On the Spectrum

Autism, broader autism phenotype, temperament, and families. It turns out that everyone is on the spectrum.

The advent of genomic sequencing and the hunt for disease-causing mutations has been notably unhelpful for most mental diseases. Possible or proven disease-causing mutations pile up, but they do little to illuminate the biology of what is going on, and even less towards treatment. Autism is a prime example, with hundreds of genes now identified as carrying occasional variants with causal roles. The strongest of these variants affect synapse formation among neurons, and a second class affects long-term regulation of transcription, such as turning genes durably on or off during developmental transitions. Very well- that all makes a great deal of sense, but what have we gained?

Clinically, we have gained very little. What is affected are neural developmental processes that can't be undone, or switched off in later life with a drug. So while some degree of understanding slowly emerges from these studies, translating that to treatment remains a distant dream. One aspect of the genetics of autism, however, is highly informative, which is the sheer number of low-effect and common mutations. Autism can be thought of as coming in two types, genetically- those due to a high effect, typically spontaneous or rare mutation, and those due to a confluence of common variants. The former tends to be severe and singular- an affected child in a family that is otherwise unaffected. The latter might be thought of as familial, where traits that have appeared (mildly) elsewhere in the family have been concentrated in one child, to a degree that it is now diagnosable.

This pattern has given rise to the very interesting concept of the "Broader Autism Phenotype", or BAP. This stems from the observation that families of autistic children have higher rates where ... "the parents, grandparents, and collaterals are persons strongly preoccupied with abstractions of a scientific, literary, or artistic nature, and limited in genuine interest in people." Thus there is not just a wide spectrum of autism proper, based on the particular confluence of genetic and other factors that lead to a diagnosis and its severity, but there is also, outside of the medical spectrum, quite another spectrum of traits or temperaments which tend toward autism and comprise various eccentricities, but have not, at least to date, been medicalized.

The common nature of these variants leads to another question- why are they persistent in the population? It is hard to believe that such a variety and number of variations are exclusively deleterious, especially when the BAP seems to have, well, rather positive aspects. No, I would suggest that an alternative way to describe BAP is "an enhanced ability to focus", and develop interests in salient topics. Ever meet people who are technically useless, but warm-hearted? They are way off on the non-autistic part of the spectrum, while the more technically inclined, the fixers of the world and scholars of obscure topics, are more towards the "ability to focus" part of the spectrum. Only when such variants are unusually concentrated by the genetic lottery do children appear with frank autistic characteristics, totally unable to deal with social interactions, and given to obsessive focus and intense sensitivities.

Thus autism looks like a more general lens on human temperament and evolution, being the tip of a very interesting iceberg. As societies, we need the politicians, backslappers, networkers, and con men, but we also need, indeed increasingly as our societies and technologies developed over the centuries, people with the ability and desire to deal with reality- with technical and obscure issues- without social inflection, but with highly focused attention. Militaries are a prime example, fusing critical needs of managing and motivating people, with a modern technical base of vast scope, reliant on an army of specialists devoted to making all the machinery work. Why does there have to be this tradeoff? Why can't everyone be James Bond, both technically adept and socially debonaire? That isn't really clear, at least to me, but one might speculate that in the first place, dealing with people takes a great deal of specialized intelligence, and there may not be room for everything in one brain. Secondly, the enhanced ability to focus on technical or artistic topics may actively require, as is implicit in doing science and as was exemplified by Mr. Spock, an intentional disregard of social niceties and motivations, if one is to fully explore the logic of some other, non-human, world.

• Autistic comedy?
• What happened to the war on poverty?
• How to think about cancer treatments.
• 95 year old judges, really? 

Founders, Schmounders

Elie Mystal rakes constitutional originalism over the coals, in "A Black Guy's Guide to the Constitution".

I was raised to revere the founders and the elegant, almost scriptural document they constructed to rule our society. But suppose I was a black person, knowing that these founders were the rich white guys of their time, owners and abusers of slaves? I might think that while their aspirations were rhetorically high, their constitution was rather more utilitarian in its denial of true democracy to most people living in the colonies, its indirect and unjust approach to the democracy it did allow, and its euphemistically stated, but absolute, denial of freedom to "other persons". I would have experienced the US legal and cultural system as one of systematic oppression, dedicated to the proposition that while white, rich, men might be equal in some way and enjoy a rules-based system, the larger point of the system was to maintain power in their hands, and deny it to all others.

At least that is the sense one gets from Mystal's book, which, along with a lot of colorful language and wry jokes, assembles a trenchant rebuke of the American constitution, of conservatives, of Republicans, and especially of the originalist ideology of jurisprudence. Every hot button topic gets its due, and every amendment its contrarian interpretation. The second amendment is easy- it is about a regulated militia, after all, not about some commandment handed down from Charlton Heston to the ammosexuals of the nation to stock up on AR-15s and have a mass shooting if they are feeling a little antsy. 

Police brutality, prejudice, impunity, and immunity from accountabiliy is another easy, if painful, target. Mystal describes how he has been profiled and roughed up, for no other reason than being black. The legal system seems to have driven a semi through the fourth amendment against unreasonable searches when it comes to vehicles owned by black people, for one thing. And the fifth amendment comes into play as well- why do we allow police to play cat and mouse with suspects, trying to trip them up and get them to confess, cutting corners and playing games with their Miranda rights? Mystal makes a strong case for doing away with this whole theater of intimidation, with its slippery slope to fraud and torture, by barring police from eliciting or transmitting confessions at all, period. He notes that anyone with even a glancing acquaintance with the legal profession has learned to say nothing to police without a lawyer by her side.

Mystal's approach to abortion, however, is where this book really shines. Was Roe "wrongly decided"? Hardly. In the first place, Mystal provides an interesting discussion of "substantive" due process, (fifth amendment, and fourteenth), meaning that the rights and protections of the constitution are not to be taken merely literally or trifled with by twisting their meanings. They must be afforded by realistic means and set in a legal / civil system that supports their spirit. And that means that the right to privacy is a thing. While its poetic origin may be in the "penumbras" of the constitution, it is integral to the very idea of much of it- the concept unreasonable searches, of rights against self-incrimination, of any sort of rights of the individual vs the state. This is not to mention the ninth amendment, which asserts that just because the constitution and bill of rights mentions some rights explicitly, that others by their ommission are not covered. Privacy would, in general terms, clearly fall in this category.

But where else could a right to abortion be found? Plenty of places. One is the equal protection clause of the fourteenth amendment. Mystal, and many others, note that this should be taken as applying to women, making the whole equal rights amendment (ERA) unnecessary, given a modicum of enlightened interpretation. It could also be taken to afford men and women equal protections regarding reproduction, meaning that the penalty for a roll in the hay should not be grossly unequal, as it is when abortion is banned. Mystal goes on to suggest that the eighth amendment against cruel and unusual punishment could be invoked as well. If men were faced, as a penalty for sex, months of mental and physical torment, and then the excruciating labor of birth, one could be sure that no court would consider banning abortion for a nanosecond. And how much more cruel and vindictive is it be if that pregnancy arose from rape? There is also, after all, the thirteen amendment against involuntary servitude/labor.

