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The bouillabaisse of the synaptic cleft

The synaptic cleft is so small ( under 400 Angstroms — 40 nanoMeters ) that it can’t be seen with the light microscope ( the smallest wavelength of visible light 3,900 Angstroms — 390 nanoMeters).  This led to a bruising battle between Cajal and Golgi a just over a century ago over whether the brain was actually made of cells.  Even though Golgi’s work led to the delineation of single neurons he thought the brain was a continuous network.  They both won the Nobel in 1906.

Semifast forward to the mid 60s when I was in medical school.  We finally had the electron microscope, so we could see synapses. They showed up as a small CLEAR spaces (e.g. electrons passed through it easily leaving it white) between neurons.  Neurotransmitters were being discovered at the same time and the synapse was to be the analogy to vacuum tubes, which could pass electricity in just one direction (yes, the transistor although invented hadn’t been used to make anything resembling a computer — the Intel 4004 wasn’t until the 70s).  Of course now we know that information flows back and forth across the synapse, with endocannabinoids (e. g. natural marihuana) being the major retrograde neurotransmitter.

Since there didn’t seem to be anything in the synaptic cleft, neurotransmitters were thought to freely diffuse across it to being to receptors on the other (postsynaptic) side e.g. a free fly zone.

Fast forward to the present to a marvelous (and grueling to read because of the complexity of the subject not the way it’s written) review of just what is in the synaptic cleft [ Cell vol. 171 pp. 745 – 769 ’17 ] (It is likely behind a paywall).  There are over 120 references, and rather than being just a catalogue, the single author Thomas Sudhof extensively discusseswhich experimental work is to be believed (not that Sudhof  is saying the work is fraudulent, but that it can’t be used to extrapolate to the living human brain).  The review is a staggering piece of work for one individual.

The stuff in the synaptic cleft is so diverse, and so intimately involved with itself and the membranes on either side what what is needed for comprehension is not a chemist but a sociologist.  Probably most of the molecules to be discussed are present in such small numbers that the law of mass action doesn’t apply, nor do binding constants which rely on large numbers of ligands and receptors. Not only that, but the binding constants haven’t been been determined for many of the players.

Now for some anatomic detail and numbers.  It is remarkably hard to find just how far laterally the synaptic cleft extends.  Molecular Biology of the Cell ed. 5 p. 1149 has a fairly typical picture with a size marker and it looks to be about 2 microns (20,000 Angstroms, 2,000 nanoMeters) — that’s 314,159,265 square Angstroms (3.14 square microns).  So let’s assume each protein takes up a square 50 Angstroms on a side (2,500 square Angstroms).  That’s room for 125,600 proteins on each side assuming extremely dense packing.  However the density of acetyl choline receptors at the neuromuscular junction is 8,700/square micron, a packing also thought to be extremely dense which would give only 26,100 such proteins in a similarly distributed CNS synapse. So the numbers are at least in the right ball park (meaning they’re within an order of magnitude e.g. within a power of 10) of being correct.

What’s the point?

When you see how many different proteins and different varieties of the same protein reside in the cleft, the numbers for  each individual element is likely to be small, meaning that you can’t use statistical mechanics but must use sociology instead.

The review focuses on the neurExins (I capitalize the E  to help me remember that they are prEsynaptic).  Why?  Because they are the best studied of all the players.  What a piece of work they are.  Humans have 3 genes for them. One of the 3 contains 1,477 amino acids, spread over 1,112,187 basepairs (1.1 megaBases) along with 74 exons.  This means that just over 1/10 of a percent of the gene is actually coding for for the amino acids making it up.  I think it takes energy for RNA polymerase II to stitch the ribonucleotides into the 1.1 megabase pre-mRNA, but I couldn’t (quickly) find out how much per ribonucleotide.  It seems quite wasteful of energy, unless there is some other function to the process which we haven’t figured out yet.

