Breaking Secrets

A small way to increase labor power.

Why is inflation so persistently low? Even when the government is on a spending and tax-forgiveness binge, and interest rates have been rock-bottom for a decade? I have been spending some time with a left-inflected economics textbook from the 80's by Samuel Bowles et al., which gives a view of our situation that contrasts significantly from the mainstream free-market, neoliberal economics we have been fed for the last few decades. Perhaps its basic point is that capitalism only works when labor is exploited, yielding a surplus product. No profits = no capitalism. Thus the overarching aim of capitalists is to extract excess value from labor, over what is being paid out.

This extraction process has many dimensions, but a few of the salient ones deal with a odd role of markets in capitalism. Most people working in the capitalist system are not working in markets. They are employees, whose work is not bid on an hourly basis, who do not personally sell what they personally make, in a market. They exist in a command economy, quite divorced from this fantasm called "the free market". If they do not get along with their boss, they are fired. They are evaluated, not by market outcomes, but by subjective opinions of others around them, and are subject to a complex bureaucracy of control by the firm they are employed by. While the firm has market interactions with the outside, on the inside it is hardly different from a communist enterprise, indeed a good deal more heartless. Much of what corporations and the capitalist class lobbies for is not freer markets (heaven forbid!), but more ways to control workers, whether that is by right-to-work, weakening unions, keeping disputes out of open court, colluding with each other to not poach workers, staging "team-building" activities, stealing worker pay, reducing safety net programs, etc. So, contrary to the right-wing ideology of freedom, one of the main tasks of capitalists and their political servants is to reduce the freedom of workers.

The principal sword dangling over the employee is unemployment. That is the ultimate sanction, and is essential to the functioning of the whole system. Unlike other markets for goods, the labor market never clears, or settles on the stable demand/supply point. As the book comments, employers do not need to have a line of unemployed machines standing outside the gates to encourage the machines inside the factory to work harder. But they do need unemployement, both to support the command economy inside the firm, and also to keep the wages paid below the actual value given by labor. This connects additionally to one of the reasons for the business cycle- to raise unemployment and thereby "discipline" worker demands, in addition to moderating input prices and clearing out inefficient firms. It turns out that the full business cycle, including recessions, is as central to capitalism as capital itself. We can not have only good times, if corporations are going to clear profits by exploiting workers.

Which ultimately brings us back to inflation. We had a "great" recession in 2008, which led to very high unemployment and durably reduced output. Workers were very well disciplined, to the point that large numbers left the work force entirely. One consequence of all this discipline and lowered expectation has been that employers could get away with not raising pay. The trend of economic growth/benefits going entirely to the capitalists and rich, and none to workers, has continued at an accelerated pace through the period. A side effect of all this low pay is low inflation. This is in dramatic contrast to the late 1960's and 1970's, when worker power was high, unionization was high, and demands for pay were high. Workers expected not just cost of living raises, but seniority and productivity raises as well. Incidentally, the public sector, which is highly unionized and in a special position with political power over its employers, is a relic of that outdated world, resulting in bloated pay and pensions, which are now unheard of in the trenches of the real economy.

Workers have not gained from productivity increases for forty years.

So things are, from a long-term perspective, unbalanced. And what did voters in their wisdom do about it in 2016? They elected a hypercapitalist, who conned them into thinking that he wanted to do something for workers. Ha! Obviously, the progressive agenda is far more pertinent to workers, seeking to reduce instead of increase capitalist power. Progressives seek to increase worker power in a myriad of ways- regulation, a higher minimum wage, better safety net, more public services, higher wealth and income taxes. The strongest proposals so far aim at the lowest end of the scale- setting a living minimum wage, and also establishing the principle of jobs for all- a job guarantee that would set an even more robust floor for the job market and seriously impair the fear that unemployment inspires. Will capitalism survive? I think so- the Scandinavian countries have far more civilized regimes of public goods and worker protection, and seem to do OK.

But what about the bulk of workers in the middle rungs of the economy? Some additional thinking needs to be done to bolster their prospects in the fight with capitalists. While unions are highly beneficial for their members, their benefits are intrinsically balkanized and can be highly damaging to their industries- think of the car industry. A better way is to institutionalize broadly some of the benefits that unions have pioneered, such as the weekend, regulatory worker protections, and rights of political and economic organization.

One idea that I think would be very useful would be to break the secrecy on salary. One of the principal benefits of union membership is the transparency that it provides to workers- knowlege of what everyone is being paid, as a step to negotiating contracts. One of the greatest powers that corporations have, to steal pay and discriminate against classes of employees, is to keep pay secret, as though it were some kind of sacred trust. But many workplaces have transparent pay structures, such as union shops, boardrooms, and professional sports teams, and the sky has not fallen. What average workers need is government mandated transparency on pay in every workplace, so that everyone can see how they and others are being treated. Few measures would as effectively show injustice, generate fairer treatment, and give workers a more realistic picture of their prospects at a current or a future employer.

Would we get more inflation? Perhaps. But there are many ways to skin that cat, with credit, monetary and fiscal policy, rather than worker suppression. It is time for a little capitalist suppression- to right an economy, and a society, far out of kilter.

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That's Cool: Adolescent Brain Development

Brain power and integration increases with development, particularly in the salience network and in the wakeful, attentive beta waves.

We see it happen, but it is still amazing- the mental powers that come on line during child development. Neurobiologists are starting to look inside and see what is happening mechanistically- in anatomical connectivity, activity networks, and brain wave patterns. Some recent papers used fMRI and magnetoencephalography to look at activity correlations and wave patterns over adolescent development. While the methods and analyses remain rather abstruse and tentative, it is clear that such tendencies as impulsivity and cognitive control can be associated with observations about stronger brain wave activity at higher frequencies, lower activity at lower frequencies, and inter-network integration.

