Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)

Pyrrhus

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Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)

Authors: Xiaoyu Che, Christopher R. Brydges, Yuanzhi Yu, Adam Price, Shreyas Joshi, Ayan Roy, Bohyun Lee, Dinesh K. Barupal, Aaron Cheng, Dana March Palmer, Susan Levine, Daniel L. Peterson, Suzanne D. Vernon, Lucinda Bateman, Mady Hornig, Jose G. Montoya, Anthony L. Komaroff, Oliver Fiehn, W. Ian Lipkin
https://www.medrxiv.org/content/10.1101/2021.06.14.21258895v1.full

This is a (non-peer-reviewed) preprint from Ian Lipkin and a whole host of collaborators.

This metabolomics paper found decreased levels of certain membrane phospholipids in ME patients compared to controls, notably phosphatidyl-choline, phosphatidyl-ethanolamine, and related plasmalogens. This confirms previous research findings of decreased membrane phospholipids.

Phosphatidyl-choline and phosphatidyl-ethanolamine are the two most abundant phospholipids in cells and are important components of cell membranes and mitochondrial membranes, especially in the nervous system.

1626042816369.png


The authors suggest that this finding might indicate metabolic changes to the Kennedy Pathway, also known as the CDP-choline pathway, which is one of two metabolic pathways for synthesizing phosphatidyl-choline in the body. The other pathway is the CDP-ethanolamine pathway, which synthesizes phosphatidyl-ethanolamine, and then converts it to phosphatidyl-choline with the use of a methyl donor (AdoMet/SAMe).

The authors also suggest that their findings might indicate metabolic changes to the Tricarboxylic Acid Cycle (TCA), also known as the Citric Acid Cycle, which is the main energy-generating metabolic pathway in the cell.

The authors further suggest that the observed metabolite differences might serve as a biomarker for ME, especially in females.

Excerpt:
Che et al 2021 said:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance and gastrointestinal problems. The pathogenesis is not fully understood.

Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.

In ME/CFS cases, the regression, Bayesian and enrichment analyses all revealed abnormal levels of several membrane lipids indicating dysregulation of the Kennedy pathway: decreased plasma levels of plasmalogens, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, and phospholipid ethers. Enrichment analyses revealed decreased levels of cholines, ceramides and carnitines, and increased levels of long chain triglycerides, dicarboxylic acids, hydroxy-eicosapentaenoic acid, and the tricarboxylic acid cycle intermediates alpha-ketoglutarate and succinate.

Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873). Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight specific abnormalities that may provide insights into the pathogenesis of ME/CFS.
(spacing added for readability)
 
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Thank you, @Pyrrhus for this recent influx of journal articles. I don't have the energy for all of them right now, but this one caught my eye because it relates to some other reading I've done recently. The other articles are on my to-do list.

This study's main finding was that the blood plasma of ME/CFS sufferers was relatively depleted in a bunch of phospholipids, lipids, and related compounds, and was relatively oversaturated with hydroxy-eicosapentaenoic acids (HEPEs), dicarboxylic acids, and unsaturated long chain triglycerides. These compounds are deeply involved in a staggering number of metabolic processes, and since I'm no expert, I'll just point out a couple things that stood out to me.

One compound that appears to be depleted is Resolvin D1. Resolvins are a really interesting category of lipid compounds that are involved in the 'cessation' stage of inflammatory response. For instance, It's possible that the synthesis of resolvins from EPA/DHA etc. accounts for the purported anti-inflammatory effects of fish oil supplementation. Resolvins are pretty simple molecules and I don't see why we couldn't synthesize them, though I haven't seen any resolvin supplements on the market and we don't really know if there would be issues with systemic or local bioavailability. Still, it's something that might be a fruitful area of research.

Resolvins are synthesized in the body by lipoxygenase as well as cyclooxygenase-2 (COX-2), the latter of which is the main target of NSAIDs. In my opinion, this calls into question how helpful NSAIDs are for ME/CFS inflammation - we already know they're a risk factor for gastritis.

