How Infants learn language – V

Infants don’t learn language like neural nets do. Unlike nets, no feedback is involved, which amazingly, makes learning faster.

As is typical of research in psychology, the hard part is thinking of something clever to do, rather than actually carrying it out.

[ Proc. Natl. Acad. Sci. vol. 117 pp. 26548 – 26549 ’20 ] is a short interview with psychologist Richard N. Aslin. Here’s a link — hopefully not behind a paywall — https://www.pnas.org/content/pnas/117/43/26548.full.pdf.

He was interested in how babies pull out words from a stream of speech.

He took a commonsense argument and ran with it.

“The learning that I studied as an undergrad was reinforcement learning—that is, you’re getting a reward for responding to certain kinds of input—but it seemed that that kind of learning, in language acquisition, didn’t make any sense. The mother is not saying, “listen to this word…no, that’s the wrong word, listen to this word,” and giving them feedback. It’s all done just by being exposed to the language without any obvious reward”

So they performed an experiment whose results surprised them. They made a ‘language’ of speech sounds which weren’t words and presented them 4 per second for a few minutes, to 8 month old infants. There was an underlying statistical structure, as certain sounds were more likely to follow another one, others were less likely. That’s it. No training. No feedback. No nothin’, just a sequence of sounds. Then they presented sequences (from the same library of sounds) which the baby hadn’t heard before and the baby recognized them as different. The interview didn’t say how they knew the baby was recognizing them, but my guess is that they used the mismatch negativity brain potential which automatically arises to novel stimuli.

Had you ever heard of this? I hadn’t but the references to the author’s papers go back to 1996 ! Time for someone to replicate this work.

So our brains have an innate ability to measure statistical probability of distinct events occurring. Even better we react to the unexpected event. This may be the ‘language facility’ Chomsky was talking about half a century ago. Perhaps this innate ability is the origin of music, the most abstract of the arts.

How infants learn language is likely inherently fascinating to many, not just neurologists.

Here are links to some other posts on the subject you might be interested in.

https://luysii.wordpress.com/2013/06/03/how-infants-learn-language-iv/

https://luysii.wordpress.com/2011/10/10/how-infants-learn-language-iii/

https://luysii.wordpress.com/2010/10/03/how-infants-learn-language-ii/

https://luysii.wordpress.com/2010/09/30/how-infants-learn-language/

Cells are not bags of cytoplasm

How Ya Gonna Keep ’em Down on the Farm (After They’ve Seen Paree) is a song of 100+ years ago when World War I had just ended. In 1920, for the first time America was 50/50 urban/rural. Now it’s 82%.

What does this have to do with cellular biology? A lot. One of the first second messengers to be discovered was cyclic adenosine monophosphate (CAMP). It binds to an enzyme complex called protein kinase A (PKA), activating it, making it phosphorylate all sorts of proteins changing their activity. But PKA doesn’t float free in the cell. We have some 47 genes for proteins (called AKAPs for protein A Kinase Anchoring Protein) which bind PKA and localize it to various places in the cell. CAMP is made by an enzyme called adenyl cyclase of which we have 10 types, each localized to various places in the cell (because most of them are membrane embedded). We also have hundreds of G Protein Coupled Receptors (GPCRs) localized in various parts of the cell (apical, basal, primary cilia, adhesion structures etc. etc.) many of which when activated stimulate (by yet another complicated mechanism) adenyl cyclase to make CAMP.

So the cell tries to keep CAMP when it is formed relatively localized (down on the farm if you will). Why have all these ways of making it if its going to run all over the cell after all.

Actually the existence of localized signaling by CAMP is rather controversial, particularly when you can measure how fast it is moving around. All studies previous to Cell vol. 182 pp. 1379 – 1381, 1519 – 1530 ’20 found free diffusion of CAMP.

This study, found that CAMP (in low concentrations) was essentially immobile, remaining down on the farm where it was formed.

