Category Archives: Uncategorized

A Touching Mother’s Day Story

Yes, a touching mother’s day story for you all. It was 47 years ago, and I was an intern at a big city hospital on rotation in their emergency room. 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 47 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— “

The weirdness of gravity

We experience gravity every waking moment, so it’s hard to recognize just how strange the gravitational ‘force’ actually is. Push a toy sailboat, a rowboat, and a yacht with the same amount of force (effort). What happens?

The smaller the boat, the faster it moves. Physicists would say the acceleration (change in velocity over time e.g. from the boat not moving at all to moving somewhat) is inversely proportional to the mass of the boat. This is Newton’s famous second law force = mass * acceleration. This isn’t actually what he said which you’ll find at the end.

So in every force except gravity, the bigger the force the more the acceleration. In Galileo’s famous experiment (which Wikipedia says might actually not have occurred), he dropped 2 objects of different masses from the leaning tower of Pisa and found that they hit the ground at the same time, so the acceleration of both due to the ‘force’ of gravity is the for all objects regardless of their different masses.

This implies that gravity is a force that adjusts itself to the mass of the object it is pushing on to produce the same acceleration. Weird, but true.

General relativity says, that the motion must be considered not just in space and time, but in 4 dimensional space-time where space can become our conventional time and vice versa. Here all paths are as straight as possible — because the 4 dimensional space-time we inhabit has an intrinsic curvature, produced by the masses found within it.

What Newton said: “The change of motion is proportional to the motive force impressed and is made in the direction of the straight line in which that force is impressed” By motion Newton means what we call momentum — mass * velocity.

The change in momentum is of course a change in velocity — which is what acceleration actually is. Note that mass is assumed constant regardless of how fast the object is moving. This isn’t even true in special relativity (which doesn’t include gravity — that’s what general relativity is all about).

While reading the research literature is a joy, sometimes it isn’t

“In this sense, enhanced connectivity of an essential node [e.g., in this study, as suggested by the previous analysis by Wühle et al. (17), the secondary somatosensory cortex, S2; for the issue of whether S1 is an essential node, see ref. 22] to brain structures, which render information consciously accessible, constitute predefined or privileged pathways along which neural information can propagate when confronted with an appropriate stimulus.”

I won’t tell you where this is from, but it’s but one horrible sentence among many. Even worse, the paper, is about something quite interesting — how much of the brain (and which parts) have to be activated before a barely perceptible stimulus is reported (e.g. when and where does consciousness begin).

Old and New Year’s Resolutions

I haven’t posted in a while because I was preparing for and recovering from some ‘minor’ surgery. As a practicing clinical neurologist, I was called in multiple times after people didn’t wake up, or stroked out from what was thought by all to be trouble free surgery. I came to the conclusion that there is no such thing as minor surgery. Although mine has gone well, I knew all the things which could go wrong, having seen nearly all of them. This sort of thing has a way of concentrating the mind, leaving room for little else.

So the old year’s resolutions are to get a few of the posts I’ve been sitting on out before the end of the year (probably not in this exact order)

Post #1 — further death of the synonymous codon

Post #2 — Heraclitus was right (about the nervous system) — you can’t step into the same brain twice

Post #3 — Book Review of Duncan Watts book

Post #5 — Unhappy 50th birthday for the War on Poverty

Post #6 — Gloating about the minimal hurricane season despite dire predictions about it

Post #7 — What sleep does and why babies sleep so much

Post #8 — The mating dance of ligand and receptor

The new year resolution — to go through the text on relativity by a classmate I hadn’t met until my 50th reunion. I’ve been through most of the math behind it (I hope). It’s the only time (I think) I’ve used the old school tie gambit to get something I wanted. He’s incredibly busy, still writing papers with Hawking etc. etc. but will answer at least a few questions when I get stuck (as I’m certain to do) purely because we were classmates. I doubt that he’d do this for any other 75 year old retired non physicist.

As my kids say, knowing someone can get you in the door, but you have to perform once you’re inside.

The old Ivy League school tie ain’t what it used to be. A cousin’s kid couldn’t get into a grad school in a subtype of English Lit despite a recent degree from one. Back in the day, it did mean a lot. If you were a premed at my institution and the premed advisor put his hand on your shoulder to say you were okay, you got into Columbia Med School. He was already famous and an operation named for him is still in use. A classmate, a smart guy, majored in Near East studies just because he was interested in it. That was enough for Chase which hired him as a banker. He never went near the mideast in his career.