Most of the molecule resides in the synaptic cleft.  There are 6 LNS domains with 3 interspersed EGFlike repeats, a cysteine loop domain, a transmembrane region and a cytoplasmic sequence of 55 amino acids. There are 6 sites for alternative splicing, and because there are two promoters for each of the 3 genes, there is a shorter form (beta neurexin) with less extracellular stuff than the long form (alpha-neurexin).  When all is said and done there are over 1,000 possible variants of the 3 genes.

Unlike olfactory neurons which only express one or two of the nearly 1,000 olfactory receptors, neurons express mutiple isoforms of each, increasing the complexity.

The LNS regions of the neurexins are like immunoglobulins and fill at 60 x 60 x 60 Angstrom box.  Since the synaptic cleft is at most 400 Angstroms long, the alpha -neurexins (if extended) reach all the way across.

Here the neurexins bind to the neuroligins which are always postsynaptic — sorry no mnemonic.  They are simpler in structure, but they are the product of 4 genes, and only about 40 isoforms (due to alternative splicing) are possible. Neuroligns 1, 3 and 4 are found at excitatory synapses, neuroligin 2 is found at inhibitory synapses.  The intracleft part of the neuroligins resembles an important enzyme (acetylcholinesterase) but which is catalytically inactive.  This is where the neurexins.

This is complex enough, but Sudhof notes that the neurexins are hubs interacting with multiple classes of post-synaptic molecules, in addition to the neuroligins — dystroglycan, GABA[A] receptors, calsystenins, latrophilins (of which there are 4).   There are at least 50 post-synaptic cell adhesion molecules — “Few are well understood, although many are described.”

The neurexins have 3 major sites where other things bind, and all sites may be occupied at once.  Just to give you a taste of he complexity involved (before I go on to  larger issues).

The second LNS domain (LNS2)is found only in the alpha-neurexins, and binds to neuroexophilin (of which there are 4) and dystroglycan .

The 6th LNS domain (LNS6) binds to neuroligins, LRRTMs, GABA[A] receptors, cerebellins and latrophilins (of which there are 4)_

The juxtamembrane sequence of the neurexins binds to CA10, CA11 and C1ql.

The cerebellins (of which there are 4) bind to all the neurexins (of a particular splice variety) and interestingly to some postsynaptic glutamic acid receptors.  So there is a direct chain across the synapse from neurexin to cerebellin to ion channel (GLuD1, GLuD2).

There is far more to the review. But here is something I didn’t see there.  People have talked about proton wires — sites on proteins that allow protons to jump from one site to another, and move much faster than they would if they had to bump into everything in solution.  Remember that molecules are moving quite rapidly — water is moving at 590 meters a second at room temperature. Since the synaptic cleft is 40 nanoMeters (40 x 10^-9 meters, it should take only 40 * 10^-9 meters/ 590 meters/second   60 trillionths of a second (60 picoSeconds) to cross, assuming the synapse is a free fly zone — but it isn’t as the review exhaustively shows.

It it possible that the various neurotransmitters at the synapse (glutamic acid, gamma amino butyric acid, etc) bind to the various proteins crossing the cleft to get their target in the postsynaptic membrane (e.g. neurotransmitter wires).  I didn’t see any mention of neurotransmitter binding to  the various proteins in the review.  This may actually be an original idea.

I’d like to put more numbers on many of these things, but they are devilishly hard to find.  Both the neuroligins and neurexins are said to have stalks pushing them out from the membrane, but I can’t find how many amino acids they contain.  It can’t find how much energy it takes to copy the 1.1 megabase neurexin gene in to mRNA (or even how much energy it takes to add one ribonucleotide to an existing mRNA chain).

Another point– proteins have a finite lifetime.  How are they replenished?  We know that there is some synaptic protein synthesis — does the cell body send packages of mRNAs to the synapse to be translated there.  There are at least 50 different proteins mentioned in the review, and don’t forget the thousands of possible isoforms, each of which requires a separate mRNA.

Old Chinese saying — the mountains are high and the emperor is far away. Protein synthesis at the synaptic cleft is probably local.  How what gets made and when is an entirely different problem.

