Students Deserve Mentors

The best form of education is personal mentoring. More of our educational and work system should get back to that model.

We learned some important things from the Covid pandemic. One is that fiscal stimulus really works. Another is that mRNA vaccines are highly effective, and their rapid and flexible development cycle makes them a superior platform for future vaccines. And another is that social interaction is deeply important, especially for young people. We all got used to Zoom, but for school children, that was a poor substitute, when it was even possible. Children were left significantly behind both academically and socially.

A recent segment on the PBS NewsHour touched on this in a discussion of adolescent development. Its message was that learning requires challenging opportunities and human relationships. Adolescents are going on a heroic quest to become adults. They thrive on active engagement with the world and need models of successful adulthood to learn from. How to provide these key functions in an optimal way? We know how to do this- by apprenticeship and mentorship. This model has been understood forever, from the schools of Athens to the medieval trade guilds to the graduate schools of contemporary academia. My grandfather was a baker in Germany, and in his turn trained many apprentices and journeymen to be bakers. I went to graduate school, which turned out to be a glorified apprenticeship under a renowned researcher, then went on to a journeyman position (aka post-doc) with another mentor. This model is an education in many dimensions- the technical ingredients of a craft, the management practices that make a successful organization, how to participate in a larger community that pursues socially important goals, and the discipline and moral integrity it takes to be a competent adult, capable of leadership.

Example of a certificate of attainment of mastery, 1927, for a bricklayer, attested by his mentors and examiners.

However, as a society, we are reluctant to make these kinds of investments in children and adolescents. Efficiency demands that class sizes be large, colleges impersonal, and money squeezed out of the system. Companies clamor for fully trained job candidates, expecting students to go into debt in trade schools before being hired into a paying job. Few young people get the kind of lengthy, personal training that they would most benefit from. Mentorship becomes a hazard of chance, if a boss in an early job takes an interest, or a teacher decides to make extra time.

Principally, I fault the corporate system, which has sloughed off its civic responsibilities to train people and propagate cultural knowledge. The economy is full of interesting and important jobs representing exquisite technical knowledge and other expertise. As a culture and economy, we are not going to maintain a high standard if we keep losing these skills and knowledge with every generation. Just look what has happened to the industries we have ceded to China. Innovation hubs like Silicon Valley are successful in part because training becomes a shared enterprise. New companies benefit from a large pool of experienced workers, who can switch between organizations with ease. No individual company carries the whole burden of training, but as companies become larger and more specialized, they have to take on the costs of training a larger proportion of their incoming employees. Yet they still benefit from the cross-fertilization of being in a highly skilled employment ecosystem.

To better serve young people, we need to make integration into corporate skills training more accessible and normal. The idea that students should be battling for unpaid internships is absurd and insulting- all internships should be paid, and they should be longer as well. The German trades system is an example, where companies and government cooperate in providing training to young people. The companies get a much better familiarity with future hires, who are also better trained. Many trades/sectors have a communal "training tax", which all companies pay, and which funds salaries to trainees and other training costs. This is one accomplishment of the union system in Germany, which is much stronger and better integrated into their industries than that in the US.

This model could be made more general in the US as a federal program, crossing all organizations in the public and private sector, funding internships and training for more students than is now done, setting up a more lengthy and regular apprenticeship system. The training/salary costs would grade over the first few years of employment from tax-supported to company-supported. Lowering the burden of a young first hire, both in financial terms and terms of knowing the candidates better, should encourage more hiring and more training by employers. 

Companies are often citadels of hermetic wisdom, when they are not going off the rails as predatory enterprises. Integrating more young people and an additional purpose of training into US corporate culture would counteract both of these problems, while helping the youth and preserving / propagating cultural knowledge more effectively.

• Mentoring, Shanghai style.
• Surrender Dorothy!
• Mini-me and the future of Ukraine.
• Free buses work.
• Crypto, on the other hand, remains a criminal enterprise.
• Biology is not so easy. Really.

Ground Truth for Genetic Mutations

Saturation mutagenasis shows that our estimates of the functional effect of uncharacterized mutations are not so great.

Human genomes can now be sequenced for less than $1,000. This technological revolution has enabled a large expansion of genetic testing, used for cancer tissue diagnosis and tracking, and for genetic syndrome analysis both of embryos before birth and affected people after birth. But just because a base among the 3 billion of the genome is different from the "reference" genome, that does not mean it is bad. Judging whether a variant (the modern, more neutral term for mutation) is bad takes a lot of educated guesswork.

A recent paper described a deep dive into one gene, where the authors created and characterized the functional consequence of every possible coding variant. Then they evaluated how well our current rules of thumb and prediction programs for variant analysis compare with what they found. It was a mediocre performance. The gene is CDKN2A, one of our more curious oddities. This is an important tumor suppressor gene that inhibits cell cycle progression and promotes DNA repair- it is often mutated in cancers. But it encodes not one, but two entirely different proteins, by virtue of a complex mRNA splicing pattern that uses distinct exons in some coding portions, and parts of one sequence in two different frames, to encode these two proteins, called p16 and p14. 

One gene, two proteins. CDKN2A has a splicing pattern (mRNA exons shown as boxes at top, with pink segments leading to the p14 product, and the blue segments leading the p16 product) that generates two entirely different proteins from one gene. Each product has tumor suppressing effects, though via distinct mechanisms.

Regardless of the complex splicing and protein coding characteristics, the authors generated all possible variants in every possible coded amino acid (156 amino acids in all, as both produced proteins are relatively short). Since the primary roles of these proteins are in cell cycle and proliferation control, it was possible to assay function by their effect when expressed in cultured pancreatic cells. A deleterious effect on the protein was revealed as, paradoxically, increased growth of these cells. They found that about 600 of the 3,000 different variants in their catalog had such an effect, or 20%.

This is an expected rate of effect, on the whole. Most positions in proteins are not that important, and can be substituted by several similar amino acids. For a typical enzyme, for instance, the active site may be made up of a few amino acids in a particular orientation, and the rest of the protein is there to fold into the required shape to form that active site. Similar folding can be facilitated by numerous amino acids at most positions, as has been richly documented in evolutionary studies of closely-related proteins. These p16 and p14 proteins interact with a few partners, so they need to maintain those key interfacial surfaces to be fully functional. Additionally, the assay these researchers ran, of a few generations of growth, is far less sensitive than a long-term true evolutionary setting, which can sift out very small effects on a protein, so they were setting a relatively high bar for seeing a deleterious effect. They did a selective replication of their own study, and found a reproducibility rate of about 80%, which is not great, frankly.

