Mycoplasma genitalium

Mycoplasma genitalium
Gene map of Mycoplasma genitalium. Circularly arranged coloured bands are the genes (525 in number) in their position in the DNA. The genome has 580,070 nucleotide base pairs (580 kb).
Scientific classification
Kingdom: Bacteria
Phylum: Tenericutes
Class: Mollicutes
Order: Mycoplasmatales
Family: Mycoplasmataceae
Genus: Mycoplasma
Species: M. genitalium
Binomial name
Mycoplasma genitalium
Tully et al., 1983[1]

Mycoplasma genitalium (MG,[2] commonly known as Mgen), is a sexually transmitted, small and pathogenic bacterium that lives on the ciliated epithelial cells of the urinary and genital tracts in humans.[3] Mgen is a recognised sexually transmitted infection,[4] with increasing prevalence[5][6] worldwide resistance to multiple antibiotics,[5] including azithromycin which until recently was the most reliable line of antimicrobial defence. The causative agent was first isolated from meatal swabs (urogenital tract) of humans in 1981,[7] and was eventually identified as a new species of Mycoplasma in 1983.[1] It can cause significant morbidity in men and women. It is also a recognised risk factor for HIV transmission[8] with higher occurrences in homosexual men and those previously treated with the azithromycin antibiotics.[5][9]

Specifically, it causes urethritis in both men and women, and also cervicitis and pelvic inflammation in women.[10] It presents clinically similar symptoms to that of Chlamydia trachomatis infection and has shown higher incidence rates, compared to both Chlamydia trachomatis and Neisseria gonorrhoeae infections in some populations.[11] Its complete genome sequence was published in 1995 (size 0.58 Mbp, with 475 genes).[12] It was regarded as a cellular unit with the smallest genome size (in Mbp) until 2003 when a new species of Archaea, namely Nanoarchaeum equitans, was sequenced (0.49 Mbp, with 540 genes). However, Mgen still has the smallest genome of any known (naturally occurring) self-replicating organism and thus is often the organism of choice in minimal-genome research.

The synthetic genome of Mgen named Mycoplasma genitalium JCVI-1.0 (after the research centre, J. Craig Venter Institute, where it was synthesised) was produced in 2008, becoming the first organism with a synthetic genome. In 2014, a protein was described called Protein M from M. genitalium.[13]

Signs and symptoms

Infection with Mgen produces a combination of clinical symptoms, but can be asymptomatic. It causes inflammation in the urethra (urethritis) both in men and women, which is associated with mucopurulent discharge in the urinary tract, and burning while urinating. In women, it causes cervicitis and pelvic inflammatory diseases (PID), including endometritis and salpingitis.[10] Women may also experience bleeding after sex and it is also linked with tubal factor infertility.[14][15][3] For men, the most common signs are painful urination or a watery discharge from the penis.[16] Polymerase chain reaction analyses indicated that it is a cause of acute non-gonococcal urethritis (NGU) and probably chronic NGU. It is strongly associated with persistent and recurring non-gonococcal urethritis (NGU) responsible for 15 percent to 20 percent of symptomatic NGU cases in men.[17] Unlike other Mycoplasma, the infection is not associated with bacterial vaginosis.[18] It is highly associated with the intensity of HIV infection.[19] Some scientists are doing research to see if Mgen could play a role in the development of prostate and ovarian cancers and lymphomas in some individuals. These studies have yet to find conclusive evidence to suggest a link.[20]

Genome

The genome of M. genitalium consists of 525 genes[21] in one circular DNA of 580,070 base pairs.[12] Scott N. Peterson and his team at the University of North Carolina at Chapel Hill reported the first genetic map using pulsed-field gel electrophoresis in 1991.[22] They performed an initial study of the genome using random sequencing in 1993, by which they found 100,993 nucleotides and 390 protein-coding genes.[23] Collaborating with researchers at the Institute for Genomic Research, which included Craig Venter, they made the complete genome sequence in 1995 using shotgun sequencing.[12] Only 470 predicted coding regions (out of 482 protein encoding genes) were identified, including genes required for DNA replication, transcription and translation, DNA repair, cellular transport, and energy metabolism. It was the second complete bacterial genome ever sequenced, after Haemophilus influenzae. In 2006, the team at the J. Craig Venter Institute reported that only 382 genes are essential for biological functions.[24] The small genome of M. genitalium made it the organism of choice in The Minimal Genome Project, a study to find the smallest set of genetic material necessary to sustain life.[25]