HEPEs also jumped out at me, even though the article doesn't discuss them that much. Like resolvins, HEPEs are a product of lipoxygenase, and have an anti-inflammatory effect that is mediated by peroxisome proliferator–activated receptors (PPARs), though unlike Resolvin D1, HEPEs are increased in ME/CFS sufferers. Clearly, there is some dysregulation in the fatty acid pathways, and I think PPARs stand out as a target. This was something I was already looking into because my immunologist (Dr. Susan Levine) suggested that I try fenofibrate, a relatively old drug used to treat dyslipidemia even before the discovery of statin drugs. Its mechanism of action is by activation of PPAR-alpha, which increases lipolysis. Another supplement I'm aware of which acts as a PPAR-alpha agonist is palmitoylethanolamide, which is actually an endogenous compound, and is widely available as a supplement, seeing some usage for treating pain and inflammation.

On a separate topic - for all this study's discussion of phospholipids, I find it a little bit unusual that they did not consider the involvement of antiphospholipid syndrome (APS) in ME/CFS. There is at the very least a subset of ME/CFS sufferers for whom this autoimmune disease is present. Hypercoagulation is usually the focus when it comes to the disease's effects, but since mitochondria can synthesize several phospholipids, it wouldn't surprise me if APS more directly affects mitochondrial function.

I think APS is an important factor to consider in light of the article's suggestion that choline depletion might be to blame for some aspects of ME/CFS. The line of reasoning is that choline is an important precursor to all these phospholipids, and also of acetylcholine which is an important neurotransmitter in regulating the autonomic nervous system. However it's unclear to me whether choline depletion is a cause or a result of the disease process - they seem to imply the former, but I can just as easily imagine that the destruction of phospholipids by AP antibodies increases the metabolic demand for choline. Critically, we must consider whether choline depletion is in some sense protective against APS inflammation and hypercoagulation. We already know that dietary choline can increase thrombosis risk due to production of TMAO and it would be a shame if it also somehow upregulated AP antibodies by increasing synthesis of particular phospholipids. I would be nervous to supplement with choline without first fully ruling out APS.

Overall, there is a lot of good data in this paper and even though the sample size is a little small, the analysis seems pretty solid. I'm hopeful that this will link up with a lot of other metabolomic profiles that are currently being worked on to help paint a clearer picture of the whole inflammation and mitochondrial dysfunction region of ME/CFS pathophysiology.
 

mariovitali

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Just to give my two cents. Please see below a thread where a Network Analysis graph is shown (2017) :

https://forums.phoenixrising.me/threads/machine-learning-assisted-research-on-cfs.51283/#post-846815

Choline deficiency, Peroxisome proliferators have been identified as potentially "Central" concepts of ME/CFS.


Ever since i've been trying to identify why these concepts (along with others) have been there. One of the major nodes (not shown on the thread post above) is Hepatotoxicity. Please note that the Network Analysis shown was run taking into account a number of other syndromes including Gulf War Ilness syndrome, Post-accutane syndrome, Post-Finasteride syndrome etc.

The hypothesis generated was that we have a Liver Injury that takes place via toxic substances, certain medications and =of course- certain viruses. This is the common factor between all ME/CVFS triggers.

Vitamin K is also there as a central node (NO avoidance or supplementation of Vitamin K is implied). The full version of the network analysis generated is the following :


network-clean.png





We see nodes related to Oxidation, Bile acids metabolism (CYP7B1, CYP27A1), Liver issues (NAFLD, Steatohepatitis), Peroxisomes (peroxisome, pparalpha,ppargamma) , Mitochondria (PGC1) .

Hydrolysis is way to broad of subject but it may be helping us if Hydrolysis matches a broader hypothesis on the main mechanism.

We just have to use such techniques where all past and present findings will be added and we should then investigate "where all ends meet"
 

nerd

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Another important step in showing the metabolic issues of ME. This also supports the CAC hypotheses.