"Of variants identified in patients with cancer and previously reported to be functionally deleterious in published literature and/or reported in ClinVar as pathogenic or likely pathogenic (benchmark pathogenic variants), 27 of 32 (84.4%) were functionally deleterious in our assay"

"Of 156 synonymous variants and six missense variants previously reported to be functionally neutral in published literature and/or reported in ClinVar as benign or likely benign (benchmark benign variants), all were characterized as functionally neutral in our assay "

"Of 31 VUSs previously reported to be functionally deleterious, 28 (90.3%) were functionally deleterious and 3 (9.7%) were of indeterminate function in our assay."

"Similarly, of 18 VUSs previously reported to be functionally neutral, 16 (88.9%) were functionally neutral and 2 (11.1%) were of indeterminate function in our assay"

Here we get to the key issues. Variants are generally classified as benign, pathogenic/deleterious, or "variant of unknown/uncertain significance". The latter are particularly vexing to clinical geneticists. The whole point of sequencing a patient's tumor or genomic DNA is to find causal variants that can illuminate their condition, and possibly direct treatment. Seeing lots of "VUS" in the report leaves everyone in the dark. The authors pulled in all the common prediction programs that are officially sanctioned by the ACMG- Americal College of Medical Genetics, which is the foremost guide to clinical genetics, including the functional prediction of otherwise uncharacterized sequence variants. There are seven such programs, including one driven by AI, AlphaMissense that is related to the Nobel prize-winning AlphaFold. 

These programs strain to classify uncharacterized mutations as "likely pathogenic", "likely benign", or, if unable to make a conclusion, VUS/indeterminate. They rely on many kinds of data, like amino acid similarity, protein structure, evolutionary conservation, and known effects in proteins of related structure. They can be extensively validated against known mutations, and against new experimental work as it comes out, so we have a pretty good idea of how they perform. Thus they are trusted to some extent to provide clinical judgements, in the absence of better data. 

Each of seven programs (on bottom) gives estimations of variant effect over the same pool of mutations generated in this paper. This was a weird way to present simple data, but each bar contains the functional results the authors developed in their own data (numbers at the bottom, in parentheses, vertical). The bars were then colored with the rate of deleterious (black) vs benign (white) prediction from the program. The ideal case would be total black for the first bar in each set of three (deleterious) and total white in the third bar in each set (benign). The overall lineup/accuracy of all program predictions vs the author data was then overlaid by a red bar (right axis). The PrimateAI program was specially derived from comparison of homologous genes from primates only, yielding a high-quality dataset about the importance of each coded amino acid. However, it only gave estimates for 906 out of the whole set of 2964 variants. On the other hand, cruder programs like PolyPhen-2 gave less than 40% accuracy, which is quite disappointing for clinical use.

As shown above, the algorithms gave highly variable results, from under 40% accurate to over 80%. It is pretty clear that some of the lesser programs should be phased out. Of programs that fielded all the variants, the best were AlphaMissense and VEST, which each achieved about 70% accuracy. This is still not great. The issue is that, if a whole genome sequence is run for a patient with an obscure disease or syndrome, and variants vs the reference sequence are seen in several hundred genes, then a gene like CDKN2A could easily be pulled into the list of pathogenic (and possibly causal) variants, or be left out, on very shaky evidence. That is why even small increments in accuracy are critically important in this field. Genetic testing is a classic needle-in-a-haystack problem- a quest to find the one mutation (out of millions) that is driving a patient's cancer, or a child's inherited syndrome.

Still outstanding is the issue of non-coding variants. Genes are not just affected by mutations in their protein coding regions (indeed many important genes do not code for proteins at all), but by regulatory regions nearby and far. This is a huge area of mutation effects that are not really algorithmically accessible yet. As a prediction problem, it is far more difficult than predicting effects on a coded protein. It will requiring modeling of the entire gene expression apparatus, much of which remains shrouded in mystery.

• Oh, no! Not the shopping cart!
• Jevons and Malthus will have their say, if we do not get our act together.
• It is time to scrap GDP, and the mania for growth.
• Blaming the victim.
• Everything crypto will be just perfect.
• Can I play piano with my mind?
• We are killers.

The Submission Drive

Humans have a drive for social and intellectual submission, which is extremely dangerous.

There was a time when psychological "drives" were all the rage. The idea that humans have instincts much as other animals do was just entering the scientific consciousness, so finding and classifying them was an important task- the great work of figuring out the human unconscious, or subconscious. Drives for food, security, sex, dominance, and much else were found. Freud even elaborated a "death drive". But our current political epoch suggests another one- a submission drive.

To an independent minded scholar and skeptic, the behavior on the Republican side of the political spectrum is revolting. Falling all over themselves to fawn over a narcissistic megalomaniac? Check. Thinking nothing of flagrant corruption that makes Warren Harding look like a choir boy? Check. Explaining away gross incompetence and pointless cruelty across the entire policy space from economics to foreign policy? Check. What causes people to join and defend what amount to cults? For that matter, what causes people to join religions?

At one level, submission is eminently rational. Groups are always more powerful than individuals. The American archetype of the loner, the Clint Eastwood or John Wayne character riding alone to mete out justice and bucking the system- that is a fantasy. It is powerful precisely because it is so romantic and unrealistic. It is compensatory psychic food for the hemmed-in and submissive. In reality, the system always wins. Militaries win when they can gather up a bigger army than the other guys. Corporations win when they have bought all their competition and become the biggest on the block. Our social instincts lead us to join groups to gain power. 

But the submission drive seems to go way beyond this, allowing us to swallow alternate realities and even seek domination by others. An interesting form is when whole cultures convert their religion. Many times, such as during the colonial era, during the Christian conquests of Northern Europe, and during the Muslim conquests, the winning power foists its religion on another culture, a culture that grows quite rapidly to accept and adopt it as its own. Was one religion true-er or better than the other? Not at all. The new one is often significantly worse in many dimensions than the old. This is purely a power transaction where those who had submitted themselves to one archetype and narrative of cultural and supernatural power find themselves convinced that social and military coercion is a pretty important form of power too, perhaps signifying a new narrative that they should submit to. But once converted, the same psychic events happen. Leaders are idolized, scriptures are memorized, vestments are accessorized. In return, those who submit seek safety and guidance, buying into a (new) father figure archetype.

Joining a group inserts you into a hierarchy of domination. There are rewards for working your way up the ranks, being able to get others to serve you, having more influence and status. This most obvious in the military, with its obsession with colorful gradations, decorations, and uniforms. But it is true everywhere- in corporations, politics, organized crime, families. Submission is the price of entry, and it seems that to properly submit, one has to take on the a great deal more than just a signed contract. Members of organizations are constantly being tested for their loyalty, their buy-in to the ethics and goals of the organization, and its wider world-view. At IBM, they used to sing the company song. Modern corporate life is a complex compromise where some of the submittee's personal life is allowed to be separated from corporate control, and many boundaries are set by legal regime to prevent the organization from turning into a criminal entity and bar total domination of its employees, customers, business partners. 