A large part of the review concerns mutations in all these proteins associated with neurologic disease (particularly autism).  This whole area has a long and checkered history.  A high degree of cynicism is needed before believing that any of these mutations are causative.  As a neurologist dealing with epilepsy I saw the whole idea of ion channel mutations causing epilepsy crash and burn — here’s a link —’ve-found-the-mutation-causing-your-disease-not-so-fast-says-this-paper/

Once again, hats off to Dr. Sudhof for what must have been a tremendous amount of work


Antibodies without antibodies

If you knew exactly how an important class of antibodies interacted with its target, could you design a (relatively) small molecule to act the same way.  These people did, and the work has very exciting implications for infectious disease [ Science vol. 358 pp. 450 – 451, 496 – 502 ’17 ].

The influenza virus is a very slippery target.  Its genome is made of RNA, and copying it is quite error prone, so that mutants are formed all the time.  That’s why the vaccines of yesteryear are useless today.   However there are things called broadly neutralizing antibodies which work against many strains of the virus.  It attacks a vulnerable site on the hemagglutinin protein (HA) of the virus.  It is in the stem of the virus, and binding of the antibody here prevents the conformational change required for the virus to escape the endosome, a fact interesting in itself in that it implies that it only works after the virus enters the cell, although the authors do not explicitly state this.

Study of one broadly neutralizing antibody showed that binding to the site was mediated by a single hypervariable loop.  So the authors worked with a cyclic peptide mimicking the loop.  This has several advantages, in particular the fact that the entropic work of forcing a floppy protein chain into the binding conformation is already done before the peptide meets its target.

The final cyclic peptide contained 11 amino acids, of which 5 weren’t natural. It neutralized pandemic H1 and avaian H5 influenza A strains at nanoMolar concentration.

It’s important that crystal structures of the broadly neutralizing antibody binding to HA were available — this requires atomic level resolution.  I’m not sure cryoEM is there yet.

Time for a funny

Members of the Massachusetts Caucus of Women Legislators are calling for additional steps to combat sexual harassment on Beacon Hill  — including mandatory training.  For those from other states, Beacon Hill is the site of the Massachusetts legislature in Boston.

One irate lawmaker complained that mandatory training was a waste of hard-earned taxpayer dollars as he was already quite adept at it.

The current composition of the legislature is 123 Democratic 34 Republican 1 Independent 2 Vacancies.

How a first rate mathematician thinks

For someone studying math on their own far from academe, the Math Stack Exhange is a blessing.  There must be people who look at it all day, answering questions as they arise, presumably accumulating some sort of points (either real points or virtue points).  Usually answers to my questions are answered by these people within a day (often hours).  But not this one.

“It is clear to me that a surface of constant negative Gaussian curvature satisfies the hyperbolic axiom (more than one ‘straight’ line not meeting a given ‘straight’ line). Hartshorne (Geometry: Euclid and Beyond p. 374) defines the hyperbolic plane as the Hilbert plane + the hyperbolic axiom.

I’d like a proof that this axiomatic definition of the hyperbolic plane implies a surface of constant negative Gaussian curvature. ”

Clearly a highly technical question.  So why bore you with this?  Because no answer was quickly forthcoming, I asked one of my math professor friends about it.  His response is informal, to the point, and more importantly, shows how a first rate mathematician thinks and explains things.  I assure you that this guy is a big name in mathematics — full prof for years and years, author of several award winning math books etc. etc.  He’s also a very normal appearing and acting individual, and a very nice guy.  So here goes.

” Proving that the axiomatic definition of hyperbolic geometry implies constant negative curvature can be done but requires a lot of work. The first thing you have to do is prove that given any two points p and q in the hyperbolic plane, there is an isometry that takes p to q. By a basic theorem of Gauss, this implies that the Gaussian curvature K is the same at p and q. Hence K is constant. Then the Gauss-Bonnet Theorem says that if you have a geodesic triangle T with angles A, B, C, you have

A+B+C = pi + integral of K over T = pi + K area(T)

since K is constant. This implies K area(T) = A+B+C-pi < 0 by a basic result in hyperbolic geometry. Hence K must be negative, so we have constant negative curvature.

