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Fidelity of target site duplication and sequence preference during XMRV integration

Discussion in 'XMRV Research and Replication Studies' started by subtr4ct, Apr 28, 2010.

  1. subtr4ct

    subtr4ct Senior Member

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    Abstract is here. I am browsing from work, so it is hard to tell, but I think the whole paper is avaialble free here.
     
  2. lansbergen

    lansbergen Senior Member

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  3. hvs

    hvs Senior Member

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    Gee, hard to parse, but it seems to me that it simply states that the researchers believe XMRV will prove capable of promoting disease in humans.

    Because it is bio-mechanically possible, they conclude:
     
  4. Funkster

    Funkster

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    Silverman et al with new paper. Seems like excellent work. Gerwyn, ready to comment on it?

    "The site and fidelity of integration have significant implications for the fate of both the virus and the host cell. Although the present study shows that XMRV integration proceeds with high fidelity, further analysis of additional XMRV integration sites in human tissues would be necessary to clarify whether insertional mutagenesis plays a pathogenic role during XMRV infection. Many viruses from the gammaretrovirus genus of the Retroviridae family, such as MLV, feline leukemia virus, and koala retrovirus, are responsible for leukemogenesis and other diseases in their respective host species [60]. Therefore, the recent evidence of authentic infections of humans by XMRV and the association of XMRV infection with prostate cancer and chronic fatigue syndrome [1], [6], [7] are alarming and warrant further investigations to determine the causal relationship and pathogenic mechanisms."

    They are consistantly using prostata cancer and Chronic Fatigue Syndrome.

    We are not alone...
     
  5. jimbob

    jimbob ME/CFS84-XMRV+

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    the scarier it is for them, the better it is for us!
     
  6. usedtobeperkytina

    usedtobeperkytina Senior Member

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    Again, I think when discussing XMRV with people in the public we should compare it to FeLV, not HIV.

    Tina
     
  7. kwietsol

    kwietsol

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    "Alarming" is good.

    Hello, world! Time to pay attention!
     
  8. gracenote

    gracenote All shall be well . . .

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    Here's a look at it's funding.

     
  9. subtr4ct

    subtr4ct Senior Member

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    That's about all I could get out of it, too. If I only had a more appropriate educational background! Assuming we are interpreting the general gist correctly, this goes along with what Gerwyn was saying re: mitochondria recently in another thread. I.e., there are specific biological mechanisms that imply that the idea that XMRV causes CFS is not far-fetched.
     
  10. Gerwyn

    Gerwyn Guest

    The science is excellent.It is what I have been hoping for. XMRV was originally found inserted within CREB genes.CREB genes are regulatory genes which affect systems all over the body. I have the hypothesis that XMRV does irs dirty work by causing the creb gene to malfunction.Untill this paper there was no actual evidence that XMRV could affect the CREB gene in this way.Insertional mutagenesis is such a mechanism.Xmrv can act as a duplication mutation or a deletion.Either way the proteins formed from CREB would be abnormal and affect their regulatory function.with this paper at last we have a mechanism how such a "simple" virus could cause multi systemic disease.We have an explanatory model to club Drs with.
     
  11. kwietsol

    kwietsol

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    Thank you, Gerwyn!
     
  12. alphahusky

    alphahusky

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    Thank you, Gerwyn. The weather here today is just terrible, and I'm so strongly affected by the weather, I can't make sense of anything scientific. Well, quite honestly, lately I just can't. Being up every morning with my daughter and not getting to sleep during my strongest sleep hours (even though I would still have to take meds to sleep) in the morning, everything is turning to mush in my head. But you always help make sense of stuff.
     
  13. natasa778

    natasa778 Senior Member

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    Hi Gerwyn, have you had a chance to look at the other transcription factor NFATc3?

    XMRV provirus integration sites were mapped in DNA isolated from human prostate tumor tissue to genes for two transcription factors (NFATc3 and CREB5) and to a gene encoding a suppressor of androgen receptor transactivation (APPBP2/PAT1/ARA67).
    http://www.si-rna.com/showabstract.php?pmid=17234809

    also interesting that mouse leukemia virus was found integrated by a chemokine receptor gene
     
  14. natasa778

    natasa778 Senior Member

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    NFAT transcription factor - T cell function and obesity

    Antigen receptor engagement on T lymphocytes activates transcription factors important for stimulating cytokine gene expression. This is critical for clonal expansion of antigen-specific T cells and propagation of immune responses. Additionally, under some conditions antigen receptor stimulation initiates apoptosis of T lymphocytes through the induced expression of CD95 ligand and its receptor. Here we demonstrate that the transcription factor, NFAT, which is critical for the inducible expression of many cytokine genes, also plays a critical role in the regulation of T cell receptor-mediated CD95 ligand expression....