An interesting theme in the field is the recognition that not only is the brain organized physically in various crinkles, folds, nodules, etc., and by functional areas like the motor and sensory cortexes or Broca's area, involved in speech production, but that it is also organized in connectivity "networks" that can cross anatomical boundaries, yet show coherence, being coordinately activated inside much more densely than outside the network. An example is the default mode network (DMN, or task-negative network), which happens when adults are just resting, not attending to anything in particular, but also not asleep. This is an example of the brain being "on" despite little conscious mental work being done. It may be our unconscious at work or play, much like it is during sleep on a much longer leash. As one might imagine for this kind of daydreaming activity, it is strongly self-focused, full of memories, feelings, social observations, and future plans. Anatomically, the DMN extends over much of the brain, from the frontal lobes to the temporal and parietal lobes, touching on regions associated with the functions mentioned, like the hippocampus involved in memory, temperoparietal areas involved in sociality/ theories of mind, etc. There are roughly twenty such networks currently recognized, which activate during different mental fuctions, and they provide some answers to the question of how different brain areas are harnessed together for key functions typical of mental activity.

Two networks relevant to this current work are the salience network (SN) and the cingulo-opericular network (CN or CO). The latter is active during chronic attention- our state of being awake and engaged for hours at a time, termed tonic alertness. (This contrasts with phasic alertness, which is much shorter-term / sporadic and reactive).  It is one of several task-positive networks that function in attention and focus. The salience network spans cortical (anterior insula an dorsal anterior cingulate) and subcortical areas (amygdala and central striatum) binding together locations that play roles in salience- assigning value to new events, reacting to unusual events. It can then entrain other brain networks to take control over attention, behavior, thoughts, etc.

fMRI studies of the activity correlations between brain networks. The cingulo-opercular and salience network connections (gray) take a large jump in connectivity to other regions in early adolescence. At the same time, fronto-parietal network connections (yellow), characteristic of frontal control and inhibition of other networks, take a dive, before attaining higher levels going into adulthood.

Here we get to brain waves, or oscillations. Superimposed on the constant activity of the brain are several frequencies of electrical activity, from the super-slow delta waves (~ 1Hz) of sleep to the super-fast gamma waves (~50 Hz) which may or may not correlate with attention and perception. The slower waves seem to correlate with development, growth, and maintenance, while the faster waves correlate with functions such as attention and behavior. Delta waves are thought to function during the deepest sleep in resetting memories and other brain functions, and decline sharply with age, being pervasive in infants, and disappearing by old age. Faster waves such as theta (5-9 Hz), alpha (8-12), and beta (14-26 Hz) correlate with behavior and attention, and are generally thought to help bind brain activities together, rather than transmitting information as radio waves might. Attention is a clear example, where large brain regions are bound by coordinated waves, depending on what is being attended to. Thus the "spotlight of attention" is characterized both by the activation of selected relevant brain areas, and also by their binding via phase-locked neural oscillations. These are naturally highly variable and jumbled as time goes on, reflecting the saccadic nature of our mental lives.

One of the papers above focused on theta and beta waves, finding that adolescents showed a systematic move from lower to higher frequencies. While fMRI scans of non-oscillatory network activity showed greater integration with age, studies of oscillations showed that the main story was *de-coupling mainly at the lower frequencies. What this all seems to add up to is a reduction of impulsivity, via reduced wave/phase coupling between especially between the salience and other networks, at the same time as control over other networks is more integrated and improved, via increased connectivity. So control by choice goes up, while involuntary reactivity goes down. It is suggested that myelination of axons, as part of brain development along with pruning extra cells and connections, makes long-range connections faster, enabling greater power in these higher frequency binding/coordination bands.

Brain wave phase coordination between all areas of the brain, measured by frequency and age. Low frequencies associated with basal arousal, motor activity, and daydreaming are notably less correlated in adults, while beta-range frequencies about 25 Hz, associated with focused attention, are slightly more correlated. 

Is this all a little hand-wavy at this point? Yes indeed- that is the nature of a field just getting to grips with perhaps the most complicated topic of all. But the general themes of oscillations as signs/forms of coordination and binding, and active sub-networks as integrating units of brain/mental activity on top of the anatomical and regional units are interesting developments that will grow in significance as more details are filled in.

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Addiction, Exorcism, and the American Dream

Review of Beautiful Boy.

Why is drug addiction such a widespread and dangerous scourge? A lot has been made of the despair of the working class especially in declining rural areas- a crisis of meaning and survival at the short end of the capitalist system. But there is higher anxiety everywhere in our unequal, precarious, and atomized system. Even in wealthy Marin, where the story of this movie originates, parents are in what seems like fight to the death to get their offspring into colleges to fulfil an overwhelming set of competitive expectations. No wonder young adults, even when well-to-do, already feel themselves in a rat race which it would be pleasant to check out of, momentarily. Then add in the viciousness of modern drugs like crystal meth and fentanyl, and you have a lethal witches' brew.

Still from the movie. Timothee Chalamet playing Nic Sheff, and Steve Carrel playing David Sheff.

We used to regard Russia as a demographic basket case, with declining population riven with alcoholism in the wake of the Soviet collapse. Now we are facing a similar downward dynamic- a social rot punctuated by self-destruction through drugs and suicide. The ultimate source seems to be broad insecurity, which was precisely the point of the economic and cultural reforms of the recent Republican epoch, starting with Ronald Reagan. The benefits of competition and division were trumpeted, and the rich were feted as job creators and entrepreneurs, and given absurd benefits like a tax rate on investment profits half as high as the rate on labor income. Companies developed an ideology of serving profits to the exclusion of all other goals, which meant the destruction of stable life schedules, stable jobs, and stable communities. The Reagan era gave rise to wide-spread homelessness, the ultimate warning to labor to keep its head down. And a broad reduction of safety nets of all sorts, from corporate pensions to onerous rules for welfare, which was divided into a puzzle of ungenerous programs.

How ironic, then, that Donald Trump offered to fix all this for workers, restoring the greatness and jobs of America. Who suspected that he came from a Republican tradition whose first order of business, when given power, has been to hand money to the rich? Who suspected that his policy ideas came more from the tabloid headlines of the 80's and 90's (not to say his fascist forebears in the 30's) than from the issues the working class face today? Who suspected that the greatest epoch in American history, after World War 2, was actually our period of highest taxation, culminating in, not coincidentally, the Apollo space program, which was hardly a capitalist venture?