To get real numbers into the HIlbert plane H, you need to impose "rulers" on the lines of H. The idea is that you pick one line L in H and mark two points on it. The axioms then give a bijection from L to the real numbers R that takes the two points to 0 and 1, and then every line in H gets a similar bijection which gives a "ruler" for each line. This allows you to assign lengths to all line segments, which gives a metric. With more work, you get a setup that allows you to get a Riemannian metric on H, hence a curvature, and the lines in H become geodesics in this metric since they minimize distance. All of this takes a LOT of work.

It is a lot easier to build a model that satisfies the axioms. Since the axioms are categorical (all models are isomorphic), you can prove theorems in the model. Doing axiomatic proofs in geometry can be grueling if you insist on justifying every step by an axiom or previous result. When I teach geometry, I try to treat the axioms with a light touch."

I responded to this

"Thanks a lot. It certainly explains why I couldn’t figure this out on my own. An isometry of the hyperbolic plane implies the existence a metric on it. Where does the metric come from? In my reading the formula for the metric seems very ad hoc. "

He got back saying —

"Pick two points on a line and call one 0 and the other 1. By ruler and compass, you can then mark off points on the line that correspond to all rational numbers. But Hilbert also has an axiom of completeness, which gives a bijection between the line and the set of real numbers.

The crucial thing about the isometry group of the plane is that it transitive in the sense of group actions, so that if something happens at one point, then the same thing happens at any other point.

The method explained in my previous email gives a metric on the plane which seems a bit ad-hoc. But one can prove that any two metrics constructed this way are positive real number multiples of each other. "

We don’t understand amyloid very well

I must admit I was feeling pretty snarky about our understanding of amyloid and Alzheimer’s after the structure of Abeta42 was published.  In particular the structure explained why the alanine 42–> threonine 42 mutation was protective against Alzheimer’s disease while the alanine 42 –> valine 42 mutation increases the risk.  That’s all explained in the last post — — but a copy will appear at the end.

In that post I breathlessly hoped for the structure of aBeta40 which is known to be less toxic to neurons.  Well it’s here and it shows how little we understand about what does and what doesn’t form amyloid.  The structure appears in a paper about the amyloid formed by another protein (FUS) to be described later — Cell 171, 615–627, October 19, 2017 — figure 7 p. 624.

Now all Abeta40 lacks are the last 2 amino acids of Abeta42 — isoleucine at 41 and alanine at 42.  So solve the Schrodinger equation for it, and stack it up so it forms amyloid, or use your favorite molecular dynamics or other modeling tool.  Take a guess what it looks like.

Abeta42 is a dimer, a beta40 is a trimer, even though the first 40 amino acids of both are identical.

It gets worse. FUS (FUsed in Sarcoma) is a 526 amino acid protein which binds to RNA and is mostly found in the nucleus.  Neurologists are interested in it because over 50 mutations in have been found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).   FUS contains a low complexity domain (LCD) of 214 amino acids, 80% of which are one of 4 amino acids (glycine, serine, glutamine and tyrosine).  At high protein concentrations this domain of FUS forms long unbundled fibrils with the characteristic crossBeta structure of amyloid.  Only 57/214 of the LCD amino acids are part of the structured core of the amyloid — the rest are disordered.

Even worse the amino acids forming the amyloid core (#39 -#95) are NOT predicted by a variety of computational methods predicting amyloid formation (Agrescan, FISH, FOLDamyloid, Metamyl, PASTA 2.0).  The percentages of gly, ser, gln and tyr in the core forming region are pretty much the same as in the whole protein.  The core forming region has no repeats longer than 4 amino acids.

The same figure 7 has the structure of the amyloid formed by alpha-synuclein, which accumulates in the Lewy bodies of Parkinson’s disease.  It just has one peptide per layer of amyloid.