Originalists brazenly throw their so-called principles out the window when it comes to abortion. Unenumerated rights? Never heard of them. Keeping the state out of the most sacred precincts of our private lives? No comment. Colonial attitudes towards abortion were very loose, nothing like the personhood-at-conception garbage we get today from the right/Catholic wing. It just goes to show that a little knowledge (here, of biology) can be a dangerous thing.

It is really originalism and conservatism, however, that is the overarching and corrosive topic Mystal takes on. The founders were people of their time, and that was a white supremacy kind of time. They wrote a constitution with hopeful ideals and judicious language which insulated it somewhat (though hardly enough!) from the prejudices of their day. To say that our current interpretation of their words should be confined to whatever psychoanalysis we can make of their meanings at the time would lock our whole political and legal system into those same prejudices that they were trying to overcome. To take the second amendment, Mystal argues (I am not sure how successfully) that its "militias" were most keenly understood to mean bands of Southern planters gathering together to prevent or put down slave revolts. Southerners did not want to be dependent on Federal sympathy and arms, and thus insisted that a right to raise their own militias for their own peculiar needs should be enshrined in the constitution. Well, if we were to restrict outselves to such an interpretation, that would have significant effects on our practice of the second amendment. Gun control would be allowed in the North, just not in the South, allowing guns to white males with certain property qualifications, perhaps, and certain mental proclivities.

Even the civil war amendments would be infected with originalism, since very few people at that time envisioned the full social equality of black citizens. It is remarkable to consider the flurry of anti-miscegenation laws passed during the Jim Crow era, after the Southern slave owners had spent a century or two conducting forced miscegenation. Whence the squeemishness? Anyhow, consistent originalism would never have struck down such laws, or abetted the civil rights movement for blacks, let alone gays. Mystal imagines the nettlesome questioning of a prospective conservative justice going like: "Do you believe that Loving v. Virgina was rightly decided?" This case was about the social system of the South, which Mystal tries to separate from the legal and political aspects, and clearly on originalist principles could not be decided as it was. And much more so on Obergefell, which draws on the fourteenth amendment's due process concept to free personal choices (of gay people) from government intrusion, again doubtless totally in contradiction to the social vision and intention of any of its authors.

Instead of fixating on the past so much, in constitutional interpretation, we might think about the future more.

So originalism, for all its rhetorical seductiveness, (after one has been properly indoctrinated in the divine virtues of the founding fathers), is an absurdity for a country with even the tiniest ambition towards social progress, or change of any kind. It amounts to extreme conservatism, pure and simple. Mystal is relentlessly dismissive of the conservative mindset, tied as it is (ever more explicitly in our polarized moment) to regressive, even violent, racial anti-minority politics. 

What is the deal with conservatives? I think there is another unenumerated right that undergirds all these tensions, which is the right to win, and win by inheriting what our forebears wrought- physically, monetarily, politically, socially. America is a highly competitive country- we compete in making money, in politics, in sports, in war. In any society there is an inherent tension between the cohesiveness required to build common structures, like a constitution, or a military, and the the competitiveness that, if channeled properly, can also build great things, but if let loose, can tear down everything. The right to succeed in business, and to bequeath those gains to one's children- that is a widely shared dream. Our founders saw that there had to be limits to this dream, however. The creaky aristocracies of Europe fed on centuries of priviledge and inheritance. America was fundamentally opposed to noble privileges, but in their slaveholding and other businesses, the founders were far from averse to hereditary privileges in general.

It was the whites who won all this- won the American continent from its native inhabitants, won the slaves from their native hearths, invented the technologies like the cotton gin, devised the capitalist system, etc., etc. Who has a right to inherit all these winnings? Conservatives subscribe to a fundamentally competitive system. That is why Trump won the hearts of a rabid base. Lying isn't a bug, it is a feature, an intrinsic part of winning in a duplicitous cultural competition- and winning is everything. To conservatives, social justice is a fundamental affront. Who said the world was fair? Not us! Constitutional originalism is way of expressing this denial of social progress and justice in concrete, and superficially palatable, terms. For as Mystal reiterates, the justices are not calling balls and strikes- constitutional interpretation runs rather freely, as we can see from second amendment jurisprudence. That is why capture of the supreme court has been such a existential project of the right for decades.

Counterpoised to the conservative conception of (lack of) justice in America is that of the left, perhaps best exemplified by the California Reparations task force. If one looks back and considers the losses of enslaved and oppressed Americans, one quickly reaches astronomical levels of reparations that would be required in a just world. How to make up for death and torture? How to make up for the bulldozing of entire communities? How to make up for centuries of economic, social, political, and legal disadvantage? There is simply no way to make up what has been lost, and to do so would open up many other claims, especially by Native Americans, all inhabitants of Vietnam, Iraq, and Afghanistan, not to mention countless other victims of historical processes going back centuries and ranging world-wide. Justice is a massive can of worms, if looking back in time. But how about something simple, like affirmative action, giving formerly oppressed people a small leg up in the current system? Conservatives can't stand that either, and cry anti-white racism. 

It frankly boggles the mind, how greedy some people can be. But I think the problem of inheritance remains a central touchstone. In each generation, does everyone share equally in the inheritances from the past, or does one race inherit more, do children of the rich inherit more, do the well-connected send their children into the halls of power? The only way to insure a fresh and fair start for each generation is to, not only demolish the idea of inherited nobility as our founders did, (and which we are edging back toward with extreme economic inequality), but go a little beyond that to end other forms of inheritance ... of money and power. The meritocratic systems of higher education did a great deal in the twentieth century to advance this ideal, allowing students from all backgrounds to aspire to, and achieve, all kinds of success. This made the US incredibly powerful and the envy of the world. Liberals should continue this tradition by attacking all forms of entrenched and inherited power, from private schools to the shameful lack of inheritance taxation. The better way to make reparations is to pay it forward, with more just future world.

• Entering blackness.
• "Private jets are on average 10 times more carbon intensive than commercial flights"
• The perils of ransomware.
• The incredible and thoughtless craven-ness of Republicans.
• Our problem with futile medicine.
• Wow- lots of papers (in bad science journals) are duplicated, plagiarized, or fake ... the paper mills.

The Development of Metamorphosis

Adulting as a fly involves a lot of re-organization.

Humans undergo a slight metamorphosis, during adolescence. Imagine undergoing pupation like insects do and coming out with a totally new body, with wings! Well, Kafka did, and it wasn't very pleasant. But insects do it all the time, and have been doing it for hundreds of millions of years, taking to the air and dominating the biosphere. What goes on during metamorphosis, how complete is its refashioning of the body, and how did it evolve? A recent paper (review) considered in detail how the brains of insects change during metamorphosis, finding a curious blend of birth, destruction, and reprogramming among their neurons.

