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Laura Manuelidis

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Laura Manuelidis is a physician and neuropathologist at Yale University.

Career

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Manuelidis earned her B.A. degree from Sarah Lawrence College, where she studied poetry, and her M.D. is from Yale Medical School. She is head of the section of Neuropathology in the department of Surgery at Yale[1] and is also a member of the Neuroscience and Virology faculty. She has been active on numerous government committees including the Advisory Panel on Alzheimer's disease and US FDA advisory panel, has been a member of editorial boards, and chair of international meetings. She has also published 3 books of poetry.

Achievements

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Manuelidis has made major contributions in two areas: A) the discovery of large chromosomal DNA repeats and the elucidation of their role in the organization and structure of chromosomes in metaphase and interphase nuclei; B) the experimental investigation of the infectious agents that cause human Transmissible Encephalopathy (TSE) diseases including Creutzfeldt–Jakob disease (CJD), kuru and BSE ("mad cow disease"). Transmission to small animals and cells in culture exposed basic biologic and molecular agent facts most consistent with an exponentially replicating ~25 nm viral particle that contains an essential but unknown nucleic acid for infection.[citation needed] This contrasts with the assertion that the host encoded amyloid forming prion protein, without nucleic acid, is the infectious agent.

Chromosome Sequence and Structure

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Early in her career, Manuelidis discovered major unknown DNA sequence motifs, and demonstrated their megabase organization in metaphase chromosomes and interphase nuclei. Using restriction enzymes on whole human DNA and extracting specific gel bands, an approach no one had used previously for whole mammalian genomes, she discovered human complex repeated (α satellite) DNA sequences and localized them in centromeres.[2][3] They were homologous to simian, but not simpler mouse centromere repeats.[4] These late replicating sequences, that contain few if any genes, define all human chromosome centromeres as shown by the development of high resolution in-situ hybridization.[5] As in other mammalian cells, centromeres are critical for proper segregation of chromosomes between two new daughter cells during mitosis, and the discovery and localization of these satellite sequences have facilitated diagnosis of trisomy and chromosomal aberrations in genetic diseases and tumors. Manuelidis also discovered, isolated, and sequenced the human long interspersed L1 repeats (LINES) and showed they contained a transcriptional open reading frame.[6] She found these abundant L1 repeats concentrated in Giemsa dark bands on chromosome arms that contain many tissue-specific genes[7] whereas ALU short repeats concentrate in light bands with the majority of housekeeping genes. L1 repeats are conserved in evolution and show 70% homology to mouse L1 repeats. After retroviral HIV was sequenced, others deduced that L1 repeats were retroviral. It thus became clear that these ancient large retroviral invaders entered the genome and were symbiotically transfigured, or pathologically tamed, during evolution to attain a structural, and possibly functional role in megabase chromosome band domains.The enormous sizes of L1 and Alu rich domains were also demonstrated by pulse-field electrophoresis.[8] Additional endogenous retroviral DNAs, such as those that produce retroviral intracisternal A particles (IAP) in rodents, as well as less numerous human endogenous retroviral repeats, are also integrated in specific chromosome locations.[9] This further undermines the assumption repeated DNAs are parasitic "junk".

Manuelidis also opened up the field of 3-dimensional chromosome structure in the interphase nucleus of differentiated cells by combining optical serial sections and high resolution in-situ hybridization of specific DNA sequences. These studies dramatically transfigured the picture of interphase nuclei. Previously, interphase compartments were viewed as ill-defined dense heterochromatic blobs beside unorganized euchromatic chromatin spaghetti with no cohesive 3-D structure. In differentiated neurons very distinct patterns of individual centromere positions were demonstrated for each neuronal subtype. These positions are conserved in evolution even though centromeric DNA repeats are species-specific.[10] By charting the movement of the X chromosome in large neurons in epilepsy,[11] and the movement of centromeres during post-mitotic neuronal development,[12] dynamic changes of large chromosome were illuminated. High-resolution mapping of whole individual human chromosomes in mouse and hamster-hybrid human cells further showed each chromosome was compact and occupied its own individual space or "territory".[13][14]