Reagan, George W. Bush, and Trump each cloaked themselves as shamans for an anxious society, ready to exorcise the demons of economic malaise and insecurity, as well as those of Vietnam. While Democrats offered laundry lists of melioration, Republicans could do no such thing, their object being to strengthen hierarchy and help the better-off. They have instead lighted on a more tribally / religiously tinged approach, offering a broad ideology of conservatism (however radical the implementation, and departure from the existing system) and order, which would by some mystery of compassionate conservatism redound to the benefit of all after generous payouts to the few.

On the military front, they authored a series of military misadventures that climaxed with the criminal debacle in Iraq. On the economic front, they pushed hard-line capitalism as the cure-all to bring economic growth, starving the state with deregulation, outsourcing, and bitter budget / deficit battles as a purgatorial nostrum that would rejuvenate an ailing system. Curiously, however, the treatment never worked for the middle class and poor, keeping them economically static and ever more insecure, while the rich and super-rich pocketed all the proceeds.

Economic vitality needs some dynamism and destruction. But people and communities need stability and a basic level of egalitarianism to feel human and have basic freedoms. The founders foresaw that rising wealth and inequality might make of America the same class-ridden culture they had fled in Europe. Their hopes were tied not just to the new republican structure they were building, but also, in economic terms, to the frontier- the jobs-for-all program of its day- which would continue to offer all Americans (and immigrants from all over the world) the option of a decent and hard-working living, preventing excessive inequality.

Now the frontier is gone, the population continues to rise, and the only solution from the "conservative" right is to squeeze the middle class and poor relentlessly in a spiral of anxiety that drives everyone to work and live under ever less humane conditions. We need a better balance that builds more unifying social structures and public goods, reels back the excesses of extreme capitalism, and gives people breathing space and freedom to dream of being more than cogs in a machine.

RB: Short Name For a Complicated Protein

A key cancer protein operates in a huge network of regulatory protein interactions.

RB stands for retinoblastoma, one of the first diseases tied to a causal oncogene, now also called RB. For lack of time, this will be a very short post about a very lengthy story- how complicated one protein can be. The RB protein doesn't really do much on its own. It isn't an enzyme, or bind DNA, or do other dramatic things. But it binds to a lot of other proteins- 322 have been documented to date. And one protein that it binds to and represses, the transcription factor (family) E2F, is a key activator of cell division, promoting transcription of many other genes including cyclins and cyclin-dependent kinases that run the cell cycle. So RB is typically a key actor that keeps cells quiescent in G1 phase, the normal non-dividing state most of our cells are in. And this is how mutations in RB promote cancer, by removing this brake.

A recent paper expanded this story by investigating some of the regulation of the RB protein, which has at least 15 sites where it gets a phosphate group added (phosphorylated) by regulatory proteins called kinases. The most prominent regulatory kinases are the cell cycle dependent kinases, or CDK. Naturally when a cell does really want to divide, these function to turn RB off, via certain of these phosphorylations. The authors erased each of these phosphorylation sites, and then restored one at a time, asking what binds to them and their effect is. The upshot is that each site turned out to show a distinct pattern of downstream effects, indicating that different proteins bind more or less well to each phosphorylated form. These proteins include transcriptional regulators of a wide variety of kinds, and affect differentially the expression of key genes like BRCA1, 2, and MSH2, and processes ranging from DNA repair to oxidative phosphorylation to protein secretion.

Diagram of the sites of phosphorylation of RB by other proteins. The amino acid sequence goes from left to right, and functional regions of RB that bind to other proteins are colored.

"Collectively, this mass spectrometric analysis identified 438 proteins with a statistically significant enrichment in complexes with at least one of the 16 forms of RB examined. The 22 proteins significantly enriched with all forms of RB included multiple E2F and DP [E2F partner] proteins."

Evolution has had several billion years to tinker with these systems. So while the solution sometimes has been elegance incarnate, (like the DNA molecule), other times it is a messy network of sprawling and mystifying scope. It is one reason why biologists will remain tied to their benches for decades to come.

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Patterns of American Extremism

John Calhoun and the coming of the Civil War. Review of "Heirs of the Founders", by H. W. Brands.

Our politics are straining under back-breaking burdens. We are still saddled with several undemocratic compromises of the founders, are corrupted by money and corporate interests, and profess a democracy which in even its best incarnations is, historically, a brief reprieve betwixt tyrannies and oligarchies of various forms, inevitably brought down by the greed, fears, and passions of its subjects. We are experiencing division to a degree not seen since the civil war, and corruption, even treason at the highest levels of government. Where is all this going?

A recent multi-biography focused on the leading politicians of the early to mid-1800's: Daniel Webster, from Massachusetts, Henry Clay, from Kentucky, and John Calhoun, from South Carolina. Yoking them together this way is common in the teaching of this era, but it does something of a disservice to their strikingly divergent contexts and paths. Webster was a natural supporter of Northern interests, including Union, tariffs, but not abolition. He eventually agreed with the compromise of 1850 that enforced the fugative slave policy of the South, since that policy was written explicitly into the constitution. Clay was the most ambitious of the set, leading the Senate through decades of policy and legislative compromise. His lodestar was also Union, made increasingly difficult by the relative economic decline of the South, the entrenchment of slavery, and the fatal compromises that had already been made in the original constitution.

Mysterious, Romanesque bust of John Calhoun, senator and vice president from South Carolina.