Time is on the Y axis, and the emergence of later, more advanced types of insects is on the X axis. This shows the progressive elaboration of non-metamorphosis (ametabolous), partially metamorphosing (hemimetabolous), and fully metamorphosing (holometabolous) forms. Dragonflies are only partially metamorphosing in this scheme, though their adult forms are often highly different from their larval (nymph) form.

Insects evolved from crustaceans, and took to land as small silvertail-like creatures with exoskeletons, roughly 450 million years ago. Over 100 million years, they developed the process of metamorphosis as a way to preserve the benefits of their original lifestyle for early development, in moist locations, while conquering the air and distance as adults. Early insect types are termed ametabolous, meaning that they have no metamorphosis at all, developing straight from eggs to an adult-style form. These go through several molts to accommodate growth, but don't redesign their bodies. Next came hemimetabolous development, which is exemplified by grasshoppers and cockroaches. Also dragonflies, which significantly refashion themselves during the last molt, gaining wings. In the nymph stage, those wings were carried around as small patches of flat embryonic tissue, and then suddenly grow out at the last molt. Dragonflies are extreme, and most hemimetabolous insects don't undergo such dramatic change. Last came holometabolous development, which involves pupation and a total redesign of the body that can go from a caterpillar to a butterfly.

The benefit of having wings is pretty clear- it allows huge increases in range for feeding and mating. Dragonflies are premier flying predators. But as a larva, wallowing in fruit juice or leaf sap or underwater, as dragonflies are, wings and long legs would be a hindrance. This conundrum led to the innovation of metamorphosis, based on the already somewhat dramatic practice of molting off the exoskeleton periodically. If one can grow a whole new skeleton, why not put wings on it, or legs? And metamorphosis has been tremendously successful, used by over 98% of insect species.

The adult insect tissues do not come from nowhere- they are set up as arrested embryonic tissues called imaginal discs. These are small patches that exist in the larva at specific positions. During pupation, while much of the rest of the body refashions itself, imaginal discs rapidly develop into future tissues like wings, legs, genitalia, antennas, and new mouth parts. These discs have a fascinating internal structure that prefigures the future organ. The leg disc is concentrically arranged with the more distant future parts (toes) at its center. Transplanting a disc from one insect to another or one place to another doesn't change its trajectory- it will still become a leg wherever it is put. So it is apparent that the larval stage is an intermediate stage of organismal development, where a bunch of adult features are primed but put on hold, while a simpler and much more primitive larval body plan is executed to accommodate its role in early growth and its niche in tight, moist, hidden places.

The new paper focuses on the brain, which larva need as well as adults. So the question is- how does the one brain develop from the other? Is the larval brain thrown away? The answer is that no, the brain is not thrown away at all, but undergoes its own quite dramatic metamorphosis. The adult brain is substantially bigger, so many neurons are added. A few neurons are also killed off. But most of the larval neurons are reprogrammed, trimmed back and regrown out to new regions to do new functions.

In this figure, the neurons are named as mushroom body outgoing neuron (MBON) or dopaminergic neuron (DAN, also MBIN for incoming mushroom body neuron), mushroom body extrinsic neuron to calyx (MBE-CA), and mushroom body protocerebral posterior lateral 1 (PPL1). MBON-c1 is totally reprogrammed, MBON-d1 changes its projections substantially, as do the (teal) incoming neurons, and MBON-12 was not operational in the larval stage at all. Note how MBON-c1 is totally reprogrammed to serve new locations in the adult.

The mushroom body, which is the brain area these authors focus on, is situated below the antennas and mediates smell reception, learning, and memory. Fly biologists regard it as analogous to our cortex- the most flexible area of the brain. Larvae don't have antennas, so their smell/taste reception is a lot more primitive. The mushroom body in drosophila has about a hundred neurons at first, and continuously adds neurons over larval life, with a big push during pupation, ending up with ~2200 neurons in adults. Obviously this has to wire into the antennas as they develop, for instance.

The authors find that, for instance, no direct connections between input and output neurons of the mushroom body (MBIN and MBON, respectively) survive from larval to adult stages. Thus there can be no simple memories of this kind preserved between these life stages. While there are some signs of memory retention for a few things in flies, for the most part the slate is wiped clean. 

"These MBONs [making feedback connections] are more highly interconnected in their adult configuration compared to their larval one: their adult configuration shows 13 connections (31% of possible connections), while their larval configuration has only 7 (17%). Importantly, only three of these connections (7%) are present in both larva and adult. This percentage is similar to the 5% predicted if the two stages were wired up independently at their respective frequencies."

Interestingly, no neuron changed its type- that is, which neurotransmitter it uses to communicate. So, while pruning and rewiring was pervasive, the cells did not fundamentally change their stripes. All this is driven by the hormonal system (juvenile hormone, which blocks adult development, and ecdysone, which drives molting, and in the absence of juvenile hormone, pupation) which in turn drives a program of transcription factors that direct the genes needed for development. While a great deal is known about neuronal pathfinding and development, this paper doesn't comment on those downstream events- how it is that selected neurons are pruned, turned around, and induced to branch out in totally new directions, for instance. That will be the topic of future work.

• Corrupt business practices. Why is this lawful?
• Why such easy bankruptcy for corporations, but not for poor countries?
• Watch the world's mesmerizing shipping.
• Oh, you want that? Let me jack up the price for you.
• What transgender is like.
• "China has arguably been the biggest beneficiary of the U.S. security system in Asia, which ensured the regional stability that made possible the income-boosting flows of trade and investment that propelled the country’s economic miracle. Today, however, General Secretary of the Chinese Communist Party Xi Jinping claims that China’s model of modernization is an alternative to “Westernization,” not a prime example of its benefits."

War is Politics by Other Means

What happened in the American war in Vietnam?

I am watching the lengthy PBS series on Vietnam, which facilitates a great deal of sober reflection. This dates me, but I recall (barely) the nightly body counts on TV, and the arguments with family about what was going on, both abroad and in the US in reaction to the war. I was too young to be particularly anti-war or pro-war, but I was very perplexed. The US was the greatest nation ever, had nuclear bombs and aircraft carriers, and had sent people to the moon. What power did this tiny country so far away have that we did not have?

The salve of time helps to clarify that we had lost this war long before it ended. Because, in the Clausewitzian dictum, war is politics by other means. The North Vietnamese had something that we didn't, which was an unassailable political position and ideology. They were in effective charge of much of the South, especially rural areas, for most of the war. The North Vietnamese had the double political distinction of military victory against the French, and of effective land reform against the landlords. In comparison, the South Vietnamese government was a bumbling, corrupt holdover from the French, which spent its time alienating the majority religion of the country, Buddhism, and keeping the landlords in power over the peasants of the countryside. Who was going to win this battle for hearts and minds?