    http://www.jbc.org/content/272/50/31427.abstract


    And
    Role of Transcription Factor NFAT in Glucose and Insulin Homeostasis
    Compromised immunoregulation contributes to obesity and complications in metabolic pathogenesis. Here, we demonstrate that the nuclear factor of activated T cell (NFAT) group of transcription factors contributes to glucose and insulin homeostasis... Together, these results establish a role for NFAT in glucose/insulin homeostasis and expand the repertoire of NFAT function to metabolic pathogenesis and adipokine gene transcription. http://mcb.asm.org/cgi/content/abstract/26/20/7372

    Bingo!

    Now on to what to do about it
     
  15. natasa778

    natasa778 Senior Member

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    Nuclear factor of activated T-cells (NFAT) is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems.

    The NFAT transcription factor family consists of five members NFATc1, NFATc2, NFATc3, NFATc4, and NFAT5.[1] NFATc1 through NFATc4 are regulated by calcium signaling. Calcium signaling is critical to NFAT activation because calmodulin (CaM), a well known calcium sensor protein, activates the serine/threonine phosphatase calcineurin (CN). Activated CN rapidly dephosphorylates the serine rich region (SRR) and SP-repeats in the amino termini of NFAT proteins resulting in a conformational change that exposes a nuclear localization signal resulting in NFAT nuclear import. Nuclear import of NFAT proteins is opposed by maintenance kinases in the cytoplasm and export kinases in the nucleus. Export kinases, such as PKA and GSK-3β, must be inactivated for NFAT nuclear retention. NFAT proteins have weak DNA binding capacity. Therefore, to effectively bind DNA NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn.[2] This important feature of NFAT transcription factors enables integration and coincidence detection of calcium signals with other signaling pathways such as ras-MAPK or PKC. Additionally, this signaling integration is involved in tissue specific gene expression during development.
     
  16. Gerwyn

    Gerwyn Guest

    bingo indeed speak soon
     
  17. JillBohr

    JillBohr Senior Member

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    Hey Natasa and Gerwyn, I know you both speak English being UK citizens and all but can you translate this into American? I am so looking forward to you both writing an XMRV for Dummies book.
     
  18. Gerwyn

    Gerwyn Guest

    Hi Jillbohr

    Sorry the excitement of the paper sent me into geek mode

    Ok this is my take home message(s)

    Our automatic body processes are contolled by the autonomic nervous system.If this becomes dysfunctional then we are left with the neuroendocrine symptoms of ME sensitivity to lights sound ,high resting heartrate POTs poor temperature control and so on.The organic thermostat that controls all these functions is the hypothalamus.When any function such as heart rate strays outside the normal range this is detected by the hypothalamus and brought back into normal ranges by the action of the pituitaty gland and the Adrenal cortex(and medulla).If this control system breaks down our autonomic functions go haywire.

    The "molecular thermostat" of the immune system is the NFATgene (amoung others).By inserting into this gene XMRV can act as a "molecular dimmer switch" for this gene and affect the levels of its activity and in turn the levels of various chemical components of the immune system

    One eample would be that if the NFAT gene was upregulated by the "dimmer switch" being turned up then the level of circulating cytokines would be high.There would be chronic levels of inflammation in multiple body systems

    This leads to a number of pretty horrible consequences.

    Raised levels of abdominal fat

    Impaired Glucose tolerance and increased insulin resistance

    Altzheimers type symptoms and cardiovascular abnormalities increase risk of stroke and pots type symptoms impaired blood flow to brain.

    these cytokine levels(interferon and interleukins) can lead to metabolic syndrome.

    Raised interferon levels lead to hyper stimulation of TFN alpha gene. This can lead to high levels of Nitric oxide which in turn depletes glutathione directly and indirectly damaging mitochondria and creating a partial block in the methylation cycle.

    Raised TFN alpha leads to muscle fatigue and pain .This also reduces BDFN gene expression(also caused by blocking creb) reducing fat oxidation and further compounding problems with fatigue cognitive problems like memory dyscalculia dyslexia and so on

    CREB and NFAT co regulate each other just to make life really interesting!!!!


    Hope this helps

    All the best Gerwyn
     
  19. Wonko

    Wonko Senior Member

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    many thanks for the explaination Gerwyn
     
  20. Countrygirl

    Countrygirl Senior Member

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