I'm not sure what configuration of HEPE they found. If we knew this, we could make specific estimations on its origin and if it serves protective effects or not. But my overall impression is that EPAs might be in the center here, since they are not only the precursor of HEPEs but also a potential origin of the dicarboxylic acids. I'm not sure how this actually links to IBS though.

My EPA levels in the blood were very low when compared to DHA levels. This would be consistent in that EPAs might serve as hydroxyl scavengers (10.19080/NFSIJ.2019.09.555752). But it has to be something specific that only EPA is affected and not DHA. Maybe it only affects a certain organ or cell type? If we knew the configuration, some conclusions could be drawn. It could be the heart, it could be the pancreas, the liver... My first guess would be the heart because we already know the role of monocyte migration and endothelial dysfunction and 18-HEPE from migrated macrophages serves a protective role in the heart (10.1084/jem.20132011).

I found this paper helpful for understanding omega-3 fatty acids:
Omega-3 fatty acid-derived mediators that control inflammation and tissue homeostasis (2019) [10.1093/intimm/dxz001]
 

Learner1

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Phospholipids have been thought to be involved for quite awhile, glad some attention is being brought to this
 

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Pyrrhus

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Thanks everyone for the great analyses!

One compound that appears to be depleted is Resolvin D1. Resolvins are a really interesting category of lipid compounds that are involved in the 'cessation' stage of inflammatory response. For instance, It's possible that the synthesis of resolvins from EPA/DHA etc. accounts for the purported anti-inflammatory effects of fish oil supplementation.
Yes, resolvins may indeed be one of the ways that omega-3 fatty acids exert their potent anti-inflammatory effects. But there are also other ways in which omega-3 fatty acids are anti-inflammatory.

On a separate topic - for all this study's discussion of phospholipids, I find it a little bit unusual that they did not consider the involvement of antiphospholipid syndrome (APS) in ME/CFS.
Very interesting point.

I think APS is an important factor to consider in light of the article's suggestion that choline depletion might be to blame for some aspects of ME/CFS. The line of reasoning is that choline is an important precursor to all these phospholipids, and also of acetylcholine which is an important neurotransmitter in regulating the autonomic nervous system. However it's unclear to me whether choline depletion is a cause or a result of the disease process - they seem to imply the former, but I can just as easily imagine that the destruction of phospholipids by AP antibodies increases the metabolic demand for choline.
It's also important to remember that the CDP-choline pathway (Kennedy pathway) is not the only metabolic pathway for synthesizing phosphatidyl-choline. There is also the CDP-ethanolamine pathway, which synthesizes phosphatidyl-ethanolamine and then uses a methyl donor (AdoMet/SAMe) to convert phosphatidyl-ethanolamine into phosphatidyl-choline.

This CDP-ethanolamine pathway for synthesizing phosphatidyl-choline is so important that it has been estimated to account for a large percentage (perhaps more than 50%) of all methyl donor (AdoMet/SAMe) use in the body. If the body's methylation capacity is reduced, this might reduce synthesis of phosphatidyl-choline.

Related discussion:
https://forums.phoenixrising.me/thr...the-methylation-cycle-trap-or-blockage.83459/

We already know that dietary choline can increase thrombosis risk due to production of TMAO
I believe this only occurs with excessive doses of choline, which are not fully absorbed in the intestines, where intestinal microbes then degrade the excess choline into TMAO...

This was something I was already looking into because my immunologist (Dr. Susan Levine) suggested that I try fenofibrate
I presume you saw that Levine is one of the authors!

Just to give my two cents. Please see below a thread where a Network Analysis graph is shown (2017) :

https://forums.phoenixrising.me/threads/machine-learning-assisted-research-on-cfs.51283/#post-846815

Choline deficiency, Peroxisome proliferators have been identified as potentially "Central" concepts of ME/CFS.
That's very interesting! Thanks.

My EPA levels in the blood were very low when compared to DHA levels.
I believe that is to be expected. EPA has a shorter half-life in plasma (2-3 days), whereas DHA has a longer half-life in plasma (3-5 days). In addition, EPA appears to have a shorter half-life in cell membranes (1-5 days), whereas DHA has a longer half-life in cell membranes (months? years?). Once EPA is incorporated into cell membranes, it appears to be converted into DPA (docosapentaenoic acid), palmitoleic acid, or phosphatidyl-serine. Of course, these half-lives are approximate and highly dependent upon dosing schedule and dose amounts.
 
