CJD, Amyloid and K26R
The latest Kevin McCairn stream edited and split into three videos. The first is a short video expanding on the topic from the previous video: Global Prion Disease Treatment Market – Industry Trends and Forecast to 2028
Mad cows or crazy people? (5 mins)
Amyloid plaques (1 hour)
Resources
Presence of a SARS-CoV-2 Protein Enhances Amyloid Formation of Serum Amyloid A
GISAID Initiative
NCBI Sars CoV-2 Resources
Second entry looking for E-protein (envelope protein)
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/product=”envelope protein”
/protein_id=”UBC57849.1″
/translation=”MYSFVSEETGTLIVNSVLLFLAFVVFLLVTLAILTALRLCAYCC
NIVNVSLVKPSFYVYSRVKNLNSSRVPDLLV”
=====================
Paste sequence in PLAAC:
MYSFVSEETGTLIVNSVLLFLAFVVFLLVTLAILTALRLCAYCCNIVNVSLVKPSFYVYSRVKNLNSSRVPDLLV
PLAAC: Prion-Like Amino Acid Composition
Another paper on amyloid formation:
Interactions between SARS-CoV-2 N-protein and α-synuclein accelerate amyloid formation
ACE2 and the JEW: K26R to bind or not to bind that is the question? (15 min)
The following paper was published in Nature on 12 April 2021: Human ACE2 receptor polymorphism and altered susceptibility to SARS-CoV-2
"Among the variants tested, ACE2 K26R, consistent with its increased affinity for S-RBD observed in the biochemical assay, was the most effective (Ki 30 nM; ~33 fold greater than WT) in blocking viral entry (Fig. 5 and Table 1)".
"We also show that another ACE2 residue, K26, plays an important role in controlling the susceptibility to viral infections via a similar mechanism. Our structural analysis has suggested that K26R mutation will weaken coordination of the N90-linked glycan presumably interfering with its ability to shield the host from the viral infection. Our biochemical binding assays confirmed the predicted increased affinity for K26R ACE2 for S-protein. In fact, K26R ACE2 was the most effective among mutants tested for their ability to enhance viral entry, suggesting that this frequent polymorphism, very likely increases susceptibility to SARS-CoV-2 (Fig. 5 and Table 1)".
The above article in Nature says that K26R blocks the virus….in other words Ashkenazi Jews would be the most susceptible to covid. This goes completely contrary articles which state that the Jews are the least susceptible to covid such as this one: ACE2 coding variants in different populations and their potential impact on SARS-CoV-2 binding affinity. Look at the bar chart in the tweet below at the binding energy of K26R.
We also have another study that states;
Amish (AMI) and Ashkenazi Jewish (ASJ) populations do not appear to carry such variants in ACE2 coding regions (Fig. 1b).
New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis
So who is correct? A far as I am concerned anything published in Nature is suspect. The Indian author Somasekar Seshagiri works for Modmab Therapeutics Corporation is located in Foster City California and received a Coronavirus-related PPP loan from the SBA of $124,434.00 in April, 2020. Moreover, he went to the University of Georgia (in Athens, GA, US) where the Institute of Bioinformatics (founded 2002) with links to CDC has as director Jessica Kissinger. Now Kissinger is an unusual name. I am sure I heard it somewhere else (lolz). Is she related to Henry? Henry and his brother both have children and grand children. His mother (Mrs Kissinger) who died age 97 (Henry is 96 now) was survived by two sons, as well as six grandchildren and six great-grandchildren.
These authors contributed equally: Kushal Suryamohan, Devan Diwanji, Eric W. Stawiski.
Cardiovascular Research Institute, University of California San Francisco. The article they have just released was based on one that was written nearly exactly a year earlier (April 10, 2020). From memory this was about the time that the NYT posted an web article showing the complete genome sequence including 3D models of all the proteins. The one released a year earlier Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility says something similar:
"....and thereby potentially alter host susceptibility. In particular, human ACE2 variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R are predicted to increase susceptibility".
It has many more authors (who seem to be have fallen away from this version): Eric W. Stawiski, Devan Diwanji, Kushal Suryamohan, Ravi Gupta, Frederic A. Fellouse, J. Fah Sathirapongsasuti, Jiang Liu, Ying-Ping Jiang, Aakrosh Ratan, Monika Mis, Devi Santhosh, Sneha Somasekar, Sangeetha Mohan, Sameer Phalke, Boney Kuriakose, Aju Antony, Jagath R. Junutula, Stephan C. Schuster, Natalia Jura, Somasekar Seshagiri.
This was a comment that I found under the article (the first one):
Comment: Ivan Shabalin
The paper describes an interesting idea, but the structural analysis and the predictions of the effects of the mutations are unsubstantiated and should be significantly revised.
For example, the presented analysis of the first mutation - K26R - has the following red flags:
- Figure 3b shows sugar labelled as "mannose", whereas the first sugar in glicosilated mammalian proteins should be N-acetylglucosamine (GlcNAc, or NAG), as it is in the crystal structures used for the analysis.
