Laura Manuelidis

Last updated
Laura Manuelidis
Born
Laura Kirchman

Brooklyn, New York, United States
Education Sarah Lawrence College, B.A. 1963
Yale Medical School, M.D. 1967
Occupation(s)Physician, professor
Years active1967–present
Known forResearch into Creutzfeldt-Jakob disease
Spouse Elias E. Manuelidis
Children2

Laura Manuelidis (born Laura Kirchman [1] ) is an American physician and neuropathologist. She is the head of neuropathology at Yale University, where she teaches and conducts research. [2]

Contents

Career

Laura Manuelidis was born Laura Kirchman in Brooklyn, New York to a teacher and an architect. [1] [3] Manuelidis earned her B.A. from Sarah Lawrence College in 1963, where she studied poetry, and she received her M.D. from Yale Medical School in 1967.

Manuelidis is the head of neuropathology in the surgery department at Yale [4] and is also a member of the neuroscience and virology faculty. She has been active on numerous government committees, including the Alzheimer's disease advisory panel and the US Food and Drug Administration advisory panel, has been a member of editorial boards, and chair of international meetings. She has also published three books of poetry.

Achievements

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 spongiform encephalopathy (TSE) diseases including Creutzfeldt–Jakob disease (CJD), kuru and bovine spongiform encephalopathy ("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

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. [5] [6] They were homologous to simian, but not simpler mouse centromere repeats. [7] 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. [8]

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. [9] She found these abundant L1 repeats concentrated in Giemsa dark bands on chromosome arms that contain many tissue-specific genes, [10] 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 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. [11]

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. [12] 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. [13] By charting the movement of the X chromosome in large neurons in epilepsy, [14] and the movement of centromeres during post-mitotic neuronal development, [15] 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". [16] [17]

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. [18] Mapping of whole individual chromosomes using high resolution DNA hybridization of chromosome specific libraries developed here [19] [20] 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. [21] 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

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. [22] [23] [24] This made it possible to demonstrate fundamental mechanisms of infection, including TSE agent uptake and spread via myeloid cells of the blood, [25] [26] a common route for most viruses. A lack of maternal transmission of sporadic CJD (sCJD) in long lived guinea pigs, [27] 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, [28] bovine-linked vCJD, [29] 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. [30] Additionally, the correct sugar sequence of PrP was first demonstrated in the Manuelidis lab by sequential deglycosylation and unmasking of sugar residues. [31] 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. [32] 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. [33] 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 [34] whereas two different strains can both simultaneously infect cells. [35]

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. [32] These include early microglial responses. [36] [37] [38] 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. [39] [40]

Prion hypothesis

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. [41] 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. [42] 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. [43]

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. [44] As originally proposed, misfolded PrP amyloid might be an infectious structure or a pathological response protein. [45] Later evidence favored the pathological concept, with infectious viral particles binding to and converting receptor PrP to an amyloid form. [46] 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. [47] [48] [49] In fact, one can remove all detectable forms of PrP from infectious brain particles, yet these particles retain high infectivity. [50] Thus, PrP may not be an integral or required component of the infectious particle. [51] On the other hand, all high infectivity scrapie and CJD fractions contain nucleic acids when analyzed using modern amplification strategies. [52] When these nucleic acids are destroyed with nucleases that have no effect on PrP, 99.8% of the infectious titer is abolished. [53] 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, [54] further demonstrate TSE agents are recognized as foreign infectious invaders. Misfolded PrP does not elicit this effect.

See also

References

  1. 1 2 Saxon, Wolfgang (November 12, 1992). "Elias E. Manuelidis, Yale Neurologist, 74; Viral-Disease Expert". New York Times.
  2. "Laura Manuelidis, MD". Yale School of Medicine.
  3. "Association of Yale Alumni in Medicine Distinguished Alumni Award". Yale School of Medicine. June 2, 2018.
  4. "Home > Manuelidis Lab - Surgery - Neuropathology - Yale School of Medicine". medicine.yale.edu.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 1 2 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. 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.,
  41. "Stanley B. Prusiner - Autobiography". NobelPrize.org. Retrieved 2007-01-02.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. 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.
  47. 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.
  48. 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.
  49. 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.
  50. 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.
  51. Kipkorir, T; Colangelo, CM; Manuelidis, Laura (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.
  52. 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.
  53. 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.
  54. 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.