What Adulthood Looks Like in the Brain

A gene expression turning point in the mid-20's correlates with onset of schizophrenia, among other things.

Are brains magic? No. They may be magic-al in how they bring us the world in living color, but it is mechanism all the way down, as can be seen from the countless ailments that attack the brain and its functions, such as the dramatic degradation that happens in boxers and football players who have been through excessive trauma. All that amazing function relies on highly complex mechanisms, but we are only beginning to understand them.

One way to look at the brain is through its components, the proteins expressed from our genomes. Those proteins run everything, from the structural building program to the brain's metabolism and exquisitely tuned ion balances. Current technology in molecular biology allows researchers to tabulate the expression of all genes in any tissue, such as the brain or parts thereof. This is sort of like getting a quantitative parts list for all the vehicles active in one city at a particular time. It might tell you a little about the balance between mass transit and personal cars, and perhaps about brand preferences and wealth in the city, but it would be hard to conclude much about detailed activity patterns or traffic issues, much less the trajectories or motivations of the individual cars- why they are going where they are going.

So, while very high-tech and big-data, this kind of view is still crude. A recent paper deployed these methods to look at gene expression in the brain over time, in humans and mice, to find global patterns of change with age, and attempt to correlate them with diseases that are known to have striking age-related characteristics, like schizophrenia.

They duly found changes of gene expression over time, and tried to concentrate on genes that exhibit dramatic changes, reversing course over time, or plateauing at times that they call turning points. Below are a few genes that show a dramatic decline in mice, from youth to adolescence.

Expression of selected proteins in frontal cortex of mice, with age, showing turning points in early adulthood, which is about five months here in mice. These genes each have variants or other known associations with schizophrenia.

Perhaps the most interesting result was that, if they tabulate all the cases of turning points, most seem to occur at early adulthood. The graphs below show rates of genes with turning points at various age points. One can see that by about age 30 and certainly 40, (about age 7 months in mice), the brain is set in stone, gene-wise. There is little further change in gene expression.

Number of genes by age when their expression shifts direction, either up, down, or plateauing.

In contrast, age 15 to 30 is a very active time, with the most genes changing direction, and the largest changes of expression peaking about age 28. Given the many genes and complex patterns available, the authors reasoned that they could do some reverse engineering, predicting a sample's age from its expression pattern. And using only 100 genes, they show that they can reliably estimate the age of the source, within about 5 years. Secondly, they broke the gene sets down by the cell type where they are expressed, and found distinct patterns, like genes typical of endothelial cells attaining peaks of expression very early, before 10 years of age, as physical growth of the brain is maximal, while genes typical of pyramidal neurons, one of the most important and complex types of neurons, reach their inflection points much later, in the mid-twenties.

Types of genes and their rough times of expression shift, by age. Most key neuronal genes seem to settle into unchanging patterns in early adulthood. PSD is post-synaptic density, typical of synapses where learning takes place.

Particularly interesting to the authors are genes associated with post-synaptic density, part of the learning and plasticity system where connections between neurons are managed. These genes were especially enriched with turning points in early adulthood, and also feature a disproportionate number of genes implicated in schizophrenia, whose onset occurs around this time. The genes tended to be turned down at this time, in neurons. While these observations correlate with the age-specific nature of schizophrenia, they do not go much farther, unless it could be shown that the genetic variants that confer susceptibility are perhaps mal-regulated and more active than they are supposed to be, or some other mechanism that makes the connection between the defect (all of which so far which have very weak effects), and the outcome. For example, one such variation was found to increase expression of its gene, which is present and functional in the post-synaptic densities.

It is interesting to see the developmental program of our brains portrayed in this new way, but it is only a glimpse into issues that require far more detailed investigation.

• Bob Cringely loses his house.
• Inherit the wind... or at least track it.
• Money + Stupidity + Democracy = Power

Vegas

A brief post.

Since no ideological, political, or religious motive has yet emerged for the massacre in Vegas, I would tend to interpret it as a terminal case of gun nuttery. We have long heard how violent video games and movies were supposed to be damaging our brains. Well, I think gun fetishization is an even stronger deranging influence. One can read it in the gun blogs, where a discourse of fear and power, of tactical preparedness and no retreat turn into a machismo echo chamber. And actually owning guns seems to have similar effects, turning owners minds to the power they wield, somehow generating the need for more and more, and more elaborate fantasies of what to do with them. Apparently 3% of gun owners own half the guns in the US. It is a disease, is culpable, and should be in the DSM.

• How to be a good parent.
• The 2009 infrastructure spending program turned instead into a fiscal lifeline for the states.

Father Dearest

Toxicities, perversions and archetypes around the father role. Based on Raised Right by Jeffrey Dudas, and Toxic Parents, by Susan Forward.

The father archetype looms large over our personal and collective lives. Fathers are inescapable, for better or worse, in their shaping of our identity, meaning, and purpose. Most cultures, including all those of Indo-European descent, are patriarchial. Father figures are central to our political lives and mythology. God is a father.

Our current political divide is steeped in the father archetype. Democrats are the mommy party, Republicans the daddy party. Never has that been clearer than with the current occupant of the White House, who seems to think that his orange patriarchial aura should suffice to get the entire country to fall in line behind every tweeted emission. But it is nothing to make light of- the psychology of these polar tendencies is fundamental to humanity and probably many other beings. Perpetual contrasts exist between competition and cooperation, risk and security, discipline and forgiveness, war and love, yang and yin.