However, other organizations are not so limited. Religion and politics are a bit less hemmed-in, and demand sometimes extraordinary kinds of fealty for the rewards on offer. In their variety of styles and cultures, they attract different temperaments of devotee. Overall, one has to say that people more prone to submission and participation in hierarchies tend to go to right-wing political, military, and religious organizations. Contrary to the cultivated image of hard-headedness and independence, conservatives turn out to submit more readily to domination by others. It is notorious that organizing Democrats is like herding cats. Likewise, university faculty tend towards independence and disorganization. Liberal churches are notoriously light on discipline and free with their theology. 

Conversely, Republican and conservative organizations spring up like weeds and have, aside from gobs of funding, remarkable discipline. The MAGA swoon for the current president is just one example of the lengths to which thought patterns can be bent in favor of the dominant leader of the moment. The corollary of greater mental submission by the followers is greater rewards and wider scope of action for the leaders. Making it to the top of such disciplined heap seems to turn psychology on its head, from submission to domination. Napoleon is a case study, working his way up the ranks, literally, to a position of ultimate power. Which promptly went to his head, causing him to veer in a conservative direction, and to wreck half of Europe. Cult leaders have time and again shown how poorly adapted we are to this much-sought after, but rarely successful, psychological transition.

The fascist/authoritarian moment that is glowering around the world has reactivated these extreme domination/submission dynamics, such as between Russia and Ukraine, and within so many far-right movements and the poitical systems they target. Fortunately, there are just fundamental temperamental barriers to the attractiveness of such movements, forcing them to take extra-legal measures if they are truly dedicated to overcome the resistence of the less submissive members of their societies.

• Much of this is drawn from a classic book, "Instincts of the Herd in Peace and War".
• Report card on the courts.
• Waymo is hitting the highway.
• Plastic.

Links Only

Due to the press of other activities, only links this week.

• Wingnut medicine.
• Video of a fault slipping during an earthquake... look in the background.
• The original unitary executive.
• How about some free mid-day electricity?
• More Supreme injustice.
• Jay Bhattacharya is a stooge.

Modeling Human Attention

How attention works in the brain is becoming clearer through empirical and computer modeling work.

The current World Series is a tour de force of mental concentration and attention. Batters intently watch a pitch, and have milliseconds to decide that it isn't any good. Pitchers study the opposing batters for any signs of gullibility. Managers face excruciating decisions on when to pull a pitcher in danger. Spectators decide whether to get drawn into the pitcher's duel, or chat with their neighbors. Advertisers measure attention in dollars and cents.

The economics of attention may have reached a fever pitch, but the physiology of attention is only slowly being revealed. Attention is obviously closely aligned with consciousness, so progress on one implies progress on the other as well. The current paper is a computer modeling project, trying to simulate the core connections and behavior between the thalamus and cortex that are involved in sensory perception. For instance, mice are given a slight push on a whisker. If they respond to that, it shows they perceived it. At a very light threshold level, the chances of perception can tuned to 50%, and perceptual events can have more to do with the mental status of the mouse and the history of whisker stimulation than it does with the (consistent) strength of the stimulus. A similar threshold phenomenon holds in other forms of sensing and perception, such as binocular rivalry. Indeed, in binocular rivalry of vision, there is a slow switching back and forth between each image, based on neural accommodation after a few seconds attending to one of the images. Such threshold levels of perception are the bread and butter of research on attention.

"Given the ubiquity of the thalamocortical circuit architecture across sensory modalities, we, along with others, have proposed that reverberant bursting activity in L5PT [thick-tufted layer 5 pyramidal-tract neurons]– matrix thalamus loops may be a necessary component part in a domain general mechanism of perceptual awareness."

"Optogenetic excitation of the apical dendrites reduced the animal’s threshold for awareness, increasing both hits and false-alarms. In turn, pharmocological inhibition of the apical dendrites and POm [posteromedial thalamic nucleus] (a matrix-rich higher-order thalamic nucleus with closed loop connections to barrel cortex) increased the animal's perceptual threshold."

The model was based on the physiology of thalamo-cortical loops, which are very common in sensory, motor, and other circuits. Attention is not something that "happens" in one place, but rather appears to be a state of the network, after negotiation between upper and lower levels. Strong stimuli, such as the roar of the crowd after a home run, push their way to the top of the attention chain. Conversely, a quest for a hot dog can lead to highly focused top-down attention on planning and making a trip to the concession stand, while ignoring everything else going on in the game.

A bit of physiology, showing how mouse neurons connect between cortical and thalamus levels, and how they look at various levels within the cortical sheet. 

These researchers found that by making a faithful model of the neurons and connections found by physiology, they could then functionally model quite faithfully the actions of this loop, including its perceptual thresholds, stochastic activation, and tendency to accommodate (dampen) repeated stimuli. A key aspect of the physiology is the layering of the cortex. Evolution has left clear marks in brain areas of various vintages, in the form of layer organization. The most primitive areas like the brain stem and cerebellum have no layering at all, but rather have anatomical structures, bulbs, and sub-nuclei. Less primitive subcortical (limbic) areas have roughly three layers of cells, whereas the neocortex has a structure that is a uniform sheet, modularized not so much into structural bulbs, knobs, etc, but in a more regularized arrangement of six distinct layers, with columns of activity for parcellation of function. This regular arrangement is replicated all over the cortex and (re-)used for innumerable functions, from sensation and motor control to decision making and emotional control. In general, the middle layer (4) contains the most cell bodies, (called the granular layer), and connects extensively to the other layers. The upper layers (numbered 1,2,3, and closest to the outside of the brain) receive inputs from the thalamus and other areas, while the lower layers (5 and 6 ) send outputs to lower areas of the brain, for motor control, attention control, etc.

The authors simulate cells and connections from the known physiology. Cortical levels shown on left, and an example of one set of connected, active, firing cells on right.

The thalamocortical loop, therefore, as illustrated by the authors, is a cycle of connections from the thalamus into cortical layer 1, which connects to cells stationed in layer 5, which then send axons out back to the thalamus. The thalamus is a large structure nested within/under the hippocampus, basal ganglia, and corpus collosum, that mediates cortical signals to and from the rest of the nervous system, including senses. The authors basically find that they can reproduce the signature bursting behavior of this circuit that others have argued is a sign of attention. That is, the brief set of six pulses between 0.1 and 0.2 seconds above, which is quickly shut down by continuing activity from the inhibitory basket cells (orange, BC). I can't speak to the details either of the modeling or the physiology it is based on, but the authors try their best to hew to realistic cells and physiological circuits, making the case that the neural behavior they get out is a realistic simulation, which can then be used for other perturbations and studies of this system. 