Pathophysiology

There is a consistent association of M. genitalium infection and female reproductive tract syndromes. M. genitalium infection was significantly associated with increased risk of preterm birth, spontaneous abortion, cervicitis, and pelvic inflammatory disease. Infertility risk is also strongly associated with infection with M. genitalium, although evidence suggests it is not associated with male infertility.[26] When M. genitalium is a co-infectious agent risk associations are stronger and statistically significant.[27] M. genitalium is strongly associated with HIV-1.[3]

Treatment

The U.S. Centers for Disease Control and Prevention has one specific recommended regimen with azithromycin and another specific recommended regimen with doxycycline.[28] As alternative regimens, the agency has specific regimens each with erythromycin or erythromycin ethylsuccinate or ofloxacin or levofloxacin.[28]

Treatment of Mycoplasma genitalium infections is becoming increasingly difficult due to rapidly growing antimicrobial resistance.[29] Diagnosis and treatment is further hampered by the fact that Mycoplasma genitalium infections are not routinely tested.[30] Studies have demonstrated that a 5-day course of azithromycin has a superior cure rate compared to a single, larger dose. Further, a single dose of azithromycin can lead to the bacteria becoming resistant to azithromycin.[31] Among Swedish patients, doxycycline was shown to be relatively ineffective (with a cure rate of 48% for women and 38% for men); and treatment with a single dose of azithromycin is not prescribed due to it inducing antimicrobial resistance. The five-day treatment with azithromycin showed no development of antimicrobial resistance.[32] Based on these findings, UK doctors are moving to the 5-day azithromycin regimen. Doxycycline is also still used, and moxifloxacin is used as a second-line treatment in case doxycyline and azithromycin are not able to eradicate the infection.[33][34] In patients where doxycycline, azithromycin and moxifloxacin all failed, pristinamycin has been shown to still be able to eradicate the infection.[33]

Clinical diagnostics

Recent research shows that prevalence of Mgen is currently higher than other commonly occurring STIs (Sexually Transmitted Infections).[35] Mgen is a fastidious organism with prolonged growth durations. This makes detection of the pathogen in clinical specimens and subsequent isolation, extremely difficult.[36] Lacking a cell wall, mycoplasma remains unaffected by commonly used antibiotics.[37] The absence of specific serological assays leaves nucleic acid amplification tests (NAAT) as the only viable option for detection of Mgen DNA or RNA.[38] However, samples with positive NAAT for the pathogen should be tested for macrolide resistance mutations, which are strongly correlated to azithromycin and doxycycline treatment failures, owing to rapid rates of mutation of the pathogen.[5] Mutations in the 23S rRNA gene of Mgen have been linked with clinical treatment failure and high level in vitro macrolide resistance.[39] Macrolide resistance mediating mutations have been observed in 20-50% of cases in the UK, Denmark, Sweden, Australia, and Japan.[5] Resistance is also developing towards the second-line antimicrobials like fluoroquinolone.[40]

According to the European guidelines, the indication for commencement of diagnosis for Mgen infection are:[38]

  1. Detection of nucleic acid (DNA and/or RNA) specific for Mgen in a clinical specimen
  2. Current partners of individuals who tested positive for Mgen should be treated with the same antimicrobial as the index patient
  3. If current partner does not attend for evaluation and testing, treatment with the same regimen as given to the index patient should be offered on epidemiological grounds
  4. On epidemiological grounds for sexual contacts in the previous 3 months; ideally, specimens for a Mgen NAAT should be collected before treatment and treatment should not be given before the result are available

Screening for Mgen with a combination of detection and macrolide resistance mutations will provide the adequate information required to develop personalised antimicrobial treatments, in order to optimise patient management and control the spread of antimicrobial resistance (AMR).[38][41]

Detection of resistance

Owing to the widespread macrolide resistance, samples that are positive for Mgen should ideally be followed up with an assay capable of detecting mutations that mediate antimicrobial resistance. The European Guideline on Mgen infections, in 2016,[42] recommended complementing the molecular detection of Mgen with an assay capable of detecting macrolide resistance-associated mutations.

