The Extermination of Tibet

China is culturally cleansing Tibet. "Seven Years in Tibet", by Heinrich Harrer, and "My Land and My People", by the Dalai Lama.

It may be falling off the world's radar screen, but Tibet remains a tragically oppressed land, well worth our remembrance and sympathy. Two books, "Seven Years in Tibet", and "My Land and My People" describe the heartbreaking slide from a happy, innocent, and isolated region to the Orwellian horrors that succeeded and continue today. One of the first significant acts of the new communist government of China, fresh from its civil war against the government that actually faught the Japanese, was to fulfill not any orthodox communist aims or development for its people, but the most rapacious and ancient ambition of Chinese governments, to subjugate its neighbor to the West, Tibet. Amid a blizzard of lies, China invaded the virtually defenseless state, oppressing Tibetans from the start in an ever-escalating war of cultural extermination. After almost ten years of trying to get along with the overlords and calm the waters, amid general rioting, the Dalai Lama fled in a dramatic escape from occupation, to welcome refuge in India, where he and the Tibetan exile community remain today.

Tibet was, frankly, a medieval culture, with economic relations ranging from nomadic to feudal. But medieval in the best sense, of a people thoroughly engaged in a set of archetypes that yielded a richly nourishing, dramatic life experience as well as a durable social structure. Tibetan Buddhism is very demanding, taking a fair fraction of men and resources into monasteries where they live off the rest of population and devote themselves to philo/theological hairsplitting. But they also devote themselves to various traditional arts, and most of all to the cultivation of peace and compassion- the touchstones of Buddha's solution to the suffering of this world. After a long and martial history, Tibet eventually put itself under the control of its most respected leaders, the Lamas, creating a system that was peaceful and benevolent, if also hidebound and conservative.

Take the story of how the current Dalai Lama was found and put in power. It is a veritable fairy tale of portents, dreams, signs and wonders. It has a sort of Wizard of Oz quality, which obviously resonanates, not only with us as a romantic tale, but with Tibetans as a great origin myth. And one can make a case on a practical level that choosing a humble and obviously bright peasant child to rule one's land may be a superior method to one which relies on the most ambitious people to sell themselves in some way to various institutions of power, and to the populace every four years. How often do we fantasize that any halfway intelligent person could do as good a job as the current office holder? Especially if that person were from early on steadfastly dedicated to the cultivation of peace and compassion in him or herself and others?

Likewise, the Dalai Lama's secret and arduous escape from Tibet was again the stuff of legend, binding him to his own people, and endearing him to people around the world. The Tibetan system values spiritual attainment, expressed in the extremely pacifist ideology of Buddhism, combined with a great deal of pre-buddhist folk religion and symbology. The culture was thus temperate and peaceful, perhaps too peaceful for its own good, but surely a model to emulate in our spiritually unbalanced times. The Chinese, in contrast, brought rapacious domination, racism, and cruelty. They were and remain atheist. But it seems that their compassionless spiritual vacuity (which is quite a different thing) was more important, leading them (especially through the cultural revolution) to despoil the cultural treasures, institutions, and people of Tibet.

We may wonder whether China is more culpable in all this than the US was in its virtual extermination of Native Americans and their many cultures. The answer is clearly yes. The gulf between the American cultures was far wider, and the state of historical consciousness lower. Native Americans had no continent-wide governments of centuries standing, no meticulously recorded written histories and philosophical traditions, and little basis for common ground or negotiation with the colonists and their successors. We have belatedly granted Native Americans limited sovereignity in their institutions and barren territories, while China keeps pouring more Han Chinese into Tibet and keeps 100% social control. The world had just fought a war to end all wars, and to liberate peoples from totalitarian military oppression, including those of South Korea. But Tibet was a bridge too far- we could not lift a finger in China's back yard, and now hardly say a peep.

• Some numbers.
• Expert talk.
• This, as most other times, would be a good time for a job guarantee.
• Who is in charge here?
• How dare she?
• Poor people deserve less.
• Buddhist action thriller of the week- Milarepa.

Coronavirus Testing Update

A review of how testing is done, and where we are at.

