Concept as a Shadow of Percept

Binding and grounding- How does our brain organize concepts, properties, and relations?

Evolutionarily, brains developed to interact with the outside world, developing out of senses to orient the organism for food and defense. The basic senses came first, and then the ever more complex networks / computations to deduce what their signals mean and ultimately to build an entire world model, against which to evaluate changes in perception. While perception is now heavily influenced by such mental models, it did not begin there.

This history informs the question of where concepts reside in the brain. The wetness of water is something we feel, and our conception of it is naturally tied to our perception / sensation of it. Our language makes unending use of metaphors that extend this concrete perception-based ontology to the highest abstractions. If someone is a dirty scoundrel, they are only metaphorically dirty, and the visual and tactile aspects of dirtiness are evoked to enrich and clarify the abstraction. While one might imagine that, like computers, our brains store this conceptual data of definitions, categories, properties, etc. just about anywhere, whether in a distributed holographic engram or in dedicated storage areas, the fact is that data storage is localized, such that lesions in various parts of the brain can disrupt recall of specific classes of skills, properties, facts, faces, experiences, etc.

It is also apparent that much of this storage is coincident with our perceptual apparatus (and motor and emotional apparatus). Thus, a brain scan of someone asked to think about and apple and how it differs from a grape will light up areas in the later visual system where incoming perceptions of apples and grapes are decoded into the shape, color, size, etc., which we understand as being their respective properties. Perhaps olfactory and tactile areas come into play as well. Likewise, thinking about a guitar might generate activity in the motor planning areas, providing concepts about playing one. So, analogous to a spotlight of attention, we also have back-casting mini-spotlights of classification and conceptualization that connect "higher" areas in the frontal cortex (which are perhaps asking the questions) to motor, emotional, and perceptual areas, allowing the system to encode complex conceptual schemes once only, where they are first established, in the grounded areas such as in perceptual processing. Once there, they can serve both the immediate perceptual needs of classification, and the evidently related needs of rendering the same classes as concepts.

"Not only is object property information distributed across different locations, but also, these locations are highly predictable on the basis of our knowledge of the spatial organization of the perceptual, action, and affective processing systems. Conceptual information is not spread across the cortex in a seemingly random, arbitrary fashion, but rather follows a systematic plan."

This is the subject of a review, and of a recent paper which attempts to show that it is white matter tracts that constitute the property recognizing units of the brain, not the grey matter targets of their communication. They call this model "representation by connection", and their case is not well made. Yet the overall topic is extremely interesing, so here goes. The fact that this characteristic distribution of property storage in the peripheral systems exists is not in dispute. What is still uncertain is how it is all knit together and what, exactly, is being communicated back and forth. And, of course, what out of these ingredients constitutes the resulting gestalt of consciousness.

The new paper tries to make a big distinction between grey matter (the dense cellular areas of the brain) and white matter (the tracts of myelinated connecting axons, which have recently been so beautifully traced by DTI MRI. They collected 80 people who have suffered lesions in various localized areas of the brain, due to strokes, hemorrhage, or trauma, and correlate their deficits in object property recall / naming, which are specific and diverse, with separately derived maps of white matter tracts, and semantic / notional distance between the same concepts, as provided by a sampling of normal college students. The latter was taken in several dimensions, including properties of color, manipulability, motion, phonological, shape, usage, and others, but only set up a conceptual space field- it was not explicitly correlated with brain anatomy.

"Distributed GM (grey matter) regions that represent different attribute dimensions (e.g., shape, color, manner of interaction) of the same object are connected by WM (white matter). The WM linking pattern itself would then contain multiple dimensions of information in these GM regions and, importantly, additional information about the manner of mapping among various attributes. The incorporation of these elements has been argued to be necessary for the “higher-order” semantic similarity relationships, which are not explained by attribute-specific spaces, to emerge."

The authors developed anatomical maps of normal white matter tracts, and then developed a map of semantic correlations given the defects in the brain damaged patients, over-laying their cognitive defects, on the same object classification tasks as above, over their individual brain defect regions. The question was then, once the semantic defects were anatomically mapped, are their relative positions correlated with the mapping in conceptual space done by normal volunteers? One would naturally expect that yes, cognition of similar objects (scissors, knives) would happen in spatially close areas of the brain. This was indeed found. What it means, however, especially for the author's theory, is extremely hard to say. It is especially hard as the paper is not well written, (the group is from China), leaving their core ideas rather murky.

"In conclusion, using a structural-property-pattern-based RSA (representational similarity analysis) approach, we found that the WM (white matter) structures mainly connecting occipital/middle temporal regions and anterior temporal regions represent fine-grained higher-order semantic information. Such semantic relatedness effects were not attributable to modality-specific attributes (shape, manipula- tion, color, and motion) or to the representation contents of the cortical regions that they connected and were above and beyond the broad categorical distinctions. By connecting multiple modality-specific attributes, higher-order semantic space can be formed through patterns of these connections."

Example of one finding. Two brain areas of gray matter in the left hemisphere (red, superior temporal gyrus; and green, the calcarine sulcus) are linked by a mapped white matter tract. The graph shows a significant r-value for the correlation between the neural similarity (map of white matter lesions by properties reported to be defective) and the author's custom mapping of semantic similarity.

They do claim explicitly that the corresponding gray matter maps from the brain-damaged patients did not correlate as well with the semantic space patterns as did the white matter maps. But this is not so surprising, as gray matter regions (which could be imagined as the CPUs of the brain) are all connected via the white matter (the networking cables). So for a process that depends on the collation of numerous pieces of information, (the concept property units harvested from each percept / action planning/ emotion region), it would be natural to expect that cutting the cables might be a cleaner way to cause particular property type deficits. That doesn't mean, however, that it is the cables that are conscious, or that are doing the most important processing.

So I think, aside from the operational issues, which look rather daunting in this paper and whose resulting correlation maps are only marginally compelling, there are serious theoretical issues that indicate that while this field is ripe for advancement, this does not seem to be the paper to get us there.

A much more through and positive review than this one.

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• Nature -and- nurture.

Heroes, Superheroes, and Saviors

What do we see in the hero myth? With apologies to Joseph Campbell.

I was watching the TV version of Dune, which, while much better than the movie, hardly matches the book. Seeing it again made it painfully clear how this story, so gripping to my younger self, is a formulaic hero tale, just as Harry Potter would be for the next generation, Frodo Baggins was for the one before, and Arthur, Beowulf, Jesus, Buddha, Rama, and Odysseus have been since antiquity. What do we see in them, and why are they so riveting?

Obviously, these tales speak to the meaning of life, in a direct and comprehensive way. Though mostly for males- Heroes and their students are, as a rule, male. They go on adventures, lead others, resolve mysteries, and ultimately solve communal problems. What they achieve is status, renown, and perhaps the hand of the princess, who is the typical hero of the female archetypal tale (though see also Dorothy, Alice, Mulan, et al.).

These qualities have relatively little to do with one's purely individual path through life, judged by, say, happiness, or one's success in earning a living, attending to the humdrum affairs of personal life, comfort, and family. Rather, it is a wider social role and service that is the point, and fame is the coin of this realm. The hero slays monsters that have terrified the people and despoiled their crops. Or he retrieves the chalice that gives everlasting life and salvation. Or he uses a mysterious force to lead a rebel alliance against the totalitarian galactic empire.

