Happy 4th of July to the world’s second worst economist — Larry Summers

Any scientist who made such massively incorrect explanations and predictions would be laughed out of town. Not so, one of the ‘smartest guys in the room’ and former Harvard President Larry Summers.

Here’s Larry in December 2013 coming up with ‘secular stagnation’ to explain why the recovery from recession was one of the weakest and slowest on record and why this was the way things would be, and we’d better get used to it.

Here’s the link — http://larrysummers.com/2013/12/15/why-stagnation-might-prove-to-be-the-new-normal/

Here’s a direct quote from the beginning of the article

” Is it possible that the US and other major global economies might not return to full employment and strong growth without the help of unconventional policy support? I raised that notion – the old idea of “secular stagnation” – recently in a talk hosted by the International Monetary Fund.

My concern rests on a number of considerations. First, even though financial repair had largely taken place four years ago, recovery has only kept up with population growth and normal productivity growth in the US, and has been worse elsewhere in the industrial world.

Second, manifestly unsustainable bubbles and loosening of credit standards during the middle of the past decade, along with very easy money, were sufficient to drive only moderate economic growth.

Third, short-term interest rates are severely constrained by the zero lower bound: real rates may not be able to fall far enough to spur enough investment to lead to full employment.

Fourth, in such situations falling wages and prices or lower-than-expected are likely to worsen performance by encouraging consumers and investors to delay spending, and to redistribute income and wealth from high-spending debtors to low-spending creditors.”

There’s more but (mercifully) this is enough to give you the gist.

Then we have Larry from May 2017 — here’s the link

What history tells us about Trump’s budget fantasy

Here’s Larry talking about the Trump claim of 3% economic growth “The Trump economic team has not engaged in serious analysis or been in dialogue with those who are capable of it so they have had nothing to say in defense of their forecast except extravagant claims for their policies. Taking their supply-side perspective, do they really believe that through tax cuts and deregulation they are going to accomplish more than Ronald Reagan, who after all reduced the top tax rate from 70 to 28 percent? Between 1981 and 1988, GDP per adult grew by an average of 2.5 percent, distinctly slower than what they are forecasting. Even this figure reflects a substantial cyclical tail wind from the decline in unemployment from 7.6 percent to 5.5 percent (which from Okun’s law implies adding about half a percent to GDP growth) — something unavailable in the present context.”

Now follow the following link to the actual numbers — https://www.statista.com/statistics/188185/percent-chance-from-preceding-period-in-real-gdp-in-the-us/.

At the time Larry was writing in 2nd quarter of 2017, economic growth that quarter would hit 3% right under his nose.

Of the 8 quarters from then through the 1st quarter of 2019 (2nd quarter results not in yet), economic growth was 3% or greater in half, and always over 2.5 in the other half.

OK back to the science in subsequent posts.

For the world’s worst economist  — see https://luysii.wordpress.com/2019/07/03/happy-fourth-of-july-to-the

Advertisements

‘Happy Fourth of July to the world’s worst economist — Paul Krugman

 3 July 2019

https://www.msn.com/en-us/money/markets/stocks-close-at-record-highs-on-hopes-for-a-rate-cut-this-month/ar-AADEIuX

Stocks closed at record highs Wednesday as traders bet on a potential rate cut from the Federal Reserve later this month after the release of weaker-than-expected economic data.The Dow gained 179 points, notching intraday and closing all-time highs. The Nasdaq advanced 0.75%.The S&P 500 also rose 0.75% as the real estate and consumer sectors powered the broad index to record levels. Tech boosted the index, rising 0.7% to a record high. The S&P 500 closed just 0.1% below 3,000.

 

 

 

 

 

 

Here is Paul Krugman Nobel Laureate in Economics writing in the New York Times 9 November 2016, the day after Trump was elected

“It really does now look like President Donald J. Trump, and markets are plunging. When might we expect them to recover?

Frankly, I find it hard to care much, even though this is my specialty. The disaster for America and the world has so many aspects that the economic ramifications are way down my list of things to fear.

Still, I guess people want an answer: If the question is when markets will recover, a first-pass answer is never.

Under any circumstances, putting an irresponsible, ignorant man who takes his advice from all the wrong people in charge of the nation with the world’s most important economy would be very bad news. What makes it especially bad right now, however, is the fundamentally fragile state much of the world is still in, eight years after the great financial crisis.

