P, Mao, W, Marvin-Dowle, K, Mason, LD, Merideth, B, Merino-Plaza, MJ, Merlaen, B, Messina, R, Mishra, AK, Muhammad, J, Musinguzi, C, Nanou, A, Naqash, A, Nguyen, JT, Nguyen, TTH, Ni, D, Nida, Notcovich, S, Ohst, B, Ollivier, QR, Osses, DF, Peng, X, Plantinga, A, Pulia, M, Rafiq, M, Raman, A, Raucher-Chene, D, Rawski, R, Ray, A, Razak, LA, Rudolf, K, Rusch, P, Sadoine, ML, Schmidt, A, Schurr, R, Searles, S, Sharma, S, Sheehan, B, Shi, C, Shohayeb, B, Sommerlad, A, Strehlow, J, Sun, X, Sundar, R, Taherzadeh, G, Tahir, NDM, Tang, J, Testa, J, Tian, Z, Tingting, Q, Verheijen, GP, Vickstrom, C, Wang, T, Wang, X, Wang, Z, Wei, P, Wilson, A, Wyart, Yassine, A-A, Yousefzadeh, A, Zare, A, Zeng, Z, Zhang, H, Zhou, J, Zhu, D, Adamo, V, Adeyemo, AA, Aggelidou, M, Al-Owaifeer, AM, Al-Riyami, AZ, Alzghari, SK, Andersen, V, Angus, K, Asaduzzaman, M, Asady, H, Ato, D, Bai, X, Baines, RL, Ballantyne, M, Ban, B, Beck, J, Ben-Nafa, W, Black, E, Blancher, A, Blankstein, R, Bodagh, N, Borges, PAV, Brooks, A, Brox-Ponce, J, Brunetti, A, Canham, CD, Carninci, P, Carvajal, R, Chang, SC, Chao, J, Chatterjee, P, Chhatriwalla, AK, Chikowe, I, Chuang, T-J, Collevatti, RG, Valera-Cornejo, DA, Cuenda, A, Dao, M, Dauga, D, Deng, Z, Devkota, K, Doan, LV, Elewa, YHA, Fan, D, Faruk, M, Feifei, S, Ferguson, TS, Fleres, F, Foster, EJ, Foster, CS, Furer, T, Gao, Y, Garcia-Rivera, EJ, Gazdar, A, George, RB, Ghosh, S, Gianchecchi, E, Gleason, JM, Hackshaw, A, Hall, A, Hall, R, Harper, P, Hogg, WE, Huang, G, Hunter, KE, IJzerman, AP, Jesus, C, Jian, G, Lewis, JS, Kanj, SS, Kaur, H, Kheir, F, Kichatova, VS, Kiyani, M, Klein, R, Kovesi, T, Kraschnewski, JL, Kumar, AP, Labutin, D, Lazo-Langner, A, Leclercq, G, Li, M, Li, Q, Li, T, Liao, W-T, Liao, Z-Y, Lin, J, Lizer, J, Lobreglio, G, Lowies, C, Lu, C, Majeed, H, Martin, A, Martinez-Sobrido, L, Meresh, E, Middelveen, M, Mohebbi, A, Mota, J, Mozaheb, Z, Muyaya, L, Nandhakumar, A, Ng, SHX, Obeidat, M, Oh, D-H, Owais, M, Pace-Asciak, P, Panwar, A, Patterson, C, Penagos-Tabaree, F, Pianosi, PT, Pinzi, V, Pridans, C, Psaroulaki, A, Pujala, RK, Pulido-Arjona, L, Qi, P-F, Rahman, P, Rai, NK, Rassaf, T, Refardt, J, Ricciardi, W, Riess, O, Rovas, A, Sacks, FM, Saleh, S, Sampson, C, Schmutz, A, Sepanski, R, Sharma, N, Spearman, P, Subramaniapillai, M, Swali, R, Tan, CM, Tellechea, JI, Thomas, L-M, Tong, X, Veys, R, Vitriol, V, Wang, H-D, Waugh, J, Webb, SA, Williams, BA, Workman, AD, Xiang, T, Xie, L-X, Xu, T, Yang, C, Yoon, JG, Yuan, CM, Zaritsky, A, Zhao, H, Zuckerman, H, Lyu, R, Pullan, W, and Zhou, Y

Published
2019

10. Moraxella catarrhalis Restriction-Modification Systems Are Associated with Phylogenetic Lineage and Disease

Author

Blakeway, LV, Tan, A, Lappan, R, Ariff, A, Pickering, JL, Peacock, CS, Blyth, CC, Kahler, CM, Chang, BJ, Lehmann, D, Kirkham, L-AS, Murphy, TF, Jennings, MP, Bakaletz, LO, Atack, JM, Peak, IR, Seib, KL, Blakeway, LV, Tan, A, Lappan, R, Ariff, A, Pickering, JL, Peacock, CS, Blyth, CC, Kahler, CM, Chang, BJ, Lehmann, D, Kirkham, L-AS, Murphy, TF, Jennings, MP, Bakaletz, LO, Atack, JM, Peak, IR, and Seib, KL

Abstract

Moraxella catarrhalis is a human-adapted pathogen, and a major cause of otitis media (OM) and exacerbations of chronic obstructive pulmonary disease. The species is comprised of two main phylogenetic lineages, RB1 and RB2/3. Restriction-modification (R-M) systems are among the few lineage-associated genes identified in other bacterial genera and have multiple functions including defense against foreign invading DNA, maintenance of speciation, and epigenetic regulation of gene expression. Here, we define the repertoire of R-M systems in 51 publicly available M. catarrhalis genomes and report their distribution among M. catarrhalis phylogenetic lineages. An association with phylogenetic lineage (RB1 or RB2/3) was observed for six R-M systems, which may contribute to the evolution of the lineages by restricting DNA transformation. In addition, we observed a relationship between a mutually exclusive Type I R-M system and a Type III R-M system at a single locus conserved throughout a geographically and clinically diverse set of M. catarrhalis isolates. The Type III R-M system at this locus contains the phase-variable Type III DNA methyltransferase, modM, which controls a phasevarion (phase-variable regulon). We observed an association between modM presence and OM-associated middle ear isolates, indicating a potential role for ModM-mediated epigenetic regulation in OM pathobiology.

Published
2018

11. Complete Genome Sequence of Moraxella catarrhalis Strain CCRI-195ME, Isolated from the Middle Ear

Author

Tan, A, Blakeway, LV, Bakaletz, LO, Boitano, M, Clark, TA, Korlach, J, Jennings, MP, Peak, IR, Seib, KL, Tan, A, Blakeway, LV, Bakaletz, LO, Boitano, M, Clark, TA, Korlach, J, Jennings, MP, Peak, IR, and Seib, KL

Abstract

Moraxella catarrhalis is an important bacterial pathogen that causes otitis media and exacerbations of chronic obstructive pulmonary disease. Here, we report the complete genome sequence of M. catarrhalis strain CCRI-195ME, which contains the phase-variable epigenetic regulator ModM3.

Published
2017

12. The Capricious Nature of Bacterial Pathogens: Phasevarions and vaccine Development

Author

Tan, A, Atack, JM, Jennings, MP, Seib, KL, Tan, A, Atack, JM, Jennings, MP, and Seib, KL

Abstract

Infectious diseases are a leading cause of morbidity and mortality worldwide, and vaccines are one of the most successful and cost-effective tools for disease prevention. One of the key considerations for rational vaccine development is the selection of appropriate antigens. Antigens must induce a protective immune response, and this response should be directed to stably expressed antigens so the target microbe can always be recognized by the immune system. Antigens with variable expression, due to environmental signals or phase variation (i.e., high frequency, random switching of expression), are not ideal vaccine candidates because variable expression could lead to immune evasion. Phase variation is often mediated by the presence of highly mutagenic simple tandem DNA repeats, and genes containing such sequences can be easily identified, and their use as vaccine antigens reconsidered. Recent research has identified phase variably expressed DNA methyltransferases that act as global epigenetic regulators. These phase-variable regulons, known as phasevarions, are associated with altered virulence phenotypes and/or expression of vaccine candidates. As such, genes encoding candidate vaccine antigens that have no obvious mechanism of phase variation may be subject to indirect, epigenetic control as part of a phasevarion. Bioinformatic and experimental studies are required to elucidate the distribution and mechanism of action of these DNA methyltransferases, and most importantly, whether they mediate epigenetic regulation of potential and current vaccine candidates. This process is essential to define the stably expressed antigen target profile of bacterial pathogens and thereby facilitate efficient, rational selection of vaccine antigens.

Published
2016

13. Distribution of the type III DNA methyltransferases modA, modB and modD among Neisseria meningitidis genotypes: implications for gene regulation and virulence

Author

Tan, A, Hill, DMC, Harrison, OB, Srikhanta, YN, Jennings, MP, Maiden, MCJ, Seib, KL, Tan, A, Hill, DMC, Harrison, OB, Srikhanta, YN, Jennings, MP, Maiden, MCJ, and Seib, KL

Abstract

Neisseria meningitidis is a human-specific bacterium that varies in invasive potential. All meningococci are carried in the nasopharynx, and most genotypes are very infrequently associated with invasive meningococcal disease; however, those belonging to the 'hyperinvasive lineages' are more frequently associated with sepsis or meningitis. Genome content is highly conserved between carriage and disease isolates, and differential gene expression has been proposed as a major determinant of the hyperinvasive phenotype. Three phase variable DNA methyltransferases (ModA, ModB and ModD), which mediate epigenetic regulation of distinct phase variable regulons (phasevarions), have been identified in N. meningitidis. Each mod gene has distinct alleles, defined by their Mod DNA recognition domain, and these target and methylate different DNA sequences, thereby regulating distinct gene sets. Here 211 meningococcal carriage and >1,400 disease isolates were surveyed for the distribution of meningococcal mod alleles. While modA11-12 and modB1-2 were found in most isolates, rarer alleles (e.g., modA15, modB4, modD1-6) were specific to particular genotypes as defined by clonal complex. This suggests that phase variable Mod proteins may be associated with distinct phenotypes and hence invasive potential of N. meningitidis strains.

Published
2016

14. The potential impact of vaccination on the prevalence of gonorrhea

Author

Craig, AP, Gray, RT, Edwards, JL, Apicella, MA, Jennings, MP, Wilson, DP, Seib, KL, Craig, AP, Gray, RT, Edwards, JL, Apicella, MA, Jennings, MP, Wilson, DP, and Seib, KL

Abstract

© 2015 The Authors.Gonorrhea, one of the most common sexually transmitted infections worldwide, can lead to serious sequelae, including infertility and increased HIV transmission. Recently, untreatable, multidrug-resistant Neisseria gonorrhoeae strains have been reported. In the absence of new antibiotics, and given the speed with which resistance has emerged to all previously used antibiotics, development of a vaccine would be the ideal solution to this public health emergency. Understanding the desired characteristics, target population, and expected impact of an anti-gonococcal vaccine is essential to facilitate vaccine design, assessment and implementation. The modeling presented herein aims to fill these conceptual gaps, and inform future gonococcal vaccine development. Using an individual-based, epidemiological simulation model, gonococcal prevalence was simulated in a heterosexual population of 100,000 individuals after the introduction of vaccines with varied efficacy (10-100%) and duration of protection (2.5-20 years). Model simulations predict that gonococcal prevalence could be reduced by at least 90% after 20 years, if all 13-year-olds were given a non-waning vaccine with 50% efficacy, or a vaccine with 100% efficacy that wanes after 7.5 years. A 40% reduction in prevalence is achievable with a non-waning vaccine of only 20% efficacy. We conclude that a vaccine of moderate efficacy and duration could have a substantive impact on gonococcal prevalence, and disease sequelae, if coverage is high and protection lasts over the highest risk period (. i.e., most sexual partner change) among young people.

Published
2015

15. Specificity of the ModA11, ModA12 and ModD1 epigenetic regulator N-6-adenine DNA methyltransferases of Neisseria meningitidis

Author

Seib, KL, Jen, FE-C, Tan, A, Scott, AL, Kumar, R, Power, PM, Chen, L-T, Wu, H-J, Wang, AH-J, Hill, DMC, Luyten, YA, Morgan, RD, Roberts, RJ, Maiden, MCJ, Boitano, M, Clark, TA, Korlach, J, Rao, DN, Jennings, MP, Seib, KL, Jen, FE-C, Tan, A, Scott, AL, Kumar, R, Power, PM, Chen, L-T, Wu, H-J, Wang, AH-J, Hill, DMC, Luyten, YA, Morgan, RD, Roberts, RJ, Maiden, MCJ, Boitano, M, Clark, TA, Korlach, J, Rao, DN, and Jennings, MP

Abstract

Phase variation (random ON/OFF switching) of gene expression is a common feature of host-adapted pathogenic bacteria. Phase variably expressed N(6)-adenine DNA methyltransferases (Mod) alter global methylation patterns resulting in changes in gene expression. These systems constitute phase variable regulons called phasevarions. Neisseria meningitidis phasevarions regulate genes including virulence factors and vaccine candidates, and alter phenotypes including antibiotic resistance. The target site recognized by these Type III N(6)-adenine DNA methyltransferases is not known. Single molecule, real-time (SMRT) methylome analysis was used to identify the recognition site for three key N. meningitidis methyltransferases: ModA11 (exemplified by M.NmeMC58I) (5'-CGY M6A: G-3'), ModA12 (exemplified by M.Nme77I, M.Nme18I and M.Nme579II) (5'-AC M6A: CC-3') and ModD1 (exemplified by M.Nme579I) (5'-CC M6A: GC-3'). Restriction inhibition assays and mutagenesis confirmed the SMRT methylome analysis. The ModA11 site is complex and atypical and is dependent on the type of pyrimidine at the central position, in combination with the bases flanking the core recognition sequence 5'-CGY M6A: G-3'. The observed efficiency of methylation in the modA11 strain (MC58) genome ranged from 4.6% at 5'-GCGC M6A: GG-3' sites, to 100% at 5'-ACGT M6A: GG-3' sites. Analysis of the distribution of modified sites in the respective genomes shows many cases of association with intergenic regions of genes with altered expression due to phasevarion switching.

Published
2015

17. Phasevarions Mediate Random Switching of Gene Expression in Pathogenic Neisseria

Author

Seifert, HS, Srikhanta, YN, Dowideit, SJ, Edwards, JL, Falsetta, ML, Wu, H-J, Harrison, OB, Fox, KL, Seib, KL, Maguire, TL, Wang, AH-J, Maiden, MC, Grimmond, SM, Apicella, MA, Jennings, MP, Seifert, HS, Srikhanta, YN, Dowideit, SJ, Edwards, JL, Falsetta, ML, Wu, H-J, Harrison, OB, Fox, KL, Seib, KL, Maguire, TL, Wang, AH-J, Maiden, MC, Grimmond, SM, Apicella, MA, and Jennings, MP

Abstract

Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae, the random switching of the modA gene controls expression of a phase-variable regulon of genes (a "phasevarion"), via differential methylation of the genome in the modA ON and OFF states. Phase-variable mod genes are also present in Neisseria meningitidis and Neisseria gonorrhoeae, suggesting that phasevarions may occur in these important human pathogens. Phylogenetic studies on phase-variable mod genes associated with type III restriction modification (R-M) systems revealed that these organisms have two distinct mod genes--modA and modB. There are also distinct alleles of modA (abundant: modA11, 12, 13; minor: modA4, 15, 18) and modB (modB1, 2). These alleles differ only in their DNA recognition domain. ModA11 was only found in N. meningitidis and modA13 only in N. gonorrhoeae. The recognition site for the modA13 methyltransferase in N. gonorrhoeae strain FA1090 was identified as 5'-AGAAA-3'. Mutant strains lacking the modA11, 12 or 13 genes were made in N. meningitidis and N. gonorrhoeae and their phenotype analyzed in comparison to a corresponding mod ON wild-type strain. Microarray analysis revealed that in all three modA alleles multiple genes were either upregulated or downregulated, some of which were virulence-associated. For example, in N. meningitidis MC58 (modA11), differentially expressed genes included those encoding the candidate vaccine antigens lactoferrin binding proteins A and B. Functional studies using N. gonorrhoeae FA1090 and the clinical isolate O1G1370 confirmed that modA13 ON and OFF strains have distinct phenotypes in antimicrobial resistance, in a primary human cervical epithelial cell model of infection, and in biofilm formation. This study, in conjunction with our previous work in H. influenzae, indicates that phasevarions

Published
2009

18. The Key Role of Genomics in Modern Vaccine and Drug Design for Emerging Infectious Diseases

Author

Schork, NJ, Seib, KL, Dougan, G, Rappuoli, R, Schork, NJ, Seib, KL, Dougan, G, and Rappuoli, R

Abstract

It can be argued that the arrival of the "genomics era" has significantly shifted the paradigm of vaccine and therapeutics development from microbiological to sequence-based approaches. Genome sequences provide a previously unattainable route to investigate the mechanisms that underpin pathogenesis. Genomics, transcriptomics, metabolomics, structural genomics, proteomics, and immunomics are being exploited to perfect the identification of targets, to design new vaccines and drugs, and to predict their effects in patients. Furthermore, human genomics and related studies are providing insights into aspects of host biology that are important in infectious disease. This ever-growing body of genomic data and new genome-based approaches will play a critical role in the future to enable timely development of vaccines and therapeutics to control emerging infectious diseases.

