Advice for first time high school students entering the Ivy League in the fall

The Ivy league can be and was very intimidating for students from small high schools, particularly if they are the first from their school or family to ever go there.  Here are a few stories about similar Freshmen entering Princeton in 1956.  We all wondered if we were smart enough.

First yours truly.  The first intimidation was the guy next door who built a tesseract, a 3 dimensional model of a 4 dimensional cube.  The second was his story about another guy in the class so smart that he looked at the Freshmen Herald with 700+ pictures and names, and knew everyone in the class by name by the next day.  He wound up in the top 7 members of the class (Junior Phi Beta Kappa).   Fortunately at an assembly during orientation, a dean told us not to worry, that they knew we would be able to do the work, and that only emotional trouble or misbehavior would get us out.  This happened to a member of the class, schizophrenia often presents in late adolescence (one name for it used to be dementia praecox), and another member was expelled for stealing stuff from other rooms.  Then there were the preppies (about 50% of the class back then) who basically had the first month of classes and appeared to know it all.   After a month or two I knew I would make it, but the first few months were scary.

Then there was the guy who was recruited because of his character.  He went to a small high school in New Jersey and played on their basketball team, which was getting creamed by an affluent suburban school.  At nearly the end of the game, they slacked off and he ran through the whole team and scored a basket.  An alum came up to him and asked him why he did it.  He said he wanted to show the other team that they beat his team, but they didn’t beat him.  The alum promptly recruited him to Princeton.  His father was a factory worker, and took him down, and my friend was impressed, saying to his father that he didn’t think he belonged there.  The father said something to the effect of give it a shot and don’t tell them.  Subsequently he got a PhD in ceramics and worked at Los Alamos.

Then there was a guy from a little town in Maine, whose school was so proud when he got in, that they announced it over the intercom (as did my high school).  Similarly intimidated at the time, he became an endocrinologist and was involved in drug development writing 45 papers in the process.

Another guy was recruited by an alum from a larger school in western New York, and went through on a ROTC scholarship, becoming a naval officer, joining the state department and becoming an ambassador to a central American country.

None of us knew any of this at the time.  It came out 50 years later as we gathered after Princeton football games.  Although we were intimidated we didn’t let on and did fine — and you will too.

James Hartle R. I. P.

Jim Hartle, one of the smartest guys in my college class has died, and of Alzheimer’s disease, showing once again that intelligence does not absolutely protect against Alzheimer’s (although the more educated you are the less likely you are to get it [ Int. J. Epidemiol. Volume 49, Issue 4, August 2020, Pages 1163–1172 ].

He studied with John Wheeler as a Princeton undergraduate, got his PhD with Murray Gell-Mann and worked so extensively with Stephen Hawking that he was asked to speak at Hawking’s funeral.

My total person to person contact with Jim may have lasted 10 minutes (at my 50th reunion).  I knew all sorts of physics majors in the class, but he wasn’t one of them.  I knew about him only because I read our  50th reunion book, and found out how distinguished he was.  I found him relaxed, friendly and far from overbearing, like some of the physics majors I knew.

This was typical of just about everyone at the 50th.  A classmate’s wife (from Chile) described classmates at the 25th as a bunch of roosters.

We did correspond a bit, and he did send me the answer sheets to the problems in his book on Gravity (which I’ve never gone through preferring to get the math under my belt first rather than mouth various incantations which I didn’t understand).  Jim is the reason I started studying Math and Physics in earnest, hoping to have something intelligent to say to him at the next reunion.  He wasn’t present at the 55th,   COVID19 ended the 60th and now he’s gone.

Two more examples of brilliant men you might know of who died of Alzheimer’s are Daniel Quillen Harvard ’61 who won the Fields Medal and Claude Shannon.

