Freud was right, there is an unconscious mind and it’s pretty smart.

Freud has fallen out of favor, with his analogies of the workings of the mind to a steam engine (drives, pressures, releases, displacements), the dominant technology of his day–as the computer is to ours. However, the following paper [ Proc. Natl. Acad. Sci. vol. 113 pp. E616 – E6125 ’16 ] shows that we have an unconscious mind, and that it is mathematically sophisticated (although I don’t think the authors made this point).

[ Proc. Natl. Acad. Sci. vol. 113 pp. E616 – E625 ’16 ] The work used magnetoencephalography (MEG) https://en.wikipedia.org/wiki/Magnetoencephalography, to record brain activity in response to a series of tone pips. MEG is conceptually quite similar to the electrocardiogram (EKG) or the electroencephalogram (EEG), both measuring voltage differences between two electrodes over time. Well, a voltage difference causes an electric current to flow through a conductor, and the nice wet brain is nothing if not that. Anyone who has studied how an electric motor works, knows that an electric current produces a magnetic field, which is what the MEG measures. The great advantage of MEG is that it is temporally precise, and changes can be measured in milliSeconds.

So what did they do? They presented tone pips to an unspecified number of subjects. The relation of one pip to another could either be completely random (RAND) or part of a repeating pattern — say pip pip pip silence silence pip pip pip silence silence (PAT). In one series of experiments, subjects were asked to press a button as soon as the pip sequence went from random to patterned (RAND –> PAT), all this while the MEG was being recorded. In another, they were asked to do this for PAT –> RAND. The subjects were as good as something called the the mathematical ideal observer of the variable order Markov model. It only took one or two random pips after a patterned sequence to notice it and press the button. They could also pick up that a pattern was formed midway through the second repetition of a pattern.

The MEG showed abrupt changes at either transition (RAND –> PAT or PAT –> RAND). The work didn’t stop with just sequences of just one tone. They could use an ‘alphabet of tones’. The subjects could pick up when the number of tones in the alphabet changed, again with MEG values to match.  So they had an independent signal from the MEG show that the brain picked up the transition without requiring any cooperation from the subjects.  All very nice, but anyone who likes music can do this.

Then the subjects were then asked to perform the n-back task, in which the subject is presented with a sequence of stimuli;  and the task consists of indicating when the current stimulus matches the one from n steps earlier in the sequence. Tricky isn’t it? Certainly, something that requires concentration. The load factor n can be adjusted to make the task more or less difficult. You’ve got to hold the sequence just presented in your head so the n-back task is a test of working memory.

Drum roll —

If the tone pips were presented while the subjects were doing the n-back task, the MEG still picked up RAND –> PAT and PAT –> RAND transitions, something the subjects weren’t consciously trying to do.

We know the brain does all sorts of things unconsciously — e.g. breathing. But they are pretty simple. The tests here are conceptually subtle. Your unconscious brain picks up statistical regularities and irregularities without your consciously trying. Who knows what else it does — maybe Freud was right.

Why should this be useful? Well, you’d want to know if a predator is sneaking up on you. The same work should be done with animals performing a task they’ve been trained to do.

Bad news on the AIDs front

Bad news for those hoping for an AIDs cure. As you know, the active virus (HIV1) has a genome made of RNA. However, thanks to an enzyme it possesses called reverse transcriptase (which has led to Nobel prizes), it copies itself into DNA and integrates into the genome of lymphocytes. There it sits presumably doing nothing, but it’s always capable of activating and producing more infectious virus.

We seem to have fought the virus to a draw, using a cocktail of drugs which attack different aspects — HAART (Highly Active Antiretroviral Therapy). Success is usually considered being unable to detect viral RNA in the blood (see later). However blood cells are short-lived. What about the longer living lymphocytes found in the lymph nodes and spleen.

That’s what was studied in a current paper [ Nature vol. 530 pp. 5` – 45 ’16 ] but in only 3 people. All had no detectable virus in the blood (under 48 copies/milliLiter — an incredibly tiny amount — see later). What they did was to biopsy lymph nodes in the groin on study entry and at 3 and 6 months.

Then they sequenced the genomes of the lymphocytes from the nodes, to study the HIV1 DNA integrated into the genome. They found that the genome changed with time. This is very bad. Why?

