A beautiful molecule

OK class.  Pop quiz.  Draw the structure of C304 H264 (not a misprint).  To help you out there are 6 sharp NMR peaks (roughly the same size) between 7.8 and 8.5, a doublet at 8.6  and a large peak at 1.45.  This obviously tells you the molecule is quite symmetric.

Give up?   You can read about it’s elegant synthesis and structure in  Science vol. 363 pp. 151 – 155 ’19.  I doubt that Woodward ever thought of a molecule like this, but do not doubt that he would have loved the elegance of its synthesis, using techniques and reagents not available to him years ago.

Give up?  Does the fact the the molecule contains 40 benzene moieties help?  How about the 16 tButyl groups?

Does the fact that the dimensions of the molecule are 17.4 x 16.4 x 16.4 Angstroms help?  How about the fact that the molecule contains a central space which can comfortably fit a buckyball inside?

I’ll fill in some details tomorrow for those without access to the paper.  I’d love to see the NMR of a cyclophane derivative (which the authors haven’t made yet).

Bravo to all concerned in the paper.

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A mathematical kludge and its repair

If you are in a train going x miles an hour and throw a paper airplane forward at x feet per second (or x * 3600/5280 miles per hour, relative to someone outside the train sees the plane move a bit faster than x miles an hour.  Well that’s the whole idea of the Galilean transformation.  Except that they don’t really see velocities adding that way for really fast velocities (close to the speed of light).

Relativity says that there are no privileged sites of observation and that no matter how fast two observer frames are moving relative to each other light will zing past both at the same speed (3 x 10^8 meters/second, 186,000 miles/second).

All of Newton’s mechanics and force laws obeys the Galilean transformation (e.g. velocities add).  Maxwell conceived a series of 4 laws linking electricity and magnetism together, which predicted new phenomena (such as radio waves, and the fact that light was basically a form of wave traveling through space).

Even though incredibly successful, Maxwell’s laws led to an equation (the wave equation) which didn’t obey the Galilean transformation.  This led Lorentz to modify it so the wave equation did obey Galileo.  If you’ve got some mathematical background an excellent exposition of all this is to be found in “The Geometry of Spacetime” by James J. Callahan pp. 22 – 27.

The Lorentz transformation is basically a kludge which makes things work out.  But he had no understanding of why it worked (or what it meant).  The equations produced by the Lorentz transformation are ugly.

Here are the variables involved.

t’ is time in the new frame, t in the old, x’ is position in the new frame x in the old. v is the constant velocity at which the two observation frames are moving relative to each other. c is the common symbol for the velocity of light.

Here are the two equations

t’ =  ( t – vz/c^2 )/ sqrt (1 – v^2/c^2)

x’ = ( z – vt ) /  sqrt (1 – v^2/c^2)

Enter Einstein — he derived them purely by thought.  I recommend Appendix 1 in Einstein’s book “Relativity”.  Amazingly you do not need tensors or even calculus to understand his derivation — just high school algebra (and not much of that — no trigonometry etc. etc.)  You will have the pleasure of watching the power of a great mind at work.

One caveat.  The first few equations won’t make much sense if you hit the appendix without having read the rest of the book (as I did).

Light travels at c miles/hour, so multiplying c by time gives you where it is after t seconds.  In equations x = ct.  This is also true for another reference frame x’ = ct’.

This implies that both x – ct =  0 and x’ – ct’ = 0

Then Einstein claims that these two equations imply that

(x – ct) = lambda * (x’ – ct’) ; lambda is some nonzero number.

Say what?  Is he really saying  0 = lambda * 0.

This is mathematical fantasy.  Lambda could be anything and the statement lacks mathematical content.

Yes, but . . .

It does not lack physical content, which is where the rest of the book comes in.