John Calhoun was different altogether. While the others tacked repeatedly to maintain the Union and its institutions, Calhoun lit out towards a bitter and uncompromising pro-Southern, pro-slavery position. He was the one who repeatedly threatened secession before the Congress. He was the one who turned intellectual and moral summersaults to defend slavery as consonant with the constitution, the founders, and human decency and progress. This was a time, of course, when Native Americans did not even get this level of discussion- they were packed off to Oklahoma with hardly a bleeding heart on their side. Racism was endemic, and the point of America was not harmony, but the manifest destiny of the Europeans who were remaking the continent. Still, the blatant FOX-news quality of Calhoun's arguments is unmistakable. Here he compares the state of African Americans in Massachusetts to those in the South:

"By the very latest authentic accounts, there was one our of every twenty-one of the black population in jails of houses of correction, and one out of every thirteen was either deaf and dumb, blind, idiot, insane, or in prison. ... The condition of the African race throughout all the states where the ancient relation between the two races has been retained enjoys a degree of health and comfort which may well compare with that of the laboring population of any coiuntry in Christendome; and it may be added that in no other condition or in any other age or country, has the negro race ever attained so high an elevation in morals, intelligence, or civilization."

All this led to a clear break:

"I have, Senators, believed from the first that the agitation of the subject of slavery would, if not prevented by some timely and effective measure, end in disunion. Entertaining this opinion, I have, on all proper occasions, endeavored to call the attention of each of the two great parties which divide the country to adopt some measure to prevent so great a disaster, but without success. The agitation has been permitted to proceed, with almost no attempt to resist it, until it has reached a period where it can no longer be denied or disguised that the Union is in danger. You have thus forced upon you the greatest and the gravest question that can ever come under your consideration: How can the Union be preserved?"

Calhoun brooked no embarrassment or qualm about slavery. As an institution, it was good, not bad; growing, not dying. While Clay and the founders generally hoped that it would wither away, though economic evolution and plain moral decency, Calhoun stood for its unrepentant expansion. The constitution was also behind him. The constitution gave Southern states the representation of 3/5 of its slaves, but none of their voting. The constitution said nothing about any powers the Union might have to restrict slavery in new states. The constution explicitly forbade the harboring of runaway slaves. The country had lost sight of its duties to the South, and were the abolitionists not muzzled from speaking their inconvenient moral truths, the South would have no more of it.

It is a story of a whole section of America gone off its moral rocker, in service of plain greed and conservatism. A religion has also evolved in the South that seems to blend the authoritarianism and social conservatism of Catholicism with independent elite governance and a scrim of protestant theology. When the South did secede, the Union government let loose a torrent of progressive legislation. One senses strongly that we could and would do the same today but for the anchor of a Southern political culture still petrified by true equality, dedicated to feudal economic relations, and to defend itself, still spouting the mantra of state's rights. The map of Red states tells the story.

Political divisions over the last sixty years, by presidential election.

But it is the media and media leaders that serve to normalize immoral positions. Climate change is only an example, but perhaps the clearest and most dire of our time. Failure to act is simply criminal- an act of sabatoge against the future of every citizen and the entire biosphere. A fair portion of our culture, driven by right wing media and its nexus of money and fear, drives an utterly immoral political culture of denial, mean-ness, and blind conservatism. Trump has nowhere near the intellect or facility of John Calhoun, but the brazen support of palpably destructive policies, the headlong divisiveness, the antipodean moral compass have a certain resemblance.

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Deranged Transcription

.. in autism, schizophrenia, and bipolar syndromes.

It is clear that human evolution over the last few millenia has been particularly rapid for mental/cognitive traits. This seems to have created the hazard of unintended consequences in the form of mental illness, when this high-strung and finely tuned system goes haywire. There has been a steady stream of genome variants discovered to be associated with prominent mental illnesses like schizophrenia, autism, and bipolar disorder. These variants are inherited (not sporadic, like the mutations responsible for most cancers) and tend to be either rare or have very slight effects, for obvious reasons.

"The majority of disease-associated genetic variation lies in noncoding regions enriched for noncoding RNAs (ncRNAs) and cis-regulatory elements that regulate gene expression and splicing of their cognate coding gene targets."

One feature that stands out among the genetic variants that have been found to date are that they are rarely in coding regions, thus do not affect the sequence of the protein encoded by the affected gene. Instead, they affect regulation- the delicate mechanisms by which genes are turned on and off in particular places and times. It is now common knowledge that humans have hardly more genes than fish or potatoes. It is gene regulation that makes us what we are, and recent decades have revealed whole new mechanisms and participants in this regulation, such as long non-coding RNAs.

A recent paper conducted a fishing expedition to find how gene regulation varies among people with mental illness, in a quest to find causal changes and molecular patterns characteristic of these syndromes. They had access to thousands of brain samples, and put them through a modern analysis of transcripts, including from 16,541 protein-coding genes and 9,233 genes expressing short or long regulatory RNAs. One theme that came up is that they found many differences among gene splice forms. Most eukaryotic genes are spliced after they are transcribed, being composed on the genome of a series of separate coding exons. This splicing (removing the intervening intronic RNA and joining the coding exons) is highly regulated and for many genes, fundamentally influential on what protein they ultimately produce. Some genes have dozens of different splice forms, many with significantly different roles. For example, a key functional domain like an inhibitor or a DNA-binding region may be left out of one form, converting its encoded protein into one that performs functions precisely opposite to those of the full-length form.

Screen shot from the NIH gene resource, showing the human gene titin, which encodes the largest known protein, which structurally spans the muscle sarcomere. Each green segment is an exon, totalling 363. Each horizontal line is a distinct splice form, varying in which exons are included. Skeletal and cardiac muscle express different splice forms of this protein, and sequence variations in this gene are responsible for some syndromes such as dilated cardiomyopathy.

After putting their brain tissue samples through purification and sequencing of all the RNAs, and alignment with known sequences, the authors came up with a set of differences of gene expression between affected and control subjects. They claim that a quarter of all the genes they looked at were noticeably affected by one of the three disorders they looked at- autism, schizophrenia, and bipolar disorder. Naturally, this finding may be a consequence of wide-spread structural and functional changes in affected brains that may be well downstream from any causative factor. There was relatively little overlap between the three. Schizophrenia showed the most differentially expressed genes/splice forms by far (several-fold more than the others), and shared about half of those seen differentially expressed in bipolar disorder, and one-fifth of those in autism. One might speculate that on the whole, schizophrenia is a more severe disorder which would lead to more dramatic differences in gene expression in an absolute sense.