It’s true that we’ve been adding jobs at a pretty good pace and are quite close to full employment. But we’ve been doing O.K. only thanks to extremely low interest rates. There’s nothing wrong with that per se. But what if something bad happens and the economy needs a boost? The Fed and its counterparts abroad basically have very little room for further rate cuts, and therefore very little ability to respond to adverse events.

Now comes the mother of all adverse effects — and what it brings with it is a regime that will be ignorant of economic policy (Luysii — praise be to God) and hostile to any effort to make it work. Effective fiscal support for the Fed? Not a chance. In fact, you can bet that the Fed will lose its independence, and be bullied by cranks.

So we are very probably looking at a global recession, with no end in sight. I suppose we could get lucky somehow. But on economics, as on everything else, a terrible thing has just happened.”

If that wasn’t enough here’s Krugman in 2010 writing about ‘peak oil

“Oil is back above $90 a barrel. Copper and cotton have hit record highs. Wheat and corn prices are way up. Over all, world commodity prices have risen by a quarter in the past six months.

So what’s the meaning of this surge?

Is it speculation run amok? Is it the result of excessive money creation, a harbinger of runaway inflation just around the corner? No and no.

What the commodity markets are telling us is that we’re living in a finite world, in which the rapid growth of emerging economies is placing pressure on limited supplies of raw materials, pushing up their prices. And America is, for the most part, just a bystander in this story.

Some background: The last time the prices of oil and other commodities were this high, two and a half years ago, many commentators dismissed the price spike as an aberration driven by speculators. And they claimed vindication when commodity prices plunged in the second half of 2008.

But that price collapse coincided with a severe global recession, which led to a sharp fall in demand for raw materials. The big test would come when the world economy recovered. Would raw materials once again become expensive?

Well, it still feels like a recession in America. But thanks to growth in developing nations, world industrial production recently passed its previous peak — and, sure enough, commodity prices are surging again.

This doesn’t necessarily mean that speculation played no role in 2007-2008. Nor should we reject the notion that speculation is playing some role in current prices; for example, who is that mystery investor who has bought up much of the world’s copper supply? But the fact that world economic recovery has also brought a recovery in commodity prices strongly suggests that recent price fluctuations mainly reflect fundamental factors.

What about commodity prices as a harbinger of inflation? Many commentators on the right have been predicting for years that the Federal Reserve, by printing lots of money — it’s not actually doing that, but that’s the accusation — is setting us up for severe inflation. Stagflation is coming, declared Representative Paul Ryan in February 2009; Glenn Beck has been warning about imminent hyperinflation since 2008.

Yet inflation has remained low. What’s an inflation worrier to do?

One response has been a proliferation of conspiracy theories, of claims that the government is suppressing the truth about rising prices. But lately many on the right have seized on rising commodity prices as proof that they were right all along, as a sign of high overall inflation just around the corner.

You do have to wonder what these people were thinking two years ago, when raw material prices were plunging. If the commodity-price rise of the past six months heralds runaway inflation, why didn’t the 50 percent decline in the second half of 2008 herald runaway deflation?

Inconsistency aside, however, the big problem with those blaming the Fed for rising commodity prices is that they’re suffering from delusions of U.S. economic grandeur. For commodity prices are set globally, and what America does just isn’t that important a factor.

In particular, today, as in 2007-2008, the primary driving force behind rising commodity prices isn’t demand from the United States. It’s demand from China and other emerging economies. As more and more people in formerly poor nations are entering the global middle class, they’re beginning to drive cars and eat meat, placing growing pressure on world oil and food supplies.

And those supplies aren’t keeping pace. Conventional oil production has been flat for four years; in that sense, at least, peak oil has arrived. True, alternative sources, like oil from Canada’s tar sands, have continued to grow. But these alternative sources come at relatively high cost, both monetary and environmental.

Also, over the past year, extreme weather — especially severe heat and drought in some important agricultural regions — played an important role in driving up food prices. And, yes, there’s every reason to believe that climate change is making such weather episodes more common.

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. This won’t bring an end to economic growth, let alone a descent into Mad Max-style collapse. It will require that we gradually change the way we live, adapting our economy and our lifestyles to the reality of more expensive resources.