An architectural model of chromosomes as they transit from metaphase to interphase fits the known DNA compaction in diploid cells and allows for rapid transitions and segregation during mitosis, as well as local extensions that accommodate transcription.[15] Mapping of whole individual chromosomes using high resolution DNA hybridization of chromosome specific libraries developed here[16][17] subsequently were useful for resolving chromosome changes in complex genetic diseases and tumor progression. Finally, the insertion of a huge 11 megabase transgene of the globin exon (lacking introns) was recognized by cells, and silenced by compaction together with transcriptionally inert heterochromatic centromeres in neurons.[18] This demonstrates that uninterrupted repeats are capable of inducing specific functional and structural changes during interphase. It is likely that this feature operates sequentially during cell differentiation.

Human TSE agents: Biology, structure and infectious characteristics

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The lab of EE Manuelidis and L Manuelidis was the first to serially transmit human Creutzfeldt–Jakob disease (CJD) to guinea pigs and small rodents.[19][20][21] This made it possible to demonstrate fundamental mechanisms of infection, including TSE agent uptake and spread via myeloid cells of the blood,[22][23] a common route for most viruses. A lack of maternal transmission of sporadic CJD (sCJD) in long lived guinea pigs,[24] contrasts with the proposed germline inheritance of sCJD. As with viruses, different species vary in their susceptibility to specific TSE agent strains. Major agent strain distinctions from scrapie are encoded by different human TSE agents, such as sCJD, kuru of New Guinea,[25] bovine-linked vCJD,[26] and Asiatic CJD. These were discovered and documented though experimental transmissions to normal mice, hamsters and monotypic cell cultures at Yale. Prion protein bands fail to distinguish very different TSE strains in standard mouse brains.

Manuelidis and colleagues were the first to show that prion protein amyloid was derived from a glycosylated 34kd precursor protein using lectins. PrP antibodies and selected lectins bound to the same protein in both normal and CJD and scrapie infected brain fractions.[27] Additionally, the correct sugar sequence of PrP was first demonstrated in the Manuelidis lab by sequential deglycosylation and unmasking of sugar residues.[28] Manuelidis and colleagues also developed monotypic cell cultures infected by many different human and sheep scrapie TSE strains, and developed rapid quantitative assays of infectious titers of 1 million fold or more for each strain.[29] As in the brain, misfolded PrP amounts show less than a 5 fold increase and could not even distinguish greater than 100 fold differences in infectivity of cultured agent strains. These culture studies further showed that PrP band patterns are cell-type dependent. Only rare strains show a PrP folding pattern that is distinctive in either brain or in monotypic cells, and a change in PrP bands does not induce any change in strain characteristics.[30] Moreover, TSE strains modify each other's replication in a virus-like fashion. Experiments in mice, and GT hypothalamic neuronal cells in culture, show both inhibitory and additive infectivity by two different TSE strains: one TSE strain can inhibit replication of a second more virulent strain[31] whereas two different strains can both simultaneously infect cells.[32]

Finally, dramatic changes in agent doubling time (weeks to a day) were documented for many TSE strains. TSE agents replicate every 24 hrs in culture, in marked contrast to their very slow and strain specific replication in the brain. This rapid agent replication in culture is likely due to release of agent constraints from the many complex host immune system in animals.[29] These include early microglial responses.[33][34][35] PrP amyloid itself can also behave as a defensive innate immune response to TSE agent infection, and high levels of PrP amyloid can abolish 99.999% of infectivity.[36][37]

Prion hypothesis

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Manueldis has challenged the dominant assertion that host prion protein (PrP), without any nucleic acid, is the causal infectious agent in TSEs. The prion hypothesis was put forth by Stanley B. Prusiner, who won the 1997 Nobel Prize in Physiology or Medicine.[38] In contrast to the amyloid or "infectious form of host PrP", Manuelidis and colleagues showed that infectious CJD 25nm brain particles had a homogeneous viral density and size and separated from most prion protein. Disruption of CJD nucleic acid-protein complexes destroys infectivity.[39] Comparable 25 nm particles were also identified within CJD and scrapie infected cell cultures, but not in uninfected controls. As with isolated 25 nm brain particles, cultured cells particles did not bind PrP antibodies.[40]