We in the US are flying blind through the current epidemic, with cases popping up all over, testing done on very few people, and the rest ranging between nervousness and panic. What is the death rate? We still do not know. Did China contain its outbreak by draconian measures, or by wide-spread infection and natural burnout? How about South Korea, or Taiwan? Everyone claims the former, but it far from certain what actually happened. We need more testing, and particularly scientifically sampled population testing, and post-infection exposure testing. The basics of epidemiology, in other words.

SARS-CoV-2 is the virus, and COVID-19 is the disease. Most people do not seem to have mortality risk from infection, other than the elderly and infirm. In these respects, and in its great infectiousness, this disease resembles influenza. Testing from patient samples is done by RT-PCR, which stands for reverse-transcription polymerase chain reaction. The reverse transcription part employs specialized enzymes to copy the viral genomes, which are RNA, from the patient sample, into DNA, the more stable molecule that can be used in PCR. And PCR is the revolutionary method that won a Nobel prize in 1993, which uses a DNA polymerizing enzyme, and short segments of DNA (primers), to repetitively (and exponentially) replicate a chosen stretch of DNA. In this way, a minuscule amount of a pathogen can be processed to an easily detectable amount of DNA. The FDA mandates using three target regions of the new Coronavirus N protein encoding gene for its tests, but will accept one target, if the test is otherwise properly validated. They point test makers to the NAID resource that provides positive control material- RNA genomes from SARS-CoV-2.

 Just the primers, Ma'am. These tubes contained dried DNA- the short primers with specific sequences needed to amplify specific portions of the SARS-CoV-2 viral genome. Using these requires quite of bit of other laboratory equipment and expertise.

Schematic of PCR, the exponential amplification of small amounts of DNA to huge amounts. Primers are in green, nucleotides are light blue, and the target template is dark blue.

So far, so good. But there are a range of test technologies and ways to do this testing, from the bare-bones set of primers, to a roboticized, fully automated system, each appropriate to different institutions and settings. To use the basic primer set, the lab would have to have RNA extraction kits or methods to purify the viral genomes from patient samples, then a reverse transcription kit or method, then a PCR machine and the other materials (nucleotides, high-temperature DNA polymerase, purified water and other proper solution ingredients). The PCR machine is basically a heater that cycles rapidly between the low temperature required for polymerizing and primer annealing, and the higher temperature required to melt all the DNA strands apart so that another round of primer annealing can take place. And all this needs to happen in very clean conditions, since PCR is exceedingly sensitive (of course) to small amounts of contamination. Lastly, the DNA product is typically detected by trace fluorescent markers that light up only double-stranded DNA, and can generally be detected right in the tube, with an advanced PCR machine.

Automated sample handling machines are used in clinical labs.

Virtually all of this can be mustered by any competent molecular biology lab. Results would take a few days, due to the work involved in all the setup steps. The PCR itself and analysis of its results would take a few hours. But such labs do not operate at the requisite scale, or for this purpose. That is the province of clinical testing labs, which come in various sizes, from a small hospital in-house operation to a multinational behemoth. The latter run these tests on a vast, mechanized scale. They might manufacture the DNA primers themselves, or buy them in bulk, and have the proper logistical structures to do these tests from scratch in a reproducible way, to a high standard. Providers at these scales need different kinds of materials for their testing. A small provider may need a turn-key solution that comes with pre-packaged cassettes that just need the sample added before plugging into the machine, while a larger provider would save costs by using bulk reagents and massively robotized sample handling and PCR machines.

A one-hour test in a turn-key package. But at relatively high cost.

So who are the players and what is the status? The CDC did not, for some reason, use the WHO test, or tests already developed in China, whose capacity for such manufacturing and testing is prodigious. The CDC at first didn't allow anyone else to run the tests, and when they did, they did not work correctly. It has been a bad scene and much valuable time has been lost- time that resulted in the US losing any chance of containment. Now, the FDA is authorizing others to run these tests, with detailed instructions about sampling, extraction, and machinery to be used, and is slowly granting authorization to selected manufacturers and kit makers for more kinds of tests.