Published
2009

19. Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Author

Zeineb, Zian, Brown, Peter, Tan, Aik-Choon, El-Esawi, Mohamed A., Liehr, Thomas, Blanck, Oliver, Gladue, Douglas P., Almeida, Gabriel M. F., Cernava, Tomislav, Sorzano, Carlos O., Yeung, Andy W. K., Engel, Michael S., Chandrasekaran, Arun Richard, Muth, Thilo, Staege, Martin S., Daulatabad, Swapna V., Widera, Darius, Zhang, Junpeng, Meule, Adrian, Honjo, Ken, Pourret, Olivier, Yin, Cong-Cong, Zhang, Zhongheng, Cascella, Marco, Flegel, Willy A., Goodyear, Carl S., Raaij, Mark J. van, Bukowy-Bieryllo, Zuzanna, Campana, Luca G., Kurniawan, Nicholas A., Lalaouna, David, Hüttner, Felix J., Ammerman, Brooke A., Ehret, Felix, Cobine, Paul A., Tan, Ene-Choo, Han, Hyemin, Xia, Wenfeng, McCrum, Christopher, Dings, Ruud P. M., Marinello, Francesco, Nilsson, Henrik, Nixon, Brett, Voskarides, Konstantinos, Yang, Long, Costa, Vincent D., Bengtsson-Palme, Johan, Bradshaw, William, Grimm, Dominik G., Kumar, Nitin, Martis, Elvis, Prieto, Daniel, Sabnis, Sandeep C., Amer, Said E. D. R., Liew, Alan W. C., Perco, Paul, Rahimi, Farid, Riva, Giuseppe, Zhang, Chongxing, Devkota, Hari P., Ogami, Koichi, Basharat, Zarrin, Fierz, Walter, Siebers, Robert, Tan, Kok-Hian, Boehme, Karen A., Brenneisen, Peter, Brown, James A. L., Dalrymple, Brian P., Harvey, David J., Ng, Grace, Werten, Sebastiaan, Bleackley, Mark, Dai, Zhanwu, Dhariwal, Raman, Gelfer, Yael, Hartmann, Marcus D., Miotla, Pawel, Tamaian, Radu, Govender, Pragashnie, Gurney-Champion, Oliver J., Kauppila, Joonas H., Zhang, Xiaolei, Echeverría, Natalia, Subhash, Santhilal, Sallmon, Hannes, Tofani, Marco, Bae, Taeok, Bosch, Oliver, Cuív, Páraic O., Danchin, Antoine, Diouf, Barthelemy, Eerola, Tuomas, Evangelou, Evangelos, Filipp, Fabian V., Klump, Hannes, Kurgan, Lukasz, Smith, Simon S., Terrier, Olivier, Tuttle, Neil, Ascher, David B., Janga, Sarath C., Schulte, Leon N., Becker, Daniel, Browngardt, Christopher, Bush, Stephen J., Gaullier, Guillaume, Ide, Kazuki, Meseko, Clement, Werner, Gijsbert D. A., Zaucha, Jan, Al-Farha, Abd A., Greenwald, Noah F., Popoola, Segun I., Rahman, Md Shaifur, Xu, Jialin, Yang, Sunny Y., Hiroi, Noboru, Alper, Ozgul M., Baker, Chris I., Bitzer, Michael, Chacko, George, Debrabant, Birgit, Dixon, Ray, Forano, Evelyne, Gilliham, Matthew, Kelly, Sarah, Klempnauer, Karl-Heinz, Lidbury, Brett A., Lin, Michael Z., Lynch, Iseult, Ma, Wujun, Maibach, Edward W., Mather, Diane E., Nandakumar, Kutty S., Ohgami, Robert S., Parchi, Piero, Tressoldi, Patrizio, Xue, Yu, Armitage, Charles, Barraud, Pierre, Chatzitheochari, Stella, Coelho, Luis P., Diao, Jiajie, Doxey, Andrew C., Hu, Pingzhao, Kaiser, Stefan, Mitchell, Kate M., Salama, Mohamed F., Shabalin, Ivan G., Song, Haijun, Stevanovic, Dejan, Yadollahpour, Ali, Zeng, Erliang, Zinke, Katharina, Alimba, C. G., Beyene, Tariku J., Cao, Zehong, Chan, Sherwin S., Gatchell, Michael, Kleppe, Andreas, Piotrowski, Marcin, Torga, Gonzalo, Woldesemayat, Adugna A., Cosacak, Mehmet I., Haston, Scott, Ross, Stephanie A., Williams, Richard, Wong, Alvin, Abramowitz, Matthew K., Effiong, Andem, Lee, Senhong, Abid, Muhammad Bilal, Agarabi, Cyrus, Alaux, Cedric, Albrecht, Dirk R., Atkins, Gerald J., Beck, Charles R., Bonvin, A. M. J. J., Bourke, Emer, Brand, Thomas, Braun, Ralf J., Bull, James A., Cardoso, Pedro, Carter, Dee, Delahay, Robin M., Ducommun, Bernard, Duijf, Pascal H. G., Epp, Trevor, Eskelinen, Eeva-Liisa, Fallah, Mazyar, Farber, Debora B., Fernandez-Triana, Jose, Feyerabend, Frank, Florio, Tullio, Friebe, Michael, Furuta, Saori, Gabrielsen, Mads, Gruber, Jens, Grybos, Malgorzata, Han, Qian, Heinrich, Michael, Helanterä, Heikki, Huber, Michael, Jeltsch, Albert, Jiang, Fan, Josse, Claire, Jurman, Giuseppe, Kamiya, Haruyuki, Keersmaecker, Kim de, Kristiansson, Erik, Leeuw, Frank-Erik de, Li, Jiuyong, Liang, Shide, Lopez-Escamez, Jose A., Lopez-Ruiz, Francisco J., Marchbank, Kevin J., Marschalek, Rolf, Martín, Carmen S., Miele, Adriana E., Montagutelli, Xavier, Morcillo, Esteban, Nicoletti, Rosario, Niehof, Monika, O’Toole, Ronan, Ohtomo, Toshihiko, Oster, Henrik, Palma, Jose-Alberto, Paterson, Russell, Peifer, Mark, Portilla, Maribel, Portillo, M. C., Pritchard, Antonia L., Pusch, Stefan, Raghava, Gajendra P. S., Roberts, Nicola J., Ross, Kehinde, Schuele, Birgitt, Sergeant, Kjell, Shen, Jun, Stella, Alessandro, Sukocheva, Olga, Uversky, Vladimir N., Vanneste, Sven, Villet, Martin H., Viveiros, Miguel, Vorholt, Julia A., Weinstock, Christof, Yamato, Masayuki, Zabetakis, Ioannis, Zhao, Xin, Ziegler, Andreas, Aizat, Wan M., Atlas, Lauren, Bridges, Kristina M., Chakraborty, Sayan, Deschodt, Mieke, Domingues, Helena S., Esfahlani, Shabnam S., Falk, Sebastian, Guisado, J. L., Kane, Nolan C., Kueberuwa, Gray, Lau, Colleen L., Liang, Dai, Liu, Enwu, Luu, Andreas M., Ma, Chuang, Ma, Lisong, Moyer, Robert, Norris, Adam D., Panthee, Suresh, Parsons, Jerod R., Peng, Yousong, Pinto, Inês Mendes, Reschke, Cristina R., Sillanpää, Elina, Stewart, Christopher J., Uhle, Florian, Yang, Hui, Zhou, Kai, Zhu, Shu, Ashry, Mohamed, Bergsland, Niels, Berthold, Maximilian, Chen, Chang-Er, Colella, Vito, Cuypers, Maarten, Eskew, Evan A., Fan, Xiao, Gajda, Maksymilian, Gonzálezlez-Prendes, Rayner, Goodin, Amie, Graham, Emily B., Groen, Ewout J. N., Gutiérrez-Sacristán, Alba, Habes, Mohamad, Heffler, Enrico, Higginbottom, Daniel B., Janzen, Thijs, Jayaraman, Jayakumar, Jibb, Lindsay A., Jongen, Stefan, Kinyanjui, Timothy, Koleva-Kolarova, Rositsa G., Li, Zhixiu, Liu, Yu-Peng, Lund, Bjarte A., Lussier, Alexandre A., Ma, Liping, Mier, Pablo, Moore, Matthew D., Nagler, Katja, Orme, Mark W., Pearson, James A., Prajapati, Anilkumar S., Saito, Yu, Tröder, Simon E., Uchendu, Florence, Verloh, Niklas, Voutchkova, Denitza D., Abu-Zaid, Ahmed, Bakkach, Joaira, Baumert, Philipp, Dono, Marcos, Hanson, Jack, Herbelet, Sandrine, Hobbs, Emma, Kulkarni, Ameya, Kumar, Narendra, Liu, Siqi, Loft, Nikolai D., Reddan, Tristan, Senghore, Thomas, Vindin, Howard, Xu, Haotian, Bannon, Ross, Chen, Branson, Cheung, Johnny T. K., Cooper, Jeffrey, Esnakula, Ashwini K., Feghali, Karine A., Ghelardi, Emilia, Gnasso, Agostino, Horbar, Jeffrey, Lai, Hei M., Li, Jian, Ma, Lan, Ma, Ruiyan, Pan, Zihang, Peres, Marco A., Pranata, Raymond, Seow, Esmond, Sydes, Matthew, Testoni, Ines, Westermair, Anna L., Yang, Yongliang, Afnan, Masoud, Albiol, Joan, Albuquerque, Lucia G., Amiya, Eisuke, Amorim, Rogerio M., An, Qianli, Andersen, Stig U., Aplin, John D., Argyropoulos, Christos, Asmann, Yan W., Assaeed, Abdulaziz M., Atanasov, Atanas G., Atchison, David A., Avery, Simon V., Avillach, Paul, Baade, Peter D., Backman, Lars, Badie, Christophe, Baldi, Alfonso, Ball, Elizabeth, Bardot, Olivier, Barnett, Adrian G., Basner, Mathias, Batra, Jyotsna, Bazanova, O. M., Beale, Andrew, Beddoe, Travis, Bell, Melanie L., Berezikov, Eugene, Berners-Price, Sue, Bernhardt, Peter, Berry, Edward, Bessa, Theolis B., Billington, Craig, Birch, John, Blakely, Randy D., Blaskovich, Mark A. T., Blum, Robert, Boelaert, Marleen, Bogdanos, Dimitrios, Bosch, Carles, Bourgoin, Thierry, Bouvard, Daniel, Boykin, Laura M., Bradley, Graeme, Braun, Daniel, Brownlie, Jeremy, Brühl, Albert, Burt, Austin, Butler, Lisa M., Byrareddy, Siddappa N., Byrne, Hugh J., Cabantous, Stephanie, Calatayud, Sara, Candal, Eva, Carlson, Kimberly, Casillas, Sònia, Castelvetro, Valter, Caswell, Patrick T., Cavalli, Giacomo, Cerovsky, Vaclav, Chagoyen, Monica, Chen, Chang-Shi, Chen, Dong F., Chen, Hao, Chen, Hui, Chen, Jui-Tung, Chen, Yinglong, Cheng, Changxiu, Cheng, Jianlin, Chinapaw, Mai, Chinopoulos, Christos, Cho, William C. S., Chong, Lillian, Chowdhury, Debashish, Chwalibog, Andre, Ciresi, A., Cockcroft, Shamshad, Conesa, Ana, Cook, Penny A., Cooper, David N., Coqueret, Olivier, Corea, Enoka M., Costa, Elisio, Coupland, Carol, Crawford, Stephanie Y., Cruz, Aparecido D., Cui, Huijuan, Cui, Qiang, Culver, David C., D’Angiulli, Amedeo, Dahms, Tanya E. S., Daigle, France, Dalgleish, Raymond, Danielsen, Håvard E., Darras, Sébastien, Davidson, Sean M., Day, David A., Degirmenci, Volkan, Demaison, Luc, Devriendt, Koenraad, Ding, Jiandong, Dogan, Yunus, Dong, X. C., Donner, Claudio F., Dressick, Walter, Drevon, Christian A., Duan, Huiling, Ducho, Christian, Dumaz, Nicolas, Dwarakanath, Bilikere S., Ebell, Mark H., Eisenhardt, Steffen, Elkum, Naser, Engel, Nadja, Erickson, Timothy B., Fairhead, Michael, Faville, Marty J., Fejzo, Marlena S., Festa, Fernanda, Feteira, Antonio, Flood-Page, Patrick, Forsayeth, John, Fox, Simon A., Franks, Steven J., Frentiu, Francesca D., Frilander, Mikko J., Fu, Xinmiao, Fujita, Satoshi, Galea, Ian, Galluzzi, Luca, Gani, Federica, Ganpule, Arvind P., García-Alix, Antonio, Gedye, Kristene, Giordano, Maurizio, Giunta, Cecilia, Gleeson, Paul A., Goarant, Cyrille, Gong, Haipeng, Gora, Diop, Gough, Michael J., Goyal, Ravinder, Graham, Kathryn E., Grande-Pérez, Ana, Graves, Patricia M., Greidanus, Harm, Grice, Darren, Grunau, Christoph, Gumulya, Yosephine, Guo, Yabin, Gurevich, Vsevolod V., Gusev, Oleg, Hacker, Elke, Hage, Steffen R., Hagen, Guy, Hahn, Steven, Haller, Dagmar M., Hammerschmidt, Sven, Han, Jianwei, Han, Renzhi, Handfield, Martin, Hapuarachchi, Hapuarachchige C., Harder, Timm, Hardingham, Jennifer E., Heck, Michelle, Heers, Marcel, Hew, Khe F., Higuchi, Yohei, Hilaire, Cynthia St, Hilton, Rachel, Hodzic, Enisa, Hone, Andrew, Hongoh, Yuichi, Hu, Guoku, Huber, Heinz P., Hueso, Luis E., Huirne, Judith, Hurt, Lisa, Idborg, Helena, Ikeo, Kazuho, Ingley, Evan, Jakeman, Philip M., Jensen, Arne, Jia, Hong, Jia, Husen, Jia, Shuqin, Jiang, Jianping, Jiang, Xingyu, Jin, Yi, Jo, Daehyun, Johnson, Andrew M., Johnston, Marie, Jonscher, Karen R., Jorens, Philippe G., Jorgensen, Jens O. L., Joubert, Johan W., Jung, Sin-Ho, Junior, Antonio M., Kahan, Thomas, Kamboj, Sunjeev K., Kang, Yong-Kook, Karamanos, Yannis, Karp, Natasha A., Kelly, Ryan, Kenna, Ralph, Kennedy, Jonathan, Kersten, Birgit, Khalaf, Roy A., Khalid, Javaria M., Khatlani, T., Khider, Tarig, Kijanka, Gregor S., King, Sarah R. B., Kluz, Tomasz, Knox, Paul, Kobayashi, Tatsuya, Koch, Karl-Wilhelm, Kohonen-Corish, Maija R. J., Kong, Xiangpeng, Konkle-Parker, Deborah, Korpela, Kalevi M., Kostrikis, Leondios G., Kraiczy, Peter, Kratz, Harald, Krause, Günter, Krebsbach, Paul H., Kristensen, Søren R., Kumari, Prerna, Kunimatsu, Akira, Kurdak, Hatice, Kwon, Young D., Lachat, Carl, Lagisz, Malgorzata, Laky, Brenda, Lammerding, Jan, Lange, Matthias, Larrosa, Mar, Laslett, Andrew L., LeClair, Elizabeth E., Lee, Kyung-Woo, Lee, Ming-Yih, Lee, Moon-Soo, Li, Genyuan, Li, Jiansheng, Lieb, Klaus, Lim, Yau Y., Lindsey, Merry L., Line, Paul-Dag, Liu, Dengcai, Liu, Fengbin, Liu, Haiyan, Liu, Hongde, Lloyd, Vett K., Lo, Te-Wen, Locci, Emanuela, Loidl, Josef, Lorenzen, Johan, Lorkowski, Stefan, Lovell, Nigel H., Lu, Hua, Lu, Wei, Lu, Zhiyong, Luengo, Gustavo S., Lundh, Lars-Gunnar, Lysy, Philippe A., Mabb, Angela, Mack, Heather G., Mackey, David A., Mahdavi, S. R., Maher, Pamela, Maher, Toby, Maity, Sankar N., Malgrange, Brigitte, Mamoulakis, Charalampos, Mangoni, Arduino A., Manke, Thomas, Manstead, Antony S. R., Mantalaris, Athanasios, Marsal, Jan, Marschall, Hanns-Ulrich, Martin, Francis L., Martinez-Raga, Jose, Martinez-Salas, Encarnacion, Mathieu, Daniel, Matsui, Yoichi, Maza, Elie, McCutcheon, James E., McKay, Gareth J., McMillan, Brian, McMillan, Nigel, Meads, Catherine, Medina, Loreta, Merrick, B. Alex, Metzger, Dennis W., Meunier, Frederic A., Michaelis, Martin, Micheau, Olivier, Mihara, Hisaaki, Mintz, Eric M., Mizukami, Takuo, Moalic, Yann, Mohapatra, D. P., Monteiro, Antonia, Montes, Matthieu, Moran, John V., Morozov, Sergey Y., Mort, Matthew, Murai, Noriyuki, Murphy, Denis J., Murphy, Susan K., Murray, Shauna A., Naganawa, Shinji, Nammi, Srinivas, Nasios, Grigorios, Natoli, Roman M., Nguyen, Frederique, Nicol, Christine, Nieuwerburgh, Filip van, Nilsen, Erlend B., Nobile, Clarissa J., O’Mahony, Margaret, Ohlsson, Sophie, Olatunbosun, Oluremi, Olofsson, Per, Ortiz, Alberto, Ostrikov, Kostya, Otto, Siegmar, Outeiro, Tiago F., Ouyang, Songying, Paganoni, Sabrina, Page, Andrew, Palm, Christoph, Paradies, Yin, Parsons, Michael H., Parsons, Nick, Pascal, Pigny, Paul, Elisabeth, Peckham, Michelle, Pedemonte, Nicoletta, Pellizzon, Michael A., Petrelli, M., Pichugin, Alexander, Pinto, Carlos J. C., Plevris, John N., Pollesello, Piero, Polz, Martin, Ponti, Giovanna, Porcelli, Piero, Prince, Martin, Quinn, Gwendolyn P., Quinn, Terence J., Ramula, Satu, Rappsilber, Juri, Rehfeldt, Florian, Reiling, Jan H., Remacle, Claire, Rezaei, Mohsen, Riddick, Eric W., Ritter, Uwe, Roach, Neil W., Roberts, David D., Robles, Guillermo, Rodrigues, Tiago, Rodriguez, Cesar, Roislien, Jo, Roobol, Monique J., Rowe, J. Alexandra, Ruepp, Andreas, Ruitenbeek, Jan van, Rust, Petra, Saad, Sonia, Sack, George H., Santos, Manuela, Saudemont, Aurore, Sava, Gianni, Schrading, Simone, Schramm, Alexander, Schreiber, Martin, Schuler, Sidney, Schymkowitz, Joost, Sczyrba, Alexander, Seib, Kate L., Shi, Han-Ping, Shimada, Tomohiro, Shin, Jeon-Soo, Shortt, Colette, Silveyra, Patricia, Skinner, Debra, Small, Ian, Smeets, Paul A. 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W., Xu, Jianping, Xue, Bin, Yalcin, Suayib, Yan, Hong, Yang, En-Cheng, Yang, Shiqi, Yang, Wei, Ye, Yuzhen, Ye, Zhi-Qiang, Yli-Kauhaluoma, Jari, Yoneyama, Hiroshi, Yu, Ying, Yuan, Guo-Cheng, Yuh, Chiou-Hwa, Zaccolo, Manuela, Zeng, Chen, Zevnik, Branko, Zhang, Chi, Zhang, Li, Zhang, Yingkai, Zhang, Yusen, Zhang, Zhiyong, Zhang, Zhong-Yin, Zhao, Yuan, Zhou, Min, Zuberbier, Torsten, Aanei, Carmen M., Ahmad, Rafi, Al-Lawama, Manar, Alanio, Alexandre, Allardyce, Judith, Alonso-Caneiro, David, Atack, John M., Baier, Dirk, Bansal, Abhisheka, Benezeth, Yannick, Berbesque, Colette, Berrevoet, Frederik, Biedermann, Peter H. W., Bijleveld, Erik, Bittner, Florian, Blombach, Fabian, Bos, Wouter van den, Boudreau, Shellie A., Bramoweth, Adam D., Braubach, Oliver, Cai, Yufeng, Campbell, Matthew, Cao, Zanxia, Catry, Thibault, Chen, Xin, Cheng, Shuiqin, Chung, Hee-Jung, Chávez-Fumagalli, Miguel A., Conway, Aaron, Costa, Bruno M., Cyr, Normand, Dean, Lorraine T., Denzel, Martin S., Dlamini, S. V., Dudley, Kevin J., Dufies, Maeva, Ecke, Thorsten, Eckweiler, Denitsa, Eixarch, Elisenda, El-Adawy, Hosny, Emmrich, Julius V., Eustace, Alex J., Falter-Wagner, Christine M., Fuss, Johannes, Gao, Jianzhao, Gill, Martin R., Gloyn, Liz, Goggs, Robert, Govinden, Usha, Greene, Garrett, Greiff, Victor, Grundle, D. S., Grüneberg, Patrick, Gumede, Nicksy, Haore, Gbaguidi, Harrison, Pille, Hoenner, Xavier, Hojsgaard, Diego, Hori, Hikaru, Ikonomopoulou, Maria P., Jeurissen, Patrick, Johnson, Daniel M., Kabra, Dhiraj, Kamagata, Koji, Karmakar, Chandan, Kasian, Olga, Kaye, Linda K., Khan, Murad M., Kim, Yong-Min, Kish, J. K., Kobold, Sebastian, Kohanbash, Gary, Kohls, Gregor, Kugler, Jan-Michael, Kumar, Gyanendra, Lacy-Colson, Jon, Latif, Asam, Lauschke, Volker M., Li, Bingling, Lim, Chinten J., Liu, Fang, Liu, Xiaodong, Lu, Jin-Jian, Lu, Qiang, Mahavadi, Poornima, Marzocchi, Ugo, McGarrigle, Christine A., Meerten, Tom van, Min, Rogier, Moal, Iain, Molari, Massimiliano, Molleman, Lucas, Mondal, Saiful R., Mortel, Thea van de, Moss, W. 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A., Lin, Li, Ling, Tong, Liu, Yuchen, Liu, Zhonghua, Lu, Yao, Lum, Fok M., Luo, Hang, Machhi, Jatin, Macleod, Angus, Macwan, Isaac, Madala, Hanumantha R., Madani, Nima, Maio, Nicola de, Makowiecki, Kalina, Mallinson, Daniel J., Margelyte, Ruta, Maria, Caracausi, Markonis, Y., Marsili, Luca, Mavoa, Suzanne, McWilliams, Lorna, Megersa, Moa, Mendes, Caetano S. M., Menichetti, Julia, Mercieca-Bebber, Rebecca, Miller, Jack J., Minde, David-Paul M., Minges, Alexander, Mishra, Eleanor, Mishra, Virendra R., Moores, Carly, Morrice, Nicola, Moskalensky, Alexander E., Navarin, Nicolò, Negera, Edessa, Nolet, Philippe, Nordberg, Ana, Nordén, Rickard, Nowicki, Jessica P., Olova, Nelly, Olszewski, Paweł, Onzima, Robert, Pan, Chih-Long, Park, Charny, Park, Dong Ik, Park, Seyoung, Patil, Chandrashekhar D., Pedro, Sansoa A., Perry, Samuel R., Peter, Jessica, Peterson, Brent M., Pezzuolo, Andrea, Pozdnyakov, Ilya, Qian, Siyu, Qin, Lei, Rafe, Ali, Raote, Ishier, Raza, Ali, Rebl, Henrike, Refai, Osama, Regan, Tim, Richa, Tambi, Richardson, Mark F., Robinson, K. R., Rossoni, Luca, Rouet, Romain, Safaei, Soroush, Schneeberger, Pierre H. H., Schwotzer, Daniela, Sebastian, Agata, Selinski, Jennifer, Seltmann, Stefanie, Sha, Feng, Shalev, Nir, Shang, Jin-Long, Singer, Josef, Singh, Mandeep, Smith, Taylor, Solomon-Moore, Emma, Song, Lijuan, Soraggi, Samuele, Stanley, Ryan, Steckhan, Nico, Strobl, Frederic, Subissi, Lorenzo, Supriyanto, Irwan, Surve, Chinmay R., Suzuki, Tomo, Syme, Caitlin, Sörelius, Karl, Tang, Young, Tantawy, Marwa, Tennakoon, Sumudu, Teseo, Serafino, Toelzer, Christine, Tomov, Nikola, Tovar, Miguel, Tran, Linh, Tripathi, Sushil, Tuladhar, Anil M., Ukubuiwe, Azubuike C., Ung, Carolina O. L., Valgepea, Kaspar, Vatanparast, Hamid, Vidal, Arnau, Wang, Fang, Wang, Qing, Watari, Ricky, Webster, Rebecca, Webster, Ruth, Wei, Junnian, Wibowo, David, Wingenbach, Tanja S. 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M., Tang, Jun, Testa, Jean, Tian, Zhiqi, Tingting, Qian, Verheijen, Geert P., Vickstrom, Casey, Wang, Teng, Wang, Xiaomin, Wang, Zhenxing, Wei, Pan, Wilson, Alex, Wyart, Yassine, Abdul-Amir, Yousefzadeh, Abbas, Zare, Asma, Zeng, Zhen, Zhang, Chengrong, Zhang, Haowen, Zhang, Linxing, Zhang, Tongchuan, Zhang, Weijia, Zhang, Zhe, Zhou, Jianyu, Zhu, Dongjie, Adamo, Vincenzo, Adeyemo, Adebolajo A., Aggelidou, Maria, Al-Owaifeer, Adi M., Al-Riyami, Arwa Z., Alzghari, Saeed K., Andersen, Vibeke, Angus, Kathryn, Asaduzzaman, Muhammad, Asady, Hadi, Ato, Dai, Bai, Xiaoyong, Baines, Rebecca L., Ballantyne, Maghan, Ban, Bo, Beck, Jill, Ben-Nafa, Walid, Black, Emma, Blancher, Antoine, Blankstein, Ron, Bodagh, Neil, Borges, Paulo A. 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A., Williams, Brendan A., Workman, Alan D., Xiang, Tingxiu, Xie, Li-Xin, Xu, Jun, Xu, Taosheng, Yang, Chongjun, Yoon, Jihoon G., Yuan, Christina M., Zaritsky, Arno, Zhang, Yao, Zhao, Haochen, Zuckerman, Hannah, Lyu, Ran, Pullan, Wayne, Zhou, Yaoqi, Gobet, Angélique, Sadoine, Margaux L., Ontwikkelingspsychologie (Psychologie, FMG), British Lung Foundation, Brown, P, Zhou, Y, Tan, A, El-Esawi, M, Liehr, T, Blanck, O, Gladue, D, Almeida, G, Cernava, T, Sorzano, C, Yeung, A, Engel, M, Chandrasekaran, A, Muth, T, Staege, M, Daulatabad, S, Widera, D, Zhang, J, Meule, A, Honjo, K, Pourret, O, Yin, C, Zhang, Z, Cascella, M, Flegel, W, Goodyear, C, van Raaij, M, Bukowy-Bieryllo, Z, Campana, L, Kurniawan, N, Lalaouna, D, Huttner, F, Ammerman, B, Ehret, F, Cobine, P, Tan, E, Han, H, Xia, W, Mccrum, C, Dings, R, Marinello, F, Nilsson, H, Nixon, B, Voskarides, K, Yang, L, Costa, V, Bengtsson-Palme, J, Bradshaw, W, Grimm, D, Kumar, N, Martis, E, Prieto, D, Sabnis, S, Amer, S, Liew, A, Perco, P, 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Univ Calif Irvine, Univ Hosp Leuven, Chongqing Med Univ, Childrens Hosp Kings Daughters, China Three Gorges Univ, and Xiangtan Univ

