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9th Invest in ME International ME Conference, 2014 - Part 1: Autoimmunity and ME
Mark Berry begins a series of articles on the 9th Invest in ME International ME Conference in London, with a look at three presentations on autoimmunity
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Proteins of the XMRV retrovirus Christopher Carter

Discussion in 'XMRV Research and Replication Studies' started by pollycbr125, Jul 17, 2010.

  1. pollycbr125

    pollycbr125 Senior Member

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    http://precedings.nature.com/documents/4669/version/1

    Proteins of the XMRV retrovirus implicated in chronic fatigue syndrome and prostate cancer are homologous to human proteins relevant to both diseases.


    Received 15 July 2010 01:56 UTC; Posted 15 July 2010
    Subjects:
    Cancer, Immunology, Microbiology, Neuroscience
    Tags:
    xmrv virus chronic fatigue syndrome prostate cancer viral mimicry
    Abstract:
    The XMRV retrovirus has been implicated in chronic fatigue syndrome and prostate cancer. A homology search comparing retroviral with human proteins revealed short contiguous amino acid strings (typically 5-8 aa) matching human proteins whose dysfunction might be expected to cause fatigue, including mitochondrial proteins related to oxidative phosphorylation, glutamate receptors and their synaptic scaffolds, muscular acetylcholine receptor scaffolds and structural proteins, components of the immune system, and phosphatidylinositol signalling inter alia. Viral proteins are also homologous to members of the oestrogen, peroxisome proliferator, and CREB activated receptor networks, all of which are implicated in prostate cancer, and to a protein, SRCAP, that controls the expression of the prostate-specific antigen. These short matches are often predicted to be antigenic, and antibodies to XMRV proteins may target their human homologues. This is supported by the presence of autoantibodies to muscarinic receptors , vimentin and LAMINB1 (all XMRV homologues) in chronic fatigue syndrome sufferers. Homologous XMRV proteins might also interfere with the protein interactomes of their human homologues. Viral mimicry of human proteins is extensive and often relevant to disease. For example Epstein-Barr viral proteins aligns with multiple sclerosis autoantigens, while HIV-1 proteins align with several components of the immune system. Mutant proteins in Huntington's disease and cystic fibrosis also align with proteins from common phages or viruses. This suggests a common theme of viral derived autoimmunity/network interference in many human disorders, which could radically change the shape of future therapy. Such viral mimicry likely relates to the idea that life evolved from viruses, leaving behind a legacy of viral derived human proteins whose homology to the current virome may be responsible for many human diseases and syndromes. Vaccination programmes or immunosuppression may be beneficial in many of these conditions
  2. Rafael

    Rafael XMRV+ Member

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    Thanks for posting this.
    I don't understand all the terms but my takeaway is:
    - the findings increase the probability that XMRV is at least a co-factor in ME and PC.
    - this is a nice vehicle for scientists to share pre-official-publication findings (if they want to, and aren't afraid of getting slowed down by too many questions)
    - Another strong reason for greater research investment in ME: "common theme of viral derived autoimmunity/network interference in MANY human disorders, which could radically change the shape of future therapy"
  3. gu3vara

    gu3vara Senior Member

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    I don't know about you, but at this point I just CAN'T believe anymore that CFS isn't caused by XMRV, the stack of scientific evidence is adding up. That's great for us!

    I doubted about this whole thing for a while but recently I just have to admit it's looking pretty damn good now
  4. judderwocky

    judderwocky Senior Member

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    Thinking of Jerry Maguire..... " You had me at retrovirus"
  5. VillageLife

    VillageLife Senior Member

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    THE FULL PAPER

    Proteins of the XMRV retrovirus implicated in chronic fatigue syndrome and prostate
    cancer are homologous to human proteins relevant to both conditions.
    C.J.Carter