Manuelidis stated that "Although much work remains to be done, there is a reasonable possibility these are the long sought viral particles that cause transmissible spongiform encephalopathies". She claims that misfolded prion protein probably is not infectious, and that there is no independent confirmation that recombinant PrP can be converted to an infectious form. However, the Prusiner group has published evidence of precisely the kind of conversion that Manueldis claims there is no evidence for.[41] As originally proposed, misfolded PrP amyloid might be an infectious structure or a pathological response protein.[42] Later evidence favored the pathological concept, with infectious viral particles binding to and converting receptor PrP to an amyloid form.[43] Much additional evidence points to an exogenous source of infectious TSE agents, and the claim that recombinant PrP can be made infectious has not been reproducible.[44][45][46] In fact, one can remove all detectable forms of PrP from infectious brain particles, yet these particles retain high infectivity.[47] Thus, PrP may not be an integral or required component of the infectious particle.[48] On the other hand, all high infectivity scrapie and CJD fractions contain nucleic acids when analyzed using modern amplification strategies.[49] When these nucleic acids are destroyed with nucleases that have no effect on PrP, 99.8% of the infectious titer is abolished.[50] Novel circular SPHINX DNAs from the microbiome of 1.8kb and 2.4kb have been identified in isolated infectious particles, but their role in infection and/or disease is not yet clear because they are also present at much lower levels in non-infectious preparations. Only a few infectious particle nucleic acid sequences have been analyzed to date. Nevertheless, host innate immune responses, including a remarkably strong interferon response to infection,[51] further demonstrate TSE agents are recognized as foreign infectious invaders. Misfolded PrP does not elicit this effect.