Yes, North Vietnam was run by communists, and is still. But their propaganda and policies were effective to the mass of the population, in selling themselves as nationalists first and foremost- victors over the Japanese, the French, and later on the Americans too. Who would mess with that kind of record? Unfortunately, to put it in LBJ terms, we got into a pissing match with the North Vietnamese. No one wanted to "lose" South Vietnam, or let communism snatch one more country, or be the first president to lose a war. So it was our pride vs the North Vietnamese pride. Sadly, this did not translate into political support or governing competence in South Vietnam. Its government crumbled in our hands, and no amount of napalm was going to fix that.

We should at this point (that is to say, roughly 1963) have reframed the whole effort in Vietnam as one strictly in support of the South Vietnamese government. The US military is never going to win hearts and minds in foreign countries, not unless, as in World War 2, we have utterly destroyed those countries first and brought all their civilians to their knees in thankfullness for ridding them of their demented fascist government. Not conditions that come around very often, thankfully. The more time we spend somewhere, (say, Afghanistan, or Iraq), the worse it gets. The fact that the US had previously propped up the French position in Vietnam didn't help either. So all we can realistically do is support the native government (and even that may bring taints of colonialism and racism, rendering that support rather poisonous). And in this case, the government of South Vietnam was a mess, and should have been left to die on its own. That is what the politics dictated at the time, and the PBS series makes it clear that this was apparent to those who knew what was going on. They showed a great passage by an ex-soldier from the North, to the effect that, were it not for the US, the North would have taken Saigon by 1966.

It is instructive to compare our effort in Korea. North Korea tried to set up a Viet Cong-style insurgency in the South as well, but it was crushed by our client there, Syngman Rhee. North Korea tried to drape itself in the banner of anti-Japanese militancy, but that didn't play particularly, since the overwhelming US role in defeating Japan was so clear. South Korea instituted effective land reform in 1948 as well, which was key to dampening enthusiasm for communism. One might wonder why communism excites enthusiasm at all, but to landless peasants whose rent is half their crop, and who suffer countless other humiliations, it is a pretty easy sell, at least before the collectivization drive begins(!) So the political position of South Korea, destitute as it was, was far better than that of South Vietnam vs their respective northern antagonists. One might also add ancient cultural patterns, whereby modern Vietnam was created over the preceeding millenium by the gradual southward military expansion of the North Vietnamese, after they had successfully defended themselves against the Mongol and Chinese empires. 

Ho Chi Minh city, present day. Is this communism?

So, communism. Vietnam suffered terribly upon reunification due to a decade of doctrinaire communism, as if the aftermath of our brutal war hadn't been bad enough. After the wonderous dispensation of market-Leninism (!), begun in 1986, it is now a moderately prosperous but still one-party state with a miserable human rights record. Vietnam is reaping rewards from the US-China trade tensions as it becomes a top destination for low cost manufacturing. The US is its top export market. Its citizens have 1.4 cell phone subscriptions per capita, and its Gini coefficient is now similar to that of the US. Buddhism remains the leading religion, which, while confined to a state-run Sangha and political impotence, is relatively free otherwise. 

The US was right to be against communism. States like North Korea, Cuba, China and Vietnam show that communism, even after all the reforms and backtracking on Marxist theory, is antithetical to fundamental human freedoms, due to its Leninist / Stalinist greed for single party political control, which implies vast intrusion into all aspects of civic, social, and personal life. Russia is backsliding into that mindset, and we are right to stand once again with a friend in need, this time Ukraine, against its onslaught. But the new war just goes to show the critical importance of having a friend able to stand on its own feet, politically. Our military help would be pointless if Ukraine were a rotten state, with Russian insurgents and sympathizers, say, running 70% of the rural communities, and the central government pursuing vendettas against the Orthodox church instead of shoring up its support on all fronts.

Integral to the politics of warfare are economic factors like land reform and inequality. It was the corruption and steadfast lack of recognition of the peasant's plight that destroyed South Vietnam. The Viet Cong would not have been able to mount an insurgency were the peasants not desperate and open to well-honed propaganda based on economic equality / opportunity. Ruthless terrorism played a role, as it did for the Taliban. But the basic position of hopelessness versus an uncaring state and economic system was fatal. We are facing similar issues ourselves, as people in rural areas feel left behind and neglected, despite being the beneficiaries of such various and generous handouts from the state that would make welfare recipients blush. No matter- the US has become incredibly unequal and economically/socially stagnent, which is a recipe for populism and revolt, of which we recently had a taste. As inequality rises in China and Vietnam, will they face class-based revolt, driven by some new ideology of equality, fraternity, and liberty?

• Krugman on inequality.
• Photos of Vietnam.
• A green transition.
• A plague of bad plates.

Deep Inside the Ribosome Factory

Hundreds of processes are involved in cranking out ribosomes. One is carried out by an RNA helicase.

Our evolutionarily older molecules have been through a lot, and show the scars of billions of years of jury-rigging. The ribosome is among the oldest, and most ornately decorated, with dozens of extra proteins pasted around the outside, chemical modifications of its RNA and proteins, and a system of scaffolding and maturation factors. It even has its own organelle to develop in- the nucleolus. The nucleolus organizes spontaneously around the portions of the genome that encode the ribosomal RNA (rRNA), which are transcribed in prodigious amounts and whose products go through a lengthy maturation process.

To give an idea of the scale of all this, the ribosomal RNA is about five thousand nucleotides long, and about a hundred of these nucleotides are chemically altered by extra processes, all of which are highly unsual, at least versus normal messenger RNAs. At least three sites are cleaved during maturation, and seventy nine different proteins are added that join the mature structure. There are also over two hundred accessory proteins and seventy-six small RNAs that do not join the mature ribosome, but are needed to facilitate the various folding and chemical modifications during the construction process, which is all done in an ordered fashion. In a cell like yeast, two thousand ribosomes are assembled per minute, taking up a huge share of cellular resources. For example, the ribosomal proteins take up about sixty percent of the mRNA production machinery in a growing yeast cell.

Overview of ribosomal RNA maturation. 25S is the large subunit precursor rRNA segment, while 18S is the small subunit precursor. The ITS segments are intervening  portions that are clipped out of the original long RNA. The small subunit (orange) has a somewhat quicker maturation path than the large subunit (red). Shapes change extensively as the nascent RNAs get prodded and pulled into their final shapes, as if the nucleolus were a tiny little hair salon.

The two halves of the ribosome, the small and large subunits, are separately made and matured, (with all the various constituent and helper proteins being imported back from the cytoplasm to take up their places in these nascent structures) and then exported from the nucleolus out to nucleus and on to the cytoplasm, where some final maturation steps take place, including removal of any remaining accessory factors, Last comes a test run through a fake synthesis cycle without any mRNA or tRNA substrates, after which defective ribosomes are destroyed.

This system is truly daunting in its complexity, but obviously not complexity borne of design. Rather, it is borne of desperation, as bandaid after bandaid has been applied to produce the massive machine that currently sits at the heart of protein synthesis. It is a classic snowball effect, where items added to provide a modicum of extra stability, speed, or accuracy each reinforce the conservation of the core mechanism, making it increasingly impossible to create any radical change or redesign. Optimization in this case has been the enemy of efficiency, since the core of the enzyme, based on RNA, is so intrinsically inefficient.