A question that arises is the relationship of consciousness with attention. Are the neural patterns characteristic of attention all that is required to also be conscious? A review of the field says no, they are different, or at least that consciousness is a broader concept that contains attention, but also can contain bare awareness without specific focus. I am not so sure, since attention can presumably be directed inside to our own thoughts and memories, that constitutes the floating kind of awareness of bare consciousness. Without attention to anything, we lack conscious content, and thus, perhaps consciousness itself. The idea that we can meditate our way to a content-less consciousness is time and again disproven by the practice of meditation. It finds that a focus is essential, not to empty the mind of all contents, which I believe is impossible, but to control those mental contents and attain a controlled level of lucid dreaming or mantra-driven reduced consciousness that seems to be the goal of meditation.

The authors of this paper mention that their view of attention is very compatible with each of several reigning theories of consciousness, inchoate as those are, so we do seem to be heading, ever so slowly, towards a solution of this long-standing problem.

• The last time the President and military were at such loggerheads.
• China knows what it is doing.
• Make more market housing.
• The NewsHour asks scientists how they are doing.
• We are going there.

The First Invasion by the US

History pre-peated itself in our 1775 invasion of Canada.

Rick Atkinson's enormous history of the American Revolutionary war is stuffed with fascinating detail. Some may not be entirely documentary in origin, but his color and flair are undeniable. Having but begun this long read, I was struck by an early episode, the invasion of Canada. The colonies had not quite yet declared independence, nor had they resolved the seige of British-occupied Boston. They were undersupplied, short of manpower, and still on shaky ground politically with a large loyalist population. Yet, they got it into their heads to storm Montreal and then Quebec in the middle of winter, 1775 to 1776, expecting to be greeted by adoring natives as liberators. The fact that our 47th president has once again threatened to invade Canada can be taken as evidence that the expedition did not go as expected.

Within the thirteen colonies, the revolution began in a promising landscape. British governors were hated up and down the Atlantic seaboard, many reduced to bobbing offshore on Navy vessels while they begged for reinforcements that might, in their imaginations, turn the population back in their favor. Rebel congresses were formed, including the Continental Congress, which from Lexongton and Concord onwards realized that it was more than a political body- it was also a military body, responsible for fending off British attempts to cow the colonists with superior naval might, well-trained troops, ability to raise mercenaries all over Europe, and reserves of good will with loyalists and Native Americans. 

But the US is nothing if not a land-greedy society, and the Continental Congress cast its eyes northward, imagining that the recently (fifteen years before) captured colony of New France might want to cast its lot with the American rebels rather than its British overlords. However the way they went about this project spoke volumes. Instead of sending diplomats, rabble-rousers, or writers, they sent an army. In all, about three thousand men tramped north to subjugate the province of Quebec. 

Map of the campaign.

A virtually undefended Montreal was successfully besieged, and surrendered in November, 1775. Quebec, to the north, was another matter, however. It was far more stoutly defended, well supplied, and had competent walls and entrenchments. Conversely, the Americans were farther from their bases, camped in miserable conditions in the middle of winter, beset by disease, and could not make headway against even modest resistance. When the first British relief ship sailed into the harbor after breakup on the St Lawrence, the jig was up, and the Americans fled in disarray.

Transport was awful, with a lot of portaging between rivers.

Meanwhile, the American rule over Montreal hardly won the US any friends either. The governor treated the inhabitants like enemies, even closing Catholic churches. Benjamin Franklin was sent North to awe the natives and save the situation in April 1776, but the time for diplomacy was long past. 

Does all this sound familiar? What starts with high hopes and condescension, looking to win hearts and minds with guns, ends up winning nothing at all. The Philippines, Vietnam, Iraq, Afghanistan.. one wonders whether the invasion of Quebec was ever taught to US military students, or remembered by its politicians.

• 100 years before, same story.
• The Covid vaccine fights cancer!
• Warfare and social growth.
• Voting systems literally owned by Republicans?
• Crypto, crime, corruption.

When the Battery Goes Dead

How do mitochondria know when to die?

Mitochondria are the energy centers within our cells, but they are so much more. They are primordial bacteria that joined with archaea to collaborate in the creation of eukaryotes. They still have their own genomes, RNA transcription and protein translation. They play central roles in the life and death of cells, they divide and coalesce, they motor around the cell as needed, kiss other organelles to share membranes, and they can get old and die. When mitochondria die, they are sent to the great garbage disposal in the sky, the autophagosome, which is a vesicle that is constructed as needed, and joins with a lysosome to digest large bits of the cell, or of food particles from the outside.

The mitochondrion spends its life (only a few months) doing a lot of dangerous reactions and keeping an electric charge elevated over its inner membrane. It is this charge, built up from metabolic breakdown of sugars and other molecules, that powers the ATP-producing rotary enzyme. And the decline of this charge is a sign that the mitochondrion is getting old and tired. A recent paper described how one key sensor protein, PINK1, detects this condition and sets off the disposal process. It turns out that the membrane charge does not only power ATP synthesis, but it powers protein import to the mitochondrion as well. Over the eons, most of the mitochondrion's genes have been taken over by the nucleus, so all but a few of the mitochondrion's proteins arrive via import- about 1500 different proteins in all. And this is a complicated process, since mitochondria have inner and outer membranes, (just as many bacteria do), and proteins can be destined to any of these four compartments- in either membrane, in the inside (matrix), or in the inter-membrane space. 

Textbook representation of mitochondrial protein import, with a signal sequence (red) at the front (N-terminus) of the incoming protein (green), helping it bind successively to the TOM and TIM translocators. 

The outer membrane carries a protein import complex called TOM, while the inner membrane carries an import complex called TIM. These can dock to each other, easing the whole transport process. The PINK1 protein is a somewhat weird product of evolution, spending its life being synthesized, transported across both mitochondrial membranes, and then partially chopped up in the mitochondrial matrix before its remains are exported again and fully degraded. That is when everything is working correctly! When the mitochondrial charge declines, PINK1 gets stuck, threaded through TOM, but unable to transit the TIM complex. PINK1 is a kinase, which phosphorylates itself as well as ubiquitin, so when it is stuck, two PINK1 kinases meet on the outside of the outer membrane, activate each other, and ultimately activate another protein, PARKIN, whose name derives from its importance in parkinson's disease, which can be caused by an excess of defective mitochondria in sensitive tissues, specifically certain regions and neurons of the brain. PARKIN is a ubiquitin ligase, which attaches the degradation signal ubiquitin to many proteins on the surface of the aged mitochondrion, thus signaling the whole mess to be gobbled up by an autophagosome.