History

Mycoplasma genitalium was originally isolated in 1980 from urethral specimens of two male patients suffering from non-gonococcal urethritis in the genitourinary medicine (GUM) clinic at St Mary's Hospital, Paddington, London.[43][44] It was reported in 1981 by a team led by Joseph G. Tully.[7] Under electron microscopy, it appears as a flask-shaped cell with a narrow terminal portion that is crucial for its attachment to the host cell surfaces.[45] The bacterial cell is slightly elongated somewhat like a vase, and measures 0.6-0.7 μm in length, 0.3-0.4 μm at the broadest region, and 0.06-0.08 μm at the tip. The base is broad while the tip is stretched into a narrow neck, which terminates with a cap. The terminal region has a specialised region called nap, which is absent in other Mycoplasma. Serological tests indicated that the bacterium was not related to known species of Mycoplasma. The comparison of genome sequences with other urinogenital bacteria, such as M. hominis and Ureaplasma parvum, revealed that M. genitalium is significantly different, especially in the energy-generating pathways, although it shared a core genome of ~250 protein-encoding genes.[46]

Synthetic life

On 6 October 2007, Craig Venter announced that a team of scientists led by Nobel laureate Hamilton Smith at the J. Craig Venter Institute had successfully constructed a synthetic DNA using which they planned to make the first synthetic genome. Reporting in The Guardian, Venter said that they have stitched together a DNA strand of 381 genes long and contained 580,000 base pairs, based on the genome of M. genitalium.[47] On 24 January 2008, they announced the successful creation of a synthetic bacterium, which they named Mycoplasma genitalium JCVI-1.0 (the name of the strain indicating J. Craig Venter Institute with its specimen number).[48] They synthesised and assembled the complete 582,970-base pair genome of the bacterium. The final stages of synthesis involved cloning the DNA into the bacterium E. coli for nucleotide production and sequencing. This produced large fragments of approximately 144,000 base pairs or 1/4th of the whole genome. Finally, the products were cloned inside the yeast Saccharomyces cerevisiae to synthesize the 580,000 base pairs.[49][50] The molecular size of the synthetic bacterial genome is 360,110 kilodaltons (kDa). Printed in 10-point font, the letters of the genome cover 147 pages.[51]

On 20 July 2012, Stanford University and the J. Craig Venter Institute announced successful simulation of the complete life cycle of a Mycoplasma genitalium cell, in the journal Cell.[52] The entire organism is modeled in terms of its molecular components, integrating all cellular processes into a single model. Using object oriented programming to model the interactions of 28 categories of molecules, including DNA, RNA, proteins, and metabolites, and running on a 128-core Linux cluster, the simulation takes 10 hours for a single M. genitalium cell to divide once — about the same time the actual cell takes — and generates half a gigabyte of data.[53]

Research

The discovery of Protein M, a new protein from M. genitalium, was announced in February 2014.[13] The protein was identified during investigations on the origin of multiple myeloma, a B-cell hematologic neoplasm. To understand the long-term Mycoplasma infection, it was found that antibodies from multiple myeloma patients' blood were recognised by M. genitalium. The antibody reactivity was due to a protein never known before, and is chemically responsive to all types of human and nonhuman antibodies available. The protein is about 50 kDa in size, and composed of 556 amino acids.[54]