Structure of the ribosome at an intermediate state, when helicase Spb4 (pink) is attached. All of the colored proteins, in fact, are modifier/accessory factors and are destined to fall off eventually. The ITS2 is the intervening sequence from the ribosomal RNA which has also not yet been cleaved and prised off the structure, but will be soon.

A recent paper sought to look at one small part of this byzantine construction process- where a helicase attaches and participates in one of the later steps as the nascent large ribosomal subunit exits from the nucleolus to the nucleoplasm. Helicases are enzymes that help nucleic acids unwind, (and rewind), which is just the kind of thing the ribosomal RNA so desperately needs as it wends its way from a linear RNA to the compact final structure. The authors use the new method of cryo-electron microscopy to obtain atomic structures of the large subunit in various stages of dress. One image, below, shows some detail about how helicase SPB4 (pink) holds on to one small segment of the ribosomal RNA, wrenches it apart, and thus enables its small structural transition.

Closer structure of Spb4, showing how it grips the ribosomal RNA, which is denoted by the high numbers, G1919 to G1948, based on the nucleotide positions. It is also an ATPase, which powers its helicase activities. RecA1 and RecA2 refer to proteins domains within Spb4 that are characteristic of helicase enzymes, as their "hands". CTD refers to the end of the protein, its carboxy-terminal domain.

The paper is a long-winded discussion of the many protein-protein contacts being made among these accessory factors,  which come on first, then next, then which force others off, etc. Their conclusions are shown below, as a sequence of states where, though at first glance nothing seems to have happened, the final state is quite different in detail from the state C coming in, not only in terms of the accessory proteins present, but also in the structure of the core ribosome. Only eight different proteins are in play here, so this is a tiny slice of the whole process. What is happening to the ribosomal RNA, the target of all this activity? They provide a rundown of some of Spb24's effects as follows, though a full appreciation of its role remains unclear:

The accommodation of the rRNA substrate between the two RecA-like domains induces bending and strand separation of the rRNA around the base of ES27, resulting in an alternate base-pairing of helices H62/H63/H63a compared to nucleoplasmic maturation intermediates and mature 60S subunits. This may explain why the rRNA area at the base of 25S domain IV initially appears to form stable duplexes, while it becomes more flexible and accessible for chemical modification in presence of Spb4, suggesting that the helicase disrupts this region upon its association. In addition to the catalytic domain, Spb4’s essential CTD appears significantly involved in inducing substrate RNA strand disruption and establishing this alternate conformation. In the obtained substrate- bound state, the first half of the CTD (aa 406-499) is tightly docked onto the C-terminal RecA- like domain (RecA2) and binds H62/H63 nucleotides A1936 to C1941, thereby maintaining separation of the rRNA strands. Furthermore, a conserved tryptophan (W536) within the flexible C-terminal tail of the CTD (aa 500-606) intercalates between nucleotides of the immature H62/H63/H63a rRNA, which later adopts its mature-like fold in nucleoplasmic pre-60S particles. - Authors; (ES27 denotes a region of the ribosomal RNA near the active site, as does domain IV. H62/63 denote helices of rRNA, as shown in the diagram above.)

 

Schematic of what is happening to the large ribosomal subunit during these few steps. Accessory factors by the dozens are coming and falling off as the whole process happens, while also guiding the ribosome through its transport process from nucleolus out to the cytoplasm, while in addition doing various QC steps that can shunt defective complexes to cellular waste bins.

• Thelonious.
• All about reading.

Prisons as Social Prisms, Mirrors, and Shadows

From deTocqueville to BLM by way of Solzhenitsyn.

Carl Jung promoted the concept of the psychological shadow- that part of ourselves that is dark, bad, and repressed. It tends to be what we project on others, leading to the kind of political and cultural polarization we see so much of today. For individuals, integrating the shadow, (that is, at least perceiving it, if not valuing it), is difficult but an important path to a more mature and integrated self. Societies have similar psychological characteristics, and have shadows that they project on others, both other cultures and unfortunate classes in their own system. Unlike shadow elements in individual psychology, which are all too easily hidden and ignored, people are harder to keep out of sight, so societies do a lot of explicit work to heap opprobrium on the lower classes- minorities and the poor, in a social process that keeps the social hierarchy stable, and keeps the majority self-satisfied.

A big product of the shadow work of society has appeared in prisons. In primitive times, no one had prisons, and criminals were tortured, killed or ostracized. Now, the world is too small, ethical standards have risen somewhat, and we have turned to prisons as a general purpose punishment- a modern form of ostracism. Prisons express (and contain) our attitudes and definitions of antisocial activity and contagion. Alexis de Toqueville came to the early US to investigate our prisons, as a way of gaining insight into our society, before being waylaid into a much more general tour of this vibrant country. But his instincts were sound. France had been through its revolution only forty years prior, with its gruesome imprisonments and executions, which mirrored the tumultuous reversals of the social order. In the US, de Toqueville found a relatively unsophisticated and small carceral system, as money was short and there was plenty of room for criminals to disappear out west. It did not turn out to be an interesting prism on American life.

Today things are vastly different. The gangster era of the 20's and 30's led to a new focus on crime, noir, and high-profile prisoners like Al Capone. The crime and drug era of the 80's and 90's led to an almost four-fold increase in the prison population, so that now the US leads the world with a prison population of roughly 0.5% of the population behind bars. The BLM movement and defund the police movements were in part about recognizing that something had gone serious astray here. Whether it originated from environmental lead poisoning, or social breakdown, or drug cartels, the result was a huge population of ostracized, mostly male, and disproportionately minority people locked away. On top of that, the society had lost interest in rehabilitation amidst its turn to more conservative attitudes that valorize the rich and powerful and disparage the poor and disadvantaged. 

Our prisons today say alot about us as a society. Not that prisons are not needed, and that there aren't true criminals and insidious criminal organizations that prey on the rest of society; but our lack of empathy and lack of a wider social vision is palpable. Particularly, our attachment to property, its "rights", its local and parochial control, and particularly its inheritance, has gotten a little extreme. It is the perpetuation of privileges through property and wealth that explain a lot of the persistent lack of social mobility, the vast industries of greed/tax avoidance, easily politicized fears. Capitalism is at its heart competitive, and having winners of billions implies also having losers- those who sleep on the street, and those locked up, not to mention the hordes of low-wage workers who make everything go.