The authors used a fluorescent analog of CAMP which allowed them to use fluorescence fluctuation spectroscopy which gives the probability distribution function of an individual molecule occupying a given position in space and time (SpatioTemporal Image correlation Spectroscopy — STICS).

Fascinating as the study is, it is ligh tyears away from physiologic — the fluorescent CAMP analog was not formed by anything resembling a physiologic mechanism (e.g. by adenyl cyclase). A precursor to the fluorescent CAMP was injected into the cell and broken down by ‘intracellular esterases’ to form the fluorescent CAMP analog.

Then the authors constructed a protein made of three parts (1) a phosphodiesterase (PDE) which broke down the fluorescent CAMP analog and (2) another protein — the signaler — which fluoresced when it bound the CAMP analog. The two were connected by (3) a flexible protein linker e.g. the ‘ruler’ of the previous post. The ruler could be made of various lengths.

Then levels of fluorescent CAMP were obtained by injecting it into the cell, or stimulating a receptor.

If the sensor was 100 Angstroms away from the PDE, it never showed signs of CAMP, implying the the PDE was destroying it before it could get to the linker implying that diffusion was quite slow. This was at low concentrations of the fluorescent CAMP analog. At high injection concentrations the CAMP overcame the sites which were binding it in the cell and moved past the signaler.

It was a lot of work but it convincingly (to me) showed that CAMP doesn’t move freely in the cell unless it is of such high concentration that it overcomes the binding sites available to it.

They made another molecule containing (1) protein kinase A (2) a ruler (3) a phophodiesterase. If the kinase and phosphodiesterase were close enough together, CAMP never got to PKA at all.

Another proof that phosphodiesterase enzymes can create a zone where there is no free CAMP (although there is still some bound to proteins).

Hard stuff (to explain) but nonetheless impressive, and shows why we must consider the cell a bunch of tiny principalities jealously guarding their turf like medieval city states.

*****

A molecular ruler

Time to cleanse your mind by leaving the contentious world of social issues and entering the realm of pure thought with some elegant chemistry. 

You are asked to construct a molecular ruler with a persistence length of 150 Angstroms. 

Hint #1: use a protein

Hint #2; use alpha helices

Spoiler alert — nature got there first. 

The ruler was constructed and used in an interesting paper on CAMP nanoDomains (about which more on the next post).

It’s been around since 2011 [ Proc. Natl. Acad. Sci. vol. 108 pp. 20467 – 20472 ’11 ] and I’m embarrassed to admit I’d never heard of it.

It’s basically a run of 4 negatively charged amino acids (glutamic acid or aspartic acid) followed by a run of 4 positively charged amino acids (lysine, arginine). This is a naturally occurring motif found in a variety of species. 

My initial (incorrect) thought was that this couldn’t work as the 4 positively charged amino acids would bend at the end and bind to the 4 negatively charged ones. This can’t work even if you make the peptide chain planar, as the positive charges would alternate sides on the planar peptide backbone.

Recall that there are 3.5 amino acids/turn of the alpha helix, meaning that between a run of 4 Glutamic acid/Aspartic acids and an adjacent run of 4 lysines/arginines, an ionic bond is certain to form between the side chains (and not between adjacent amino acids on the backbone, but probably one 3 or 4 amino acids away)

Since a complete turn of the alpha helix is only 5.4 Angstroms, a persistence length of 150 means about 28 turns of the helix using 28 * 3.5 = 98 amino acids or about 12 blocks of ++++—- charged amino acids. 

The beauty of the technique is that by starting with an 8 amino acid ++++—- block, you can add length to your ruler in 12 Angstrom increments. This is exactly what Cell vol. 182 pp. 1519 – 1530 ’20 did. But that’s for the next post. 

247 ZeptoSeconds

247 ZeptoSeconds is not the track time of the fastest Marx brother. It is the time a wavelength of light takes to travel across a hydrogen molecule (H2) before it kicks out an electron — the photoelectric effect.