Future considerations

Future research must focus on the development of novel antimicrobials and treatment algorithms that emphasize on dual antimicrobial therapy and AMR testing in treatment protocols. Importantly, most patients with MG are treated syndromically and this treatment is even more compromised by the emerging resistances to several antimicrobials. This also stresses the importance of evidence-based knowledge regarding the activity of novel antimicrobials against several pathogens that cause STIs. The rapid development of AMR in Mgen suggests that single-dose antimicrobial monotherapy may be inappropriate even for uncomplicated STIs. For Mgen, antimicrobial combination therapy and AMR testing, in conjunction with the development and evaluation of new classes of antimicrobials, are of utmost importance. Some of the novel antimicrobials, particularly the fluoroketolide solithromycin, might at least temporarily replace azithromycin in the treatment of Mgen. Ultimately, the only sustainable solution to control these infections might be the development of vaccines, a task that remains to be incredibly difficult with most pathogens of commonly occurring STIs, being unculturable.

See also

References

  1. 1 2 Tully, J. G.; Taylor-Robinson, D.; Rose, D. L.; Cole, R. M.; Bove, J. M. (1983). "Mycoplasma genitalium, a New Species from the Human Urogenital Tract". International Journal of Systematic Bacteriology. 33 (2): 387–396. doi:10.1099/00207713-33-2-387.
  2. ↑ Roberts, Michelle (11 July 2018). "Emerging sex disease 'could be superbug'" – via www.bbc.co.uk.
  3. 1 2 3 Weinstein, Scott A.; Stiles, Bradley G. (2012-01-01). "Recent perspectives in the diagnosis and evidence-based treatment of Mycoplasma genitalium". Expert Review of Anti-infective Therapy. 10 (4): 487–499. doi:10.1586/eri.12.20. ISSN 1478-7210. PMID 22512757.
  4. ↑ Workowski K. A., Bolan G. A. "Sexually transmitted diseases treatment guidelines, 2015". MMWR Recomm. Rep. 64: 1–137.
  5. 1 2 3 4 5 Jensen JS, Bradshaw C (2015). "Management of Mycoplasma genitalium infections—Can we hit a moving target". BMC Infect Dis. 15: 343. doi:10.1186/s12879-015-1041-6.
  6. ↑ Manhart LE, Holmes KK, Hughes JP; et al. (2007). "Mycoplasma genitalium among young adults in the United States: An emerging sexually transmitted infection". Am J Public Health. 97: 1118–1125. doi:10.2105/ajph.2005.074062. PMC 1874220.
  7. 1 2 Tully, Joseph G.; Cole, Roger M.; Taylor-Robinson, David; Rose, David L. (1981). "A newly discovered Mycoplasma in the human urinogenital tract". The Lancet. 317 (8233): 1288–1291. doi:10.1016/S0140-6736(81)92461-2.
  8. ↑ World Health Organization (WHO). Laboratory diagnosis of sexually transmitted infections, including human immunodeficiency virus. Switzerland: World Health Organization 2013
  9. ↑ Barberá M, et al. Mycoplasma genitalium macrolide and fluoroquino-lone resistance: prevalence and risk factors among a 2013–2014 cohort of patients in Barcelona Sexually Transmitted Diseases: Spain, 2017; In Press
  10. 1 2 Wiesenfeld, Harold C.; Manhart, Lisa E. (2017-07-15). "Mycoplasma genitalium in Women: Current Knowledge and Research Priorities for This Recently Emerged Pathogen". The Journal of Infectious Diseases. 216 (suppl_2): S389–S395. doi:10.1093/infdis/jix198. ISSN 1537-6613. PMID 28838078.