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Yes, resolvins may indeed be one of the ways that omega-3 fatty acids exert their potent anti-inflammatory effects. But there are also other ways in which omega-3 fatty acids are anti-inflammatory.
You're right, my statement was not broad enough. In fact I think that this bespeaks a natural advantage of diet-based interventions - that they act more broadly, via the myriad pre-existing pathways that have been forged by evolution to make use of available resources. Though of course there are many times when a targeted pharmaceutical intervention is advantageous for other reasons.

It's also important to remember that the CDP-choline pathway (Kennedy pathway) is not the only metabolic pathway for synthesizing phosphatidyl-choline. There is also the CDP-ethanolamine pathway, which synthesizes phosphatidyl-ethanolamine and then uses a methyl donor (AdoMet/SAMe) to convert phosphatidyl-ethanolamine into phosphatidyl-choline.
This CDP-ethanolamine pathway for synthesizing phosphatidyl-choline is so important that it has been estimated to account for a large percentage (perhaps more than 50%) of all methyl donor (AdoMet/SAMe) use in the body. If the body's methylation capacity is reduced, this might reduce synthesis of phosphatidyl-choline.
That's a very good point. Since the Kennedy pathway 'uses up' choline and might contribute to deficit in acetylcholine, I wonder if it might actually be helpful to inhibit the pathway. You would be in some sense trading phosphatidylcholine for acetylcholine (and both are necessary, obviously), but if the increased acetylcholine improves dysregulation in autonomic nerve function which is so important for controlling inflammation, it might reduce the cause for what seems to be a pathologically high turnover of phosphatidylcholine to begin with. That's pure speculation though.

I believe this only occurs with excessive doses of choline, which are not fully absorbed in the intestines, where intestinal microbes then degrade the excess choline into TMAO...
This is true, but I think the risk of microbial degradation of choline is much higher in ME/CFS sufferers, particularly due to the prevalence of SIBO/malabsorption type issues.

I presume you saw that Levine is one of the authors!
Hahaha, I actually did not see that (curse my visual processing!) but now it all makes sense. :headslap:
 

junkcrap50

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Resolvins are pretty simple molecules and I don't see why we couldn't synthesize them, though I haven't seen any resolvin supplements on the market and we don't really know if there would be issues with systemic or local bioavailability. Still, it's something that might be a fruitful area of research.
You can buy Resolvins as a supplement. But lots of studies show DHA and EPA supplementation readily convert to resolvins. https://www.lifeextension.com/vitamins-supplements/item02223/pro-resolving-mediators
 

ljimbo423

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You can buy Resolvins as a supplement. But lots of studies show DHA and EPA supplementation readily convert to resolvins.
I've been taking 3-5 grams a day of DHA/EPA, from fish oil for a few years. Shortly after I started taking them, I noticed a reduction in how often I got ME/CFS flares but not PEM.

I still get PEM whenever I do to much physically but I only get flares now every 3-4 months. I think I use to get them about every month or so before I started the high dose fish oil.

The flares I get feel exactly like the flu and usually reduce me to not doing more than a very basic routine but only last about 24 hours. So to only get them every 3-4 months now is a BIG plus!
 
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You can buy Resolvins as a supplement. But lots of studies show DHA and EPA supplementation readily convert to resolvins. https://www.lifeextension.com/vitamins-supplements/item02223/pro-resolving-mediators
Wow, I must have missed that one! I'd be curious to try it out, myself. I know that generally DHA and EPA convert to resolvins, but the study posted here seems to show that the pathway for resolvin synthesis is impaired in people with ME/CFS, since they seem to have lower levels of it. Perhaps DHA/EPA supplementation helps somewhat, but it might turn out that supplementing with resolvins themselves is superior.

