The Rhyothemis princeps Brain Externalization Project

 Learned about PON1 and PD yesterday by attending web conference presentation by Beate Ritz: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922777/ Anthocyanins increase PON1 and are thought to protective against PD, but they also increase NO production - hmm .... ~ Vitamin D levels are decreased in PD: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267215/ "After the discovery that the VDR and 1α-hydroxylase, the enzyme that converts vitamin D to its active form, were highly expressed in the substantia nigra, it was hypothesized that inadequate levels of circulating vitamin D may lead to dysfunction or cell death within the substantia nigra ( 25 , 26 )." Active vit D (calcitriol) is mainly produced in the kidneys, as is klotho. a-syn is produced in the kidneys throughout lifespan.  ~ Chronic kidney disease prevalence is lower in PD patients: https://www.mdsabstracts.org/abstract/prevalence-of-chronic-kidney-disease-in-patients-with-idiopathic-parkinsons-disease-in-a-tertia...

MCC950, an NLRP3 inflammasome inhibitor, was shown to reverse symptoms in two Parkinson's disease mouse models and was reported to have no toxicity issues. The only reason given in the following article for not pursuing clinical trials is that it is off-patent: https://www.genengnews.com/news/parkinsons-disease-drug-that-cools-brains-on-fire-could-enter-human-trials-in-2020/   Given its mechanism of action it could be broadly effective against neurodegenerative diseases and even spinal cord injury ( https://www.frontiersin.org/articles/10.3389/fmolb.2020.00037/full ).   Infections due to immunosuppression may be a problem, but there are reasons to think that MCC950 would be safer than immunosuppressive agents currently used to treat inflammatory conditions:   "Thus, specific targeting of NLRP3 will not result in the complete blockade of IL-1β during infection and antimicrobial responses may remain intact. MCC950 may therefore have less immunosuppressive effects when ...

Autophagy and Neurodegeneration │ Prof. David Rubinsztein   https://www.youtube.com/watch?v=BgIk9ehY09k 30:00 screening for mTOR independent autophagy inducing drugs 37:08 felodipine, a Ca channel blocker, induces autophagy and clears protein aggregates 46:00 vicious cycle of protein aggregates impairing autophagy -> more protein aggregates ~  Glycine and tryptophan lower uric acid levels in patients with mild hyperuricemia: https://pubmed.ncbi.nlm.nih.gov/30845731/ Glycine is inversely correlated  with serum uric acid in healthy people and in lifestyle-related diseases: https://www.nature.com/articles/s41598-017-17710-6 The Nature article also notes men are more likely to have hyperuricemia and that estrogen promotes uric acid excretion. The SURE-PD trial of inosine to increase serum and CSF urate was halted due to lack of efficacy, BUT inosine was found to be effective in increasing urate and decreased rate of progression in women: https://pubmed.ncbi.nlm.nih.gov/314...

  Genetic Mutations in Parkinson's Disease | 2019 Udall Center Research Symposium, presented by Dr Valina Dawson Some very nice slides. 18:18 - 3:00 - 3:26   19:25 It is disappointing to see therapies targeting NLRP3 inflammasome inhibition are not more advanced, considering the success of MCC950 in mouse models and how broadly effective it could be for neurodegenerative diseases as well as spinal cord injury . Index   3:00 autosomal recessive PD (ARPD) genes & their functions   3:26 interaction of ARPD genes - 'linked in circuits' - leading to inactivation of Parkin & activation of PARP1 resulting in death of neurons   4:56 autosomal dominant - point mutations in alpha synuclein which facilitate its misfolding; a- syn can be duplicated or triplicated     6:00 VPS 35 - vacuolar sorting protein     6:54 LRRK2 - sporadic PD - spontaneous mutations occur at high frequency - 1-7% of PD patients of European origin and 20-40% of ...

Getting even worse at keeping up with / track of things. So this week I read more about amino acids.   Lysine + arginie was found to help with anxiety and depression in a brief (7 day) trial. https://pubmed.ncbi.nlm.nih.gov/17510493 Lysine, threonine and histidine were found to inhibit mTOR in bone marrow derived mast cells and also ameliorate autism symptoms in a mouse model. https://pubmed.ncbi.nlm.nih.gov/27640900 A bit weird that histidine ameliorated autism symptoms since histidine converts to histamine and there is indirect evidence of mast cell involvement in autism. However, histidine supplements are used by naturopaths to treat allergy since there is apparently a paradoxical effect -  I need to find a peer-reviewed reference source for this. A metabolomics study found threonine to be elevated in a mouse model of PD; glycine was lowered and urea was higher. Mannose was elevated. https://pubmed.ncbi.nlm.nih.gov/32937957 Came across an anecdote on amazon reviews of ...

Read a bit about lipid metabolism in PD https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099649/ "Since oligomers seem to be the toxic species rather than fibrils, we believe that the increasing DHA concentration in the cell could worsen toxicity rather than having a protective role." oh dear Eating fish is associated with reduced risk of PD - but maybe the benefit is from beta parvalbumin?? ~ A clinical trial published in 2019 found omega-3 from flax plus vitamin E to be beneficial in PD - though of course flax does not contain DHA, but ALA which may be converted to DHA - but not very efficiently & there are sex differences (reproductive age women do so more efficiently than others) https://www.sciencedirect.com/science/article/abs/pii/S0303846718304633 ~ Seems like fibrates would be helpful, but one study in a rat models says no https://pubmed.ncbi.nlm.nih.gov/28403913/ but brilliant blue G, a P2X7R anatgonist, was beneficial ~ Cereblon - "Our study reveals a novel ...

