Biden is in early dementia

I am having much trouble with the wordpress editor and hope to have a full post out soon with links and video clips showing exactly what I mean. Forget the spin in the text of the links, just look at the clips and make up your own mind. Sorry.

Addendum 21 June ’21

Many apologies for posting the above without documentation. I’m still working with WordPress to get a functional editor.

In the meantime, I strongly suggest that you look at Biden’s press conference of 14 June ’21 https://www.youtube.com/watch?v=PAWRHM4i3Dg
particularly the segment at 15 minutes where his response makes little sense, and then he shuts down completely for 7 seconds, apparently quite confused. That’s my reading of the video.

Here’s the data. Reach your own conclusion about what you are seeing. 

More to follow when I get the editor working.

People with early dementia act like this intermittently, with normal functioning most of the time. I’ve certainly seen this in two very high functioning family members. We’d say things like ‘it must have been the heat’, or he/she ‘must have been very tired’.

Nightmare on Wall Street

I’ve written several posts about Cassava Biosciences (symbol SAVA) and their potential drug for Alzheimer’s (see the end). The recent approval of Biogen’s ineffective (but highly lucrative) therapy Aducanumab for the disease brings forth the following nightmare. At a cost of > $50,000/year and millions of desperate famililes, Biogen will soon be rolling in money. The Cassava drug is orally available and should cost a fraction of that. Even better — it may actually work, although I think serious side effects are likely. Given the sketchy data getting Aducanumab through the FDA, Cassava’s drug represents a real threat to Biogen.

It will be perfectly legal for Biogen to outright buy Cassava and stop development. They will have the money. They won’t be able to do it on the sly, as any position of one company (or individual) in another greater than 5% of the value of the company must be reported to the SEC where it becomes public knowledge.

This from a cousin who is a stock market guru. His wife wasn’t available when I called being next door taking care of a woman with early Alzheimer’s, whose husband had to leave as his father suddenly passed away. She can’t be left alone. Such is the market for Aducanumab.

So will my friend Lindsay and her husband have the moral strength to resist Biogen?

Back in the day when I was in the service in Denver, a very wealthy stockbroker (who had brought the waterPik public) bought up many of beautiful old mansions on the west side of Cheeseman park. He then sold them to people he trusted (such as ourselves), so they wouldn’t be broken up into apartments (which was quite lucrative). I asked why the other people living on Humboldt street didn’t do the same. He said they had so much money they didn’t need character. The folks at Cassava don’t have a hell of a lot of money but hopefully they do have character.

Other posts on Cassava should you be interested are

The science behind Cassava Sciences (SAVA)

Another virus escapes from a lab

Given the excitement over the possibility that the pandemic virus (SARS-CoV-2) escaped from a lab in Wuhan, it’s time to shamelessly republish a clairvoyant science fiction story of mine first published 19 November 2019.

A science fiction story (for the cognoscenti) — answer to the puzzle and a bit more

Comrade Chen we have a serious problem.

Don’t tell me one of our bugs escaped confinement.

Worse.  One of theirs did.  And it’s affecting the PLA (People’s Liberation Army).  Some are turning into pacifists.

It doesn’t kill them?

No. But for our purposes it might as well.

It’s a typical adenoassociated virus (AAV) like we use.

Well, what does the genome look like?

We’ve sequenced it and among other things, it codes for a protein which enters the brain and alters behavior.

What?

Well, the enemy has some excellent biologists, one of whom works on Wolbachia.

What’s that?

It’s a rickettsial organism which changes the sex life of some insects.

I don’t believe that.

Do you have a cat?

Yes.

Well many cats contain another organism (toxoplasma gondi).

So what.

Rats infected by the organism become less afraid of cats.

Another example please.

A fungus infecting carpenter ants causes the ant to leave its colony, climb a tree, chomp down on the underside of a leaf and die, freeing fungal spores to fall on the ground where they can reinfect new ants.