All this came to mind as I read Aleksandr Solzhenitsyn's Gulag Archipelago. It is a vast tome, befitting the vast archipelago it describes, its huge population, its protracted duration, its unimaginable suffering, and what it says about its society. While unexpectedly enjoyable to read, as Solzhenitsyn is joking the whole time in various sarcastic and dark modes, it is an indictment of Soviet Russia on a comprehensive basis. One particularly striking theme that he weaves through is comparison with the Tsarist period that came before. Solzhenitsyn meets prisoners, often dedicated socialist revolutionaries, who had done time under the Tsar, and regarded that experience as heaven compared to what they were faced with now, under Stalin. To put it very bluntly, Russia used to be a civilized country. Now, under the Bolsheviks, torture of the most vile kinds is practiced, less vile kinds are routine, execution is carried out on a whim, and law and justice are a mockery. The Gulag is loaded up with many orders of magnitude more political prisoners than the Tsar had ever contemplated and works them mercilessly to early graves.

Breaking rocks in the gulag.

While this all mostly reflected the paranoia and totalitarian genius of Stalin, he was only following his model, Lenin, as Solzhenitsyn lays out in particularly damning detail. The larger Russian society clearly had, and still has, an ambivilent nature, as close students and subjects of the Mongols, but also as eager to engage with and learn from Western Europe. Who knew that the most left-tinged and idealistic ideology to be imported from the West would so quickly curdle into a second coming of Ivan the terrible? But so it did, and Solzhenitsyn describes what that really meant in human suffering, in this book that may have done more than any other to delegitimize and ultimately destroy that system.

• The neighborhood to prison pipeline in the US.
• The questionable science of ice cream.
  

Molecules That See

Being trans is OK: retinal and the first event of vision.

Our vision is incredible. If I was not looking right now and experiencing it myself, it would be unbelievable that a biological system made up of motley molecules could accomplish the speed, acuity and color that our visual system provides. It was certainly a sticking point for creationists, who found (and perhaps still find) it incredible that nature alone can explain it, not to mention its genesis out of the mists of evolutionary time. But science has been plugging away, filling in the details of the pathway, which so far appear to arise by natural means. Where consciousness fits in has yet to be figured out, but everything else is increasingly well-accounted. 

It all starts in the eye, which has a curiously backward sheet of tissue at the back- the retina. Its nerves and blood vessels are on the surface, and after light gets through those, it hits the photoreceptor cells at the rear. These photoreceptor cells come in two types, rods (non-color sensitive) and cones (sensitive to either red, green, or blue). The photoreceptor cells have a highly polarized and complicated structure, where photosensitive pigments are bottom-most in a dense stack of membranes. Above these is a segment where the mitochondria reside, which provide power, as vision needs a lot of energy. Above these is the nucleus of the cell (the brains of the operation) and top-most is the synaptic output to the rest of the nervous system- to those nerves that network on the outside of the retina. 

A single photoreceptor cell, with the outer segment at the very back of the retina, and other elements in front.

Facing the photoreceptor membranes at the bottom of the retina is the retinal pigment epithelium, which is black with melanin. This is finally where light stops, and it also has very important functions in supporting the photoreceptor cells by buffering their ionic, metabolic, and immune environment, and phagocytosing and digesting photoreceptor membranes as they get photo-oxidized, damaged, and sloughed off. Finally, inside the photoreceptor cells are the pigment membranes, which harbor the photo-sensitive protein rhodopsin, which in turn hosts the sensing pigment, retinal. Retinal is a vitamin A-derived long-chain molecule that is bound inside rhodopsin or within other opsins which respectively confer slightly shifted color sensitivity. 

These opsins transform the tickle that retinal receives from a photon into a conformational change that they, as GPCRs (G-protein coupled receptors), transmit to G-proteins, called transducin. For each photon coming in, about 50 transducin molecules are activated. Each of activated transducin G-protein alpha subunits induce (in its target cGMP phosphodisterase) about 1000 cGMP molecules to be consumed. The local drop in cGMP concentration then closes the cGMP-gated cation channels in the photoreceptor cell membrane, which starts the electrical impulse that travels out to the synapse and nervous system. This amplification series provides the exquisite sensitivity that allows single photons to be detected by the system, along with the high density of the retinal/opsin molecules packed into the photoreceptor membranes.

Retinal, used in all photoreceptor cell types. Light causes the cis-form to kick over to the trans form, which is more stable.

The central position of retinal has long been understood, as has the key transition that a photon induces, from cis-retinal to all-trans retinal. Cis-retinal has a kink in the middle, where its double bond in the center of the fatty chain forms a "C" instead of a "W", swinging around the 3-carbon end of the chain. All-trans retinal is a sort of default state, while the cis-structure is the "cocked" state- stable but susceptible to triggering by light. Interestingly, retinal can not be reset to the cis-state while still in the opsin protein. It has to be extracted, sent off to a series of at least three different enzymes to be re-cocked. It is alarming, really, to consider the complexity of all this.

A recent paper (review) provided the first look at what actually happens to retinal at the moment of activation. This is, understandably, a very fast process, and femtosecond x-ray analysis needed to be brought in to look at it. Not only that, but as described above, once retinal flips from the dark to the light-activated state, it never reverses by itself. So every molecule or crystal used in the analysis can only be used once- no second looks are possible. The authors used a spray-crystallography system where protein crystals suspended in liquid were shot into a super-fine and fast X-ray beam, just after passing by an optical laser that activated the retinal. Computers are now helpful enough that the diffractions from these passing crystals, thrown off in all directions, can be usefully collected. In the past, crystals were painstakingly positioned on goniometers at the center of large detectors, and other issues predominated, such as how to keep such crystals cold for chemical stability. The question here was what happens in the femto- and pico-seconds after optical light absorption by retinal, ensconced in its (temporary) rhodopsin protein home.

Soon after activation, at one picosecond, retinal has squirmed around, altering many contacts with its protein. The trans (dark) conformation is shown in red, while the just-activated form is in yellow. The PSB site on the far end of the fatty chain (right) is secured against the rhodopsin host, as is the retinal ring (left side), leaving the middle of the molecule to convey most of the shape change, a bit like a bicycle pedal.

And what happens? As expected, the retinal molecule twists from cis to trans, causing the protein contacts to shift. The retinal shift happens by 200 femtoseconds, and the knock-on effects through the protein are finished by 100 picoseconds. It all makes a nanosecond seem impossibly long! As imaged above, the shape shift of retinal changes a series of contacts it has with the rhodopsin protein, inducing it to change shape as well. The two ends of the retinal molecule seem to be relatively tacked down, leaving the middle, where the shape change happens, to do most of the work. 

"One picosecond after light activation, rhodopsin has reached the red-shifted Batho-Rh intermediate. Already by this early stage of activation, the twisted retinal is freed from many of its interactions with the binding pocket while structural perturbations radiate away as a transient anisotropic breathing motion that is almost entirely decayed by 100 ps. Other subtle and transient structural rearrangements within the protein arise in important regions for GPCR activation and bear similarities to those observed by TR-SFX during photoactivation of seven-TM helix retinal-binding proteins from bacteria and archaea."

All this speed is naturally lost in the later phases, which take many milliseconds to send signals to the brain, discern movement and shape, to identify objects in the scene, and do all the other processing needed before consciousness can make any sense of it. But it is nice to know how elegant and uniform the opening scene in this drama is.