A recent book about icons of the right argues that father mythology pervades the personal and political conceptions of the right. Fathers only have authority in the family if the state moderates its nanny-ish tendencies. CEOs only have proper authority if the state does not meddle in their companies. And the country is properly run only when a father figure lays down the law on standards of morality and behavior, however much that conflicts with the first two aims. Many prominent figures on the right have frought, to say the least, relations with their own fathers. Newt Gingrich comes to mind, but the author Jeffrey Dudas profiles William Buckley (absent, though overbearing, father), Ronald Reagan (drunk, weak father), and Clarence Thomas (deserted father, replaced by totalitarian grandfather). Each found a personal and political mythology in constructing a new image of the father figure, mostly drawn on the founding fathers.

It is the usual authoritarian / patriarchal story- what ails the world (read- the self, or the early self) is lack of discipline, and masculine modeling, which is supplied by the authoritarian leader who will restore order, law, and the scope for other elements of the patriarchy down the line (corporate, police-state, and family) to do likewise, will heal the society. This resolves the chaos resulting from lack of boundaries and discipline, and lack of social hierarchy. All this is claimed in the name of freedom- the true freedom of the orderly citizen, not that of the malcontent and rabble-rouser. Reagan provided an especially clear vision of this condition of the state, set in contrast to the hippie protesters on whom he cut his teeth as governor of California. And he justified it in terms of the American dream of freedom and equal opportunity for all- all virtuous and deserving citizens, that is.

All is well with this nuclear family, enjoying its driverless car in 1957.  Each person's role is well-defined and secure.

The problem is that, while the patriarchial virtues certainly have merit, they are hardly the only virtues. Worse, they tend to paper over a great deal of presumption about the fairness of the current starting conditions, and the ability of its stated virtues to afford the promised success, not to mention the sterling virtues and talents of those currently at the top of the heap. That is why Horatio Alger stories are such a staple of the right. If Clarence Thomas can make it, or Steve Jobs, or Jack Kemp, or .. fill in the blank... then anyone can, with enough gumption.

That is, however, a sucker's game, as likely to raise up the masses as is the local Indian Casino. Not only should success or even a decent life not depend on such extraordinary efforts and talents, but it clearly does not for the well-to-do, who bequeath countless social, material, and political advantages on their offspring, resulting in the remarkable lack of social and wealth mobility that we see in the US today. The starting blocks are starkly different for different people, and it is absurd to preach individual morality tales when material and other forms of inequality are so tragically and obviously responsible for the lack of freedom and prosperity for most citizens. Where are the reparations for slavery, for example? Also missing is any model or justification for communal, public goods. Life becomes a competition of atomized individuals, with family structure and discipline separating the wheat from the chaff, but without a rationale for wider social cooperation and institutions, such as public schools or anti-corruption mechanisms in government, or business regulation, that render the level playing field which the patriarchial myth assumes and depends on, but refuses to address.

Which is not to say that personal virtues, just saying no, stick-to-it-ive-ness, discipline, and the like, are not good things. The wise and benevolent father figure is also a very good thing. Yet, as Susan Forward points out, toxic, abusive, and even incestuous, parents are all too common. One in ten families, by her estimation, experience incest. It is shocking and horrifying, yet preaching from on high is not going to help, particularly as the perpetrators are often the very ones, through the magically empowering nature of the archetype, doing the hypocritical preaching.

Indeed, it is the damaged children who seem to end up on the right, latching on to the one certainty they have learned, that their own efforts avail them something in the rough-and-tumble of life. Desperate for good parenting, they seek father figures and a father mythology that will heal. And one is naturally ready to hand, in the patriarchy, the founding fathers, orginalism. Virtually every religion furnishes the same tale- a father who is both loving and strict, giving commandments and boundaries with one hand, while providing hope of temporal and supernatural power with the other. Most people don't take it too seriously, but if the need is intense enough, if the child within is damaged enough, this patriarchal solution seems to become a template for everything- how to live one's own life, and how the nation should be run as well.

As Dudas writes:

"Not exclusive to modern American conservatism, this longing for stability, for an end to what Willam Connolly calls the 'homesickness' of the human condition, is a hallmark of modern living. Modern times, Connolly argues, are defined by the widespread loss of belief in transcendent purpose (in 'myth') and, accordingly, by an eruption of nihilism. But this nihilism, and the felt loss of meaning that accompanies it, (of Kristeva's 'melancholia'), is so upsetting that it has been the subject of an astonishing range of ameliorative attempts. Hence the feverish devotion to those human projects that attempt to establish the sorts of 'antimyths' that Fitzpatrick locates at the heart of modernity: projects of science, reason, and the state, for example, with which human life might be organized and infused with the noncontingent foundations that existed before (to paraphrase Nietzsche) humans killed off God.
...
But as with all other modern attempts to forestall nihilism, it turns out that the melancholic's desire is 'impossible'. ... The desire for the stable object is impossible and magical because the object (Father) is oversaturated with meaning; it is itself a floating signifier that is purposed and repurposed according to the endless demands of desire rather than to the rigors of logic or intellectual coherence."

Our current president is a damaged child, from a totalitarian father, who reproduces the same parenting style with his own children, and now towards the rest of us as well. Add in desperate narcissim, and the result appears to be pathological lying and manipulativeness, as well as complete blindness to the perspectives of those not on his favorite cable news channels. We have all become victims of bad parenting, and need to redouble our efforts to break the cycle.

• Back when the government ran finance, not Wall Street.
• Too many old savers leads to persistent low interest rates and inflation.
• The market is quite high.
• North Korea has very effective deterrence.
• The rich are still getting richer.
• Getting a PhD is not so great for your job prospects.
• Annals of feudalism, cont... workers are about to be stripped of legal recourse for abuse.
• Economic graph of the week. Robbing the poor to give to the rich, under the proposed tax "plan".