The most interesting paper I’ve read in the past 5 years — Introduction and allegro

Have a look at Nature vol. 495 pp. 111 – 115 ’13, and the accompanying editorial (ibid. pp. 57 – 58) and see if you can find out why I think it is so fascinating. It has to do with my background and interests over the last 50+ years which are unlikely to be completely the same as the readers of this blog.

This post will be about computers, and how they can be completely understood in terms of their components (because humans constructed them). The next will be a boiled down version of the 6 articles https://luysii.wordpress.com/category/molecular-biology-survival-guide/.

Well, for nearly all my professional career 1962 – 2000 I was a neurologist and neurologists must deal with the brain and attempt to understand how it works (which we still don’t). The brain (and mind) has always been interpreted using the dominant technology of the day.

Freud (1856 – 1939) formulated his work when steam power was widely known and used. He studied with most eminent neurologist of the time (Charcot) after getting his M. D. His conception of the mind and it’s pathology had to do with powerful urges and the way they were channeled through the pipes of the psyche. In particular, traumatic events if allowed to build up in the system, could create pressures and wreck the psychiatric machinery. Hence the emphasis on discovering the blockages and releasing them before the steam engine exploded into pathology. This approach is alive and well today — can you say PTSD ?

Presently the brain is thought of in terms of the current dominant technology — the computer. It runs programs. Use of this analogy goes back to the dawn of the computer age way before they became widespread. John von Neumann who invented the stored program computer, in which programs and data looked the same, wrote “The Computer and the Brain” before his death in 1957.

So as a neurologist (and general techie) I was fascinated with them when they came out for the general public. Obviously, they could be completely understood because we created them. I bought an alpha Micro (long gone) which was the fruits of some engineers who worked at Digital Equipment Compancy (DEC — long gone), which was sold to Compaq (also long gone), back in the early 80’s.

Don’t laugh at what I bought; it was state of the art at the time. It had 64 kiloBytes of memory, of which 32 kiloBytes was taken up by the operating system, and the other 32 was used for programs. I read about the logic behind computers, and quickly realized that everything important happened inside the ALU (Arithmetic and Logical Unit), which had places to store data (registers) and a place to store one instruction (another register called the instruction pointer). The instructions were 16 bits (2 bytes long). The disc was state of the art at the time — all of 80 megaBytes — it looked (and sounded) like a washing machine, with removable platters which looked like giant thick frisbies.

I’d read up on how registers could be built up from logic gates (AND, OR, NOR, NAND). So, on paper, I built logical registers from these elements. I had a clock as well (a black box) which could send signals to the gates coordinating things. I quickly understood that for the simplest instruction == Add register A to register B, further instructions were necessary — this is the microcode — e.g. move register A to the ALU, open register B, use it as input along with the instruction code for Add, to perform the addition, then store it someplace.

Then after understanding how the instructions operated, I wrote a program to take the ones and zeros of the instructions of the operating system, and turn them into something readable e.g. 0110101000001111 into ADD A, B. This allowed me to see how instructions were turned into a functioning machine.

Why do it? Well, it was interesting, and at the end of all this an understanding of how computers work could be had. Clearly the output depended on the internal structure of the computer (which didn’t change) and the program fed into it (which did). Once you understood the structure of the computer and the language of the instructions, all you needed to understand its output was the program (e.g. the code).

As all this was going on, people were deciphering the chemical nature of the genetic code. Know the sequence of nucleotides in the code and you’d know everything was the zeitgeist. By an enormous effort the first sequence of an organism became available in 1977 — it was of a DNA virus PhiX-179. It had all of 5,386 base pairs and was a huge amount of work. The human genome project was decades away.

This sort of genetic hubris is the subject of the next post in the series. If you’ve read the paper, can you now see why I find it so fascinating? Stay tuned.

That’s why they’re called the blues

A fascinating paper. [ Proc. Natl. Acad. Sci. vol. 110 pp. 8836 - 8841 '13 ] 18 selections of classical orchestral music by Bach, Mozart and Brahms were played to Americans and Mexicans. People from both cultures chose colors suggested by the music the same way. Faster music in the major mode produces color choices which are more saturated, lighter and yellower. Slower, minor music produces the opposite pattern (desaturated, darker and BLUER).

That’s why they’re called the blues.

Although I’m a lifelong musician (piano) music has never suggested any colors to me at all.

The New Clayden pp. 852 – 876

This is a great chapter, showing what I think are state of the art stereochemical control mechanisms in actual natural product syntheses in the literature.  It’s exactly why I’m reading the new Clayden before trying to read blogs like Totally Synthetic (to get up to speed with what’s going on now after reading the first edition). Probably the syntheses presented at chapter’s end are at the graduate level, but they use nothing that hasn’t already been discussed.