But that’s for the future. Right now, rising commodity prices are basically the result of global recovery. They have no bearing, one way or another, on U.S. monetary policy. For this is a global story; at a fundamental level, it’s not about us.  ”

Nonetheless Krugman can currently be found on the editorial pages of the New York Times authoritatively pronouncing on matters political

For the world’s second worse economist please see https://luysii.wordpress.com/2019/07/04/happy-4th-of-july-to-the-worlds-second-worst-economist-larry-summers/

How general anesthesia works

People have been theorizing how general anesthesia works since there has been general anesthesia.  The first useful one was diethyl ether (by definition what lipids dissolve in).  Since the brain has the one of the highest fat contents of any organ, the mechanism was obvious to all.  Anesthetics dissolve membranes.  Even the newer anesthetics look quite lipophilic — isoflurane CF3CHCL O CF2H screams (to the chemist) find me a lipid to swim in.  One can show effects of lipids on artificial membranes but the concentrations to do so are so high they would be lethal.

Attention shifted to the GABA[A] receptor, because anesthetics are effective in potentiating responses to GABA  — all the benzodiazepines (valium, librium) which bind to it are sedating.  Further evidence that a protein is involved, is that the optical isomers of enflurane vary in anesthetic potency (but not by very much — only 60%).  Lipids (except cholesterol) just aren’t optically active.  Interestingly, alfaxolone is a steroid and a general anesthetic as well.

Well GABA[A] is an ion channel, meaning that its amino acids form alpha helices which span the membrane (and create a channel for ion flow).  It would be devilishly hard to distinguish binding to the transmembrane part from binding to the membrane near it. [ Science vol. 322 pp. 876 – 880 2008 ] Studied 4 IV anesthetics (propofol, ketamine, etomidate, barbiturate) and 4 gasses (nitrous  oxide, isoflurance, devoflurane, desflurane) and their effects on 11 ion channels — unsurprisingly all sorts of effects were found — but which ones are the relevant.

All this sort of stuff could be irrelevant, if a new paper is actually correct [ Neuron vol. 102 pp. 1053 – 1065 ’19 ].  The following general anesthetics (isoflurane, propofol, ketamine and desmedtomidine) all activate cells in the hypothalamus (before this anesthetics were thought to work by ultimately inhibiting neurons).  They authors call these cells AANs (Anesthesia Activated Neurons).

They are found in the hypothalamus and contain ADH.  Time for some anatomy.  The pituitary gland is really two glands — the adenohypophysis which secretes things like ACTH, TSH, FSH, LH etc. etc, and the neurohypophysis which secretes oxytocin and vasopressin (ADH) directly into the blood (and also into the spinal fluid where it can reach other parts of the brain.  ADH release is actually from the axons of the hypothalamic neurons.  The AANs activated by the anesthetics release ADH.

Of course the workers didn’t stop there — they stimulated the neurons optogenetically and put the animals to sleep. Inhibition of these neurons shortened the duration of general anesthesia.

Fascinating (if true).  The next question is how such chemically disparate molecules can activate the AANs.  Is there a common receptor for them, and if so what is it?

Happy fiscal new year !

A sad (but brilliant) paper about autophagy

Over the past several decades I’ve accumulated a lot of notes on autophagy (> 125,000 characters).  It’s obviously important, but in a given cell or disease (cancer, neurodegeneration) whether it helps a cell die gracefully or is an executioner is far from clear.  Ditto for whether enhancing or inhibiting it in a given situation would be helpful (or hurtful).

A major reason for the lack of clarity despite all the work that’s been done can be found in the following excellent paper [ Cell vol. 177 pp.1682 – 1699 ’19 ].  Some 41 proteins are involved in autophagy in yeast and more in man.  Many are described as ATGnn (AuTophagy Gene nn).

Autophagy is a complicated business: forming a membrane, then engulfing various things, then forming a vacuole,  then fusing with the lysosome so that the engulfees are destroyed.

The problem with previous work is that if a protein was found to be important in autophagy, it was assumed to have that function and that function only.   The paper shows that core autophagy proteins are involved in (at least) 5 other processes (endocytosis, melanocyte formation, cytokinesis, LC3 assisted phagocytosis and translocation of vesicles from the Golgi to the endoplasmic reticulum).

Experiments deleting or  increasing a given ATGnn were assumed to produce their biological effects by affecting autophagy.

The names are unimportant.  Here is a diagram of 6 autophagy proteins forming a complex producing autophagy

1 2 3

4 5 6

So 2 binds to 1, 3 and 5

But in endocytosis

1 2 3

5

form an important complex

In cytokinesis the complex formed by

2 3

5

is important.

