tirsdag den 1. september 2020

ZFR suppresses the antiviral response, but not in ME? Is macroH2A1/H2AFY involved?

ME peripheral blood mononuclear cell (PBMC) proteomes reveal decreased level of zinc finger RNA-binding protein (ZFR), foldchange = 0,52, p-value = 0,00047 (1).

ZFR suppresses interferon-beta induction and the antiviral response. ZFR controls interferon signaling by preventing aberrant splicing and nonsense-mediated decay (NMD) of histone variant macroH2A1/H2AFY mRNAs (2).

Serum from ME patients contains an activity which induces a powerful antiviral state, but it seems like the interferon response has been ruled out in the ME pathomechanism (3, 4).

However, macroH2A1 has also been shown to bind and repress interferon-stimulated genes (ISG) promoters, raising the possibility that the constitutive ISG induction in ZFR-depleted cells could be partially due to loss of direct action of macroH2A1 on these genes. Taking the available data together, macroH2A1 appears to both suppress the initiation of type I interferon signaling by inhibiting IFNB1 transcription and by modulating the consequences of IFNB1 transcription by directly repressing ISG promoters (2).

The gene macroH2A1/H2AFY is differentially methylated in PBMC from ME patients. Read the blogpost:

H2AFY and ME
https://followmeindenmark.blogspot.com/2018/10/h2afy-and-me.html

Is dysregulated macroH2A1/H2AFY involved in the ME pathomechanism?

MacroH2A1 can buffer transcriptional noise associated with the antiviral response

Knockdown of macroH2A causes a dramatic change in the antiviral gene expression program. Genes that normally do not respond to virus infection get activated or repressed (5).



References

preprint 1) Eiren Sweetman, Torsten Kleffmann, Christina Edgar, Michel de Lange, Rosamund Vallings Howick Warren Tate: A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
https://assets.researchsquare.com/files/rs-52172/v1/6b319d19-80fb-46e3-b56e-3687ae1c7203.pdf

2) Haque N, Ouda R, Chen C, Ozato K, Hogg JR. ZFR coordinates crosstalk between RNA decay and transcription in innate immunity. Nat Commun. 2018;9(1):1145. Published 2018 Mar 20. doi:10.1038/s41467-018-03326-5
https://www.nature.com/articles/s41467-018-03326-5

3) Schreiner P, Harrer T, Scheibenbogen C, et al. Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Immunohorizons. 2020;4(4):201-215. Published 2020 Apr 23. doi:10.4049/immunohorizons.2000006
https://pubmed.ncbi.nlm.nih.gov/32327453/

4) Corbitt M, Eaton-Fitch N, Staines D, Cabanas H, Marshall-Gradisnik S. A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID). BMC Neurol. 2019;19(1):207. Published 2019 Aug 24. doi:10.1186/s12883-019-1433-0

5) Lavigne MD, Vatsellas G, Polyzos A, et al. Composite macroH2A/NRF-1 Nucleosomes Suppress Noise and Generate Robustness in Gene Expression. Cell Rep. 2015;11(7):1090-1101. doi:10.1016/j.celrep.2015.04.022

fredag den 28. august 2020

Atrogin 1 mRNA is elevated in muscle biopsies of ME patients

 Quote reference 1):
"Levels of Atrogin 1 mRNA were significantly elevated in muscle biopsies of patients with ME/CFS compared with HCs 
(Healthy Controls) suggesting an increase in protein degradation processes in muscles of patients with ME/CFS compared with HCs. Atrogin-1 binds to polyubiquitinated proteins to direct them for subsequent degradation by the 26S proteasome and as such is an important regulator of ubiquitin-mediated protein degradation in skeletal muscle (69). Increased levels of Atrogin-1 mRNA are associated with reduced muscle mass (69) and in this study Atrogin-1 was associated with a significant reduction in muscle fibre size, although a detailed examination of muscle protein degradation was not undertaken."