One of my musician friends asked, what I was going to use the math I’m reading for.  We’d just finished playing a great Dvorak piano trio and I told her the same thing we used the trio for.   To me, at least, it’s all the same.  I get esthetic kicks from music, math and clever organic syntheses.  The quality of esthetic pleasure is differs among the three, but it’s esthetic nonetheless.

p. 854 — “For a stereospecific alkene transformation, choose the right geometry of the starting material to get the right diasteroisomer of the product.   Don’t try to follow any ‘rules’ just work through the mechanism.”   Amen.  Let it be a sign on the doorposts of thy house.

p. 856 – 857 — I’m not trying to be obnoxious, but the discussion of prochirality seems to embed what is simple stereochemistry in a plethora of unnecessary terms. 

p 859 – 860 — It’s clear from the level of discussion of the conformations of phenyl methyl acetaldehyde, that the book was written by multiple authors.  This particular author is addressing the first time student (or at least this part is).  Nothing wrong with a little hand holding in an elementary textbook. 

p. 861 — ALthough Dolastatin is said to be ‘one of the most powerful anticancer agents known’  it isn’t in clinical use.  It inhibits mitosis, so probably side effects kept it away from the bedside. 

pp. 858 – 865 — The discussion of stereoselectivity, Felkin Anh, chelation, electron donating substituents on the alpha carbon next to the ketone is elegant.  You don’t have to memorize anything — just think.  However, all is so well explained, that it’s unlikely that there is further research to be done on the subject, except when you’re trying to make something new.  

p. 865 — Any ideas why the lowest energy conformation of the carbon next to a double bond has one of the atoms attached to this carbon in the plane of the double bond (e. g. eclipsing the double bond).  Ken Houk was impressive as an undergraduate, and was already solving problems in the (subsequently legendary) Woodward seminars.

p. 872 — The synthesis of methyl mycaminoside with 5 asymmetric centers in a 6 membered ring, and reminds me of Woodward’s synthesis of reserpine, which also has 5 asymmetric centers in a 6 membered ring.   Particularly nice the way the synthesis used many of the stereochemical principles seen earlier in the chapter. 

p. 875 — I don’t see how the stereochemistry of L-isoleucine is preserved when the NH2 group is diazotized and then replaced by OH.   Well, I didn’t see it at first reading, but a few paragraphs later it was explained.  Shows that I’m still conscious I guess. 

Away for a bit

Off to my wife’s 50th high school reunion (classmate Jim Morrison, older matriculee — Mama Cass).  Back in a bit with the answer why big Pharma is imploding.  It’s basically what Derek Lowe has been saying — we are screwing around with a system we don’t understand fully.  The latest example of previously unsuspected cellular control mechanisms involves microRNAs, junk DNA, pseudogenes, and the difference in size between the genomes of leprosy and TB.   That’s just for openers — so rest up, see a few old friends and relax, maybe look at the Molecular Biology Survival Guide for Chemists if the terms make you feel anxious.

Back in the Saddle Again

Followers of this blog probably wonder where all the chemistry went.  I was in the middle of Anslyn and Dougherty when my iMac G5 began crashing earlier  this summer. So I had to put things on hold — for just why see — https://luysii.wordpress.com/2011/07/19/posting-intermittency-hypercard-r-i-p/.

I’ve now been able to transfer the HyperCard Data to FileMaker Pro 11, a program actively supported by the company that makes it, and a large user community.  Learning to program it was one of the most frustrating intellectual experiences I’ve ever had.

Readers of blogs like this one likely are always trying to learn new things, and invariably run up against concepts hard to understand the first time around.  I’m still trying to see how the various definitions of tensors are really about the same thing.  Mathematicians describe them as being over modules rather than vector spaces.  Physicists use vector spaces over the real numbers.  Other definitions stress multilinearity.  The concept of phase transition and what a renormalization group really does to explain it are currently beyond me.  I don’t think that anything in chemistry is that subtle (assuming you don’t get into the quantum mechanics of it all).  In medicine, it’s acid base balance and electrolytes, everything else is pretty simple once you memorize 50,000 facts.

But there’s always a place you can go to find the answers to your questions.

Not so, with learning FileMaker Pro.  There are reams of documentation, all sorts of bells and whistles of the program.  The problem is finding answers to the simplest of questions.