But what is a zeptosecond anyway? There are 10^21 zeptoSeconds in a second. That’s a lot. A thousand times more than the number of seconds since the big bang which is only 60 x 60 x 24 x 365 x 13.8 x 10^9 = 4. 35 x 10^17. Not that big a deal to a chemist anyway since 10^21 is 1/600th of the number of molecules in a mole.

You can read all about it in Science vol. 370 pp. 339 – 341 ’20 — https://science.sciencemag.org/content/sci/370/6514/339.full.pdf it you have a subscription.

Studying photoionization allows you to study the way light is absorbed by molecules, something important to any chemist. The 247 zeptoseconds is the birth time of the emitted electron. It depends on the travel time of the photon across the hydrogen molecule.

They don’t quite say trajectory of the photon, but it is implied even though in quantum mechanics (which we’re dealing with here), there is no such a thing as a trajectory. All we have is measurements at time t1 and time t2. We are not permitted to say what the photon is doing between these two times when we’ve done measurements. Our experience in the much larger classical physics world makes us think that there is such a thing.

It is the peculiar doublethink quantum mechanics forces on us. Chemists know this when they think about something as simple as the S2 orbital, something spherically symmetric, with electron density on either side of a node. The node is where you never find an electron. Well if you don’t, find it here, how can it have a trajectory from one side to the other.

Quantum mechanics is full of conundrums like that. Feynman warned us not to think about them, but it will take your mind off the pandemic (and if you’re good, off the election as well)..

It’s worth reading the article in Quanta which asks if wavefunctions tunnel through a barrier at speeds faster than light — here’s a link — https://www.quantamagazine.org/quantum-tunnel-shows-particles-can-break-the-speed-of-light-20201020/. It will make your head spin.

Here’s a link to an earlier post about the doublethink quantum mechanics forces on us

https://luysii.wordpress.com/2009/12/10/doublethink-and-angular-momentum-why-chemists-must-be-adept-at-it/

Here’s the post itself

Doublethink and angular momentum — why chemists must be adept at it

Chemists really should know lots and lots about angular momentum which is intimately involved in 3 of the 4 quantum numbers needed to describe atomic electronic structure. Despite this, I never really understood what was going until taking the QM course, and digging into chapters 10 and 11 of Giancoli’s physics book (pp. 248 -310 4th Edition).

Quick, what is the angular momemtum of a single particle (say a planet) moving around a central object (say the sun)? Well, its magnitude is the current speed of the particle times its mass, but what is its direction? There must be a direction since angular momentum is a vector. The (unintuitive to me) answer is that the angular momemtum vector points upward (resp. downward) from the plane of motion of the planet around the center of mass of the sun planet system, if the planet is moving counterclockwise (resp. clockwise) according to the right hand rule. On the other hand, the momentum of a particle moving in a straight line is just its mass times its velocity vector (e.g. in the same direction).

Why the difference? This unintuitive answer makes sense if, instead of a single point mass, you consider the rotation of a solid (e.g. rigid) object around an axis. All the velocity vectors of the object at a given time either point in different directions, or if they point in the same direction have different magnitudes. Since the object is solid, points farther away from the axis are moving faster. The only sensible thing to do is point the angular momentum vector along the axis of rotation (it’s the only thing which has a constant direction).

Mathematically, this is fairly simple to do (but only in 3 dimensions). The vector from the axis of rotation to the planet (call it r), and the vector of instantaneous linear velocity of the planet (call it v) do not point in the same direction, so they define a plane (if they do point in the same direction the planet is either hurtling into the sun or speeding directly away, hence not rotating). In 3 dimensions, there is a unique direction at 90 degrees to the plane. The vector cross product of r and v gives a vector pointing in this direction (to get a unique vector, you must use the right or the left hand rule). Nicely, the larger r and v, the larger the angular momentum vector (which makes sense). In more than 3 dimensions there isn’t a unique direction away from a plane, which is why the cross product doesn’t work there (although there are mathematical analogies to it).