Who pays what under the new plan?

Profiles in Greed

Ulysses S Grant, Carl Icahn, and the character of capitalism.

Listening to a long podcast series about the Civil War, I was struck once again by the unusual character of our 18th president. Every one who knew him agreed that he had no sense for business. Yet he led the US army to a series of strategic victories, and wrote one of the great military autobiographies, and clearly did not lack intelligence. What makes the difference?

To contrast, a recent profile of Carl Icahn, paragon of US business and hero of Donald Trump, paints a character of quite a different color. Highly intelligent, yes, but with the added characteristics of intense greed and minimal scruples- apparently a modern-day Ebenezer Scrooge.

Grant was a forthright person, in love and war. Indeed, the archtypal story of his childhood was about a negotiation for a horse where he told the seller straight out what he was willing to offer, which thus became what he paid. Grant was very good with horses, possibly a mark of a character with less guile than normal. People, with their less scrupulous machinations, were more difficult, which clearly led to many of the disasters of his presidency. Does warfare require guile? On some, very strategic level, yes. But generally, clarity, consistency, attention to detail, and courage are more significant virtues. I don't think his Civil War campaigns were marked by strategic cleverness or deceit, but more by sound military reasoning, siezing strong points, deploying overwhelming numbers, fighting doggedly, and pursuing advantages opportunistically.

Ulysses Grant, colorized

Many of these virtues are relevant to business, but evidently one needs something more to succeed. The profile of Icahn describes in detail how he tried to use his influence with the president and his position as a semi-official economic adviser for personal gain- to rescind a rule requiring oil refiners, one of which Icahn owns, to blend ethanol or else buy offsets on a special market. His refiner could not blend ethanol, so was subject to a quite volatile market in RIN offsets. While unsuccessful, the effort was flagrantly unethical and illustrated Ichan's intense greed, his great skill in manipulating others, and his consistent practice of skirting the law whenever possible and advantageous. What a contrast to Grant! And something of a contrast to our current president as well, who isn't smart enough to be in the same league, and looks up to Icahn as a hero who sits on a far larger pile of money.

There was a brief period in the mid-20th century when business leaders were thought of as civic leaders as well. After the period of the robber barrons and Gilded Age, when the business community had been chastened by the great depression and the spectre of communism, (not to mention bitter union fights), and when the whole country had been brought together by the world wars. There was an ethic of fair dealing and paternalism towards workers, and of viewing the corporation as a public, civic entity, not just there to make money, but to play a supporting role in the American way of life. Perhaps I am looking back with rose colored glasses. At any rate, that period, however amicable, is long over. The captains of our current corporate landscape, especially those in finance, are poor models of any kind of ethics; scofflaws who are fined repeatedly, even in our attenuated enforcement landscape, providing models of greed, entitlement, and callousness.

How anyone could imagine that today's celebrity business leaders would make proper and positive civic leaders, particularly someone as twisted as our current president, is unimaginable (Michael Bloomberg excepted, perhaps). So now we are in an insult contest with North Korea, (among others), at an abysmal level of rhetoric which expresses perfectly the level of intellect and ethics our leader is bringing to the table, but which should surprise no one watching his business career or those of his colleages in the contemporary business world.

• I should be very unhappy right about now.
• Enemies bond groups.
• Francis Crick.
• State's rights, but only for crappy policy.
• Puerto Rico brings to mind.. guns and ammo, of course.

Bullets of Poison

Lead, condors, and the toxic legacy of right-wing politics.

Of the many ways we have ravaged our environment, some of the most heartbreaking are the silent killers- DDT, other insecticides, PCBs, trash, CFCs, CO2, PFOA, and lead. The same technologies that have conjured out of our environment the many wonders of modernity have also unlocked demons, like plutonium and other radioactive poisons, which we struggle to control and dispose of.

But our thoughtless dumping of pesticides and other poisons doesn't even rate that kind of drama. It took an especially gifted writer, Rachel Carson, to bring the ravages of DDT to light 50 years ago, and we have since slipped into an amnesia through which other poisons like the neonicotinoids have seeped into astonishingly widespread use, making arthropod wastelands of our most fertile country.

One of the more insidious poisons is lead. Through the Flint water crisis, we have learned once again that lead is pervasive, and an enormous health threat. Why have we tolerated it for so long? It has taken painstaking public efforts to get lead out of gasoline, out of paint, and out of new water pipes. Yet it is still common in old pipes, and in coal ash, killing and impairing Americans continuously. And it is common in firearm ammunition.

Poisoning oneself and one's family by hunting with lead is one thing, and tragic enough. But it turns out that other animals can be even more strongly affected, particularly the California Condor. This magnificent bird, North America's largest, is, naturally, attracted to carcasses and viscera left by hunters, and is not a picky eater when it comes to lead. But even if they were, it would be impossible to avoid lead from such carcasses, since lead bullets leave a wide swath of fragments and contamination in the victim. Condors also have particularly strong digestive juices that mobilize more of the lead they ingest than do those of other predators and scavangers, making lead the leading cause of death among the painstakingly re-established and tiny wild population. Indeed, that population can not grow until lead is eliminated from its food supply.

California has, with great political effort, established a ban on hunting with lead ammunition, to take effect within a couple of years. The Obama administration likewise set up a ban on use of lead ammunition in federal wildlife refuges. But the new administration, in line with the rest of its immoral and mindless policies, reinstated the use of lead ammunition. It is one more example of the sheer meanness and spitefulness that seems to pervade this sector of American politics- a segment of the elite and the electorate that could not care less about nature, about justice, and about the future in general. As long as they are "winning" over their perceived enemies, in a zero sum spiral of death, scientists, truth, justice, and the future of humanity, not to mention the biosphere, can be damned. Even the US Army has recognized that the costs of creating enormous toxic waste dumps out of their firing ranges and conflict zones (not to mention the manufacturing stream) is too high a price to pay, and has switched to unleaded ammunition. (Though uranium- that is a different story!).