Subjects
Technology and Engineering, SCIENTIFIC SEARCH, Expert-curated database, Biokemia, solu- ja molekyylibiologia - Biochemistry, cell and molecular biology, Databases, RElevant LIterature SearcH consortium, Medicine and Health Sciences, Biomedical research, benchmarking, Biology, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Settore MED/42 - IGIENE GENERALE E APPLICATA, database, Computer. Automation, Science & Technology, 0804 Data Format, relisch, Scientific research in health sciences, Mathematics and Statistics, litearture search, relisch , database, biomedical research, Biomedical literature, Original Article, RELISH, Mathematical & Computational Biology, RECOMMENDER-SYSTEMS, Life Sciences & Biomedicine, Mathematics, 0807 Library and Information Studies
Abstract

Made available in DSpace on 2020-12-11T01:57:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-10-29 Griffith University Gowonda HPC Cluster Queensland Cyber Infrastructure Foundation Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research. Griffith Univ, Sch Informat & Commun Technol, Gold Coast, Qld 4222, Australia Griffith Univ, Inst Glyc, Gold Coast, Qld 4222, Australia Univ Colorado, Dept Med Med Oncol, Anschutz Med Campus, Denver, CO USA Tanta Univ, Fac Sci, Bot Dept, Tanta, Egypt Friedrich Schiller Univ, Jena Univ Hosp, Inst Human Genet, Jena, Germany Univ Med Ctr Schleswig Holstein, Dept Radiat Oncol, Campus Kiel, Kiel, Germany ARS, USDA, Plum Isl Anim Dis Ctr, Greenport, NY 11944 USA Univ Jyvaskyla, Dept Biol & Environm Sci, Jyvaskyla, Finland Graz Univ Technol, Inst Environm Biotechnol, Graz, Austria CSIC, CNB, Natl Biotechnol Ctr, Dept Macromol Struct, Madrid, Spain Univ Hong Kong, Fac Dent, Oral & Maxillofacial Radiol Appl Oral Sci & Commu, Hong Kong, Peoples R China Univ Kansas, Div Entomol, Biodivers Inst, Lawrence, KS 66045 USA SUNY Albany, RNA Inst, Albany, NY 12222 USA Robert Koch Inst, Dept Methods Dev & Res Infrastruct, Berlin, Germany Martin Luther Univ Halle Wittenberg, Dept Surg & Conservat Pediat & Adolescent Med, Halle, Germany Indiana Univ Purdue Univ, IU Sch Informat & Comp, Dept BioHlth Informat, Indianapolis, IN 46202 USA Univ Reading, Sch Pharm Stem Cell Biol & Regenerat Med, Reading, Berks, England Dali Univ, Sch Engn, Dali City, Yunnan, Peoples R China Univ Hosp Munich LMU, Dept Psychiat & Psychotherapy, Munich, Germany Univ Tsukuba, Fac Life & Environm Sci, Ibaraki, Japan UniLaSalle, Aghyle, Beauvais, France Henry Ford Hlth Syst, Dept Immunol, Detroit, MI USA Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Emergency, Hangzhou 310016, Zhejiang, Peoples R China Ist Nazl Tumori Fdn Pascale IRCCS, Anesthesia & Pain Med, Naples, Italy NIH, Dept Transfus Med, Bethesda, MD USA Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow, Lanark, Scotland Polish Acad Sci, Inst Human Genet, Poznan, Poland Univ Padua, Dept Surg Oncol & Gastroenterol DISCOG, Padua, Italy Eindhoven Univ Technol, Biomed Engn, Eindhoven, Netherlands Univ Strasbourg, IBMC, Strasbourg, France Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany Univ Notre Dame, Psychol, Notre Dame, IN 46556 USA Harvard Med Sch, Massachusetts Gen Hosp, Radiol & Pathol, Boston, MA 02115 USA Auburn Univ, Dept Biol Sci, Auburn, AL 36849 USA KK Womens & Childrens Hosp, KK Res Ctr, Singapore, Singapore Univ Alabama, Educ Psychol, Tuscaloosa, AL USA UCL, Wellcome EPSRC Ctr Intervent & Surg Sci, London, England Maastricht Univ, Dept Nutr & Movement Sci, Maastricht, Netherlands Univ Arkansas Med Sci, Dept Radiat Oncol, Little Rock, AR 72205 USA Univ Padua, Dept Land Environm Agr & Forestry, Padua, Italy Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden Univ Newcastle, Prior Res Ctr Reprod Sci, Callaghan, NSW, Australia Univ Cyprus, Med Sch, Nicosia, Cyprus Shandong Agr Univ, Coll Plant Protect, Agr Big Data Res Ctr, Tai An, Shandong, Peoples R China NIMH, Neuropsychol Lab, Bldg 9, Bethesda, MD 20892 USA Univ Wisconsin, Wisconsin Inst Discovery, Madison, WI USA Univ Oxford, Struct Genom Consortium, Oxford, England Weihenstephan Triesdorf Univ Appl Sci, TUM Campus Straubing Biotechnol & Sustainabil, Bioinformat, Straubing, Germany Univ Michigan, Cardiovasc Res, Ann Arbor, MI 48109 USA Bombay Coll Pharm, Pharmaceut Chem, Mumbai, Maharashtra, India Inst Invest Biol Clemente Estable, Dev Neurobiol, Montevideo, Uruguay Gem Hosp & Res Ctr, Surg Gastroenterol & HPB Surg, Coimbatore, Tamil Nadu, India Kafr El Sheikh Univ, Fac Sci, Dept Zool, Kafr Al Sheikh, Egypt Med Univ Innsbruck, Dept Internal Med 4, Innsbruck, Austria Australian Natl Univ, Div Biomed Sci & Biochem, Canberra, ACT, Australia Univ Cattolica Sacro Cuore, Appl Technol Neuropsychol Lab, Milan, Italy Shandong Inst Parasit Dis, Med Entomol, Jinan, Shandong, Peoples R China Kumamoto Univ, Sch Pharm, Kumamoto, Japan Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Biol Chem, Nagoya, Aichi, Japan Univ Karachi, ICCBS, PCMD, Jamil ur Rahman Ctr Genome Res, Karachi 75270, Pakistan Labormed Zentrum Dr Risch, Vaduz, Liechtenstein Univ Otago, Med, Dunedin, New Zealand KK Womens & Childrens Hosp, Maternal Fetal Med, Singapore, Singapore Albert Ludwigs Univ Freiburg, GERN Tissue Replacement Regenerat & Neogenesis, Dept Orthoped & Trauma Surg, Med Ctr,Fac Med, Freiburg, Germany Heinrich Heine Univ, Inst Biochem & Mol Biol, Dusseldorf, Germany Natl Univ Ireland Galway, Surg, Galway, Ireland Univ Western Australia, Inst Agr, Perth, WA, Australia Univ Oxford, Nuffield Dept Med, Oxford, England SingHlth Polyclin, Punggol Polyclin, Singapore, Singapore Med Univ Innsbruck, Bioctr, Div Biol Chem, Innsbruck, Austria La Trobe Univ, La Trobe Inst Mol Sci, Biochem & Genet, Melbourne, Vic, Australia Univ Bordeaux, INRA, Bordeaux, France Agr & Agri Food Canada, Lethbridge Res & Dev Ctr, Lethbridge, AB, Canada St George Hosp, Trauma & Orthopaed, London, England Max Planck Inst Dev Biol, Dept Prot Evolut, Tubingen, Germany Med Univ Lublin, Dept Gynaecol 2, Lublin, Poland ICIT, ICSI Analyt Natl Res & Dev, Ramnicu Valcea, VL, Romania Univ KwaZulu Natal, Occupat Therapy, Westville Campus, Durban, South Africa Inst Canc Res, Joint Dept Phys, London, England Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden Wenzhou Med Univ, Affiliated Hosp 2, Orthopaed, Wenzhou, Zhejiang, Peoples R China Univ Republica, Fac Ciencias, Ctr Invest Nucl, Lab Virol Mol, Montevideo, Uruguay Univ Gothenburg, Dept Med Biochem & Cell Biol, Gothenburg, Sweden Charite Med Univ Berlin, Pediat Cardiol, Berlin, Germany Bambino Gesu Pediat Hosp, Dept Neurosci & Neurorehabil, Neurorehabil Unit, Rome, Italy Indiana Univ Sch Med Northwest, Microbiol & Immunol, Gary, IN USA Univ Regensburg, Dept Behav & Mol Neurobiol, Regensburg, Germany Univ Queensland, Diamantina Inst, Brisbane, Qld, Australia Translat Res Inst, Brisbane, Qld, Australia Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China St Jude Childrens Res Hosp, Pharmaceut Sci Dept, 332 N Lauderdale St, Memphis, TN 38105 USA Univ Durham, Mus, Durham, England Univ Ioannina, Med Sch, Dept Hyg & Epidemiol, Ioannina, Greece Tech Univ Munich, Sch Life Sci Weihenstephan, Maximus von Imhof Forum 3, D-85354 Freising Weihenstephan, Germany Univ Hosp Essen, Inst Transfus Med, Essen, Germany Virginia Commonwealth Univ, Comp Sci, Richmond, VA USA Univ Queensland, Inst Social Sci Res, Brisbane, Qld, Australia Univ Lyon, Ctr Int Rech Infectiol, Lyon, France Griffith Univ, Sch Allied Hlth Sci, Gold Coast, Qld, Australia Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic, Australia Indiana Univ Purdue Univ, Dept Biohlth Informat, Sch Informat & Comp, Indianapolis, IN 46202 USA Philipps Univ Marburg, Inst Lung Res, Marburg, Germany Indiana Univ, Dept Biol, Bloomington, IN USA Univ Florida, Oral Biol, Gainesville, FL USA Univ Colorado, Dept Biochem, Boulder, CO 80309 USA Kyoto Univ, Ctr Promot Interdisciplinary Educ & Res, Kyoto, Japan Friedrich Loeffler Inst, Inst Virus Diagnost, Greifswald, Germany Univ Oxford, Dept Zool, Oxford, England Tech Univ Munich, Dept Bioinformat, Munich, Germany Univ Adelaide, Sch Anim & Vet Sci, Adelaide, SA, Australia Stanford Univ, Canc Biol, Palo Alto, CA 94304 USA Covenant Univ, Dept Elect & Informat Engn, Ota, Nigeria Heinrich Heine Univ, Inst Stem Cell Res & Regenerat Med, Dusseldorf, Germany Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada Albert Einstein Coll Med, Psychiat, New York, NY USA Akdeniz Univ, Med Biol & Genet, Antalya, Turkey NIMH, NIH, Bethesda, MD 20892 USA Med Univ Hosp, Internal Med 1, Tubingen, Germany NET ESolut, Netelabs, Mclean, VA USA Univ Southern Denmark, Inst Publ Hlth, Odense, Denmark John Innes Ctr, Mol Microbiol, Norwich, Norfolk, England Univ Adelaide, Waite Res Precinct, Australian Res Council, Ctr Excellence Plant Energy Biol, Adelaide, SA, Australia Univ Cambridge, Cambridge Inst Publ Hlth, Cambridge, England Univ Munster, Inst Biochem, Munster, Germany Australian Natl Univ, Natl Ctr Epidemiol & Populat Hlth RSPH, Canberra, ACT, Australia Stanford Univ, Neurobiol & Bioengn, Palo Alto, CA 94304 USA Univ Birmingham, Geog Earth & Environm Sci, Birmingham, W Midlands, England Murdoch Univ, Sch Vet & Life Sci, Perth, WA, Australia George Mason Univ, Ctr Climate Change Commun, Fairfax, VA 22030 USA Univ Adelaide, Sch Agr Food & Wine, Adelaide, SA, Australia Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China Stanford Univ, Pathol, Palo Alto, CA 94304 USA Univ Bologna, Dept Expt Diagnost & Specialty Med, Bologna, Italy Univ Padua, Dept Gen Psychol, Padua, Italy Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Dept Bioinformat & Syst Biol, Key Lab Mol Biophys,Minist Educ, Wuhan, Hubei, Peoples R China Huazhong Univ Sci & Technol, Collaborat Innovat Ctr Biomed Engn, Wuhan, Hubei, Peoples R China Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld, Australia French Natl Ctr Sci Res, CNRS, Inst Biol Physicochim, Paris, France Univ Warwick, Dept Sociol, Coventry, W Midlands, England European Mol Biol Lab, Struct & Computat Biol, Heidelberg, Germany Univ Cincinnati, Coll Med, Canc Biol, Cincinnati, OH USA Univ Waterloo, Biol, Waterloo, ON, Canada Sorbonne Univ, CNRS, Integrat Biol Marine Models LBI2M, SBR, Roscoff, France Univ Manitoba, Biochem & Med Genet, Winnipeg, MB, Canada Max Planck Inst Solid State Res, Ultrafast Solid State Spect, Stuttgart, Germany Imperial Coll London, Sch Publ Hlth, Dept Infect Dis Epidemiol, London, England Mansoura Univ, Fac Vet Med, Biochem, Mansoura, Egypt Univ Virginia, Mol Physiol & Biol Phys, Charlottesville, VA USA China Univ Geosci, State Key Lab Biogeol & Environm Geol, Wuhan, Hubei, Peoples R China Clin Neurol & Psychiat Children & Youth, Child Psychiat, Belgrade, Serbia Ahvaz Jundishapur Univ Med Sci, Med Phys, Ahwaz, Iran Univ Iowa City, Coll Dent, Div Biostat & Computat Biol, Dept Prevent & Community Dent, Iowa City, IA USA Univ Iowa City, Coll Dent, Div Biostat & Computat Biol, Dept Biomed Engn, Iowa City, IA USA Univ Iowa City, Coll Dent, Div Biostat & Computat Biol, Dept Biostat, Iowa City, IA USA Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany Univ Ibadan, Dept Zool, Ibadan, Nigeria Kansas State Univ, Coll Vet Med, Manhattan, KS 66506 USA Univ Tasmania, Sch Technol Environm & Design, Discipline ICT, Hobart, Tas, Australia Childrens Mercy Hosp, Radiol, Kansas City, MO 64108 USA Stockholm Univ, Dept Phys, Stockholm, Sweden Oslo Univ Hosp, Inst Canc Genet & Informat, Oslo, Norway CSIRO, CSIRO Mfg, Pullenvale, Qld, Australia Johns Hopkins Sch Med, Urol, Baltimore, MD USA Univ South Africa, Life & Consumer Sci, Johannesburg, South Africa German Ctr Neurodegenerat Dis, Mech Induced Plast Brain, Bonn, Germany UCL, Inst Child Hlth, Dev Biol & Canc, London, England Simon Fraser Univ, Biomed Physiol & Kinesiol, Burnaby, BC, Canada Univ Manchester, Ctr Hlth Informat, Manchester, Lancs, England Univ Queensland, Sch Human Movement & Nutr Sci, Brisbane, Qld, Australia Albert Einstein Coll Med, Dept Med, New York, NY USA Georgetown Univ, Kennedy Inst Eth, Washington, DC 20057 USA Dermatol Skin & Canc Fdn, Carlton, Vic, Australia Med Coll Wisconsin, Div Hematol, Milwaukee, WI 53226 USA Med Coll Wisconsin, Div Oncol, Milwaukee, WI 53226 USA Med Coll Wisconsin, Div Infect Dis, Milwaukee, WI 53226 USA US FDA, Off Biotechnol Prod, Washington, DC 20204 USA Worcester Polytech Inst, Biomed Engn, Worcester, MA 01609 USA Univ Adelaide, Ctr Orthopaed & Trauma Res, Adelaide, SA, Australia Publ Hlth England, Natl Infect Serv, Bristol, Avon, England Univ Utrecht, Fac Sci Chem, Utrecht, Netherlands Natl Univ Ireland Galway, Pathol, Galway, Ireland Imperial Coll London, NHLI, London, England Danube Private Univ, Neurodegenerat, Krems Donau, Austria Imperial Coll London, Dept Chem, London, England Univ Helsinki, Finnish Museum Nat Hist, Helsinki, Finland Univ Sydney, Sch Life & Environm Sci, Sydney, NSW, Australia Univ Nottingham, Nottingham Digest Dis Ctr, Nottingham, England Univ Toulouse, CNRS, ITAV, USR3505, Toulouse, France ASCR, Inst Mol Genet, CZ Openscreen, Prague, Czech Republic Univ Turku, Inst Biomed, Turku, Finland York Univ, Sch Kinesiol & Hlth Sci, Toronto, ON, Canada Univ Calif Los Angeles, Stein Eye Inst, Ophthalmol, Los Angeles, CA USA Agr & Agri Food Canada, Ottawa Res & Dev Ctr, Ottawa, ON, Canada Helmholtz Zentrum Geesthacht, Mat Design & Characterizat, Geesthacht, Germany Unvers Genova, Internal Med, Genoa, Italy Otto von Guericke Univ, Intelligent Catheter INKS, Magdeburg, Germany Univ Toledo, Canc Biol, 2801 W Bancroft St,Hlth Sci Campus, Toledo, OH 43606 USA CRUK Beatson Inst, Struct Biol, Glasgow, Lanark, Scotland Leibniz Inst Primate Res, Med RNA Biol, Gottingen, Germany Univ Limoges, PEIRENE, EA 7500, Limoges, France Hainan Univ, Vet Med, Haikou, Hainan, Peoples R China UCL, Sch Pharam, Pharmacognosy & Phytotherapy, London, England Univ Oulu, Ecol & Genet Res Unit, Oulu, Finland Rhein Westfal TH Aachen, Inst Biochem & Mol Immunol, Aachen, Germany Univ Stuttgart, Inst Biochem & Tech Biochem, Stuttgart, Germany Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, Shenzhen, Peoples R China GIGA Res Inst, Med Oncol, Liege, Belgium CHULiege, Liege, Belgium Fdn Bruno Kessler, MPBA, Trento, Italy Hokkaido Univ, Grad Sch Med, Dept Neurobiol, Sapporo, Hokkaido, Japan Univ Leuven, Oncol, Leuven, Belgium Chalmers Univ Technol, Dept Math Sci, Gothenburg, Sweden Radboud Univ Nijmegen, Med Ctr, Dept Neurol, Nijmegen, Netherlands Univ South Australia, Sch Informat Technol & Math Sci, Adelaide, SA, Australia Bio Thera Solut Ltd, Dept Computat Biol, Guangzhou, Guangdong, Peoples R China Inst Invest Biosanitario Granada IBS, Otolaryngol, Granada, Spain Curtin Univ, Sch Mol & Life Sci, Perth, WA, Australia Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England Goethe Univ, Biol DCAL, Inst Pharm, Frankfurt, Germany Univ Lyon, ICBMS, UMR 5246, Lyon, France Inst Pasteur, Dept Genomes & Genet, Paris, France Univ Valencia, Pharmacol, Valencia, Spain Council Agr Res & Econ, Res Ctr Olive Citrus & Tree Fruit, Caserta, Italy Fraunhofer Inst Toxicol & Expt Med ITEM, Preclin Pharmacol & Vitro Toxicol, Hannover, Germany Univ Tasmania, Sch Med, Hobart, Tas, Australia Chugai Pharmaceut Co Ltd, Oncol Lifecycle Management Dept, Tokyo, Japan Univ Lubeck, Inst Neurobiol, Lubeck, Germany NYU, Sch Med, Neurol, New York, NY USA Univ Putra Malaysia, Dept Plant Pathol, Seri Kembangan, Malaysia Univ N Carolina, Biol, Chapel Hill, NC 27515 USA Univ Southampton, Fac Hlth Sci, Southampton, Hants, England Univ Highlands & Islands, Genet & Immunol Res Grp, Inverness, Scotland Heidelberg Univ, Inst Pathol, Heidelberg, Germany Indraprastha Inst Informat Technol, Dept Computat Biol, New Delhi, India Glasgow Caledonian Univ, Sch Hlth & Life Sci, Glasgow, Lanark, Scotland Liverpool John Moores Univ, Pharm & Biomol Sci, Liverpool, Merseyside, England Parkinsons Inst & Clin Ctr, Basic Res, Sunnyvale, CA USA Luxembourg Inst Sci & Technol, Environm Res & 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Kansas, Med Ctr, Family Med Res Div, Kansas City, KS 66103 USA ASTAR, Inst Mol & Cell Biol, Multimodal Mol Biol, Singapore, Singapore Univ Leuven, Dept Chron Dis Metab & Ageing, Leuven, Belgium Int Iberian Nanotechnol Lab INL, Braga, Portugal Anglia Ruskin, Comp & Technol, Cambridge, England Max Planck Inst Biochem, Struct Cell Biol, Planegg, Germany Univ Seville, Dept Comp Architecture & Technol, Seville, Spain Univ Colorado, EBIO, Boulder, CO 80309 USA Univ Manchester, Canc Sci, Manchester, Lancs, England Australian Natl Univ, Res Sch Populat Hlth, Canberra, ACT, Australia Singapore MIT Alliance Res & Technol, Biosyst, Singapore, Singapore Australian Catholic Univ, Mary MacKillop Inst Hlth Res, Musculoskeletal Hlth & Ageing Res Program, Melbourne, Vic, Australia Ruhr Univ Bochum, Gen Surg, St Josef Hosp, Bochum, Germany Northwest A&F Univ, Coll Life Sci, Xianyang, Shaanxi, Peoples R China Australian Natl Univ, Res Sch Biol, Div Plant Sci, Canberra, ACT, Australia Battelle Mem Inst, 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Univ Bari, Dept Vet Med, Bari, Italy Radboud Univ Nijmegen, Med Ctr, Primary & Community Care, Nijmegen, Netherlands EcoHlth Alliance, New York, NY USA Mayo Clin, Cardiovasc Dept, Rochester, MN USA Med Univ Silesia, Sch Med Katowice, Dept Epidemiol, Katowice, Poland Univ Lleida, Anim Sci, Lleida, Spain Univ Florida, Coll Pharm, Pharmaceut Outcomes & Policy, Gainesville, FL USA Pacific Northwest Natl Lab, Earth & Biol Sci Directorate, Richland, WA 99352 USA Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh, Midlothian, Scotland Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA Univ Penn, Radiol, Philadelphia, PA 19104 USA Humanitas