This also explains why I never understood momentum (angular or otherwise) till now. It’s very easy to conflate linear momentum with force and I did. Get hit by a speeding bullet and you feel a force in the same direction as the bullet — actually the force you feel is what you’ve done to the bullet to change its momentum (force is basically defined as anything that changes momentum).

So the angular momentum of an object is never in the direction of its instantaneous linear velocity. But why should chemists care about angular momentum? Solid state physicists, particle physicists etc. etc. get along just fine without it pretty much, although quantum mechanics is just as crucial for them. The answer is simply because the electrons in a stable atom hang around the nucleus and do not wander off to infinity. This means that their trajectories must continually bend around the nucleus, giving each trajectory an angular momentum.

Did I say trajectory? This is where the doublethink comes in. Trajectory is a notion of the classical world we experience. Consider any atomic orbital containing a node (e.g. everything but a 1 s orbital). Zeno would have had a field day with them. Nodes are surfaces in space where the electron is never to be found. They separate the various lobes of the orbital from each other. How does the electron get from one lobe to the other by a trajectory? We do know that the electron is in all the lobes because a series of measurements will find the electron in each lobe of the orbital (but only in one lobe per measurement). The electron can’t make the trip, because there is no trip possible. Goodbye to the classical notion of trajectory, and with it the classical notion of angular momentum.

But the classical notions of trajectory and angular momentum still help you think about what’s going on (assuming anything IS in fact going on down there between measurements). We know quite a lot about angular momentum in atoms. Why? Because the angular momentum operators of QM commute with the Hamiltonian operator of QM, meaning that they have a common set of eigenfunctions, hence a common set of eigenvalues (e.g. energies). We can measure these energies (really the differences between them — that’s what a spectrum really is) and quantum mechanics predicts this better than anything else.

Further doublethink — a moving charge creates a magnetic field, and a magnetic field affects a moving charge, so placing a moving charge in a magnetic field should alter its energy. This accounts for the Zeeman effect (the splitting of spectral lines in a magnetic field). Trajectories help you understand this (even if they can’t really exist in the confines of the atom).

Action at a distance comes to chemistry

Allostery is an abstract concept in protein chemistry, far removed from everyday life. Far removed except if you like to breathe, or have ever used a benzodiazepine (Valium, Librium, Halcion, Ativan, Klonopin, Xanax) for anything. Breathing? Really? Yes — Hemoglobin, the red in red blood cells is really 4 separate proteins bound to each other. Each of the four can bind one oxygen molecule. Binding of oxygen to one of the 4 proteins produces a subtle change in the structure of the other 3, making it easier for another oxygen to bind. This produces another subtle change in structure of the other making it easier for a third oxygen to bind. Etc.

This is what allostery is, binding of molecule to one part of a protein causing changes in structure all over the protein.

Neurologists are familiar with the benzodiazepines, using them to stop continuous seizure activity (status epilepticus), treat anxiety (Xanax), or seizures (Klonopin). They all work the same way, binding to a complex of 5 proteins called the GABA receptor, which when it binds Gamma Amino Butyric Acid (GABA) in one place causes negative ions to flow into the neuron, inhibiting it from firing. The benzodiazepines bind to a completely different site, making the receptor more likely to open when it binds GABA.

The assumption about all allostery is that something binds in one place, pushing the atoms around, which push on other atoms which push on other atoms, until the desired effect is produced. This is the opposite of action at a distance, where an effect is produced without the necessity of physical contact.

Even though Newton invented a theory of gravity, which worked beautifully, he was disturbed by the fact that it acted through empty space. Here’s what he wrote in a letter to Bentley

“That gravity should be innate inherent & {essential} to matter so that one body may act upon another at a distance through a vacuum without the mediation of any thing else by & through which their action or force {may} be conveyed from one to another is to me so great an absurdity that I beleive no man who has in philosophical matters any competent faculty of thinking can ever fall into it. “

So physicists invented the ether which was physical, and allowed objects to push each other around by pushing on the ether between them.