Well you get the idea.  Knocking out 2 has cellular effects on far more than autophagy.  So a lot of work has to be re-thought and probably repeated.

Notice that all 6 functions involve movement of membranes.  So just regard the 6 proteins as gears of different diameters which can form the guts of different machines as they combine with each other (and proteins specific to the other 5 processes mentioned) to move things around in the cell.

Set points, a mechanism for one at last.

Human biology is full of set points.  Despite our best efforts few can lose weight and keep it off.  Yet few count calories and try to eat so their weight is constant.  Average body temperature is pretty constant (despite daily fluctuations).  Neuroscientists are quite aware of synaptic homeostasis.

And yet until now, despite their obvious existence, all we could do is describe setpoints, not explain the mechanisms behind them.  Most ‘explanations’ of them were really descriptions.

Here is an example:

Endocrinology was pretty simple in med school back in the 60s. All the target endocrine glands (ovary, adrenal, thyroid, etc.) were controlled by the pituitary; a gland about the size of a marble sitting an inch or so directly behind the bridge of your nose. The pituitary released a variety of hormones into the blood (one or more for each target gland) telling the target glands to secrete, and secrete they did. That’s why the pituitary was called the master gland back then.  The master gland ruled.

Things became a bit more complicated when it was found that a small (4 grams or so out of 1500) part of the brain called the hypothalamus sitting just above the pituitary was really in control, telling the pituitary what and when to secrete. Subsequently it was found that the hormones secreted by the target glands (thyroid, ovary, etc.) were getting into the hypothalamus and altering its effects on the pituitary. Estrogen is one example. Any notion of simple control vanished into an ambiguous miasma of setpoints, influences and equilibria. Goodbye linearity and simple notions of causation.

As soon as feedback (or simultaneous influence) enters the picture it becomes like the three body problem in physics, where 3 objects influence each other’s motion at the same time by the gravitational force. As John Gribbin (former science writer at Nature and now prolific author) said in his book ‘Deep Simplicity’, “It’s important to appreciate, though, that the lack of solutions to the three-body problem is not caused by our human deficiencies as mathematicians; it is built into the laws of mathematics.” The physics problem is actually much easier than endocrinology, because we know the exact strength and form of the gravitational force.

A recent paper [ Neuron vol. 102 pp. 908 – 910, 1009 – 1024 ’19 ] is the first to describe a mechanism behind any setpoint and one of particular importance to the brain (and possibly to epilepsy as well).

The work was done at significant remove from the brain — hippocampal neurons grown in culture.  They synapse with each other, action potentials are fired and postsynaptic responses occur.  The firing rate is pretty constant.  Block a neurotransmitter receptor, and the firing rate increases to keep postsynaptic responses the same.  Increase the amount of neurotransmitter released by an action potential (neuronal firing) and the firing rate descreases.  This is what synaptic homeostasis is all about.  It’s back to baseline transmission across the synapse regardless of what we do, but we had no idea how this happened.

Well we still don’t but at least we know what controls the rate at which hippocampal neurons fire in culture (e.g. the setpoint).  It has to do with an enzyme (DHODH) and mitochondrial calcium levels.

DHODH stands for Di Hydro Orotate DeHydrogenase, an enzyme in mitochondria involved in electron transfer (and ultimately energy production).   Inhibit the enzyme (or decrease the amount of DHODH around) and the neurons fire less.  What is interesting about this, that all that is changed is the neuronal firing rate (e.g. the setpoint is changed).  However, there is no change in the intrinsic excitability of the neurons (to external electrical stimulation), the postsynaptic response to transmitter, the number of mitochondria, presynaptic ATP levels etc.

Even better, synaptic homeostasis is preserved.  Manipulations increasing or decreasing the firing rate are never permanent, so that changes back to the baseline rate occur.

Aside from its intrinsic intellectual interest, this work is potentially quite useful.  The firing rate of neurons in people with epilepsy is increased.  It is conceivable that drugs inhibiting DHODH would treat epilepsy.  Such drugs (teriflunomide) are available for the treatment of multiple sclerosis.

The paper has some speculation of how DHODH inhibition would lead to decreased neuronal firing (changes in mitochondrial calcium levels etc. etc) which I won’t go into here as it’s just speculation (but at least plausible spectulation).