Large suppliers like Roche and ThermoFisher have just been approved to supply clinical labs with testing systems. Most significant is Roche, whose tests are pre-positioned and ready to go already at clinical labs around the country. The biggest clinical lab, ominously named LabCorp, offers a home-made test, but only "several thousand tests per day", which is not yet the capacity needed. So capacity for testing will rise very rapidly, and soon enable the diagnostic and surveillance testing that is so important, and has been missing to date.

• Notes on previous pandemics.

Post script:

An aspect I forgot to include is how to select the portions of the viral genome sequence to include in testing kits. Different institutions have clearly come up with primers to different genes, few as they are, and regions within those genes. For example, "The primers currently target the N1, N2, and RP genes of the virus, but these are subject to change."; "In particular, the test detects the presence of SARS-CoV-2’s E gene, which codes for the envelope that surrounds the viral shell, and the gene for the enzyme RNA-dependent RNA polymerase." There is a balance between finding regions and primer sites that are unique to the particular virus you are interested in, so cross-reaction to other viruses is 100% eliminated, and the problem of viral drift and mutation. Some regions of viral genomes mutate much more rapidly than others, but these viruses tend to mutate at pretty high rates overall, so keeping a test current from one year to the next can be challenging. That is also what our immune systems have to deal with, as cold and flu viruses change continually to evade our defenses. So the specific DNA primer targets of a test need to be relatively highly conserved, but not too highly conserved, to put it in evolutionary terms, and the regulating agencies have to keep a close eye on this issue as they approve various test versions, to find a proper balance of high specificity and long-term usability.

Post-Post script:
Yet more significant testing solutions have emerged by late March, including a rapid (~10 minute) system from Abbot, and rapid antigen testing kits that also render results in the ~10 minute range. This speed is enormously helpful, obviously, from the patient, provider, and health system perspectives. The Abbot system is based on something called isothermal PCR, which gets rid of the temperature cycling described above. It is run at an intermediate temperature (~60 degrees C) where the DNA is somewhat loose, and primers can invade duplex strands, and also used a DNA polymerase that can displace duplex DNA as it plows ahead. This plus some other clever tricks allows the DNA amplification process to happen continuously in the reaction tube, going to completion in the rapid time quoted for these tests. These tests also tend to be tough- relatively robust to junk in the samples, and variations in temperature and other conditions.

The antigen tests that are coming on line are particularly significant, since they can be used for wide-spread population surveillance, to figure out what proportion of the population has been exposed, even if no active infection is present. Due to what seems like a complete or virtually complete lack of contact tracing + quarantine, the current pandemic will only stop once most of the population has been exposed, providing herd immunity. Before that point, anytime we give up self-isolation, it will start over again, due to the relatively high rate of low- or asymptomatic cases, and their lengthy course. Health care workers that have been exposed and recovered will have a special role before then by being able to freely staff hospitals that otherwise may be in dire straights.

Actin's Other Life

How cell movement and migration are managed by internal actin structures.

We are familiar with actin in muscles, where actin filaments occur in almost crystalline arrays, interdigitated by structural proteins, myosin cables, and nerve / ionic regulators, causing the macroscopic flexing we rely on to get around. But how to individual cells get around? They use actin too, but very differently.

Most cells have actin and myosin inside, but they have many roles, forming a "cytoskeleton" that helps shape and move the cell, but also forming avenues of transport, where myosin attaches to actin on its motor end, and to other things like organelles or vesicles of proteins to be secreted on its other end. For cell movement, actin extends at the leading part of cells through its own polymerization, not by being pushed or pulled by myosin. Then, once the leading edge finds a place outside it that likes and adheres to, myosin acts on the actin network behind to drag the rest of the cell along.

A neuronal growth cone, with actin stained in red, microtubules in green. Actin polymerization is the motive force at the leading edge where cells figure out where they want to go.