    The XMRV retrovirus has been implicated in chronic fatigue syndrome and
    prostate cancer. A homology search comparing retroviral with human proteins
    revealed short contiguous amino acid strings (typically 5-8 aa) matching human
    proteins whose dysfunction might be expected to cause fatigue, including
    mitochondrial proteins related to oxidative phosphorylation, glutamate receptors and
    their synaptic scaffolds, muscular acetylcholine receptor scaffolds and structural
    proteins, components of the immune system, and phosphatidylinositol signalling inter
    alia. Viral proteins are also homologous to members of the oestrogen, peroxisome
    proliferator, and CREB activated receptor networks, all of which are implicated in
    prostate cancer, and to a protein, SRCAP, that controls the expression of the prostatespecific
    antigen. These short matches are often predicted to be antigenic, and
    antibodies to XMRV proteins may target their human homologues. This is supported
    by the presence of autoantibodies to muscarinic receptors , vimentin and LAMINB1
    (all XMRV homologues) in chronic fatigue syndrome sufferers. Homologous XMRV
    proteins might also interfere with the protein interactomes of their human
    homologues. Viral mimicry of human proteins is extensive and often relevant to
    disease. For example Epstein-Barr viral proteins aligns with multiple sclerosis
    autoantigens, while HIV-1 proteins align with several components of the immune
    system. Mutant proteins in Huntington’s disease and cystic fibrosis also align with
    proteins from common phages or viruses. This suggests a common theme of viral
    derived autoimmunity/network interference in many human disorders, which could
    radically change the shape of future therapy. Such viral mimicry likely relates to the
    idea that life evolved from viruses, leaving behind a legacy of viral derived human
    proteins whose homology to the current virome may be responsible for many human
    diseases and syndromes. Vaccination programmes or immunosuppression may be
    beneficial in many of these conditions.


    Introduction.

    Chronic fatigue syndrome is an unexplained medical condition characterised
    by extreme mental and physical fatigue 25. and by cognitive impairment, depression
    and muscular pain and excessive sensitivity to light, sound and smell 41. The condition
    has a very high prevalence, for example a figure of 30% of the general population was
    recently reported in a study from the Netherlands 46 and there are as many as four
    million sufferers in the USA. 7 Perhaps most of the population will experience this
    condition at some time in their lives. It may be triggered by infection or trauma or by
    vaccination against hepatitis b 33 or against multiple infectious agents (suggested as
    the cause of Gulf War syndrome31,49) . The syndrome appears to have an autoimmune
    component and antibodies to silicone, squalene , muscarinic receptors and nuclear
    envelope antigens have all been reported

    The syndrome is treated by low dose antidepressants which are palliative at
    best 48, has been considered as a psychiatric phenomenon 47 and can indeed benefit
    from cognitive therapy 49. The lack of effective therapy has encouraged the use of
    alternative medicine whose effectiveness remains to be verified by the scientific
    community 49. Many studies have linked viral infection to the syndrome and
    implicated the cytomegalovirus, the Epstein-Barr virus, human herpes virus 6 and 7 ,
    hepatitis C, an intestinal enterovirus , the Nipah virus and parvovirus B19
    5,10,11,15,32,42,49. Microbial infections are also common in these patients 52,
    Perhaps the most intensively studied and hotly debated 21 viral cause of chronic
    fatigue syndrome is the XMRV retrovirus (Xenotropic murine leukemia virus-related
    virus) initially reported by Lombardi and colleagues 24. This virus has also been
    implicated in prostate cancer 4. As shown below, this virus expresses proteins which
    are homologous to several human proteins which are relevant to all of the symptoms
    encountered in chronic fatigue syndrome and to the proteins implicated in prostate
    cancer.