But action at a distance without one atom pushing on the next etc. etc. is exactly what an incredible paper found [ Proc. Natl. Acad. Sci. vol. 117 pp. 25445 – 25454 ’20 ]. Here’s a link but it’s probably behind a paywall — https://www.pnas.org/content/pnas/117/41/25445.full.pdf

The paper studied TetR, a protein containing 203 amino acids. If you’ve ever thought about it, almost all the antibiotics we have come from bacteria, which they use on other bacteria. Since we still have bacteria around, the survivors must have developed a way to resist antibiotics, and they’ve been doing this long before we appeared on the scene.

TetR helps bacteria resist tetracycline, an antibiotic produced by bacteria. When tetracycline binds to TetR it causes other parts of the protein to change so it binds DNA causing the bacterium, among other things, to make a pump which moves tetracyline out of the cell. Notice that site where tetracycline binds on TetR is not the business end where TetR binds DNA, just as where the benzodiazepines bind the GABA receptor is not where the ion channel is.

This post is long enough already without describing the cleverness which allowed the authors to do the following. They were able to make TetRs containing every possible mutation of all 203 positions. How many is that — 203 x 19 = 3838 different proteins. Why 19? Because we have 20 amino acids, so there are 19 possible distinct changes at each of the 203 positions in TetR.

Some of the mutants didn’t bind to DNA, implying they were non-functional. The 3 dimensional structure of TetR is known, and they chose 5 of nonfunctional mutants. Interestingly these were distributed all over the protein.

Then, for each of the 5 mutants they made another 3838 mutants, to see if a mutation in another position would make the mutant functional again. You can see what a tremendous amount of work this was.

Here is where it gets really interesting. The restoring mutant (revertants if you want to get fancy) were all over the protein and up to 40 – 50 Angstroms away from the site of the dead mutation. Recall that 1 Angstrom is the size of a hydrogen atom, a turn of the alpha helix is 5.4 Angstroms and contains 3.5 amino acids per turn.The revertant mutants weren’t close to the part of the protein binding tetracycline or the part binding to DNA.

Even worse the authors couldn’t find a contiguous path of atom pushing atom pushing atom, to explain why TetR was able to bind DNA again. So there you have it — allosteric action at a distance.

There is much more in the paper, but after all the work they did it’s time to let the authors speak for themselves. “Several important insights emerged from these results. First, TetR exhibits a high degree of allosteric plasticity evidenced by the ease of disrupting and restoring function through several mutational paths. This suggests the functional landscape of al- lostery is dense with fitness peaks, unlike binding or catalysis where fitness peaks are sparse. Second, allosterically coupled residues may not lie along the shortest path linking allosteric and active sites but can occur over long distances “

But there is still more to think about, particularly for drug development. Normally, in developing a drug for X, we have a particular site on a particular protein as a target, say the site on a neurotransmitter receptor where a neurotransmitter binds. But the work shows that sites far removed from the actual target might have the same effect

A paper everyone should look at

Proc. Natl. Acad. Sci. vol. 117 pp. 25237–25245 ’20 presumably is ‘freely shared’. Here’s the link — https://www.pnas.org/content/pnas/117/41/25237.full.pdf

The authors set up a mist of fine water droplets in front of a speaker and watch what the emitted air does to them (using high speed cameras). Sentences with a lot of plosives (such as p) e.g. peter piper picked a peck of pickled peppers produce a jet which barrels along for a few meters. Different sound produce air flows in different directions. The pictures are incredible. If viruses are carried along with this, the implications for the pandemic flu are obvious. Wear a mask when talking to strangers.