The physics department at University of California Santa Barbara has an obituary describing much of his work

https://www.physics.ucsb.edu/news/announcement/2132

Transcriptional Chaff

The first results of the ENCODE project (ENCyclopdeia Of Dna Elements) were pretty controversial when they came out 16 years ago–https://en.wikipedia.org/wiki/ENCODE.  We knew that only 1 – 2% of our 3.2 billion basepair genome codes for protein, with well over half being made from repetitive elements (LINEs, Alu elements, transposons, satellite DNA, etc. etc.).

ENCODE said, ‘junk’ or not, careful study of the RNAs present in cells and matching them to the sequence of our DNA, showed that just about every position in our DNA was copied (technical term — transcribed) into RNA by the cell’s machinery — RNA polymerases I, II and III.

Could  all this RNA possibly have a function?  Or was it the turnings of a block of wood on a lathe, a byproduct of what was actually being made by the lathe, transcriptional chaff if you will.

A recent paper [ Nature vol. 617 pp. 395 – 402 ’12 ] describes a protein complex which chops up RNA produced from the 98% of the genome not coding for protein. It goes by the ugly acronym BAG6 complex (what it stands for is even uglier — BCL2 Associated Athanogene cochaperone 6).  The complex contains 3 proteins and it associates with ribosomes trying to translate RNA into protein (do distinguish translation from transcription).  Here BAG6 looks for newly made ribosomal protein products to bind to.

How does the BAG6 complex distinguish proteins or peptides made from the 98% of the genome not coding for protein?  Because such proteins have a lot of hydrophobic amino acids (leucine, isoleucine, valine, alanine, phenylalanine) which makes them excellent candidates for insertion into membranes (which are made of lipids and inherently hydrophobic).  However if they don’t get into membranes their hydrophobic amino acids make them insoluble in the cytoplasm, and persona non grata,   Once BAG6 finds such insoluble proteins or peptides, it calls an enzyme which adds ubiquitin to them, and off they go to the proteasome for destruction.

Here is where the paper becomes truly fascinating, showing me that despite decades of reading molecular biology, there is a Hell of lot that I didn’t know.  I’ll bet that most people reading this post didn’t know it either.

It turns out that there is an intrinsic nucleotide bias in the 98% of our genome not coding for protein.  It contains a lot of Uracil when transcribed into RNA from a Thymine  (RNA uses Uracil rather than Adenine).  RNA containing lots of U (Uracil) tends to code for hydrophobic amino acids.  Did you know that?  I didn’t.

It you look at our 20,000 proteins you’ll find that their carboxy terminal 30 amino acids or so avoid having hydrophobic amino acids in this position.

Just the opposite occurs in parts the nonCoding (for protein) of the genome — introns, 3′ untranslated regions, large noncoding RNAs (lncRNAs)  — they don’t exclude hydrophobic amino acids.

So the existence of the BAG6 complex is good evidence that the cell isn’t using all the RNA transcribed from the genome, and does work to get rid of it.

More fascination awaits.  The genomes of other animals (particularly primates) tells us a lot about our own.  A recent issue of Science had a lot of fascinating papers on this called Zoonomia (the subject of a future post).

So it’s easy to find human proteins unique to us, now that we have the genome of the Chimpanzee, out closest evolutionary relative, diverging from us 4 to 6 million years ago.  And guess what — they have the highest carboxy terminal hydrophobicity of all our 20,000 or so protein coding genes, essentially proving that they arose from the 98% of the genome previously not coding for protein.  Maybe that’s why we have so much DNA not coding for protein, evolutionary soil if you will for new protein formation

 

What about Long COVID?

A friend was happy to hear that the pandemic was winding down (see old post below the ****), but was still worried about ‘long COVID’.  He’d heard that it was very common and debilitating.  So I looked up the latest [Nature vol. 616 pp. 228 – 229 ’23, Science vol. 379 pp. 1174 – 1175 ’23].

There have been a variety of definitions of long COVID, but anyone still symptomatic 3 months after the initial infection probably has it.