  11. ↑ Miller WC, Ford CA, Morris M; et al. (2004). "Prevalence of chlamydial and gonococcal infections among young adults in the United States". JAMA. 291: 2229–2236. doi:10.1001/jama.291.18.2229.
  12. 1 2 3 Fraser, C. M.; Gocayne, J. D.; White, O.; Adams, M. D.; Clayton, R. A.; Fleischmann, R. D.; Bult, C. J.; Kerlavage, A. R.; Sutton, G.; Kelley, J. M.; Fritchman, J. L.; Weidman, J. F.; Small, K. V.; Sandusky, M.; Fuhrmann, J.; Nguyen, D.; Utterback, T. R.; Saudek, D. M.; Phillips, C. A.; Merrick, J. M.; Tomb, J.-F.; Dougherty, B. A.; Bott, K. F.; Hu, P.-C.; Lucier, T. S. (1995). "The Minimal Gene Complement of Mycoplasma genitalium". Science. 270 (5235): 397–404. doi:10.1126/science.270.5235.397. PMID 7569993.
  13. 1 2 "The Ultimate Decoy: Scripps Research Institute Scientists Find Protein that Helps Bacteria Misdirect Immune System". The Scripps Research Institute (TSRI). Retrieved 9 August 2014.
  14. ↑ Manhart, Lisa E. (2013). "Mycoplasma genitalium: An emergent sexually transmitted disease?". Infectious Disease Clinics of North America. 27 (4): 779–792. doi:10.1016/j.idc.2013.08.003. PMID 24275270.
  15. ↑ Williams gynecology. Schorge, John O.,, Hoffman, Barbara L.,, Bradshaw, Karen D.,, Halvorson, Lisa M.,, Schaffer, Joseph I.,, Corton, Marlene M., (Third ed.). New York. p. 65. ISBN 9780071849081. OCLC 944920918.
  16. ↑ Health.com, Kristine Thomason,. "What you should know about this 'new' STD - CNN".
  17. ↑ Lis R, Rowhani-Rahbar A, Manhart LE. Mycoplasma genitalium infection and female reproductive tract disease: a meta-analysis. Clin Infect Dis. 2015;61(3):418-426
  18. ↑ Taylor-Robinson, D. (2002). "Mycoplasma genitalium - an up-date". International Journal of STD & AIDS. 13 (3): 145–151. doi:10.1258/0956462021924776. PMID 11860689.
  19. ↑ Weinstein, Scott A; Stiles, Bradley G (2013). "Recent perspectives in the diagnosis and evidence-based treatment of". Expert Review of Anti-infective Therapy. 10 (4): 487–499. doi:10.1586/eri.12.20. PMID 22512757.
  20. ↑ Zarei, Omid; Rezania, Simin; Mousavi, Atefeh (2013). "Mycoplasma genitalium and Cancer: A Brief Review". Asian Pacific Journal of Cancer Prevention. 14 (6): 3425–3428. doi:10.7314/APJCP.2013.14.6.3425. ISSN 1513-7368.
  21. ↑ "Birth of the digital bacteria". New Scientist. 215 (2875): 19. 2012-07-28. doi:10.1016/s0262-4079(12)61932-0.
  22. ↑ Peterson, Scott N.; Schramm, Nara; Hu, Ping-chuan; Bott, Kenneth F.; Hutchison, Clyde A. (1991). "A random sequencing approach for placing markers on the physical map of". Nucleic Acids Research. 19 (21): 6027–6031. doi:10.1093/nar/19.21.6027. PMC 329062. PMID 1945886.
  23. ↑ Peterson, SN; Hu, PC; Bott, KF; Hutchison CA, 3rd (1993). "A survey of the Mycoplasma genitalium genome by using random sequencing". Journal of Bacteriology. 175 (24): 7918–7930. doi:10.1128/jb.175.24.7918-7930.1993. PMC 206970. PMID 8253680.
  24. ↑ Glass, J. I.; Assad-Garcia, N.; Alperovich, N.; Yooseph, S.; Lewis, M. R.; Maruf, M.; Hutchison, C. A.; Smith, H. O.; Venter, J. C. (2006). "Essential genes of a minimal bacterium". Proceedings of the National Academy of Sciences. 103 (2): 425–430. doi:10.1073/pnas.0510013103. PMC 1324956. PMID 16407165.
