Community Symposium on molecular basis of MECFS! DISCUSSION THREAD!

Ben H

OMF Correspondent
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From the separate thread but thought all here would like to see the culmination as it were of the Symposium:


Here is a roundup of the amazing MECFS17 Community Symposium that many of you watched and commented on :)




Open Medicine Foundation (OMF)




Ron Davis Gets Standing Ovation!
Very rare for a scientific presentation!

August 12 was an amazing day at OMF’s Community Symposium on the Molecular Basis of ME/CFS at Stanford University. The room was buzzing with positive energy. The researchers' presentations were incredible and showed great insights into this disease. There were renowned scientists from all over the world, and from related fields revealing interesting new insights into ME/CFS research. Patients, caregivers, clinicians, and other researchers attending interacted with these scientists during breaks, lunch and an evening reception, and there was so much excitement and optimism in the room.

Here are some of the highlights from this amazing meeting (stay tuned for more!):
  • Additional comprehensive evidence that ME/CFS is a molecular disease was presented.(Yet another nail in the PACE coffin!)

  • Experts in metabolism, immunology, genomics, neurophysiology, electrical engineering and bioinformatics presented data.

  • We learned about innovative ways to find new pain drugs and saw elegant evidence of a clear connection between the immune system and the brain.

  • The scientists decided to continue as a “Working Group”, and are already planning multiple new ways to work together to facilitate and accelerate progress.

  • Nobel laureate Mario Capecchi noted how important patient participation is in studying any disease, and how impressed he was with the amount of ME/CFS patient participation!

  • In Ron Davis’ concluding remarks he stated that it is clear that what is missing is funding. He described ME/CFS as “a horribly underfunded disease”. Progress has been impressive despite the limited resources, but it is clear that more funding is needed to unravel this mystery and find treatments and a cure fast.
We need your help to accelerate the pace!

Every Donation of Every Size Brings Us Closer to A Cure.
To End ME/CFS, the world is counting on brilliant researchers working collaboratively.

If you have ever thought to donate to our End ME/CFS project, NOW IS THE TIME! We need to keep the momentum going and leverage the expanding interest in finding a cure.

Thank you for giving what you can today.

Sincerely,



Linda Tannenbaum
CEO/President

PS - Please forward this message to family and friends. Encourage them to join you in your support of OMF's research for treatments and a cure.



Thanks guys,


B

@Janet Dafoe (Rose49) @AshleyHalcyoneH
 

Kati

Patient in training
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From the separate thread but thought all here would like to see the culmination as it were of the Symposium:


Here is a roundup of the amazing MECFS17 Community Symposium that many of you watched and commented on :)




Open Medicine Foundation (OMF)




Ron Davis Gets Standing Ovation!
Very rare for a scientific presentation!

August 12 was an amazing day at OMF’s Community Symposium on the Molecular Basis of ME/CFS at Stanford University. The room was buzzing with positive energy. The researchers' presentations were incredible and showed great insights into this disease. There were renowned scientists from all over the world, and from related fields revealing interesting new insights into ME/CFS research. Patients, caregivers, clinicians, and other researchers attending interacted with these scientists during breaks, lunch and an evening reception, and there was so much excitement and optimism in the room.

Here are some of the highlights from this amazing meeting (stay tuned for more!):
  • Additional comprehensive evidence that ME/CFS is a molecular disease was presented.(Yet another nail in the PACE coffin!)

  • Experts in metabolism, immunology, genomics, neurophysiology, electrical engineering and bioinformatics presented data.

  • We learned about innovative ways to find new pain drugs and saw elegant evidence of a clear connection between the immune system and the brain.

  • The scientists decided to continue as a “Working Group”, and are already planning multiple new ways to work together to facilitate and accelerate progress.

  • Nobel laureate Mario Capecchi noted how important patient participation is in studying any disease, and how impressed he was with the amount of ME/CFS patient participation!

  • In Ron Davis’ concluding remarks he stated that it is clear that what is missing is funding. He described ME/CFS as “a horribly underfunded disease”. Progress has been impressive despite the limited resources, but it is clear that more funding is needed to unravel this mystery and find treatments and a cure fast.
We need your help to accelerate the pace!

Every Donation of Every Size Brings Us Closer to A Cure.
To End ME/CFS, the world is counting on brilliant researchers working collaboratively.

If you have ever thought to donate to our End ME/CFS project, NOW IS THE TIME! We need to keep the momentum going and leverage the expanding interest in finding a cure.

Thank you for giving what you can today.

Sincerely,



Linda Tannenbaum
CEO/President

PS - Please forward this message to family and friends. Encourage them to join you in your support of OMF's research for treatments and a cure.



Thanks guys,


B

@Janet Dafoe (Rose49) @AshleyHalcyoneH
The like button is too mild here, we need ♥️
 

ash0787

Senior Member
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I did not see every section of the talk, was there any mention of a plan to mass produce the nano needle thing ? could patients buy one to prove to disbelievers there is something fundamentally different ? or would it be useless without a cell seperation machine and various other laboratory tools to hand ?