A data-rich figure 1 from the paper shows purification of the tagged complex (top), and then the EM structure at bottom. While the purification (B, C) show the presence of TIM subunits, they did not show up in the EM structures, perhaps becuase they were not stable enough or frequent enough in proportion to the TOM subunits. But the PINK1+TOM_VDAC2 structures are stunning, helping explain how PINK1 dimerized so easily when it translocation is blocked.

The current authors found that PINK1 had convenient cysteine residues that allowed it to be experimentally crosslinked in the paired state, and thus freeze the PARKIN-activating conformation. They isolated large amounts of such arrested complexes from human cells, and used electon microscopy to determine the structure. They were amazed to see, not just PINK1 and the associated TOM complex, but also VDAC2, which is the major transporter that lets smaller molecules easily cross the outer membrane. The TOM complexes were beautifully laid out, showing the front end (N-terminus) of PINK1 threaded through each TOM complex, specifically the TOM40 ring structure.

What was missing, unfortunately, was any of the TIM complex, though some TIM subunits did co-purify with the whole complex. Nor was PARKIN or ubiquitin present, leaving out a good bit of the story. So what is VDAC2 doing there? The authors really don't know, though they note that reactive oxygen byproducts of mitochondrial metabolism would build up during loss of charge, acting as a second signal of mitochondrial age. These byproducts are known to encourage dimerization of VDAC channels, which naturally leads by the complex seen here to dimerization and activation of the PINK1 protein. Additionally, VDACs are very prevalent in the outer membrane and prominent ubiquitination targets for autophagy signaling.

To actually activate PARKIN ubiquitination, PINK1 needs to dissociate again, a process that the authors speculate may be driven by binding of ubiquitin by PINK1, which might be bulky enough to drive the VDACs apart. This part was quite speculative, and the authors promise further structural studies to figure out this process in more detail. In any case, what is known is quite significant- that the VDACs template the joining of two PINK1 kinases in mid-translocation, which, when the inner membrane charge dies away, prompts the stranded PINK1 kinases to activate and start the whole disposal cascade. 

Summary figure from the authors, indicating some speculative steps, such as where the reactive oxygen species excreted by VDAC2 sensitise PINK1, perhaps by dimerizing the VDAC channel itself. And where ubiquitin binding by PINK1 and/or VDAC prompts dissociation, allowing PARKIN to come in and get activated by PINK1 and spread the death signal around the surface of the mitochondrion.

It is worth returning briefly to the PINK1 life cycle. This is a protein whose whole purpose, as far as we know, is to signal that mitochondria are old and need to be given last rites. But it has a curiously inefficient way of doing that, being synthesized, transported, and degraded continuously in a futile and wasteful cycle. Evolution could hardly have come up with a more cumbersome, convoluted way to sense the vitality of mitochondria. Yet there we are, doubtless trapped by some early decision which was surely convenient at the time, but results today in a constant waste of energy, only made possible by the otherwise amazingly efficient and finely tuned metabolic operations of PINK1's target, the mitochondrion.

• More on mitochondria.
• The Hitler thing is becoming.. a thing.
• What Mormonism is all about.
• Injustice reigns supreme.
• Death on the roads.
• Graph of the week- sea level over the last four million years.

Note that at the glacial maxima, sea levels were almost 500 feet (150 meters) lower than today. And today, we are hitting a 3 million year peak level.

The Role of Empathy in Science

Jane Goodall's career was not just a watershed in ethology and primate psychology, but in the way science is done.

I vividly remember reading Jane Goodall's descriptions of the chimpanzees in her Gombe project. Here we had been looking for intelligent alien life with SETI, and wondering about life on Mars. But she revealed that intelligent, curious personalities exist right here, on Earth, in the African forest. Alien, but not so alien. Indeed, they loved their families, suffered heartbreaking losses, and fought vicious battles. They had cultures, and tools, deviousness and generosity. 

What was striking was not just the implications of all this for us as humans and as conservationists, but also what it overturned about scientific attitudes. Science had traditionally had a buttoned-up attitude- "hard science", as it were. This reached a crescendo with behaviorism, where nothing was imputed to the psychology of others, whether animals or children, other than machine-like input/output reflexes. Machines were the reigning model, as though we had learned nothing since Descartes. 

Ask a simple question, get a simple answer.

This was appalling enough on its own terms, but it really impoverished scientific progress as well. Goodall helped break open this box by showing in a particularly dramatic way the payoff possible from having deep empathy with one's scientific object. Scientists have always engaged with their questions out of interest and imagination. It is a process of feeling one's way through essentially a fantasy world, until one proves that the rules you have divined actually are provable via some concrete demonstration- doing an experiment, or observing the evidence of tool use by chimpanzees. It is intrinsically an empathetic process, even if the object of that empathy is a geological formation, or a sub-atomic particle. 

But discipline is needed too. Mathematics reigns supreme in physics, because, luckily, physics follows extremely regular rules. That is what is so irritating and uncomfortable about quantum mechanics. That is a field where empathy sort of fails- notoriously, no one really "understands" quantum mechanics, even though the math certainly works out. But in most fields, it is understanding we are after, led by empathy and followed by systematization of the rules at work, if any. This use of empathy has methodological implications. We become attached to the objects of our work, and to our ideas about them. So discipline involves doing things like double-blind trials to insulate a truth-finding process from bias. And transparency with open publication followed by open critique.

In the 20th century, science was being overwhelmed by the discipline and the adulation of physics, and losing the spark of inspiration. Jane Goodall helped to right that ship, reminding us that scientific methods and attitudes need to match the objects we are working with. Sure, math might be the right approach to electrons. But our fellow animals are an entirely different kettle of fish. For example, all animals follow their desires. The complexities of mating among animals means that they are all driven just as we are- by emotions, by desire, by pain, by love. The complexity may differ, but the intensity of these emotions can not possibly be anything but universal.

• "He will pretend false votes, foul play, hold possession of the reins of government."

Cycles of Attention

 A little more research about how attention affects visual computation.

Brain waves are of enormous interest, and their significance has gradually resolved over recent decades. They appear to represent synchronous firing of relatively large populations of neurons, and thus the transfer of information from place to place in the brain. They also induce other neurons to entrain with them. The brain is an unstable apparatus, never entraining fully with any one particular signal (that way lies epilepsy). Rather, the default mode of the brain is humming along with a variety of transient signals and thus brain waves as our thoughts, both conscious and unconscious, wander over space and time.