Here’s a quote from the paper “We show that the transport distance of exhaled material versus time, in the form of three distinct scal- ing laws, represents the typical structure of the flow, including 1) a short (<0.5 m) distance, with large angular variations, where the complexity of language is evident and responsible for mate- rial transport in a fraction of a second; 2) a longer distance, out to approximately 1 m, where directed transport occurs driven by individual vortical puffs corresponding roughly to individual plo- sive sounds; and 3) a distance out to about 2 m, or even farther, where spoken sentences with plosives, corresponding effectively to a train of puffs, create conical, jet-like flows. “

Well, those are just words — if you do nothing else, look at the pictures in the paper.

The death of the synonymous codon – V

The coding capacity of our genome continues to amaze. The redundancy of the genetic code has been put to yet another use. Depending on how much you know, skip the following four links and read on. Otherwise all the background you need to understand the following is in them.

https://luysii.wordpress.com/2011/05/03/the-death-of-the-synonymous-codon/

https://luysii.wordpress.com/2011/05/09/the-death-of-the-synonymous-codon-ii/

https://luysii.wordpress.com/2014/01/05/the-death-of-the-synonymous-codon-iii/

https://luysii.wordpress.com/2014/04/03/the-death-of-the-synonymous-codon-iv/

There really is no way around the redundancy producing synonymous codons. If you want to code for 20 different amino acids with only four choices at each position, two positions (4^2) won’t do. You need three positions, which gives you 64 possibilities (61 after the three stop codons are taken into account) and the redundancy that comes along with it. The previous links show how the redundant codons for some amino acids aren’t redundant at all but used to code for the speed of translation, or for exonic splicing enhancers and inhibitors. Different codons for the same amino acid can produce wildly different effects leaving the amino acid sequence of a given protein alone.

The latest example — https://www.pnas.org/content/117/40/24936 Proc. Natl. Acad. Sci. vol. 117 pp. 24936 – 24046 ‘2 — is even more impressive, as it implies that our genome may be coding for way more proteins than we thought.

The work concerns Mitochondrial DNA Polymerase Gamma (POLG), which is a hotspot for mutations (with over 200 known) 4 of which cause fairly rare neurologic diseases.

Normally translation of mRNA into protein begins with something called an initator codon (AUG) which codes for methionine. However in the case of POLG, a CUG triplet (not AUG) located in the 5′ leader of POLG messenger RNA (mRNA) initiates translation almost as efficiently (∼60 to 70%) as an AUG in optimal context. This CUG directs translation of a conserved 260-triplet-long overlapping open reading frame (ORF) called  POLGARF (POLG Alternative Reading Frame — surely they could have come up something more euphonious).

Not only that but the reading frame is shifted down one (-1) meaning that the protein looks nothing like POLG, with a completely different amino acid composition. “We failed to find any significant similarity between POLGARF and other known or predicted proteins or any similarity with known structural motifs. It seems likely that POLGARF is an intrinsically disordered protein (IDP) with a remarkably high isoelectric point (pI =12.05 for a human protein).” They have no idea what POLGARF does.

Yet mammals make the protein. It gets more and more interesting because the CUG triplet is part of something called a MIR (Mammalian-wide Interspersed Repeat) which (based on comparative genomics with a lot of different animals), entered the POLG gene 135 million years ago.

Using the teleological reasoning typical of biology, POLGARF must be doing something useful, or it would have been mutated away, long ago.

The authors note that other mutations (even from one synonymous codon to another — hence the title of this post) could cause other diseases due to changes in POLGARF amino acid coding. So while different synonymous codons might code for the same amino acid in POLG, they probably code for something wildly different in POLGARF.

So the same segment of the genome is coding for two different proteins.

Is this a freak of nature? Hardly. We have over an estimated 368,000 mammalian interspersed repeats in our genome — https://en.wikipedia.org/wiki/Mammalian-wide_interspersed_repeat.