Horses? This quest needs no horses!

Hero tales are formative for those in formation- the maturing child, who instinctively yearns to accomplish something significant, which is the path to status in the collective, and thus to relative power and reproductive success. But what defines success and significance? It is necessarily the collective that must define what is important, via its bards who recite its problems both perennial and topical, provide the grist of heroic adventure and conflict, and award fame for their successful conclusion. Whether it is raging beasts in the countryside, Orwellian tyranny, taunting goddesses, or a world-wide conspiracy of death-eaters, the threat is not individual, but collective, and thus the hero serves the collective, something "greater than himself", as many people express their seeking behavior. Success of any kind is attractive, but to be truly compelling, success needs to resolve big problems and be valued by others. (Though in fairness, the hero may toil in obscurity and only be recognized in retrospect, perhaps long after his death, to have solved the momentous problem. Such a tale may have additional romance, and happen in reality all too often, but is not typically what a reader wishes to emulate for her or his own life path.)

One characteristic element of the standard hero tale is the reckoning with the father. Luke Skywalker finally meets his maker in a climactic scene. Jesus naturally has mixed emotions about his father, whoever that might be, who has left him up on the cross. The father represents the existing system, which has formed the hero, but which also perpetuates all the problems that he exists to solve. The father must be transcended for the tale to conclude successfully. Paul Atreides has spiritual and temporal powers far beyond his father's, and succeeds where the father had failed. More interestingly, Jesus, while always respectful of the father and putatively acting in his service, ends up totally upending the father's theology and bringing a new dispensation, whether that was "in reality" his intention or not.

Sometimes the goal of a quest is so abstract and theologically attenuated as to be absurd. Maybe the quest was the important thing after all.

More complicated is the role of the special gift. Harry Potter has the mark of the lightning flash, and special powers of leadership and magic. All the Marvel heros have some special power. Heroes are typically born of noble houses, though they may be unrecognized or abused for some of the story. What is the function of all this apparatus? Isn't the point of the hero tale to inspire normal boys to seek glory for themselves from/for their collective? Why start with abnormal heroes? The quest needs to be done in a noble way, morally upright. But that hardly requires a particular form of birth.

I think much of this has to do with the inner quest, which is another aspect of the hero tale. In order to seek outer glory, the hero needs first an inner quest, to find the confidence, knowledge, and personal resources to do extraordinary things. Jesus grappled with satan in the desert, while Paul Atreides grapples with sandworms in the desert (always an epic setting; Lawrence of Arabia grappled there with a recalcitrant, but noble, Arab culture). Each person has some special gifts and skills, and an important aspect of life, particularly adolescence, is to find what those might be. The ability to be clairvoyant, or to accumulate The Force are symbolic of momentous discoveries about the self which happen during growth to adulthood. While few of us will find nirvanna, or that we are the son of god, nevertheless whatever we do find will be the key to our ability to differentiate ourselves from the crowd, while earning its respect. Each person follows this archetypal path, and it is typically a difficult and uncertain one, thus the universal interest it evokes.

The noble house and lineage aspect seems more atavistic. One of the hero's special gifts / typical traits (which is key to the story's cultural and pedagogical significance) is to be naturally noble in deportment, morals, and martial prowess. Given our instinctive racism and appreciation for inheritance of traits, it is then natural to make this occur by having the hero some secret child of the king, or an acknowledged child who breaks out of the mold and takes a different path (Buddha). Or who comes both from a noble family and from the planet Krypton. Surely we could come up with a more modern way to handle this! Even the Black Panther is of noble birth. Tolkein gets points on this score for his low-class heroes in the Lord of the Rings.

But there is also a superstitious element. Luck is one thing the hero needs to have on his side, and this has traditionally been bound up with cosmic forces and mysteries, instinctively (and animistically) personified. Special forms of communication with these forces, or at least encouraging signs from them, would by this primitive instinct, be essential to success. One can take this in more rational way, however, to indicate a certain humility and appreciation before the complex and often inscrutable real forces that form our basis of operations, including the social forces that may not be ready for the hero's revolutionary work and need to be brought along by way of their primitive beliefs, whatever their nature and value.

Maybe a little self-flagellation would help?

It is particularly pathetic when a hero is so venerated and his boons are so attractive that his devotees make a fetish or even religion of him, employing a priesthood to retail third-hand boons of a studiously invisible nature. Generally, the emulation of nobility, and inner quests modeled on that of the hero, are not a bad thing. But the whole point of the tale was to find and develop one's own self and one's own resources- one's unique gifts and path in life- rather than to adopt another's wholesale, or worse yet, to fantasize about fictional powers and benefits that can be cadged via supplication and abasement. That would be to fundamentally misunderstand the point of the hero archetype, going so far as to reverse it as an engine for the most unheroic behavior. Thankfully, such overblown renditions have been relatively rare over the recent centuries (though Scientology, and before that, Mormonism, stand as significant and unfortunate counter-examples). Yet overall, absurd hero-religions, mostly stemming from more distant epochs, remain all too common.

The quality of the hero story plays an important role in its society, of which it is a gauge and exemplar. Just think of the pervasive influence of Homer's epics, or of Christianity. It defines not only the archetypal problems to be faced, but the standard of morality / nobility the aspiring hero must have to engage in its quest / solution. Star Wars cast the enemy as a Stalinist totalitarianism, while Buddhism cast the enemy as Maya and attachment to outer and fleeting things. While moral good and bad are perennial problems of the human condition, other aspects can change. The balance between inner and outer quests is a key indicator of a tale's maturity and spiritual content. Our current tales seem to center on the Marvel universe, of which I know very little. But it seems generally dedicated to extravagant violence and justice, with a somewhat infantile/regressive tone, overall. There is limited inner focus. They seem on the level of the Bond franchise, but without the understatement or style. It was extremely disturbing when, after 9/11, there was a rash of corner-cutting hero tales that supported the use of torture.

John Cleese strikes a heroic pose.

At this time when the actual culture is run by those fitting an antihero archetype, (technically, the heel), and the planet truly in peril, it is even more imperative that the stories that form our hero mythology and guide our questing youth be well-constructed, compelling, positive, and timely in their selection and portrayal of problems. Vietnam was a watershed in this regard, sending us from the morally simple comforts of the old Westerns and Hollywood classics, into self-lacerating work like Apocalypse Now and The Deer Hunter, and most recently, Game of Thrones. This depressing trajectory reflects changes in American culture, which has become more complicated and self-doubting, (perhaps mature), even mean. Realistic? That is hardly the point of the hero tale, frankly. Many recent film-makers have tried their hand at the saving-the-planet story, surely the one we need most of all, (from Avatar to Independence Day), but none seem to have become canonical. Someone needs to do a better job painting the deep challenges of the day for tomorrow's heroes.

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• New tech, same as the old tech.
• Liberals sometimes can't help drinking the right-wing economic koolaid.

Feelings, Nothing More Than Feelings ...

Charles De Gaulle and the greatness of France. Review of his war memoirs.