Well what is the genome of the virus?

It has some very unusual sequences, and one which proves that the Wolbachia biologist on the other side has a very large ego.

How so.

Well in addition to the brain infecting protein, there is a very unusual triplet of peptides all in a row.

Methionine Alanine Aspartic Acid Glutamic acid, then a stop codon, then Isoleucine Asparagine, than a stop codon, then Threonine Alanine Isoleucine Tryptophan Alanine Asparagine.  We think that the first two in some way cause readthrough of the stop codons so the protein following the short peptides is made.

Where does the big ego come in?

Sir, proteins can have hundreds and hundreds of amino acids.  People got tired of writing their full names out, so each of the 20 amino acids was given a single letter to stand for it.

M – Methionine

A – Alanine

D – Aspartic acid

What does D have to do with Aspartic acid?

Nothing sir, look on the letters as Chinese characters.

E -Glutamic Acid

I – isoleucine

What about the stop codon between Glutamic acid and Isoleucine

Just regard it as a space.

N – Asparagine

Nooo! ! ! I I’m beginning to get the picture.

Yes sir, it stands for MADE IN TAIWAN

—-

A few years later

Well the Taiwanese biologist outsmarted himself (or herself).   The Taiwanese soldiers wouldn’t fight either as the virus spread.  Most conflicts between nation states pretty much ended (Russia/Ukraine, North Korea/South Korea) etc. etc.  The Taiwanese biologist was nominated for the Nobel Peace Prize, and did receive it in absentia, as every military type in the world was looking for him (or  her), so he (or she) went into hiding, and is believed to be living in an Ashram near Boulder, Colorado.

Unfortunately, the idea of using viruses to change human behavior spread past nation states, and private groups with their own agendas began using it.

The ‘new soviet man’ of the previous century looked rather benign compared to what subsequently happened.

The next story for the scientific cognoscenti will describe the events leading up to the impeachment trial of President Jon Tester in 2028.

An intentional social and epidemiological experiment

Back in the day, mutations causing disease were called experiments of nature, something I thought cruel because as a budding chemist I regarded experiments as something intentional, and mutations occuring outside the lab are anything but intentional.

Massachusetts entered an intentional social and epidemiological experiment today. I hope it turns out well, but I seriously doubt it.

Unvaccinated people are ‘urged’ to wear masks. The state “advises all unvaccinated residents to continue to wear masks in indoor settings and when they can’t socially distance.” Lots of luck with that.

So I went to the working class cafe where I get coffee every day. A place where irony is unknown. In a 25 – 25 foot space (my guess) were 50 people in 6 booths and about 6 tables, none wearing masks. I doubt that all were vaccinated. Fortunately the cafe staff has all been vaccinated.

The cafe is in an old building with at most a 9 foot ceiling. Service was likely slow because of the crowd. So they’d likely spend 30 – 60 minutes breathing each other’s air, a perfect way to transmit the virus if any of the 50 would be infected. For details please see https://www.erinbromage.com/post/the-risks-know-them-avoid-them.

The clientele is not a healthy lot, and I’d estimate that 40% of those present had BMIs over 30.

For some reason the classic editor won’t let me put in links. So I’m publishing this as is.

Anti-vaxers, what is it that you know that we don’t ?

32 members of the University of Pennsylvania Medical School class of 1966 held a 55th reunion by Zoom a week ago.  All 32 have been (voluntarily) vaccinated.

Among the attendees were 

l. Mike Brown — Nobel Laureate whose work led to the statins — https://en.wikipedia.org/wiki/Michael_Stuart_Brown

2. Jerry Gardner — All American Basketball Player Kansas ’62  — https://kuathletics.com/roster/jerry-gardner/ — but far from a dumb jock — established a GastroIntestinal program at the National Institutes of Health

3. An (emeritus) professor of neurology at the University of Rochester Medical School 

4. The (emeritus) director of the radiology residency program at Yale Medical School

5. An (emeritus)  professor of medicine at Albert Einstein Medical school

6. A (retired) Rear Admiral in the US Navy

There are several more deans and professors among the 32, but you get the idea.