These notes are to keep track of things I am reading up on and thinking about and perhaps may write a post on in future. I making them public because - why not? Also, I may never get a chance to write a full post on them. ~~~ MSA, glycine & EPO    Related references are tagged MSA-EPO-Gly on my zotero account and listed below. Lithium trial for multiple system atrophy (MSA) had to be stopped as it caused harm - quite severe harm. One proposed MOA for lithium for biopolar and other disorders where it has been found to be therapeutic is that it increases glycine levels in the brain. However, this hypothesis appears to have been abandoned in recent years and does not have much empirical support - though nothing in the way of  disconfirming findings has turned up so far in literature searches, either. Elevated levels of glycine in cerebrospinal fluid (CSF) have been found in DLB, ALS and MS. Results of studies on PD patients has been conflicting, but the bulk of evidence ...

Is it possible that machine learning-assisted anthropometric analysis could provide better risk assessment than genetic screening for cancer or other conditions (e.g., connective tissue disorders, heart failure, etc.)?  Relative proportions are reflective of relative growth rates of organs and tissues which in turn are the product of both genes and environment and are dependent on factors such as the balance of growth hormones and nutrient intakes. It seems that if a large number of individuals were scanned photographically - or much better with MRI (since more interesting measurements could be taken, e.g. width of the aorta) and the scans were provided as input, along with data from their health records, to an appropriately designed  machine learning algorithm, it may be possible to  predict risk of various diseases based on anthropometric parameters alone. This occurred to me just prior to learning that a new company, Ezra, is offering whole body MRI scans for ...

Since March, I have been hoping someone would study whether covid-19 patients with type 2 diabetes (T2D) on metformin fare better than those on other types of anti-diabetes medications. Many of the risk factors associated with severe covid-19 (e.g., obesity, diabetes, hypertension, older age) relate to AMPK signalling and metformin, a drug that improves AMPK signalling, has been found to benefit these conditions.  My question has finally been answered  - T2D patients on metformin have a 70% reduced  risk of death as compared with those on other anti-diabetic medications [1,2]. Unfortunately the study did not control for other important factors such as age, degree of blood sugar control, BMI, and time since diagnosis; a future study designed specifically to examine metformin in covid-19 should be conducted that controls for these factors. The study authors discuss the potential role of AMPK signalling in covid-19, delineating a number of possible mechanisms by which it cou...

In trying to find information on the effect of radiation on aquaporins, a paper came up on a treatment for radiation-induced salivary hypofunction: Baum, Bruce J., Changyu Zheng, Ana P. Cotrim, Linda McCullagh, Corinne M. Goldsmith, Jaime S. Brahim, Jane C. Atkinson, et al. “Aquaporin-1 Gene Transfer to Correct Radiation-Induced Salivary Hypofunction.” Handbook of Experimental Pharmacology , no. 190 (2009): 403–18. https://doi.org/10.1007/978-3-540-79885-9_20 .           " Indeed, IR leads to a dramatic loss of the fluid secreting salivary acinar cells, resulting in severe glandular hypofunction (a diminished production of saliva) in most patients ( Vissink et al. 2003 ; Nagler and Baum 2003 ). The reason for this damage remains enigmatic, as salivary acinar cells are well differentiated and very slowly dividing, the opposite of the classical target cell for IR sensitivity [emphasis added] . If patients have sufficient functional acinar tissue p...

Dr Ruslan Medzhitov presented 'What is a disease' at the inaugural meeting of the International Society for Evolution, Medicine and Public Health held March 19-21, 2015. Interesting perspective on the causes of type 2 diabetes and diseases of aging. 9:13 Robustness, resilience and vulnerability   15:45 Anna Karenina Principle in Life History Theory - only one way an environment can be perfect and many ways it can be hostile   16:00 Homeostasis - Maintenance - Defense 17:58 taking out the garbage is not part of homeostasis, it's a function of maintenance   20:24 Extrinsic and Intrinsic Mortality - investment in maintenance programs is dictated by extrinsic mortality rates   32:00 systems that have adjustable set points are vulnerable to dysregulation example: insulin signalling pathway - change in glucose allocation to fetus in pregnancy or to immune system in infection "That built-in property to change the set point of the insulin system also makes it vulner...

While most proteins are degraded during digestion, some fibrinolytic enzymes and prions can be resistant to digestion and there is evidence for their intestinal absorption. Nattokinase has been reported to be orally bioavailable [1], though some have told me they discount the study by Ero et al. (2013), citing that it was  funded by a supplement maker that sells nattokinase (I can't verify the sponsorship of the study since the article is paywalled). Of course, clinical trials for most new prescription drugs sold in the United States are funded by the pharmaceutical companies that make them. Gastrointestinal absorption of lumbrokinase was also demonstrated by Yan et al. (2010) [2]; the authors propose some possible mechanisms: "Gastrointestinal absorption of macromolecules, such as, proteins can be explained by three mechanisms as follows [16,17]. First, proteins are absorbed via receptor mediated endocytosis are as some growth factors. Second, proteins are absorbed by ...