Thus much of the story of cell movement, especially at the leading edge, as in neurons trying to find their way around to the right destination in the developing brain, comes down to the selective polymerization of actin, which is, naturally, a carefully regulated process. A recent paper discussed the role of actin-binding proteins in this regulation. It has long been known that cells have some proteins that encourage actin polymerization (profilin, Arp2, thymosin beta 4, formins), and others that inhibit polymerization, or even cleave existing filaments (CAPz, cofilin, gelsolin, severin), or medate crosslinking and branching (fascin, filamin). These proteins are all generally regulated by phosphorylation, so they can be quickly and reversibly controlled by the various signaling cascades that receive signals from the local cell surface and result in a variety of protein kinase (phosphorylation) activities. Thus the main research question is filling in the details of how actin management at the leading edge of cells is orchestrated. And this has been quite difficult, since the scales are very small in time and space, and the tuning quite subtle. Delete a gene, and it may have paradoxical effects, this being such a crude manipulation.

The current authors decided to look into a relatively simple question- how is actin polymerization controlled by profilin, its most typical binding partner in the monomeric state, by its own ATP hydrolysis, and by formins, which are the main actors in speeding up actin polymerization? Actin all by itself polymerizes quite enthusiastically. Thus the cell keeps non-filamentous actin in dimers with various controlling partners such as profilin and thymosin beta 4, to keep a lid on excess polymerization. Profilin is the major partner, and binds actin very tightly. It strictly restricts actin addition to + ends of filamentous actin, not to the - ends, and not other actin monomer commplexes. It also impedes polymerization to a slight degree, even on + ends of actin filaments, due to its sticking a small finger into the interface where the next actin molecule would bind.

Structures of actin (teal and green) and profilin (pink) at the + end of a polymerizing filament (bottom). Profilin sticks a small structure into the cleft where the next actin monomer would add (zoom), slowing polymerization slightly.

The authors create a set of mutant profilin proteins, with altered binding strength to actin. The only useful ones were very subtle alterations. Binding too well inhibited actin polymerization completely, while poor binding rendered profilin entirely useless. But changes of about 5-fold in binding strength were telling in their effect.

The growth of actin filaments is strongly affected by the binding strength of profilin to actin. Profilin mutants that are weaker binders (pink) accelerate polymerization, while a stronger binder (purple) slows it down drastically.

The next step was to add in the effect of formin, a protein that binds to the actin-profilin dimer at the growing end of actin filaments in such a way as to encourage profilin to leave, and also encourage the next actin-profilin dimer to add on. Formin also induces a helical shape change in the actin filament that makes it more stable, resistant to the action of, for example, cofilin, which breaks it down. Thus addition of formins had dramatic effects, speeding up actin polymerization by several-fold, depending on which of a variety of formin versions was used. Not only that, but this system of formin + profilin managed actin monomers rendered the polymerization reaction almost entirely insensitive to the concentration of profilin / actin dimers and actin in general, as long as there was enough profilin to soak up all the free actin.

The growth of actin filaments is strongly accelerated by formin, a protein that binds to the profilin-actin complex at the growing ends of actin filaments, dissociating them to allow more units to add. DAAM1 is a weak formin, while mDia2 and mDia1 are progressively stronger formins, which show progressively faster acceleration of filament growth, in these direct microscopic assays. The arrow marks the growing actin filament end, and at bottom, graphs of actin growth, where the two dimensions above are reduced to one to give a time vs elongation graph.

This leads to the basic finding of the paper, which is that, assuming that free actin is immediately taken up into complexes of various kinds, either in new filaments or with profilin and other monomer binding proteins, the cell does not regulate actin growth by making more of it or altering the bulk amount of the actin:profilin dimers. There certainly isn't the time. Cells use the various specialized accessory proteins to orchestrate actin activities, and then regulate those in turn by the signal-driven phosphorylation events, which constitute an enormous field we won't get into here.

When formins and profilins are present at physiological concentrations vs actin, polymerization rates are insensitive to actin monomer concentrations, and instead depend on the identity of the formin, and presumably its post-translational regulation.

Yet one oddity remains- that actin is itself an ATP-ase. What is the role of this ornate property? The authors demonstrate quite conclusively that disabling the ATP-ase of actin does not alter the assembly and growth characteristics they are studying. Profilin still binds, heterodimers still polymerize, and formin still accelerates that polymerization. This is contrary to at least some old models, which rely on profilin being known to be an exchange factor for actin monomers, promoting the exchange of ADP for fresh ATP. Which was then thought to be essential for actin polymerization. Not at all - ATP does something else as part of actin, which seems to be to create a two-state system where actin with ATP is competent to for some functions, such as profilin binding, and stabilizing existing filaments, while actin with ADP is competent for other things, like release of actin from the other (-) ends of filaments. But the actual hydrolysis is immaterial to actin polymerization. All this was, sadly, already known over a decade ago, so it is not entirely clear why these observations were made in this article. At any rate, it is good that groups are still working on actin and applying ever more modern methods to quantitative studies of its function.