  25. ↑ Razin, S (1997). "The minimal cellular genome of mycoplasma". Indian Journal of Biochemistry & Biophysics. 34 (1–2): 124–30. PMID 9343940.
  26. ↑ C. Huang; H.L. Zhu; K.R. Xu; S.Y. Wang; L.Q. Fan; W.B. Zhu (September 2015). "Mycoplasma and ureaplasma infection and male infertility: a systematic review and meta-analysis". Andrology. 3 (5): 809–816. doi:10.1111/andr.12078. PMID 26311339.
  27. ↑ Lis, R.; Rowhani-Rahbar, A.; Manhart, L. E. (2015). "Mycoplasma genitalium Infection and Female Reproductive Tract Disease: A Meta-Analysis". Clinical Infectious Diseases. 61: 418–426. doi:10.1093/cid/civ312. ISSN 1058-4838. PMID 25900174.
  28. 1 2 "CDC - Diseases Characterized by Urethritis and Cervicitis - 2010 STD Treatment Guidelines". www.cdc.gov.
  29. ↑ "Yaws" (PDF). World Health Organization. World Health Organization. 2013. Retrieved 8 December 2017.
  30. ↑ Suneta, Soni; Parkhouse, Andy; Gillian, Dean (24 April 2017). "Macrolide and quinolone-resistant Mycoplasma genitalium in a man with persistent urethritis: the tip of the British iceberg?". Sexually Transmitted Infections: sextrans-2016–053077. doi:10.1136/sextrans-2016-053077.
  31. ↑ Yew, H. S.; Anderson, T.; Coughlan, E.; Werno, A. (2011). "Induced macrolide resistance in Mycoplasma genitalium isolates from patients with recurrent nongonococcal urethritis". Journal of Clinical Microbiology. 49 (4): 1695–1696. doi:10.1128/JCM.02475-10. PMC 3122813. PMID 21346049.
  32. ↑ Anagrius, Carin; Loré, Britta; Jensen, Jørgen Skov; Coenye, Tom (2013). "Treatment of Mycoplasma genitalium. Observations from a Swedish STD Clinic". PLoS ONE. 8 (4): e61481. doi:10.1371/journal.pone.0061481. PMC 3620223. PMID 23593483.
  33. 1 2 Unemo, Magnus; Jensen, Jorgen S. (10 January 2017). "Antimicrobial-resistant sexually transmitted infections: gonorrhoea and Mycoplasma genitalium". Nature Reviews Urology. 14: 139–125. doi:10.1038/nrurol.2016.268.
  34. ↑ "Mycoplasma Genitalium Treatment Choices". www.theonlineclinic.co.uk.
  35. ↑ Taylor-Robinson D, Jensen JS. Mycoplasma genitalium: from chrysalis to multicolored butterfly. Clin Microbiol Rev. 2011;24(3):498–514
  36. ↑ Jensen, J. S., Hansen, H. T. & Lind, K. Isolation of Mycoplasma genitalium strains from the male urethra. J. Clin. Microbiol. 34, 286–291 (1996)
  37. ↑ Centers for Disease Control and Prevention, 2015 Sexually Transmitted Diseases Treatment Guidelines.
  38. 1 2 3 Jensen, M Cusini, M Gomberg. 2016 European guideline on Mycoplasma genitalium infections
  39. ↑ Jensen JS.; et al. (2008). "Azithromycin Treatment Failure in Mycoplasma genitalium–Positive Patients with Nongonococcal Urethritis Is Associated with Induced Macrolide Resistance". Clin. Infect. Dis. 47 (12): 1546–1553. doi:10.1086/593188.
  40. ↑ Unemo, M. & Jensen, J.S. ‘Antimicrobial-resistant sexually transmitted infections: gonorrhoea and Mycoplasma genitalium’. 2016. Nat. Rev. Urol..268. Published online 10 Jan 2017. doi:10.1038/nrurol
  41. ↑ Tabrizi SN et al. Multiplex Assay for Simultaneous Detection of Mycoplasma genitalium and Macrolide Resistance Using PlexZyme and PlexPrime Technology. PLoS ONE. 2016. 11(6): e0156740. doi:10.1371/journal.pone.0156740