When you really understand something you can predict things, not just describe them as they are revealed.


Abeta42 at last

It’s easy to see why cryoEM got the latest chemistry Nobel.  It is telling us so much.  Particularly fascinating to me as a retired neurologist is the structure of the Abeta42 fibril reported in last Friday’s Science (vol. 358 pp. 116 – 119 ’17).

Caveats first.  The materials were prepared using an aqueous solution at low pH containing an organic cosolvent — so how physiologic could the structure actually be?  It probably is physiologic as the neurotoxicity of the fibrils to neurons in culture was the same as fibrils grown at neutral pH.  This still isn’t the same as fibrils grown in the messy concentrated chemical soup known as the cytoplasm.  Tending to confirm their findings is the fact that NMR and Xray diffraction on the crystals produced the same result.

The fibrils were unbranched and microns long (implying at least 2,000 layers of the beta sheets to be described).  The beta sheets stack in parallel and in register giving the classic crossBeta sheet structure.  They were made of two protofilaments winding around each other.  Each protofilament contains all 42 amino acids of Abeta42 and all of them form a completely flat beta sheet structure.

Feast your eyes on figure 2 p. 117.  In addition to showing the two beta sheets of the two protofilaments, it shows how they bind to each other.  Aspartic acid #1 of one sheet binds to lysine #28 of the other.  Otherwise the interface is quite hydrophobic.  Alanine2 of one sheet binds to alanine42 of the other, valine39 of one sheet binds to valine 39 of the other.  Most importantly isoLeucine 41 of one sheet binds to glycine38 of the other.

This is important since the difference between the less toxic Abeta40 and the toxic Abeta 42 are two hydrophobic amino acids Isoleucine 41 and Alanine 42.  This makes for a tighter, longer, more hydrophobic interface between the protofilaments stabilizing them.

That’s just a guess.  I can’t wait for work on Abeta40 to be reported at this resolution.

A few other points.  The beta sheet of each protomer is quite planar, but the planes of the two protomers are tilted by 10 degrees accounting for the helicity of the fibril. The fibril is a rhombus whose longest edge is about 70 Angstroms.

Even better the structure explains a mutation which is protective against Alzheimer’s.  This remains the strongest evidence (to me at least) that Abeta peptides are significantly involved in Alzheimer’s disease, therapeutic failures based on this idea notwithstanding.  The mutation is a change of alanine2 to threonine which can’t possibly snuggle up hydrophobically to isoleucine nearly as well as alanine did. This should significantly weaken the link between the two protofilaments and make fibril formation more difficult.

The Abeta structure of the paper also explains another mutation. This one increases the risk of Alzheimer’s disease (like many others which have been discovered).  It involves the same amino acid (alanine2) but this time it is changed to the morehydrophobic valine, probably resulting in a stronger hydrophobic interaction with isoLeucine41 (assuming that valine’s greater bulk doesn’t get in the way sterically).

Wonderful stuff to think and speculate about, now that we actually have some solid data to chew on.

Collusion !


With apologies to West Side Story (and Maria)


I’ve just found a thing called collusion

And suddenly that game

will never be the same

To me

Collusion !

I’ve just found the source of collusion

And suddenly I’ve found

How wonderful a source can be

Collusion !

Say it loud and there’s Hillary running

Say it soft to the media, it’s stunning


I’ll never stop saying collusion


The most beautiful sound I ever heard

WASHINGTON — The presidential campaign of Hillary Clinton and the Democratic National Committee paid for research that was included in a dossier made public in January that contained salacious claims about connections between Donald J. Trump, his associates and Russia.

A spokesperson for a law firm said on Tuesday that it had hired Washington-based researchers last year to gather damaging information about Mr. Trump on numerous subjects — including possible ties to Russia — on behalf of the Clinton campaign and the D.N.C.

The revelation, which emerged from a letter filed in court on Tuesday, is likely to fuel new partisan attacks over federal and congressional investigations into Russia’s attempts to disrupt last year’s election and whether any of Mr. Trump’s associates assisted in the effort.