"Importantly, we found that ATPase-deficient actin was able to elongate actin filaments with nearly the same rates as wildtype actin at saturating profilin-actin concentrations. This clearly demonstrates that profilin release from the barbed end does not require cleavage of the β-γ phosphodiester bond of ATP in actin. More generally, the lack of assembly-related defects for ATPase deficient actin is consistent with the notion that ATP hydrolysis serves an essential function unrelated to filament assembly."

• When Anthony Fauci is muzzled, we have a problem.
• If we didn't feed them, we wouldn't have rats.
• Yes, we can make the drugs we need.
• Total abdication of judicial and constitutional responsibility in the McGann decision.
• What happens when Texas runs an election.
• Maybe Biden should keep a low profile.

Greedy, Hateful, Lustful Bastards

The shadow in Jungian psychology. Our motive force, but also our deepest secret.

As the Buddhists know very well, this thing we call the "I" is not a single thing, and may not be anything at all. It certainly isn't a coherent story of perseverence and triumph. The deeper you go, the less identifiable and singlular it is, since we knit together vast numbers and scales of activity, from the reactions of metabolism to the synapsing of neurons and the drive for social success, even to communal and shared culture, into this being entitled "I". Even on the psychological level, there are myriad unconscious elements, making the quest to know one's self a life-long and generally unsuccessful endeavor, for those who are so inclined.

In Freudian psychology, the contents of the unconscious (referred to sometimes as the subconscious) are uniformly bleak. It is the realm of lusts and drives, a pandora's box to be kept firmly repressed, in order for its custodian to be a functioning member of society. But the effort of repression is draining and costly, leading to a sort of hydraulic theory of the unconscious, where the more material there is to repress, the more effort is required, to the point that people "break down" from the strain. Likewise, releases of pressure through swearing, or watching violent films, or thrill-seeking and similar forms of "fun" relieve some strain, and help maintain the proper psychological pressure.

Jungian psychology sees the unconscious as a much larger and varied entity. It forms the basis of our positive as well as negative motivations, and operates, among many levels, at a level of archetypal symbology that is richly descriptive and informative when allowed expression via dreams, free association, and creative activities like writing and visual arts. It includes our intuition, and can be tremendously healing, persistently giving us images / glimmers of needed changes and goals.

Tibetan Buddhism hosts a large collection of monster and shadow figures. This is Palden Lhamo, who is a protector, but a wrathful one who rides through a lake of blood, spreading death and destruction to Tibet's enemies. Not enough to keep out the Chinese, unfortunately.

But even in Jungian psychology, the unconscious has a dark side- the shadow, which comprises the motivations we try to deny or hide. But can not get rid of- they are always with us and part of us. The greed, hate, and lust that undeniably drive us, but which we do not want as part of our persona- our face to the world. In the theatrical presentation of the self, we are good, virtuous, and respectful. Repression is the order of the day. While much of Jungian psychology is devoted to interpreting positive messages from the unconscious, managing the negative and the dark is very much a focus as well, as these aspects are universal and persistent. It is the work of consciousness to integrate the shadow into the ego / personality, in a controlled and accepting way.

One particular specialty of the shadow is projection, causing us to consciously reject bad traits in ourselves by ascribing them to others. Our president is a master of projection, insulting others, accusing them of the very things he himself is guilty of, as a way of keeping himself sane and narcissistically coherent. Why anyone else puts up with it is hard to fathom, but then certain bloggers have similar problems of casting stones from glass houses. There are also collective projections, like the concept of hell. An important goal of depth psychology is to come to a mature accommodation with all of one's own facets, in order to be able withdraw projections of this sort, to own one's behavior, good and bad, and thus to master the shadow, without giving up its motivating virtues.