The first strain of the virus was called alpha, and 46% of those affected were still symptomatic at 3 months.  So my friend was right.  It made the news as it should have, everyone being concerned and worried about where the new pandemic was taking us.  Alpha was replaced by the milder delta variant, and here long COVID dropped to 35%.  Then the Omicron strain took over, and the risk of long COVID dropped to 14%.  The paper noted that the risk of long COVID in 97,000 ‘healthy’ people infected with Omicron was 4.5%.  No headlines trumpeted this.  Good news just doesn’t sell.

Things are probably even better now as the new strain, XBB.1.16, is milder still and isn’t covered in the papers (it couldn’t be as it wasn’t around when the papers were written and submitted).

Now you don’t have to go to medical school to know that it takes longer to recover from a severe case (of anything) than a mild one.   So the decline in the incidence of long COVID is another piece of evidence that the pandemic is winding down and that successive variants are less virulent (or the populace is becoming immunologically immune due to asymptomatic infections).

The symptoms of long COVID and chronic fatigue syndrome are the same.As a neurologist I saw a lot of people who were chronically tired and fatigued, because neurologists deal with muscle weakness and diseases like myasthenia gravis which are associated with fatigue.  Once I ruled out neuromuscular disease as a cause, I had nothing to offer them (nor did medicine).  Some of these patients were undoubtedly neurotic, but there was little question in my mind that many others had something wrong that medicine just hadn’t figured out yet — not that it hasn’t been trying.

Infections of almost any sort are associated with fatigue, most probably caused by components of the inflammatory response.  Anyone who’s gone through mononucleosis knows this.    The long search for an infectious cause of chronic fatigue syndrome (CFS) has had its ups and downs — particularly downs — see https://luysii.wordpress.com/2011/03/25/evil-scientists-create-virus-causing-chronic-fatigue-syndrome-in-lab/

At worst many people with these symptoms are written off as crazy; at best, diagnosed as depressed  and given antidepressants.  The fact that many of those given antidepressants feel better is far from conclusive, since most patients with chronic illnesses are somewhat depressed.

*****

The serious part of the pandemic is over, but the virus is here to stay

Massachusetts has some of the best statistics in the country on hospitalizations due to COVID-19.  Everybody admitted to the hospital gets tested for the virus so they won’t spread it.  However Massachusetts distinguishes people in the hospital withCOVID-19 from people in the hospital because of COVID-19.  Statistics come out every Thursday usually after 5 PM — https://www.mass.gov/info-details/covid-19-response-reporting#covid-19-interactive-data-dashboard-

On 3 January ’23 there were 1,336 people hospitalized with COVID-19 and 437 hospitalized because of COVID-19.

On 9 May ’23 there were 172 people hospitalized with COVID-19 and 42 hospitalized because of COVID-19.

COVID-19 will always be with us, but it is acting differently than the season flu, as waves of high levels of mostly mild infections due to new variants (as shown by testing), without waves of hospitalization occur all year long,  so the new variants are milder.

The latest strain is XBB.1.16 which now accounts for 11% of USA cases (without a surge in hospitalizations or deaths).

The virus is still a killer, but you have to be old (like my wife and I) or seriously ill with something else to die from it.  That’s good news for just about everyone.

Remember when COVID-19 was being touted as a disease of the unvaccinated (by the CDC and everyone else) in an attempt to get people vaccinated.  All year long the percentage of ‘fully vaccinated’ people hospitalized with/for COVID-19 in Massachusetts has ranged from 60 to 71%.  Some humility is in order

The serious part of the pandemic is over, but the virus is here to stay

Massachusetts has some of the best statistics in the country on hospitalizations due to COVID-19.  Everybody admitted to the hospital gets tested for the virus so they won’t spread it.  However Massachusetts distinguishes people in the hospital with COVID-19 from people in the hospital because of COVID-19.  Statistics come out every Thursday usually after 5 PM — https://www.mass.gov/info-details/covid-19-response-reporting#covid-19-interactive-data-dashboard-

On 3 January ’23 there were 1,336 people hospitalized with COVID-19 and 437 hospitalized because of COVID-19.

On 9 May ’23 there were 172 people hospitalized with COVID-19 and 42 hospitalized because of COVID-19.