Because it implies that, even though you the virus in the blood, the virus was not staying latent in the lymph nodes, but coming out of the lymphocytes and forming infectious virus which then mutated. Subsequently the mutated virus integrated into the genome of another lymphocyte. So even with what we consider excellent control, the virus is not purely latent. Drug resistance could arise from mutations (although they didn’t see it in this study).

Clearly, more people need to be studied this way (but serial biopsies? It will probably be done in prisoners, if such things are still done).

It’s worthwhile thinking about how incredibly selective and accurate our methods of analysis are. 48 copies of the viral RNA per milliLiter of blood is the lower limit of detection. Remember that water has a molecular weight of 18, so a liter of distilled water is 1000 grams / 18 grams = 55.5 Molar. A mole has 6 x 10^23 molecules. A milliLiter is 10^-3 liters. So 1 milliLiter of distilled water has 55 * 6 * 10^23 * 10^-3 == 3 * 10^22 molecules of water in it so the assay is finding 48 or more molecules of HIV1 RNA in the water haystack. Even figuring that the concentration of water in blood is 1/10 that of distilled water, this is still impressive.

smORFs, dwORFs and now uORFs

A recent post described small Open Reading Frames (smORFs) and DWarf Open Reading Frames (DWORFS) — see the link at the bottom. Now it’s time for uORFs (upstream Open Reading Frames). Upstream of what you might ask? Well messenger RNA is grabbed by the ribosome at one end (called the 5′ end). The current thinking was that the ribosome marched along the mRNA from the 5′ to the 3′ direction looking for the sequence Adenine Uridine Guanine (AUG) which codes for methionine. It then begins reading the mRNA 3 nucleotides at a time and tacking amino acids onto the methionine. This is called translating mRNA into protein. What about the 5′ end of the mRNA before the AUG is reached (perhaps hundreds of nucleotides later) — it isn’t translated which is why its called the 5′ UTR (5′ UnTranslated Region). In bacteria its only a few nucleotides, but our 5′ UTRs can have thousands — https://en.wikipedia.org/wiki/Five_prime_untranslated_region.

Two other terms of art are upstream and downstream. Since the ribosome flows from 5′ to 3′ on mRNA, any nucleotide 5′ to a given point is called upstream, and anything 3′ is called downstream. Logical terminology — what a pleasure.

So a uORF is an upstream Open Reading Frame. Upstream to what? Why to the AUG (the initiator codon). The assumption had always been that since there was no initiator AUG codon on this region — that proteins couldn’t be made from the uORF. Wrong.

This is where [ Science vol. 351 p. 465 aad2867 – 1 –> 9 ’16 ] comes in. It turns out that the ribosome can translate some of these uORFs in protein, and the paper describes a clever technique (called 3T) they developed to find them. One of the problems in finding uORF proteins is that some are quite small, and are missed in the usual protein assays. One uORF from ATF4 contains only3 amino acids which is so small that mass spectrometry can’t see it.

The paper makes the amazing statement that — Nearly half of all mammalian mRNAs harbor uORFs in the 5′ UTRs, and many are initiated with nonAUG start codons. They may be a general mechanism to regulate downstream coding sequence expression and gives two citations that I must have missed in my reading .

For instance Binding immunoglobulin Protein (BiP aka Heat Shock Protein family A member 5 – HSPA5 ) contains uORFs exclusively initiated by UUG and CUG start codons (not AUG).

What might the functions of uORF actually be? The obvious one is that the proteins made from them might actually be doing something. What could a 3 amino acid protein possibly do? Lots. Consider thyrotropin releasing hormone which helps control your thyroid — it is pyroglutamic acid histidine proline. Then there is met-encephalin which has 5 amino acids and is one of the endogenous opiate peptides your brain uses.

Another possibility is that just translating the uORF into protein controls the translation of the protein starting with the AUG codon. This isn’t so far fetched. A recent paper [ Nature vol. 529 pp. 551 – 554 ’16 ] gave a 3 dimensional structure for RNA polymerase II transcribing a DNA template into mRNA. The authoress (Carrie Bernecky) was kind enough to supply the dimensions of the complex when I wrote her. Remember you can consider the DNA double helix as a cylinder 20 Angstroms in diameter. It is roughly 150 x 150 x 160 Angstroms. Figuring 3 stacked nucleotides/10 Angstroms, this is enough to obstruct 45 nucleotides of DNA upstream of the actual start site.