    Methods

    A homology search between the XMRV genome (NC_007815.1) or the
    XMRV proteins and human proteins (blastx; nucleotide search vs proteins or Blastp;
    protein vs protein) was undertaken using the NCBI server 2. Only proteins with
    matches containing pentapeptide strings were included, except in the case of longer
    strings with few gaps or where several contiguous strings were identified. The results
    in Tables 1-10 record the position of the match within the viral genome or viral
    protein and the position within the matching human proteins, (whose DNA will also
    evidently match that of the viral genome) Accession numbers and a brief definition
    of function, as recorded in Entrez gene are provided. The B-cell immunogenecity of
    different amino acids was calculated using the B-epitope prediction server (Bepipred)
    23 http://www.cbs.dtu.dk/services/BepiPred/
    and high scoring amino acids are tagged (*) in the various tables

    Results
    XMRV proteins are homologous to a variety of human proteins as shown in
    Table 1-10. Perhaps the most relevant in relation to fatigue are the mitochondrial
    proteins involved in respiration and oxidative phosphorylation (eg ATP801, COX11)
    (Table 1, Fig 1). Glutamate is the primary excitatory brain neurotransmitter and
    XMRV homology to the AMPA receptor GRIA4 and to members of the presynaptic
    (Bassoon, piccolo) and postsynaptic machinery (DLGAP3)might also contribute to
    cognitive defects (Table 2, Fig 1) as might members of the phosphatidylinositol,
    phosphodiesterase and Rho signalling networks (Table 3, Fig 1).. The muscular pain
    experienced by chronic fatigue sufferers might well be related to homology with
    proteins involved in acetylcholine receptor scaffolding (Table 2, Fig 1) and to
    structural muscle elements (Table 4, Fig 1, and the sensitivity to smell to homology
    with several olfactory receptors (Table 2 , Fig 1).
    XMRV proteins are also homologous to proteins of the growth factor signalling
    networks (e.g. tyrosine kinases FLT3 and TYRO3) (Table 5) which are relevant to
    cancer-related growth (Fig 2)


    They are also homologous to the TAP1 and TAP2 antigen transporter and to a number
    of immunoglobulins and cytokine-related proteins (Table 6, Fig 2).
    Other classes involved include a number of proteins related to nuclear receptors,
    several of which (oestrogen and PPAR receptors and CREB) are directly implicated in
    prostate cancer 6,30,50, and to a protein (SRCAP) that controls the expression of the
    prostate-specific antigen the 39 ,marker for prostate cancer (Table 7, Fig 2) . Other
    homologous classes include transcription factors (Table 8, Fig 2),adhesion molecules
    (Table 9, Fig 1 and 2) , proteases and protein processors (Table 11) and a number of
    miscellaneous or unknown proteins (Table 13).
    Some of the viral translated genome matches to human proteins do not appear
    to relate to any known XMRV protein (certain olfactory receptors the phosphatase
    PPAPDC2 and the phosphodiesterase ENPP6). This may be related to viral open
    reading frames that have not yet been characterised , for example a new ORF has just
    been described for the cytomagalovirus 29 , or that may shift with mutation. However
    in these cases viral DNA remains homologous to that of the human target.
    Different amino acids have different antigenicity depending on their charge
    and hydrophobicity characteristics and the B-epitope antigenicity index for each
    amino acid is shown in Table 14 23. It should be noted that such indices can change
    markedly depending on the number of amino acids in the contiguous string or on the
    identity of the neighbouring amino acids. Marked synergy exists when antigenic
    amino acids form contiguous stretches. This individual index serves as a rough gauge
    of the antigenic potential of the peptide. The top 5 antigenic amino acids are marked
    with an asterisk in the various tables, and contiguous antigenic amino acids, which are
    the most likely epitope and cross-reactive candidates, are highlighted in grey. It can
    be seen that a number of matching proteins are predicted to be highly antigenic.
    These include the mitochondrial proteins CHCHD10 ,acetyl CoA carboxylase and the
    sulfite oxidase SUOX, (Table 1), the glutamate receptor GRIA4 (Table 2) the TBCC
    tumour suppressor (Table 7) numerous growth regulators (FLT3, TYRO3,WNT10B
    and EIF4B ) (Table 5) the antigen transporter TAP1 (Table 6) the PPAR and
    oestrogen receptor and PSA regulators, PELP1, PPRC1 and SRCAP (Table 7), the
    transcription factor FOXO6 (Table 8) , pleckstrin 3 (Table 9) the metalloprotease
    ADAMTS9 and ubiquilin 3 (Table 10).