Fin de siècle France was a mess. After a century of social and political enervation, France was not the powerful country she was over most of Western history. Proust is a fair barometer, obsessed by the distant glories of the noble houses, but met in the present with their dissipated exemplar, Baron de Charlus. World War 1 was billed by some as a romantic rite of purification by blood, but turned out to be throughly ruinous and horrible, leaving the France even more adrift and traumatized, despite having "won".

Naturally, France then failed to face up to the rapidly developing threat from the East, and crumpled igominiously once the Germans came, entering into the quasi-occupation / collaboration that was Vichy. Who was appalled by this? Everyone, even the Germans. And especially Charles de Gaulle, a government minister and military figure who had argued over the prior decade for military mechanization and mobilization, to supplement the static Maginot line. He was incensed that the government chose to surrender and enter into collaboration, instead of spiriting off what and who they could to France's extensive overseas possessions and continuing the war from there (while leaving the French continental population to whatever administration the Germans saw fit to impose).

Seeing no one else stepping up to that task, he took it on himself, powered by the radio broadcasting resources of the BBC. He stands as one of the great statesmen of the century, single-handedly organizing the Free French resistance against what turned out to be the millenarian and cataclysmic Hitlerian regime, leading the French state during the very delicate and difficult post-war period, and also re-organizing the French state (the Fifth Republic) along new lines, within which it still exists today.

At the liberation.

Vain? Yes. Monomanical? Absolutely. A selective memoirist? Yes. A born politician? Evidently. De Gaulle was obsessed with the greatness of France, a phrase that comes up time and again in his memoir. He most potent weapon was the word "No". When Britain wanted to get some payback for all its assiduous help, by, say, acquiring some of the French possessions in the Middle East like Lebanon and Syria, De Gaulle said no, and fought them off. De Gaulle faught tooth and nail for every colonial backwater, and later on for every inch of German territory he could wrest out of the Allies. This "No" rose out of the power De Gaulle developed as head of the French people, nurturing their feelings of pride, and victimization, and hope, through the long years of occupation, and the slow process of liberation.

The most interesting aspect of the book is the careful (if self-adulatory) accounting De Gaulle constantly keeps of how his listeners are feeling- how the spiritual bond between him and troops being reviewed, or crowds hearing his speaches, or the French community at large, is developing. It is feelings which are the object of propaganda, the sinews of civic community, and the foundation of national power. These feelings start off rather tenatively, but via the radio broadcasts, and through slow persistence on the ground, first setting up shop in England, then Brazzaville (then part of the French empire, wrested from Vichy), then Algiers, and finally Paris, De Gaulle gains the hearts of the French, and enters into uncontested administration of post-war France. De Gaulle also carefully took charge of the internal French resistance, by supplying arms, other logistics, and leadership.

A sample quote: De Gaulle, installed back in Paris, receives a communication from Marshal Pétain, earlier the titular head of the Vichy regime, now on his way to imprisonment in Germany, to the effect that Petain would like to negotiate with De Gaulle about the transfer of formal powers of administration in France, i.e. his own surrender, in order to prevent civil unrest.

"But what reply could I make to this communication? In such matters, sentiment could not stand in the face of the rights of the state. The Marshal referred to civil war. If by that he meant the violent confrontation of two factions of the French people, the hypothesis was quite out of the question. For among those who had been his partisans, no one, now, rose up against my power. There was not, on liberated soil, one department, one city, one commune, one official, one soldier, not even one individual who professed to oppose De Gaulle our of loyalty to Pétain. As for reprisals, if certain factions of the resistance might commit retaliatory actions against the people who had persecuted them in collaboration with the enemy,  it devolved upon the public authority to oppose itself to such actions, while insuring the action of justice. In this matter, no compromise was conceivable."

It is an object lesson for our time, in making a nation great again. Firstly, De Gaulle writes very well, in style that is admired in France, and also communicates his clarity of intellect, even in translation. Secondly, he generates increasingly representative advisory councils as he goes along, always taking the temperature of the major threads of French resistance (including the communists whom he loathes). Instead of tearing down state structures, he continually builds up new ones, in preparation for effective administration of ever larger populations and areas. Thirdly, he is never a poodle for foreign powers, standing up for French interests at every point, even when there is no France to stand up for. And fourth, his mind is always on the big picture. There are no scandals in this book, only high policy and monomaniacal focus on the objectives of a healthy France, Europe, and world.

He sees that in order to conduct the resistance from colonial territories, he will have to promise their independence, at least in principle. But getting from there presents enormous problems, especially when the British push Arab and Islamist agitation. De Gaulle ended up being the one to wind up the bitter Algerian war, (1962), selling out the various pied noir (settlers, in current parlance) to grant Algerian independence. When the US dreamt up the United Nations, De Gaulle viewed it with suspicion (and, in view of the ill-fated League of Nations, with some distain), even as he successfully got a seat on the security council. While this council may seem an absurd anachronism today, its original aim was rather evidently to serve as an anti-German league, consisting of all the Allied powers from WW2, particularly those surrounding Germany.

De Gaulle with Willy Brandt. De Gaulle was intent on building good relations with Germany, and integrating Germany into a new pan-European economic and security system.

In addition to his bitterness about Britain's greed, De Gaulle was bitter about the US as well. Roosevelt never took him seriously, and continually tried to circumvent De Gaulle in setting up occupation administrations and in conferring with the "big" allies. It is not entirely clear what the basis of this distaste was. It was putatively about De Gaulle's upstart status, as one who created his own state out of nothing, rather than sitting atop a pre-existing apparatus, not to mention a lack of democratic credentials. It was also about France's weakness- her ignominious military defeat left a sour taste, for sure. There was also France's unproductive treatment of Germany after WW1, first demanding huge reparations that prostrated and embittered Germany, then lacking the backbone to back them up or productively renegotiate them, rather allowing Hitler to thumb his nose at the Versailles regime and embark on his mad buildup to WW2. Or there may have been something else. But De Gaulle got his revenge later on, when he entangled the US in Vietnam, which was one jewel he was exceedingly reluctant to yield out of the colonial empire, especially to a bunch communists. All in all, our relations with France are a lesson on focusing on the current war and the friends you have, not the last one, or the ones you wish you had.

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The Right Wing Mind: Lost, Revealed, or Manufactured?

A review of How The Right Lost Its Mind, by Wisconsin conservative talk show host Charles Sykes.

Oh, where are the decent Republicans? The Ronald Reagans, the Newt Gingriches, the Paul Ryans? Thus goes the lament of Charles Sykes, who writes a searching and impassioned book decrying the moral and intellectual collapse of Conservatism into right-wingnut demagoguery and authoritarianism. Like any theologian, he is not willing to go the whole distance and question the fundamental nature of American conservatism and its pieties (which he refers to as "truths" with some frequency). But he is remarkably honest about the rot that characterizes the party, even as it is ascedent politically. I recommend his work, though obviously he remains staunchly (if nicely) conservative. Being from Wisconsin, and all. He had, indeed, played a central role in denying Trump the Wisconsin primary, from his talk show perch.