Also any plans to treat whitney in the short term ? suramin or something ? I think I heard ritximab did not help
 

mariovitali

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@Janet Dafoe (Rose49)

As discussed in our messages, i am sending you the latest findings. i would kindly ask from Dr Davis to review this information.


cc : @JaimeS @A.B. @Snow Leopard @alex3619 @Jonathan Edwards

I am CC ing you because i feel that -hopefully- this is a very important post.

The role of Endoplasmic Reticulum Stress, Myosins, Liver X Receptor, Unfolded Protein Response , Autophagy, TAM Receptors, D3 (CYP27A1 and GC Genes) and T Cells activation.

Some excerpts :


Regarding VDBP/ GCMAF according to [6] :

VDBP, a glycosylated-globulin, plays an important role not only in transporting vitamin D and circulating metabolites, but also in other biological functions to affect carcinogenesis. It is a member of the circulating actin scavenger system that prevents formation of F-actin networks and harmful effects following from cell or tissue damage12. VDBP is involved in macrophage activation by converting as group-specific component protein derived macrophage activating factor (GcMAF) and neutrophil chemotaxis by enhancing the chemotactic effect of complement-derived peptides

LXR Receptor - TAM Receptors - T Cells

From [1] we read :

“Additionally, cholesterol-dependent activation of Liver X receptor (LXR) transcription factors has been shown to upregulate the expression of Mer in macrophages as a positive feedback mechanism promoting engulfment of apoptotic cells and immunosuppression

“Thus, TAM receptors are responsible for creating an anti-inflammatory and reparative setting around apoptotic sites that prevents inflammatory responses towards self-derived antigens and restores tissue homeostasis.”


TAM receptors regulate the bilateral communication between dendritic and lymphoid T cells in different immunostimulatory conditions. Once activated, adaptive immune cells must communicate back with innate cells to avoid uncontrolled and chronic activation of the immune system”

You may also see the Liver X Receptor in Network Analysis here (posted on May 2017) :




MYOSINS

Please note : The first mention of MYO9B on Phoenix Rising :


http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-85#post-759322


Myosins comprise a superfamily of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other motility processes in eukaryotes. They are responsible for actin-based motility

In [3] we find yet another association of MERTK with phagocytosis and Myosin :


Mertk can drive redistribution of dynamic protein, myosin II, from F-actin bundles to the sites of phagocytic cup [27]. A large body of evidence shows that Mertk plays an essential role in phagocytosis through activation of its downstream signaling which is critical for cytoskeletal rearrangement during phagocytosis.”

Interestingly, MYO9B is also found to be associated with impaired Phagocytosis as found in [5] :

“The rapid recruitment of phagocytic cells to inflammatory “hot spots” is a basic function of the innate immune system. Given the profound effect of Myo9b deficiency on membrane protrusive activity and motility, it would be reasonable to expect that monocyte recruitment is impaired in vivo. Indeed, we found that the accumulation of monocytes and macrophages in the peritoneal cavity of Myo9b−/− mice intraperitoneally injected with the chemoattractant C5a was severely blunted. Hence, Myo9b clearly has an important function in innate immune responses. Another essential function of professional “big eaters” such as macrophages is phagocytosis. Rho-family GTPases are intimately involved in controlling the cytoskeletal dynamics during phagocytosis (44), and we would predict that Myo9b is also important for the local coordination of membrane extensions and particle internalization.”


It is time now to look at the involvement on how Endoplasmic Reticulum Stress, Misfolded Proteins and the Unfolded Protein Response is pertinent to the information shown above :


According to [8] :

In response to the challenge of misfolded proteins, autophagy has a crucial function as an adaptive ‘self-eating’ process by which cellular components are encapsulated within autophagosomes and degraded. Similarly to the unfolded protein response (UPR), autophagy can result in either cell survival or cell death167,168. The mechanisms by which the UPR induces autophagy are incompletely understood, but probably involve signalling through PKR-like ER kinase (PERK)–eukaryotic translation initiation factor 2α (eIF2α) and inositol-requiring enzyme 1α (IRE1α)169.


Relevant Genes :


GAS6 , MERTK, GGCX, VKORC1,TYRO3,PLCG1, FASLG, MYO9B, SH2B3, RHOA,PROS1,GC,NR1H3, CYP27A1, NR1H4


Example run using Machine Learning : We notice how the ML Algorithm identifies Liver disease, FAS Ligand, Phagocytosis, T Cells, Vitamin D3 as relevant.




Original post : http://algogenomics.blogspot.com/2017/08/new-findings-myosin-d3-actins.html



References



[1]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082387/

[2] : https://www.ncbi.nlm.nih.gov/pubmed/25624460

[3]: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117787

[4] : http://www.rug.nl/research/portal/p...on(4efdb8a4-b704-4d42-8ea2-f9d875ddab89).html

[5] : http://www.pnas.org/content/107/27/12145.full

[6[ : https://www.nature.com/articles/srep07956

[7] : https://www.ncbi.nlm.nih.gov/pubmed/10891358

[8] : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310224/
 
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valentinelynx

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Mike VanElzakker talks about the same difficulty in how to look into the idea, because is not possible to biopsy the vagus.
Indicates the necessity of autopsy studies of ME/CFS patients. I am ignorant in this area: what is the best way to increase the likelihood of one's body being donated for specific research purposes? Is there a pathway or pathways for donating to a tissue bank for ME/CFS study?
 

mariovitali

Senior Member
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I just received a message from a CFS/ Fibromyalgia patient saying that her Fibroscan has shown an F3 Fibrosis stage. (8.6 kPa). She will send me the actual test results later today and i will post them,.