    Discussion.

    The XMRV virus expresses predicted proteins with homology to human
    proteins that are clearly highly relevant to the symptoms encountered in this disease,
    including fatigue (mitochondrial respiration), cognitive deficits 49 (glutamate, PI
    signalling) problems related to olfaction 41(olfactory receptors) muscular pain 41
    (acetylcholine receptor and muscle related structural proteins) and the association
    with many active viral and microbial infections 19 (immune related proteins).
    .XMRV viral proteins are also highly homologous to components of peroxisome
    proliferator-activated receptor gamma (PPARG) or oestrogen receptor signalling
    networks both of which have been implicated in prostate cancer 6,30 A viral protein is
    also homologous to SRCAP which controls the expression of the prostate specific
    antigen, the cardinal marker of prostate cancer39.
    Although these matching strings are short, they are often contiguous and the
    viral homologues may interfere with their human counterparts in a number of ways.
    Firstly, many of these stretches are predicted to be antigenic and antibodies to the
    virus may also target the human homologues. Indeed autoantibodies to muscarinic
    receptors, cellular cytoskeletal components, including vimentin and other Lamina
    related proteins and to nuclear envelope proteins including Lamin A and LAMIN B1
    have been reported in chronic fatigue syndrome 22,44. These were all identified as
    XMRV homologues in this survey (specifically muscarinic receptor, CHRM2, Lamin
    B1 and Vimentin and generally the cytoskeletal components in Table 4).
    Viral DNA will also match that of the human target and possibly sequester host
    transcription factors or microRNA of influence splicing of the homologous human
    gene.
    These homologies, targeted at highly relevant proteins support the implication
    of the virus in both chronic fatigue syndrome and prostate cancer.
    Several studies have failed to detect the virus in chronic fatigue syndrome and
    the issue is hotly debated 14,21,28. Because the viral proteins are homologous to human
    proteins, it is likely that any anybodies generated in response to the virus would target
    their human homologues. This is supported by the high predicted antigenicity of a
    number of viral matching proteins and by the presence of autoantibodies to viral
    matching proteins in chronic fatigue sufferers. As the human proteins are persistently
    encountered by the antibody, such an autoimmune response would become selfsustaining,
    thus no longer requiring the presence of the virus. Indeed, the more
    successful the immune response against the virus, the greater the risk of
    autoimmunity, a disastrous pyrrhic victory. This scenario could thus explain the
    failure to detect the virus in several studies.
    It has recently been shown that Raltegravir potently inhibits XMRV
    replication and clinical trials in chronic fatigue syndrome and prostate cancer have
    already been proposed 38 a suggestion supported by the results of this survey.
    However, it is possible that the effects of the virus, in the form of autoimmunity
    persist after viral elimination and different strategies including immunosuppression
    might be considered in such cases.
    Viral mimicry of human proteins appears to be a near universal phenomenon.
    For example several viruses (almost 100), including those implicated in late-onset
    Alzheimer’s disease, express proteins that are homologous to beta-amyloid .The
    autoantigens in multiple sclerosis, myasthenia gravis, systemic lupus erythromatosus,
    Pemphigus Vulgaris and Sjogrens syndrome align with proteins from their respective
    reported viral risk factors (and novel suspects), and HIV-1 proteins align with
    important components from all compartments of the human immune system. This
    even applies to human genetic disorders, as the APP mutations in Alzheimer’s disease
    convert the surrounding peptide to sequences that match proteins from commensal
    bacteria and from the Norovirus and common cold virus. The mutant proteins in
    Huntington’s disease and cystic fibrosis also align with proteins expressed by very
    common viruses or phages 8,9. This suggests that a large number of diseases have an
    autoimmune component triggered by viral antigens with homology to important
    human proteins.
    Viruses or phages were long ago proposed as the origin of life 13,17. While
    responsible for our existence, they appear to have left behind a legacy of viral derived
    human proteins containing short but contiguous and often immunogenic amino acid
    stretches homologous to current viral antigens. The autoimmune defence so triggered
    may be responsible for a large number of human illnesses. The therapeutic
    implications of such mimicry are clearly extensive as it suggests an autoimmune
    component in a variety of disorders which might thus benefit from vaccination against
    the appropriate pathogen, immunosuppression and pathogen elimination.