All classmates who spent their careers taking care of the sick (such as yours truly) were board certified in their specialties.  Some were even board examiners for certification in their specialties (such as yrs trly).

Don’t do as I do, do as I say never works.  Anyone who’s raised kids knows that.  The Penn Med class of 1966 has put its money where its mouth is.

So what is it that you know about vaccines that we don’t?  Please get vaccinated.  The new strain (B.1.1.7) is 50% more lethal and much more infectious than the original pandemic virus  [ Nature vol. 593 pp. 270 – 274 ’21 ].

Addendum 20 May:  I thought the following comment and my response were worth placing in the body of the post.

From DH :The one thing everyone in your sample has in common is old age and thus relatively high risk of death if infected with COVID. A lot of the people I argue with online are not absolute anti-vaxxers, but claim that for healthy people under 30, the risk-reward calculus favors not getting vaccinated (e.g., because the vaccines were “rushed”).

I disagree with them, but to be fair to them, your class of 1966 example is not an argument that addresses their claim.

Response:  DH — thanks for commenting: I quite agree with what you say, but there are larger issues. My sample is small but I know several antiVaxers in their 70s. The proportion of unvaccinated minorities is larger than their proportion in the population. Many of them live in multigenerational households so an infected 30 year old could kill granny. Just look at what’s going on in India.

Even worse is the fact that the newer mutations may be more virulent as well as more infectious. This has now been shown to be the case for B.1.1.7 [ Nature vol. 593 pp. 270 – 274 ’21 ]. Even if the vaccines aren’t quite as effective (in vitro) against the new strains, they still offer protection. We will inevitably continue to see new mutants. A vaccinated population is our best hope.

Ashkenazi Jews are extremely inbred

Neurologists are inherently interested in  psychosis, not least because too much dopamine in the form of L-DOPA can trigger it.  I’ve always found it remarkable that dopamine blocking agents (phenothiazines, and most antipsychotics) can attack psychotic thought itself.  This is much more impressive to me than the ability of other drugs (alcohol, coffee, marijuana, cocaine) to affect mood.

So it’s always worthwhile to read another paper about the genetics of schizophrenia, a very hereditary disease.  All the risk factors we’ve found by GWAS (Genome Wide Association Studies) account for at most of 1/3 of genetic risk in schizophrenia.  For details please see https://luysii.wordpress.com/2014/08/24/tolstoy-rides-again-schizophrenia/.

So I was interested in another crack at finding more genetic causes of schizophrenia  [ Neuron 109, 1465–1478, May 5, 2021 ].  As often happens, the most interesting thing in the paper was something totally tangential  to my original interest in it. 

Here it is —   ”  For example, the Ashkenazi Jewish (AJ) population, currently numbering >10 million individuals world- wide, effectively derives from a mere 300 founders 750 years ago ” (Carmi et al., 2014;Nat. Commun. volume 5, 4835.).  

I find this assertion incredible.  But, as explained below, there is pretty good evidence (although subtle and quite technical) that it’s correct.

Ashkenazi Jews are those previously found only in Europe and the Americas, as opposed to Sephardic Jews, previously found only in the mideast and Africa.  Both are now found in Israel.  Ashkenazi Jews were chosen for the study because any deleterious genes producing schizophrenia  present in the original 300 wouldn’t have been washed out by natural selection in just 30 generations in 750 years. 

The Ashkenazim make the inbreeding among French Canadians look like pikers — a population of 2 million derived from a founder population of 9000 people over the next 170 years — for details please see https://luysii.wordpress.com/2019/07/17/the-wages-of-inbreeding/.  Note that neither population tried to inbreed, it’s just that there was no one else geographically available to breed with for the French Canadians, and no one else culturally available for the Ashkenazi’s.  