@Janet Dafoe (Rose49)

I am quoting you only if i believe that it is absolutely necessary. I will post one more important (brand new) piece of Information - shortly after this. Please forward to Dr Davis :



From [1] , see References at bottom:

Conditions that induce ER stress also induce autophagy. It is well-established that autophagy constitutes a major protective mechanism that allows cells to survive in response to multiple stressors, and it helps organ- isms to defend against degenerative, in ammatory, infectious, and neoplastic disorders. It needs to be noted that ER stress itself is capable of activating autophagy, while impaired autophagy can promote ER stress.


DATE : December 1st 2005

PGI = Persian Gulf War Ilness, FM = Fibromyalgia.Please note the mention of Gelsolin (in blue color).

This pilot investigation demonstrated that the CFS, PGI and FM subjects had a significant overlap between their syndromes. Despite the differences in their original case designations, they had very similar responses on questionnaire, quality of life and nociceptive measures. Again, despite the differences in the diagnostic label applied to them for study entry, their cerebrospinal fluid proteomes demonstrated reproducible constituents. The CFS – related proteome was essentially the same for the two independent CFS cohorts. The proteome was remarkable for the number of proteins associated with protein misfolding and cerebrovascular amyloidosis syndromes. These included gelsolin, amyloid β protein (APLP1), Ig λ, C3, C4, chromogranin B, α2-macroglobulin and α-1-antichymotrypsin antiproteases, the heme and iron scavengers haptoglobin, hemopexin, and orosomucoid 2, angiogenic and antiangiogenic prohormones such as autotaxin and PEDF, and the structural proteins gelsolin, BEHAB and keratin 16. Their presence in the CFS – associated proteome suggested a potential pathophysiological link. We propose the hypothesis that CFS may be a nonlethal, protein – misfolding, cerebrovascular amyloidosis – like syndrome.
https://link.springer.com/article/10.1186/1471-2377-5-22




You will also recall we discussed about Actins in : http://algogenomics.blogspot.com/2017/08/new-findings-myosin-d3-actins.html


A Google search in Phoenix Rising finds this :

These researchers found that the levels of the G or monomeric actin fragments in the PBMC’s of CFS patients were positively correlated with levels of the 37-kDa fragment. Tests showed that caspase 3, m-calpain, and PBMC extracts from CFS patients were all able to fragment G-actin in vitro.
<SNIP>
Two actin ‘capping’ proteins, villin and gelsolin, prepare monomeric actin for polymerization. When cells die both G and F actin are released into the bloodstream where they undergo polymerization.This results in increased plasma viscosity.
<SNIP>

This suggests that actin, along with RNase L and the other proteins, is being fragmented in the cells of CFS patients. Given actins immune activities the authors believe that actin fragmentation ‘undoubtedly’ further contributes to the immune problems seen in CFS. G-actin fragmentation could, by taking away the supply of usable actin, negatively impact membrane integrity, phagocytosis, cell adhesion and T-cell activation.
Link :

http://phoenixrising.me/research-2/...irleir-m-d-ph-d-crc-press-washington-d-c-2002

We note "actin fragmentation" and gelsolin is being mentioned. But apparently MERTK comes to the rescue :

Mertk Deficiency Affects Macrophage Directional Migration via Disruption of Cytoskeletal Organization

<SNIP>

"Such random movement was observed on the Mertk-/- cells. Our results indicate that Mertk mutation not only affects the polymerization of actin filaments and the distribution of dynamic protein myosin II, but also MTOC formation and localization. Collectively, this abolished the directional movement by Mertk-/- macrophages."

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117787




References

[1] : Autophagy, Volume 8, ISBN: 978-0-12-802937-4
 
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since I seem to be overlooked on twitter, and here, I'm throwing my bodyparts in the mix ;)



this is happening all along the nervus vagus or HPA-axis or whatever it's called, in my brain it's releasing neurotransmitters, it started after (alternative) treatment of several common bugs, ergo my ME is a blockage of nerve endings, or rather was because I'm improving slowly but steadily
 

mariovitali

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Just received the following Fibroscan from a CFS Patient. Yet one more patient with Liver Fibrosis (this one is F2)

See attached file (sorry for the duplicate file)

Has anyone else here performed a Fibroscan?
 

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msf

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since I seem to be overlooked on twitter, and here, I'm throwing my bodyparts in the mix ;)



this is happening all along the nervus vagus or HPA-axis or whatever it's called, in my brain it's releasing neurotransmitters, it started after (alternative) treatment of several common bugs, ergo my ME is a blockage of nerve endings, or rather was because I'm improving slowly but steadily
I might be wrong, but I don´t think the HPA axis is actually a physical axis.