Will flickering light treat Alzheimer’s disease ? — Take II

30 months ago, a fascinating paper appeared in which flickering light improved a mouse model of Alzheimer’s disease.  The authors (MIT mostly) have continued to extend their work.   Here is a copy of the post back then.  Their new work is summarized after the ****

Big pharma has spent zillions trying to rid the brain of senile plaques, to no avail. A recent paper shows that light flickering at 40 cycles/second (40 Hertz) can do it — this is not a misprint [ Nature vol. 540 pp. 207 – 208, 230 – 235 ’16 ]. As most know the main component of the senile plaque of Alzheimer’s disease is a fragment (called the aBeta peptide) of the amyloid precursor protein (APP).

The most interesting part of the paper showed that just an hour or so of light flickering at 40 Hertz temporarily reduced the amount of Abeta peptide in visual cortex of aged mice. Nothing invasive about that.

Should we try this in people? How harmful could it be? Unfortunately the visual cortex is relatively unaffected in Alzheimer’s disease — the disease starts deep inside the head in the medial temporal lobe, particularly the hippocampus — the link shows just how deep it is -https://en.wikipedia.org/wiki/Hippocampus#/media/File:MRI_Location_Hippocampus_up..png

You might be able to do this through the squamous portion of the temporal bone which is just in front of and above the ear. It’s very thin, and ultrasound probes placed here can ‘see’ blood flowing in arteries in this region. Another way to do it might be a light source placed in the mouth.

The technical aspects of the paper are fascinating and will be described later.

First, what could go wrong?

The work shows that the flickering light activates the scavenger cells of the brain (microglia) and then eat the extracellular plaques. However that may not be a good thing as microglia could attack normal cells. In particular they are important in the remodeling of the dendritic tree (notably dendritic spines) that occurs during experience and learning.

Second, why wouldn’t it work? So much has been spent on trying to remove abeta, that serious doubt exists as to whether excessive extracellular Abeta causes Alzheimer’s and even if it does, would removing it be helpful.

Now for some fascinating detail on the paper (for the cognoscenti)

They used a mouse model of Alzheimer’s disease (the 5XFAD mouse). This poor creature has 3 different mutations associated with Alzheimer’s disease in the amyloid precursor protein (APP) — these are the Swedish (K670B), Florida (I716V) and London (V717I). If that wasn’t enough there are two Alzheimer associated mutations in one of the enzymes that processes the APP into Abeta (M146L, L286V) — using the single letter amino acid code –http://www.biochem.ucl.ac.uk/bsm/dbbrowser/c32/aacode.html.hy1. Then the whole mess is put under control of a promoter particularly active in mice (the Thy1 promoter). This results in high expression of the two mutant proteins.

So the poor mice get lots of senile plaques (particularly in the hippocampus) at an early age.

The first experiment was even more complicated, as a way was found to put channelrhodopsin into a set of hippocampal interneurons (this is optogenetics and hardly simple). Exposing the channel to light causes it to open the membrane to depolarize and the neuron to fire. Then fiberoptics were used to stimulate these neurons at 40 Hertz and the effects on the plaques were noted. Clearly a lot of work and the authors (and grad students) deserve our thanks.

Light at 8 Hertz did nothing to the plaques. I couldn’t find what other stimulation frequencies were used (assuming they were tried).

It would be wonderful if something so simple could help these people.

For other ideas about Alzheimer’s using physics rather than chemistry please see — https://luysii.wordpress.com/2014/11/30/could-alzheimers-disease-be-a-problem-in-physics-rather-than-chemistry/

****

The new work appears in two papers.

First [ Cell vol. 1777 pp. 256 – 271 ’19 ] 7 days of auditory tone stimuli at 40 cycles/second (40 Hertz) for just one hour a day reduced amyloid in the auditory cortex of the same pathetic mice described above (the 5XFAD mice).  They call this GENUS (Gamma ENtrainment Using sensory Stimuli).  Neurologists love to name frequencies in the EEG, and the 40 Hertz is in the gamma range.

The second paper [ Neuron vol. 102 pp. 929 – 943 ’19 ] is even better.  Alzheimer’s disease is characterized by two types of pathology — neurofibrillary tangles inside the remaining neurons and the senile plaque outside them.  The tangles are made of the tau protein, the plaques mostly of fragments of the amyloid precursor protein (APP).  The 5XFAD mouse had 3 separate mutations in the APP and two more in the enzyme that chops it up.