Univ & Res Hosp, Asthma & Allergy Unit, Biomed Sci Personalized Med, Rozzano, Italy Australian Natl Univ, Dept Quantum Sci, Canberra, ACT, Australia Carl von Ossietzky Univ Oldenburg, Ecol Genom, Oldenburg, Germany Int Med Univ, Paediat Dent & Orthodont, Kuala Lumpur, Malaysia Univ Ottawa, Sch Nursing, Ottawa, ON, Canada Maastricht Univ, Dept Educ Support, Maastricht, Netherlands Univ Manchester, Math, Manchester, Lancs, England Kings Coll London, Fac Life Sci & Med, Sch Populat Hlth Sci, London, England Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia Harbin Med Univ, Publ Hlth Sch, Epidemiol, Harbin, Heilongjiang, Peoples R China UiT Arctic Univ Norway, Dept Chem, Tromso, Norway Cornell Univ, Biol Stat & Computat Biol, Ithaca, NY USA East China Normal Univ, Sch Ecol & Environm Sci, Shanghai Key Lab Urban Ecol Proc & Ecorestorat, Shanghai, Peoples R China Johannes Gutenberg Univ Mainz, Fac Biol, Mainz, Germany Univ Massachusetts, Food Sci, Amherst, MA 01003 USA Max Planck Inst Terr Microbiol, Complex Adapt Traits Res Grp, Marburg, Germany NIHR Biomed Res Ctr Resp, Ctr Exercise & Rehabil Sci, Leicester, Leics, England Yale Univ, Dept Internal Med, Sect Endocrinol, New Haven, CT USA Sardar Patel Univ, Dept Biosci, Anand, Gujarat, India Univ Tokyo, Dept Appl Phys, Tokyo, Japan Univ Cologne, Vivo Res Facil ivRF, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany Natl Open Univ Nigeria, Dept Publ Hlth Sci, Lagos, Nigeria Univ Hosp Regensburg, Dept Radiol, Regensburg, Germany Natl Univ Singapore, Geog, Singapore, Singapore Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia Abdelmalek Essaadi Univ, Fac Sci & Techn Tangier, Biomed Genom & Oncogenet Res Lab, Tetouan, Morocco Tech Univ Munich, Fac Sport & Hlth Sci, Exercise Biol Grp, Munich, Germany Univ Santiago de Compostela, Dept Psicoloxia Social Basica & Metodoloxia, Galiza, Spain Griffith Univ, Signal Proc Lab, Brisbane, Qld, Australia Univ Ghent, Dept Neurol, Ghent, Belgium Ghent Univ Hosp, Ghent, Belgium Univ Ghent, Fac Vet Med, Merelbeke, Belgium Albert Einstein Coll Med, Inst Clin & Translat Res, New York, NY USA Anglia Ruskin Univ, Fac Med Sci, Cambridge, England Peking Univ, Coll Chem & Mol Engn, Beijing, Peoples R China Herlev & Gentofte Hosp, Dept Dermatol & Allergy, Hellerup, Denmark Lady Cilento Childrens Hosp, Med Imaging & Nucl Med, Brisbane, Qld, Australia Univ Gambia, Sch Med & Allied Hlth Sci, Nursing & Reprod Hlth, Brikama, Gambia Univ Sydney, Woolcock Inst Med Res, Sydney, NSW, Australia Wayne State Univ, Comp Sci, Detroit, MI USA Aberdeen Royal Infirm, Otolaryngol, Aberdeen, Scotland Univ Toronto, Lab Med & Pathobiol, Toronto, ON, Canada Chinese Univ Hong Kong, Inst Ageing, Hong Kong, Peoples R China Univ Nebraska Med Ctr, Emergency Med, Omaha, NE USA Univ Florida, Coll Med, Pathol, Gainesville, FL USA Univ Texas MD Anderson Canc Ctr, Radiat Oncol, Houston, TX 77030 USA Univ Pisa, Translat Res NTMS, Pisa, Italy Magna Grecia Univ, Clin & Expt Med, Catanzaro, Italy Univ Vermont, Larner Coll Med, Pediat, Burlington, VT USA Sun Yat Sen Univ, Canc Ctr, Diagnost & Intervent Ultrasound, Guangzhou, Guangdong, Peoples R China Fudan Univ, Inst Brain Sci, Shanghai, Peoples R China Shanxi Agr Univ, Coll Agron, Jinzhong, Shanxi, Peoples R China Univ Toronto, Inst Med Sci, Toronto, ON, Canada Univ Adelaide, ARCPOH, Adelaide, SA, Australia Pelita Harapan Univ, Fac Med, Cardiol & Vasc Med, Tangerang, Indonesia Inst Mental Hlth, Res Div, Singapore, Singapore UCL, MRC Clin Trials Unit, London, England Univ Padua, Dept Philosophy Sociol Educ & Appl Psychol FISPPA, Padua, Italy Univ Lubeck, Dept Psychiat & Psychotherapy, Lubeck, Germany Dalian Univ Technol, Ctr Mol Med, Dalian, Liaoning, Peoples R China Tianjin United Family Healthcare, Reprod Med, Tianjin, Peoples R China Univ Autonoma Barcelona, Dept Engn Quim Biol & Ambiental, Barcelona, Spain Sao Paulo State Univ UNESP, Dept Anim Sci, Sao Paulo, Brazil Helmholtz Zentrum Munchen, Inst Computat Biol, Canc Syst Biol, Ingolstadter Land Str 1, D-85764 Munich, Germany Univ Tokyo, Dept Cardiovasc Med, Tokyo, Japan Sao Paulo State Univ, Vet Clin, Sao Paulo, Brazil Zhejiang Univ, Inst Biotechnol, Hangzhou, Zhejiang, Peoples R China Aarhus Univ, Dept Mol Biol & Genet, Aarhus, Denmark Univ Manchester, St Marys Hosp, Maternal & Fetal Hlth, Manchester, Lancs, England Univ New Mexico, Internal Med, Albuquerque, NM 87131 USA Mayo Clin, Div Biomed Stat & Informat, Jacksonville, FL 32224 USA King Saud Univ, Plant Prod, Riyadh, Saudi Arabia Polish Acad Sci, Inst Genet & Anim Breeding, Dept Mol Biol, Warsaw, Poland Queensland Univ Technol, Optometry & Vis Sci, Brisbane, Qld, Australia Univ Nottingham, Sch Life Sci, Nottingham, England Canc Council Queensland, Canc Res Ctr, Brisbane, Qld, Australia Umea Univ, Dept Chem, Umea, Sweden Publ Hlth England, Ctr Radiat Chem & Environm Hazards, Bristol, Avon, England Univ Campania L Vanvitelli, DISTABIF, Caserta, Italy Bartshealth, Obstet & Gyanecol, London, England Univ Clermont Auvergne, GReD Lab, Clermont Ferrand, France INRA Abeilles & Environm, Avignon, France Queensland Univ Technol, Sch Publ Hlth & Social Work, Brisbane, Qld, Australia Univ Penn, Psychiat, Philadelphia, PA 19104 USA Novosibirsk State Univ, Res Inst Physiol & Basic Med, Novosibirsk, Russia UCL, Dept Chem, London, England La Trobe Univ, Anim Plant & Soil Sci, Melbourne, Vic, Australia Univ Arizona, Epidemiol & Biostat, Tucson, AZ USA Univ Groningen, Univ Med Ctr Groningen, ERIBA, Groningen, Netherlands Univ Gothenburg, Inst Clin Sci, Dept Radiat Phys, Gothenburg, Sweden SUNY Upstate Med Univ, Biochem & Mol Biol, Syracuse, NY 13210 USA Fundacao Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, Salvador, Bahia, Brazil Inst Environm Sci & Res ESR, Food Water & Environm Microbiol, Christchurch, New Zealand Univ Otago, Food Sci, Dunedin, New Zealand Florida Atlantic Univ, Biomed Sci, Boca Raton, FL 33431 USA Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia Univ Hosp Wurzburg, Inst Clin Neurobiol, Wurzburg, Germany Inst Trop Med, Publ Hlth, Antwerp, Belgium Univ Thessaly, Sch Hlth Sci, Fac Med, Dept Rheumatol & Clin Immunol, Larisa, Greece Univ Basel, UZB Univ Ctr Dent Med, Dept Orthodont & Pediat Dent, Basel, Switzerland Sorbonne Univ, Museum Natl Hist Nat, Inst Systemat Evolut Biodiversite ISYEB, MNHN,CNRS,UMR 7205,EPHE, Paris, France CNRS, Inst Adv Biosci, Paris, France Univ Western Australia, Sch Mol Sci, Perth, WA, Australia Univ Ft Hare, Biochem & Microbiol, Alice, South Africa Univ Tubingen, Phys, Tubingen, Germany Griffith Univ, Sch Environm & Sci, Brisbane, Qld, Australia Philosoph Theol Hsch Vallendar, Stat & Standardised Methods, Vallendar, Germany Imperial Coll London, Life Sci, London, England Univ Adelaide, Adelaide Med Sch, Adelaide, SA, Australia Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE USA Technol Univ Dublin, FOCAS Res Inst, Dublin, Ireland INSERM, Natl Inst Hlth & Med Res, Canc Res Ctr Toulouse, Paris, France Univ Santiago de Compostela, Dept Bioloxia Func, Grp BRAINSHARK, Galiza, Spain Univ Nebraska, Biol, Kearney, NE USA Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain Univ Pisa, Chem & Ind Chem, Pisa, Italy Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Manchester, Lancs, England Univ Montpellier, CNRS, Inst Human Genet, Montpellier, France Czech Acad Sci, Inst Organ Chem & Biochem, Prague, Czech Republic CSIC, Natl Ctr Biotechnol CNB, Computat Syst Biol Grp, Madrid, Spain Natl Cheng Kung Univ, Dept Biochem & Mol Biol, Tainan, Taiwan Harvard Med Sch, Schepens Eye Res Inst, Ophthalmol, Boston, MA 02115 USA Lanzhou Univ, Hosp 2, Dept Gen Surg, Lanzhou, Gansu, Peoples R China Univ Technol Sydney, Sch Life Sci, Sydney, NSW, Australia JT Chen Clin, Gynecol, Tokyo, Japan Univ Western Australia, Sch Agr & Environm, Perth, WA, Australia Beijing Normal Univ, Fac Geog Sci, Beijing, Peoples R China Univ Missouri, Elect Engn & Comp Sci, Columbia, MO USA Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, Dept Publ & Occupat Hlth, Amsterdam, Netherlands Semmelweis Univ, Med Biochem, Budapest, Hungary Queen Elizabeth Hosp, Dept Clin Oncol, Hong Kong, Peoples R China Univ Pittsburgh, Chem, Pittsburgh, PA USA GB Pant Inst Post Grad Med Educ & Res, Neurol, New Delhi, India Univ Copenhagen, Vet & Anim Sci, Copenhagen, Denmark Univ Palermo, Biomed Dept Internal & Specialist Med DIBIMIS, Sect Endocrinol, Palermo, Italy UCL, NPP, London, England Univ Florida, Microbiol & Cell Sci, Gainesville, FL USA Univ Salford, Sch Hlth Sci, Manchester, Lancs, England Cardiff Univ, Inst Med Genet, Cardiff, S Glam, Wales INSERM, ICO Canc Ctr, Angers, France Univ Colombo, Fac Med, Microbiol, Colombo, Sri Lanka Beijing Univ Chinese Med, Sch Chinese Mat Med, Beijing, Peoples R China Univ Porto, Fac Pharm, Porto, Portugal Univ Nottingham, Div Primary Care, Nottingham, England Univ Illinois, Pharm Syst Outcomes & Policy, Chicago, IL USA Pontificia Univ Catolica Goias, Escola Ciencias Agr & Biol, Goiania, Go, Brazil China Japan Friendship Hosp, Dept Oncol, Beijing, Peoples R China Boston Univ, Chem, Boston, MA 02215 USA Amer Univ, Environm Sci, Washington, DC 20016 USA Carleton Univ, Neurosci, Ottawa, ON, Canada Univ Regina, Chem & Biochem, Regina, SK, Canada Univ Montreal, Microbiolgy, Montreal, PQ, Canada Univ Leicester, Dept Genet & Genome Biol, Leicester, Leics, England Univ Queensland, Sch Agr & Food Sci, Gatton, Qld, Australia CNRS, BIOM, Paris, France UCL, Hatter Cardiovasc Inst, London, England Flinders Univ S Australia, Sci & Engn, Adelaide, SA, Australia Univ Warwick, Engn, Coventry, W Midlands, England Katholieke Univ Leuven, Ctr Human Genet, Leuven, Belgium Fudan Univ, Dept Macromol Sci, Shanghai, Peoples R China Dokuz Eylul Univ, Biol Educ, Izmir, Turkey Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA Mondo Med, Pulm Dis, Borgomanero, Italy US Naval, Res Lab, Ctr Bio Mol Sci & Engn, Washington, DC USA Univ Oslo, Inst Basic Med Sci, Dept Nutr, Oslo, Norway Peking Univ, Dept Mech & Engn Sci, Beijing, Peoples R China Saarland Univ, Dept Pharm Pharmaceut & Med Chem, Saarbrucken, Germany INSERM, Natl Inst Hlth & Med Res, Skin Res Inst, Paris, France Shanghai Proton & Heavy Ion Ctr, Res & Dev, Shanghai, Peoples R China Univ Georgia, Epidemiol, Athens, GA 30602 USA Univ Freiburg, Med Ctr, Dept Plast & Hand Surg, Freiburg, Germany Sidra Med, Res, Doha, Qatar Rostock Univ, Med Ctr, Dept Oral Maxillofacial & Plast Surg, Rostock, Germany Harvard Med Sch, Brigham & Womens Hosp, Emergency Med, Boston, MA 02115 USA AgResearch, Forage Sci, Palmerston North, New Zealand Univ Calif Los Angeles, Med, Los Angeles, CA USA Arizona State Univ, Biodesign Inst, Virginia G Piper Ctr Personalized Diagnost, Tempe, AZ USA Sheffield Hallam Univ, Res Inst, Mat & Engn, Sheffield, S Yorkshire, England Aneurin Bevan Univ Healthboard, Resp Med, Newport, Shrops, England Univ Calif San Francisco, Neurol Surg, San Francisco, CA 94143 USA Univ Western Australia, UWA Dent Sch, Perth, WA, Australia Fordham Univ, Biol Sci, Bronx, NY 10458 USA Univ Helsinki, Inst Biotechnol, Helsinki, Finland Fujian Normal Univ, Coll Life Sci, Fuzhou, Fujian, Peoples R China Univ Fukui, Dept Frontier Fiber Technol & Sci, Fukui, Japan Univ Southampton, Fac Med, Clin & Expt Sci, Southampton, Hants, England Univ Urbino, Dept Biomol Sci, Urbino, Italy Osped San Luigi, Allergol Unit, Turin, Italy Muljibhai Patel Urol Hosp, Dept Urol, Nadiad, Gujarat, India Univ Granada, Stratig & Paleontol, Granada, Spain Massey Univ, Sch Vet Sci, Auckland, New Zealand CNR, High Performance Comp & Networking Inst, Naples, Italy Univ Childrens Hosp Zurich, Div Metab, Zurich, Switzerland Univ Childrens Hosp Zurich, Childrens Res Ctr, Zurich, Switzerland Univ Melbourne, Biochem & Mol Biol, Parkville, Vic, Australia Inst Pasteur, Leptospirosis Res & Expertise Unit, Noumea, New Caledonia Tsinghua Univ, Sch Life Sci, Beijing, Peoples R China Cheikh Anta Diop Univ UCAD, Sci Fac, Biol Anim Dept, Dakar, Senegal Providence Portland Med Ctr, Earle A Chiles Res Inst, Portland, OR USA Agr & Agri Food Canada, Lacombe Res & Dev Ctr, Lacombe, AB, Canada Alberta Innovates, Performance Management & Evaluat, Edmonton, AB, Canada Univ Malaga, CSIC, Inst Hortofruticultura Subtrop Mediterranea La Ma, IHSM,UMA, Malaga, Spain James Cook Univ, Coll Publ Hlth Med & Vet Sci, Cairns, Qld, Australia European Commiss, Joint Res Ctr, Ispra, Italy Univ Montpellier, Montpellier, France CSIRO, Floreat, WA, Australia Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangzhou, Guangdong, Peoples R China Vanderbilt Univ, Pharmacol, 221 Kirkland Hall, Nashville, TN 37235 USA RIKEN, KFU RIKEN Translat Genom Unit, Yokohama, Kanagawa, Japan Univ Tubingen, Neurobiol Vocal Commun, Tubingen, Germany Univ Colorado, UCCS Ctr Biofrontiers Inst, Colorado Springs, CO 80907 USA Fred Hutchinson Canc Ctr, Div Basic Sci, Seattle, WA USA Univ Geneva, Fac Med, Primary Care Unit, Geneva, Switzerland Ernst Moritz Arndt Univ Greifswald, Dept Mol Genet & Infect Biol, Greifswald, Germany East China Univ Sci & Technol, Dept Fine Chem, Shanghai, Peoples R China Ohio State Univ, Surg, Columbus, OH 43210 USA Oragenics, R&D, Tampa, FL USA Natl Environm Agcy, Environm Hlth Inst, Singapore, Singapore Friedrich Loeffler Inst, Inst Diagnost Virol, Greifswald, Germany Queen Elizabeth Hosp, Oncol, Woodville, SA, Australia USDA, Emerging Pests & Pathogens Res Unit, Ithaca, NY USA Univ Freiburg, Med Ctr, Dept Neurosurg, Epilepsy Ctr, Freiburg, Germany Univ Hong Kong, Fac Educ, Informat & Technol Studies, Hong Kong, Peoples R China Univ Tokyo, Grad Sch Agr & life Sci, Agr & Environm Biol, Tokyo, Japan Univ Pittsburgh, Dept Med, Pittsburgh Heart Lung & Blood Vasc Med Inst, Pittsburgh, PA USA Guys & St Thomas NHS Fdn Trust, Directorate Transplant Renal & Urol, London, England Univ Sarajevo, Clin Ctr, Clin Heart Blood Vessel & Rheumat Dis, Sarajevo, Bosnia & Herceg Univ Kent, Sch Math Stat & Actuarial Sci, Canterbury, Kent, England Tokyo Inst Technol, Dept Life Sci & Technol, Tokyo, Japan Univ Appl Sci Munich, Laser Ctr Dept Appl Sci & Mechatron, Munich, Germany CIC NanoGUNE, Nanodevices, San Sebastian, Spain Vrije Univ Amsterdam Med Ctr, Gynaecol, Amsterdam, Netherlands Cardiff Univ, Med Sch, Div Populat Med, Cardiff, S Glam, Wales Karolinska Inst, Dept Med, Solna, Sweden Natl Inst Genet, Ctr Informat Biol, Mishima, Shizuoka, Japan Murdoch Univ, Harry Perkins Inst Med Res, Perth, WA, Australia Univ Limerick, Phys Educ & Sport Sci, Limerick, Ireland Ruhr Univ Bochum, Campus Clin Gynecol, Univ Str, Bochum, Germany Southwest Med Univ, Sch Publ Hlth, Epidemiol & Biostat, Luzhou, Sichuan, Peoples R China Beijing Canc Hosp, Minist Educ Beijing, Key Lab Carcinogenesis & Translat Res, Ctr Mol Diagnost, Beijing, Peoples R China Chinese Acad Sci, Chengdu Inst Biol, Herpetol Dept, Chengdu, Sichuan, Peoples R China Key Lab Nano Biol Effects & Safety, Beijing, Peoples R China NIBR, PK Sci, Basel, Switzerland Daejeon St Marys Hosp, Pain Ctr, Daejeon, South Korea Univ Western Ontario, Sch Hlth Studies, London, ON, Canada Univ Aberdeen, Hlth Psychol Grp, Aberdeen, Scotland Univ Colorado, Anesthesiol, Anschutz Med Campus, Boulder, CO 80309 USA Univ Antwerp, UZA Antwerp Univ Hosp, Crit 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Res Ctr, Stem Cell & Regenerat Med, Riyadh, Saudi Arabia Univ Bahri, Ind Pulp & Paper, Khartoum, Sudan Univ Queensland, Mater Med Res Inst, Mater Res Inst, Brisbane, Qld, Australia Colorado State Univ, NREL, Ft Collins, CO 80523 USA Rzeszow Univ Hosp, Ob Gyn Dept, Rzeszow, Poland Univ Leeds, Fac Biol Sci, Leeds, W Yorkshire, England Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA Carl von Ossietzky Univ Oldenburg, Neurosci, Oldenburg, Germany UNSW, St George & Sutherland Clin Sch, Microbiome Res Ctr, Sydney, NSW, Australia NYU, Sch Med, Dept Biochem, New York, NY 10016 USA NYU, Sch Med, Dept Mol Pharmacol, New York, NY USA Univ Mississippi, Med Ctr, Med Infect Dis, Jackson, MS 39216 USA Tampere Univ, Fac Social Sci Psychol, Tampere, Finland Univ Cyprus, Dept Biol Sci, Nicosia, Cyprus Goethe Univ, Inst Med Microbiol & Infect Control, Frankfurt, Germany Charite Med Univ Berlin, Inst Radiol, Berlin, Germany Univ Cologne, Univ Hosp Cologne, Internal Med 1, Cologne, Germany Univ Calif Los Angeles, Sch Dent, Sect Periodont, Los Angeles, CA 90024 USA Aalborg Univ Hosp, Dept Clin Biochem, Aalborg, Denmark Manipal Acad Higher Educ, Pharm Practice, Manipal, Karnataka, India Univ Tokyo, Inst Med Sci, Dept Radiol, Tokyo, Japan Cukurova Univ, Family Med, Fac Med, Adana, Turkey Catholic Univ Korea, Coll Med, Dept Humanities & Social Med, Seoul, South Korea Univ Ghent, Food Technol Safety & Hlth, Ghent, Belgium UNSW Sydney, Sch Biol Earth & Environm Sci BEES, Sydney, NSW, Australia St Vincent Shoulder & Sports Clin, Res Unit, Vienna, Austria Cornell Univ, Biomed Engn, Ithaca, NY USA Leibniz Inst Plant Genet & Crop Plant Res IPK, Res Grp Bioinformat & Informat Technol, Gatersleben, Germany Univ Europea Madrid, Sch Doctoral Studies, Madrid, Spain CSIRO Mfg, Biomed Mfg, Melbourne, Vic, Australia Depaul Univ, Biol Sci, Chicago, IL 60604 USA Konkuk Univ, Dept Anim Sci & Technol, Seoul, South Korea Chang Gung Univ, Grad Inst Med Mechatron, Taoyuan, Taiwan Korea Univ, Coll Med, Psychiat, Seoul, South Korea Princeton Univ, Chem, Princeton, NJ 08544 USA Henan Univ Chinese Med, Henan Key Lab Chinese Med Resp Dis, Zhengzhou, Henan, Peoples R China Univ Med Ctr Mainz, Dept Psychiat & Psychotherapy, Mainz, Germany Monash Univ Malaysia, Sch Sci, Selangor, Malaysia Univ Mississippi, Med Ctr, Physiol & Biophys, Jackson, MS 39216 USA Univ Oslo, Dept Transplantat Med, Oslo, Norway