A similar story has played out tragically in India, where an antibiotic used in cattle turned out to kill vultures, wiping out the population, and causing some very unpleasant ecological consequences in a country in dire need of efficient trash and carcass collection. While we should not stifle all progress with overly cautious regulation, once a tragic consequence from some technological innovation (or ancient practice) becomes apparent, we should recognize our own power in the role of the government to set rules for the good of our long-term collective interests- interests which surely include preservation of our own health and that of wild animals.

• Defenseless animals are next.
• Krugman: it isn't just science at stake, but civilization.
• The irony of Texas.
• Silencers- as American as apple pie.
• Bias in the biomedical literature.
• Incentives only go so far. Character counts for a lot as well- about half.
• Problems with the upcoming Vietnam War.

A Cosmos of Fear

Not Your Father's Star Trek Federation: Cixin Liu's dark vision in "The Dark Forest". (Warning: Spoiler alert)

After slacking off most of the book, Luo Ji gets down to the business of saving humanity in the last couple of chapters, even as he is spat upon by his beneficiaries as a false prophet. It has not been easy for the wallfacers project, which Earth developed after learning not only that there are extra-terrestrial aliens, but that they are intent on taking over Earth, and are also listening in to everything humans are doing. The idea was to nominate a few super-people to think and scheme in the privacy of their own minds, where the Trisolarians (aka Alpha Centurians), couldn't listen in. Sure, this involves a total lack of accountability. But on the other hand, it is humanity's only hope for secure strategic innovation. Sadly, Luo Ji's three colleagues have either committed suicide or disgraced themselves with schemes bordering on insanity.

Luo Ji's strategic insight is borne of a shockingly negative view of how intelligent civilizations would operate and relate in the greater cosmos. It incidentally offers a fascinating and neat hypothesis to the question of why we have never detected, let alone been visited by, aliens. The hypothesis is that natural selection operates in a particularly brutal way among rapidly developing, and far-distant civilizations. Communication is essentially impossible due to the distances involved. Yet the technological scope of civilizations that have a billion or two years on us is still remarkable, including missiles made of strong-force matter, vastly harder than regular matter, missiles capable of destroying whole stars, star-based amplification of messages that can easily be heard by the entire galaxy, and manipulation of sub-atomic / string theory dimensions to create protons with special computational and communication properties. The upshot is that a civilization can grow to highly threatening capability before others even know of its existence. All civilizations at some far level  of advancement are mortal threats, in principle, to others they know about, and given some with fewer scruples, some of them will simply extinguish any local threats they learn of, before asking too many questions.

Thus the cosmos becomes a very dark place, where announcing your existence is tantamount to a death sentence, there being far, far more advanced civilizations always listening and on the lookout for either room to grow, or just threats to their own comfort and security. Nothing could be farther from the positive vision of Gene Roddenberry, which, admittedly, was developed out of a social agenda rather than a study of galactic sociology and biological imperatives.

What is one to think of all this? Firstly, much of the science underpinning this vision is fictional, such as star-killing technologies, and matter manipulation at theoretical or inconceivable scales. Secondly, insofar as the model is biological evolution, it takes far too dim a view of the possibilities and benefits of cooperation. Evolution has shown countless times that there is room for cooperation even amidst the struggle to survive, and that cooperation is the only way to gain truly vast benefits, such as from multicellularity, eukaryotic organelle specialization, and human sociality. Thirdly, we also know from our strategic games with existentially destructive weapons, such as is presently playing out with North Korea, that deterrence rather than offense becomes the principal goal among those having achieved such powers. Would deterrence work in cosmic game theory? It is a problem, since, given a star-killing capability that takes many years to travel to its target and presumably could not be detected at launch or perhaps even at close proximity, offense might happen with impunity. (The Milky Way is about 100,000 light years across.)

But perhaps the most persuasive argument is simple morality- that despite the cold logic Cixin Liu develops, intelligent beings of such vast sophistication are probably more likely to wish to learn about other civilizations than to destroy them, whether out of boredom or out of a Prime-Directive kind of respect and interest. It is sort of unimaginable, to me at least, that the explicit goal of any advanced civilization would be to sterilize its environment so completely, even if unadvanced human history does offer that as a common, blood-drenched, theme.

• Toles on the maelstrom.
• Noonan, defending the indefensible.
• Do we want open borders? Not if we want a welfare state and other public goods.

PIWI and Friends Fight Zombie DNA!

How tiny RNAs fight the good fight to keep mindless, selfish junk DNA from eating the rest of the genome.

Our genomes are full of junk. Only about 5 to 10% of it has any function at all. Not only is the rest junk, but over half of the genome is made up of transposable elements (also called transposons) in various states of mutational disrepair, mostly fossils and relics. These are selfish DNA "organisms" (about 6500 basepairs long) that when fully functional can reproduce by making copies which insert themselves elsewhere into the DNA. They are like zombies, mindless and simple, knowing nothing other than an implacable desire to reproduce by using the other machinery of the cell to attack the rest of genome with yet more copies of themselves, and continuing to do havoc even when partially diabled. This kind of thing can, naturally, be very damaging. That is why our germ cells have special protection through tiny RNAs called PIWI RNAs, or piRNAs.

piRNAs, at about 26 to 31 nucleotides in length, are even smaller than the transposable elements they defend against. In the typical case, they are encoded by one of thousands of clusters sprinkled around the genome. They are expressed mostly in the germ cells, where it is naturally of particular importance to keep transposons under control. After being processed to their mature size, they bind to partner proteins of the PIWI family forming a guided missile that finds the matching (i.e. complementary) sequence among other RNAs in the cell- those made by its target transposon- and destroys that RNA by chopping it up. We have tens of thousands of these piRNAs, and if their action is inactivated, transposons start jumping around at a hundred-fold the normal rate, and the sperm (this is usually studied in males) is infertile, because of all the damage, though also because of other roles piRNAs have in this process.