    Table 1 to 10
    Human proteins that match proteins from the translated XMRV genome. The
    alignment is shown and accession numbers are provided together with a brief
    description of the function of the protein. Unless specifically referenced, these are
    copied from the gene descriptions in ENTREZ gene. The matching peptide sequence
    in each case is highlighted in bold and contiguous amino acids of 5 or more or longer
    stretches of contiguity with few gaps are boxed. The asterisks represent the 5 highest
    scoring antigenic amino acids (Table 14) and the grey highlights illustrate contiguous
    antigenic stretches that are the most likely B-cell epitopes, and the most likely
    candidates for cross-reactivity.
  6. VillageLife

    VillageLife Senior Member

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    Some things I thought were interesting from the paper,

  7. VillageLife

    VillageLife Senior Member

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    :eek::eek::eek:
  8. camas

    camas Senior Member

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    Interesting find. Thanks for posting it, pollycbr125.
  9. judderwocky

    judderwocky Senior Member

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    i posted it on my site so there is a hard link if it gets moved
  10. judderwocky

    judderwocky Senior Member

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    ZOMG it has homologues to Cytochrome and to Glutamate... cytochrome is essential to mitochondrial function and the... krebbs cycle depends on it, and... and glutamate .... isn't glutamate overactivity implicated in a number of psychiatric disorders ( i know studies in germany on OCD peeps with treatment refractory ocd and some studies on pschizophrenia have been done_) this could explain a lot of the weird psychological and neurological effects.... isnt that big in autism????

    the more im reading through this study the more i'm astonished.... it makes soo much sense

    it looks like there are four homologues to human olfactory receptors????

    and GABA???? GABA related
    AAB18827.1 gammaaminobutyraldehyde
    dehydrogenase

    wow.... all of the symptoms....would make soo much sense.

    /faint
  11. Merry

    Merry Senior Member

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    Thanks so much for posting, Pollycbr. I have't seen anything on this subject before. Exciting work.

    Merry
  12. Bob

    Bob

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    Interesting thoughts, thanks judderwocky... It makes you think doesn't it!

    There's so many possibilities and then they all suddenly come together in a brain-storm and it all suddenly makes so much sense, when you see a bit of research like this!

    (I love your 'faint' at the end of your post.)
  13. Bob

    Bob

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    Thanks for posting, Pollycbr... I'm still thinking about it all and the possibilities... very interesting!
  14. CateK

    CateK

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    Does anyone know anything about Christopher Carter - other research, academic field, specialty, etc. ?
  15. judderwocky

    judderwocky Senior Member

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    Ive been looking over the full text version... he throws some interesting ideas out for discussion about autoimmuniyt and bio evolution... but i think there are some holes in them. I think his work on the homologue pairs is very solid, he tosses out some very large and generic discussion pieces... about the origin of life and what not... but the protein homologues are the important bits and that at least will stick even if people don't buy into the viral origin of life question he puts forward or the cuasation for the failed studies (i'm not sure how he thinks someone clears a retroviral infection lol) ... but i think he's just trying to throw ideas up to move the discussion forward. Its already been proven at least in Germany that the "failed" study was unable to find XMRV in the healhty population that new studies have shown is there (in both PC and CFS cohorts). So I think that while he has some interesting connections, the most important really can't be generalized beyond the immediate implications of auto antigens... I think it would also be dangerous to jump to immunusuppresive therapy while we don't know what the viral load... we need follow studies done on these "negative" cohorts to determine phenotype issues well before we assume its simply not present... but the implication of homologue pairs should be investigated