There are many threads that lead from there to here, and I will break out a few of them below. The arc of his story is that the sainted William Buckley exiled the wingnuts from the Republican party, preparing it for several decades of intellectual growth and political dominance. Now they are back with a vengeance. Sykes spends most of the book describing the many ways this happened, but explaining *why it happened in any deep way is another matter altogether. One might also ask why they were there in the first place, and where did they go in the meantime?

Media: from responsible to clickbait

The fact that Trump, after all we have seen, still has a solid 35 to 40% of the population on his side indicates that America is up to its gills in wingnuts. Have they always been there? No, to a large degree, we are responsive to our social environment. People can be led. The soothing chamber of commerce environment of past Republican generations did a great deal to dampen nuttiness. Now, the spittle-drenched ravings of FOX and its analogs are doing the opposite, driving otherwise pleasant and reasonable people to embrace the very worst devils of their nature.

What is equally bad, the new media has comprehensively replaced careful, professional curation of news with a downward spiral of virality and clickbait. Facebook's business model is explicity to reward clicks. "News" that gets clicks gets paid in ad money, and wins, which means replication over the platform and from its content providers, be they basement trolls or foreign operatives. No worse information system could be designed. Facebook is sort of a machine to bring out the worst in people, mistaking titiliation for news, let alone thought. For Google search, the analysis of linking and clicking is a valuable feature, winnowing the internet down to the most significant sites. But for news, this practice has obviously disastrous consequences, given human proclivities and weaknesses. That is why news organizations came to be in the first place, over the last century.

Propaganda exhibit A. The dossier was created by one of the world's leading experts on Russia, and no significant revelation from it has been disproven. It continues to be corroborated by, and serve as the spark for Muller's and the FBI's investigation.

One example of this problem, which Sykes should have delved into, but didn't, is the villainization of Hillary Clinton. When you sit down and compare the relative merits of Trump and Clinton, in terms of experience, aptitude, scandalous behavior, poor judgement, family stench, and corruption, there is no comparison. Yet because of the totally unhinged nature of the right-wing media, which the mainstream media could not help but cover (calling it "controversial", and other normalizing locutions), the vitriolic wingnut narrative seeped into the public consciousness, to the point that "jail her" was publically acceptable as a mantra by Trump himself and his campaign.

Is conservatism authoritarian?

This leads to Sykes's most significant insight and claim, that conservatism is not the same as authoritarianism. It was the wingnuts who were and are again, authoritarian, while true conservatives do not look to a maximum leader to deliver them from political impotence, but value compromise, core values, and legal and civic norms. Here I disgree strongly. There is clearly a long and close relationship between the two. The spectre of left-authoritarianism is certainly possible. But as a rule, authoritarians are right-wing. Conservatives, as Sykes describes, work long and hard to keep this id under control, not always successfully. Law and order, xenophobia, traditionalism, religion- all these tend to be shared themes which animate both strands of the right, and of which the Trumpists are merely a more extreme manifestation. Republicans have been cultivating the "Southern Strategy" for decades, and what is more authoritarian than this concerted effort to maintain the white terror of the South?

Patriarchy is the point

Similarly, manliness, strength, and similar macho themes are very much conservative touch points, as are anti-abortion, hostility to birth control, and other measures to keep women subjugated. The Trumpist trolls are merely more open about it than their patrician forebears. We owe Sykes and his (few) colleagues in the never-Trump section of the party a great debt for their resistance, both during the campaign and ongoing. But they should not kid themselves that their cherished pieties are somehow different in policy terms than the crudities now on display in the White House.

In this respect, as in so many others, FOX has lead the way in normalizing and activating the basest instincts of the right, whether conservative or authoritarian. And now, with social media, Trump appears to have not only FOX and friends, but also legions of trolls on his side, ready to visciously attack any Republican who utters anything less than complementary. I used to think that Trump did not have his own paramilitary, so he could not get very far in subverting our establishment. But these social media forces seem to be his Brown Shirts, and have brought the rest of the Republican party to a whimpering state. Politicians who stray are subjected to relentless attacks, which for some reason they pay attention to, as though the trolls on facebook and twitter are somehow representative of the public interest. As if the thorough-going financial corruption of both parties were not bad enough!

 Or is it stupidity?

Choosing to listen to the very worst that America has to offer is a sin of legislators, but they are observing, as do we all, that these propaganda and troll armies are having an effect on the electorate, influencing the easily led. This raises the question of why, in a country whose educational system was supposed to be the envy of the world, and whose people are, on the whole, the richest. What happened? Sykes certainly does not delve into that conundrum, confining himself to the mantra that as long as we stick to conservative verities of small government and high tax cuts, all with be well. But the basic fact is that human nature is to a great degree conservative, and the unthinking position is in favor of the status quo. Reform is the business of intellectuals, which some Republicans may have been, briefly, at one point. But now, dumb is their brand, and they are increasingly proud of it.

Pot calling the teacup black.

But I think there is one further hypothesis that might be considered. A recent New Yorker article mulled over the steep drop in crime over the last two decades, not only in the US, but in all developed countries. It did not come to any particular solution or explanation, other then aggressive policing policies. But I have one- lead. Our cities were drenched in lead from gasoline for decades, peaking in the 1970's before lead was banned from gasoline. Lead is known to affect cognitive development, meaning that we had demographic cohorts from that time who were likely heavily damaged by exposure to lead. While crime is a pursuit of the young, and the crime wave in the US tracks the rise and fall of lead in gasoline quite closely, politics is a more mature pursuit. Thus one can theorize that the lead-affected cohorts of the 70's peak might be the ones now responsible for the political and media system, both as voters and as participants. This would be a somewhat shocking hypothesis, yet also a hopeful one, as we are assured of a return to normalcy in a few decades, at least.

A problem of compassion

At any rate, conservatism is the unthinking choice in politics, the dedication to keeping things as they are, to stasis. While liberals express hope in the future and compassion for others, conservatives (not to mention right wingnut trolls) express fear- of others, of social innovation, of change in general, and of the state and its role in antagonizing traditional power centers like the church, the corporation, and the patriarchy. Indeed, one might paint conservatives as the faction of fear, which turns into hate on the authoritarian end of the spectrum. The mantra of small government is implicitly a mantra of big power elsewhere- of big and bullying companies, of monopoly, financialization, unemployment, and all the other ills that the modern state stands ready to remedy and regulate. Can the ideals and compassion of the left get carried away? Communism certainly proves that. But broadly speaking, the concept of a compassionate conservative is an oxymoron, and that informs both the thesis Sykes is trying to sell, and also the larger question of why this moment has brought out the Trumpist shadow.

Population pressure

One issue that seems also to get short shrift is overpopulation. The culture in the US has changed from one of hopeful frontier values with land for anyone who wanted an independent existence, to an intensely urbanized one. Most urban areas have also reached a sclerotic state of development, having "built-out" decades ago, and now find it virtually impossible to even imagine building new interstates or other substantial infrastructure that would be required to relieve (in some areas) incredible traffic problems and housing shortages. Thus we experience an increasingly zero-sum game where the 1%, instead of thinking about the future of the country and growth, are instead grabbing what they can from the system as it exists, with little thought for tomorrow, or for others. In such a frustrating environment, the appeal of rage- of blowing things up, burning it down, and starting from scratch is somewhat understandable, but only as an impulse, not a policy.