Atrogin 1, also known as muscle atrophy F-box (MAFbx), is encoded by FBXO32. Atrogin 1 degrades various muscle proteins, such as titin, nebulin, troponin, myosin-binding protein C, myosin light chains 1 and 2 and myosin heavy chains (2).

Increased degradation of myosin light chain proteins may lead to increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine (TMAP) (3). 


Read the blogpost:
Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients
http://followmeindenmark.blogspot.com/2020/02/


References:
preprint: 1) Arief Gusnanto, Kate Elizabeth Earl, George K Sakellariou, Daniel J Owens, Adam Lightfoot, Sandra A Fawcett, Euan Owen, Caroline A Staunton, Tu Shu, Fiona C Croden, Manuel Fenech, Melanie A Sinclair, Libuse Ratcliffe, Kasia A Whysall, Rebecca I Haynes, Nicola M Wells, Malcolm J Jackson, Graeme L Close, Clare L Lawton, Michael BJ Beadsworth, Louise Dye, Anne MCARDLE:
Discriminatory cytokine profiles predict muscle function, fatigue and cognitive function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
doi: https://doi.org/10.1101/2020.08.17.20164715
https://www.medrxiv.org/content/10.1101/2020.08.17.20164715v1

2) Steinbacher and Eckl: Impact of oxidative stress on exercising skeletal muscle. Biomolecules  2015 Apr 10;5(2):356-77.
doi: 10.3390/biom5020356.
https://pubmed.ncbi.nlm.nih.gov/25866921/

3) Velenosi, T.J., Thomson, B.K.A., Tonial, N.C. et al. Untargeted metabolomics reveals N, N, N-trimethyl-L-alanyl-L-proline betaine (TMAP) as a novel biomarker of kidney function. Sci Rep 9, 6831 (2019). https://www.nature.com/articles/s41598-019-42992-3
https://doi.org/10.1038/s41598-019-42992-3 PMID: 31048706 PMCID: PMC6497643

fredag den 31. juli 2020

Mutationer i muciner kan måske forklare øget immun aktivering og kemikalie intolerance hos ME patienter

Muciner er en gruppe glykoproteiner, som findes i slimhinderne i luftveje, tarm, skede urinrør og øjne.

Muciner sørger for at slimhinde-laget bliver tykt og højviskøst, så slimhinden bliver svær gennemtrængelig for virus, bakterier, skimmel og toxiner. Samtidig virker mucinerne som lokkemad for mikroorganismerne, der klistrer sig fast til sukkermolekylerne på mucinerne. Herved kan mikroorganismerne udstødes fra kroppen sammen med den slim, som kontinuerlig udskilles fra slimhinderne.

Under slimhindelaget findes et lag epitel med immunceller, som aktiveres hvis mikroorganismer eller toxiner alligevel slipper igennem slimhindelaget. Mutationer i muciner kan påvirke slimhindernes beskaffenhed, således at der sker en større indtrængning af mikroorganismer og toxiner til epitelet. Herved vil immunforsvaret hyppigt aktiveres (1).

Muciner og ME
Der er fundet mutationer i muciner hos ME patienter, og det danner baggrund for en ny hypotese: 

Mutations in ME/CFS nasal mucins result in compromised protective barriere

  • an altered nasal microbiome
  • a highly sensitive and irritated epithelial layer
  • chronic low grade non-allergic inflammatory response
  • exacerbation of ME/CFS symptomatology


Hypotesen er fremlagt i et webinar. Indslaget begynder til tiden cirka 1 time og 55 minutter:
INIM Webinar - Understanding ME/CFS Today: A Clinical & Research Approach

https://www.youtube.com/watch?v=QfrCF2atQxI&feature=youtu.be&t=8591

Forskerne bag studiet oplyser, at en mutation i mucin19 (MUC19) har særlig betydning for en beskadiget slimhinden i næse/øvre luftveje. Dette kan medføre øget følsomhed over for de kemikalier, som vi indånder. Det betyder at mutiple chemical sensitivity (MCS) kan forklares med hypotesen. MUC19 mutationen er nævnt i reference 2. 