Sichuan Agr Univ, Triticeae Res Inst, Yaan, Sichuan, Peoples R China Guangzhou Univ Chinese Med, Gastroenterol, Guangzhou, Guangdong, Peoples R China Southeast Univ, Sch Biol Sci & Med Engn, Suzhou, Jiangsu, Peoples R China Mt Allison Univ, Biol, Sackville, NB, Canada Ithaca Coll, Biol, Ithaca, NY 14850 USA Univ Cagliari, Dept Med Sci & Publ Hlth, Monserrato, Italy Univ Vienna, Chromosome Biol, Vienna, Austria Univ Zurich, Nephrol, Zurich, Switzerland Friedrich Schiller Univ, Inst Nutr Sci, Jena, Germany UNSW Sydney, Grad Sch Biomed Engn, Sydney, NSW, Australia Tulane Univ, Sch Med, Biochem & Mol Biol, 1430 Tulane Ave, New Orleans, LA 70112 USA NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA NIH, NCBI, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA LOreal Res & Innovat, Aulnay Sous Bois, France Lund Univ, Dept Psychol, Malmo, Sweden Catholic Univ Louvain, Inst Rech Expt & Clin, Brussels, Belgium Georgia State Univ, Neurosci Inst, Atlanta, GA 30303 USA Univ Melbourne, Ophthalmol, Surg, Parkville, Vic, Australia Univ Western Australia, Ctr Ophthalmol & Visual Sci, Perth, WA, Australia Iran Univ Med Sci, Med Phys, Fac Med, Tehran, Iran Salk Inst Biol Studies, Cellular Neurobiol, La Jolla, CA USA Imperial Coll London, Fibrosis Res Grp, London, England Univ Texas MD Anderson Canc Ctr, Genitourinary Med Oncol, Houston, TX 77030 USA Univ Liege, GIGA Neurosci, Liege, Belgium Univ Crete, Sch Med, Urol, Iraklion, Greece Flinders Univ S Australia, Flinders Med Ctr, Dept Clin Pharmacol, Adelaide, SA, Australia Max Planck Inst Immunobiol & Epigenet, Bioinformat, Breisgau, Germany Cardiff Univ, Sch Psychol, Cardiff, S Glam, Wales Imperial Coll London, Chem Engn, London, England Lund Univ, Skane Univ Hosp, Clin Sci, Malmo, Sweden Sahlgrens Acad, Inst Clin Sci, Dept Mol & Clin Med, Gothenburg, Sweden Univ Cent Lancashire, Sch Pharm & Biomed Sci, Preston, Lancs, England Hosp Univ Doctor Peset, Psychiat & Clin Psychol, Valencia, Spain Ctr Biol Mol Severo Ochoa, Genome Dynam & Funct, Madrid, Spain Unvivers Hosp Lille, Dept Intens Care, Lille, France Kansai Med Univ, Surg, Osaka, Japan Univ Toulouse, Inst Natl Polytech Toulouse, Ecole Natl Super Agron Toulouse, Lab Genom & Biotechnol Fruit, Toulouse, France UiT Arctic Univ Norway, Inst Psychol, Tromsto, Norway Queens Univ, Ctr Publ Hlth, Belfast, Antrim, North Ireland Univ Manchester, Ctr Primary Care & Hlth Serv Res, Manchester, Lancs, England Griffith Univ, Menzies Hlth Inst, Gold Coast, Qld, Australia Anglia Ruskin Univ, FHSCE, Cambridge, England Univ Lleida, Dept Expt Med, Lleida, Spain NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA Albany Med Coll, Immunol & Microbial Dis, Albany, NY 12208 USA Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Univ Kent, Sch Biosci, Canterbury, Kent, England Univ Bourgogne Franche Comte, INSERM, LNC, UMR 1231, Besancon, France Ritsumeikan Univ, Coll Life Sci, Dept Biotechnol, Shiga, Japan Kent State Univ, Biol Sci, Kent, OH 44242 USA Natl Inst Infect Dis, Dept Safety Res Blood & Biol Prod, Tokyo, Japan European Inst Marine Studies, Lab Microbiol Extreme Environm, Plouzane, France Univ Iowa, Dept Pharmacol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA Natl Univ Singapore, Biol Sci, Singapore, Singapore Conservatoire Natl Arts & Metiers, Lab GBA, EA4627, Paris, France Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA Lomonosov Moscow State Univ, Belozersky Inst Physicochem Biol, Moscow, Russia Jikei Univ, Sch Med, Dept Mol Biol, Tokyo, Japan Univ South Wales, Genom & Computat Biol, Treforest, Wales Duke Univ, Med Ctr, Obstet & Gynecol, Durham, NC USA Univ Technol Sydney, Climate Change Cluster, Sydney, NSW, Australia Nagoya Univ, Grad Sch Med, Dept Radiol, Nagoya, Aichi, Japan Western Sydney Univ, Sch Sci & Hlth, Sydney, NSW, Australia TEI Epirus, Dept Speech & Language Therapy, Ioannina, Greece Indiana Univ Purdue Univ, Orthopaed Surg, Indianapolis, IN 46202 USA Oniris, Vet Pathol, Nantes, France Royal Vet Coll, Pathobiol & Populat Sci, Hatfield, Herts, England Univ Ghent, Lab Pharmaceut Biotechnol, Ghent, Belgium Norwegian Inst Nat Res, Terr Ecol, Trondheim, Norway Univ Calif Merced, Mol & Cell Biol, Merced, CA USA Univ Dublin, Trinity Coll Dublin, Sch Engn, Ctr Transport Res, Dublin, Ireland Lund Univ, Inst Clin Sci, Nephrol, Malmo, Sweden Univ Birmingham, Mech Engn, Birmingham, W Midlands, England Lund Univ, Inst Clin Sci, OB GYN, Lund, Sweden Fdn Jimenez Diaz Hosp, Nephrol & Hypertens, Madrid, Spain Queensland Univ Technol, Sch Chem Phys & Mech Engn, Brisbane, Qld, Australia Otto von Guericke Univ, Psychol, Magdeburg, Germany Univ Med Ctr Gottingen, Dept Expt Neurodegenerat, Gottingen, Germany Harvard Med Sch, Spaulding Rehabil Hosp, Phys Med & Rehabil, Boston, MA 02115 USA Quadram Inst Biosci, Sci Operat, Norwich, Norfolk, England Ostbayer Tech Hsch Regensburg OTH Regensburg, Regensburg Med Image Comp ReMIC, Regensburg, Germany Deakin Univ, Fac Arts & Educ, Melbourne, Vic, Australia Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England INSERM, Natl Inst Hlth & Med Res, Biochem & Mol Biol, Paris, France Univ Liege, Tax Inst, Liege, Belgium Univ Leeds, Sch Mol & Cellular Biol, Leeds, W Yorkshire, England IRCCS Ist Giannina Gaslini, UOC Genet Med, Genoa, Italy Res Diets Inc, Sci, New Brunswick, NJ USA Univ Perugia, Dept Phys & Geol, Perugia, Italy Walter Reed Natl Mil Med Ctr, Cellular Immunol, Bethesda, MD USA Univ Fed Santa Catarina, Biol Sci Ctr, Microbiol Immunol & Parasitol Dept, Florianopolis, SC, Brazil Univ Edinburgh, Royal Infirm, Ctr Liver & Digest Disorders, Edinburgh, Midlothian, Scotland Orion Pharma, Crit Care Proprietary Prod Div, Espoo, Finland MIT, Dept Civil & Environm Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA Univ Turin, Dept Vet Sci, Turin, Italy Univ G dAnnunzio, Dept Psychol Hlth & Territorial Sci, Chieti, Italy NYU, Sch Med, OB GYN, New York, NY USA Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland Univ Turku, Dept Biol, Turku, Finland Tech Univ Berlin, Bioanalyt, Berlin, Germany Univ Goettingen, Inst Phys Biophys 3, Gottingen, Germany Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Translat Res Adv Therapeut & Innovat Oncol TRACTI, Houston, TX 77030 USA Univ Liege, Life Sci, Liege, Belgium Tarbiat Modares Univ, Fac Med Sci, Dept Toxicol, Tehran, Iran ARS, USDA, Stoneville, MS USA Univ Regensburg, RCI Regensburg Ctr Intervent Immunol, Regensburg, Germany Univ Nottingham, Sch Psychol, Nottingham, England NIH, Pathol Lab, Bethesda, MD 20892 USA Univ Carlos III Madrid, Elect Engn, Madrid, Spain Inst Med Mol, Chem Biol, Lisbon, Portugal Univ Costa Rica, CIET, San Jose, Costa Rica Univ Stavanger, Fac Hlth Sci, Stavanger, Norway Erasmus MC, Urol, Rotterdam, Netherlands Univ Edinburgh, Sch Biol Sci, Edinburgh, Midlothian, Scotland German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Bioinformat & Syst Biol IBIS, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany Leiden Univ, Huygens Kamerlingh Onnes Lab, Leiden, Netherlands Univ Vienna, Nutr Sci, Vienna, Austria Kolling Inst Med Res, Med, St Leonards, NSW, Australia Johns Hopkins Sch Med, Biol Chem, Baltimore, MD USA Univ Montreal, Med Nutr & Microbiome Lab, Montreal, PQ, Canada GlaxoSmithKline, Cell & Gene Therapy, Stevenage, Herts, England Univ Trieste, Life Sci, Trieste, Italy Rhein Westfal TH Aachen, Dept Radiol, Aachen, Germany Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr, Dept Med Oncol, Essen, Germany Med Univ Vienna, Obstet & Gynecol, Vienna, Austria FHI 360, Social & Behav Hlth Sci Div, Washington, DC USA KU Leuven VIB, Switch Lab, Leuven, Belgium Bielefeld Univ, Fac Technol, Bielefeld, Germany Capital Med Univ, Beijing Shijitan Hosp, Dept Clin Nutr, Dept Gastrointestinal Surg, Beijing, Peoples R China Meiji Univ, Dept Agr Chem, Kawasaki, Japan Yonsei Univ, Coll Med, Microbiol, Seoul, South Korea Johnson & Johnson EAME, Maidenhead, Berks, England Penn State Coll Med, Pediat, Hershey, PA USA Univ N Carolina, Dept Social Med, Chapel Hill, NC 27515 USA Univ Western Australia, ARC CoE Plant Energy Biol, Perth, WA, Australia Wageningen Univ, Div Human Nutr & Hlth, Wageningen, Netherlands Kings Coll London, Dept Neuroimaging, London, England Univ Murcia, Biochem & Mol Biol, Murcia, Spain Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA Monash Univ, Biochem & Mol Biol, Melbourne, Vic, Australia Chinese Acad Sci, Inst Genet & Dev Biol, Beijing, Peoples R China Univ Pittsburgh, Pharmacol & Chem Biol, Pittsburgh, PA USA Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland Univ Queensland, Sch Pharm, Brisbane, Qld, Australia Leibniz Inst Plant Genet & Crop Plant Res IPK Gat, Genebank, Gatersleben, Germany Piramal Imaging, Res & Dev, Berlin, Germany Univ Leeds, Civil Engn, Leeds, W Yorkshire, England Univ Missouri, Chem & Biochem, St Louis, MO 63121 USA US Geol Survey, Coastal & Marine Geol Program, Pacific Coastal & Marine Sci Ctr, Santa Cruz, CA USA Ajinomoto Genet Res Inst, Moscow, Russia Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Plant Biotechnol, Krakow, Poland Univ Puerto Rico, Engn Sci & Mat, Mayaguez, PR USA Univ Regina, Dept Chem & Biochem, Regina, SK, Canada Argonne Natl Lab, Ctr Nanoscale Mat, 9700 S Cass Ave, Argonne, IL 60439 USA Univ Sunshine Coast, Sunshine Coast Mind & Neurosci Thompson Inst, Sippy Downs, Qld, Australia Chinese Peoples Liberat Army Gen Hosp, Dept Gastroenterol & Hepatol, Beijing, Peoples R China Griffith Univ, Griffith Ctr Social & Cultural Res, Gold Coast, Qld, Australia Tohoku Univ, Inst Dev Aging Canc, Dept Mol Oncol, Sendai, Miyagi, Japan Indiana Univ, Comp Sci, Bloomington, IN USA Fukushima Med Univ, Sch Med, Dept Pulm Med, Fukushima, Japan MEDIVIR AB, Biol, Huddinge, Sweden Western Sydney Univ, Neuroimmunol, Sydney, NSW, Australia Univ Jordan, Nutr & Food Technol, Amman, Jordan Thunen Inst Forest Genet, Fed Res Ctr Rura Areas Forestry & Fisheries, Inst Biodivers, Grosshansdorf, Germany Univ Edinburgh, Inst Cell Biol, Edinburgh, Midlothian, Scotland Univ Edinburgh, Ctr Integrat Physiol, Edinburgh, Midlothian, Scotland Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada Canadian Mem Chiropract Coll, Grad Educ & Res, Toronto, ON, Canada Agilent Technol, R&D, Leuven, Belgium Univ British Columbia, Sch Nursing, Vancouver, BC, Canada Monash Univ, Monash Hlth, Sch Clin Sci, Stroke & Ageing Res,Dept Med, Melbourne, Vic, Australia French Natl Canc Inst, Innovat, Transfer, Biol, Boulogne, France Ludwig Maximilians Univ Munchen, Phys Chem, NanoBioSci, Munich, Germany Bandung Inst Technol, Sch Pharm, Med Chem, Bandung, Indonesia Univ Luxembourg, Life Sci Res Unit, Luxembourg, Luxembourg Lund Univ, Skane Univ Hosp, Dept Gastroenterol, Malmo, Sweden Millennium Hlth, Translat Genet, San Diego, CA USA Aristotle Univ Thessaloniki, Med Dept 2, Clin Res & Evidence Based Med Unit, Thessaloniki, Greece Jan Kochanowski Univ Humanities & Sci, Piotrkow Trybunalski Branch, Dept Psychol, Kielce, Poland McMaster Univ, Engn Phys, Hamilton, ON, Canada Marche Polytech Univ, Dept Agr Food & Environm Sci, Ancona, Italy Kuwait Univ, Fac Med, Microbiol, Kuwait, Kuwait Fujita Hlth Univ, Dept Breast Surg, Toyoake, Aich, Japan North West Reg Spinal Injuries Ctr, Spinal Injuries Ctr, Southport, Merseyside, England Luxembourg Inst Hlth, Competence Ctr Methodol & Stat, Luxembourg, Luxembourg Nestle Inst Hlth Sci SA, Metab Hlth, Ecublens, Vaud, Switzerland Ctr Inflammat Res VIB, Ghent, Belgium Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium Univ Lisbon, Inst Educ, Curriculo Formacao Prof & Tecnol, Lisbon, Portugal Univ Edinburgh, Ctr Inflammat Res, Edinburgh, Midlothian, Scotland Univ Melbourne, Sch BioSci, Parkville, Vic, Australia Northumbria Univ, Comp & Informat Sci, Newcastle Upon Tyne, Tyne & Wear, England Univ Valencia, Endocrinol, Valencia, Spain INRS, Inst Armand Frappier, Laval, PQ, Canada Univ Laval, INAF, Sch Nutr, Quebec City, PQ, Canada Univ Konstanz, Dept Biol, Constance, Germany Univ Cote dAzur, LAMHESS, Nice, France Scion, Syst Ecol, Christchurch, New Zealand CUNY, Grad Sch Publ Hlth & Hlth Policy, Epidemiol & Biostat, New York, NY 10021 USA Univ Queensland, Sch Dent, Brisbane, Qld, Australia George Inst Global Hlth, Renal & Metab Div, Sydney, NSW, Australia Wuhan Univ, Coll Chem & Mol Sci, Wuhan, Hubei, Peoples R China Griffith Univ, Sch Environm & Sci, Gold Coast, Qld, Australia Univ Minnesota, Radiat Oncol, Minneapolis, MN USA Goethe Univ, Fac Med, Frankfurt, Germany Natl Yunlin Univ Sci & Technol, Dept & Grad Sch Safety & Environm Engn, Touliu, Yunlin, Taiwan Massey Univ, Sch Sport Exercise & Nutr, Auckland, New Zealand Univ Florida, Wildlife Ecol & Conservat, Gainesville, FL USA Bournemouth Univ, Dept Psychol, Poole, Dorset, England Robert Koch Inst, Project Grp P2, Berlin, Germany Univ Edinburgh, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland Univ Basel, Biozentrum, Basel, Switzerland Univ Wollongong, Sch Med, Wollongong, NSW, Australia Univ Cologne, Inst Human Genet, Cologne, Germany Rural Econ Branch, Econ Res Serv, Washington, DC USA Uivers Bordeaux, CNRS, Inst Neurosci Cognit & Integrat Aquitaine, Bordeaux, France Univ Calif Riverside, Dept Chem & Environm Engn, Riverside, CA 92521 USA Univ Calif Riverside, Mat Sci & Engn Program, Riverside, CA 92521 USA Mackay Med Coll, Dept Med, New Taipei, Taiwan Univ Bern, Div Anim Welf, Bern, Switzerland Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Med Sci, Shanghai, Peoples R China McMaster Univ, Biol, Hamilton, ON, Canada Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL USA Hacettepe Univ, Inst Canc, Med Oncol, Ankara, Turkey City Univ Hong Kong, Dept Elect Engn, Hong Kong, Peoples R China Natl Taiwan Univ, Dept Entomol, Taipei, Taiwan Chinese Acad Agr Sci, Inst Environm & Sustainable Dev Agr, Ecol Secur, Beijing, Peoples R China Florida State Univ, Inst Mol Biophys, Chem & Biochem, Tallahassee, FL USA Peking Univ, Shenzhen Grad Sch, State Key Lab Chem Oncogen, Lab Computat Chem & Drug Design, Shenzhen, Peoples R China Univ Helsinki, Fac Pharm, Div Pharmaceut Chem & Technol, Drug Res Program, Helsinki, Finland Tohoku Univ, Microbial Biotechnol, Sendai, Miyagi, Japan Tianjin Med Univ, Sch Basical Med Sci, Dept Pharmacol, Tianjin, Peoples R China Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA Natl Hlth Res Inst, Inst Mol & Genom Med, Zhunan, Taiwan 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Eccles Inst Neurosci, John Curtain Sch Med Res, Canberra, ACT, Australia John Innes Ctr, Metab Biol, Norwich, Norfolk, England USDA ARS, Genom & Bioinformat Res Unit, Raleigh, NC 27695 USA Med Univ Graz, Inst Med Informat Stat & Documentat, Holzinger Grp, Graz, Austria Ajou Univ, Pharm, Suwon, South Korea City Univ Hong Kong, Sch Energy & Environm, Hong Kong, Peoples R China Univ British Columbia, Sch Kinseiol, Vancouver, BC, Canada Univ Copenhagen, Marine Biol Sect, Dept Biol, Copenhagen, Denmark Univ Vienna, Dept Commun, Vienna, Austria Univ Dundee, Sch Social Sci, Dundee, Scotland Tech Univ Dresden, Inst Bot, Dresden, Germany Univ Oxford, Div Struct Biol, Oxford, England Natl Univ Hlth Syst, Med, Singapore, Singapore Univ Canterbury, Sch Biol Sci, Christchurch, New Zealand Univ Hosp Southern Denmark, Focused Res Unit Mol Diagnost & Clin Res, Odense, Denmark Univ Oxford, Primary Care Hlth Sci, Oxford, England Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 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Network, Lab Microbial Immun, Singapore, Singapore Cent South Univ, State Key Lab Powder Met, Changsha, Hunan, Peoples R China Univ Aberdeen, Inst Appl Hlth Sci, Aberdeen, Scotland Univ Bridgeport, Biomed Engn, Bridgeport, CT 06601 USA Texas Tech Univ, Hlth Sci Ctr, Pharmaceut Sci, Lubbock, TX 79430 USA Univ Montana, Ecosyst & Conservat Sci, Missoula, MT 59812 USA Univ Goettingen, Dept Syst Neurosci, Gottingen, Germany NHLBI, Lab Syst Genet, Bldg 10, Bethesda, MD 20892 USA Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Imaging, Las Vegas, NV USA Flinders Univ S Australia, Coll Nursing & Hlth Sci, Nutr & Dietet, Adelaide, SA, Australia Univ Padua, Dept Math, Padua, Italy Lund Univ, Fac Law, Lund, Sweden Univ Gothenburg, Dept Microbiol & Immunol, Gothenburg, Sweden NARO, Kachwekano Zardi, Entebbe, Uganda Natl Yunlin Univ Sci & Technol, Bachelor Program Interdisciplinary Studies, Touliu, Yunlin, Taiwan Aarhus Univ, Dept Biomed, Danish Res Inst Translat Neurosci DANDRITE, Aarhus, Denmark Eduardo 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Bogota, Colombia Univ Hosp Essen, Cardiol & Vasc Med, Essen, Germany Univ Hosp Basel, Endocrinol, Basel, Switzerland Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany Univ Hosp Munster, Div Gen Internal Med Nephrol & Rheumatolog, Dept Med D, Munster, Germany Univ Kentucky, Dept Nephrol, Lexington, KY USA Univ Freiburg, Dept Anaesthesiol & Crit Care, Med Ctr, Freiburg, Germany Univ Calif Irvine, Dept Med, Orange, CA 92668 USA Univ Hosp Leuven, Dept Urol, Leuven, Belgium Chinese Acad Sci, Coll Life Sci, Beijing, Peoples R China Univ Florida, Orthopaed & Rehabil, Gainesville, FL USA Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China Tsinghua Univ, Dept Chem Engn, Beijing, Peoples R China Yonsei Univ, Coll Med, Dept Pharmacol, Seoul, South Korea Childrens Hosp Kings Daughters, Eastern Virginia Med Sch, Dept Pediat, Norfolk, VA USA China Three Gorges Univ, Coll Sci, Dept Math, Yichang, Peoples R China Xiangtan Univ, Coll Informat Engn, Xiangtan, Hunan, Peoples R China Univ Hlth Network, Mood Disorders & Psychopharmacol, Toronto, ON, Canada Sao Paulo State Univ UNESP, Dept Anim Sci, Sao Paulo, Brazil Sao Paulo State Univ, Vet Clin, Sao Paulo, Brazil