I've been taking 3-5 grams a day of DHA/EPA, from fish oil for a few years. Shortly after I started taking them, I noticed a reduction in how often I got ME/CFS flares but not PEM.

I still get PEM whenever I do to much physically but I only get flares now every 3-4 months. I think I use to get them about every month or so before I started the high dose fish oil.

The flares I get feel exactly like the flu and usually reduce me to not doing more than a very basic routine but only last about 24 hours. So to only get them every 3-4 months now is a BIG plus!
I'm glad DHA/EPA works out for you, and that seems to make sense in the context of this study's results. I've been taking 2g of omega 3's for quite a while now and I don't think it's helped my symptoms particularly. Perhaps I could up the dosage a bit.

dr levine prescribed me this just two days ago. i’ll be starting the fenofibrate tomorrow!
Same with me! I hope it ends up working out. I'm a little nervous about the possible gastrointestinal side effects because I have horrible IBS spectrum symptoms and food sensitivities. Also apparently myopathy/rhabdomyolysis are possible side effects, and given how much muscle pain I normally have, it might be harder for me to assess whether there's something additional happening.
 

ljimbo423

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I've been taking 2g of omega 3's for quite a while now and I don't think it's helped my symptoms particularly. Perhaps I could up the dosage a bit.
If I remember right, I was also taking about 2 grams a day of EPA/DHA and didn't notice anything. When I bumped it up to 3, that's when I started to notice I was getting my ME/CFS flares less often.

I don't know if that will work for you. We each seem to respond to supplements very individually.
 
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Pyrrhus

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Since the Kennedy pathway 'uses up' choline and might contribute to deficit in acetylcholine, I wonder if it might actually be helpful to inhibit the pathway. You would be in some sense trading phosphatidylcholine for acetylcholine (and both are necessary, obviously)
I'm not sure it's accurate to say that the Kennedy pathway 'uses up' choline, since the end result is phosphatidyl-choline, which I believe functions as the main storage form of choline in the body. Choline can then be "liberated" from the phosphatidyl-choline as needed...

This is true, but I think the risk of microbial degradation of choline is much higher in ME/CFS sufferers, particularly due to the prevalence of SIBO/malabsorption type issues.
That may well be!

There is also the CDP-ethanolamine pathway, which synthesizes phosphatidyl-ethanolamine and then uses a methyl donor (AdoMet/SAMe) to convert phosphatidyl-ethanolamine into phosphatidyl-choline.

This CDP-ethanolamine pathway for synthesizing phosphatidyl-choline is so important that it has been estimated to account for a large percentage (perhaps more than 50%) of all methyl donor (AdoMet/SAMe) use in the body. If the body's methylation capacity is reduced, this might reduce synthesis of phosphatidyl-choline.

Related discussion:
https://forums.phoenixrising.me/thr...the-methylation-cycle-trap-or-blockage.83459/
@mariovitali If you're not already aware, I forgot to mention that the CDP-ethanolamine pathway only takes place in the liver:
https://en.wikipedia.org/wiki/Phosphatidylethanolamine_N-methyltransferase
 

mariovitali

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@Pyrrhus

I searched a bit more for CDP-ethanolamine using a custom-built Information retrieval system. It was very interesting to find that CDP-ethanolamine along with other phospholipids are critical elements of mitochondrial function (based on my limited understanding)

Machine Learning has previously identified MAMs (Mitochondria-associated Membranes) as a critical factor of ME pathology (hypothesis) and the following paper explains how phospholipids (including cardiolipin which we found that ME patients have AntiCardiolipin antibodies) and mitochondrial function are tightly related

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660828/

Regarding Anticardiolipin antibodies and ME

https://pubmed.ncbi.nlm.nih.gov/19623655/
 
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Pyrrhus

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Machine Learning has previously identified MAMs (Mitochondria-associated Membranes) as a critical factor of ME pathology (hypothesis) and the following paper explains how phospholipids (including cardiolipin which we found that ME patients have AntiCardiolipin antibodies) and mitochondrial function are tightly related

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660828/
Thanks- that's a great paper!