A recent paper developed this growing insight a bit further, by analyzing forward and backward brainwave relations in visual perception. Perception takes place in a progressive way at the back of the brain in the visual cortex, which develops the raw elements of a visual scene (already extensively pre-processed by the retina) into more abstract, useful representations, until we ... see a car, or recognize a face. At the same time, we perceive very selectively, only attending to very small parts of the visual scene, always on the go to other parts and things of interest. There is a feedback process, once things in a scene are recognized, to either attend to them more, or go on to other things. The "spotlight of attention" can direct visual processing, not just by filtering what comes out of the sausage grinder, but actually reaching into the visual cortex to direct processing to specific things. And this goes for all aspects of our cognition, which are likewise a cycle of search, perceive, evaluate, and search some more.

Visual processing generates gamma waves of information in an EEG, directed to, among other areas, the frontal cortex that does more general evaluation of visual information. Gamma waves are the highest frequency brain oscillations, (about 50-100 Hz), and thus are the most information rich, per unit time. This paper also confirmed that top-down oscillations, in contrast, are in the alpha / beta frequencies, (about 5-20 Hz). What they attempted was to link these to show that the top-down beta oscillations entrain and control the bottom-up gamma oscillations. The idea was to literally close the loop on attentional control over visual processing. This was all done in humans, using EEG to measure oscillations all over the brain, and TMS (transcranial magnetic stimulation) to experimentally induce top-down currents from the frontal cortex as their subjects looked at visual fields.

Correlation of frontal beta frequencies onto gamma frequencies from the visual cortex, while visual stimulus and TMS stimulation are both present. At top left is the overall data, showing how gamma cycles from the hind brain fall into various portions of a single beta wave, (bottom), after TMS induction on the forebrain. There is strong entrainment, a bit like AM radio amplitude modulation, where the higher frequency signal (one example top right) sits within the lower-frequency beta signal (bottom right). 

I can not really speak to the technical details and quality of this data, but it is clear that the field is settling into this model of what brain waves are and how they reflect what is going on under the hood. Since we are doing all sorts of thinking all the time, it takes a great deal of sifting and analysis to come up with the kind of data shown here, out of raw EEG from electrodes merely placed all over the surface of the skull. But it also makes a great deal of sense, first that the far richer information of visual bottom-up data comes in higher frequencies, while the controlling information takes lower frequencies. And second, that brain waves are not just a passive reflection of passing reflections, but are used actively in the brain to entrain some thoughts, accentuating them and bringing them to attention, while de-emphasizing others, shunting them to unconsciousness, or to oblivion.

• Similar processes occur in working memory.
• Most beautiful film of the year.
• A new low from the supremes.
• MAGA and bad taste.
• Silence.
• Where was the cradle of Austronesians?

Dopamine: Get up and Go, or Lie Down and Die

The chemistry of motivation.

A recent paper got me interested in the dopamine neurotransmitter system. There are a limited number of neurotransmitters, (roughly a hundred), which are used for all communication at synapses between neurons. The more common transmitters are used by many cells and anatomical regions, making it hazardous in the extreme to say that a particular transmitter is "for" something or other. But there are themes, and some transmitters are more "niche" than others. Serotonin and dopamine are specially known for their motivational valence and involvement in depression, schizophrenia, addiction, and bipolar disorder, among many other maladies.

This paper described the reason why cancer patients waste away- a syndrome called cachexia. This can happen in other settings, like extreme old age, and in other illnesses. The authors ascribe cachexia (using mice implanted with tumors) to the immune system's production of IL6, one of scores of cytokines, or signaling proteins that manage the vast distributed organ that is our immune system. IL6 is pro-inflammatory, promoting inflammation, fever, and production of antibody-producing B cells, among many other things. These authors find that it binds to the area postrema in the brain stem, where many other blood-borne signals are sensed by the brain- signals that are generally blocked by the blood-brain barrier system.

The binding of IL6 at this location then activates a series of neuronal connections that these authors document, ending up inhibiting dopamine signaling out of the ventral tegmental area (VTA) in the lower midbrain, ultimately reducing dopamine action in the nucleus accumbens, where it is traditionally associated with reward, addiction, and schizophrenia. These authors use optically driven engineered neurons at an intermediate location, the parabrachial nucleus, (PBN), to reproduce how neuron activation there drives inhibition downstream, as the natural IL6 signal also does.  

Schematic of the experimental setup and anatomical locations. The graph shows how dopamine is strongly reduced under cachexia, consequent to the IL6 circuitry the authors reveal.

What is the rationale of all this? When we are sick, our body enters a quite different state- lethargic, barely motivated, apathetic, and resting. All this is fine if our immune system has things under control, uses our energy for its own needs, and returns us to health forthwith, but it is highly problematic if the illness goes on longer. This work shows in a striking and extreme way what had already been known- that prominent dopamine-driven circuits are core micro-motivational regulators in our brains. For an effective review of this area, one can watch a video by Robert Lustig, outlining at a very high level the relationship of the dopamine and serotonin systems.

Treatment of tumor-laden mice with an antibody to IL6 that reduces its activity relieves them of cachexia symptoms and significantly extends their lifespans.

It is something that the Buddhists understood thousands of years ago, and which the Rolling Stones and the advertising industry have taken up more recently. While meditation may not grant access to the molecular and neurological details, it seems to have convinced the Buddha that we are on a treadmill of desire, always unsatisfied, always reaching out for the next thing that might bring us pleasure, but which ultimately just feeds the cycle. Controlling that desire is the surest way to avoid suffering. Nowhere is that clearer than in addiction- real, clinical addictions that are all driven by the dopamine system. No matter what your drug of choice- gambling, sugar, alcohol, cocaine, heroin- the pleasure that they give is fleeting and alerts the dopamine system to motivate the user to seek more of the same. There are a variety of dopamine pathways, including those affecting Parkinson's and reproductive functions, but the ones at issue here are the mesolimbic and mesocortical circuits, that originate in the midbrain VTA and extend respectively to the nucleus accumbens in the lower forebrain, and to the cerebral cortex. These are integrated with the rest of our cognition, enabling motivation to find the root causes of a pleasurable experience, and raise the priority of actions that repeat those root causes. 