Published
2019

20. The RNA Chaperone Hfq Is Involved in Stress Response and Virulence in Neisseria meningitidis and Is a Pleiotropic Regulator of Protein Expression

Author

Francesca Oriente, Vincenzo Scarlato, Elena Cartocci, Kate L. Seib, Isabel Delany, Francesca Ferlicca, Marzia Monica Giuliani, Laura Fantappiè, Matteo M. E. Metruccio, Fantappiè L, Metruccio MM, Seib KL, Oriente F, Cartocci E, Ferlicca F, Giuliani MM, Scarlato V, and Delany I

Subjects
PROTEIN EXPRESSION, Virulence Factors, Immunology, Mutant, Colony Count, Microbial, Virulence, Host Factor 1 Protein, Neisseria meningitidis, Microbiology, Mass Spectrometry, HFQ, Gene Knockout Techniques, Bacterial Proteins, Stress, Physiological, POSTTRANSRIPTIONAL REGULATOR, STRESS RESPONSE, Animals, Humans, Electrophoresis, Gel, Two-Dimensional, RNA CHAPERONE, Hfq protein, Regulation of gene expression, Genetics, Messenger RNA, Microbial Viability, biology, Gene Expression Profiling, Genetic Complementation Test, Gene Expression Regulation, Bacterial, Molecular Pathogenesis, Phenotype, Rats, Meningococcal Infections, Blood, Infectious Diseases, Chaperone (protein), Transfer RNA, biology.protein, Parasitology
Abstract

The well-conserved protein Hfq has emerged as the key modulator of riboregulation in bacteria. This protein is thought to function as an RNA chaperone and to facilitate base pairing between small regulatory RNA (sRNA) and mRNA targets, and many sRNAs are dependent on the Hfq protein for their regulatory functions. To address the possible role of Hfq in riboregulated circuits in Neisseria meningitidis , we generated an Hfq mutant of the MC58 strain, and the knockout mutant has pleiotropic phenotypes; it has a general growth phenotype in vitro in culture media, and it is sensitive to a wide range of stresses, including those that it may encounter in the host. Furthermore, the expression profile of a vast number of proteins is clearly altered in the mutant, and we have identified 27 proteins by proteomics. All of the phenotypes tested to date are also restored by complementation of Hfq expression in the mutant strain. Importantly, in ex vivo and in vivo models of infection the Hfq mutant is attenuated. These data indicate that Hfq plays a key role in stress response and virulence, and we propose a major role for Hfq in regulation of gene expression. Moreover, this study suggests that in meningococcus there is a large Hfq-mediated sRNA network which so far is largely unexplored.

Published
2009

21. Refinement and optimisation of Neisseria gonorrhoeae NHBA and MetQ vaccine candidates.

Author

Taha, Eskandari S, Slesarenko VA, Haselhorst T, Semchenko EA, and Seib KL

Abstract

Neisseria gonorrhoeae has a significant impact on reproductive health with an estimated 82 million new cases of infection per year worldwide. Due to the ongoing emergence of multidrug-resistant N. gonorrhoeae strains, the high number of asymptomatic cases, and the risk of disease sequelae, the development of a gonococcal vaccine is urgently needed. We have previously described two potential gonococcal vaccine antigens, cNHBA (C-terminal fragment of the Neisseria Heparin Binding Antigen) and MetQ (methionine-binding protein). This study aimed to optimise these antigens for improved immune responses and to facilitate vaccine production, by investigating cNHBA fusions with the full-length MetQ protein or N-terminal and C-terminal MetQ fragments (Met1 and Met2, respectively) adjuvanted with aluminium hydroxide. The cNHBA and MetQ fragments and fusion antigens were all immunogenic in mice, generating a predominantly IgG1 response. Antibodies mediated bacterial killing via both serum bactericidal activity (SBA) and opsonophagocytic activity (OPA), and reduced adherence to cervical and urethral epithelial cells. Among the antigen fusions tested, MetQ-cNHBA and cNHBA-Met2 generated the highest SBA, OPA and adherence blocking titres and are proposed as promising optimised antigens for N. gonorrhoeae vaccine development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KL Seib reports financial support was provided by National Health and Medical Research Council. KL Seib and EA Semchenko has patent pending to Griffith University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Published
2024
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22. WHO global research priorities for sexually transmitted infections.

Author

Gottlieb SL, Spielman E, Abu-Raddad L, Aderoba AK, Bachmann LH, Blondeel K, Chen XS, Crucitti T, Camacho GG, Godbole S, de Leon RGP, Gupta S, Hermez J, Ishikawa N, Klausner JD, Kurbonov F, Maatouk I, Mandil A, Mello MB, Miranda AE, Mosha FS, Okeibunor JC, Ong JJ, Peters RPH, Pérez F, Seguy N, Seib KL, Sharma M, Sladden T, Van Der Pol B, White PJ, Wi T, and Broutet N

Subjects
Humans, Research, Health Priorities, Biomedical Research, Sexually Transmitted Diseases prevention & control, Sexually Transmitted Diseases epidemiology, World Health Organization, Global Health
Abstract

Sexually transmitted infections (STIs) are widespread worldwide and negatively affect sexual and reproductive health. Gaps in evidence and in available tools have long hindered STI programmes and policies, particularly in resource-limited settings. In 2022, WHO initiated a research prioritisation process to identify the most important STI research areas to address the global public health need. Using an adapted Child Health and Nutrition Research Initiative methodology including two global stakeholder surveys, the process identified 40 priority STI research needs. The top priorities centred on developing and implementing affordable, feasible, rapid point-of-care STI diagnostic tests and new treatments, especially for gonorrhoea, chlamydia, and syphilis; designing new multipurpose prevention technologies and vaccines for STIs; and collecting improved STI epidemiologic data on both infection and disease outcomes. The priorities also included innovative programmatic approaches, such as new STI communication and partner management strategies. An additional six research areas related to mpox (formerly known as monkeypox) reflect the need for STI-related research during disease outbreaks where sexual transmission can have a key role. These STI research priorities provide a call to action for focus, investment, and innovation to address existing roadblocks in STI prevention, control, and management to advance sexual and reproductive health and wellbeing for all., Competing Interests: Declaration of interests SLG received support from the Bill & Melinda Gates Foundation paid to WHO for work on therapeutic human papillomavirus vaccines and on COVID-19 vaccines and pregnancy, and the Gates Foundation travel support to meetings on maternal immunisation and women's health innovations. LHB received royalties for book editing on Sexually Transmitted Infections in HIV-infected Adults and Special Populations. JDK received grants and support from the US National Institutes of Health (NIH), US Centers for Disease Control and Prevention, and Open Philanthropy; royalties and licences from UpToDate and McGraw-Hill; one-time consulting fees from Visby Medical, Diagnostics Direct, and Biofire; payment or honoraria from AIDS Healthcare Foundation; and payment for expert testimony from Gray Robinson. He is currently President of the non-profit organisation Herpes Cure Advocacy. JJO received grant support paid to his institution from the Australian National Health and Medical Research Council (NHMRC) and US NIH; and honoraria for presentations or other speaking events and support for attending meetings from Gilead Sciences. He is currently Board Director for the Australian Society for HIV, Hepatitis and Sexual Health Medicine and for Health Equity Matters and is a World Executive Committee member for the International Union against Sexually Transmitted Infections (IUSTI). RPHP received grants from NIH, Global AMR Innovation Fund–Foundation for Innovative New Diagnostics, Open Philanthropy, Global Antibiotic Research and Development Program–South African Medical Research Council, and the Swiss National Science Foundation. KLS received grants paid to her institute from the Australian NHMRC (numbers 1182443, 2017383, and 2002182). She has also received airfare and conference registration support from the International Pathogenic Neisseria Conference and the IUSTI World Congress. PJW received support from the UK Medical Research Council and National Institute for Health and Care Research, salary from the UK Health Security Agency and Imperial College London, and consulting fees from Pfizer and the National Institute for Public Health and the Environment. BVDP received consulting fees as an advisory board member for Abbot Rapid Diagnostics and Detect, consulting fees from Preventx, and speaking honoraria from Roche. She is President of the International Society for STD Research. NB received a consultancy contract from WHO for assistance with this project and had a contract with the Daffodil Centre on cervical cancer elimination. All other authors report no competing interests., (This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Published
2024
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23. Review of mathematical models of Neisseria gonorrhoeae vaccine impact: Implications for vaccine development.

Author

Padeniya TN, Hui BB, Wood JG, Regan DG, and Seib KL

Subjects
Humans, Vaccine Development, Prevalence, Vaccine Efficacy, Gonorrhea prevention & control, Gonorrhea epidemiology, Gonorrhea immunology, Neisseria gonorrhoeae immunology, Bacterial Vaccines immunology, Bacterial Vaccines administration & dosage, Models, Theoretical
Abstract

An effective prophylactic vaccine for prevention of Neisseria gonorrhoeae infection would have a major impact on sexual and reproductive health worldwide. Interest in developing gonorrhoea vaccines is growing due to the reported high rates of N. gonorrhoeae infections globally, and the threat of antimicrobial resistance. Several gonorrhoea vaccine candidates are currently under evaluation and various mathematical models have been used to assess the potential population-level impact a gonorrhoea vaccine may have once available. Here we review key aspects of gonorrhoea vaccine mathematical modelling studies, including model structures, populations considered, and assumptions used as well as vaccine characteristics and implementation scenarios investigated. The predicted vaccine impact varied between studies, ranging from as little as ∼17 % reduction in N. gonorrhoeae prevalence after 30 years up to 100 % reduction after 5 years. However, all studies predicted that even a partially effective gonorrhoea vaccine could have a substantial impact in reducing N. gonorrhoeae prevalence or incidence, particularly when high coverage is achieved within either important risk groups or the overall sexually active population. As expected, higher vaccine efficacy against acquisition of N. gonorrhoeae and longer duration of protection were linked to greater reductions in infections. A vaccine that alters onward transmission could also substantially reduce infections. Several gaps and research needs have been identified by researchers in the field and via this narrative literature review. For example, future modelling to inform gonorrhoea vaccine development and implementation should consider additional populations that are at high risk of N. gonorrhoeae infection, especially in low- and middle-income settings, as well as the impact of vaccination on the potential adverse sexual and reproductive health outcomes of infection. In addition, more detailed and robust epidemiological, biological, and behavioural data is needed to enable more accurate and robust modelling of gonorrhoea vaccine impact to inform future scientific and public health decision-making., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thilini Padeniya reports financial support was provided by National Institutes of Health. Kate Seib reports financial support was provided by National Institutes of Health. Kate Seib reports financial support was provided by National Health and Medical Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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24. Vaccine value profile for Neisseria gonorrhoeae.

Author

Lyu Y, Choong A, Chow EPF, Seib KL, Marshall HS, Unemo M, de Voux A, Wang B, Miranda AE, Gottlieb SL, Mello MB, Wi T, Baggaley R, Marshall C, Abu-Raddad LJ, Abara WE, Chen XS, and Ong JJ

Subjects
Humans, Cross Protection immunology, Bacterial Vaccines immunology, Bacterial Vaccines administration & dosage, Gonorrhea prevention & control, Neisseria gonorrhoeae immunology, Neisseria gonorrhoeae drug effects
Abstract

Neisseria gonorrhoeae infection (gonorrhoea) is a global public health challenge, causing substantial sexual and reproductive health consequences, such as infertility, pregnancy complications and increased acquisition or transmission of HIV. There is an urgency to controlling gonorrhoea because of increasing antimicrobial resistance to ceftriaxone, the last remaining treatment option, and the potential for gonorrhoea to become untreatable. No licensed gonococcal vaccine is available. Mounting observational evidence suggests that N. meningitidis serogroup B outer membrane vesicle-based vaccines may induce cross-protection against N. gonorrhoeae (estimated 30%-40% effectiveness using the 4CMenB vaccine). Clinical trials to determine the efficacy of the 4CMenB vaccine against N. gonorrhoeae are underway, as are Phase 1/2 studies of a new gonococcal-specific vaccine candidate. Ultimately, a gonococcal vaccine must be accessible, affordable and equitably dispensed, given that those most affected by gonorrhoea are also those who may be most disadvantaged in our societies, and most cases are in less-resourced settings. This vaccine value profile (VVP) provides a high level, holistic assessment of the current data to inform the potential public health, economic and societal value of pipeline vaccines. This was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships and multi-lateral organizations. All contributors have extensive expertise on various elements of the N. gonorrhoeae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using published data obtained from peer-reviewed journals or reports., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JJO reports financial support from the World Health Organization and Australian National Health and Medical Research Foundation. Some of the authors are present or former staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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25. Prevalence of cefixime-resistant Neisseria gonorrhoeae in Melbourne, Australia, 2021-2022.

Author

Chow EPF, Stevens K, De Petra V, Chen MY, Bradshaw CS, Sherry NL, Barbee LA, Vodstrcil LA, Aguirre I, Seib KL, Maddaford K, Williamson DA, Howden BP, and Fairley CK

Abstract

While ceftriaxone remains the first-line treatment for gonorrhoea, the US CDC recommended cefixime as a second-line treatment in 2021. We tested 1176 Neisseria gonorrhoeae isolates among clients attending the Melbourne Sexual Health Centre in 2021-2022. The prevalence of cefixime resistance was 6.3% (74/1176), azithromycin resistance was 4.9% (58/1176) and ceftriaxone resistance was 0% (0/1176). Cefixime resistance was the highest among women (16.4%, 10/61), followed by men-who-have-sex-with-women (6.4%, 7/109), and men-who-have-sex-with-men (5.8%, 57/982). The prevalence of cefixime-resistant N. gonorrhoeae exceeds the threshold of the 5% resistance level recommended by the World Health Organization; and thus, cefixime treatment would have limited benefits in Australia., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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2024
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26. Multicentre double-blind randomised placebo-controlled trial evaluating the efficacy of the meningococcal B vaccine, 4CMenB (Bexsero), against Neisseria gonorrhoeae infection in men who have sex with men: the GoGoVax study protocol.

Author

Seib KL, Donovan B, Thng C, Lewis DA, McNulty A, Fairley CK, Yeung B, Jin F, Fraser D, Bavinton BR, Law M, Chen MY, Chow EPF, Whiley DM, Mackie B, Jennings MP, Jennison AV, Lahra MM, and Grulich AE

Subjects
Male, Humans, Homosexuality, Male, Neisseria gonorrhoeae genetics, Randomized Controlled Trials as Topic, Multicenter Studies as Topic, Gonorrhea epidemiology, Gonorrhea prevention & control, Gonorrhea drug therapy, Meningococcal Vaccines therapeutic use, Meningococcal Infections epidemiology, Sexual and Gender Minorities, Anti-Infective Agents, HIV Infections drug therapy
Abstract

Introduction: Gonorrhoea, the sexually transmissible infection caused by Neisseria gonorrhoeae , has a substantial impact on sexual and reproductive health globally with an estimated 82 million new infections each year worldwide. N. gonorrhoeae antimicrobial resistance continues to escalate, and disease control is largely reliant on effective therapy as there is no proven effective gonococcal vaccine available. However, there is increasing evidence from observational cohort studies that the serogroup B meningococcal vaccine four-component meningitis B vaccine (4CMenB) (Bexsero), licensed to prevent invasive disease caused by Neisseria meningitidis , may provide cross-protection against the closely related bacterium N. gonorrhoeae . This study will evaluate the efficacy of 4CMenB against N. gonorrhoeae infection in men (cis and trans), transwomen and non-binary people who have sex with men (hereafter referred to as GBM+)., Methods and Analysis: This is a double-blind, randomised placebo-controlled trial in GBM+, either HIV-negative on pre-exposure prophylaxis against HIV or living with HIV (CD4 count >350 cells/mm 3 ), who have had a diagnosis of gonorrhoea or infectious syphilis in the last 18 months (a key characteristic associated with a high risk of N. gonorrhoeae infection). Participants are randomised 1:1 to receive two doses of 4CMenB or placebo 3 months apart. Participants have 3-monthly visits over 24 months, which include testing for N. gonorrhoeae and other sexually transmissible infections, collection of demographics, sexual behaviour risks and antibiotic use, and collection of research samples for analysis of N. gonorrhoeae -specific systemic and mucosal immune responses. The primary outcome is the incidence of the first episode of N. gonorrhoeae infection, as determined by nucleic acid amplification tests, post month 4. Additional outcomes consider the incidence of symptomatic or asymptomatic N. gonorrhoeae infection at different anatomical sites (ie, urogenital, anorectum or oropharynx), incidence by N. gonorrhoeae genotype and antimicrobial resistance phenotype, and level and functional activity of N. gonorrhoeae -specific antibodies., Ethics and Dissemination: Ethical approval was obtained from the St Vincent's Hospital Human Research Ethics Committee, St Vincent's Hospital Sydney, NSW, Australia (ref: 2020/ETH01084). Results will be disseminated in peer-reviewed journals and via presentation at national and international conferences., Trial Registration Number: NCT04415424., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

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2024
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27. Neisseria gonorrhoeae vaccines: a contemporary overview.