The present work looked at the other half of Alzheimer’s the neurofibrillary tangle.  They had mice with the P301S mutation in the tau protein found in a hereditary form of dementia (not Alzheimer’s) and also with excessive levels of CK-p25 which also results in tangles.

Again chronic visual GENUS worked in this (completely different) model of neurodegeneration.

This is very exciting stuff, but I’d love to see a different group of researchers reproduce it.  Also billions have been spent and lost on promising treatments of Alzheimer’s (all based on animal work).

Probably someone is trying it out on themselves or their spouse.  A EE friend notes that engineers have been trying homebrew transcranial magnetic and current stimulation using themselves or someone close as guineapigs for years.

Book Review — The Universe Speaks in Numbers

Let’s say that back in the day, as a budding grad student in chemistry you had to take quantum mechanics to see where those atomic orbitals came from.   Say further, that as the years passed you knew enough to read News and Views in Nature and Perspectives in Science concerning physics as they appeared. So you’ve heard various terms like J/Psi, Virasoro algebra, Yang Mills gauge symmetry, Twisters, gluons, the Standard Model, instantons, string theory, the Atiyah Singer theorem etc. etc.  But you have no coherent framework in which to place them.

Then “The Universe Speaks in Numbers” by Graham Farmelo is the book for you.  It will provide a clear and chronological narrative of fundamental physics up to the present.  That isn’t the main point of the book, which is an argument about the role of beauty and mathematics in physics, something quite contentious presently.  Farmelo writes well and has a PhD in particle physics (1977) giving him a ringside seat for the twists and turns of  the physics he describes.  People disagree with his thesis (http://www.math.columbia.edu/~woit/wordpress/?p=11012) , but nowhere have I seen anyone infer that any of Farmelo’s treatment of the physics described in the book is incorrect.

40 years ago, something called the Standard Model of Particle physics was developed.  Physicists don’t like it because it seems like a kludge with 19 arbitrary fixed parameters.  But it works, and no experiment and no accelerator of any size has found anything inconsistent with it.  Even the recent discovery of the Higgs, was just part of the model.

You won’t find much of the debate about what physics should go from here in the book.  Farmelo says just study more math.  Others strongly disagree — Google Peter Woit, Sabine Hossenfelder.

The phenomena String theory predicts would require an accelerator the size of the Milky Way or larger to produce particles energetic enough to probe it.  So it’s theory divorced from any experiment possible today, and some claim that String Theory has become another form of theology.

It’s sad to see this.  The smartest people I know are physicists.  Contrast the life sciences, where experiments are easily done, and new data to explain arrives weekly.

 

 

What is legionella trying to tell us?

10 years out of Med School, a classmate in the Public Health service had to deal with the first recognized outbreak of Legionnaire’s disease, at the Bellevue Stratford hotel in Philly, about one air mile from Penn Med where we went.   The organism wasn’t known at the time and caused 182 cases with 29 deaths.  We’ve learned a lot more about Legionella Pneumophila since 1976 and the organism continues to instruct us.

The most recent lesson concerns one of the 300 or so proteins Legionella injects into a cell it attacks.  This is remarkable in itself.  The organism uses them to hijack various cellular mechanisms to build a home for itself in the cell (the LCV — Legionella Containing Vacuole).  Contrast this with diphtheria which basically uses one protein (diphtheria toxin) to kill the cell.

One of the 300 proteins is called SidJ and looks like a protein kinase (of which our genome has over 500).  However [ Science vol. 364 pp. 787 – 792 ’19 ] shows that SidJ carries out a different different reaction.SidJ is activated by host-cell calmodulin to polyglutamylate the SidE family of ubiquitin (Ub) ligases inhibiting them. Crystal structures of the SidJ-calmodulin complex reveal a protein kinase fold that catalyzes ATP-dependent isopeptide bond formation between the amino group of free glutamate and the gamma carboxyl group in the catalytic center of SidE a ubiquitin ligase.   This, instead of just esterifying the hydroxyl group of serine or threonine or tyrosine with the terminal phosphate of ATP as a kinase is supposed to do.

Why is this important? The only protein known to have polyglutamic acid added to it is tubulin, the protein from which microtubules (neurotubules to the neurologist).  The work is important because some of the 500+ protein kinases in our genome might be doing something else.  Has the chemistry each and every member of the group been studied?  Probably not..