"Notably, 48 DS [differentially spliced] genes (10%; FDR = 8.8 × 10−4) encode RNA binding proteins or splicing factors, with at least six splicing factors also showing DTE [differential overall transcript expression] in ASD [autism spectrum disorders] (MATR3), SCZ [schizophrenia] (QKI, RBM3, SRRM2, U2AF1), or both (SRSF11)."

Interestingly, the authors also tested (in animals) whether drugs used to treat these major disorders could generate the differences seen above. The answer was no- differential expression was somewhat affected by lithium, but not significantly by the others tested. Secondly, the authors wheeled in a separate method, sifting through genomic variations to find other genes with variations known to be causally associated with these diseases, and guess whether these variations (aka mutations) might affect transcriptional expression. The results did not overlap very well. For bipolar disorder, none of the 17 genes identified by this latter method overlapped with the differentially expressed genes identified by the first method.

Part of the general scheme of the experiment, and schematic results. Isoforms of some genes show differences in disease vs control tissues, and patterns from many such genes and differences can be assembled to diagnose particular cells or processes that are being notably affected. But note in the middle panel that the quantitative difference in the alternative splicing pattern between disease and control for this particular example is minuscule- in the 1 to 4% range. It may be statistically significant, but could be minor in effect. The last panel illustrates fold-change ranges for non-coding long RNAs among the different syndromes and known patterns of cell-type expression, in a schematic sense. Genes known to be expressed in microglia showed particularly significant changes.

So what did they get? Mainly a lot of little fish, and quite a few that had already been suggested to be important for brain function by other methods. One prominent theme was the involvement of immune-related genes. Genes characteristic of astrocyte and microglia cell expression, and of interferon responses, among other signatures, were significantly up-regulated. This agrees with other work indicating that inflammatory mechanisms are used to prune synapses and cells generally in the brain, and this process is over-active in schizophrenia. An example gene is complement C4A, which encodes part of a key immune system that identifies and clears foreign material with the help of phagocytes. It used to be thought that the central nervous system was immune-privileged, i.e. not surveiled by it or affected by it. But that turns out to be very far from the truth, and this gene's overexpression is genetically identified as a causal factor for schizophrenia.

Another big fish they caught was a gene called RBFOX1. Certain spliced forms were significantly less abundant in the affected tissues, supporting a long line of work identifying variations in this gene as candidate causal factors for autism, and its function as an RNA binding protein that regulates the alternative splicing of other genes as well as their later transcript stability and lifetime. Reduced function of this protein is known to increase neuronal excitability and increase seizures. It seems thus to be a key node in neuronal development and functional regulation, through its control of the expression of other genes.

Did these authors find anything new? That is naturally hard to say at this point, since such conclusions would require quite a bit of followup work to analyze the function of novel genes that were found. The expedition showed that it was technically capable of hauling in not only a lot of fish, but many known already to be significant in these syndromes, either causally or as markers and downstream effects. Choosing which to track down to their actual biology is a difficult question- one that must come next. It is a catch that may provide sustenance for many students and post-docs to come.

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Music Notation Needs a Redo

Music notation can be better.

Music notation is one of those conventions that solidified long before it was critically analyzed, and well before the advent of even remotely modern usage. The fact that sharps and flats involve special symbols, either in the key signature or as "accidentals", is a sure sign of a hack that has ossified into a standard- one that is painful to learn and use. But the most painful aspect of modern music notation is that the same note appears in contrasting places in different octaves- on different staffs, and in different locations on a single staff. For example, for normal piano music, where both treble and bass staffs are provided, and the note "C" sometimes hits a line, but elsewhere sits between lines. The position alternates going up the staves because the (C) major scale on which the notation is based has an odd number of notes- seven per octave.

Early music notation, dating from roughly 1000 CE. We don't need no sharps or flats!

These characteristics make note reading, not to mention sight reading, very difficult to learn, a big turnoff to the young students who may otherwise be quite enthusiastic about making music. Ranging from the central hand position is made substantially more difficult by the precisely opposite locations that the farther-ranging notes have in this notation system. All this becomes second nature eventually for advanced and professional musicians, but it is clearly a long and arduous process, needlessly difficult. Indeed, many famous musicians never learned to read music, maybe in part because of its notational difficulty.

One solution is to make smaller staffs, only one per octave, with a one-tone gap between each. This would make each octave look identical, and successive octaves could be stacked as needed. Modern printing could surely make such a system as compact as the current 5-line staff, which carries two octaves, if one counts one supplementary line below and two above.

A chromatic notation with each of the twelve tones on its own level, and an even number of notes occupying a full staff, ready to repeat in a regular way to other octaves.

Another solution is to lay out the whole chromatic scale, which has a separate position for each note in the customary Western 12-tone scales including sharps and flats, as separate notes. The number of notes per octave becomes even (twelve), providing consistency in note position. And the need for sharp and flat notation is reduced if not obviated. A downside is that the representation of chords would change dramatically, relative to the typical triads or sevenths that look so regular on a conventional staff.

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• Bill Mitchell on modern economics as a pro-capitalist cabal.
• Surveillance capitalism.
• If you use VPN, you have trust your provider completely.

At the Climate's Mercy

Volcanic eruptions have interrupted our fragile existence.

A recent research article made the news, telling of the worst year to be alive: 536 AD. This was surely the darkest moment of a dark age, and scientists have tracked its source to volcano(s) in Iceland. It darkened skies around the world, led to a ~4ºF drop in temperature, and crop failures throughout Europe and the near east, and crop delays in China. There seem to have been repeated eruptions over the ensuing years, though perhaps volcanos elsewhere contributed. The result was the coldest decade in at least 2,000 years, and a plague in 541-3 that wiped out at least 1/3 of the Byzantine population, among others. It took decades for Europe to recover, notably shown by ice cores with high lead pollution about 640 AD, showing that silver mining in France had recovered, presumably being pursued for minting coins.