This is because the two frames (x, t) and (x’ , t’) are said to be in ‘standard configuration which is a complicated state of affairs. We’ll see why y, y’, z, z’ are left out shortly

The assumptions of the standard configuration are as follows:

  • An observer in frame of reference K defines events with coordinates t, x
  • Another frame K’ moves with velocity v relative to K, with an observer in this moving frame K’ defining events using coordinates t’, x’
  • The coordinate axes in each frame of reference are parallel
  • The relative motion is along the coincident xx’ axes (y = y’ and z = z’ for all time, only x’ changes, explaining why they are left out)
  • At time t = t’ =0, the origins of both coordinate systems are the same.

Another assumption is that at time t = t’ = 0 a light pulse is emitted by K at the origin (x = x’ = 0)

The only possible events in K and K’ are observations of the light pulse. Since the velocity of light (c) is independent of the coordinate system, K’ will see the pulse at time t’ and x’ axis location ct’, NOT x’-axis location ct’ – vt’ (which is what Galileo would say). So whenever K sees the pulse at time t and on worldline (ct, t), K’ will see the pulse SOMEWHERE on worldline (ct’, t’).

The way to express this mathematically is by (3) (x – ct) = lambda * (x’ – ct’)

This may seem trivial, but I spent a lot of time puzzling over equation (3)

Now get Einstein’s book and watch him derive the complicated looking Lorentz transformations using simple math and complex reasoning.

Science fiction for the cognoscenti – III — not all the background you need will be explained

Now that every team in the NFL has its own molecular biologist and antiVirologist, you might be interested in knowing how it all started.  Like most technologies affecting our lives it had a military origin.

The escape of the Taiwanese pacifist virus started it all –https://luysii.wordpress.com/2018/11/19/a-science-fiction-story-for-the-cognoscenti-answer-to-the-puzzle-and-a-bit-more.

The technology of infectious gene transfer by recombinant adeno-associated virus  (AAV) was well advanced long before there were garage molecular biologists.

The NFL wars began with the New England Patriots, (who else?), they of deflategate and other nefarious ways to win.

Tom Brady was getting all set to win superbowl LVII in 2023 at age 45 when the first counterattack was successful.

His wife, the beautiful Gisele, hated the idea of him playing so long, being very worried about dementia pugilista from all the head trauma.  Tom had agreed to yearly PET scans with Pittsburgh compound B, an uncharged derivative of thioflavin T which gets through the blood brain barrier and which stains senile plaques.  They showed no evidence of plaques (although plenty of demented people don’t have them) so he kept on playing behind Belichick’s not so secret weapon — 400 pound linemen.  Even though he’d lost a step or two, his eye and arm were still good and the linemen gave him plenty of time to throw.

Football players have always been bulking up.  Even the early experience with extra testosterone (which causes testicular atrophy in high doses) didn’t dissuade them.  Newer anabolic steroids had somewhat fewer testicular effects.  Eventually players took to using HCG to help normalize things, but some testicular atrophy was a price they were willing to pay.  The cheerleaders felt a lot safer around those using them.

So how did the Patriots have 400 pound linemen when no one else did?  The answer goes back to Piedmontese and Belgian Blue cattle which were bred for their large muscles.  They turned out to have inactivating mutations in the gene for myostatin, a protein which causes muscles to stop growing.

Boston isn’t known as the home of biotech for nothing, and Belichick contracted with an as yet un-named biotech firm (their depositions having been sealed by the court) to come up with a small molecule (compound M) absorbable through the skin which inhibited myostatin.

No one caught on why Belicheck had separate showers installed for the lineman and defensive backs, but they had to use them and got  dosed that way.  Testing for performance enhancing drugs was always negative. The linemen loved it, as their testicles grew back to normal size.  The cheerleaders didn’t.

So there the Patriots were, about to play the Arizona Cardinals, a team only winning 3 games in 2018 in superbowl LVII. No one understood how the Cardinals turned around and how they got those very slippery running backs.

No one, except the molecular biologist they hired.  But that’s for next time.

Another way to study Alzheimer’s

Until I read the paper PLOS Genet. 14, e1007791 (2018)., I thought that this was a sure way to win Nobel prize.  It’s still pretty interesting.  The abstract in Science was misleading, implying that there was an APOE4 variant which was actually protective against Alzheimer’s disease. That would have been fantastic, as it would provide a clue as to just what the APOE4 allele was doing to increase the risk of Alzheimer’s disease.