The authors close with “In summary, our results underscore the diversity and catalytic versatility of the protein kinase superfamily. We propose that ATP-dependent ligation reactions may be a common feature among the vast diversity of eukaryotic protein kinase–like enzymes found in nature (25). There are more than 500 protein kinases in humans and our results suggest that they should be ex- amined for alternative activities.”

I couldn’t agree more.

Memorial day war stories

Tomorrow is memorial day, so it’s time for some stories about how various wars have affected family and friends.

First a still living 92 year old vet I met at Harvard Graduate Alumni day a few years ago.  He piloted a landing craft at the Normandy invasion.  After the war he entered Harvard Law, didn’t like it and got a masters in History.  Last seen a month ago, and in great shape having retired from a career that you’d never guess.

OK guess !  What do you think he did?

He was a successful football coach in the NFL — Marv Levy of the Buffalo Bills.

Second, third, fourth and fifth — family members.

Uncle #1 kept it quiet that he was on the Rutgers rifle team, was an officer in the MPs. He was stationed in India and China.  He had a weekly?/monthly? beer ration to distribute to his men and figured out a way to get them cold beer in India in the 1940’s.  Can you guess what he did?

Pilots in India would fly materiel over the hump (Himalayas) to China, in unheated airplanes.  For a cut they’d fly the beer over and back cooling it.  My wife told this story to a friend of hers at a workshop.  Her eyes got wider and wider, saying ‘the beer story’.  Her father had been one of the pilots.

Uncle #2 became an artillery officer, stationed in New Guinea and the Philippines, and later Japan.  In New Guinea one of the men thought he saw something move and fired his rifle (not a gun).  The bullet bounced off a rock coming back, and he and his men fought an hours long battle against the rocks.  He didn’t there was a Japanese soldier within miles.

He was absolutely convinced that the atomic bomb saved his life, as next up was the invasion of Japan. It would have been bloody, even 6 years ago in Kyoto and Osaka I saw little old men wearing caps of the Japanese defense forces.

Uncle #3 was a doc pushed through med school in 3 years (as they all were back then).  He was at the battle of Kasserine Pass in North Africa.  Despite what you may read about it, he said that the generals were quite frightened of Rommel, as reconnaissance was minimal and they had no idea where he was.

As is typical of men who have been in war they didn’t talk about it much.  Uncle #2 also went to Rutgers, and I saw him there in the 90s at a reunion with his roommate a very small man.  Later uncle #2 told me that the little guy had been in the Battle of the Bulge.  I found this amazing and later told uncle #3 about it, who said that he was also in the Battle of the Bulge — this 50 years or so later and the first time I’d heard of it.

The fourth family member was possibly the bravest of all.  He was a German Jew who managed to escape Europe landing in England where he was given a new identity.  He became a commando and was dropped behind enemy lines in France before the Normandy invasion.  Of course he spoke perfect German, but you can only imagine what might have happened had he been caught and they found out what he was.  He became a family member after the war as he married my father’s cousin. A very mild mannered individual.

All four led productive lives after the service, with no PTSD disability etc. etc. I think one used the GI bill.  Just as the war changed the orientation of Herman Wouk, so did it change uncle #3 who lies buried in a military cemetery.

Which brings me up to the Vietnam war.  A high school classmate who became a dentist was over there in the early years.  The country has a hot dry season and a hot wet season.  They had open air showers to remain comfortable, but it was disconcerting to him to have villagers standing around looking at how hairy we was.  Lots of hair is not a survival value in such a place and the Vietnamese are a relatively hairless lot.

I was an Air Force Captain in the Medical Corps stationed at one of the best army hospitals (Fitzsimons in Denver) because they were short of neurologists.  Now Vietnam is like Chile, a long strip of a country along a coast.  As a result, no wounded soldier was more than 20 minutes away by chopper from a fully equipped surgical field hospital, so the people surviving were far more gravely injured than those in world war II.

I thought we took very good care of our patients, far better than at the University of Colorado Medical Center where I finished up my residency after discharge.  They were fat and happy with the nearest academic medical center 500 miles away (St. Lake City, Omaha etc. etc.) resulting in no competition.

The only brave thing I did  while in the service was writing a letter to the General resigning from the officer’s club, because some little Nazi there refused to let a psych resident from Colorado who was helping us out into the club because he had a beard.  I can still see the little bastard’s smirk as he said he was ‘just following orders’.  I was sure I’d be shipped out to Plok Tic or something like it the next day, but the general (who was in the medical Corps) wrote to the resident apologizing and the rule was changed.