Is inequality the American way?

This hardly needs expansion in this post.

The culture war

The long-standing left-right culture war over recent decades has many fronts, and conservatives generally feel that they have lost on most of them. Abortion has been fought (so far) to a draw, outside of the reddest states where it has been exterminated in practice. The gay rights fight has be excruciatingly disasterous, however. Liberal compassion was really flying its freak flag there, and it has made the traditionalist conservatives, and their troll shadow army, outraged. The culture has moved relentlessly on, and yelling stop has had little effect in most precincts. There is one front, however, where the right has clearly won, and that is guns. This is where the most rabid partisans have occupied and expanded their ground, providing the model for scorched-earth, vitriolic, irrational, feed-the-worst-instincts propaganda. Is it fascist-inflected? Authoritarian? Or just conservative? Whatever it is, it certainly occupies the most right part of the spectrum, and it is no surprise, after its signal success in cowing legislators and advancing its agenda that this community has been taken as a model for success on the wider field of right-wing causes.

A little light relief, courtesy of Colbert.

The South

Enough said.

Ideas, shmydeas

This is perhaps the most important thread, especially in considering Sykes's work. He is tirelessly admiring of William Buckley and Paul Ryan, as substantive, thoughtful conservatives. His arc is from serious conservatism of yesteryear, and of Wisconsin, to the degraded Alt-right petulance of today. But what if the ideas were no good to start with? What if these have always been convenient and irrational fronts for serving the rich and the powerful? The Republican's attitude towards deficits has shown, as nothing else can, their shameless hypocrisy about their so-called "ideas". When Democrats are in office, deficits are disastrous and spending evil. When Republicans are in office, quite the reverse. Nor have any of the tax cuts generated Laffer-ian economic growth, merely Keynesian growth, along with deficits. The record of conservative "ideas" has been abysmal, and the new Trumpians merely recognize that this was always the case, and dispense with ideas altogether, in favor of e-motivated politics like trade bashing, immigrant-bashing, and tweeting. Then they do what they want, which is evidently to make the rich much richer, and screw everyone else, workers, the poor, the environment, the world at large.

Likewise with small government. When it comes to compassion and equality, cuts and small government are in order. But when abortion comes up, or a bloated military, the sky is the limit. No, the ideas were never more than a cover than support for patriarchy, property, and hierarchy- conservatism of the oldest kind, whether in patrician clothes, or something more swastiky. Indeed, the media issues raised above, and the lead issue, gross inequality, and all the other issues that have causal relevance for the decline of our political system, come back to a role for government itself to regulate and improve our physical and social environment. Government is our means to solve big problems, and frequently has to be big to do so.

In the end, Charles Sykes is likable and thoughtful. And his urgency in turning the Republican party back towards civility and a concern for institutions, law, and other people, is heartfelt and important. However, the idea of putting the crazies back into the closet, and reverting to the platitudes of God, Tax Cuts, and Small Government, is not viable. Sykes says so himself, urging new ideas to be developed, whose nature, however, he leaves in great obscurity. My suggestion? Join the Democratic party.

• Sinclair is another fair and balanced network.
• Bactra is back, however.
• After capitalism.
• The corruption is just endless.
• And it would be nice if our president weren't a Russian asset.
• If police want respect, they need to earn it.
• Ignorance of MMT would be better for everyone!

How Can Cells Divide When DNA Looks Like Spaghetti?

Topoisomerases untangle the mess, very carefully, with itty-bitty molecular scissors.

DNA is incredibly elegant as a solution to information storage and heredity. But it is also an enormous mess, with the genome of humans extending to five feet in combined length. (Imagine 9,000 miles of garden hose.) So each cell, which contains this whole amount, has a nucleus resembling an incredibly convoluted nest of spaghetti. Yet at mitosis, the chromosomes condense, separate, and neatly partition to each new cell. Some of the solution consists in how the DNA lies in the interphase cell- it is already somewhat pre-organized there. But most of the solution comes from enzymes that do not bother disentangling it- they cut the Gordian knot with enzymatic swords. Genomes were able to surmount the length problem over evolutionary time by the development of topoisomerases, which cut and religate DNA with extraordinary precision.

There are two main types of topoisomerase (named for altering topology, or the organization / twisting of DNA, without changing its energy, sequence, or composition). Topisomerase I cuts only one strand of the double-standed DNA, and can thus relieve coiling tension. Some forms can wind up the tension, using ATP. Topoisomerase II cuts both strands, and is the main enzyme that allows complete de-catenation / detangling of DNA during replication, transcription, meiosis, as well as mitosis. A recent paper looked deeply into the mechanism of this class of enzymes.

As one can imagine, the minimal requirements of a Topoisomerase II is that it hold on to both ends of the DNA it has cut, while passing through the other DNA strand which has, by virtue of general tangling, come up against it. This condition of collision needs to be detected, prior to being resolved, so that the enzyme is properly positioned. The complex also has to detect that the process has finished, and reset to the starting state, including religation of the cleaved strand of DNA. It is a tall order for a mere chemical confection to carry out, frankly.

But it turns out that enzymes can have hands, if not brains. The authors provide, on the basis of a great deal of past work as well as their own, a compelling model of how this topoisomerase performs its amazing feats.

Molecular structure of a typical topoisomerase II, composed of two copies of Top6A (green and red; second copy in gray) and two copies of Top6B (yellow, purple, and orange; second copy in gray). The G-segment DNA (~70 bp) is strung along the underside, and the T-segment DNA will shortly be accommodated in the middle, upon which the top portions clamp together. Cylinders represent alpha helices, the common secondary structure of proteins. Key domains for the activity of this protein complex are noted- the H2TH domain, which notifies Top6B that a G-segment is present- the KGRR domain, which notifies the same enzyme that a T-segment is present, and to keep the clamp closed. And lastly, the stalk/WKxY domain, which in addition to helping to bind the G-segment communicates between Top6B and Top6A that cleavage of the G-segment can happen. The G-segment will be cleaved in half at the bottom of the structure, later to be re-ligated after the T-segment has passed through. 

The enzyme (it is a tetramer made up of dimers of two separate proteins, Top6A and Top6B) forms a large hoop, with arms outstretched that will join during its action. One DNA segment, the one to be cut (the G-segment, for gate) is first bound by the underside of the hoop, centered at the middle active site which does the cutting, holding, and religation. The outstretched arms encompass the other DNA strand (the T-segment, for transit). Both top and bottom of the complex have ATPase activity, though for different purposes.

The key finding made by these authors is that the G-segment DNA is bound not only near the cleavage site (in Top 6A), but by the entire arm structure, up to a domain in Top6B that the authors call H2TH. About 70 basepairs of the G-segment DNA are bound, overall. This not only stabilizes and holds this DNA while it is being cut and the T-segment is being passed through, but it also allows the Top6B portion of the enzyme to sense the status of the whole complex, so that it can properly sequence its activities.