A huge amount of work has been done on APOE4.   Googling produced 433,000 results (0.46 seconds).  Theories abound but we still don’t know.

The authors studied Blacks and Puerto Ricans and found that if you inherited the APOE4 allele from an African source (rather than a European source), your chance of developing Alzheimer’s disease was significantly less.  A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study.

The numbers: ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background).

Note that the ORs are still up for Alzheimer’s if you have APOE4, but the differences are significant and certainly real given the size of the study.

The authors think it’s the area around the APOE  gene, rather than the total genetic background (African vs. European etc. etc.)

It still might be worth doing the following.  Take skin fibroblasts from all four types of people (Puerto Ricans with APOE4 on African background, Puerto Ricans with APOE4 on European background, Blacks with APOE4 on African background, APOE4 on a European background).

Make induced pluripotent stem cells (iPSCs) from them (the technology to do so is quite advanced). Differentiate these iPSCs into neurons  and others into glia (technology quite available).  Study protein and mRNA expression, epigenetic modifications in neurons and glia from all 4 groups.  This might tell you just what APOE4 was doing in high and lower risk people, and possibly might give a clue as to how it was increasing Alzheimer’s risk.

My hopes were really up, because the abstract in Science implied that APOE4 in Blacks and Puerto Ricans was actually absolutely rather than relatively protective, which would have given us some serious clues to Alzheimer pathogenesis, when APOE4 protective cells were contrasted with APOE4 increased risk cells.

Oh well.

A tragic way to start the new year !

Durgin Park is closing ! ! ! ! https://www.masslive.com/news/2019/01/durgin-park-at-faneuil-hall-one-of-bostons-oldest-restaurants-to-close.html.

This is tragic.  In the fall of 1960 a bunch of us newly minted chemistry grad students went there and found that the life of a struggling graduate student wasn’t hard at all. A giant slab of roast beef, followed by a large bowl of strawberry shortcake all for $5 (minimum wage 1$).  Sad ! ! !

Update 10 Jan ’19 —

‘They’ve come out of the woodwork;’ business booms at Durgin Park as historic Boston restaurant prepares to close

https://www.masslive.com/news/2019/01/theyve-come-out-of-the-woodwork-business-booms-at-durgin-park-as-historic-boston-restaurant-prepares-to-close.html

Even sadder ! ! ! !

Happy New Year

Off to see the grandkids.  Next post next year.  All the best to you and yours.

If you liked or were interested in https://luysii.wordpress.com/2018/12/16/bye-bye-stoichiometry/ and have nothing better to do over the holidays, I suggest reading Cell vol. 175 pp.1842 – 1855 ’18 in which phase changes are described at enhancers and possibly a universal phenomenon at the start of mRNA transcription by pol II.

The Impeachment Trial of President Tester 2027

It’s almost Christmas. Time for some R&R. Here’s another science fiction story for the cognoscenti, which assumes you have some scientific chops.  Not all will be explained.

After the Taiwanese biologic agent turned the world’s armed forces into pacifists, you’d think that the end of history had arrived. For how this happened see the first story — https://luysii.wordpress.com/2018/11/19/a-science-fiction-story-for-the-cognoscenti-answer-to-the-puzzle-and-a-bit-morea-science-fiction-story-for-the-cognoscenti/.

Well, thought all sorts of garage molecular biologists, maybe humanity could be further improved, or those not of the right sort eliminated.   The Syrians learned this the hard way creating a biologic agent which attacked Jews, not realizing that Syrians were closer genetically to them than anyone else [ Proc. Natl. Acad. Sci. vol. 97 pp. 6769 – 6774 ’00 ].  The Israeli’s saw this coming and had a defense ready.   The midEast became a lot quieter.

The touchy feely types thought of other ways to improve humanity, particularly a group of vegetarian molecular biologists at Montana State University.