This is just another example of room at the bottom, where all sorts of small molecule metabolites, small RNAs, small DNAs are just being unearthed and their structure determined. For more on this please see the following link

SmORFs and DWORFs — has molecular biology lost its mind?

A prospective experiment for you all to do at home

Here is a prospective journalistic experiment for you all to do in the privacy of your own home. Then it’s time for me to get back to the science.

The previous post (https://luysii.wordpress.com/2016/02/03/helping-hillary-along/) showed how the New York Times is working very hard to brand Rubio as a member of the Republican establishment and as their preferred candidate. Well, he might be just that, but if there ever was a candidate of the Democratic establishment it is Hillary Clinton.

So here’s the experiment for you to do. Pick a media outlet you follow (NPR, New York Times, Washington Post, any TV channel of your choice etc. etc.). Then count the number of times the term establishment is used in stories about Rubio and about Hillary. Since I read the NYT daily, I’ll choose them. I get the WSJ but never plow through the whole thing — just the first section.

There’s no point in being a scientific type if you don’t make predictions. Mine is that the word establishment will be used at least twice as often (if not more) in stories about Rubio than in stories about Hillary (this includes op-eds).

So pick your outlet and start tomorrow. Send your results here by writing a comment on this post.

Helping Hillary along

A friend of my son once said that all you needed was the first one or two measures of anything Bach wrote to know how the rest of the piece would go. So it is with the New York Times. The lead about the primary campaign 3 Feb ’16 contains the terms “Army, Attack, Dispatches” and the sublead contains the term “Establishment”.

Do you think this article is about Hillary?

Of course not. This is branding at its finest. Of whom? Of a viable Republican candidate (Rubio), so you’ll know just what to think about him without even reading the article.

Another article on the front page has a nice picture of Hillary. They mention that she won Iowa by the narrowest of margins, but nothing about how surprising this was given that she has the entire mainstream press and Democratic party establishment (term not used) on her side.

It’s why the mainstream press must be read the way the Russians (and the CIA) read Pravda during the cold war.

Addendum 4 Feb ’16 — When Barack Obama won the Iowa caucus in 2008, the press went bananas and noted that this was the first time a Black candidate won the Iowa caucus.

Have you read anything about the first Latino to win the Iowa caucus (Cruz) or that another came in third (Rubio) and that a Black candidate came in fourth (Carson), the three receiving an aggregate 60% of the vote in lily white Iowa?  I thought not.   That’s because the narrative that Republicans are racist must be upheld at all costs.

Second addendum 4 Feb ’16 — I should have looked at the editorial page of the Times before writing the above.  There is still nothing in the mainstream ‘news’ feeds about the Latino victory even now.  The Op-ed page contains “The Latino Political First We’re Ignoring”.  The victories of Rubio and Cruz are noted. The op-ed notes that “it is not being celebrated”.  So who is “we” and who is not celebrating?  “No less an arbiter than Jorge Ramos the Univision anchor” and La Opinion, the nation’s largest Spanish language newspaper.  One must ask who elected the arbiter and the editorial board of the La Opinion?  No one.  More media types holding forth in their echo chamber  Another example of self selected spokesmen being blindsided by events.

On the same opinion page we are told “The Republican establishment is thrilled”  about Rubio by Gail Collins.  This continues the meme on the front page yesterday of Rubio being the establishment.

I have no problem with Collins or the op-ed about Cruz and Rubio’s victory.  They are opinions and on the opinion page where they belong.  The problem was yesterday’s front page opinion piece masquerading as news.

 

 

A book recommendation, not a review

My first encounter with a topology textbook was not a happy one. I was in grad school knowing I’d leave in a few months to start med school and with plenty of time on my hands and enough money to do what I wanted. I’d always liked math and had taken calculus, including advanced and differential equations in college. Grad school and quantum mechanics meant more differential equations, series solutions of same, matrices, eigenvectors and eigenvalues, etc. etc. I liked the stuff. So I’d heard topology was cool — Mobius strips, Klein bottles, wormholes (from John Wheeler) etc. etc.

So I opened a topology book to find on page 1

A topology is a set with certain selected subsets called open sets satisfying two conditions
l. The union of any number of open sets is an open set
2. The intersection of a finite number of open sets is an open set

Say what?