• Down with lead.
• Medicare advantage, cont.
• Ukraine, cont.
• What the heck is going on in Wisconsin?
• Graph of the week- world power needs from solar, modeled to 2050. We are only scratching the surface so far.

Consciousness and the Secret Life of Plants

Could plants be conscious? What are the limits of consciousness and pain? 

Scientific American recently reviewed a book titled "Planta Sapiens". The title gives it all away, and the review was quite positive, with statements like: 

"Our senses can not grasp the rich communicative world of plants. We therefore lack language to describe the 'intelligence' of a root tip in conversation with the microbial life of the soil or the 'cognition' that emerges when chemical whispers ripple through a lacework of leaf cells."

This is provocative indeed! What if plants really do have a secret life and suffer pain with our every bite and swing of the scythe? What of our vaunted morals and ethics then?

I am afraid that I take a skeptical view of this kind of thing, so let's go through some of the aspects of consciousness, and ask how widespread it really is. One traditional view, from the ur-scientific types like Descartes, is that only humans have consciousness, and all other creatures, have at best a mechanism, unfeeling and mechanical, that may look like consciousness, but isn't. This, continued in a sense by B. F. Skinner in the 20th century, is a statement from ignorance. We can not fully communicate with animals, so we can not really participate in what looks like their consciousness, so let's just ignore it. This position has the added dividend of supporting our unethical treatment of animals, which was an enormous convenience, and remains the core position of capitalism generally, regarding farm animals (though its view of humans is hardly more generous).

Well, this view is totally untenable, from our experience of animals, our ability to indeed communicate with them to various degrees, to see them dreaming, not to mention from an evolutionary standpoint. Our consciousness did not arise from nothing, after all. So I think we can agree that mammals can all be included in the community of conscious fellow-beings on the planet. It is clear that the range of conscious pre-occupations can vary tremendously, but whenever we have looked at the workings of memory, attention, vision, and other components assumed to be part of or contributors to conscious awareness, they all exist in mammals, at least. 

But what about other animals like insects, jellyfish, or bacteria? Here we will need a deeper look at the principles in play. As far as we understand it, consciousness is an activity that binds various senses and models of the world into an experience. It should be distinguished from responsiveness to stimuli. A thermostat is responsive. A bacterium is responsive. That does not constitute consciousness. Bacteria are highly responsive to chemical gradients in their environment, to food sources, to the pheromones of fellow bacteria. They appear to have some amount of sensibility and will. But we can not say that they have experience in the sense of a conscious experience, even if they integrate a lot of stimuli into a holistic and sensitive approach to their environment. 

The same is true of our own cells, naturally. They also are highly responsive on an individual basis, working hard to figure out what the bloodstream is bringing them in terms of food, immune signals, pathogens, etc. Could each of our cells be conscious? I would doubt it, because their responsiveness is mechanistic, rather than being an independent as well as integrated model of their world. Simlarly, if we are under anaesthesia and a surgeon cuts off a leg, is that leg conscious? It has countless nerve cells, and sensory apparatus, but it does not represent anything about its world. It rather is built to send all these signals to a modeling system elsewhere, i.e. our brain, which is where consciousness happens, and where (conscious) pain happens as well.

So I think the bottom line is that consciousness is rather widely shared as a property of brains, thus of organisms with brains, which were devised over evolutionary time to provide the kind of integrated experience that a neural net can not supply. Jellyfish, for instance, have neural nets that feel pain, respond to food and mates, and swim exquisitely. They are highly responsive, but, I would argue, not conscious. On the other hand, insects have brains and would count as conscious, even though their level of consciousness might be very primitive. Honey bees map out their world, navigate about, select the delicacies they want from plants, and go home to a highly organized hive. They also remember experiences and learn from them.

This all makes it highly unlikely that consciousness is present in quantum phenomena, in rocks, in bacteria, or in plants. They just do not have the machinery it takes to feel something as an integrated and meaningful experience. Where exactly the line is between highly responsive and conscious is probably not sharply defined. There are brains that are exceedingly small, and neural nets that are very rich. But it is also clear that it doesn't take consciousness to experience pain or try to avoid it, (which plants, bacteria, and jellyfish all do). Where is the limit of ethical care, if our criterion shifts from consciousness to pain? Wasn't our amputated leg in pain after the operation above, and didn't we callously ignore its feelings? 

I would suggest that the limit remains that of consciousness, not that of responsiveness to pain. Pain is not problematic because of a reflex reaction. The doctor can tap our knee as often as he wants, perhaps causing pain to our tendon, but not to our consciousness. Pain is problematic because of suffering, which is a conscious construct built around memory, expectations, and models of how things "should" be. While one can easily see that a plant might have certain positive (light, air, water) and negative (herbivores, fungi) stimuli that shape its intrinsic responses to the environment, these are all reflexive, not reflective, and so do not appear (to an admittedly biased observer) to constitute suffering that rises to ethical consideration.

Journey to the Center of the Ribosome

And to the origin of the ribosome as well.

The ribosome is a relic. It is slow and inefficient, and therefore needed and made in huge amounts in all cells. It is absurdly large, with some of the most highly conserved sequences in all of life and dozens of later additions, ingloriously pasted on the outside. While those later additions are all proteins, its catalytic core is made of RNA, explaining both its age and its slowness. For it is a relic of the RNA world, and itself marks the beginning of the mechanism of protein synthesis that would provide the catalytic capacity to transcend that world. But the ribosome itself would never be superceded, only jury-rigged and augmented. While other molecules like lipids and metabolites are also crucial to biogenesis, this early phase is called the RNA world because RNA is widely thought to be the main catalytic and informational molecule.

Schematic of the ribosome, showing decoding on the small subunit, and peptide synthesis on the large subunit (top). Sausage-like tRNAs are shown lining up preparatory step (RF, also called the A site), the transferring step (P), and the exit step (E). The peptidyl transferase core is made of RNA, so all key aspects of this machine are run by RNA.

So where did the ribosome begin? Its core function is to line up an RNA message that carries the genetic code, to which other RNAs dock, by sequence recognition. These special (transfer RNAs, or tRNAs) have amino acids stuck on their other ends, which then likewise line up and get linked together, forming the nascent protein. It is pretty clear that, while the genetic code now has three nucleotides per unit (codon), enabling 64 possibilities and in fact coding for 20 amino acids, it began with only two, offering 16 possible amino acids. About half of current amino acids are now coded by "degenerate" codons, where the last letter doesn't make any difference- all four (say, GGU, GGC, GGA, GGG, for glycine) code for the same amino acid. 

A more detailed structure of the ribosome, with RNA shown in thin orange helixes, and proteins shown in teal and green ribbons. The tRNAs are shown in gray (E), orange (P) and purple (A).