  42. ↑ Jensen JS, Cusini M, Gomberg M, Moi H (2016). "2016 European guideline on Mycoplasma genitalium infections". J Eur Acad Dermatol Venereol. 30: 1650–1656. doi:10.1111/jdv.13849. PMID 27505296.
  43. ↑ Taylor-Robinson, D.; Horner, P. J. (2001). "The role of Mycoplasma genitalium in non-gonococcal urethritis". Sexually Transmitted Infections. 77 (4): 229–231. doi:10.1136/sti.77.4.229. PMC 1744340. PMID 11463919.
  44. ↑ Daley, G.; Russell, D.; Tabrizi, S.; McBride, J. (2014). "Mycoplasma genitalium: a review". International Journal of STD & AIDS. 25 (7): 475–487. doi:10.1177/0956462413515196. PMID 24517928.
  45. ↑ Taylor-Robinson, D (1995). "The Harrison Lecture. The history and role of Mycoplasma genitalium in sexually transmitted diseases". Genitourinary Medicine. 71 (1): 1–8. doi:10.1136/sti.71.1.1. PMC 1195360. PMID 7750946.
  46. ↑ Blanchard, Alain; Bébéar, Cécile (2011). "The evolution of Mycoplasma genitalium". Annals of the New York Academy of Sciences. 1230 (1): E61–E64. doi:10.1111/j.1749-6632.2011.06418.x. PMID 22417108.
  47. ↑ Pilkington, Ed (6 October 2007). "I am creating artificial life, declares US gene pioneer". The Guardian. Guardian News and Media Limited. Retrieved 9 August 2014.
  48. ↑ Kowalski, Heather. "Venter Institute Scientists Create First Synthetic Bacterial Genome". J. Craig Venter Institute. Retrieved 9 August 2014.
  49. ↑ Gibson, D. G.; Benders, G. A.; Andrews-Pfannkoch, C.; Denisova, E. A.; Baden-Tillson, H.; Zaveri, J.; Stockwell, T. B.; Brownley, A.; Thomas, D. W.; Algire, M. A.; Merryman, C.; Young, L.; Noskov, V. N.; Glass, J. I.; Venter, J. C.; Hutchison, C. A.; Smith, H. O. (2008). "Complete Chemical Synthesis, Assembly, and Cloning of a Mycoplasma genitalium Genome". Science. 319 (5867): 1215–1220. doi:10.1126/science.1151721. PMID 18218864.
  50. ↑ Ball, Philip (2008-01-24). "Genome stitched together by hand". Nature News. doi:10.1038/news.2008.522.
  51. ↑ "Scientists Create First Synthetic Bacterial Genome -- Largest Chemically Defined Structure Synthesized In The Lab". ScienceDaily. 24 January 2008. Retrieved 9 August 2014.
  52. ↑ Karr, Jonathan R.; Sanghvi, Jayodita C.; Macklin, Derek N.; Gutschow, Miriam V.; Jacobs, Jared M.; Bolival, Benjamin; Assad-Garcia, Nacyra; Glass, John I.; Covert, Markus W. (2010). "A Whole-Cell Computational Model Predicts Phenotype from Genotype". Cell. 150 (2): 389–401. doi:10.1016/j.cell.2012.05.044. PMC 3413483. PMID 22817898.
  53. ↑ "In First, Software Emulates Lifespan of Entire Organism". The New York Times. 20 July 2012. Retrieved 2012-07-20.
  54. ↑ Grover, R. K.; Zhu, X.; Nieusma, T.; Jones, T.; Boero, I.; MacLeod, A. S.; Mark, A.; Niessen, S.; Kim, H. J.; Kong, L.; Assad-Garcia, N.; Kwon, K.; Chesi, M.; Smider, V. V.; Salomon, D. R.; Jelinek, D. F.; Kyle, R. A.; Pyles, R. B.; Glass, J. I.; Ward, A. B.; Wilson, I. A.; Lerner, R. A. (2014). "A structurally distinct human mycoplasma protein that generically blocks antigen-antibody union". Science. 343 (6171): 656–661. doi:10.1126/science.1246135. PMC 3987992. PMID 24503852.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.