Where did this mechanism come from? It seems to be quite ancient, as is the race between parasitic DNA elements and cellular organisms. Sponges have them, and all eukaryotes even prior to animals all have the related miRNA systems which also act to cut up or down-regulate target RNA messages. How did we accumulate so much piRNA, on the order of 6,000 clusters encoding hundreds of thousands of individual units in our genome? That was doubtless driven by the promiscuous and persistent nature of the transposable elements they are fighting against, via natural selection. But do piRNA genes develop directly from transposons in some fashion? Otherwise, the cost from randomly mutating and hitting other parts of the genome by mistake could be quite high.

Indeed, there is something called a ping-pong mechanism that generates extra piRNAs from the remaining fragments of piRNA-cleaved transposon mRNAs. This helps finish the job of defense, but whether such piRNAs can somehow lead, even rarely, to extra units of genomic piRNA, via reverse transcription or other means, is yet unkown. What is known is that the clusters from which piRNAs are expressed are graveyards of old, defunct transposons. These regions seem to be specially marked in the chromosome, in ways again dependent on the piRNA system, so that they get transcribed and processed into piRNAs, rather than other things.

Basic cycle of piRNA production, action, and ping-pong propagation. After production and processing, short piRNAs (red), docked to their PIWI protein partners (Aub), direct the cleavage and destruction of transposable element RNA (blue). Some of the resulting pieces dock with another PIWI protein (Ago3), and get likewise processed to repeat the cycle on the complementary strand, which repeats again, etc. This makes the accuracy of the original targeting critically important, of course.

To do this, piRNAs have another role, which is to direct methylation of the DNA, setting up specialized chromatin zones. While all the other defensive operations of the piRNAs have been in the cytoplasm, this takes place in the nucleus, using different PIWI-related proteins. This process targets transposons as well as the related piRNA-generating clusters, and has a two-fold point. In the first place, it strongly represses normal transcription from transposons, another form of direct defense. Secondly, it seems to switch these regions into the piRNA mode of production, where altered transcription, which is not very well understood yet, generates the long piRNA precursors (rather than the transposon messages) and initiates their processing.

As if that were not all, piRNAs are sprinkled around the rest of the genome in normal genes, which they help to regulate. At later steps of sperm production, after the major role of defense against transposable elements has passed, this other class of piRNAs destroy most of the remaining cellular mRNA, to streamline the cell down to only the essentials. How this dramatic event is controlled and restricted to these times is not understood, however.

There is a great deal more to be said and investigated about this genomic quasi-immune system. However it is already clear that it is a critically important process that mobilizes massive resources, in a quiet arms race that we are running against persistent and ancient enemies that lurk within.

• Trains are the efficient way to travel.
• A history of parochialism in modern Egypt. Is the Brotherhood a nationalist model?
• "Unfortunately half of the violent crime in the United States goes unsolved."
• A nation of laws and justice, or of one race?
• The nation state remains the fulcrum of power, for better or worse.
• Krugman- Zoning in prosperous areas strangles construction and raises housing prices, not to mention fostering homelessness.
• The Russian view of history.
• The Afghan army is not very good.

Mass Transit is Pleasant Travel

Let me count the ways.. I love mass transit.

Love to drive? Some people do. But do you love to drive in LA? The pleasure of driving goes down dramatically in congested conditions, where what was once a carefree sail down the freeway turns into a white-knuckled fight for free space, slowing to a frustrating crawl through a baking, exhaust-filled parking lot. Then there is the fear of accident and injury. Every day, the radio traffic report provides bland "injuryaccident" reports from the metro area. Driving has turned into a nightmare.

The US has not built significant infrastructure, particularly roads, for decades, and it shows in worsening traffic conditions. In parallel, housing prices go up, thanks to an unwillingness to zone for growth in housing as well as in traffic. Yet our population still goes up, despite the sclerosis in public policy. What can be done?

Entering BART trains is easy...

Some urban areas have an answer to the car, and it is mass transit, either by train or bus. The New York subway system ridership has gone up steadily, and is now at 5.7 million per day. The Bay area subway system, BART, has also experienced strong gains, to half a million riders per day. All this despite the growth of ride-share services which, while they may relieve the user of the task of driving, do nothing to resolve the uncertainty and unpleasantness of congestion on the roads.

I have recently switched to transit for a long cross-Bay Area trip, and it has been a revelation. Gone is the road rage and isolation, replaced by abundant people-watching and the ability to just look out the window, or rest (or work). The occasional stress of making a properly-timed bus or train is significantly less than the constant stress of preventing death or collision in a car. Granted, the seats are rarely very comfortable, and not everyone is friendly, or even sane. But on the whole, it is an easy call, especially since the direct costs are almost precisely the same, even before amortizing the cost of the car itself, not to mention those to the planet.

• Is Afghanistan a satrapy?
• Afghanistan: rural areas are important, Pakistan is still bad.
• Pakistan: "Who, us?"
• Science- broken, or not so bad? And do different fields have different standards and forms of corruption?
• Our media maelstrom.
• This just in: insecticides kill insects.
• Bullies and jerks.. why?
• Workers will still get the shaft.
• Russia is still there.
• How far will denialism go?
• Environmental graph of the week: California electricity grid during the eclipse. Overall peak demand is about 40,000 Megawatts, so solar generation provides roughly one quarter of peak demand in the state.