Den nye mucin hypotese er forenelig med anden ME forskning: 

Der er tidligere fundet mutationer i IDO2 genet hos meget syge ME patienter, og det danner baggrund for IDO ME hypotesen (3). IDO har betydning for nasal tolerance (4).
Læs blog: IDO-ME hypotesen er forenelig med AHR-MCS hypotesen
http://followmeindenmark.blogspot.com/2019/06/ido-me-hypotesen-er-forenelig-med-ahr.html

Det er tidligere vist, at ME patienter har nedsat sygdomtolerance, og nasal stimulation kan afhjælpe ME symptomer (5).
Læs blog: Det inflammatoriske respons og induktion af sygdomstolerance er dysreguleret hos ME patienter
http://followmeindenmark.blogspot.com/2020/03/det-inflammatoriske-respons-og.html

Proteinet cathelicidin antimicrobial peptide (CAMP) kan påvises ved inflammatorisk respons. Det er f.eks. påvist i tarmens slimhinde hos patienter med inflammatory bowel disease (IBD). Plasma niveauet af CAMP er for forhøjet hos ME patienter (6).

Mere viden om CAMP:
Topical cathelicidin (LL-37) an innate immune peptide induces acute olfactory epithelium inflammation in a mouse model https://pubmed.ncbi.nlm.nih.gov/28837619/


Læs også om mucin studiet på Health Rising bloggen:
Surprise Gene Finding Could Give Pathogens and Toxins a Leg Up in ME/CFS

https://www.healthrising.org/blog/2020/07/11/mucosal-genes-chronic-fatigue-syndrome/


Referencer:
1) S K Linden, P Sutton, N G Karlsson, V Korolik, M A McGuckin: Mucins in the mucosal barrier to infection. Mucosal Immunol 2008 May;1(3):183-97. doi: 10.1038/mi.2008.5. Epub 2008 Mar 5. https://pubmed.ncbi.nlm.nih.gov/19079178/

2) Melanie Perez et al: Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study Front Pediatr. 2019 May 24;7:206. doi: 10.3389/fped.2019.00206. eCollection 2019. https://pubmed.ncbi.nlm.nih.gov/31179255/


3) Kashi AA Davis RW and, Phair RD: The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS. Diagnostics (Basel). 2019 Jul 26;9(3). pii: E82. doi: 10.3390/diagnostics9030082. https://www.mdpi.com/2075-4418/9/3/82

4) van der Marel AP1, Samsom JN, Greuter M, van Berkel LA, O'Toole T, Kraal G, Mebius RE. Blockade of IDO inhibits nasal tolerance induction. J Immunol. 2007 Jul 15;179(2):894-900.
https://www.ncbi.nlm.nih.gov/pubmed/17617580

5) Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin: Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance
doi: https://doi.org/10.1101/2020.02.20.958249
https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract


6) Milica Milivojevic et al: Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS. PLoS One . 2020 Jul 21;15(7):e0236148. doi: 10.1371/journal.pone.0236148. eCollection 2020. https://pubmed.ncbi.nlm.nih.gov/32692761/

fredag den 29. maj 2020

Kynurenine skal afprøves til behandling af ME patienter

Open Medicine Foundation finansierer et nyt placebo-kontrolleret studie, hvor ME patienter skal behandles med kynurenine:

Kynurenine Clinical Trial for ME/CFS
https://omfcanada.ngo/kynurenine-clinical-trial-for-me-cfs/


Jonas Bergquist, MD, PhD, direktør for det svenske ME/CFS forskningscenter i Uppsala, skal stå for studiet.