See also

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References

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  1. ^ "Home > Manuelidis Lab - Surgery - Neuropathology - Yale School of Medicine". medicine.yale.edu.
  2. ^ Manuelidis, L. (November 1976). "Repeating restriction fragments of human DNA". Nucleic Acids Research. 3 (11): 3063–3076. doi:10.1093/nar/3.11.3063. ISSN 0305-1048. PMC 343151. PMID 794832.
  3. ^ Manuelidis, L. (1978-03-22). "Chromosomal localization of complex and simple repeated human DNAs". Chromosoma. 66 (1): 23–32. doi:10.1007/BF00285813. ISSN 0009-5915. PMID 639625. S2CID 2061015.
  4. ^ Manuelidis, L.; Wu, J. C. (1978-11-02). "Homology between human and simian repeated DNA". Nature. 276 (5683): 92–94. Bibcode:1978Natur.276...92M. doi:10.1038/276092a0. ISSN 0028-0836. PMID 105293. S2CID 4320503.
  5. ^ Manuelidis, L.; Langer-Safer, P. R.; Ward, D. C. (November 1982). "High-resolution mapping of satellite DNA using biotin-labeled DNA probes". The Journal of Cell Biology. 95 (2 Pt 1): 619–625. doi:10.1083/jcb.95.2.619. ISSN 0021-9525. PMC 2112973. PMID 6754749.
  6. ^ Manuelidis, L.; Biro, P. A. (1982-05-25). "Genomic representation of the Hind II 1.9 kb repeated DNA". Nucleic Acids Research. 10 (10): 3221–3239. doi:10.1093/nar/10.10.3221. ISSN 0305-1048. PMC 320702. PMID 6285293.
  7. ^ Manuelidis, L.; Ward, D. C. (1984). "Chromosomal and nuclear distribution of the HindIII 1.9-kb human DNA repeat segment". Chromosoma. 91 (1): 28–38. doi:10.1007/BF00286482. ISSN 0009-5915. PMID 6098426. S2CID 25178606.
  8. ^ Chen, Terence L.; Manuelidis, Laura (November 1989). "SINEs and LINEs cluster in distinct DNA fragments of Giemsa band size". Chromosoma. 98 (5): 309–316. doi:10.1007/bf00292382. ISSN 0009-5915. PMID 2692996. S2CID 24850090.
  9. ^ Taruscio, D.; Manuelidis, L. (December 1991). "Integration site preferences of endogenous retroviruses". Chromosoma. 101 (3): 141–156. doi:10.1007/BF00355364. ISSN 0009-5915. PMID 1790730. S2CID 24569226.
  10. ^ Manuelidis, L.; Borden, J. (1988). "Reproducible compartmentalization of individual chromosome domains in human CNS cells revealed by in situ hybridization and three-dimensional reconstruction". Chromosoma. 96 (6): 397–410. doi:10.1007/BF00303033. ISSN 0009-5915. PMID 3219911. S2CID 24792110.
  11. ^ Borden, J.; Manuelidis, L. (1988-12-23). "Movement of the X chromosome in epilepsy". Science. 242 (4886): 1687–1691. Bibcode:1988Sci...242.1687B. doi:10.1126/science.3201257. ISSN 0036-8075. PMID 3201257.
  12. ^ Manuelidis, L. (1985). "Indications of centromere movement during interphase and differentiation". Annals of the New York Academy of Sciences. 450 (1): 205–221. Bibcode:1985NYASA.450..205M. doi:10.1111/j.1749-6632.1985.tb21494.x. ISSN 0077-8923. PMID 3860180. S2CID 38297846.
  13. ^ Manuelidis, L. (1985). "Individual interphase chromosome domains revealed by in situ hybridization". Human Genetics. 71 (4): 288–293. doi:10.1007/BF00388453. ISSN 0340-6717. PMID 3908288. S2CID 21509861.
  14. ^ Schardin, M.; Cremer, T.; Hager, H. D.; Lang, M. (1985). "Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories". Human Genetics. 71 (4): 281–287. doi:10.1007/BF00388452. ISSN 0340-6717. PMID 2416668. S2CID 9261461.
  15. ^ Manuelidis, L. (1990-12-14). "A view of interphase chromosomes". Science. 250 (4987): 1533–1540. Bibcode:1990Sci...250.1533M. doi:10.1126/science.2274784. ISSN 0036-8075. PMID 2274784. S2CID 41327977.