Author

Williams E, Seib KL, Fairley CK, Pollock GL, Hocking JS, McCarthy JS, and Williamson DA

Subjects
Infant, Newborn, Humans, Neisseria gonorrhoeae, Gonorrhea drug therapy, Gonorrhea epidemiology, Gonorrhea prevention & control, Anti-Infective Agents, Vaccines
Abstract

Neisseria gonorrhoeae infection is an important public health issue, with an annual global incidence of 87 million. N. gonorrhoeae infection causes significant morbidity and can have serious long-term impacts on reproductive and neonatal health and may rarely cause life-threatening disease. Global rates of N. gonorrhoeae infection have increased over the past 20 years. Importantly, rates of antimicrobial resistance to key antimicrobials also continue to increase, with the United States Centers for Disease Control and Prevention identifying drug-resistant N. gonorrhoeae as an urgent threat to public health. This review summarizes the current evidence for N. gonorrhoeae vaccines, including historical clinical trials, key N. gonorrhoeae vaccine preclinical studies, and studies of the impact of Neisseria meningitidis vaccines on N. gonorrhoeae infection. A comprehensive survey of potential vaccine antigens, including those identified through traditional vaccine immunogenicity approaches, as well as those identified using more contemporary reverse vaccinology approaches, are also described. Finally, the potential epidemiological impacts of a N. gonorrhoeae vaccine and research priorities for further vaccine development are described., Competing Interests: The authors declare no conflict of interest.

Published
2024
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28. The potential impact of a vaccine on Neisseria gonorrhoeae prevalence among heterosexuals living in a high prevalence setting.

Author

Padeniya TN, Hui BB, Wood JG, Seib KL, and Regan DG

Subjects
Humans, Adolescent, Young Adult, Adult, Middle Aged, Heterosexuality, Prevalence, Bacterial Vaccines, Neisseria gonorrhoeae, Gonorrhea epidemiology, Gonorrhea prevention & control
Abstract

Background: Treatment of Neisseria gonorrhoeae is under threat with the emergence and spread of antimicrobial resistance. Thus, there is a growing interest in the development of a gonorrhoea vaccine. We used mathematical modelling to assess the impact of a hypothetical vaccine in controlling gonorrhoea among heterosexuals living in a setting of relatively high N. gonorrhoeae prevalence (∼3 %)., Methods: We developed a mathematical model of N. gonorrhoeae transmission among 15-49-year-old heterosexuals, stratified by age and sex, and calibrated to prevalence and sexual behaviour data from South Africa as an example of a high prevalence setting for which we have data available. Using this model, we assessed the potential impact of a vaccine on N. gonorrhoeae prevalence in the entire population. We considered gonorrhoea vaccines having differing impacts on N. gonorrhoeae infection and transmission and offered to different age-groups., Results: The model predicts that N. gonorrhoeae prevalence can be reduced by ∼50 % in 10 years following introduction of a vaccine if annual vaccination uptake is 10 %, vaccine efficacy against acquisition of infection is 25 % and duration of protection is 5 years, with vaccination available to the entire population of 15-49-year-olds. If only 15-24-year-olds are vaccinated, the predicted reduction in prevalence in the entire population is 25 % with equivalent vaccine characteristics and uptake. Although predicted reductions in prevalence for vaccination programmes targeting only high-activity individuals and the entire population are similar over the same period, vaccinating only high-activity individuals is more efficient as the cumulative number of vaccinations needed to reduce prevalence in the entire population by 50 % is ∼3 times lower for this programme., Conclusion: Provision of a gonorrhoea vaccine could lead to substantial reductions in N. gonorrhoeae prevalence in a high prevalence heterosexual setting, even with moderate annual vaccination uptake of a vaccine with partial efficacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Published
2023
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29. An open-label randomised controlled trial evaluating the efficacy of a meningococcal serogroup B (4CMenB) vaccine on Neisseria gonorrhoeae infection in gay and bisexual men: the MenGO study protocol.

Author

Thng C, Semchenko EA, Hughes I, O'Sullivan M, and Seib KL

Subjects
Humans, Male, Australia epidemiology, Clinical Trials, Phase III as Topic, Neisseria gonorrhoeae, Neisseria meningitidis, Serogroup B, Randomized Controlled Trials as Topic, Serogroup, Sexual Behavior, Gonorrhea prevention & control, Meningococcal Infections prevention & control, Meningococcal Vaccines therapeutic use, Sexual and Gender Minorities
Abstract

Background: Gonorrhoea is an ongoing public health concern due to its rising incidence and the emergence of antibiotic resistance. There are an estimated 82 million new Neisseria gonorrhoeae infections each year, with several populations at higher risk for gonococcal infection, including gay and bisexual men (GBM). If left untreated, infection can lead to serious morbidity including infertility, sepsis and increased risk of HIV acquisition. Development of a gonorrhoea vaccine has been challenging, however there is observational evidence that serogroup B meningococcal vaccines, used to protect against the closely related bacteria Neisseria meningitidis, could provide cross-protection against N. gonorrhoeae., Methods: The MenGO (Meningococcal vaccine efficacy against Gonorrhoea) study is a phase III open-label randomised control trial in GBM to evaluate the efficacy of the four-component meningococcal serogroup B vaccine, 4CMenB, against gonorrhoea. A total of 130 GBM will be recruited at the Gold Coast Sexual Health Clinic, Australia, and randomised to either receive 2 doses of 4CMenB or no intervention. Participants will be followed up for 24 months with testing for N. gonorrhoeae and other sexually transmissible infections every three months. Demographics, sexual behaviour risk, antibiotic use, and blood samples for analysis of N. gonorrhoeae-specific immune responses, will be collected during the study. The primary outcome is the number of N. gonorrhoeae infections in participants over 2 years measured by nucleic acid amplification test (NAAT). Secondary outcomes are vaccine-induced N. gonorrhoeae-specific immune responses, and adverse events in trial participants., Discussion: This trial will determine if the 4CMenB vaccine is able to reduce N. gonorrhoeae infection. If shown to be effective, 4CMenB could be used in gonococcal prevention. Analysis of 4CMenB-induced immune responses will increase understanding of the type of immune response needed to prevent N. gonorrhoeae, which may enable identification of a potential correlate of protection to aid future gonorrhoea vaccine development., Trial Registration: The trial has been registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12619001478101) on 25 October 2019., (© 2023. The Author(s).)

Published
2023
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30. Acclimation to Nutritional Immunity and Metal Intoxication Requires Zinc, Manganese, and Copper Homeostasis in the Pathogenic Neisseriae .

Author

Branch AH, Stoudenmire JL, Seib KL, and Cornelissen CN

Subjects
Acclimatization, Copper toxicity, Homeostasis, Humans, Ions, Metals, Neisseria, Neisseria gonorrhoeae, Zinc toxicity, Manganese toxicity, Neisseria meningitidis
Abstract

Neisseria gonorrhoeae and Neisseria meningitidis are human-specific pathogens in the Neisseriaceae family that can cause devastating diseases. Although both species inhabit mucosal surfaces, they cause dramatically different diseases. Despite this, they have evolved similar mechanisms to survive and thrive in a metal-restricted host. The human host restricts, or overloads, the bacterial metal nutrient supply within host cell niches to limit pathogenesis and disease progression. Thus, the pathogenic Neisseria require appropriate metal homeostasis mechanisms to acclimate to such a hostile and ever-changing host environment. This review discusses the mechanisms by which the host allocates and alters zinc, manganese, and copper levels and the ability of the pathogenic Neisseria to sense and respond to such alterations. This review will also discuss integrated metal homeostasis in N. gonorrhoeae and the significance of investigating metal interplay., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Branch, Stoudenmire, Seib and Cornelissen.)

Published
2022
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31. A Gonococcal Vaccine Has the Potential to Rapidly Reduce the Incidence of Neisseria gonorrhoeae Infection Among Urban Men Who Have Sex With Men.

Author

Hui BB, Padeniya TN, Rebuli N, Gray RT, Wood JG, Donovan B, Duan Q, Guy R, Hocking JS, Lahra MM, Lewis DA, Whiley DM, Regan DG, and Seib KL

Subjects
Bacterial Vaccines, Homosexuality, Male, Humans, Incidence, Male, Neisseria gonorrhoeae, Gonorrhea epidemiology, Gonorrhea prevention & control, Sexual and Gender Minorities
Abstract

Background: A gonococcal vaccine is urgently needed due to increasing gonorrhea incidence and emerging multidrug-resistant gonococcal strains worldwide. Men who have sex with men (MSM) have among the highest incidences of gonorrhea and may be a key target population for vaccination when available., Methods: An individual-based, anatomical site-specific mathematical model was used to simulate Neisseria gonorrhoeae transmission in a population of 10 000 MSM. The impact of vaccination on gonorrhea prevalence was assessed., Results: With a gonococcal vaccine of 100% or 50% protective efficacy, gonorrhea prevalence could be reduced by 94% or 62%, respectively, within 2 years if 30% of MSM are vaccinated on presentation for sexually transmitted infection (STI) testing. Elimination of gonorrhea is possible within 8 years with vaccines of ≥ 50% efficacy lasting 2 years, providing a booster vaccination is available every 3 years on average. A vaccine's impact may be reduced if it is not effective at all anatomical sites., Conclusions: Our study indicates that with a vaccine of modest efficacy and an immunization strategy that targets MSM presenting for STI screening, the prevalence of gonorrhea in this population could be rapidly and substantially reduced., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Published
2022
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32. Self-Inhibitory Peptides Targeting the Neisseria gonorrhoeae MtrCDE Efflux Pump Increase Antibiotic Susceptibility.

Author

Evert BJ, Slesarenko VA, Punnasseril JMJ, Taha, Zhan J, Zhou Y, Semchenko EA, and Seib KL

Subjects
Anti-Bacterial Agents metabolism, Anti-Bacterial Agents pharmacology, Azithromycin pharmacology, Bacterial Proteins genetics, Bacterial Proteins metabolism, Drug Resistance, Bacterial genetics, Humans, Microbial Sensitivity Tests, Peptides metabolism, Peptides pharmacology, Repressor Proteins genetics, Gonorrhea drug therapy, Gonorrhea microbiology, Neisseria gonorrhoeae genetics, Neisseria gonorrhoeae metabolism
Abstract

Neisseria gonorrhoeae is an increasing public health threat due to its rapidly rising incidence and antibiotic resistance. There are an estimated 106 million cases per year worldwide, there is no vaccine available to prevent infection, and N. gonorrhoeae strains that are resistant to all antibiotics routinely used to treat the infection have emerged. In many strains, antibiotic resistance is mediated by overexpression of the MtrCDE efflux pump, which enables the bacteria to transport toxic antibiotics out of the cell. Genetic mutations that inactivate MtrCDE have previously been shown to render resistant strains susceptible to certain antibiotics. Here, we show that peptides rationally designed to target and disrupt the activity of each of the three protein components of MtrCDE were able to increase the susceptibility of N. gonorrhoeae strains to antibiotics in a dose-dependent manner and with no toxicity to human cells. Cotreatment of bacteria with subinhibitory concentrations of the peptide led to 2- to 64-fold increases in susceptibility to erythromycin, azithromycin, ciprofloxacin, and/or ceftriaxone in N. gonorrhoeae strains FA1090, WHO K, WHO P, and WHO X. The cotreatment experiments with peptides P-MtrC1 and P-MtrE1 resulted in increased susceptibilities of WHO P and WHO X to azithromycin, ciprofloxacin, and ceftriaxone that were of the same magnitude seen in MtrCDE mutants. P-MtrE1 was able to change the azithromycin resistance profile of WHO P from resistant to susceptible. Data presented here demonstrate that these peptides may be developed for use as a dual treatment with existing antibiotics to treat multidrug-resistant gonococcal infections.

Published
2022
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34. Assessment of Serum Bactericidal and Opsonophagocytic Activity of Antibodies to Gonococcal Vaccine Targets.

Author

Semchenko EA, Jen FE, Jennings MP, and Seib KL

Subjects
Antibodies, Bacterial, Bacterial Vaccines, Blood Bactericidal Activity, Humans, Neisseria gonorrhoeae immunology, Gonorrhea prevention & control
Abstract

There is no vaccine available to prevent Neisseria gonorrhoeae infection, however there is currently a high level of interest in developing gonococcal vaccines due to the increasing number of cases and continuing emergence of antimicrobial resistance worldwide. A key aspect of vaccine development is the investigation of the functional immune response raised to the vaccine targets under investigation. Here, we describe two assays used to assess the functional immune response raised against gonococcal vaccine targets: the serum bactericidal assay (SBA) and the opsonophagocytic assay (OPA)., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2022
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35. Looking beyond meningococcal B with the 4CMenB vaccine: the Neisseria effect.

Author

Ruiz García Y, Sohn WY, Seib KL, Taha MK, Vázquez JA, de Lemos APS, Vadivelu K, Pizza M, Rappuoli R, and Bekkat-Berkani R

Abstract

Infections with Neisseria meningitidis and Neisseria gonorrhoeae have different clinical manifestations, but the bacteria share up to 80-90% genome sequence identity. The recombinant meningococcal serogroup B (MenB) vaccine 4CMenB consists of four antigenic components that can be present in non-B meningococcal and gonococcal strains. This comprehensive review summarizes scientific evidence on the genotypic and phenotypic similarities between vaccine antigens and their homologs expressed by non-B meningococcal and gonococcal strains. It also includes immune responses of 4CMenB-vaccinated individuals and effectiveness and impact of 4CMenB against these strains. Varying degrees of strain coverage were estimated depending on the non-B meningococcal serogroup and antigenic repertoire. 4CMenB elicits immune responses against non-B meningococcal serogroups and N. gonorrhoeae. Real-world evidence showed risk reductions of 69% for meningococcal serogroup W clonal complex 11 disease and 40% for gonorrhea after 4CMenB immunization. In conclusion, functional antibody activity and real-world evidence indicate that 4CMenB has the potential to provide some protection beyond MenB disease., (© 2021. The Author(s).)

Published
2021
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36. The Lst Sialyltransferase of Neisseria gonorrhoeae Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea.

Author

Jen FE, Ketterer MR, Semchenko EA, Day CJ, Seib KL, Apicella MA, and Jennings MP

Subjects
Antigens, Bacterial analysis, Antigens, Bacterial genetics, Antigens, Bacterial immunology, Bacterial Vaccines, Cervix Uteri microbiology, Epithelial Cells microbiology, Female, Humans, Lipopolysaccharides genetics, Lipopolysaccharides immunology, N-Acetylneuraminic Acid metabolism, Neisseria gonorrhoeae pathogenicity, Neutrophils immunology, Neutrophils microbiology, Phagocytosis immunology, beta-Galactoside alpha-2,3-Sialyltransferase, Gonorrhea prevention & control, Lipopolysaccharides metabolism, Neisseria gonorrhoeae enzymology, Neisseria gonorrhoeae genetics, Sialyltransferases genetics, Sialyltransferases metabolism
Abstract

The lipooligosaccharide (LOS) of Neisseria gonorrhoeae plays key roles in pathogenesis and is composed of multiple possible glycoforms. These glycoforms are generated by the process of phase variation and by differences in the glycosyltransferase gene content of particular strains. LOS glycoforms of N. gonorrhoeae can be terminated with an N -acetylneuraminic acid (Neu5Ac), which imparts resistance to the bactericidal activity of serum. However, N. gonorrhoeae cannot synthesize the CMP-Neu5Ac required for LOS biosynthesis and must acquire it from the host. In contrast, Neisseria meningitidis can synthesize endogenous CMP-Neu5Ac, the donor molecule for Neu5Ac, which is a component of some meningococcal capsule structures. Both species have an almost identical LOS sialyltransferase, Lst, that transfers Neu5Ac from CMP-Neu5Ac to the terminus of LOS. Lst is homologous to the LsgB sialyltransferase of nontypeable Haemophilus influenzae (NTHi). Studies in NTHi have demonstrated that LsgB can transfer keto-deoxyoctanoate (KDO) from CMP-KDO to the terminus of LOS in place of Neu5Ac. Here, we show that Lst can also transfer KDO to LOS in place of Neu5Ac in both N. gonorrhoeae and N. meningitidis Consistent with access to the pool of CMP-KDO in the cytoplasm, we present data indicating that Lst is localized in the cytoplasm. Lst has previously been reported to be localized on the outer membrane. We also demonstrate that KDO is expressed as a terminal LOS structure in vivo in samples from infected women and further show that the anti-KDO monoclonal antibody 6E4 can mediate opsonophagocytic killing of N. gonorrhoeae Taken together, these studies indicate that KDO expressed on gonococcal LOS represents a new antigen for the development of vaccines against gonorrhea. IMPORTANCE The emergence of multidrug-resistant N. gonorrhoeae strains that are resistant to available antimicrobials is a current health emergency, and no vaccine is available to prevent gonococcal infection. Lipooligosaccharide (LOS) is one of the major virulence factors of N. gonorrhoeae The sialic acid N -acetylneuraminic acid (Neu5Ac) is present as the terminal glycan on LOS in N. gonorrhoeae In this study, we made an unexpected discovery that KDO can be incorporated as the terminal glycan on LOS of N. gonorrhoeae by the alpha-2,3-sialyltransferase Lst. We showed that N. gonorrhoeae express KDO on LOS in vivo and that the KDO-specific monoclonal antibody 6E4 can direct opsonophagocytic killing of N. gonorrhoeae These data support further development of KDO-LOS structures as vaccine antigens for the prevention of infection by N. gonorrhoeae ., (Copyright © 2021 Jen et al.)

Published
2021
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37. Random Switching of the ModA11 Type III DNA Methyltransferase of Neisseria meningitidis Regulates Entner-Doudoroff Aldolase Expression by a Methylation Change in the eda Promoter Region.

Author

Jen FE, Scott AL, Tan A, Seib KL, and Jennings MP

Subjects
DNA Methylation, Epigenesis, Genetic, Humans, Meningitis, Meningococcal microbiology, Promoter Regions, Genetic, Bacterial Proteins genetics, DNA Modification Methylases genetics, Fructose-Bisphosphate Aldolase genetics, Gene Expression Regulation, Bacterial, Neisseria meningitidis genetics
Abstract

Phase-variable DNA methyltransferases (Mods) mediate epigenetic regulation of gene expression. These phase-variable regulons, called phasevarions, have been shown to regulate virulence and immunoevasion in multiple bacterial pathogens. How genome methylation switching mediates gene regulation is unresolved. Neisseria meningitidis remains a major cause of sepsis and meningitis worldwide. Previously, we reported that phase variation (rapid on/off switching) of the meningococcal ModA11 methyltransferase regulates 285 genes. Here we show a bioinformatic analysis that reveals only 26 of the regulated genes have a methylation site located upstream of the gene with potential for direct effect of methylation on transcription. To investigate how methylation changes are "read" to alter gene expression, we used a lacZ gene fusion approach. We showed a 182-nucleotide region upstream of the eda gene (Entner-Doudoroff aldolase) is sufficient to impart methylation-dependent regulation of eda. Site-directed mutagenesis of the 5'-ACGT m6 AGG-3' ModA11 site upstream of the eda gene showed that methylation of this site modulates eda expression. We show that eda is regulated by the PhoB homolog MisR, and that a MisR binding motif overlaps with the ModA11 methylation site. In a MisR mutant, regulation of eda is uncoupled from regulation by ModA11 phasevarion switching. The on/off switching of ModA11 leads to the presence or absence of a N6-methyladenine modification at thousands of sites in the genome. Most of these modifications have no impact on gene regulation. Moreover, the majority of the 285 gene regulon that is controlled by ModA11 phasevarion switching (259/285) are not directly controlled by methylation changes in the promoter region of the regulated genes. Our data are consistent with direct control via methylation of a subset of the regulon, like Eda, whose regulation will trigger secondary effects in expression of many genes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2020
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38. Epigenetic Regulation of Virulence and Immunoevasion by Phase-Variable Restriction-Modification Systems in Bacterial Pathogens.

Author

Seib KL, Srikhanta YN, Atack JM, and Jennings MP

Subjects
DNA Methylation, DNA Restriction-Modification Enzymes genetics, DNA Restriction-Modification Enzymes metabolism, Humans, Regulon, Virulence, Bacteria genetics, Bacteria pathogenicity, Epigenesis, Genetic, Gene Expression Regulation, Bacterial, Host-Pathogen Interactions, Immune Evasion
Abstract

Human-adapted bacterial pathogens use a mechanism called phase variation to randomly switch the expression of individual genes to generate a phenotypically diverse population to adapt to challenges within and between human hosts. There are increasing reports of restriction-modification systems that exhibit phase-variable expression. The outcome of phase variation of these systems is global changes in DNA methylation. Analysis of phase-variable Type I and Type III restriction-modification systems in multiple human-adapted bacterial pathogens has demonstrated that global changes in methylation regulate the expression of multiple genes. These systems are called phasevarions (phase-variable regulons). Phasevarion switching alters virulence phenotypes and facilitates evasion of host immune responses. This review describes the characteristics of phasevarions and implications for pathogenesis and immune evasion. We present and discuss examples of phasevarion systems in the major human pathogens Haemophilus influenzae , Neisseria meningitidis , Neisseria gonorrhoeae , Helicobacter pylori , Moraxella catarrhalis , and Streptococcus pneumoniae .

Published
2020
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39. Moraxella catarrhalis phase-variable loci show differences in expression during conditions relevant to disease.