So, if you gain pleasure from playing a musical instrument, then the dopamine system will motivate you to practice more. But if you gain pleasure from cocaine, the dopamine system will motivate you to seek out a dealer, and spend your last dollar for the next fix. And then steal some more dollars. This system shows specifically the dampening behavior that is so tragic in addictions. Excess activation of dopamine-driven neurons can be lethal to those cells. So they adjust to keep activation in an acceptable range. That is, they keep you unsatisfied, in order to allow new stimuli to motivate you to adjust to new realities. No matter how much pleasure you give yourself, and especially the more intense that pleasure, it is never enough because this system always adjusts the baseline to match. One might think of dopamine as the micro-manager, always pushing for the next increment of action, no matter how much you have accomplished before, no matter how rosy or bleak the outlook. It gets us out of bed and moving through our day, from one task to the next.

In contrast, the serotonin system is the macro-manager, conveying feelings of general contentment, after a life well-lived and a series of true accomplishments. Short-circuiting this system with SSRIs like prozac carries its own set of hazards, like lack of general motivation and emotional blunting, but it does not have the risk of addiction, because serotonin, as Lustig portrays it, is an inhibitory neurotransmitter, with no risk of over-excitement. The brain does not re-set the baseline of serotonin the same way that it continually resets the baseline of dopamine.

How does all this play out in other syndromes? Depression is, like cachexia, at least in part syndrome of insufficient dopamine. Conversely, bipolar disorder in its manic phase appears to involve excess dopamine, causing hyperactivity and wildly excessive motivation, flitting from one task to the next. But what have dopamine antagonists like haloperidol and clozapine been used for most traditionally? As anti-psychotics in the treatment of schizophrenia. And that is a somewhat weird story. 

Everyone knows that the medication of schizophrenia is a haphazard affair, with serious side effects and limited efficacy. A tradeoff between therapeutic effects and others that make the recipient worse off. A paper from a decade ago outlined why this may be the case- the causal issues of schizophrenia do not lie in the dopamine system at all, but in circuits far upstream. These authors suggest that ultimately schizophrenia may derive from chronic stress in early life, as do so many other mental health maladies. It is a trail of events that raise the stress hormone cortisol, which diminishes cortical inhibition of hippocampal stress responses, and specifically diminishes the GABA (another neurotransmitter) inhibitory interneurons in the hippocampus. 

It is the ventral hippocampus that has a controlling influence over the VTA that in turn originates the relevant dopamine circuitry. The theory is that the ventral hippocampus sets the contextual (emotional) tone for the dopamine system, on top of which episodic stimulation takes place from other, more cognitive and perception-based sources. Over-activity of this hippocampal regulation raises the gain of the other signals, raising dopamine far more than appropriate, and also lowering it at other times. Thus treating schizophrenia with dopamine antagonists counteracts the extreme highs of the dopamine system, which in the nucleus accumbens can lead to hallucinations, delusions, paranoia, and manic activity, but it is a blunt instrument, also impairing general motivation, and further reducing cognitive, affect, parkinsonism, and other problems caused by low dopamine that occurs during schizophrenia in other systems such as the meso-cortical and the nigrostriatal dopamine pathways.

Manipulation of neurotransmitters is always going to be a rough job, since they serve diverse cells and pathways in our brains. Wikipedia routinely shows tables of binding constants for drugs (clozapine, for instance) to dozens of different neurotransmitter receptors. Each drug has its own profile, hitting some receptors more and others less, sometimes in curious, idiosyncratic patterns, and (surprisingly) across different neurotransmitter types. While some of these may occasionally hit a sweet spot, the biology and its evolutionary background has little relation to our current needs for clinical therapies, particularly when we have not yet truly plumbed the root causes of the syndromes we are trying to treat. Nor is precision medicine in the form of gene therapies or single-molecule tailored drugs necessarily the answer, since the transmitter receptors noted above are not conveniently confined to single clinical syndromes either. We may in the end need specific, implantable and computer-driven solutions or surgeries that respect the anatomical complexity of the brain.

• Thoughts about corruption.
• The Fed is extraordinarily powerful.
• But our Stable Genius is going downhill.
• The real deal with autism.

Gold Standard

The politics and aesthetics of resentment. Warning: this post contains thought crime.

I can not entirely fathom thinking on the right these days. It used to be that policy disputes occured, intelligent people weighed in from across a reasonable spectrum of politics, and legislation was hammered out to push some policy modestly forward (or backward). This was true for civil rights, environmental protection, deregulation, welfare reform, even gay marriage. That seems to be gone now. Whether it is the atomization of attention and thought brought on by social media, or the mercenary propaganda of organs like FOX news, the new mode of politics appears to be destructive, vindictive spite. A spiral of extremism.

It also has a definite air of resentment, as though policy is not the point, nor is power, entirely, but owning the libtards is the real point- doing anything that would be destructive of liberal accomplishments and ideals. We know that the president is a seething mass of resentments, but how did that transform alchemically into a political movement?

I was reading a book (Deep South) by Paul Theroux that provides some insight. It is generally a sour and dismissive, full of a Yankee's distain for the backwardness of the South. And it portrays the region as more or less third world. Time and again, towns are shadowed by factories closed due to off-shoring.  What little industry the South had prior to NAFTA was eviscerated, leaving agriculture, which is increasingly automated and corporatized. It is an awful story of regression and loss of faith. And the author of this process was, ironically, a Southerner- Bill Clinton. Clinton went off to be a smarty-pants, learned the most advanced economic theories, and concluded that NAFTA was a good deal for the US, as it was for the other countries involved, and for our soft power in the post-world war 2 world. The South, however, and a good deal of the Rust Belt, became sacrifice zones for the cheaper goods coming in from off-shore.

What seemed so hopeful in the post-war era, that America would turn itself into a smart country, leading the world in science, technology, as well as in political and military affairs, has soured into the realization that all the smart kids moved to the coasts, leaving a big hole in the middle of the country. The meritocracy accomplished what it was supposed to, establishing a peerless educational system that raised over half the population into the ranks of college graduates. But it opened eyes in other ways as well, freeing women from the patterns of patriarchy, freeing minorities from reflexive submission, and opening our history to quite contentious re-interpretation. And don't get me started on religion!

So there has been a grand conjunction of resentment, between a population sick of the dividends of the educational meritocracy over a couple of generations, and a man instinctively able to mirror and goad those resentments into a destructive political movement. His aesthetic communicates volumes- garish makeup, obscene ties, and sharing with Vladimir Putin a love of gold-gilded surfaces. To the lower class, it may read expensive and successful, but to the well educated, it reeks of cheapness, focusing on surface over substance, a bullying, mob aesthetic, loudly anti-democratic.