- The claim "We predict that K26R would abrogate stabilizing polar
contacts with N90, impairing coordination of the glycan (Figure 3b) and lead to an increase in the affinity of the virus to the ACE2 receptor" seems completely baseless. First, K and R are positively charged residues with similar lengths; I'm not convinced this mutation would necessarily abrogate the contact with NAG. Second, why would R form the predicted interaction with D-30? why not with Glu23, which is closer? Third, the following claim is very questionable "At the same time, R26 is now primed to establish backbone and side chain interactions with ACE2 D30 which then is poised to build a salt-bridge with CoV-2 RBD K417". In what way the proposed interaction R26-D30 would make D30 more prone to forming the salt bridge with K417? If anything, it would only decrease the strength of the bridge be being a "charge competitor". And, the salt bridge D30-K417 already exists in one of the structures they analyzed (6LZG).
Similarly, there are issues in the analysis of the second mutation:
- "The T27A mutant (Figure 3c) removes side chain-backbone and backbone-backbone interactions between T27 and E30 likely increasing the local dynamics of helix α1". First, there is a typo - it is E23. Second, the stability of a helix is mostly set by the C=O...N bonds between main-chain atoms, and the elimination of a side chain H-bond is unlikely to have a significant effect on the shape of the helix. Then, "This would allow the N-terminus of α1 to bend slightly and accommodate the unique CoV-2 RBD receptor binding-ridge loop that more intimately contacts ACE2 compared to its SARS-CoV counterpart" sounds very much unsubstantiated. To draw these conclusiong, MD simulations might need to be not perfomed.
Clearly, the analysis of other mutations is also questionable.
I believe that the Nature article is involved in a cover up.
Ashkenazi Jews and the Amish people are related and they carry a similar polymorphism not just on ACE2 but other genes. Moreover, Jews are less susceptible to respiratory disease. The paragraph below is from the blog article with the title: Bio-war race targeting (McCairn1).
Ethnic Targeting
A number of questions come to my mind. In the paper discussed by Kevin the Jews and the Amish have a similar genetic polymorphism that protects them from Covid. This means that the Amish and the Jews are related. The history of the Amish church began with a schism in Switzerland within a group of Swiss and Alsatian Mennonite Anabaptists in 1693 led by Jakob Ammann. Those who followed Ammann became known as Amish. … In the early 18th century, many Amish and Mennonites immigrated to Pennsylvania for a variety of reasons. Not only do the Amish share a polymorphism with Ashkenazi Jews that makes them resistant to covid they share genetic loci for myopia (Fine-mapping of candidate region in Amish and Ashkenazi families confirms linkage of refractive error to a QTL on 1p34-p36). Anabaptists and Jews have had interactions for several centuries, since the origins of Anabaptism in the Radical Reformation in early modern Europe. Due to the insularity of many Anabaptist and Jewish communities, Anabaptist–Jewish relations have historically been limited but there are notable examples of interactions between Anabaptists and Jews. Due to some similarities in dress, culture, and language, Amish and Mennonite communities in particular have often been compared and contrasted to Hasidic Jewish communities (Wikipedia).The Mennonite Metzler family, tracing their lineage of descent through Valentine Metzler, a German immigrant who arrived in Lancaster County with his father Jacob in 1738, has close Y-DNA matches to Jewish families such as Kronik (in Belarus), Cohen and Langer (in Ukraine) and Friedman and Wengrowski (in Poland). [Anabaptisthistorians]. So, that solves that mystery. At some stage Ashkenazi Jews and Annabaptists must have interbred in Europe.
Not just the study cited by Kevin but this one also presents a similar finding:
Here, we have analyzed the genetic markers of the TMPRSS2 gene and the differences in their alternative allele frequencies (AFs) among populations to identify possible susceptibility loci to COVID-19 and to correlate them with disease epidemiology. *AF= alternative allele frequencies (AFs). Regarding the non-synonymous pathogenic variants, we observed the highest AF among the Ashkenazi Jewish (ASJ) population (Figure 1A), while the Finnish (FIN) showed the highest AF among European subpopulations (Figure S2A).
Genetic Analysis of the Coronavirus SARS-CoV-2 Host Protease TMPRSS2 in Different Populations
And this article from 2009:
DENVER — Researchers at National Jewish Health and the University of Colorado Denver have discovered a gene that is associated with improved survival among patients with acute lung injury. Acute lung injury (ALI) is often caused by a respiratory infection and results in low oxygen levels in the blood, and fluid in the lungs. It is one of the most vexing problems for intensive care units, afflicting almost 200,000 people in the United States each year, and killing 40 percent of them. https://www.nationaljewish.org/about/news/press-releases/2009/acute-lung-injury
And this paper:
The K26R (rs4646116) variant is an ACE2 variant that facilitates the binding of the S-glycoprotein effective in binding the coronavirus to the host cell and increases the susceptibility to the virus. The K26R variant, which reduces virus binding to the ACE2 receptor, has been found to be more concentrated in the Jewish population (1.2%) and, in contrast, the Asian population has the lowest allele frequency for the single nucleotide variant encoding K26R*
* Al-Mulla F, Mohammad A, Madhoun AA, Haddad D, Ali H, Eaaswarkhanth M, et al. A comprehensive germline variant and expression analyses of ACE2, TMPRSS2 and SARS-CoV-2 activator FURIN genes from the Middle East: Combating SARS-CoV-2 with precision medicine. bioRxiv 2020
Effects of Human Genetic Factors (Ethnicity and Race) on Clinical Severity of SARS-CoV-2 (COVID-19)Journal of Experimental and Basic Medical Sciences 2020;1(3):147-158