Here’s a link to the whole article —

Abeta raises its head again

Billions have been spent (and lost) by big Pharma on attempts to decrease Abeta peptide in the brain as a therapy for Alzheimer’s. Yet the theory that Abeta has something to do with Alzheimer’s won’t die because it is so compelling.

Here’s another example [Neuron vol. 96 pp. 355 – 372 ’17 ] Neurons in hippocampal slices stop forming new synapses when exposed to Abeta.  We think that synapse formation and elimination is going on all the time in our brains — it certainly is in mice.  For details see an excellent review [ Neuron vol. 96 pp. 43 – 55 ’17 ].  This is thought to be important in learning, something lost in Alzheimer’s as well as old memories. Two Alzheimer mouse models have shown defects in new synaptic spine formation.

Even better the authors found what Abeta is binding to — a well known brain protein — Nogo receptor 1 (Ngr1).  When it was knocked down in the slice (by bolistic short hairpin RNA infererence — shRNAi), spines started reforming.

So the work may explain some of the problems in Alzheimer’s disease but it says nothing about the neuronal loss which is also found.

Also, there is something fishy about the results.  The Abeta preparation used in the experiment was mostly oligomers of about 100 monomers (with a molecular mass of 500 kiloDaltons).  Monomers had no effect.  It is much easier to conceptualize a monomer binding to a receptor than an oligomer.  However, oligomer binding would tend to cluster receptors, something important in immune responses.

The strongest evidence for Abeta in my opinion is the fact that certain mutations PROTECT against Alzheimer’s — and given the structure just worked out we have a plausible explanation of just how this works — for details see —


Forgotten but not gone

Life is said to have originated in the RNA world.  We all know about the big 3 important RNAs for the cell, mRNA, ribosomal RNA and transfer RNA.  But just like the water, sewer, power and subway systems under Manhattan, there is another world down there in the cell which doesn’t much get talked about.  These are RNAs, whose primary (and possibly only) function is to interact with other RNAs.

Start with microRNAs (of which we have at least 1,500 as of 12/12).  Their function is to bind to messenger RNA (mRNA) and inhibit translation of the mRNA into protein.  The effects aren’t huge, but they are a more subtle control of protein expression, than the degree of transcription of the gene.

Then there are ceRNAs (competitive endogenous RNAs) which have a large number of binding sites for microRNAs — humans have a variety of them all with horrible acronyms — HULC, PTCSC3 etc. etc. They act as sponges for microRNAs keeping them bound and quiet.

Then there are circular RNAs.  They’d been missed until recently, because typical RNA sequencing methods isolate only RNAs with characteristic tails, and a circular RNA doesn’t have any.  One such is called CiRS7/CDR1) which contain 70 binding sites for one particular microRNA (miR-7).  They are unlike to be trivial.  They are derived from 15% of actively transcribed genes.  They ‘can be’ 10 times as numerous as linear RNAs (like mRNA and everything else) — probably because they are hard to degrade < Science vol. 340 pp. 440 – 441 ’17 >. So some of them are certainly RNA sponges — but all of them?

The latest, and most interesting class are the nonCoding RNAs found in viruses. Some of them function to attack cellular microRNAs and help the virus survive. Herpesvirus saimiri a gamma-herpes virus establishes latency in the T lymphocytes of New World primates, by expressing 7 small nuclear uracil-rich nonCoding RNAs (called HSURs).  They associate with some microRNAs, and rather than blocking their function act as chaperones < Nature vol. 550 pp. 275 – 279 ’17 >.  They HSURs also bind to some mRNAs inhibiting their function — they do this by helping miR-16 bind to their targets — so they are chaperones.  So viral Sm-class RNAs may function as microRNA adaptors.

Do you think for one minute, that the cell isn’t doing something like this.

I have a tendency to think of RNAs as always binding to other RNAs by classic Watson Crick base pairing — this is wrong as a look at any transfer RNA structure will show.  Far more complicated structures may be involved, but we’ve barely started to look.