Pick up a “FileMaker 9 Developers Reference” and you’ll find all sorts of mention of values returned by functions. They never define just what a value is. “Ditto for FileMaker Pro 11 The Missing Manual”, value isn’t in the index, even though functions about them are.  Modern languages are very strongly typed — variable names must be declared and the program told what type it is — which type of numeric, text, function etc. etc.  The first few scripts I saw in this and other books had variables defined by “Let variable = something”.  About 150+ pages into one of these books (and “FileMaker Pro 10″ by Cologon which I think is the best of the lot) do you learn that variables are brought into existence just by naming them.  Similarly, the way a given field in a table is addressed in a script was never stated explicitly in any of the books, just mentioned in passing in one of them.  Basically I had to read all 3 of these books sequentially to find what I wanted.  I still don’t have a list of key words in the language, nor do I know what characters can’t be used in an identifier.  Basically I picked it up the same way an infant learns language, — by observing usage.   It could have been much easier, if the stuff that “everybody knows” was made explicit at the start.   I’ve never been so frustrated trying to learn anything, and it’s not because the material is difficult.

Rant now over,  the next post will describe some of the incredibly complex and subtle ways that the product of a protein coding gene can have different outcomes depending . ..  I’ts of some philosophic interest because it shows how crucial (fairly simple) chemistry is to understanding what’s going on, and yet, on a higher level, inadequate or irrelevant.  Stay tuned (those of you who haven’t given up).  I can’t wait to get back to finishing Anslyn and Dougherty (and posting about it)

 

Posting Intermittency — HyperCard R.I.P.

The frequency of posts is about to diminish.  I’ve got to learn a new program, and its programming (scripting) language to shift my current database to it.  I started using HyperCard when it came out in the fall of 1987, using it for all the notes I took on my reading in various areas.  You can even draw chemical structures with it, but not easily.   It’s a marvelous program and I’d be using it still if Apple still supported it (something they’ve not done in a decade).  When I was in practice, I ran its business side using it.  It’s extremely easy to program, user friendly , enough so that I wrote my own billing software, saving a bundle.   When Apple moved to Intel processors, Hypercard didn’t move with it, and so I had to buy 2 old machines using the PowerPC and OS 9.  The first versions of OS X had a classic mode which still supported Hypercard on the PowerPC.  The newer versions of OS X will not.  Machines eventually fail and I’m not about to have all the work I’ve put in, fail with it.

The database  contains 14,093 cards in the Xref stack, which is basically text, 18,892 cards in the index stack, and 7658 in the Glossary stack.  The great thing about Hypercard is that it lets you link two cards in any stack together by buttons.  Why is this great?  Because science progresses by the unexpected.  No one would have thought that the gene for narcolepsy would be related to appetite, but it is.  All it takes is a button to link the two cards with information about either together.  So the index stack has 47,498 buttons, xref 34,282 and glossary 11572, bringing the total number of cards and buttons to a glorious 133,995.  The whole shebang takes up 72 megaBytes on Disk.

This sort of thing was foreseen years ago in a great book called “Silicon Snake Oil: Second Thoughts on the Information Highway” by Clifford Stoll.  His point, is that storing things digitally is a con, as programs and their formats are no longer supported.  It certainly happened to me, although it’s been a great 24 years.  He also wrote another very good book called the “Cuckoo’s Egg” about how, as a graduate student in Astrophysics, he came across a few accounting errors in the accounts he was called to manages — pennies only, as I remember. It led to the discovery of a ring stealing all sorts of money from accounts all over the world.  It’s well written and funny.

So I’ve decided to learn FileMaker Pro, which also has a scripting language and which appears powerful enough to do so.  I went to a training session today which introduced the basics, and was very pleased to see that the Broad Institute (of human genome project fame) and Tufts NeuroScience sent 3 people.  The program has been around a long time (in computer time, that is) and hopefully will continue.  I’ve found “FileMaker Pro 11, The Missing Manual”quite helpful, although I’ve only worked through 70 or so of its 800+ pages.

I’ve already figured out how to get the text content of the various fields stacks and the scripts of the buttons of my HyperCard stacks into a plain text file which I can simply schlep over to the newer Apples.    Now I have to learn the scripting language of FileMaker Pro to get this data into a Filemaker database (which won’t be hard to construct, since it will mimic the functionality of the old one).  If anyone out there knows of  a (free) good source explaining the FileMaker Pro scripting language, rather than just listing the commands and syntax, please  let me know.  While you can learn a new language from a dictionary, there are better ways to do it.  Today’s training session already set me back $300 (well worth it though !), and FileMaker Pro Advanced will be $500.

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