  16. ^ Lichter, P.; Cremer, T.; Borden, J.; Manuelidis, L.; Ward, D. C. (November 1988). "Delineation of individual human chromosomes in metaphase and interphase cells by in situ suppression hybridization using recombinant DNA libraries". Human Genetics. 80 (3): 224–234. doi:10.1007/BF01790090. ISSN 0340-6717. PMID 3192212. S2CID 17768808.
  17. ^ Cremer, T.; Lichter, P.; Borden, J.; Ward, D. C.; Manuelidis, L. (November 1988). "Detection of chromosome aberrations in metaphase and interphase tumor cells by in situ hybridization using chromosome-specific library probes". Human Genetics. 80 (3): 235–246. doi:10.1007/bf01790091. ISSN 0340-6717. PMID 3192213. S2CID 14660591.
  18. ^ Manuelidis, L (February 1991). "Heterochromatic features of an 11-megabase transgene in brain cells". Proceedings of the National Academy of Sciences. 88 (3): 1049–1053. Bibcode:1991PNAS...88.1049M. doi:10.1073/pnas.88.3.1049. ISSN 0027-8424. PMC 50952. PMID 1992455.
  19. ^ Manuelidis, E. E.; Kim, J.; Angelo, J. N.; Manuelidis, L. (January 1976). "Serial propagation of Creutzfeldt-Jakob disease in guinea pigs". Proceedings of the National Academy of Sciences of the United States of America. 73 (1): 223–227. Bibcode:1976PNAS...73..223M. doi:10.1073/pnas.73.1.223. ISSN 0027-8424. PMC 335873. PMID 1108016.
  20. ^ Manuelidis, E E; Gorgacz, E J; Manuelidis, L (July 1978). "Interspecies transmission of Creutzfeldt-Jakob disease to Syrian hamsters with reference to clinical syndromes and strains of agent". Proceedings of the National Academy of Sciences. 75 (7): 3432–3436. Bibcode:1978PNAS...75.3432M. doi:10.1073/pnas.75.7.3432. ISSN 0027-8424. PMC 392791. PMID 356055.
  21. ^ MANUELIDIS, ELIAS E.; GORGACZ, EDWARD J.; MANUELIDIS, LAURA (February 1978). "Transmission of Creutzfeldt–Jakob disease with scrapie-like syndromes to mice". Nature. 271 (5647): 778–779. Bibcode:1978Natur.271..778M. doi:10.1038/271778a0. ISSN 0028-0836. PMID 342977. S2CID 4201624.
  22. ^ Manuelidis, Elias E.; Gorgacs, Edward J.; Manuelidis, Laura (1978-06-02). "Viremia in Experimental Creutzfeldt-Jakob Disease". Science. 200 (4345): 1069–1071. Bibcode:1978Sci...200.1069M. doi:10.1126/science.349691. ISSN 0036-8075. PMID 349691.
  23. ^ Radebold, K.; Chernyak, M.; Martin, D.; Manuelidis, L. (2001). "Blood borne transit of CJD from brain to gut at early stages of infection". BMC Infectious Diseases. 1: 20. doi:10.1186/1471-2334-1-20. ISSN 1471-2334. PMC 59894. PMID 11716790.
  24. ^ Manuelidis, E. E.; Manuelidis, L. (February 1979). "Experiments on maternal transmission of Creutzfeldt-Jakob disease in guinea pigs". Proceedings of the Society for Experimental Biology and Medicine. 160 (2): 233–236. doi:10.3181/00379727-160-40425. ISSN 0037-9727. PMID 368815. S2CID 26985470.
  25. ^ Manuelidis, Laura; Chakrabarty, Trisha; Miyazawa, Kohtaro; Nduom, Nana-Aba; Emmerling, Kaitlin (2009-08-11). "The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt-Jakob disease and scrapie agents". Proceedings of the National Academy of Sciences of the United States of America. 106 (32): 13529–13534. Bibcode:2009PNAS..10613529M. doi:10.1073/pnas.0905825106. ISSN 1091-6490. PMC 2715327. PMID 19633190.
  26. ^ Manuelidis, Laura; Liu, Ying; Mullins, Brian (2009-02-01). "Strain-specific viral properties of variant Creutzfeldt-Jakob disease (vCJD) are encoded by the agent and not by host prion protein". Journal of Cellular Biochemistry. 106 (2): 220–231. doi:10.1002/jcb.21988. ISSN 1097-4644. PMC 2762821. PMID 19097123.
  27. ^ Manuelidis, L; Valley, S; Manuelidis, E E (June 1985). "Specific proteins associated with Creutzfeldt-Jakob disease and scrapie share antigenic and carbohydrate determinants". Proceedings of the National Academy of Sciences. 82 (12): 4263–4267. Bibcode:1985PNAS...82.4263M. doi:10.1073/pnas.82.12.4263. ISSN 0027-8424. PMC 397977. PMID 2408277.