Baggrunden for studiet er Dr. Robert Phair's ME- hypotese "den metaboliske fælde", der beskriver, at ME patienter ikke omsætter aminosyren tryptofan i tilstrækkelig omfang i nogle af vores celletyper (1). Blogindlæg om den metaboliske fælde:

ME hypotese: The Metabolic Trap - den metaboliske fælde
https://followmeindenmark.blogspot.com/2019/06/me-hypotese-metabolic-trap-den.html

Kynurenine metabolitter opstår ved omsætning af tryptofan, og disse metabolitter er vigtige for normal funktion af bl.a. hjerne og immunforsvar. Dette er vist i dette blogindlæg: 


Tryptofan metabolitten kynureninsyre har immunmodulerende egenskaber
https://followmeindenmark.blogspot.com/2019/06/tryptofan-metabolitten-kynureninsyre.html


Yderligere blogindlæg om kynurenine og den metaboliske fælde:

Is the ME hypothesis "the metabolic trap" able to explain endothelial dysfunction?
https://followmeindenmark.blogspot.com/2019/06/is-me-hypothesis-metabolic-trap-able-to.html

Kynurenine metabolisme påvirkes af motion
https://followmeindenmark.blogspot.com/2019/06/kynurenine-metabolisme-pavirkes-af.html

Omsætning af tryptofan og forgrenede aminosyrer hos ME patienter under motion
https://followmeindenmark.blogspot.com/2019/06/omstning-af-tryptofan-og-forgrenede.html

Is the kynurenic acid responsive Gpr35 involved in the ME pathomechanism?
https://followmeindenmark.blogspot.com/2019/06/is-kynurenic-acid-responsive-gpr35.html

IDO-ME hypotesen er forenelig med AHR-MCS hypotesen
https://followmeindenmark.blogspot.com/2019/06/ido-me-hypotesen-er-forenelig-med-ahr.html

Mutations in the IDO2 gene and DNA methylations in genes in the NAD/NADP synthesis pathway in ME
https://followmeindenmark.blogspot.com/2019/07/mutations-in-ido2-gene-and-dna.html


Reference: 
1) Kashi AA Davis RW and, Phair RD: The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS. Diagnostics (Basel). 2019 Jul 26;9(3). pii: E82. doi: 10.3390/diagnostics9030082. https://www.mdpi.com/2075-4418/9/3/82


mandag den 4. maj 2020

Serum fra ME patienter udviser antiviral aktivitet

Et nyt studie af Schreiner et al har vist, at serum fra ME patienter udviser antiviral aktivitet mod både DNA- og RNA-virus i en cellekultur. Samtidig blev det observeret, at serummet inducerer et fragmenteret mitokondriel netværk og nedsat cellulær ATP produktion (1).

Citat fra artiklen (1), side 213: 
"... we showed that serum from ME/CFS patients contained an activity that produced mitochondrial fragmentation, decreased mitochondrial ATP production, and induced a powerful antiviral state."

Det er ukendt, hvad det er i serum, som udløser og udøver den antivirale aktivitet. Schreiner et al har en hypotese om, at en delvis aktivering af herpesvirus (HHV-6) kan være årsag til den kroniske immunaktivering hos ME patienter. Forskerne understøtter hypotesen med et forsøg, hvor en cellekultur udsat for delvis aktivering af HHV-6 udskilder et stof som har samme effekt som serum fra ME patienter (1). 

Citat fra artiklen (1), side 206:
"...These results showed that cells containing latent HHV-6A DNA that had been transactivated by TSA (trichostatin-A) secreted a potent activity that could be adoptively transferred and induce mitochondrial fragmentation and a proinflammatory CDR (cell danger response) in naive responder cells, conferring strong protection from both DNA and RNA virus infections."

ME er tidligere sat i forbindelse med kronisk herpes infektion (2).

Schreiner et al foreslår, at nye forsøg skal vise om ME patienter har en produktion af HHV-6 proteiner (ikke hele, levende HHV-6).