COVID-19 will always be with us, but it is acting differently than the season flu, as waves of high levels of mostly mild infections due to new variants (as shown by testing), without waves of hospitalization occur all year long,  so the new variants are milder.

The latest strain is XBB.1.16 which now accounts for 11% of USA cases (without a surge in hospitalizations or deaths).

The virus is still a killer, but you have to be old (like my wife and I) or seriously ill with something else to die from it.  That’s good news for just about everyone.

Remember when COVID-19 was being touted as a disease of the unvaccinated (by the CDC and everyone else) in an attempt to get people vaccinated.  All year long the percentage of ‘fully vaccinated’ people hospitalized with/for COVID-19 in Massachusetts has ranged from 60 to 71%.  Some humility is in order

Don Sebesky R. I. P

I first heard Don Sebesky play piano when he was a Rutgers undergraduate and I was still in high school, visiting a former band member up there.  If you’re any good as a musician, you should be good enough to be in a band when you’re fourteen.  So I was in a high school band as a freshman with a drummer in the junior class, and a sophomore trumpet player.  It was assumed that I’d go to Rutgers as my father and 2 uncles went there.

Sebesky was playing piano and I’d never heard anything like it.  Although I liked jazz, the local radio didn’t have much of it, just Brubeck and Shorty Rogers and his Giants.  Unfortunately Sebesky passed away and the Times obit had nothing about piano or Rutgers — https://www.nytimes.com/2023/05/06/arts/music/don-sebesky-dead.html.   I was amazed to find out that his main instrument was the trombone, which goes to show that if you’ve got musical talent you can play just about anything.  As I write this I’m listening to the great trumpeter Arturo Sandoval play the piano on one of his CDs.

I was staggered at how very much better Sebesky was than anything I could ever hope to be, even though he was just 4 months older.  This is typical for musicians, we instinctively know how we stand talentwise.  I found it amazing that Sebesky’s first instrument of choice was the accordion.   He probably came to it through polka bands as his father was a Polish steelworker.

He worked with everybody, not confining himself to jazz.  If you want to hear just how good he was pick up his album “I remember Bill: A tribute to Bill Evans”.  Evans grew up 17 miles away in Plainfield NJ.

A Touching Mother’s day story with an untouching addeneum

Yes, a touching mother’s day story for you all. It was 56 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 56 years later and the terrible violence in the Black community continues unabated.  Nothing has changed from 1967.  Half the murdered people in this country are black with only 1 out of 7 being black.   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. 

Addendum 14 May ’23 As if on command, today’s New York Times magazine has a story about a black woman killed by a white racist in Buffalo.  If every black killed by a nonBlack or a police officer even if black) were still alive, murdered blacks as a percentage of those murdered each year would still be close to 50%.   This sort of thing is so unhelpful, and probably harmful in taking the focus away from the all to real problem of excessive black deaths.

In fairness to my white neighbors, putting signs on their lawns is about all they can do.  Any change in the carnage must come from within the Black community itself, not from well-meaning whites.

Fortunately, there is a hopeful precedent — Mother’s Against Drunk Driving (MADD).   When they were founded in 1980, the USA population was 220 million and there were 28,000 drunk driving fatalities. In 2021 our population had grown by 50% to 330 million, with 13,000 drunk driving fatalities.  Had nothing changed we would have experienced 42,000 fatalities in 2021 instead of 13,000.  MADD simply made drinking and driving socially unacceptable.

A neuron synapsing on an immune cell.

The immunologic synapse is well known.  It occurs between two types of immune cells (not between neurons), an antigen presenting cell and a T lymphocyte.  An effective immunologic synapse produces T cell activation and proliferation to kick off the immune response.

Neuroinflammation is equally well known.  Stimulate a neuron responding to painful stimuli and it releases inflammatory mediators locally and fires impulses back to the brain.  The best known example of a receptor for pain (nociceptor) is the TRPV1 channel, which responds to capsaicin, an active component of red hot chili peppers.  TRPV1 also responds to other obviously painful stimuli — heat, acid etc.  Neurons containing TRPV1 are called nociceptor neurons.