    as i see it... he is assuming affinity for immune homologue antigen receptors is going to be the same for the virus and for the human component... they are not identical and their affinity is not going to be the same... i would imagine that it would be some smaller fraction.... but i'm also confused why the paper doesn't address the direct interference that haveing a bunch of look-alike molecules is going to do... im guessing that the viral versions are less functional... and most likely will compete for binding sites with native versions... that alone could explain a host of symptoms... couldn't it? i
  16. alex3619

    alex3619 Senior Member

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    Hi judderwocky

    An interesting thread. I haven't read the original paper yet so I may have more to say later, but I want to talk about viral loads and homology problems.

    First, working out the viral load in a CFS patient is going to be very difficult. This virus doesn't exist much in the blood. The evidence is pointing to it being destroyed or inactivated in the blood stream, so it could be very hard to find indeed (although a test that could identify inactivated virus might help). That means it is probably hiding in tissues if the viral load concept has much meaning at all with this virus. The only reliable way to identify viral load would be to grind the patient up in a meat grinder and test the remains - not very useful. I suspect that we could get a close approximation (close enough for treatment purposes anyway) with a lymph node biopsy. My next choice would be to at least try to get an idea from viral load in the throat and lungs. Finally there is a spinal tap, but repeated spinal taps are likely to lead to death or paralysis in many patients, it isn't worth doing over and over during treatment. This is very probably a virus in which we can't measure viral load to objectively determine progress, if we wait for the science to catch up with this problem it could be beyond the lifetime of many of us.

    The length of homologous sequences looked at is probably not coincidental. Five to eight amino acids is about the length that antibodies look for. While I suspect some of these proteins might be able to mimic human proteins enough to interfere with cell function, this may not be the case for the most part because protein function depends upon how the protein is folded, and what other charges are on the protein, not just an amino acid sequence. The primary impact is likely to be autoantibodies, but this only explains proteins outside the cell. What is affecting inside the cell? This raises a lot more questions than answers, but that is what attracts scientists is it not? I suspect the answer will lie somewhere else, but a claim that an all out immune assault on XMRV could lead to autoimmune disease or even sudden death would not be impossible. I wonder if this is why some of us occasionally die for no obvious reason? I wonder if this could lead to studies in CFS to determine if we have autoantibodies to these other proteins?

    Of course the viral proteins may have evolved to deliberately mimic specific proteins - which they are cannot be determined by simple amino acid sequences. We definitely have to look for specific autoantibodies.

    Bye
    Alex

  17. jspotila

    jspotila Senior Member

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    Huh?

    I found these comments (in bold) from the Introduction to be troubling:

    I haven't pulled reference 46 but here is the cite: M. van't Leven, et al., "Fatigue and chronic fatigue syndrome-like complaints in the general population," Eur. J. Public Health. 20(3), 251 (2010).

    Protein homology means that the proteins were derived from a common ancestor. The paper posits that some XMRV and human proteins are derived from a common ancestor. According to the author, "Viral mimicry of human proteins appears to be a near universal phenomenon. . . . This suggests that a large number of diseases have an autoimmune component triggered by viral antigens with homology to important human proteins." But is "viral mimicry" the same thing as protein homology? And does this reasoning mean that any viral-related illness is an autoimmune disorder? This doesn't make sense to me. HIV/AIDS is not an autoimmune disorder - the immune system cannot fight external pathogens, let alone itself. I don't understand Carter's reasoning.
  18. determined

    determined Senior Member

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    Keep in mind that this is not a published paper. It is a "pre-print" that has not been peer-reviewed.
  19. beike

    beike

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    The autoimmunity hypothesis coincides very well with a study run recently that observed that three cfs patients experienced a significant decrease in all symptoms when they underwent chemotherapy. Killing off immune cells that are causing the autoimmunity seemed to at least temporarily help.

    http://www.biomedcentral.com/1471-2377/9/28/abstract
  20. aruschima

    aruschima I know nothing

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    Hi, this is a very interesting post . Who is Carter and when and where was this published?

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