You probably thought of Montana State in Bozeman as Moo U, where the sons of the soil achieved a rudimentary education.  After Jon Tester was elected president in 2024, a lot of money was poured in.  Sophisticates were appalled that Tester made it after Trump.  They should have known better– the US has elected a peanut farmer, someone from Dogpatch, a broken down actor making movies with a chimp, and the ever appalling Donald Trump.

Actually as far back as the 70s Montana had a state legislator (Kenneth Nortvedt) Junior Fellow at Harvard writing papers on alternate theories of gravity.  Biologic research was alive in Montana since 1928 at Rocky Mountain Labs in Hamilton and still kicking with prion work as of 2015 — http://klyq.com/prion-disease-study-at-hamilton-lab-is-published-youtube/.

So what happened?  Have you ever heard of the Lone Star Tick?  https://acaai.org/allergies/types/food-allergies/types-food-allergy/meat-allergy.  A single bite can make you allergic to meat.  Your body’s immune response to a tick antigen, must also in some way react with meat, the same way that the response to strep infection can sometimes cross react with the heart causing rheumatic fever.

At first it was thought that the tick injected galactose linked (alpha 1 –> 3 )to galactose, but that was quickly debunked when taking alpha-galactosidase (available at your friendly local health food store) didn’t work.

Montana attracts all sorts of people, ranging from rugged individualists to touchy feely types and points between.  There’s plenty of room out there (more cows than people at last count) so the dominant zeitgeist is live and let live.  The one unforgivable sin is putting on airs or bragging.

Thus it came to pass in the year 2025 (anno Tester #1) when the federal funding spigot was turned full force on MSU that a group of smart vegetarians from Portland Oregon overcame their scruples about living in a land whose major function was producing meat, and wound up in the newly formed Mike Mansfield department of molecular genetics at MSU.

Basically they knocked out gene after gene in the tick and looked at what disappeared in the secretions of the tick as it bit.  There were plenty of glycoproteins some of which had galactose.  It was child’s play to isolate and sequence the gene.

By this time the technology to put any protein coding gene in adeno-associated virus (AAV) and infect people was well advanced.  So they experimented on themselves, injecting virus after virus, forcing themselves to swallow their scruples as well as meat and seeing which of the tick’s proteins made them ill when they did.

The rest is history.  The virus spread quickly and suddenly no one could eat beef or pork.  The ranching industry in Montana and elsewhere died.  Ecologists rejoiced that the prairie was no longer grazed.

A group of bankrupt ranchers from all over the state (and a few from Wyoming) invaded the lab and killed every scientist there.

They were not tried in Montana, as no one would convict them, instead being tried in Vermont (Birkenstock country) and sent to prison for life.

Which brings us to the Impeachment trial of President Tester.

Can you guess what it was for?  Answer next year.

In the meantime, a very Merry Christmas and Happy New Year to all

 

What else are we not being told?

All the best to justice Ginsburg and her recent surgery for two tumors on her lung. What else are we NOT being told?  Recall that today’s release noted that the tumors were discovered 6 weeks ago when she fell and broke some ribs.  Not a word about them until today.  Typical obfuscation about the health of a major figure — see some old posts on this point with other people.

https://luysii.wordpress.com/2012/12/31/medical-tribulations-of-politicians-degrees-of-transparency/

https://luysii.wordpress.com/2012/02/26/diagnosis-by-media-release-the-continuing-saga-of-hugo-chavez/

It may well be that Ginsburg (who has total control over her medical information as all patients should have) didn’t want this released.

 

This sort of thing  happens over and over.  Arafat was doing wonderfully after being airlifted to  France (until he didn’t).  Subsequently it was found that the family (not his physicians)  was releasing this information.  Essentially he was a corpse the whole time there.  The soi-disant ‘investigative press’ was nowhere to be found.  They could have noted the source of this information (e.g. the family not the docs taking care of him)  before he died, but they didn’t.

For the pianists in your life

Shopping for a Christmas gift for that hard to please pianist on your list?  I have just the answer — The Complete Bach Concerti for solo Keyboard and Orchestra in Full Score ISBN 0-486-24929-8.  No it won’t take a truck to deliver it.  It’s just in the Dover series of music.  7 concerti, 206 pages and only $20.00 or so.  Such a deal ! ! !