The California Electric grid, 08/212017, 5 PM (top), compared to the day before (bottom).

School of Hate

13 Reasons and the dark side of high school.

Why all the hate? Hate has elected a president, and is his tireless message over the twitter-waves. Hate is loose in the Muslim world, in a campaign to instill fear in its enemies. We seem to be prone to it, and can be consumed by it, unawares.

I have been enjoying a Netflix series, thirteen reasons why, which incidentally was partly shot in my city. The titular reasons are ones for suicide, of the main character Hanna. And they are recounted by her in tapes being played after the fact, as the series progresses, by her best friend, Clay. Generally, the production is not very innovative, but the flashbacks and dream sequences are done with great care and style.

Its topic is how horrible high school is in America. Leaders of Britain may be formed on the playing fields of Eton, but American leaders are formed in the hallways and locker rooms of our public high schools. Which are not a pretty sight. The series is a very frank, if lavishly dramatized, look at how teens jockey for power and status, mostly by running down and terrorizing their schoolmates.

Most obvious are the jocks. Having bought into the official / corporate / archetypal system of status through athletics, they are children of privilege, loved by the administration, confident that even if they are not liked, they will be popular anyhow- that is just the way the social system works. They don't come off well in this show, giving in to every amoral whim from booze to bullying to social media meanness, thoughtless when they are not being mean.

From there, we go on to other dramatic dilemmas, of closeted gay students, stalking photographer, catty ex-girl friends, and so forth, salted by a variety of subplots among the adults, like the big-box "Walplex" taking over the town and the school administration covering its ass from Hanna's parents' lawsuit. Hanna was evidently failed, if not terrorized, by a fair proportion of the student body among others. I have not gotten to the end, but she will clearly have plenty of reasons when we get there.

Clay in class

But why is hate so easy? Is hate fun? Is it natural? Yes on both counts. Fascists know well that crowds and hate are a potent, even easy, combination. But it is also one of the most primitive, selfish, and useless emotions. Children hate quite easily, and have grievances that erupt into towering emotion. Growing up means putting a lid on them, so that we can work with all sorts of people, and work effectively without getting side-tracked by emotional baggage. We have created a emotional petri dish for teens by concentrating them in schools, with lots of leisure time, and little serious work. No wonder that the devil finds them such easy prey. Which is to say, their childish emotions, not quite under control or under moral direction. That we elected such an immature person as president speaks to a larger failure of our educational system- that it has failed to advance not just one, but far, far too many US citizens to an emotionally healthy and insightful adulthood.

All religious traditions have technologies of controlling hate, even if they then channel it to their own ends. Buddhists take the most uncompromising approach, decyring all such emotions as false, and engaging in lengthy love-inflected meditation to expunge such thinking. Yet Buddhists have had their wars and hate speach all the same- pacifists have a problem when faced with adversaries more willing to hate than to love. Christians have an ethic of love, yet hatred of Jews (how ironic!) flourished for centuries all the same. Muslims have the Sufi branch, their relatively pacifist brethren. But on the whole, Muslims have a simple and straighforward relation to hate- a deeply tribal approach where infidels are hated, and believers are loved. Except when they are of other sects, in which case they are hated anyhow. The Middle East is about to blow up again, along the Saudi Arabia - Iran axis of hate. So religions are a useful source of ideas and methods of human cultivation, but by no means the or a general answer to moral teaching.

Is it good that American school students go through an education in bullying, hate, and power politics? Most make it through OK, and many find highly positive environments where they find support and direction towards a happy adulthood. Does sobering, even terrorizing, interaction with the dark side build maturity, as it does in fairy tales and dreams? Perhaps so, but the costs are enormous, since many children do not make it out whole and unscathed. Simply put, children do not make a mature society when left to themselves. The under-adulted structure of public schools leaves quite a bit to be desired, in that it does not sufficiently occupy or guide young people.

• Are all males this bad?
• Mentally limited. Mentally impaired. Corrupt. Treasonous.
• Krugman- have Republicans no decency, or spines?
• A wildfire on Greenland?
• Are protests with guns different from protests without?
• Corporate concentration and lack of competition has contributed to lagging pay.
• Notes on the conventional view of unemployment.
• Summers- monetary policy can not do it alone.

Genocide, Lebensraum, and the American Dream

Overpopulation is the normal condition, with intermissions after genocide.

As a recent article pointed out, the American Dream has undergone some changes. Where in the Depression, it was an idea of human decency, equal opportunity, and basic living standards for all, it has more recently become more focused on a prosperity gospel, with owning a house as the centerpiece of "making it". This presents great problems, since our society has become so sclerotic and unequal that defining our civic values by such inflated metrics leaves a very large and increasingly restive population behind. One hears echos of "Let them eat cake".

Long before either epoch, however, the American Dream was one thing- free land. Land for the desperate paupers of Europe, land for anyone willing to work, land for the taking and "proving". Rich, beautiful, verdant, and virgin land. With occasional interludes for gold rushes where the free-for-the-taking wealth was underground rather than on the surface. It was a Dream built on the genocide and dispossession of the previous occupants of all this land- the Native Americans. While most of that work was done silently by European diseases, the nascent colonial states were not shy about cleaning up the loose ends, with a manifest destiny of taking ownership of all useful lands of any kind across the continent, leaving the native peoples, when they were not killed directly or by mistreatment, in reservations on the most miserable land available.