Reading the project 2025 plans for this administration, I had thought we would be looking at a return to the monetary gold standard. But no, gold has come up in many other guises, not that one. Gold crypto coins, Gold immigration card, Oval office gold, golden hair. But most insulting of all was the ordering up of gold standard science. The idea that the current administration is interested in, or capable of, sponsoring high quality personnel, information or policy of any kind has been thoroughly refuted by its first months in office. The resentment it channels is directed against, first and foremost, those with moral integrity. Whether civil servants, diplomats, or scientists, all who fail to bend the knee are enemies of this administration. This may not be what the voters had in mind, but it follows from the deeper currents of frustration with liberal dominance of the meritocracy and culture.

But what is moral integrity? I am naturally, as a scientist, talking about truth. A morality of truth, where people are honest, communicate in truthful fashion, and care about reality, including the reality of other people and their rights / feelings. As the quote has it, reality has a well-known liberal bias. But it quickly becomes apparent that there are other moralities. What we are facing politically could be called a morality of authority. However alien to my view of things, this is not an invalid system, and it is central to the human condition, modeled on the family. Few social systems are viable without some hierarchy and relation of submission and authority. How would a military work without natural respect for authority? And just to make this philosophical and temperamental system complete, one can posit a morality of nurture as well, modeled on mothering, unconditional love, and encouragement.

This triad of moralities is essential to human culture, each component in continual dynamic tension. Our political moment shows how hypertrophy of the morality of authority manifests. Lies and ideology are a major tool, insisting that people take their reality from the leader, not their own thoughts or from experts who hew to a morality of truth. Unity of the culture is valued over free analysis. As one can imagine, over the long run of human history, the moralities of nurture and authority have been dominant by far. They are the poles of the family system. It was the Enlightenment that raised the morality of truth as an independent pole in this system for the culture at large, not just for a few scholars and clerics. Not that truth has not always been an issue in people's lives, with honesty a bedrock principle, and people naturally caring whether predicted events really happen, whether rain really falls, the sun re-appears, etc. But as an organizing cultural principle that powers technological and thus social and cultural progress, it is a somewhat recent phenomenon.

It is notable that scientists, abiding by a morality of truth, tend to have very peaceful cultures. They habitually set up specialized organizations, mentor students, and collaborate nationally and internationally. Scientists may work for the military, but within their own cultures, have little interest in starting wars. It is however a highly competitive culture, with critical reviewing, publishing races, and relentless experimentation designed to prove or disprove models of reality. Authority has its place, as recognized experts get special privileges, and established facts tend to be hard to move. At risk of sounding presumptuous, the morality of truth represents an enormous advance in human culture, not to be lightly dismissed. And the recent decades of science in the US have been a golden age that have produced a steady stream of technological advance and international power, not to mention Nobel prizes and revelations of the beauty of nature. That is a gold standard. 

• The theme does strike a nerve.
• In the name of free speech, thought crime will be punished.
• The war against propaganda.
• How fun it is in a culture of cruelty.
• A great drying is taking place.
• Is there no limit to the corruption?
• 200 years of trains.

Action at the Heart of Action

How myosin works as a motor against actin to generate motion.

We use our muscles a lot, but do we know how they work? No one does, fully, but quite a bit is known. At the core is a myosin motor protein, which levers against actin filaments that are ordered in almost crystalline arrays inside muscle cells. This system long predates the advent of muscles, however, since all of our cells contain actin and myosin, which jointly help cells move around, and move cargoes around within cells. Vesicles, for instance, often traffic to where they are needed on roads of actin. The human genome encodes forty different forms of myosin, specialized for all sorts of different tasks. For example, hearing (and balance) depends in tiny rod-like hair cells filled with tight bundles of actin. Several myosin genes have variants associated with severe hearing loss, because they have important developmental roles in helping these structures form. Actin/myosin is one of the ancient transportation systems of life (the other is the dynein motor and microtubules).

Myosin uses ATP to power motion, and a great deal of work has gone into figuring how this happens. A recent paper took things to a new level by slowing down the action significantly. They used a mutant form of myosin that is specifically slower in the power stroke. And they used a quick mix and spray method that cut times between adding actin to the cocked myosin, and getting it frozen in a state ready for cryo-electron microscopy, down to 10 milliseconds. The cycle of the myosin motor goes like this:

• End of power stroke, myosin bound to actin
• ATP binds to myosin, unbinds from actin
• Lever arm of myosin cocks back to a primed state, as ATP is hydolyzed to ADP + Pi
• ADP is present, and myosin binds to actin again
• Actin binding triggers both power stroke of the lever, and release of Pi and ADP
• End of power stroke, myosin bound to actin

A schematic of the myosin/actin cycle. Actin is in pink, myosin in gray and green, with cargoes (if any, or bundle of other myosins as in muscle) linked below the green lever.

The structure that these researchers came up with is:

Basic structure of myosin (colors) with actin (gray), in two conformations- primed or post-power stroke. The blue domain at top (converter) is where the lever extension is attached and is the place with the motion / force is focused. But note how the rest of the myosin structure (lavender, green, yellow, red) also shifts subtly to assist the motion. 

They also provide a video of these transformations, based on molecular dynamics simulations.

Sampling times between 10 milliseconds and 120 milliseconds, they saw structures in each of the before and after configurations, but none in intermediate states. That indicates that the motor action is very fast, and the cocking/priming event puts the enzyme in an unstable configuration. The power stroke may not look like much, but the converter domain is typically hitched to a long element that binds to cargos, leading (below) to quite a bit of motion per stroke and per ATP. About 13 actin units can be traversed along the filament in a single bound, in fact. It is also noteworthy that this mechanism is very linear. The converter domain flips in the power stroke without twisting much, so that cargoes progress linearly along the actin road, without much loss of energy from side-to-side motion.

Fuller picture of how myosin (colored) with its lever extensions (blue) walks along actin (gray) by large steps, that cross up to 13 actin subunits at a time. The inset describes the very small amount of twist that happens, small enough that myosin walks in a rather straight line and easily finds the next actin landing spot without a lot of feeling about.

Finally, these authors delved into a few more details about the big structural transition of the power stroke. Each of these show subtle shifts in the structure that help the main transition along. In f/g the HCM loop dips down to bind actin more tightly. In h/i the black segment already bound to actin squinches down into a new loop, probably swinging myosin slightly over to the right. This segment is at the base of the green segment, so has strong transmission effects on the power stroke. In j/k the ATP binding site, now holding ADP and Pi, loses the phosphate Pi, and there are big re-arrangements of all the surrounding loops- green, lavender, and blue. These images do not really do justice to the whole motion, nor really communicate how the ATP site sends power through the green domain to the converter (top, blue) domain which flips for the power stroke. The video referenced above gives more details, though without much annotation.

Detailed closeups of the before/after power stroke structures. Coloring is consistent with the strucutres above.

• Reaping what one sows.
• Oh, and about guns.
• A room of one's own.