  28. ^ Sklaviadis, T; Manuelidis, L; Manuelidis, E E (August 1986). "Characterization of major peptides in Creutzfeldt-Jakob disease and scrapie". Proceedings of the National Academy of Sciences. 83 (16): 6146–6150. Bibcode:1986PNAS...83.6146S. doi:10.1073/pnas.83.16.6146. ISSN 0027-8424. PMC 386456. PMID 3090551.
  29. ^ a b Miyazawa, Kohtaro; Emmerling, Kaitlin; Manuelidis, Laura (2011). "Replication and spread of CJD, kuru and scrapie agents in vivo and in cell culture". Virulence. 2 (3): 188–199. doi:10.4161/viru.2.3.15880. ISSN 2150-5608. PMC 3149681. PMID 21527829.
  30. ^ Arjona, Alvaro; Simarro, Laura; Islinger, Florian; Nishida, Noriyuki; Manuelidis, Laura (2004-05-25). "Two Creutzfeldt–Jakob disease agents reproduce prion protein-independent identities in cell cultures". Proceedings of the National Academy of Sciences. 101 (23): 8768–8773. Bibcode:2004PNAS..101.8768A. doi:10.1073/pnas.0400158101. ISSN 0027-8424. PMC 423270. PMID 15161970.
  31. ^ Manuelidis, L. (1998-03-03). "Vaccination with an attenuated Creutzfeldt-Jakob disease strain prevents expression of a virulent agent". Proceedings of the National Academy of Sciences of the United States of America. 95 (5): 2520–2525. Bibcode:1998PNAS...95.2520M. doi:10.1073/pnas.95.5.2520. ISSN 0027-8424. PMC 19398. PMID 9482918.
  32. ^ Nishida, Noriuki; Katamine, Shigeru; Manuelidis, Laura (2005-10-21). "Reciprocal interference between specific CJD and scrapie agents in neural cell cultures". Science. 310 (5747): 493–496. Bibcode:2005Sci...310..493N. doi:10.1126/science.1118155. ISSN 1095-9203. PMID 16239476. S2CID 30401756.
  33. ^ Manuelidis, Laura; Fritch, William; Xi, You-Gen (1997-07-04). "Evolution of a Strain of CJD That Induces BSE-Like Plaques". Science. 277 (5322): 94–98. doi:10.1126/science.277.5322.94. ISSN 0036-8075. PMID 9204907.
  34. ^ Baker, Christopher A.; Martin, Daniel; Manuelidis, Laura (November 2002). "Microglia from Creutzfeldt-Jakob Disease-Infected Brains Are Infectious and Show Specific mRNA Activation Profiles". Journal of Virology. 76 (21): 10905–10913. doi:10.1128/jvi.76.21.10905-10913.2002. ISSN 0022-538X. PMC 136595. PMID 12368333.
  35. ^ Lu, Zhi Yun; Baker, Christopher A.; Manuelidis, Laura (2004-10-18). "New molecular markers of early and progressive CJD brain infection". Journal of Cellular Biochemistry. 93 (4): 644–652. doi:10.1002/jcb.20220. ISSN 0730-2312. PMID 15660413. S2CID 9285207.
  36. ^ Miyazawa, Kohtaro; Kipkorir, Terry; Tittman, Sarah; Manuelidis, Laura (2012). "Continuous production of prions after infectious particles are eliminated: implications for Alzheimer's disease". PLOS ONE. 7 (4): e35471. Bibcode:2012PLoSO...735471M. doi:10.1371/journal.pone.0035471. ISSN 1932-6203. PMC 3324552. PMID 22509412.
  37. ^ Manuelidis L (2013). "Infectious particles, stress, and induced prion amyloids: a unifying perspective". Virulence. 4 (5): 373–83. doi:10.4161/viru.24838. PMC 3714129. PMID 23633671.,
  38. ^ "Stanley B. Prusiner - Autobiography". NobelPrize.org. Retrieved 2007-01-02.
  39. ^ Manuelidis, L.; Sklaviadis, T.; Akowitz, A.; Fritch, W. (1995-05-23). "Viral particles are required for infection in neurodegenerative Creutzfeldt-Jakob disease". Proceedings of the National Academy of Sciences of the United States of America. 92 (11): 5124–5128. Bibcode:1995PNAS...92.5124M. doi:10.1073/pnas.92.11.5124. ISSN 0027-8424. PMC 41861. PMID 7761460.