Another way to engage with the shadow is to indulge it to a controlled extent, as happens in bacchanals, carnivals, video games, and Trump rallies. Giving free reign to our dark side is, in the hydraulic sense, very free-ing, re-creational, and possibly even an ecstatic experience. But it must be carefully bounded and controlled. It is no way to run a positive life or culture. One can grade various cultures and their religions on a sort of shadow scale, from the carnage of the Aztecs and Nazis to the perhaps unrealistic compassion of Buddhist culture as in pre-invasion Tibet. Many religions have shown shadow aspects, such as the duality of Zoroastrianism and Manichaeism, and the jihads and crusades of the Islamic and Christian varieties. The happiest societies seem to have the least shadow aspect- places like the Scandinavian countries, with their increasing mild secularity, and pre-invasion Tibet. In contrast, the unhappiest societies are heavily driven by shadow, like the Islamic countries of today, who not only valorize violence, but mix in plenty of "honor" and misogyny as well.

I think the lesson is that the hydraulic theory of controlled shadow release is not correct, rather, that more repression is better, when done consistently and intelligently. Releasing the shadow is bad, whatever the dose. The Buddhist technologies of meditation and cultivation in ways of charity, compassion, and love are clearly successful in cultivating a wider society that reflects those values. Conversely, having a president whose tastes tend to beauty pageants and WWE, and whose modus tweeterandi is hate, fosters a society that will be experiencing the opposite values.

• Single payer health care.
• Pence in charge of science?
• Annals of the credulous.
• Bloomberg's peeps. 
• Oops- OAS was wrong.
• Amazing ancient book of the week.

Young Americans for Freedom

Is Bernie the next Ronald Reagan?

My father was an enthusiastic Reagan supporter, and contributor to many of the right wing organs of the day, one of which was Young Americans for Freedom, or YAF. As one can imagine, its idea of freedom was freedom from government regulation, freedom to found businesses, freedom to rise as high as one's talents allow. Freedom to use one's money to go to private schools, freedom to hire workers on any basis they are willing to work, freedom to discriminate, to contaminate the environment, among much else. Reagan led a long campaign in the wilderness of the Republican right, on these ideas which became and remain the foundation of the right, of FOX, and of our current government. The Reagan revolution was far more influential than observers at the time (and from the left) anticipated, viewing the aging actor and his gouche entourage with distain. Reagan repaid that distain in spades, doddering through the Iran-Contra scandal, and finally leaving office with imminent senility. But he also was on occasion remarkably articulate- in marked contrast to our current virtually illiterate executive- and even inspiring, and was decisive at key moments. The ideology that Reagan brought into the mainstream, which now seems so stale and self-serving, was at the time taken as a significant and intellectually advanced critique of a system that had over the preceding decades so carefully balanced the public and private interests.

YAF was a melding of libertarians and conservatives, hardly hip even in its own day, but with an intellectual case to make. Today, things have changed substantially, as we are living in the world that the YAF-ers grew up and built, notably as part of the Gingrich revolution, the Tea party revolution, and the advanced propaganda organs that have succeeded the paltry efforts of YAF and its ilk. It is a new gilded age, where Mitt Romney can run for president as a "job creator", where Trump can win on the backs of the dispossessed, then turn around and give the lion's share of the spoils to the rich, where billionaires  clog our political system, where employees are routinely underpaid and abused, climate heating is denied and ignored, and homelessness and despair are rampant.

The youth of today look at this world, and find a significant lack of freedom. Freedom is not a simple concept, and changes dramatically with one's situation and with the times. Is being homeless the epitome of freedom? In our world, money buys freedom, and poverty is a sentence of servitude and shame. With enough money, one can become president if one wishes, while without money, one can not even eat. This is the world that the Reagan revolution has sharpened, if not created- one of staggering and shameless inequality, where our communal humanity is being drowned in desperate competition and fealty to corporate overlords, and where we are presumed to be worshipful towards the blizzard of vanity foundations they sponsor in lieu of nuns and priests to chant their prayers.