Turner's "Chichester Canal", of 1828, thought to reflect some of the atmospheric effects of the  1816 global volcanic pall.

There have been several similar, though less extreme, events, like the "year without a summer" in 1816, due to the eruption of Tambora in Indonesia. This vocano is estimated to have ejected 40 cubic miles of material, but only lowered temperatures in Europe by about 3ºF, yet caused substantial famine, snowfalls in June, frost in August. A much smaller eruption, of Krakatoa in 1883 also caused dramatic sunsets and world-wide cooling, but had far less devastating effects, being smaller, and because it happened in August, and did not affect the following summer as severely.

Are our agricultural systems robust enough to withstand such an event today? I doubt it. We have optimized and stretched in every direction, supporting vast urban populations, without a thought given to adverse events of global scope. The only significant failsafe is that most agricultural production goes to supporting livestock, which under duress could be used directly for human consumption.

Conversely, we are engineering a permanent climate disruption of equal proportion but in a warming direction, by our emissions of CO2. Will temperatures go up by 3ºF? 4ºF? 5ºF? We are already at 2ºF, (vs temperatures at 1900), with much more baked in from our past emissions, and from their relentless continuance and growth. Will we survive if agriculture has to move to Canada and Siberia? If Florida and New York are under water? Sure, but at what cost to ourselves and more importantly, to the natural world?

• Doonsbury's Duke, in real life.
• On the way to modern capitalism: guilds.
• We are not as prepared as we think we are.
• Medical pricing in the US is insane. Weren't insurance companies supposed to solve this problem?
• Asset? Yes. And where is the outrage?

Chromosomes Blown to Smithereens

Where do cancers and cancer relapses come from?

DNA is a treasure trove that keeps on giving. The human genome sequence was a milestone that may not have been self-interpreting, but has provided grist for leaps of technical advancement and knowledge. Ancestry studies are one example, but disease studies are of more immediate interest. Cancer is now understood to be a molecular disease where the DNA suffers mutations that release various brakes on cell proliferation. One of the most influential types of mutations are gene fusions, where one gene that has roles in proliferation is broken from its normal regulatory controls, either within its coding sequence (such as a repressing protein domain) or its upstream expression controls, and hooked up with some other gene that drives its expression in new places and high levels. A recent paper studied several cancers in detail, sequencing samples from various time points and locations, coming up with very interesting findings about the origins of these mutations and the nature of metastasis.

One example of a genome blow-up, called "chromoplexy". A few regions of the genome got caught in some kind of spindle, and came out with several breaks which then were repaired to form re-joined fusions. In this diagram (right) of one resulting fusion, of genes BCLAF1 and GRM1, the chromosome 6 parts on the outside have rejoined, while the broken parts between the rejoined ends have fused to each other and then to chromosome 16, with one small bit unassigned and perhaps ending up somewhere else. The diagram seems to indicate that GRM1 ends up upstream of BCLAF1, (these are divergently transcribed in the native chromosome), which I think is an error.

Chromoplexy is one form of a genome blowup, one that is restricted in scope (at least compared with the even more destructive chromothripsis). The best theory about its origin posits that the affected portion of the genome (typically an early-replicating and transcriptionally active region) gets caught outside the normal nucleus, forming a temporary mini-nucleus which is cut off from normal controls, causing the trapped DNA to break up. The cell has strong controls against free DNA ends, and uses end-joining DNA repair to patch things up, pasting ends together essentially at random. This is obviously quite dangerous, and leads to unexpected gene fusions, of which hundreds of different examples are now known that drive various cancers. One such fusion, diagrammed above, is between genes BCLAF1 (upstream) and GRM1 (downstream).  GRM1 is a receptor for glutamate, the most prevalent excitatory neurotransmitter. While most highly expressed in the brain, glutamate receptors act throughout the body, and malfunctions are connected with a variety of diseases. Increased expression and activation can drive cell proliferation. The other fusion partner, BCLAF1, is a promoter of cell suicide, or apoptosis. That function will be lost in the fusion, which might have some importance to the disease (though a second copy presumably remains intact elsewhere). The important part is that it is very widely expressed, especially in bone marrow. An earlier paper describing this fusion states:

"The GRM1 coding region remains intact, and 18 of 20 CMFs (90%) showed a more than 100-fold and up to 1,400-fold increase in GRM1 expression levels compared to control tissues. Our findings unequivocally demonstrate that direct targeting of GRM1 is a necessary and highly specific driver event for CMF [bone tumor chondromyxoid fibroma] development."

This pattern of mutation, and the specific fusions that resulted, became apparent due to the deep sequencing the researchers did, taking samples from the patient's tumors and from normal tissues. An important concept here is of mutational signatures. Each mechanism of mutation has its characteristic pattern of mutations left in the genome. Exposure to UV light, which causes C->T mutations, will leave a much different pattern in the genome than the localized chromoplexy blowup mentioned above. So a forensic analysis of the patient's DNA can tell what happened, in some mechanistic detail. For example, the various fusions seen in these samples were not part of extensive copy number variations- reduplications that are common in cancerous cells, which indicated that this blowup took place once as a discrete event, not repeatedly or slowly over a long period of time.

It can also tell when it happened, and here we get to a particularly interesting message from this paper. When they sequenced primary and relapsed tumors, (with comparisons to normal tissue), such tumors shared some key mutations, those which drove the overall cancer. But they failed to share many others. Indeed, the metastatic tumors carried none of several mutations that were uniformly present in the primary tumor. This says that metastases or relapse cancers, (this part of the study was specific only to Ewing's sarcoma, a bone cancer typically arising around ages 1-20), typically do not develop from the primary tumor, but from cells that carry the same driver mutation, but diverged before primary tumor formation. They are independent events, and metastatic prognosis has little to do with the fate of the primary tumor.

The author's proposed time course of Ewing's sarcoma evolution, placing the origin of metastatic and relapsing tumors well before and outside of the primary tumor at the time of diagnosis.