The KGRR feature functions to sense T-segment DNA and keep the clasp closed and ATP unhydrolyzed while the T-segment is present. The bottom graphs show ATP hydrolysis in the mutants diagrammed above, while the gel images show relaxation of the supercoiled DNA but the enzyme (moving it from the bottom to the top, left to right). ATP hydrolysis is increased to a free-wheeling state, while DNA relaxation fails to happen, in two mutant versions of the KGRR finger.

For example, the authors identify another feature near the top of Top6b, called KGRR, which is a finger that points inwards to touch the T-segment DNA. When they mutate it, they find that ATP is now freely digested in the presence of supercoiled DNA, much more actively than by the intact (wild-type) enzyme. But the enzyme is inactive ... no strand passage takes place, and supercoils are not relieved. The mutant enzyme is spinning its wheels, clasping and opening without doing anything. What this indicates is that in the normally functioning enzyme, the KGRR domain is a sensor that keeps the complex locked up till the T-segment passes out the other side, via the cleavage in the G-segment. Only then can ATP be digested by both halves of the enzyme, re-ligating the G-segment, and opening the Top6B arms to allow a new round of stress relief to take place.

Similarly, they conclude that the function of the H2TH sensor is in part to notify the Top6B part of the enzyme that a G-segment DNA is bound on the underside, allowing ATP to be bound and the clasp to close, if a T-segment also happens along. T-segments should not bind unless a G-segment is bound first. Secondly, the dramatic DNA bend adopted by the G-segment in this protein structure, especially in the locked-up conformation, draws on the supercoiling / torsional state of the DNA that is the target of action. Supercoiled DNA binds with 60-fold higher affinity than unstrained DNA.

Overall schematic of the mechanism of the enzyme- see text.

To recapitulate, the overall model is that G-segment DNA, in torsionally stressed condition, binds to the broad binding area of the underside of the enzyme. This notifies the Top6B domain that T-segment binding is acceptable. When that happens, the clasp is closed and ATP is bound, but not hydrolyzed, setting up the next step. A hinge between the two protein halves notifies Top6A that it can cut the G-segment. When that is done and the T-segment passes through, the KGRR sensor notifies the Top6B that the clasp is empty, so the ATP is hydrolyzed and the clasp releases, ready for another round.

It is an intricate molecular mouse-trap, built of ratchets and sensors of various kinds, using the jostling motion universal at this scale, plus key inputs of energy (ATP) to accomplish what on the large scale looks like an amazing feat of re-organization.

• We have a sleaze bag as president, with sleazy personal, international, business, governing, and legal ethics. Is that news?
• Why haven't we had self-driving cars for the last decade?
• Some places have fewer guns, and better policy. Some have more, and utter corruption.
• Should greed and profit be the highest societal values?
• Another introduction to MMT economics.
• Humanism.
• The new class structure, and the new left.

GWAS: Complexity in Genetic Variation and Selection

Genetic studies show that most traits have many influences, most genes affect many traits, and most variants have small effects.

Once the human genome was all sequenced, and once lots of alleles (aka variants, aka mutations) were collected from human populations, scientists started doing large scale genetic studies, called genome-wide association studies (GWAS). The dream was that now, at last, we could find the "genes for" schizophrenia, and alcoholism, and depression, and autism, and height, and cardiovascular disease, and countless other syndromes and traits which are known to be highly heritable.

But this project pretty much came to naught, for reasons that have gradually become clear, and which a recent paper (review) provides some more explicit modeling for. The variants that have been found through GWAS have generally had very low effects on the studied trait, and even adding all of them up, the heritability that is known by other genetic methods was not accounted for. This became known as "the missing heritability". Height is clearly heritable, as the path leading to Yao Ming shows. Yet add up all the known variants contributing to height, and they do not add up to that known heritability.

Firstly, these studies focused on common variants, necessarily because data was so hard to come by. If a 1000 genomes are sequenced, out of the human population, and the study requires that the variation occur more than once so that its association can be validated, that variation must be a common one. That implies in turn that it can not have a very strong selective effect, otherwise it would not be common. And that implies in turn that any effect it has on any trait has is likely to be weak.

Secondly, we have been somewhat blinded by the archetypal mendelian model of traits. The wrinkled peas, human eye color- these are simple traits, with one or a few alleles. Blue eye color is due to complete lack of the enzyme to make brown- it is either on or off. But most of our genes are more important than that, and can not be turned off without dire consequences. Most of our genes make products that participate in large pathways and networks where they intrinsically will affect many traits and have strong effects if significantly defective. Indeed, it is estimated that about 1/3 of amino acid positions in the coding genome have strongly deleterious effects if changed.

Network of genes with variants found to be genetically associated with autism. Each one, naturally, has very small effects.

This implies that most of the variation that exists around these genes will not have dramatic on/off effects, but rather be slight modifications of the sequence, or of expression- up or down, or in modestly altered locations or times- consistent with the high variability and degeneracy of that regulatory code/system. In addition, if a variant has an effect on the trait one is studying, it will likely also have effects elsewhere, given the complexity of most circuits (called pleiotropy). Thus its overall selective effect may be substantially larger than that focused solely on the trait of interest, dampening yet again one's ability to find such variation from studies on particular traits.

We are now in the world of "quantitative traits", as opposed to Mendelian traits. Not that they do not obey Mendel's laws, but that their complexity is such that a whole new form of statistics and analysis is needed to deal with them. Quantitative traits vary in a continuous way, (like height), and are composed genetically of many genes, whose many variants (at least those which occur commonly) each have small effects.

Modeling is now getting more accurate predictions of heritability explanation based on effect sizes of individual variants, and a study's ability to find them based on its size. The left panel shows how more heritability is explained (lower levels  unexplained) as the study threshold captures more variance (more alleles, with smaller effect sizes) towards the right. Overall heritability of height is supposed to be around 70%. The curve on the right, modeling how big studies (in terms of thousands of individual subjects) would have to be to get there, is unlikely to ever get there, so the modeling remains incomplete. This is even more true for BMI, whose total heritability is roughly 60%. Even with the statistics deployed here, they are not modeling the full heritability, even with extrapolation to infinite study size.

The conclusion from all this is that the missing heritability is not missing, just hidden. If we could sequence everyone, and analyze all their variants, we would find all the heritability that lineage and twin studies know is there. The paper makes the significant point that the problem is not epistasis- the non-linear interaction of different genes and variants. No, the large numbers of small effects tend to add up linearly, but just because they are so small and there are so many of them, which studies up till now are not powerful enough to find, they remain out of reach.

This is disappointing from a medical standpoint, but also biologically. One goal of finding key genes for common diseases was to understand them mechanistically, as well as to treat them. But if no one gene, or even a few, is the key to complex diseases and traits, then the climb to understand their biology, and gain practical insight to alter their course, gets that much steeper.

• Florida's bridge/political/environmental/traffic/population disaster.
• Evangelicalism as simple patrician politics.
• Millions have been killed in Iraq.. was that OK?
• My data is your data... as usual, the crime isn't what is illegal.
• A philosophical memoir of science and physical therapy.
• Corruption seems to know no bounds.

Periplasmic Space: The Final Frontier

The outer layer of bacteria, as a complex sensory and protective skin.