Activation of TRPV1 on nociceptor neurons results in the release of inflammatory mediators such as substance P, and other things (CCL2, CGRP).

Many immune cells have receptors for inflammatory mediators and direct contact with nociceptor neurons isn’t necessary.  I’ve always wondered if something like a synapse between a nerve cell and immune cell existed.

Finally a paper just cultured nociceptor neurons and a type of immune cell (the dendritic cell) together [Science vol. 379 pp. 1301 – 1302, 1315 eabm5658 pp. 1 –> 1 ’23 ].  Figure 3c on p. 4 of the paper, shows a dendritic cell plastered up along an axon, which is about as close to synapse as you are going to get.  However, the area of contact is much longer than the usual synapse.  Whether such things occur in vivo is unknown, but I’ve never seen a picture like this one.

Capsaicin was used to stimuli the neurons, and they were found to communicate wth  dendritic cells three ways

l. By producing the chemokine CCL2 which attract dendritic cells

2, By releasing Calcitonin Gene Related Peptide (CGRP) which causes dendritic cells to release another inflammatory mediator — interleukin 1 beta (IL1beta)

3. By direct electrical coupling triggering calcium flux into the dendritic cell along with membrane depolarization.  This potentiates the dendritic cell response to inflammatory stimuli.

The experimental system is far out, but anything we can learn about pain is worth having, as present therapy is far from ideal.

Impeach Earl Warren (and Clarence Thomas too) say the Democrats

It was impossible to drive anywhere in the South in the 50s and 60s without seeing “Impeach Earl Warren” billboards.  For those who weren’t even alive (or old enough to be politically conscious) back then:  Earl Warren was the Chief Justice of the Supreme court, and former Republican Governor of California under whom the landmark Brown vs. Board of Education  decision abolished segregation by race in 1954.  He was appointed by Republican president Eisenhower (Links to unfamiliar names, etc. will be provided at the end of the post)

The charge against Warren was led by a variety of Democratic Party elected officials (Governor George Wallace of Alabama, Governor Orville Faubus of Arkansas, senators Strom Thurmond of South Carolina and John Stennis of Mississippi).

Here’s what it was like back then.  The wounds were still fresh when a fellow neurology resident and I drove from Philly to San Antonio in the summer of 1968 to enter the Air Force for our 2 year tour of duty under the Berry Plan during the Vietnam War.

Our first stop was in Winchester, Virginia where the owner of the motel noted the Pennsylvania plates on our car, and asked us “What do they think of Governor Wallace, up they’ah”, which creeped us out, the Cheney, Goodman Schwerner murders occurring 4 years earlier a few miles further along our planned route.  We mumbled something that to the effect that we were doctors and  Air Force officers and couldn’t discuss politics.

We actually ate lunch in Meridian Mississippi, Cheney’s home and the people were quite friendly.    We also ate in Cameron, Louisiana on the Texas border and found wop salad on the menu.

Well times have changed. Senator Thurmond of South Carolina has been replaced by Tim Scott, a Black Republican running for president.

But they haven’t.  Here is MSNBC 5 May, a site with impeccable liberal and Democratic pedigrees  ” Enough is enough. Clarence Thomas  must resign or be Impeached” written by a white man, James Downie, of similarly impeccable credentials — https://www.msnbc.com/opinion/msnbc-opinion/clarence-thomas-ginni-supreme-court-ethics-rcna83062.