I'm going to quote an excerpt here for the benefit of others:
Flis and Daum 2013 said:
Lipid Transport between the Endoplasmic Reticulum and Mitochondria (Flis and Daum 2013)

Mitochondria are partially autonomous organelles that depend on the import of certain proteins and lipids to maintain cell survival and membrane formation. Although phosphatidylglycerol, cardiolipin, and phosphatidylethanolamine are synthesized by mitochondrial enzymes, phosphatidylcholine, phosphatidylinositol, phosphatidylserine, and sterols need to be imported from other organelles.

The origin of most lipids imported into mitochondria is the endoplasmic reticulum, which requires interaction of these two subcellular compartments. Recently, protein complexes that are involved in membrane contact between endoplasmic reticulum and mitochondria were identified, but their role in lipid transport is still unclear. In the present review, we describe components involved in lipid translocation between the endoplasmic reticulum and mitochondria and discuss functional as well as regulatory aspects that are important for lipid homeostasis.

Biological membranes are major structural components of all cell types. They protect the cell from external influences, organize the interior in distinct compartments and allow balanced flux of components. Besides their specific proteome, organelles exhibit unique lipid compositions, which influence their shape, physical properties, and function. Major lipid classes found in biological membranes are phospholipids, sterols, and sphingolipids.

The major “lipid factory” within the cell is the endoplasmic reticulum (ER). It is able to synthesize the bulk of structural phospholipids, sterols, and storage lipids such as triacylglycerols and steryl esters (van Meer et al. 2008). Furthermore, initial steps of ceramide synthesis occur in the ER providing precursors for the formation of complex sphingolipids in other organelles (Futerman 2006).

Besides the export of ceramides, the ER supplies a large portion of lipids to other organelles, which cannot produce their own lipids or have a limited capacity to do so. Organelle interaction and transport of lipids require specific carrier proteins, membrane contact sites, tethering complexes, and/or vesicle flux. These processes are highly important for the maintenance of cell structure and survival but are still a matter of dispute.

Most prominent organelle interaction partners are the ER and mitochondria. A subfraction of the ER named mitochondria-associated membrane (MAM) (Vance 1990) was described to be involved in lipid translocation to mitochondria. MAM is part of the ER network, which was shown to be in contact or close proximity to the outer mitochondrial membrane (OMM).

Contact sites between MAM and mitochondria were assumed to facilitate exchange of components between the two compartments. Interestingly, MAM harbor a number of lipid synthesizing enzymes (Gaigg et al. 1994). Recently, molecular components governing membrane contact between the two organelles were identified (Dolman et al. 2005; Csordás et al. 2006; de Brito and Scorrano 2008; Kornmann et al. 2009; Friedman et al. 2010; Lavieu et al. 2010), although the specific role of these components in lipid translocation is not yet clear.
(spacing added for readability)
 

Wishful

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"Recently, protein complexes that are involved in membrane contact between endoplasmic reticulum and mitochondria were identified,"

*sigh* I'm trying to identify biochemical differences between ruminant meat and non-ruminant meat. Most online information is about a few well-known constituents, such as the main fatty acids. Just before this I came across a report mentioning a few chemicals new to me, such as anserine and cystiamine. Whatever it is I'm trying to identify might be one of these newly discovered ones, or maybe even still unidentified ones. ***sigh*** So difficult.
 

Learner1

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Thank you for this. I am wondering what would happen (regarding replication of results) if anti-cardiolipin antibodies are applicable to a subset of ME patients.
According to Health central:

"The antiphospholipid (anticardiolipin) syndrome (APS) is characterized by recurrent venous or arterial thrombosis (clots), recurrent fetal loss, and thrombocytopenia (a reduction in the number of platelets). Antiphospholipid antibody syndrome can be either primary or secondary to other diseases such as lupus"


Two other discussions:

https://www.mayoclinic.org/diseases...holipid-syndrome/symptoms-causes/syc-20355831

https://www.hopkinslupus.org/lupus-tests/antiphospholipid-antibodies/