Citat fra artiklen (1), side 213:
"Larger multicohort studies involving ME/CFS patients from different age groups should be carried out in the future and should include methods for detecting and quantifying both productive and nonproductive (incomplete) viral reactivation events. Furthermore, potential factors affecting mitochondrial dynamics in ME/CFS patients should be systematically evaluated for their ability to induce a powerful antiviral state."


Læs også:

For ME/CFS Patients, Viral Immunities Come at a Devastating, Lifelong Cost
https://health.ucsd.edu/news/releases/Pages/2020-04-27-for-me-cfs-patients-viral-immunities-come-at-lifelong-cost.aspx

Explaining ME/CFS? Prusty / Naviaux Study Ties Infections to Energy Breakdowns
https://www.healthrising.org/blog/2020/04/26/explaining-chronic-fatigue-syndrome-naviaux-prusty/

Viden om fragmenteret mitokondriel netværk:
Mitochondria in Innate Immune Responses
https://pubmed.ncbi.nlm.nih.gov/21597473/
Figur: https://pubmed.ncbi.nlm.nih.gov/21597473/#&gid=article-figures&pid=figure-2-uid-1


Referencer:

1) Philipp Schreiner, Thomas Harrer, Carmen Scheibenbogen, Stephanie Lamer, Andreas Schlosser, Robert K. Naviaux and Bhupesh K. Prusty
Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Immunohorizons. 2020 Apr 23;4(4):201-215.
DOI: 10.4049/immunohorizons.2000006
PMID: 32327453 

2) Nuno Sepúlveda, Jorge Carneiro,  Eliana Lacerda, Luis Nacul Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections
Front Immunol 2019 Nov 21;10:2684. doi: 10.3389/fimmu.2019.02684. eCollection 2019.
https://www.frontiersin.org/articles/10.3389/fimmu.2019.02684/full

mandag den 20. april 2020

Kan POTS patienter være mindre sårbare over for COVID-19 pga mindre ACE2 aktivitet?

Coronavirus anvender et af menneskets enzymer til at komme ind i cellerne. Enzymet hedder angiotensin converting enzyme 2 (ACE2).

ACE-hæmmere er lægemidler, der anvendes til behandling af for højt blodtryk. 

Der er fremsat en hypotese om at ACE-hæmmere kan øge ACE2 og hermed fremme indtrængning af coronavirus i cellerne. Læs om emnet her: 

ACE-hæmmere øger muligvis risikoen for at dø af COVID-19
Danske forskere vil undersøge årsag til visse patienters coronadød
https://sundhedspolitisktidsskrift.dk/nyheder/3250-er-patienter-i-bestemt-behandling-i-storre-risiko-for-at-blive-alvorligt-syge-af-coronavirus.html 


COVID-19, ACE2, and the Cardiovascular Consequences
https://pubmed.ncbi.nlm.nih.gov/32228252/

Renin-Angiotensin-Aldosterone System: Double-Edged Sword in COVID-19 Infection
https://www.preprints.org/manuscript/202003.0365/v1

Der er også fremsat en hypotese om, at lupus patienter måske har øget sårbarhed over for COVID-19 på grund af mulig øget ekspression af ACE2:
"...we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2..."  
Citat fra: Epigenetic Dysregulation of ACE2 and Interferon-Regulated Genes Might Suggest Increased COVID-19 Susceptibility and Severity in Lupus Patients
https://pubmed.ncbi.nlm.nih.gov/32276140/


Der er så vidt jeg ved IKKE fremsat hypotese om COVID-19  og patienter med Postural Ortostatisk Takykardi Syndrom (POTS). Men jeg vil henlede opmærksomheden på viden fra to artikler, der omhandler POTS og ACE2:

Defects in Cutaneous Angiotensin-Converting Enzyme 2 and angiotensin-(1-7) Production in Postural Tachycardia Syndrome
https://pubmed.ncbi.nlm.nih.gov/19289653/

Abnormalities of Angiotensin Regulation in Postural Tachycardia Syndrome
https://pubmed.ncbi.nlm.nih.gov/21266211/

Citat fra sidstnævnte artikel:
"Estimated angiotensin-converting enzyme-2 (ACE2) activity was significantly lower in POTS patients than in controls (0.25 ± 0.02 vs 0.33 ± 0.03, P = .038)."