The great task of society is to impose order and discipline, but also to inspire shared values and commitment, so that all members work towards the greater good, according to their respective abilities. There is a place for capitalism and hierarchy here, to supply the former. But the latter has been sorely lacking of late, systematically denigrated by the political right, in favor of an ideology of division, greed, and, frankly, hate. It is clear that the happiest societies strike a more compassionate balance, recognizing (and funding, with various public services) a baseline of common humanity and dignity (and freedom), while leaving plenty of room for ambitious achievement in the hierarchical, capitalist mode as well.

It is high time for the pendulum in the US to swing the other way, but how is that going to happen? I have been struck by the symmetries between Bernie Sanders and Reagan. Bernie is far from a lock on the nomination, but his accession would be a fitting bookend to the Reagan revolution. Both are outside politicians, who took over their party with a grassroots / insurgent campaign and pushed it away from the center, after decades of lonely ideological battle on the political fringe. Both have strong support among the youth of their parties, indeed a curiously militant sort of support, despite themselves being, by virtue of their long-march campaign, quite old.

But Reagan never had to face the kind of propaganda organs that the right marshals today. He benefitted from a much more decent, and unified, world. Today our fellow citizens are living in a starkly separate reality, which has bled strongly into the mainstream media. It is hard to fathom how Bernie's movement is going to make serious inroads other than over the dead bodies of FOX and its copycats. And the irony is that these outlets thrive even more in opposition than when their own party is in power, making it doubly difficult to imagine how our cultural conversation is going to change, no matter how momentous the Bernie movement is. Yet, all that said, hope springs eternal, and here we have to hope in Hegelian fashion that the forces of history, or of a timely leader, are able to break the witch's spell on the right, and bring our country back to a semblance of decency and rationality. And that that someone might just be the next Democratic nominee for president.

• Watergate all over.
• I'd move to a decent state.
• Wild-life extermination and trade at fault for new virus.
• Nuclear families are only for those who can afford to go it alone.
• Another perspective on Afghanistan. And then another. How many Afghans really have a role in determining Afghanistan's future?

Cells That Eat Memories

Microglia dispose of synapses that need to be forgotten.

Memories are potent, essential, abstract, sometimes maddeningly ungraspable. But they are also physical entities, stored like so many hard-drive magnetic domains, in our brains. The last decades of research have found the "engram"- the physical trace of memory in our brains; neural synapses that connect based on the convergence of neuron activities, are painstakingly consolidated through re-enactments, and judged for permanence based on their importance. Engram cells are located in many places in the brain, supporting many kinds of memory, including memories made up of all sorts of experiences, such as multiple modes of sensation. The coordinated action of neurons, combined with emotional valence, sets up an engram event, and similarly coordinated activity at some future time can prompt its readout / recall.

A recent paper described the role of microglia- the scavangers and maintainers of the brain, in cleaning out engram synapses, resulting in forgetting. The researchers set up a typical fear response training system (by electrical foot shocks) in mice, which was remembered better after 5 days than 35 days. Treating the mice with various drugs and other methods that deplete microglia caused them to remember the bad experience much better after 35 days, indeed, virtually unchanged from the 5-day time point. The cells behind these memories are, at least in part, in the dentate gyrus, a part of the hippocampus.

Engram cells. Mice with specialized genetic elements were tracked during training, when cell activation was shown by red fluorescence (neuronal activity plus tamoxifen-activated genetic recombination leading to red fluorophore expression). Later, during memory recall, another genetic system (c-Fos expression, green) was used to track neuronal cell activation. The merging and superposition of both colors locates cells that fulfill the criteria of engram cells, i.e. memory cells. The scale bar is 20 microns.

How do the microglia do this? Well, the most important question is how stale and unimportant synapses are identified for destruction, but this paper doesn't go there quite yet. They ask instead what the microglia are doing to gobble up these synapses. They use complement, which is a tagging system commonly used in the immune system to mark cells and other detritus for destruction, and is also used during early brain development to prune vast amounts of excess neurons and synapses. So this is an obvious place to look for continued dynamic pruning during adulthood. Application of inhibitors of complement in these mice caused the same enhanced remembering of their bad experiences as did the inhibition of microglia generally. Fluorescence studies showed that the initial complement cascade component, C1q, is present right at the synapses that were previously trained and presumably are elements of engrams.