Author

Tan A, Blakeway LV, Taha, Yang Y, Zhou Y, Atack JM, Peak IR, and Seib KL

Subjects
Bacterial Adhesion genetics, Bacterial Outer Membrane Proteins genetics, Bacterial Outer Membrane Proteins metabolism, Gene Expression genetics, Humans, Microsatellite Repeats genetics, Moraxella catarrhalis pathogenicity, Moraxellaceae Infections, Otitis Media microbiology, Repetitive Sequences, Nucleic Acid genetics, Gene Expression Regulation, Bacterial genetics, Moraxella catarrhalis genetics
Abstract

Moraxella catarrhalis is a human-adapted, opportunistic bacterial pathogen of the respiratory mucosa. Although asymptomatic colonization of the nasopharynx is common, M. catarrhalis can ascend into the middle ear, where it is a prevalent causative agent of otitis media in children, or enter the lower respiratory tract, where it is associated with acute exacerbations of chronic obstructive pulmonary disease in adults. Phase variation is the high frequency, random, reversible switching of gene expression that allows bacteria to adapt to different host microenvironments and evade host defences, and is most commonly mediated by simple DNA sequence repeats. Bioinformatic analysis of five closed M. catarrhalis genomes identified 17 unique simple DNA sequence repeat tracts that were variable between strains, indicating the potential to mediate phase variable expression of the associated genes. Assays designed to assess simple sequence repeat variation under conditions mimicking host infection demonstrated that phase variation of uspA1 (ubiquitous surface protein A1) from high to low expression occurs over 72 hours of biofilm passage, while phase variation of uspA2 (ubiquitous surface protein A2) to high expression variants occurs during repeated exposure to human serum, as measured by mRNA levels. We also identify and confirm the variable expression of two novel phase variable genes encoding a Type III DNA methyltransferase (modO), and a conserved hypothetical permease (MC25239_RS00020). These data reveal the repertoire of phase variable genes mediated by simple sequence repeats in M. catarrhalis and demonstrate that modulation of expression under conditions mimicking human infection is attributed to changes in simple sequence repeat length., Competing Interests: The authors have declared that no competing interests exist.

Published
2020
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40. Gonococcal vaccines: Public health value and preferred product characteristics; report of a WHO global stakeholder consultation, January 2019.

Author

Gottlieb SL, Ndowa F, Hook EW 3rd, Deal C, Bachmann L, Abu-Raddad L, Chen XS, Jerse A, Low N, MacLennan CA, Petousis-Harris H, Seib KL, Unemo M, Vincent L, and Giersing BK

Subjects
Anti-Bacterial Agents, Humans, Neisseria gonorrhoeae, Referral and Consultation, World Health Organization, Gonorrhea prevention & control, Public Health
Abstract

Renewed interest in developing vaccines against Neisseria gonorrhoeae has been sparked by the increasing threat of gonococcal antimicrobial resistance (AMR) and growing optimism that gonococcal vaccines are biologically feasible. Evidence suggests serogroup B Neisseria meningitidis vaccines might provide some cross-protection against N. gonorrhoeae, and new gonococcal vaccine candidates based on several approaches are currently in preclinical development. To further stimulate investment and accelerate development of gonococcal vaccines, greater understanding is needed regarding the overall value that gonococcal vaccines might have in addressing public health and societal goals in low-, middle-, and high-income country contexts and how future gonococcal vaccines might be accepted and used, if available. In January 2019, the World Health Organization (WHO) convened a multidisciplinary international group of experts to lay the groundwork for understanding the potential health, economic, and societal value of gonococcal vaccines and their likely acceptance and use, and for developing gonococcal vaccine preferred product characteristics (PPCs). WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper describes the main discussion points and conclusions from the January 2019 meeting of experts. Participants emphasized the need for vaccines to control N. gonorrhoeae infections with the ultimate goals of preventing adverse sexual and reproductive health outcomes (e.g., infertility) and reducing the impact of gonococcal AMR. Meeting participants also discussed important PPC considerations (e.g., vaccine indications, target populations, and potential immunization strategies) and highlighted crucial research and data needs for guiding the value assessment and PPCs for gonococcal vaccines and advancing gonococcal vaccine development., Competing Interests: Declaration of Competing Interest Drs Gottlieb, Ndowa, Hook, Deal, Bachmann, Abu-Raddad, Chen, Low, MacLennan, Petousis-Harris, Unemo, Vincent, and Giersing report no conflicts of interest. Dr Jerse’s laboratory has conducted or is conducting research with the following companies under cooperative research and development agreements (CRADAs) or subcontracts to National Institutes of Health (NIH) grants: Chiron Corporation; Discuva, Ltd; GlaxoSmithKline; Microbiotx, Inc; The Population Council; Reoxcyn Discoveries Group; Tetraphase, Inc; Topcaid; VenatoRx; and Yaso Therapeutics. Dr Seib reports a brief consultancy with GlaxoSmithKline to provide expert advice on gonorrhoea in Australia, which occurred after the WHO Consultation in January 2019., (Copyright © 2020 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Published
2020
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41. The Neisseria gonorrhoeae Vaccine Candidate NHBA Elicits Antibodies That Are Bactericidal, Opsonophagocytic and That Reduce Gonococcal Adherence to Epithelial Cells.

Author

Semchenko EA, Day CJ, and Seib KL

Abstract

Due to the continuing emergence of multidrug resistant strains of Neisseria gonorrhoeae there is an urgent need for the development of a gonococcal vaccine. We evaluated the gonococcal Neisseria heparin binding antigen (NHBA) as a potential vaccine candidate, in terms of its sequence conservation and expression in a range of N. gonorrhoeae strains, as well as its immunogenicity and the functional activity of antibodies raised to either the full length NHBA or a C-terminal fragment of NHBA (NHBA-c). The gene encoding NHBA is highly conserved and expressed in all N. gonorrhoeae strains investigated. Recombinant NHBA is immunogenic, and mice immunized with either NHBA or NHBA-c adjuvanted with either Freund's or aluminium hydroxide (alum) generated a humoral immune response, with predominantly IgG1 antibodies. Antibodies generated by both NHBA and NHBA-c antigens promoted complement activation and mediated bacterial killing via both serum bactericidal activity and opsonophagocytic activity, with slightly higher titers seen for the NHBA-c antigen. Anti-NHBA was also able to block the functional activity of NHBA by reducing binding to heparin and adherence to cervical and urethral epithelial cells. These data suggest that the gonococcal NHBA is a promising vaccine antigen to include in a vaccine to control N. gonorrhoeae .

Published
2020
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42. Role of the Gonococcal Neisserial Heparin Binding Antigen in Microcolony Formation, and Serum Resistance and Adherence to Epithelial Cells.

Author

Semchenko EA, Mubaiwa TD, Day CJ, and Seib KL

Subjects
Bacterial Adhesion, Bacterial Outer Membrane Proteins genetics, Carrier Proteins genetics, Cervix Uteri cytology, Drug Resistance, Bacterial, Epithelial Cells physiology, Female, Gene Expression Regulation, Bacterial, Humans, Polysaccharides, Protein Binding, Urethra cytology, Bacterial Outer Membrane Proteins metabolism, Carrier Proteins metabolism, Neisseria gonorrhoeae metabolism
Abstract

The sexually transmitted infection gonorrhoea is on the rise worldwide and an increased understanding of the mechanisms of colonization and pathogenesis of Neisseria gonorrhoeae is required to aid development of new treatment and prevention strategies. In the current study, we investigate the neisserial heparin-binding antigen (NHBA) of N. gonorrhoeae and confirm its role in binding to several glycans, including heparin, and identify interactions of NHBA with both gonococcal and host cells. Furthermore, we report that a gonococcal nhba mutant displays decreased cell aggregation and microcolony formation, as well as reduced survival in human serum and reduced adherence to human cervical and urethral epithelial cells, relative to the wild-type strain. These data indicate that the gonococcal NHBA contributes to several aspects of the colonization and survival of N. gonorrhoeae and may be a target for new antimicrobial or vaccines., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Published
2020
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43. Transcriptome RNA Sequencing Data Set of Gene Expression in Moraxella catarrhalis On- and Off-Phase Variants of the Type III DNA Methyltransferase ModM3.

Author

Blakeway LV, Tan A, Peak IR, Atack JM, and Seib KL

Abstract

Moraxella catarrhalis is a leading bacterial cause of otitis media and exacerbations of chronic obstructive pulmonary disease. Here, we announce a transcriptome RNA sequencing data set detailing global gene expression in two M. catarrhalis CCRI-195ME variants with expression of the DNA methyltransferase ModM3 phase varied either on or off., (Copyright © 2020 Blakeway et al.)

Published
2020
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44. Proteome of a Moraxella catarrhalis Strain under Iron-Restricted Conditions.

Author

Blakeway LV, Tan A, Peak IR, Atack JM, and Seib KL

Abstract

Moraxella catarrhalis is a leading cause of otitis media and exacerbations of chronic obstructive pulmonary disease; however, its response to iron starvation during infection is not completely understood. Here, we announce a sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) data set describing the differential expression of the M. catarrhalis CCRI-195ME proteome under iron-restricted versus iron-replete conditions., (Copyright © 2020 Blakeway et al.)

Published
2020
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45. The Moraxella catarrhalis phase-variable DNA methyltransferase ModM3 is an epigenetic regulator that affects bacterial survival in an in vivo model of otitis media.

Author

Blakeway LV, Tan A, Jurcisek JA, Bakaletz LO, Atack JM, Peak IR, and Seib KL

Subjects
Animals, Bacterial Proteins genetics, Chinchilla, Disease Models, Animal, Epigenesis, Genetic, Female, Gene Expression, Gene Expression Regulation, Bacterial, Gene Knockout Techniques, Humans, Male, Moraxellaceae Infections microbiology, Microbial Viability genetics, Moraxella catarrhalis enzymology, Moraxella catarrhalis genetics, Otitis Media microbiology, Site-Specific DNA-Methyltransferase (Adenine-Specific) genetics
Abstract

Background: Moraxella catarrhalis is a leading cause of otitis media (OM) and chronic obstructive pulmonary disease (COPD). M. catarrhalis contains a Type III DNA adenine methyltransferase (ModM) that is phase-variably expressed (i.e., its expression is subject to random, reversible ON/OFF switching). ModM has six target recognition domain alleles (modM1-6), and we have previously shown that modM2 is the predominant allele, while modM3 is associated with OM. Phase-variable DNA methyltransferases mediate epigenetic regulation and modulate pathogenesis in several bacteria. ModM2 of M. catarrhalis regulates the expression of a phasevarion containing genes important for colonization and infection. Here we describe the phase-variable expression of modM3, the ModM3 methylation site and the suite of genes regulated within the ModM3 phasevarion., Results: Phase-variable expression of modM3, mediated by variation in length of a 5'-(CAAC) n -3' tetranucleotide repeat tract in the open reading frame was demonstrated in M. catarrhalis strain CCRI-195ME with GeneScan fragment length analysis and western immunoblot. We determined that ModM3 is an active N6-adenine methyltransferase that methylates the sequence 5'-AC m6 ATC-3'. Methylation was detected at all 4446 5'-ACATC-3' sites in the genome when ModM3 is expressed. RNASeq analysis identified 31 genes that are differentially expressed between modM3 ON and OFF variants, including five genes that are involved in the response to oxidative and nitrosative stress, with potential roles in biofilm formation and survival in anaerobic environments. An in vivo chinchilla (Chinchilla lanigera) model of otitis media demonstrated that transbullar challenge with the modM3 OFF variant resulted in an increased middle ear bacterial load compared to a modM3 ON variant. In addition, co-infection experiments with NTHi and M. catarrhalis modM3 ON or modM3 OFF variants revealed that phase variation of modM3 altered survival of NTHi in the middle ear during early and late stage infection., Conclusions: Phase variation of ModM3 epigenetically regulates the expression of a phasevarion containing multiple genes that are potentially important in the progression of otitis media.

Published
2019
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46. Non-typeable Haemophilus influenzae isolates from patients with chronic obstructive pulmonary disease contain new phase-variable modA methyltransferase alleles controlling phasevarions.

Author

Atack JM, Murphy TF, Pettigrew MM, Seib KL, and Jennings MP

Subjects
DNA Methylation, Gene Expression Regulation, Bacterial, Genotype, Haemophilus influenzae classification, Haemophilus influenzae isolation & purification, Humans, Sequence Analysis, DNA, Alleles, Haemophilus Infections microbiology, Haemophilus influenzae genetics, Periplasmic Binding Proteins genetics, Pulmonary Disease, Chronic Obstructive complications
Abstract

Phasevarions (phase-variable regulons) are emerging as an important area of bacterial gene regulation. Many bacterial pathogens contain phasevarions, with gene expression controlled by the phase-variable expression of DNA methyltransferases via epigenetic mechanisms. Non-typeable Haemophilus influenzae (NTHi) contains the phase-variable methyltransferase modA, of which multiple allelic variants exist (modA1-21). We have previously demonstrated 5 of 21 these modA alleles are overrepresented in NTHi strains isolated from children with middle ear infections. In this study we investigated the modA allele distribution in NTHi strains isolated from patients with chronic obstructive pulmonary disease, COPD. We demonstrate that the distribution of modA alleles in a large panel of COPD isolates is different to the distribution seen in middle ear infections, suggesting different modA alleles may provide distinct advantages in the differing niches of the middle ear and COPD airways. We also identified two new phase-variable modA alleles - modA15 and modA18 - and demonstrate that these alleles methylate distinct DNA sequences and control unique phasevarions. The modA15 and modA18 alleles have only been observed in COPD isolates, indicating that these two alleles may be markers for isolates likely to cause exacerbations of COPD.

Published
2019
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47. The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence.

Author

Seib KL, Haag AF, Oriente F, Fantappiè L, Borghi S, Semchenko EA, Schulz BL, Ferlicca F, Taddei AR, Giuliani MM, Pizza M, and Delany I

Subjects
Animals, Antigens, Bacterial genetics, Bacterial Outer Membrane physiology, Meningococcal Infections mortality, Neisseria meningitidis, Serogroup B genetics, Neisseria meningitidis, Serogroup B pathogenicity, Operon, Periplasmic Proteins physiology, Rats, Rats, Wistar, Regulon, Virulence, Zinc pharmacology, Antigens, Bacterial physiology, Bacterial Outer Membrane chemistry, Meningococcal Vaccines genetics
Abstract

GNA2091 is one of the components of the 4-component meningococcal serogroup B vaccine (4CMenB) vaccine and is highly conserved in all meningococcal strains. However, its functional role has not been fully characterized. Here we show that nmb2091 is part of an operon and is cotranscribed with the nmb2089, nmb2090 , and nmb2092 adjacent genes, and a similar but reduced operon arrangement is conserved in many other gram-negative bacteria. Deletion of the nmb2091 gene causes an aggregative phenotype with a mild defect in cell separation; differences in the outer membrane composition and phospholipid profile, in particular in the phosphoethanolamine levels; an increased level of outer membrane vesicles; and deregulation of the zinc-responsive genes such as znuD . Finally, the ∆2091 strain is attenuated with respect to the wild-type strain in competitive index experiments in the infant rat model of meningococcal infection. Altogether these data suggest that GNA2091 plays important roles in outer membrane architecture, biogenesis, homeostasis, and in meningococcal survival in vivo , and a model for its role is discussed. These findings highlight the importance of GNA2091 as a vaccine component.-Seib, K. L., Haag, A. F., Oriente, F., Fantappiè, L., Borghi, S., Semchenko, E. A., Schulz, B. L., Ferlicca, F., Taddei, A. R., Giuliani, M. M., Pizza, M., Delany, I. The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence.

Published
2019
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48. The Serogroup B Meningococcal Vaccine Bexsero Elicits Antibodies to Neisseria gonorrhoeae.

Author

Semchenko EA, Tan A, Borrow R, and Seib KL

Subjects
Amino Acid Sequence, Animals, Antigens, Bacterial chemistry, Antigens, Bacterial genetics, Antigens, Bacterial immunology, Bacterial Outer Membrane Proteins chemistry, Bacterial Outer Membrane Proteins genetics, Bacterial Outer Membrane Proteins immunology, Bacterial Proteins chemistry, Bacterial Proteins genetics, Bacterial Proteins immunology, Carrier Proteins chemistry, Carrier Proteins genetics, Carrier Proteins immunology, Conserved Sequence, Gonorrhea microbiology, Host-Pathogen Interactions immunology, Humans, Meningitis, Meningococcal classification, Meningitis, Meningococcal genetics, Neisseria gonorrhoeae genetics, Phylogeny, Rabbits, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins immunology, Vaccination, Cross Reactions immunology, Gonorrhea immunology, Meningitis, Meningococcal immunology, Meningococcal Vaccines immunology, Neisseria gonorrhoeae immunology, Serogroup
Abstract

Background: Neisseria gonorrhoeae and Neisseria meningitidis are closely-related bacteria that cause a significant global burden of disease. Control of gonorrhoea is becoming increasingly difficult, due to widespread antibiotic resistance. While vaccines are routinely used for N. meningitidis, no vaccine is available for N. gonorrhoeae. Recently, the outer membrane vesicle (OMV) meningococcal B vaccine, MeNZB, was reported to be associated with reduced rates of gonorrhoea following a mass vaccination campaign in New Zealand. To probe the basis for this protection, we assessed the cross-reactivity to N. gonorrhoeae of serum raised to the meningococcal vaccine Bexsero, which contains the MeNZB OMV component plus 3 recombinant antigens (Neisseria adhesin A, factor H binding protein [fHbp]-GNA2091, and Neisserial heparin binding antigen [NHBA]-GNA1030)., Methods: A bioinformatic analysis was performed to assess the similarity of MeNZB OMV and Bexsero antigens to gonococcal proteins. Rabbits were immunized with the OMV component or the 3 recombinant antigens of Bexsero, and Western blots and enzyme-linked immunosorbent assays were used to assess the generation of antibodies recognizing N. gonorrhoeae. Serum from humans immunized with Bexsero was investigated to assess the nature of the anti-gonococcal response., Results: There is a high level of sequence identity between MeNZB OMV and Bexsero OMV antigens, and between the antigens and gonococcal proteins. NHBA is the only Bexsero recombinant antigen that is conserved and surfaced exposed in N. gonorrhoeae. Bexsero induces antibodies in humans that recognize gonococcal proteins., Conclusions: The anti-gonococcal antibodies induced by MeNZB-like OMV proteins could explain the previously-seen decrease in gonorrhoea following MeNZB vaccination. The high level of human anti-gonococcal NHBA antibodies generated by Bexsero vaccination may provide additional cross-protection against gonorrhoea., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Published
2019
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49. Phasevarions of bacterial pathogens - phase-variable epigenetic regulators evolving from restriction-modification systems.

Author

Phillips ZN, Husna AU, Jennings MP, Seib KL, and Atack JM

Subjects
Bacterial Infections drug therapy, Bacterial Infections transmission, DNA Methylation, DNA Modification Methylases, DNA Restriction-Modification Enzymes metabolism, Drug Resistance genetics, Evolution, Molecular, Gene Expression Regulation, Bacterial, Haemophilus influenzae genetics, Haemophilus influenzae pathogenicity, Mycoplasma genetics, Mycoplasma pathogenicity, Neisseria genetics, Neisseria pathogenicity, Neisseria meningitidis genetics, Neisseria meningitidis pathogenicity, Bacteria immunology, Bacteria metabolism, Bacteria pathogenicity, DNA Restriction-Modification Enzymes genetics, Epigenesis, Genetic, Methyltransferases genetics, Methyltransferases metabolism
Abstract

Phase-variable DNA methyltransferases control the expression of multiple genes via epigenetic mechanisms in a wide variety of bacterial species. These systems are called phasevarions, for phase-variable regulons. Phasevarions regulate genes involved in pathogenesis, host adaptation and antibiotic resistance. Many human-adapted bacterial pathogens contain phasevarions. These include leading causes of morbidity and mortality worldwide, such as non-typeable Haemophilus influenzae , Streptococcus pneumoniae and Neisseria spp. Phase-variable methyltransferases and phasevarions have also been discovered in environmental organisms and veterinary pathogens. The existence of many different examples suggests that phasevarions have evolved multiple times as a contingency strategy in the bacterial domain, controlling phenotypes that are important in adapting to environmental change. Many of the organisms that contain phasevarions have existing or emerging drug resistance. Vaccines may therefore represent the best and most cost-effective tool to prevent disease caused by these organisms. However, many phasevarions also control the expression of current and putative vaccine candidates; variable expression of antigens could lead to immune evasion, meaning that vaccines designed using these targets become ineffective. It is therefore essential to characterize phasevarions in order to determine an organism's stably expressed antigenic repertoire, and rationally design broadly effective vaccines.

Published
2019
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50. Phase-variable bacterial loci: how bacteria gamble to maximise fitness in changing environments.

Author

Phillips ZN, Tram G, Seib KL, and Atack JM

Subjects
Bacteria genetics, DNA Modification Methylases metabolism, Epigenesis, Genetic, Gene Expression Regulation, Bacterial, Genes, Bacterial, Bacterial Physiological Phenomena
Abstract

Phase-variation of genes is defined as the rapid and reversible switching of expression - either ON-OFF switching or the expression of multiple allelic variants. Switching of expression can be achieved by a number of different mechanisms. Phase-variable genes typically encode bacterial surface structures, such as adhesins, pili, and lipooligosaccharide, and provide an extra contingency strategy in small-genome pathogens that may lack the plethora of 'sense-and-respond' gene regulation systems found in other organisms. Many bacterial pathogens also encode phase-variable DNA methyltransferases that control the expression of multiple genes in systems called phasevarions (phase-variable regulons). The presence of phase-variable genes allows a population of bacteria to generate a number of phenotypic variants, some of which may be better suited to either colonising certain host niches, surviving a particular environmental condition and/or evading an immune response. The presence of phase-variable genes complicates the determination of an organism's stably expressed antigenic repertoire; many phase-variable genes are highly immunogenic, and so would be ideal vaccine candidates, but unstable expression due to phase-variation may allow vaccine escape. This review will summarise our current understanding of phase-variable genes that switch expression by a variety of mechanisms, and describe their role in disease and pathobiology., (© 2019 The Author(s).)

Published
2019
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