Now I don’t want to fight the Vietnam war again, but there is one further thing you should know.  The tour of duty in Vietnam was 1 year, but the term of service for docs was two.  (Back then I asked one of my uncles what the term of service was in WWII — what do you think it was?   Answer — until the war was over). The people coming back after one year pretty much had their pick of the best places, and many wound up at Fitzsimons.  I talked (and worked with) a lot of them.  These were not career military with an axe to grind.  Not one of them thought we were winning.  This was ’68 – ’70 when I was in.

RIPK1

The innate immune system is intrinsically fascinating, dealing with invaders long before antibodies or cytotoxic cells are on the scene.  It is even more fascinating to a chemist because it works in part by forming amyloid inside the cell.  And you thought amyloid was bad.

The system becomes even more fascinating because blocking one part of it (RIPK1) may be a way to treat a variety of neurologic diseases (ALS, MS,Alzheimer’s, Parkinsonism) whose treatment could be improved to put it mildly.

One way to deal with an invader which has made it inside the cell, is for the cell to purposely die.  More and more it appears that many forms of cell death are elaborately programmed (like taking down a stage set).

Necroptosis is one such, distinct from the better known and studied apoptosis.   It is programmed and occurs when a cytokine such as tumor necrosis factor binds to its receptor, or when an invader binds to members of the innate immune system (TLR3, TLR4).

The system is insanely complicated.  Here is a taste from a superb review — unfortunately probably behind a paywall — https://www.pnas.org/content/116/20/9714 — PNAS vol. 116 pp. 9714 – 9722 ’19.

“RIPK1 is a multidomain protein comprising an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The intermediate domain of RIPK1 contains an RHIM [receptor interacting protein (rip) homotypic interaction motif] domain which is important for interacting with other RHIM-containing proteins such as RIPK3, TRIF, and ZBP1. The C-terminal DD mediates its recruitment by interacting with other DD-containing proteins, such as TNFR1 and FADD, and its homodimerization to promote the activation of the N-terminal kinase domain. In the case of TNF-α signaling, ligand-induced TNFR1 trimerization leads to the assembly of a large receptor-bound signaling complex, termed Complex I, which includes multiple adaptors (TRADD, TRAF2, and RIPK1), and E3 ubiquitin ligases (cIAP1/2, LUBAC complex).”

Got that?  Here’s a bit more

“RIPK1 is regulated by multiple posttranslational modifications, but one of the most critical regulatory mechanisms is via ubiquitination. The E3 ubiquitin ligases cIAP1/2 are recruited into Complex I with the help of TRAF2 to mediate RIPK1 K63 ubiquitination. K63 ubiquitination of RIPK1 by cIAP1/2 promotes the recruitment and activation of TAK1 kinase through the polyubiquitin binding adaptors TAB2/TAB3. K63 ubiquitination also facilitates the recruitment of the LUBAC complex, which in turn performs M1- type ubiquitination of RIPK1 and TNFR1. M1 ubiquitination of Complex I is important for the recruitment of the trimeric IκB kinase complex (IKK) through a polyubuiquitin-binding adaptor subunit IKKγ/NEMO . The activation of RIPK1 is inhibited by direct phosphorylation by TAK1, IKKα/β, MK2, and TBK1. cIAP1 was also found to mediate K48 ubiquitination of RIPK1, inhibiting its catalytic activity and promoting degradation.”

So why should you plow through all this?  Because inhibiting RIPK1 reduces oxygen/glucose deprivation induced cell death in neurons, and reduced infarct size in experimental middle cerebral artery occlusion.

RIPK1 is elevated in MS brain, and inhibition of it helps an animal model (EAE).  Mutations in optineurin, and TBK1 leading to familial ALS promote the onset of RIPK1 necroptosis

Inflammation is seen in a variety of neurologic diseases (Alzheimer’s, MS) and RIPK1 is elevated in them.

Inhibitors of RIPK1 are available and do get into the brain.  As of now two RIPK1 inhibitors have made it through phase I human safety trials.

So it’s time to try RIPK1 inhibitors in these diseases.  It is an entirely new approach to them.  Even if it works only in one disease it would be worth it.

Now a dose of cynicism.  Diseased cells have to die one way or another.  RIPK1 may help this along, but it tells us nothing about what caused RIPK1 to become activated.  It may be a biomarker of a diseased cell.  The animal models are suggestive (as they always are) but few of them have panned out when applied to man.