Whether this observation about metastisis applies to other tumors is naturally important to follow up. It would alter significantly how we deal with primary tumors, and informs the kind of conservative treatments (lump-ectomies, for instance) that are becoming more common. As sequencing becomes cheaper and more common for all kinds of tumors, the particular drivers, from whatever mutational source, can be identified and used to direct specific, (buzzword: "precision") treatments. GRM1 can be targeted by direct or indirect means. But if one has Ewing's sarcoma, typically associated with a fusion of EWSR1-FLI1, where FLI1 is a transcription factor that drives growth factor production and hence cell proliferation, a different set of therapies would be indicated.

• The Green dream is on.
• Our cold war with China.
• AIPAC is the NRA of foreign policy.
• Bill Mitchell on economics education, especially macro.
• Election crisis.. no problem.
• Give to the rich, take from the poor.
• Notes on experts.

Truth, Justice, and the American Way

Stephen Walt's critique of our overextended, idealist, militarized, and not very bright foreign policy: The Hell of Good Intentions.

Americans have gotten rather used to running the world. Whenever news arrives about some horror or injustice, action is expected. No matter how distant the crisis, we now have interests, and assets, close-by. It is a mindset we inherited from the Greatest Generation, who build a post-war order out of constant vigilence and activity- first to reform the perpetrators of the war, and then to forestall the spread of communism. After the Soviet Union imploded, we were left free, with a vast whirring mechanism of diplomatic and military machinery. For those raised on Lone Ranger episodes and Superman comics, which may describe a good portion of the foreign policy community over the last few decades, the answer was obvious- do good.

Stephen Walt takes direct aim at this mindset, which in his telling is borne as much from laziness and stupidity as from good intentions and US interests. We have committed terrible blunders in our rush to save people from predatory states- the prime examples being Vietnam and Iraq, which cost roughly 1.3 million and 0.5 million lives respectively, though the latter remains open-ended, due to our responsibility for creating ISIS. The people responsible for these comprehensive, mind-boggling disasters should have been tried as war criminals. But instead, our system barely batted an eye, and most of the architects of both horrors went on to continued participation in the US foreign policy commmunity, often at high levels.

This is because foreign policy is a strongly political field, at least as practiced in the US. Who would have hired Jared Kushner to run US Middle East policy? No one in their right minds, that's who. But the rot runs much deeper. Foreign policy is not science, and is difficult to evaluate, especially considering our problems with prophecy. So standards are virtually absent, replaced with a go-along-get-along ethic within a tight zone of conventional ideas. A big change since the Reagan era has been the intrusion of neoconservatives into this community, via right-wing administrations and their partisan think tanks like the Cato institute, American Enterprise Insitute, and Heritage Foundation. These were the minions who pushed the Iraq war, and they keep pushing the zone of mainstream thought rightward. Their current project is to demonize Iran. Which is odd, because Iran is a more functional democracy than Saudi Arabia, and intellectually far richer and more dynamic as well. The motivation for all this comes mostly from Israel, which has tacitly allied itself with Saudi Arabia and Egypt in a new cynical status quo ... just so long as no one says anything about the Palestinians.

The checkered career of Elliott Abrams is if anything more disturbing for those who believe that officials should be accountalbe and advancement should be based on merit. Abrams pleaded guilty to withholding information from Congress in the 1980's, after giving flase testimony about the infamous Iran-Contra affair. He received a pardon from President George H. W. Bush in December 1992, and his earlier misconduct did not stop George W. Bush from appointing him to a senior position on the National Security Council, focusing on the Middle East. 

Then, after failing to anticipate Hamas's victory in the Palestinian legislative elections in 2006, Abrams helped foment an abortive armed coup in Gaza by Mohammed Dahlan, a member of the rival Palestinian faction Fatah. This harebrained ploy backfired completely: Hamas soon learned of the scheme and struck first, easily routing Dahlan's forces and expelling Fatah from Gaza. INsted of crippling Hamas, Abrams's machinations left it in full control of the area. 

Despite this dubious resume, Abrams subsequently landed a plum job as a senior fellow at the Council on Foreign Relations, where his questional conduct continues. In 2013, he tried to derail the appointment of the decorated Vienam veteran and former senator Chuch Hagel as secretary of defense by declaring that Hagel had "some kind of problem with Jews". This baseless smear led the CFR president Richard Haass to distance the council from Abrams's action, but Haass took no other steps to reprimand him. Yet, apparently, the only thing that stopped the neophyter secretary of state Rex Tillerson from appointing Abrams as deputy secretary of state in 2017 was President Donald Trump's irritation at some critica comments Abrams had voiced during the 2016 campaign.

Naturally, Abrams has recently been appointed as the Trump Administration's envoy for the crisis in Venezuela, which should inspire confidence. The most that the mainstream press can manage as a description is that he is "controversial".

What is worse, not only are egregious blunderers and arguable criminals never held to account, (Bush, Cheney, Kissinger), but truth-tellers and whistle-blowers are routinely side-lined. Remember Eric Shinseki? He was quickly sidelined from the military in the Bush administration, after giving an accurate estimate of the number of troops needed to stabilize Iraq. He was later rescued from exile by Barack Obama, but did he re-enter the military? No, he was put in charge of the VA, safely out of the way, and in an impossible job to boot.

In September 2002, for example, thirty-three international security scholars paid for a quarter-page advertisement in the New York Times' op-ed page, declaring 'War with Iraq Is Not in the U.S. National Interest.' Published at a moment when most of the inside-the-Beltway establishment strongly favored warm the ad warned that invading Iraq would divert resources from defeating Al Qaeda and pointed out that the Unites States had no plausible exit strategy and might be stuck in Iraq for years. In the sixteen-pus years since the ad was printed, none of its signatories have been asked to serve in government or advise a presidential campaign. None are members of elite foreign policy groups such as the Aspen Strategy Group, and none have spoken at the annual meetings of the Council on Foreign Relations or the Aspen Security Forum. Many of these individuals hold prominent academic positions and continue to participate in public discourse on international affairs, but their prescience in 2002 went largely unnoticed.