At least with the French Canadians we have immigration records to tell us how large the founder population was.  How sure are we about the 300 strong founder population of present day Ashkenazi Jews?  We’re not and I’m not even though it was published in a peer reviewed reputable journal.  There is a lot of guesswork in figuring out just how large a genetic bottleneck is.  It all depends on the model used, and I don’t trust models in general.  I’ve seen too many crash and burn. (For details — https://luysii.wordpress.com/2019/03/03/i-mistrust-models-2/)

However, the Neuron paper contains a reference to another paper which provides excellent empiric evidence for a small founder population, (PLoS Genet. 14, e1007329. 2018).  Here’s a direct quote.  It’s quite a mouthful; I’ll try to explain below the quote what the terms mean, because I think many nonscientific types are likely to be interested in the idea that Ashkenazi Jews are that inbred. 

Just skip the paragraph if it’s incomprehensible, go to *** and read the explanatory material, and then read the paragraph again. 

“We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations.”

****

Explanatory material.

Our genetic material (DNA) is made of 4 different compounds A, T, G, C (called nucleotides) which are linked together in chromosomes.  The order is crucial, just as the order of letters in a word is crucial for meaning (consider united and untied).  So how many slots for the nucleotides are there in our genome ? Just 3,200,000,000.  Just as combinations of dots and dashes code for letters in Morse code, combinations of  3 nucleotides code for the 20 amino acids that make up proteins. 

Proteins are big.  For instance, the protein  (beta-globin)mutated in sickle cell anemia contains 146 amino acids, and all it takes to produce the disease is a switch from one amino acid to another at position six.  The other 145 amino acids in the chain are unchanged. So sickle cell beta globin with a change in its nucleotide sequence is an allele (alternate form) of normal beta globin.  

Every population of people contains alleles of every protein.  Some are common (over 5% of the population showing them), but most are rare.The PLoS paper looked at  73,228 alleles of all 20,000 or so proteins that we have in our genome (yes technology now can do these sorts of things) in the general population.  The authors looked at the alleles in the Ashkenazi population which were present at greater than 1/500 (.2%).  Then they looked at the frequency of the same allele in several other non-Ashkenazi population (about 5000 each of non-Finnish Europeans, African Blacks and Latinos), and found that these alleles occurred15 times less frequently (on average).   So Ashkenazi’s have alleles that are lots more common than in other populations.  Actually it’s more than some, because about 1/3 of the alleles they studied are an average of 15 times as common.

What does this mean?  It means that when a small founder population with a rare allele becomes ‘fruitful and multiplies’, the rare allele will multiply right along with it and not be lost by outbreeding (which was certainly true of the Ashkenazis for 600 of the last 750 years).

Now read the paragraph in bold above again. 

This is the evidence that current day Ashkenazi’s come from a very small founder population.  It’s pretty good.  I hope that I’ve made this somewhat comprehensible;  if not, please write a comment.

A touching Mother’s day story — with an untouching addenum

Yes, a touching mother’s day story for you all. It was 54 years ago (yes over half a century ago ! ! ), and I was an intern at a big city hospital on rotation in their emergency room in a rough neighborhood. The ER entrance was half a block from an intersection with a bar on each corner. On a Saturday night, we knew better than to try to get some sleep before 2AM or until we’d put in 2 chest tubes (to drain blood from the lungs, which had been shot or stabbed). The bartenders were an intelligent lot — they had to be quick thinking to defuse situations, and we came to know them by name. So it was 3AM 51 years ago and Tyrone was trudging past on his way home, and I was just outside the ER getting some cool night air, things having quieted down.

“Happy Mother’s day, Tyrone” sayeth I

“Thanks Doc, but every day is Mother’s day with me”

“Why, Tyrone?”