Could they be turning on transcription for other proteins that we hadn’t dreamed of. Algorithms looking for protein coding genes probably all look for AUG codons and then look for open reading frames following them.

As usual Shakespeare got there first “There are more things in heaven and earth, Horatio, Than are dreamt of in your philosophy.”

Certainly the paper of the year for intellectual interest and speculation.

A molecular ruler

Time to cleanse your mind by leaving the contentious world of social issues and entering the realm of pure thought with some elegant chemistry.

You are asked to construct a molecular ruler with a persistence length of 150 Angstroms.

Hint #1: use a protein

Hint #2; use alpha helices

Spoiler alert — nature got there first.

The ruler was constructed and used in an interesting paper on CAMP nanoDomains (about which more on the next post).

It’s been around since 2011 [ Proc. Natl. Acad. Sci. vol. 108 pp. 20467 – 20472 ’11 ] and I’m embarrassed to admit I’d never heard of it.

It’s basically a run of 4 negatively charged amino acids (glutamic acid or aspartic acid) followed by a run of 4 positively charged amino acids (lysine, arginine). This is a naturally occurring motif found in a variety of species.

My initial (incorrect) thought was that this couldn’t work as the 4 positively charged amino acids would bend at the end and bind to the 4 negatively charged ones. This can’t work even if you make the peptide chain planar, as the positive charges would alternate sides on the planar peptide backbone.

Recall that there are 3.5 amino acids/turn of the alpha helix, meaning that between a run of 4 Glutamic acid/Aspartic acids and an adjacent run of 4 lysines/arginines, an ionic bond is certain to form between the side chains (and not between adjacent amino acids on the backbone, but probably one 3 or 4 amino acids away)

Since a complete turn of the alpha helix is only 5.4 Angstroms, a persistence length of 150 means about 28 turns of the helix using 28 * 3.5 = 98 amino acids or about 12 blocks of ++++—- charged amino acids.

The beauty of the technique is that by starting with an 8 amino acid ++++—- block, you can add length to your ruler in 12 Angstrom increments. This is exactly what Cell vol. 182 pp. 1519 – 1530 ’20 did. But that’s for the next post.

The Public Service of President Trump

The number of new cases of COVID-19 is likely to significantly drop in the the coming months and we have President Trump to thank for that

Why? Because people don’t respond to abstract facts and exhortations given by people they don’t know. They do respond to particular examples.

The fact that Trump and Co. disparaged masks, and then came down with the virus will be far more convincing, than any pronouncements from Dr. Fauci or various mayors, governors, congressmen or senators.

I saw this many times in practice.

An example.

Neurologists treat migraine headaches. It is well known that migraines are triggered by stress. When someone was having a bout of several migraines under the stress of divorce, illness, finances you name it, I’d tell them this, but I could see they didn’t believe me.

So I’d say let me tell you about my wife’s migraines. She’s had them even before I met her when she was 19. And as is typical of migraine, they became less frequent and less severe as she got older.

So she had gone 18 months without one, until the afternoon that she found out that our 12 year old son, had a bone tumor in his ankle which would need surgery. Immediately, I could see the patient had bought in the particular what I’d just told them in the abstract.

I think the populace is presently saying to themselves. Maybe we ought to wear masks and only be around people wearing them. Look what happened to Trump and the Senators.

Addendum 5 October:

A sardonic friend (and retired ambassador) responded as follows

“Thanks for helping me appreciate President Trump’s public service.

The potential benefits of this style of leadership seem almost without limit.

Think, for example, of how the President could affect automotive safety if he were to demonstrate the perils of driving a car over a cliff.

Regards”

XXXX

First Debate — What did the neurologist think?

As my brother sometimes says “everyone is entitled to my opinion”.  Why should you be interested in mine?  Because I was a clinical neurologist from 1968 to 2000 seeing probably 25,000 patients over the years. Because I was board certified by the American Board of Psychiatry and Neurology.  Because later I examined candidates for certification for the same board.  Because I have an extensive experience with dementia in patients, and (unfortunately) with close friends and their kin and in our family.