  40. ^ Manuelidis L; Yu ZX; Barquero N; Mullins B (February 6, 2007). "Cells infected with scrapie and Creutzfeldt–Jakob disease agents produce intracellular 25-nm virus-like particles". Proceedings of the National Academy of Sciences. 104 (6): 1965–1970. Bibcode:2007PNAS..104.1965M. doi:10.1073/pnas.0610999104. PMC 1794316. PMID 17267596.
  41. ^ Legname, Giuseppe; Baskakov, Ilia V.; Nguyen, Hoang-Oanh B.; Riesner, Detlev; Cohen, Fred E.; DeArmond, Stephen J.; Prusiner, Stanley B. (2004-07-30). "Synthetic Mammalian Prions". Science. 305 (5684): 673–676. Bibcode:2004Sci...305..673L. doi:10.1126/science.1100195. ISSN 0036-8075. PMID 15286374.
  42. ^ Merz, P. A.; Somerville, R. A.; Wisniewski, H. M.; Manuelidis, L.; Manuelidis, E. E. (Dec 1–7, 1983). "Scrapie-associated fibrils in Creutzfeldt-Jakob disease". Nature. 306 (5942): 474–476. Bibcode:1983Natur.306..474M. doi:10.1038/306474a0. ISSN 0028-0836. PMID 6358899. S2CID 3075231.
  43. ^ Manuelidis, Laura (2013-07-01). "Infectious particles, stress, and induced prion amyloids: a unifying perspective". Virulence. 4 (5): 373–383. doi:10.4161/viru.24838. ISSN 2150-5608. PMC 3714129. PMID 23633671.
  44. ^ Timmes, Andrew G.; Moore, Roger A.; Fischer, Elizabeth R.; Priola, Suzette A. (2013). "Recombinant prion protein refolded with lipid and RNA has the biochemical hallmarks of a prion but lacks in vivo infectivity". PLOS ONE. 8 (7): e71081. Bibcode:2013PLoSO...871081T. doi:10.1371/journal.pone.0071081. ISSN 1932-6203. PMC 3728029. PMID 23936256.
  45. ^ Barron, Rona M.; King, Declan; Jeffrey, Martin; McGovern, Gillian; Agarwal, Sonya; Gill, Andrew C.; Piccardo, Pedro (October 2016). "PrP aggregation can be seeded by pre-formed recombinant PrP amyloid fibrils without the replication of infectious prions". Acta Neuropathologica. 132 (4): 611–624. doi:10.1007/s00401-016-1594-5. ISSN 1432-0533. PMC 5023723. PMID 27376534.
  46. ^ Schmidt, Christian; Fizet, Jeremie; Properzi, Francesca; Batchelor, Mark; Sandberg, Malin K.; Edgeworth, Julie A.; Afran, Louise; Ho, Sammy; Badhan, Anjna; Klier, Steffi; Linehan, Jacqueline M.; Brandner, Sebastian; Hosszu, Laszlo L. P.; Tattum, M. Howard; Jat, Parmjit (December 2015). "A systematic investigation of production of synthetic prions from recombinant prion protein". Open Biology. 5 (12): 150165. doi:10.1098/rsob.150165. ISSN 2046-2441. PMC 4703057. PMID 26631378.
  47. ^ Kipkorir, Terry; Tittman, Sarah; Botsios, Sotirios; Manuelidis, Laura (November 2014). "Highly infectious CJD particles lack prion protein but contain many viral-linked peptides by LC-MS/MS". Journal of Cellular Biochemistry. 115 (11): 2012–2021. doi:10.1002/jcb.24873. ISSN 1097-4644. PMC 7166504. PMID 24933657.
  48. ^ Kipkorir T, Colangelo CM, Manuelidis L (2015). "Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt-Jakob disease". Proteomics. 15 (17): 2983–98. doi:10.1002/pmic.201500059. PMC 4601564. PMID 25930988.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  49. ^ Manuelidis, Laura (April 2011). "Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD". Journal of Neurovirology. 17 (2): 131–145. doi:10.1007/s13365-010-0007-0. ISSN 1538-2443. PMID 21165784. S2CID 18457762.
  50. ^ Botsios Sotirios, Manuelidis Laura (2016). "CJD and Scrapie Require Agent-Associated Nucleic Acids for Infection". J. Cell. Biochem. 9999 (8): 1–12. doi:10.1002/jcb.25495. PMID 26773845. S2CID 26685867.
  51. ^ Aguilar, Gerard; Pagano, Nathan; Manuelidis, Laura (2022). "Reduced Expression of Prion Protein With Increased Interferon-β Fail to Limit Creutzfeldt-Jakob Disease Agent Replication in Differentiating Neuronal Cells". Frontiers in Physiology. 13: 837662. doi:10.3389/fphys.2022.837662. ISSN 1664-042X. PMC 8895124. PMID 35250638.
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