“Because every day I get called a mother— “

Untouching Addendum

Well, it’s 54 years later and the terrible violence in the Black community continues unabated.  Nothing has changed from 1967.  200+ murders already in Chicago.  My white neighbors drench themselves in holiness, displaying their virtue for all to see with signs on their lawns saying Black Lives Matter.  This neatly avoids facing the real problem — Black Lives Matter except to other Blacks. 

Chamber music at last !

Last night I played chamber music with two friends for the first time in over a year. It was glorious. The string players wanted the Dvorak Dumky trio. It is a very deep, beautiful and rather dark work. I wanted something joyous, and convinced them to play Beethoven Op. 1 #2, which is one of the happiest pieces he ever wrote.  It’s great fun, particularly the last movement.  

If you’re a string player, imagine being unable to tune your instrument for a year, while you played it daily.  Such was my lot, until my piano tuner got vaccinated last month.  

So, if you’re able, get out there and play some music with friends.

The solo piano literature is enormous yet, given a choice I’d rather play chamber music.   The interaction with another musical mind, particularly in the hands of a great composer, just has to be experienced.   Leonard Bernstein said something to the effect that if you could capture music in words, you’d never need to listen to it. 

God only knows how many professional musicians were lost or gave up in the past year.  Even so, I’m not ready to go to concerts.

Is there anything in the cell that has just one function — more moonlighting — this time mRNA

Able was I ere I saw Elba said Napoleon. It’s called a palindrome, and can be read either way. So can DNA which brings me to antisense transcription of DNA, particularly in two famous retroviruses –the AIDS virus (HIV1) and HTLV-1.  

Proc. Natl. Acad. Sci. vol. 118 e2014783118 ’21  shows that mRNA can moonlight to do other things than code for protein.  Here’s a direct quote to set the stage.

“Retroviruses share a similar genome structure. The integrated retroviral genome, called the provirus, has two identical long terminal repeats (LTR) located at its 5′ and 3′ ends, respectively. The 5′ LTR acts as the promoter of almost all retroviral genes and thus is indispensable for viral transcription and replication. However, selective methylation of the 5′ LTR and the subsequent viral latency have been observed in HIV-1 and HTLV-1. In contrast, the 3′ LTR of HIV-1 and HTLV-1 remains nonmethylated, and recent findings have shown that novel retroviral genes are transcribed from the 3′ LTR in an antisense direction”.

The 3′ LTR of the AIDS virus enables antisense transcription for  the unimaginatively named ASP (AntiSense Protein).  So the mRNA for ASP is transcribed in the nucleus.  But it doesn’t get out as well as it might, because its 5′ end isn’t polyAdenylated.  So it sticks around in the nucleus and binds to DNA, turning off transcription of the regular HIV1 genome — e.g. helping to maintain viral latency (and preventing a true cure of HIV1 in any individual).

This is unprecedented.  Here is an mRNA with a completely different function (e.g. regulating gene expression).  This is classic moonlighting as something else and the authors call the mRNA for ASP a bifunctional mRNA. 

The other, retrovirus HTLV-1 also has an antisense transcript making a protein called HBZ (your don’t want to know what it stands for). Unlike ASP, HBZ turns on a variety of genes. 

I’ve been fascinated by moonlighting molecules, probably because they show the depths of our ignorance of the biochemical machinations inside the cell.  Even when you think you’ve got the function of a molecule tied down, it goes off and does something else. 

 Here are some links to other posts on the subject.  To get to them just click on the titles

Moonlighting molecules

More moonlighting

A moonlighting quorum sensing molecule

Mathematics and the periodic table

It isn’t surprising that math is involved in the periodic table. Decades before the existence of atoms was shown for sure (Einstein in 1905 on Brownian motion — https://physicsworld.com/a/einsteins-random-walk/) Mendeleev arranged the known elements in a table according to their chemical properties. Math is great at studying and describing structure, and the periodic table is full of it. 