From a great deal of other work, it has been shown to be possible (though whether likely, or inevitable, is another matter) for RNAs to assemble in pre-biotic chemical conditions, and to laboriously operate on each other with catalytic effect, both in polymerization and degradation. Indeed, our mRNA splicing apparatus remains, like the ribosome, based on an RNA catalytic core. And this work suggests that RNAs of some length, like maybe under 100 nucleotides (nt) are plausible, while longer ones would be less plausible. There is some debate about whether in later epochs, the RNA world could have hosted very long RNAs, thereby making up in length and complexity what it generally lacked in conformational precision and chemical versatility. So the question arises- how much is really needed to get to the protein synthesis stage of biogenesis? How might several RNAs have come together to collaborate in this dance of protein synthesis, and what were the minimal requirements? 

The pseudo-dimeric core of the peptidyl transferase center, pulled out of the larger ribosome structure. This tiny structure is what the current workers attempted to use to simulate very early forms of protein synthesis.

The site within the ribosome where the single amino acids are linked together (polymerized) is called the peptidyl transferase center. Given properly tRNA-linked acyl-amino acids, it takes only proper steric encouragement, not extra inputs of energy such as ATP, to create the peptide bond. It turns out that the peptidyl transferase center of the ribosome can be thought of as a dimer of two ~ 60 nt long RNAs. Structures of that center show this as the extremely conserved, somewhat kinked helical dimer within all current ribosomes. But can such tiny RNAs do the job? Or do they absolutely require the kind of superstructure in which they are currently embedded? 

A recent paper shows that they can do the job by themselves, if very inefficiently.

"The actual reaction occurs within a semi-symmetrical molecular pocket that hosts the A- and P-tRNAs, situated within the peptidyl transferase center (PTC), which provides the sites for the two CCA-tRNA ends. This semi-symmetrical entity provides the framework for optimal positioning of the ribosomal substrates in a favored stereochemistry for peptide bond formation and it confines the void required for the motions associated with protein elongation. The amazingly high conservation of this semi-symmetrical site structure, which seems to be preserved throughout the entire living kingdom, indicates that it is resistant to evolution. Hence, suggesting that it could have existed as a self-folded active entity in the pre-biotic world. Therefore, called by us the protoribosome, i. e. the ancestor of the contemporary ribosome."

Ingredient 1: the mini-rRNA sequence and presumed base-pairing.

Ingredient 2: the mini-tRNA sequence and base-pairing.

The hard part was showing that this is true, which is what two groups have done, one in Japan, one in Israel. They have demonstrated slight amounts of protein synthesis using these tiny RNA molecules, in addition to other RNAs standing in for the code and the tRNAs. This was extremely difficult to do, grinding through the careers of several graduate students and post-docs. The ingredients are as follows: one putative / mini ribosomal RNA of about 71 nt, which forms the dimer of the putative peptide transferase core, and a putative transfer RNA of about 35 nt, which was pre-supplied with an attached amino acid (alanine). Given only those two inputs, they found in the reaction products the dipeptide alanyl-alanine, indicating that one step of synthesis had occurred. The template was a tag of GGU that had been added to the mini-ribosomal RNA, to match the ACCA tail of the mini-tRNA. 

So this is a highly unnatural setting, without a true template, and with pre-charged mini-tRNA molecules, and with just-detectable efficacy. But the principle is significant- not only can RNA of relatively simple sorts that we can envision occurring in the RNA world synthesize, cleave, and alter other RNAs, but they can also get to the nascent stage of protein synthesis, one of the bigger hurdles on the way to life as we know it.

• Korean women are on strike.
• A contrary view of Ukraine.
• Comments on the Jones act.

The Eye is the Window to the Brain

Alpha oscillations of the brain prefigure the saccades by which our eyes move as we read.

Reading is a complicated activity. We scan symbols on a page, focusing on some in turn, while scanning along for the next one. Data goes to the brain not in full images, but in the complex coding of differences from moment to moment. Simultaneously, various levels of processing in the brain decode the dark and light spots, the letter forms, the word chunks, the phrases, and on up to the ideas being conveyed.

While our brain is not rigidly clocked like a computer, (where each step of computation happens in sync with the master clock), it does have dynamic oscillations at several different frequencies and ranging over variable regions and coalitions of neurons that organize its processing. And the eye is really a part of that same central nervous system- an outpost that conveys so much sensitive information, both in and out.

We take in visual scenes by jerks, or saccades, using our peripheral vision to orient generally and detect noteworthy portions, then bringing our high-acuity fovea to focus on them. The eye moves about four times per second, a span that is used to process the current scene and to plan where to shift next. Alpha oscillations (about 10 per second) in the brain, which are inhibitory, are known to (anti-) correlate with motor control of the saccade period. The processing of the visual sensory system resets its oscillations with each shift in scene, so is keyed to saccades in a receiving sense. Since vision only happens in the rest/focal periods between saccades, it is helpful, conceptually, to coordinate the two processes so that the visual processing system is maximally receptive (via its oscillatory phase) at the same time that the eye comes to rest after a saccade and sends it a new scene. Conversely, the visual sensory system would presumably tell the motor system when it was done processing the last unit, to gate a shift to the next scene.

A recent paper extended this work to ask how brain oscillations relate to the specific visual task of reading, including texts that are more or less difficult to comprehend. They used the non-invasive method of magnetic encephalography to visualize electrical activity within the brains of people reading. The duration of saccades were very uniform, (and short), while the times spent paused on each focal point (word) varied slightly with how difficult the word was to parse. It is worth noting that no evidence supports the lexical processing of words out of the peripheral vision- this only happens from foveal/focused images.

Subjects spent more time focused on rare/difficult words than on easy words, during a free reading exercise (C). On the other hand, the duration of saccades to such words was unchanged (D).

In the author's main finding, alpha oscillations were correlated as the person shifted from word to word, pausing to view each one. These oscillations tracked the pausing more closely when shifting towards more difficult words, rather than to simple words. And these peaks of phase locking happened anatomically in the Brodmann area 7, which is a motor area that mediates between the visual system and motor control of the eye. Presumably this results from communication from the visual processing area to the visual motor area, just next door. They also found that the phase locking was strongest for the start of saccades, not their end, when the scene comes back into focus. This may simply be a timing issue, since there are lags at all points in the visual processing system, and since the saccade duration is relatively fixed, this interval may be appropriate to keep the motor and sensory areas in effective synchronization.

Alpha oscillation locks to some degree with initiation of saccades, and does so more strongly when heading to difficult words, rather than to easy words. Figure B shows the difference in alpha power between the easy and difficult word target. How can this be? 

So while higher frequency (gamma) oscillations participate in sensory processing of vision, this lower alpha frequency is dominant in the area that controls eye movement, in keeping with muscle control mechanisms more generally. But it does raise the question of why they found a signal (phase locking for the initiation of a saccade) for the difficulty of the upcoming word, before it was actually lexically processed. The peripheral visual system is evidently making some rough guess, perhaps by size or some other property, of the difficulty of words, prior to fully decoding them, and it will be interesting to learn where this analysis is done.

• New uses for AI in medicare advantage.
• Some problems with environmental review.
• No-compete "agreements" are no such thing, and worthless anyhow.
• We wanna be free.