In an effort to help, on page two the book provided another definition

A topology is a set with certain selected subsets called closed sets satisfying two conditions
l. The union of a finite number number of closed sets is a closed set
2. The intersection of any number of closed sets is a closed set

Ghastly. No motivation. No idea where the definitions came from or how they could be applied.

Which brings me to ‘An Introduction to Algebraic Topology” by Andrew H. Wallace. I recommend it highly, even though algebraic topology is just a branch of topology and fairly specialized at that.

Why?

Because in a wonderful, leisurely and discursive fashion, he starts out with the intuitive concept of nearness, applying it to to classic analytic geometry of the plane. He then moves on to continuous functions from one plane to another explaining why they must preserve nearness. Then he abstracts what nearness must mean in terms of the classic pythagorean distance function. Topological spaces are first defined in terms of nearness and neighborhoods, and only after 18 pages does he define open sets in terms of neighborhoods. It’s a wonderful exposition, explaining why open sets must have the properties they have. He doesn’t even get to algebraic topology until p. 62, explaining point set topological notions such as connectedness, compactness, homeomorphisms etc. etc. along the way.

This is a recommendation not a review because, I’ve not read the whole thing. But it’s a great explanation for why the definitions in topology must be the way they are.

It won’t set you back much — I paid. $12.95 for the Dover edition (not sure when).

Trumpenprolitariat

The irony is simply too delicious. Now that what Marx called the lumpenproletariat (https://en.wikipedia.org/wiki/Lumpenproletariat) has arisen and given voice to its discontents the left hates them. I speak of the Trump supporters, now described by the left as racist, homophobic, jingoistic, biased, violent — you name it. Read Slate, the Nation. They attack Trump of course, but what really disturbs them are his supporters (the Trumpenproletariat or the Proletrumpians). The times they are a’changin’.

Back in the 70s there was a fun movie called “Suppose They Gave a War and Nobody Came”

Now we have “Suppose They Gave A Proletarian Revolution and No One from the Left Came.

The left has morphed in other ways as well — see — https://luysii.wordpress.com/2015/11/22/from-banned-in-boston-to-banned-in-berkeley-in-55-years/

This just in — New York Times 30 Jan ’16 page 1 “Union Leaders Wary of Trump”  — The elites leading the unions (even the ‘more progressive’ ones such as SEIU)  are worried that “Mr Trump if not effectively encountered, may draw an unusually large numbers of union voters.”  If this isn’t the proletariat who is?

A variety of vignettes is given of various union members in unions all over the country supporting him, with estimates from 1/4 to 1/3.

This is another example of the disconnect between the political leadership (this time the unions) and the populace it claims to be speaking for.  Trump, Bernie, Cruz take your pick.  The discontent is out there.

SmORFs and DWORFs — has molecular biology lost its mind?

There’s Plenty of Room at The Bottom is a famous talk given by Richard Feynman 56 years ago. He was talking about something not invented until decades later — nanotechnology. He didn’t know that the same advice now applies to molecular biology. The talk itself is well worth reading — here’s the link http://www.zyvex.com/nanotech/feynman.html.

Those not up to speed on molecular biology can find what they need at — https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/. Just follow the links (there are only 5) in the series.

lncRNA stands for long nonCoding RNA — nonCoding for protein that is. Long is taken to mean over 200 nucleotides. There is considerable debate concerning how many there are — but “most estimates place the number in the tens of thousands” [ Cell vol. 164 p. 69 ’16 ]. Whether they have any cellular function is also under debate. Could they be like the turnings from a lathe, produced by the various RNA polymerases we have (3 actually) simply transcribing the genome compulsively? I doubt this, because transcription takes energy and cells are a lot of things but wasteful isn’t one of them.

Where does Feynmann come in? Because at least one lncRNA codes for a very small protein using a Small Open Reading Frame (SMORF) to do so. The protein in question is called DWORF (for DWorf Open Reading Frame). It contains only 34 amino acids. Its function is definitely not trivial. It binds to something called SERCA, which is a large enzyme in the sarcoplasmic reticulum of muscle which allows muscle to relax after contracting. Muscle contraction occurs when calcium is released from the endoplasmic reticulum of muscle.  SERCA takes the released calcium back into the endoplasmic reticulum allowing muscle to contract. So repetitive muscle contraction depends on the flow and ebb of calcium tides in the cell. Amazingly there are 3 other small proteins which also bind to SERCA modifying its function. Their names are phospholamban (no kidding) sarcolipin and myoregulin — also small proteins of 52, 31 and 46 amino acids.