What is surprising, is how periodic table structure arises from math that ostensibly has absolutely nothing to do with chemistry.  Here are 3 examples.

The first occurred exactly 60 years ago to the month in grad school.  The instructor was taking a class of budding chemists through the solution of the Schrodinger equation for the hydrogen atom. 

Recursion relations are no stranger to the differential equations course, where you learn to (tediously) find them for a polynomial series solution for the differential equation at hand. I never really understood them, but I could use them (like far too much math that I took back then).

So it wasn’t a shock when the QM instructor back then got to them in the course of solving the hydrogen atom (with it’s radially symmetric potential). First the equation had to be expressed in spherical coordinates (r, theta and phi) which made the Laplacian look rather fierce. Then the equation was split into 3, each involving one of r, theta or phi. The easiest to solve was the one involving phi which involved only a complex exponential. But periodic nature of the solution made the magnetic quantum number fall out. Pretty good, but nothing earthshaking.

Recursion relations made their appearance with the solution of the radial and the theta equations. So it was plug and chug time with series solutions and recursion relations so things wouldn’t blow up (or as Dr. Gouterman put it, the electron has to be somewhere, so the wavefunction must be zero at infinity). MEGO (My Eyes Glazed Over) until all of a sudden there were the main quantum number (n) and the azimuthal quantum number (l) coming directly out of the recursions.

When I first realized what was going on, it really hit me. I can still see the room and the people in it (just as people can remember exactly where they were and what they were doing when they heard about 9/11 or (for the oldsters among you) when Kennedy was shot — I was cutting a physiology class in med school). The realization that what I had considered mathematical diddle, in some way was giving us the quantum numbers and the periodic table, and the shape of orbitals, was a glimpse of incredible and unseen power. For me it was like seeing the face of God.

The second and third examples occurred this year as I was going through Tony Zee’s book “Group Theory in a Nutshell for Physicists”

The second example occurs with the rotation group in 3 dimensions, which is a 3 x 3 invertible matrix, such that multiplying it by its transpose gives the identity, and such that is determinant is +1.  It is called SO(3)

Then he tensors 2 rotation matrices together to get a 9 x 9 matrix.  Zee than looks for the irreducible matrices of which it is composed and finds that there is a 3×3, a 1×1 and a 5×5.  The 5×5 matrix is both traceless and symmetric.  Note that 5 = 2(2) + 1.  If you tensor 3 of them together you get (among other things 3(2) + 1)   = 7;   a 7 x 7 matrix.

If you’re a chemist this is beginning to look like the famous 2 L + 1 formula for the number of the number of magnetic quantum numbers given an orbital quantum number of L.   The application of a magnetic field to an atom causes the orbital momentum L to split in 2L + 1 magnetic eigenvalues.    And you get this from the dimension of a particular irreducible representation from a group.  Incredible.  How did abstract math know this.  

The third example also occurs a bit farther along in Zee’s book, starting with the basis vectors (Jx, Jy, Jz) of the Lie algebra of the rotation group SO(3).   These are then combined to form J+ and J-, which raise and lower the eigenvalues of Jz.  A fairly long way from chemistry you might think.  

All state vectors in quantum mechanics have absolute value +1 in Hilbert space, this means the eigenvectors must be normalized to one using complex constants.  Simply by assuming that the number of eigenvalues is finite, there must be a highest one (call it j) . This leads to a recursion relation for the normalization constants, and you wind up with the fact that they are all complex integers.  You get the simple equation s = 2j where s is a positive integer.  The 2j + 1 formula arises again, but that isn’t what is so marvelous. 

j doesn’t have to be an integer.  It could be 1/2, purely by the math.  The 1/2 gives 2 (1/2) + 1 e.g two numbers.  These turn out to be the spin quantum numbers for the electron.  Something completely out of left field, and yet purely mathematical in origin. It wasn’t introduced until 1924 by Pauli — long after the math had been worked out.  

Incredible.