You pianist friend need not have a full string orchestra at his/her disposal, the keyboard parts are often rich enough to stand alone.  This is particularly true of many of the glorious slow movements, where the strings aren’t really doing very much, and sometime are just doubling what the keyboard is doing with the left hand anyway.

It does look a bit intimidating to see 6 parts instead of the usual two.  The only problem with this is the frequent page turns, and I recommend getting it spiral bound at the local copy place (under 5$ where I live).

All the concerti are fairly famous (to pianists at least) and the whole point about Bach is that it’s mind music which you hear in your head.  That’s about all I played in med school having only PSOs (Piano Shaped Objects) to play.

Merry Christmas and Happy New Year ! ! !

Bye bye stoichiometry

Until recently, developments in physics basically followed earlier work by mathematicians Think relativity following Riemannian geometry by 40 years.  However in the past few decades, physicists have developed mathematical concepts before the mathematicians — think mirror symmetry which came out of string theory — https://en.wikipedia.org/wiki/Mirror_symmetry_(string_theory). You may skip the following paragraph, but here is what it meant to mathematics — from a description of a 400+ page book by Amherst College’s own David A. Cox

Mirror symmetry began when theoretical physicists made some astonishing predictions about rational curves on quintic hypersurfaces in four-dimensional projective space. Understanding the mathematics behind these predictions has been a substantial challenge. This book is the first completely comprehensive monograph on mirror symmetry, covering the original observations by the physicists through the most recent progress made to date. Subjects discussed include toric varieties, Hodge theory, Kahler geometry, moduli of stable maps, Calabi-Yau manifolds, quantum cohomology, Gromov-Witten invariants, and the mirror theorem. This title features: numerous examples worked out in detail; an appendix on mathematical physics; an exposition of the algebraic theory of Gromov-Witten invariants and quantum cohomology; and, a proof of the mirror theorem for the quintic threefold.

Similarly, advances in cellular biology have come from chemistry.  Think DNA and protein structure, enzyme analysis.  However, cell biology is now beginning to return the favor and instruct chemistry by giving it new objects to study. Think phase transitions in the cell, liquid liquid phase separation, liquid droplets, and many other names (the field is in flux) as chemists begin to explore them.  Unlike most chemical objects, they are big, or they wouldn’t have been visible microscopically, so they contain many, many more molecules than chemists are used to dealing with.

These objects do not have any sort of definite stiochiometry and are made of RNA and the proteins which bind them (and sometimes DNA).  They go by any number of names (processing bodies, stress granules, nuclear speckles, Cajal bodies, Promyelocytic leukemia bodies, germline P granules.  Recent work has shown that DNA may be compacted similarly using the linker histone [ PNAS vol.  115 pp.11964 – 11969 ’18 ]

The objects are defined essentially by looking at them.  By golly they look like liquid drops, and they fuse and separate just like drops of water.  Once this is done they are analyzed chemically to see what’s in them.  I don’t think theory can predict them now, and they were never predicted a priori as far as I know.

No chemist in their right mind would have made them to study.  For one thing they contain tens to hundreds of molecules.  Imagine trying to get a grant to see what would happen if you threw that many different RNAs and proteins together in varying concentrations.  Physicists have worked for years on phase transitions (but usually with a single molecule — think water).  So have chemists — think crystallization.

Proteins move in and out of these bodies in seconds.  Proteins found in them do have low complexity of amino acids (mostly made of only a few of the 20), and unlike enzymes, their sequences are intrinsically disordered, so forget the key and lock and induced fit concepts for enzymes.

Are they a new form of matter?  Is there any limit to how big they can be?  Are the pathologic precipitates of neurologic disease (neurofibrillary tangles, senile plaques, Lewy bodies) similar.  There certainly are plenty of distinct proteins in the senile plaque, but they don’t look like liquid droplets.

It’s a fascinating field to study.  Although made of organic molecules, there seems to be little for the organic chemist to say, since the interactions aren’t covalent.  Time for physical chemists and polymer chemists to step up to the plate.