So here is a lncRNA making an oxymoron of its name by actually coding for a protein. So DWORF is small, but so are its 3 exons, one of which is only 4 amino acids long. Imagine the gigantic spliceosome which has a mass over 1,300,000 Daltons, 10,574 amino acids making up 37 proteins, along with several catalytic RNAs, being that precise and operating on something that small.

So there’s a whole other world down there which we’ve just begun to investigate. It’s probably a vestige of the RNA world from which life is thought to have sprung.

Then there are the small molecules of intermediary metabolism. Undoubtedly some of them are used for control as well as metabolism. I’ll discuss this later, but the Human Metabolome DataBase (HMDB) has 42,000 entries and METLIN, a metabolic database has 240,000 entries.

Then there is competitive endogenous RNA –https://luysii.wordpress.com/2012/01/29/why-drug-discovery-is-so-hard-reason-20-competitive-endogenous-rnas/

Do you need chemistry to understand this? Yes and no. How the molecules do what they do is the province of chemistry. The description of their function doesn’t require chemistry at all. As David Hilbert said about axiomatizing geometry, you don’t need points, straight lines and planes You could use tables, chairs and beer mugs. What is important are the relations between them. Ditto for the chemical entities making us up.

I wouldn’t like that.  It’s neat to picture in my mind our various molecular machines, nuts and bolts doing what they do.  It’s a much richer experience.  Not having the background is being chemical blind..  Not a good thing, but better than nothing.

More Quantum Weirdness

If you put 3 pigeons in two pigeonholes, two pigeons must be in one of them. Not so says quantum mechanics in a new paper [ Proc. Natl. Acad. Sci. vol. 113 pp. 532 – 535 ’16 ]. I can’t claim to understand the paper, despite auditing a course in QM in the past decade, but at least I do understand the terms they are throwing about. I plan to print it out and really give it a workout

The paper does involve something called a beam splitter, which splits photon waves into two parts. I’ve never understood how this works on a mechanistic level. Perhaps no such understanding is possible. Another thing I don’t understand is what happens when a photon wave (or particle) is reflected from a mirror. Perhaps no such understanding is possible. Another thing I don’t understand is how a photon is diffracted when it passes through a slit. It must in some way sense the edge of the slit. I’ve certainly watched waves being diffracted by a breakwater — just go up to the bar at the top of the Sears Tower in Chicago, get an estimate on a beer and look out at lake Michigan.

Can anyone out there help?

Saepe falsus, sed numquam dubitans

Saepe falsus, sed numquam dubitans — “Sometimes wrong but never in doubt” should be on the Heraldic crest of Paul Krugman. He certainty came to mind at around noon today 20 Jan ’16 with oil breaking $27/barrel and the Dow down 550.

Here are two direct quotes from him as he held forth on the Opinion pages of the New York Times back in 2010.

“Conventional oil production has been flat for four years; in that sense, at least, peak oil has arrived.”

“So what are the implications of the recent rise in commodity prices? It is, as I said, a sign that we’re living in a finite world, one in which resource constraints are becoming increasingly binding.”

Name a commodity price that’s been rising.

He is, after all, a Nobel laureate in economics, a tenured Princeton professor, blah, blah, blah. You should take everything he writes with much salt even though, despite all this, he’s as certain as ever. It seems with such a disastrous track record that the Times could find someone better.

Here is a link to the entire column — see for yourself. http://www.nytimes.com/2010/12/27/opinion/27krugman.html?_r=0

A thank you to my niece Ruth Loop for providing the translation

Addendum 20 Jan ’16 — An unenviable economic prediction from the laureate in economics

https://en.wikiquote.org/wiki/Paul_Krugman

    • “Ricardo’s Difficult Idea,” in G. Cook (ed.), Freedom and Trade: The Economics and Politics of International Trade, Volume 2 (1998)
  • By 2005 or so, it will become clear that the Internet‘s impact on the economy has been no greater than the fax machine’s

Thanks Joe

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