Why, then, were we so exercised about the policy of the Nazis in the next century to spread eastward, over the great prairies of central Europe, in search of "Lebensraum"? Was it that those prairies were already occupied? Or was it that they were occupied by people significantly more similar to ourselves, not susceptible to the European diseases, and aready farming, and ready to complain in comprehensible languages? That of course is a bit unfair, since the Nazis authored a much wider range of mayhem, through Europe and world-wide, than just their push to the East. But it is worth re-evaluating our national epic and mythology in this light, since it brings out fundamental forces that recur through history, and promise rocky times ahead.

As Thomas Malthus observed, the natural state of any population of organisms, including humans, is overpopulation. Remissions of this state can happen by predation or catastrophe. Genocides, devastating wars, plagues, droughts, and the like can provide brief respite from this normal, cramped condition. The discovery of the Americas by Europeans was one such event, (as it had been for the Clovis people and their predecessors as well), providing an escape valve, given a total lack of compunction about stealing the lands of others. Another such event has been the technological development of the West, especially our use of fossil fuels, which have magnified our powers and particularly our farming capabilities, with new fertilizers and machinery. This has meant that through the last roughly 300 years, we (especially in North America) have faced a substantially relaxed Malthusian constraint compared to most human cultures. I recently read the biography of the famous jocky Ron Turcotte, who narrates his childhood in New Brunswick thus:

"We have four kids. A big family now is six. Back then, when we were growing up, families of twelve or thirteen were common. One family had twenty-three. We had a very strict priest. if you didn't have kids, you weren't doing what God put you on earth for." ... "The priest would come in, and if there wasn't one baby in diapers, one in the womans' arms, and one in the oven, he'd say the couple was not doing its Christian duty."

So here we are, at a state of dramatic overpopulation, using the lands, air, and minerals of earth far, far beyond her ability to sustain us, using fossil fuels which can never be replaced and which are heating the climate and destroying the biosphere. In the US, we are coming to a state of culture and class war that is a sign of stasis/crisis. The pie is not growing bigger. Overpopulation generally means, culturally, that there is an excess of workers relative to productive capacity, which gives power to capital and those who already have power. It is the kind of situation that leads to inequality, castes, feudalism, and sclerosis.

There are no more frontiers, and we are already living far beyond earth's carrying capacity. By the natural processes of selfish greed, our home is turning into a dump. For example, we are not, in all honesty, close to resolving our carbon dependence, among many other limitations- emissions are rising, not falling, let alone reversing damage already done. In the US, our population is rising relentlessly, yet we have not built significant roads for decades, or even maintained the ones we have. For various reasons of self-interest and cultural drift, we are collectively unwilling even to face up to the population we have, let alone make room for more, were that even desirable. So until we resolve our long-term sustainability issues, we should focus on population reduction, ideally with a universal one-child policy.

While the American Dream has narrowed to one of personal greed, we are at a point when we can and need to think globally, for the long term. The dream should be one of sustainability, over hundreds and thousands of years, given the momentous consequences of our current technologies and lifestyle. Giving in to rampant population growth, however natural it may be, dooms us to an ever more impoverished country and planet. It would be a tragedy, alongside the related tragedies of denying the very reality of climate change, and weakening our scientific and social consciousness of its future course and consequences.

• When psychopaths go to work.
• Though the difference from anti-social personality disorder is not very clear.
• It is all the fault of IT.
• Subversion is raising protests.
• Beauty and the brain.
• Consciousness is real?
• No wonder people in the UK are cranky.
• Drug companies- the answer is single payer.
• The Afghan government can not hold on to its own territory.
• Keynes and interest rates.

An Egg Asks: Which Way is Up?

One of the prototypical morphogens, bicoid, tells fly eggs what's head and what's tail.

Translating the digital instructions of the genome into an actual body is the complicated work of development. It is obvious that the instructions are not explicit or specific, mapping out where every organ, cell, and molecule is supposed to go. Rather, the code provides ingredients and rough guides to channel development in favorable directions, relying heavily on implicit, default processes to fill in the details.

One way to amplify a digital code is to use a morphogen- a substance with an analog character, whose concentation varies with location and can give many of those locations different instructions. Morphogens are used extensively in body and brain development, and one of the first to be found genetically was bicoid, one of the proteins responsible for telling Drosophila eggs which end is anterior, and which posterior. The name comes from bicoid mutants, which end up with two tails (bi-caudal) and no head- naturally a fatal condition.

Effects of a complete bicoid deficiency.

Bicoid mRNA is deposited by the mother in eggs in a strongly asymmetrical fashion, at their anterior poles, so they are pre-oriented. When the egg is fertilized, this mRNA starts getting translated / expressed into bicoid protein, which is the actual morphogen. This is a DNA and RNA-binding protein, and regulates the expression of other genes. Bicoid expression is inhibited in the posterior by the protein nanos, which is concentrated there. Conversely, bicoid inhibits the expression of caudal, another protein that is concentrated in the posterior and directs posterior cell fate. Bicoid regulates at least 70 other promoters/genes to activate anterior cell fates, among them the next levels of location specificity genes, the gap (hunchback, giant) and pair-rule genes (krüppel, even-skipped). The interplay of numerous positive and negative regulators of this sort, others of which take over subsequently at ever finer levels of detail, creates a relatively robust system of cell specification which allows bodies to be made consistently under a variety of temperature, nutritional, genetic, and other conditions. For details, the fly community resource is valuable, as is a reference work.

Expression of some key genes in fly embryos, bicoid at anterior (left, blue) and caudal at right (red). Evx (yellow), is a relative of even-skipped, both pair-rule genes that specify finer segmental-scale divisions in the embryo than do bicoid or caudal.