Kan POTS patienter være mindre sårbare over for COVID-19 pga mindre ACE2 aktivitet? Eller vejer ulempen ved at have en kronisk sygdom tungere på vægtskålen?

torsdag den 5. marts 2020

ME - a failure of inducing exercise tolerance?

ME hypothesis from Karolinska Institutet and Karolinska University Hospital in Sweden (1):

"ME - a failure of inducing disease tolerance upon chronic immune activation"

My question:
Is ME also a failure of inducing exercise tolerance?

At cellular level disease and inflammation result in increased reactive oxygen species (ROS) production. Stress-response pathways are countermeasures to ROS. Exercise also leads to increased ROS levels. The antioxidant enzyme superoxide dismutase 2 (SOD2) is one the primary mechanisms against ROS generated during exercise.

Quote from a review "Impact of oxidative stress on exercising skeletal muscle" (2):
"It is well established that muscle contractions during exercise lead to elevated levels of reactive oxygen species (ROS) in skeletal muscle. These highly reactive molecules have many deleterious effects, such as a reduction of force generation and increased muscle atrophy. Since the discovery of exercise-induced oxidative stress several decades ago, evidence has accumulated that ROS produced during exercise also have positive effects by influencing cellular processes that lead to increased expression of antioxidants. These molecules are particularly elevated in regularly exercising muscle to prevent the negative effects of ROS by neutralizing the free radicals. In addition, ROS also seem to be involved in the exercise-induced adaptation of the muscle phenotype.

Chronic oxidative stress is associated with an increase in protein loss and muscle atrophy. High ROS levels cause a sustained activation of NF-κB and of FoxO which then activate two muscle-specific E3 ubiquitin ligases, atrogin-1 or muscle atrophy F-box (MAFbx) and muscle RING (Really Interesting New Gene)-finger protein 1 (MuRF-1) [52]. MAFbx and MuRF-1 then degrade various proteins, such as titin, nebulin, troponin, myosin-binding protein C, myosin light chains 1 and 2 and myosin heavy chain [53,54]. Recently, it was demonstrated that excessive oxidative stress also enhances the transcription factor C/EBP homology protein (CHOP). This transcription factor also enhances expression of MuRF1, which again results in increased protein degradation [35]."

It seems like ME patients have increased muscle protein degradation:

Increased serum and urine 3-methylhistidine in ME patients
http://followmeindenmark.blogspot.com/2020/03/increased-serum-and-urine-3.html

Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients
https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html

Proline, P5C and 4-hydroxyglutamate in ME
http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html

And do remember the transcription profile analysis of skeletal muscle from ME patients (3), quote:
"In an effort to establish which pathways might be involved in the onset and development of muscle symptoms, we used global transcriptome analysis to identify genes that were differentially expressed in the vastus lateralis muscle of female and male CFS patients. We found that the expression of genes that play key roles in mitochondrial function and oxidative balance, including superoxide dismutase 2, were altered, as were genes involved in energy production, muscular trophism and fiber phenotype determination. Importantly, the expression of a gene encoding a component of the nicotinic cholinergic receptor binding site was reduced, suggesting impaired neuromuscular transmission. We argue that these major biological processes could be involved in and/or responsible for the muscle symptoms of CFS."


Are the inflammatory reponse to disease and the adaptive response to exercise dysregulated in ME through the same pathways?

Reference

1) Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin: Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance
doi: https://doi.org/10.1101/2020.02.20.958249
https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract

2) Peter Steinbacher, Peter Eckl:
Impact of Oxidative Stress on Exercising Skeletal Muscle