One interesting point that Walt makes along the way is that one capability that has atrophed due to all this dysfunction is true diplomacy. The Iran nuclear deal was one of the few recent episodes where we actually sat down with friends and enemies and hammered out a peaceful deal, agreed to by all sides. It is far more frequent these days to make big pronoucements, whether bland or insulting, then threaten punitive action like sanctions or drone strikes. Granted, the Al Qaedas and ISISs of the world are not likely to come to any Geneva tea parties, but there is a lot of good we could be doing by diplomacy, such as in Latin America and Africa, which is being left on the table. Instead, we have very secretive military activities in about 20 African countries. Militarization has colored our foreign policy to an excessive degree. And how has our "Peace Process" been going in the Middle East? This one was not a casualty of militarization, but of Israelization. Because of our failure to bring sufficient pressure to get to a Palestinian state solution, Israel continues to be an Apartheid state, and our reputation in the region is a shambles, shown to be the lapdog of Israeli interests.

The Lone Ranger brings in the bad guy to close a successful episode.

Walt's solution to these dysfunctions is to reel back our ambitions, from what he describes currently as a policy of "liberal hegemony" to one of "off-shore balancing". Liberal hegemony is the idea, which is sort of a hat-tip to Karl Marx, really, that liberal prosperous democracy is the desirable endpoint for all peoples everywhere, so we should not mind giving history a shove every now and then to get everyone there faster. The benefit for the US is clear as well- the more democracies there are, especially as encouraged by us, the more friends we have and the more stable the world in general.

Off-shore balancing, in contrast, is more hands-off, and regards US interests involved only where some region of the world is being taken over by a large hegemon, (like China), which could create such a global imbalance that we in the Western Hemisphere may be threatened. The Middle East should be left to its devices, especially as long as the Iran and Saudi axes are reasonably closely matched. Likewise, Europe is not a problem, even with Russia glowering from the east, since power is heavily diffused, and Europe even without US help is well able to take care of itself. While seemingly cynical and isolationist, this is really a very traditional approach to foreign policy, steeped in centuries of experience with Metternich-ian balance-of-power practices in Europe.

While Walt offers some very accurate and telling critiques of the state of the US foreign policy establishment, I think the prescription does not quite fit the problem and he tends to soft-pedal its implications. While the Middle East would obviously be better off with a little less US meddling, would it be better off with more Russian meddling? I have previously advocated for prompt, decisive involvement in Syria, which might have led to a better outcome than what is happening now, for both the people of Syria, and our own strategic position. But it may have been just another costly fiasco- that is what makes this field so treacherous. (Incidentally, Walt mentions the US Holocaust Museum's extensive research on Syria, especially on the prospects of US involvement. It casts a rather dubious light overall, but does suggest that early intervention can be far more effective than late intervention.) Turning to China, Walt does not mention the fate of Taiwan, of the South China sea, of the Philippines, or Japan. Would keeping Australia out of Chinese domination be a vital interest of the US? How many interests would he be willing to give up before things get truly serious?

But the deeper issue is one of stupidity. Doing less will not make us smarter. Walt gives some very positive reviews to the various anti-establishment views of Donald Trump and the demographic that he connected with in winning the presidency. Trump was all about throwing the bums out, and retrenching US foreign policy with fewer entanglements and a more modest approach. How has that turned out? Walt decries what is quite evident- our policy, which seemingly couldn't get any worse, now has gotten much worse, with a dotard and his various short-lived protectors and yes-men running things. US interests and influence throughout the world are shriveling by the hour.

A second observation is that the Iraq was not brought to us by idealism. It originated in the psychology of unfinished business on the part of Bush, Cheney, and their extended right-wing establishment. Their idealism was, as anyone could see, paper-thin pablum, matched by their total disinterest in the actual country, its people, and what was to become of them in the aftermath. Stupidity reigned supreme, and hundreds of thousands were killed, and countless more lives destroyed and ravaged for that stupidity.

The case of Vietnam was different. We had recently half-won the Korean war, and saved its Southern half from bondage- a fate that becomes more shocking every year as we view what goes on in Chinese-backed North Korea. Due to our loss of the Vietnam war, all of Vietnam remains a totalitarian state- the South would have been much better off had we/they won the war. Our involvement there was heavily idealistic. But it was stupid. The smart people knew the lay of the land, knew the experience of the French, and knew that it was a civil war that the North had a huge head start on, in comparison with the corrupt, illigitimate Southern government. It was a triumph of hope over experience.

So what we need is more experience and smarts. The US needs a better foreign policy system, not different ideals. We need to rigorously insulate our intelligence and analysis system, of which the State Department is a prominent part, from politics. That means stopping the revolving doors of personnel coming from think tanks, lobbying organizations, corporations, and political appointments. Country and region experts need to have long-term relations with their areas, not short posts. Analyses need to be given something like five-year reviews, with promotion dependent on success. Those let go should never be let back in. Accountability needs to replace hackery, corruption, and amateurism. This community needs to be de-militarized as well, which has been a rising problem for decades. These analyses should have public and secret components, with as much as possible made public so that the country can see the work that is being done, and learn what the basis of our foreign policy is. Like militarization, excessive secrecy has also degraded discourse and accountability.

Lastly, we need a more mature media discourse about foreign policy, less reactive to the news of the day, (let lone the twitter-minute), and more analytic and historically aware. Off-shore balancing is a very credible view in this discussion, but so are more idealistic approaches. Helping abused populations in foreign lands is a good thing, if it succeeds. The point is to succeeed rather than fail in our foreign policy projects, which requires deep experience, accountability, good information, and mature discussion. Perhaps we will find out that we should be doing less, once we filter out the bad ideas. Or perhaps we will find out that to do the things we might want to do (think of the second Iraq war) would be, if done properly, unrealistically expensive and unfeasible for that reason.

• Faux-ocracies are a rising challenge.
• The Taliban is weary of gaining ground in Afghanistan.
• New Taliban, same as the old Taliban.
• Yes, we are dealing with a fascist.
• Medical insurance should be left to the private sector?
• We need a wealth tax.
• And a bigger inheritance tax.