A recent paper used new methods to study the activity of bicoid in detail, turning it on and off at will. They replaced the normal version of the gene with one carrying two extra protein sequences, one of which rendered the protein conveniently fluorescent (in red), and the second of which, on exposure to light, binds to other proteins in the cell, typically turning it to an inactive state. This engineered protein provided normal bicoid function when the flies were raised in the dark, but turn on the lights, and activity dropped immediately, allowing study of exactly when it is needed, and for what. Unfortunately, this turn-off only applied to one of the protein's activities, its transcriptional activation. Its second activity, of translational repression (of caudal, among other genes) was unaffected by the light-switch protein fusion.

It had not been understood just how long during embryogenesis bicoid is needed, whether only at the start, or ongoing through many stages. What these researchers found is that bicoid is needed into surprisingly late stages, to within 10-30 minutes of gastrulation, which is very roughly the midpoint of early embryogenesis that goes from egg to hatched larva. What is bicoid doing through all these later points in time, when its fundamental job was simply to instruct the next set of location-specific genes, the gap and pair-rule genes, where to turn on- a job that is over long before gastrulation?

Impact of brief light exposure (i.e. shut-down of bicoid) on development. Note that even the briefest interruption, for 10 minutes just prior to gastrulation, causes mal-development of the anterior-most (left) head section, comparing B' and C'. "n.c." refers to nuclear division cycles, which are a standard / convenient way to time the progress of these early embryos. Proteins stained are engrailed (En), deformed (Did), sex-combs reduced (Scr), abdominal-B (Abd-B), and (not stained), ultrabithorax (Ubx).

It turns out that many genes and cell types of the anterior have evolved in the presence of bicoid, and so have come to depend on its presence. Genes farther back in the fly have to make do with lower levels of bicoid protein, are more sensitive, and need its actiavtion more briefly (such as the mid-section gap gene krüppel). But in the anterior, the large and durable amount of bicoid has fostered a dependence well beyond the early roughing-out of the segmentation pattern. For example, knirps, a gap gene with head expression, is highly sensitive to bicoid activity and plays a key role in anterior fate specification, needs bicoid activation right up till gastrulation.

Length of time bicoid is needed, with respect to position in the embryo. The colored lines depict when bicoid is required in the corresponding segment(s).

"A minimal 20 min illumination at the end of n.c. 14 abolishes the expression of the Knirps anterior domain (Kni1) capping the tip of the embryo, as well as the first Giant stripe (Gt1). "

While not terribly pathbreaking in its conclusions, this work shows progress in the level of detail being studied, enabled by remarkable technological advancements. The authors even resort to computer modelling to make sense of the complex network of regulators, only a few of which were touched on above. Fruit flies have been the leading model system of animal development for over a hundred years, and are still going strong.

• Anatomy of fake news.
• Tump's model is complete and utter corruption.
• Dedicated to class warfare, and little else.
• Annals of resentment and entitlement.
• Bill Mitchell is still at it. Australian internet is a "luxury".
• Where we are in Afghanistan: "preventing defeat".
• .. in a land of deregulation and low taxes.
• You don't have to be a free-marketer to be sad about Venezuela.
• Some Americans are not fact-based. But if not fact, then what is the motivation?
• How to defeat fear and hate.
• More about the insanity of the current health care system.
• Private currencies do not accomplish the most basic function of stability.
• How the rich, especially the real-estate rich, avoid taxes.

Prophetic Diagnosis

Using MRI to detect brain damage that leads to temporal lobe epilepsy.

Magnetic resonance imaging has been an amazing and flexible technology. It has been tailored to varying chemical targets and environments, so that both chemical and anatomical details can be visualized. A recent paper (review) deployed tractology, which uses MRI to trace water diffusion in lengthy neurons and related cells, to vizualize detailed brain organization.

They were looking for traces of damage or change that could predict or correlate with epilepsy. Their model was mice, whom they injected with kainate in their hippocampi. Kainate over-excites and rapidly kills neurons, and this particular injection is known to induce temporal lobe epilepsy, a syndrome that can be brought on by genetics or trauma in humans, and is known to cause not only seizures, but also other problems such as memory loss, depression, personality changes, and hyper-religiosity. Whether the mice start propounding new religions is naturally unknown.

Time course after injecting damaging chemicals into the hippocampus of mice, and then tracing the growth of new glia oriented cross-wise (green, in box) versus the native neural tracts.

What they did find is that they can track damage in the mice quite easily, and this brain damage takes the form, in part, of new tracts of (glial) cells that grow cross-wise versus the native neural pathways. This helps to rationalize what may be causing the epilepsy, and was supported by finding similarly deranged tracts of glia in the brains of humans suffering from temporal lobe epilepsy and hippocampal sclerosis, which is the main physiological finding associated with such epilepsy, especially forms that can not be treated by drugs. And the severity of the lesion, which in the mouse system is traceable from very early times, prior to the onset of epilepsy, correlates in both systems with the severity of the eventual epilepsy.

Our study demonstrates for the first time that the extent of epileptogenesis-associated tissue alterations in the hippocampus directly mirrors the ensuing severity of intractable mTLE [mesial temporal lobe epilepsy].

This may provide and early way to check out brain damage that may lead to this syndrome, though what to do about it is a separate question, typically answered in these cases by surgically removing the mis-grown scar tissue that was studied here.

• Lies and more lies.
• Maybe cynical corruption (and mean-ness and greed) is all the "there" there is.
• War criminals? What war criminals?
• In praise of solitude.
• Wages are not a free or rational market.
• Except when they are.
• Productivity may not measure particularly interesting things.