A theme of evolution is that sensors are better than armor. Mammals have very thin skin, with hair that has both sensory and protective roles. The reptilian and dinosaurian armor has been left far behind, in favor of a wide variety of short-range sensors innervating the skin, and long-range sensors, all choreographed with large brains. Among bacteria, a loosely analogous process took place in the development of Gram negative lineages.

Gram positive bacteria (purple) have a very thick armor of peptidoglycan, while Gram negative bacteria (lighter pink) have a second outer membrane that keeps out the Gram stand, and surrounds a much thinner peptidoglycan wall.

The Gram stain is a complex antibacterial (and purple) molecule that binds to the outer peptidoglycan wall of bacteria. This is a meshwork which is constructed outside the plasma membrane, which is the key chemical, ionic, and electrical barrier between the cell and the outside. Like the lignin cell walls of plants, the peptidoglycan wall helps to protect the cell from physical abuse and from osmotic shock / swelling. Many antibiotics, like penicillin, impair the construction of this wall, causing the target cells to lyse. Since the construction takes place on the outside, access by antibiotics is easy, and a great deal of microbial warfare has happened at this interface.

Diagram of the periplasmic space. LPS is lipopolysaccharide, composing much of the outermost leaflet. IM is inner membrane, where sensors to its own stress as well as stresses on the peptidoglycan and outer membrane reside. LPP is Braun's lipoprotein. The porin is an example of a semi-selective outer membrane channel that lets in some nutrients and ions while keeping out other, larger chemicals.

But what if some bacteria came up with an innovation to construct another membrane on the outside, encasing the peptidoglycan layer within a protective semipermiable membrane that keeps (at least some) antibiotics out? These are the Gram negative bacteria. They have an outer membrane with a specially robust outward-facing lipopolysaccharide (LPS) surface, and a very thin peptidoglycan layer, before you get to the cell's critical plasma membrane. While the Gram positive bacteria have a huge, thick armor-like peptidoglycan layer, Gram negative bacteria have a much thinner but more complicated structure, whose construction, homeostasis, and sensory capabilities are still under study. Our mitochondria are descendents of Gram negative bacteria, and also have a double-membrane, which makes the transport of the many nuclear-encoded proteins that compose them a rather involved process.

https://www.ncbi.nlm.nih.gov/books/NBK26828/

What keeps the outer membrane in place? That turns out to be the most abundant protein in bacteria like Eschericia coli, which is the prototypical Gram negative bacterium- Braun's lipoprotin. This protein serves as the strut/rivet that spans between the outer membrane and the thin peptidoglycan layer. If this protein is engineered to be longer, this tiny space widens in proportion.

Increasing the length of Braun's lipoprotein (lpp) widens the periplasmic space, in this case from 25 nm to 28.5 nm.  In the second panel, a mutant which renders lpp incapable of attaching to the peptidoglycan layer renders the periplasmic space disorganized and the outer membrane prone to vesiculation.

The whole space between the inner and outer membranes is called the periplasm, or periplasmic space. It has evolved not only for protection, but to host many processes best kept outside the cytoplasm, like pre-digestion of some nutrients, ionic and redox control, scavanging for iron and other key nutrients, stabilization of the flagellum, not to mention the construction and maintenance of its own components, including the outer membrane and the peptidoglycan wall.

This all requires quite a bit of sensory capacity, for instance to sense when the outer membrane needs more lipids to accommodate cell growth, or how thick to make the peptidoglycan. Very little of these sensory capacities are understood, but a recent paper discussed one sensor, RcsF, that somehow senses stress on both the outer membrane and peptidoglycan. This protein sticks a finger into the outer membrane, and either spans the entire periplasm or moves across it upon stress events. It then interacts with proteins on the inner, or plasma, membrane- IgaA and RcsC- which transmit its stress signal to a cascade of interior protein phosphorylation events that end up reducing cell movement and activating protective programs against stresses such as acid and membrane insufficiency, and increasing biofilm production and synthesis of proteoglycan and lipopolysaccharide.

The authors showed specifically that if the Braun lipoprotein was lengthened, widening the periplasm, then RcsF would only work (protecting against antibiotic treatment) if it was similarly lengthened. That indicates that RcsF spans at least between the outer membrane and the peptidoglycan layer, if not all the way to the inner membrane. The latter would be a total distance of 25 nm, which is equivalent, in a protein alpha helix, to 166 amino acids, which is longer than the entire RcsF protein. So some kind of migration or transfer through the periplasm must be taking place during the sensing event. It also suggests that one thing RcsF may be sensing specifically is the distance between the peptidoglycan and the outer membrane. Other stress sensors and mediators exist, so there remains a great deal to learn here. While Gram negative bacteria may not have a brain, they have a very smart skin that actively protects and defends them.

• Cosmic jets.
• Breathtakingly corrupt.
• The swampy new administration.
• It is Obamas' fault, for not ending racism.
• Is panhandling protected speech?
• Schwarze null.
• Reading, yes... but what are you reading?
• New CIA chief- a moral disaster.
• RIP
• Pterosaurs were diverse (if a little big) up till the end.

Americans, Plain and Simple

How about doing away with the term "African-American"?

It has taken me a while to realize that African Americans are far, far more American than I am. I am a naturalized citizen and immigrant. Yet the Protestant, white, suburban Boy-Scout culture fit like a glove- I was assimilated into 60's-70's America with plenty of personal and family issues, but no larger political or cultural issues.

How different that is from the black experience, where whole political parties remain dedicated to keeping black Americans down! A small part of that social antagonism and "othering" is furthered by the distinct names that have been applied to the black community. While the term "African American" is about as neutral as can be, in strict analogy to the many other ethnic terms like Irish-American, Jewish-American, German-American, Chinese-American, etc., there have in practice been some distinctions.

First, "Irish-American" is not frequently used. Most ethnic groups, especially those of such long vintage, have simply melted in to the pot of generic Americans- have assimilated or had America assimilate to them. So the continued intensive use of the term "African American" does not flow from a lack of assimilation, at least not from an African originating culture, but something quite different. Second, why is "African" lumped together so promiscuously, as if a continent as large as three Europes contained only one culture? "Latino" suffers from the same syndrome, hiding vast differences and diversity for the convenience of the dominant culture. It is a natural problem with naming and grouping of any kind, but is another sign that the "African" in "African American" doesn't really refer to Africa.

What all this does signify is continued segregation in all sorts of dimensions- social, physical, economic- based on a long cultural history of fear, disgust, hate, and social and economic oppression/powerlessness. Pride in an African heritage is admirable, but that seems so distant as to be mostly contrived; there is very little such heritage afoot in contemporary America, in any way that is distinct to one community, beyond genetics. (Though Wakanda may change all that!) A more accurate designation might be "formerly enslaved Americans", though that hardly trips off the tongue either. There have been many attempts at labels, more or less successful, (Negro, colored, minority, Urban, Afro-American, ghetto, racialized people, diverse, people of color). I would suggest the preferred usage just be "Americans" when and where possible, without further ado or elaboration.

A word-cloud of my own creation, text drawn from Wikipedia and other history sites focusing on the back experience. This  appears to militate against the thesis presented, showing "African" with high usage, and as perhaps the primary locus of identity. But the corpus was a very backward-looking, perhaps not reflective of the current cultural setting.