The main question I had before the debates, was “Is Joe Biden cognitively impaired”, given the selection of his statements and gaffes.

The short answer is no.  He held his own, and moreover did so for 90 stressful minutes.

The more nuanced answer is that there are a few things about him that are not 100%.  As the time wore on, he mispronounced and slurred more words.  Also the right corner of his mouth appeared to sag a bit more (but no one has a perfectly symmetrical face).

The most unusual feature is Biden’s upper face — it doesn’t move. The masklike face is a symptom of Parkinsonism, but if so it is the only one.  I’m ashamed to admit that I didn’t notice how often his eyes blinked, but since I didn’t notice infrequent blinking (another sign of Parkinsonism) it probably wasn’t present. The prosody of his speech  (https://en.wikipedia.org/wiki/Prosody_(linguistics)) is normal, not diminished as it would be in Parkinsonism.  Is he on botox?  He has a remarkably unlined face for a man his age.

Biden often appeared to be looking down at something — talking points?  mini-teleprompter?

Is Trump impaired cognitively?  No sign of it.  His responses were quick, sometimes funny and often not to the point.   Both men are smart, but Trump appears (to me) to be smarter.

Although Chris Wallace is from Fox News hence suspect for many,  I thought he was a tough and impartial moderator, which is exactly what I wanted.

I did look at a C-Span segment of the audience settling down before the actual debate and was horrified.  50% not wearing masks, people shaking hands, getting far closer than 6 feet from each other.   Even if they’d all been recently tested for the virus, this was irresponsible behavior and an extremely poor model for the country.

Why drug development is hard #34 — designer hallucinogens

NBOMe (2-(4-Bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl) methyl]ethanamine to you) is a potent hallucinogen, a member of the phenylethylamine series of hallucinogens.  Well that’s the same as saying the current Intel chips are a member of the Intel class of starting with the 8080. https://psychonautwiki.org/wiki/25B-NBOMe has the structure, but I count 2 methoxy groups and a bromine on the phenyl group and a methoxy benzyl group making the amine group a secondary amine.

How anyone came up with the structure will remain unknown to me as it was part of a PhD thesis written in 2003 — unfortunately in German —Ralf Heim (February 28, 2010). “Synthese und Pharmakologie potenter 5-HT2A-Rezeptoragonisten mit N-2-Methoxybenzyl-Partialstruktur. Entwicklung eines neuen Struktur-Wirkungskonzepts.” (in German). diss.fu-berlin.de. Retrieved 2013-05-10.

Like other hallucinogens (LSD, mescaline, psilocin) NBOMe binds to the 2A variety of serotonin receptor (aka 5HT2A — at least 16 serotonin receptors are known) and acts like LSD as an agonist.

Which brings me to Cell vol. 182 pp. 1574 – 1588 ’20 — https://www.cell.com/cell/fulltext/S0092-8674(20)31066-7, probably behind a paywall.  Which has beautiful cryoEM structures of 5HT2A bound to LSD, NBOMe and methiothepin, an inverse agonist.  To get pictures they had to stabilize the structure with a single chain variable fragment of an antibody (something that always makes me wonder how physiologic the structure obtained actually is).

Why use NBOMe as an example of how hard drug discovery is?  Well the binding site of LSD to 5HT2A is well known, and the paper has some beautiful pictures of LSD snuggled between the 7 transmembrane segments of 5HT2A.  What is remarkable about NBOMe is that it lies in the binding site in a completely different orientation.  Moreover NBOMe fits in a previously undescribed pocket between transmembrane segments #3 and #6 (TM3, TM6).  Actually I think NBOMe actually produces the pocket.

So even if you know the target of your drug (5HT2A) and how another drug hits the target you’re aiming for, this doesn’t help you in designing a newer and more potent drug.