Then there are the pseudogenes, which may also have a function, which is to be transcribed and sop up microRNAs and other things — I’ve already written about this —  Breast cancer cells think one (PTEN1) is important enough to stop it from being transcribed, even though it can’t be translated into protein.

Does she or doesn’t she? Only her geneticist knows for sure

Back in the day there was a famous ad for Claroil — Does she or doesn’t she? Only her hairdresser knows for sure.  Now it’s the geneticist who can sequence genes for Two Pore Channels in pigment forming cells (melanocytes) who really knows.

Except for redheads, skin and hair color is determined by how much eumelanin you have.  All human melanins are  polymers of oxidation products of tyrosine (DOPA, DOPAquinone) and indole 5,6 quinone, so its chemical structure isn’t certain.  It is made inside a specialized organelle of the melanocyte called (logically enough) the melanosome.

There is all sorts of interesting chemistry and physiology involved.  In particular a melanosome protein called Pmel17 adopts an amyloid-like structure (so not all amyloid is bad !) for the construction of melanin.  The crucial enzyme oxidizing tyrosine is tyrosinase, and its activity strongly depends on pH, being most active at pH 7 (neutral pH).

In the melanosome membrane is found TPC2, which helps control ion flow in and out of the melanosome.  Two mutations Methionine #484 –> Leucine (or M484L) and Glycine #734 –> Glutamic acid (G734E) are associated with a shift from brown to blond.  You have blond hair if your melanosomes make less melanin.  Both mutations result in an increase in TPC2 activity resulting in lower pH, lower tyrosinase activity and less melanin in the melanosome — voila — a blond.

So it doesn’t take a big (one amino acid in over 734) change in the huge TCP2 protein for the shift to occur.

A possibly useful computer tip and two social notes

Since the computer was down last week, no science to report, but here’s a possibly useful computer tip and two social notes.

If you’ve been using computers as long as we have (30+ years), you were probably told that it was better to leave the computer on all the time rather than turning the power off and on.   Not so any more — the Apple tech who fixed it told me it should be shut down then rebooted once a week.

Two narratives beloved by the mainstream press since the loss by their candidate  suffered major body blows the past week.

Narrative #1. Trump is a Nazi.  Surely you remember the way a far-Right rally was reported shortly after the election.  Read all about it as reported in the Atlantic —  It got a lot of press, here and elsewhere.  There may have been all of 300 people there.  Then there were his unfortunate comments after Charlottesville.

Unfortunately for the meme — the following appeared this week in the New York Times  —

WASHINGTON — The Trump administration announced on Thursday that it would withdraw from Unesco, the United Nations cultural organization, after years of the United States distancing itself because of what it called the group’s “anti-Israel bias.”

Here’s the link —

Narrative #2:  The Russians did everything they could to swing the election to Trump.  Well we finally are finding out just what the Russians actually did — this from Facebook and Cheryl Sandberg (hardly friends of Trump).

The following is from a Wall Street Journal article appearing 13 October 2017.  Here is the link —

“Two accounts that Facebook Inc. FB 0.69% said appear to have ties to Russian operatives amassed more than half a million followers in the past couple of years with posts, ads and events that stoked strong emotions over issues including race and immigration.

Most followers never suspected that people with possible Russian ties were behind the accounts—except for a few users who interacted in real life with the people running the sites.

Some users said the content from these accounts seemed like something their peers would share. “Blacktivist,” an account that supported causes in the black community and used hashtags such as #BlackLivesMatter, frequently posted videos of police allegedly shooting unarmed black men. ”

If the Russians were trying to elect Trump, do you think they would have thought inflaming a group that votes overwhelmingly Democratic was a good idea?.

Basically they were trying to inflame the body politic with divisive material.

The Voice of America had a similar effect behind the Iron Curtain.  The difference, of course, is that our source was quite undisguised.

The Russian government is not our friend.  I’m glad my grandparents got out of the Baltics and Poland in the late 19th century.