Obviously, from the very nature of this very article, some term is needed to refer to Americans descended from those were formerly under bondage and even more formerly kidnapped from West Equatorial Africa. "Black" seems to fit that best, if still very uncomfortably. Despite all the etymological / symbological freight, simplification, and label-i-fication, it is simple and widely used. It is also part of a deeply unifying symbology. The Ying/Yang symbol is an example, showing light and dark as part of all things, and all cycles and processes. Ebony, Jet, Black power, Black is beautiful... all have been ways to rectify the dominant-culture valence of this term.

• Another view of police.
• Worse than collusion.
• Why do we have a new nobility & feudal system?
• UBI is a symptom, not a cure.
• A network of deranged people.
• Social conformity is (partly) genetic.
• Consumer protection? Not us!
• Watch Bill Mitchell in lecture.

TP53: On a Knife Edge of Death

The difficult tradeoffs made by TP53, between tumor suppression and premature aging.

TP53 is a gene whose mutated forms are perhaps the most frequently found causes of human cancer. Its product is a transcription regulator and also interacts with a large number of other proteins to orchestrate a graded response to cellular stress. One job is to halt the cell cycle in the presence of DNA damage. But it can also order cell suicide, which makes it one of the key defenses against cancer, which is fundmantally caused by escape from these kinds of tight mechanisms of cellular surveillance and control.

Interestingly, some researchers have created over-active mutations of TP53, which in mice confer higher resistance to cancer, but also a rapid aging phenotype. By this point, there are many ways to make aging go faster, by eliminating various cell repair pathways. One lab has deleted SIRT6, a gene that is an upstream inhibitor of TP53, and has its own complex role in stress response and promoting proper DNA and other forms of cell repair. It was one of the regulators thought to be part of the "red wine" effect, such as it is. This deletion dramatically reduces the lifespan of mice, from three years to just under one year. Since some of this protein's effect goes through TP53, the researchers created mice with a half-dose of TP53, which substantially rescued the mutant mice's phenotype, increasing longevity to one and a half years and raising health and body weight.

Comparison of mutant mice. SIRT6 is part of several cellular repair pathways, and its deletion (Sirt6-/-) causes mice (middle) to have much shorter and less healthy lives, their cells going south at increased rates. This defect can be corrected in part by adding another mutation, partially reducing the amount of TP53, one key target of SIRT6 inhibition.

This all demonstates, in part, that there can be too much of a good thing, i.e. TP53. On the other hand, other studies have shown that simple over-expression of normal TP53 in otherwise normal backgrounds strongly decreases cancer rates while not affecting longevity. Thus if TP53 is under normal regulation, it does what it is supposed to do- signaling cell repair or suicide, while not attacking normal or slightly stressed cells, which seems to be the problem in aging, causing loss of tissue and especially stem cell reservoirs.

Some other clues come from naked / blind mole rats, which have evolved a subterranean and highly social existence, combined with great longevity (twenty years, which for such small animals is extremely unusual) and virtually complete resistance to cancer. Here, the TP53 genes have lost some function, becoming less capable of inducing cell suicide. This is thought to be connected to the longevity phenotype. Separate mechanisms have evolved to fight cancer, such as a dramatic and thorough necrosis of any cell population that over-proliferates, induced by interferon gamma.

The message at the end of all this is that there is great scope in human biology for manipulating our longevity and health in later life. The molecular mechanisms we currently have are good, since a life span of eighty-odd years is nothing to sneeze at. But there is room for improvement, though the complexity of the networks involved in our internal surveillance and repair processes is so high that it will be some time before we have a theoretical handle on what can be done, let alone practical interventions to implement such theories.

• God appears to be responsible!
• Death as a literary goal.
• Bob Cringely on shareholder value.
• Notes on central banking.
• Data on guns.

Shape-Shifting: The New Phrenology

Anatomical and connectivity patterns in brains correlate with behavior patterns.

Remember phrenology? This was the reading of people's traits and destinies in the shape of their skulls. While the motivation made sense, the brain being the seat of our traits and character, along with consciousness and all other mental functions, the science didn't. It turns out that the brain is far more plastic within its vault than we ever see from the outside - a skull that hardens during early childhood, long before the rest of brain and mental development is complete.

Brain visualization methods have long battled with variability. To do studies using many subjects to find some area of the brain that is "activated" during some task, the brains of those subjects need to be correlated, even though they may be shaped differently. The major landmarks of human brains are quite uniform, but on smaller scales they are not, making comparisons difficult.

But what if that variability is functional, and reflective of our capabilities and personalities? That is the subject of a recent paper, which used a style of MRI called resting state fMRI, which compares brains when they are not doing anything in particular, to see how different areas fire in relation to each other. We have what is called a "default network", which hums along even when we are consciously not doing anything. As any meditator knows, emptying the mind is virtually impossible.. there is always something going on, and these stray activities, not to mention the vast amount of unconscious processing, is the target of this rfMRI. And not just the activity per se, but the correlations between activity in different locations, which, when suitably processed, can tell us about the actual locations of functional modules of brain anatomy, and the strength of their connection.

An illustration/map of the author's data, showing variable and behavior-correlating regions by color. For example, the yellow region bottom left/right, rear of the brain, is in the parietal-occipital sulcus, associated with visually-guided behavior and planning. 

The authors devised measures of variation of region size, and correlated them with behavioral measures. Some of these were remarkably strong, indicating that small increases in a particular brain areas can have strong association with phenotypes like susceptibility to addiction and other vices, intelligence, and self-discipline. The authors focus on the technical implications of their work, which shows that inter-individual variation in functional brain structure is substantial, and makes merging/averaging for many kinds of brain studies more perilous than previously realized. It also implies that previous conclusions about variations in "coupling strength" between regions might be better interpreted as a signal of mass action caused by physically larger regions devoted to a given function.

Functions correlated with anatomical variation in the brain.

It is not surprising that, as we understand the brain better, its evident variations in effect will start to be reflected in corresponding variations in its structure and function. But it is rather disturbing as well, as this work implies that, someday down the road, brain scans may be able to tell others significant secrets about our personal lives and prospects. A "pre-crime" kind of scenario, indeed. It is, of course, one more reason to definitively separate health care from employment. It is also part of a general trend making of our lives, inside and out, an open book.

"Our results indicate that spatial variation in the topography of functional regions across individuals is strongly associated with behaviour. ... Furthermore, recent work has shown that resting state spatial maps can be used to predict task activation maps from individual subjects very accurately, and that interdigitated and highly variable subnetworks can be identified within individuals."

• TED talk on Russian information warfare.
•  ... which becomes our contemporary intelligence test.
• Arming teachers? Right.
• Why not mix a little political corruption with your business corruption?
• Supreme court says it is OK.
• Want a free AR15?
• Some people are naturally more important than other people.
• When reasonable people become socialists....
• Where do tax cuts go? Into stock buybacks.
• Our new feudal reality.

"Taken together, this evidence casts doubt on the idea that more rapid technological progress alone has been the primary driver of rising inequality over recent decades, and tends to lend support to more institutional and structural explanations."