At least the collection of Southerners above, hideous and disgusting as they were, had the intellectual integrity to say they thought Warren should be impeached because they disagreed with what he did and stood for, and not hide behind some phony moral stance.  Another lynching of a Black man by an overprivileged White.

https://en.wikipedia.org/wiki/Berry_Plan

https://en.wikipedia.org/wiki/Murders_of_Chaney,_Goodman,_and_Schwerner

https://en.wikipedia.org/wiki/Earl_Warren

https://en.wikipedia.org/wiki/George_Wallace

https://en.wikipedia.org/wiki/Orval_Faubus

https://en.wikipedia.org/wiki/Strom_Thurmond

https://en.wikipedia.org/wiki/John_C._Stennis

https://www.scott.senate.gov

Lactic acid, the mitotic spindle killer

Nature vol. 616 pp. 790 – 797 ’23 is one of the most interesting papers I’ve read in the past year, both for its contents and for the two very large issues it raises (which the authors don’t really discuss).

Simply stated, the rise in cellular lactic acid levels from 6  milliMolar at mitosis onset, to 15 – 20 when mitosis is nearly over is what ’causes’ the breakdown of the mitotic spindle.

It’s now 100 years since Otto Warburg noted that tumors metabolize glucose by glycolysis producing 2 molecules of ATP per glucose (and two molecules of lactic acid) when, with plenty of oxygen around, they could get 38 molecules of ATP using their mitochondria.   This is called aerobic glycolysis.

Tumors are said to be energy hungry, so why do they use aerobic glycolysis? Simply because using oxygen to chew up glucose gives you lots of ATP along with CO2 and water, leaving you nothing to build new tumor cells with.  All 6 carbons remain present after glycolysis

The last stage of mitosis is called anaphase, where the mitotic spindle (made of microtubules) is broken down, among other things such as reformation of the nuclear membrane, and separation of the two daughter cells.

Well protein breakdown immediately brings ubiquitin to mind which, when added to most proteins, targets them to the proteasome, a huge molecular complex which breaks proteins down completely to their constituent amino acids.

APC/C is another huge multiprotein complex (at least 13 different protein subunits with a molecular mass of 1.2 megaDaltons) which acts to add ubiquitin to components of the mitotic  spindle (made mostly of microtubules).  So APC/C is a ubiquitin ligase, a dangerous thing to have around most of the time, which it is why it is usually inhibited so the cell doesn’t destroy itself.

One APC/C subunit is APC4, which has ubiquitinLike molecules (SUMO) attached to two of its lysines (#722 and #798) to activate the ubiquitin ligase activity of APC/C.    APC4 is held in check by yet another enzyme, SENP1, which removes the SUMOs.

Where does lactic acid fit in to all this?  It binds to the active site of SENP1 when coordinated with zinc ions, inhibiting SENP1’s ability to remove SUMO.

Byzantine enough for you?  Lactic acid inhibits SENP1 which inhibits APC4 allowing uninhibited APC4 to activate APC/C which breaks down the mitotic spindle.

Lactic acid, if thought of at all, was regarded as an important part of cellular metabolism, not an enzyme inhibitor.   This is an example of moonlighting, a lot of which goes on in the cell. https://luysii.wordpress.com/2021/05/04/is-there-anything-in-the-cell-that-has-just-one-function-more-moonlighting-this-time-mrna/  with its links will get you started.

Here is one of the larger issues the paper raises — how events in the cell at all levels of structure are linked to each other.  Phillip Anderson famously said “More is Different”.  The paper shows how something very small (lactic acid fits into a 5 Angstrom (.5 nanoMeters) sphere) and yet  is responsible for breaking down something 40,000 – 100,000 times larger  (the length of a microtubule in the mitotic spindle).

Here is the other (even larger) issue — Lactic acid was found as a player in cell metabolism, e.g., it is a member of the metabolome.  I was amazed to find out how large it is — some 42,000 for in the Human Metabolome DataBase http://www.hmdb.ca/metabolites?c=hmdb_id&d=up&page=1676 — for details please see https://luysii.wordpress.com/2015/06/03/how-little-we-know-2/.  Not only do we not know what they are doing, we don’t even know the structure of most of them. State of the art untargeted metabolomics studies still report ‘up to’ 40% unidentified, but potentially important metabolitcs which can be detected reproducibly. The unknown metabolites are only rarely characterized because of the extensive work required for de novo structure determination..