But what of the selection process? The researchers devised a way to selectively inhibit the activity of the trained neurons, by adding an inhibitory protein to the genetic engineering cocktail, thus damping activity of those cells during the 35 days post-training. This treatment enhanced forgetting by one-third, while co-treatment at the same time with the drug that depleted microglia brought memory performance back to maximal levels. Thus the activity of neurons involved in engrams is important, as one would expect, to maintain memories, while the microglial disposal system is responsive to whatever system is marking inactive engram / memory synapses for removal.

This is interesting work in a very exciting and young field, starting to put meat on the bones of our knowledge of what memories are in physical terms, and how they grow and fade. Much like other tissues like muscles and bones, which are constantly regenerating and adjusting their mass and strength in response to loads, the brain dynamically responds to use as well- a lesson for those heading into older age.

• Wage optimism ... another con.
• Don't do Facebook.
• Caring about the least of these.
• Proposed budget is insane.
• Animated movie of the week- Shaun the sheep.

De-carbonize it

... Sung to the tune of Peter Tosh's "Legalize it". How are we doing on greenhouse gas emissions? Not very well, if the goal is zero.

Climate heating has, over the last few decades, changed from a theoretical spectre to a universal reality. The seasons have shifted. The weather is more extreme. The fires have ravaged whole regions. The arctic is melting, the corals are dying, and the wildlife is thinning out and winking out. But our emissions of CO2, far from declining, keep reaching yearly highs. Humanity is not facing up to this crisis.

Global CO2 emissions keep going up, while the climate has already gone out of bounds.

The goal needs to be zero. Zero emissions, not in 30 years, but as soon as humanly possible. Here in California, we pride ourselves in a progressive and leading-edge approach to climate policy. So how are we doing? A graph of CO2 emissions shows that California emissions have been going down since a peak in 2004, and now are roughly at 85% of that peak, despite increases in population and GDP. That is laudable of course. But we are still emitting hundreds of millions of metric tons of CO2 per year. Millions of tons that will be extremely difficult to recapture, as we inevitably will have to if we want to restore the Earth's climate to a semblance of the form it had for the last few million years of evolution across the biosphere.

California CO2 emissions. Going in the right direction, but far from zero. Note the Y axis cut off at 400 million metric tons CO2 per year.

Breakdown of California emissions. Note how refinery emissions alone are higher than all household emissions (principally heating).

Can we get to zero? Yes, we can if we are serious enough. There are two ingredients to get there. One is policy to drive the change, and the other is the technical means to get there. One optimal policy is a stiff carbon tax. California already has a sort-of carbon cap/pricing system, covering a fraction of emitters and using a market-based mechanism that has sent prices under $20 per metric ton. This is not enough to make a difference, being the equivalent of about 15 cents per gallon of gasoline. To be serious, we would wish to triple the cost of gasoline, which would get users off of fossil fuels in a hurry. Such a tax would come to about $700 per metric ton of CO2 emissions- an unprecedented level when you look at carbon pricing schemes around the world, but if we want results we need to think about serious policy to get there. In order to insulate such tax systems from cost-shifting to other countries, they would need a complex system of boundary taxes to make sure that imported goods and forms of energy are all subject to the same effective carbon taxation, so that in-state sources are not penalized. This is an important goal for international agreements like the Paris accords, to make such boundary taxation normal and systematic, preventing races to the bottom of emissions regulation. It is the only way that any jurisdiction can set up a strong carbon taxing/pricing system.

Can we get to zero? The technical means are not all in place, but given enough motive force from policy, we can get there very soon. The key is storage. Fossil fuels not only hold huge amounts of solar energy, but they have stably locked them up for tens of millions of years, just waiting for humanity to mine them out and burn them up. Their storability turns out to be as significant as their energy density. Solar and wind energy do not have that property, and we are just beginning to devise the means to store their energy at scale, whether by chemical means (batteries, hydrolysis of water to hydrogen) or mechanical (pumping hydro stations, spinning rotors). Whether nuclear energy enters the mix is another and very appropriate question as well, as new, safer reactor designs become common, and a strong carbon tax makes them economically viable again.
 
Natural gas is not a transitional fuel- it is another fossil fuel, only slightly less bad than coal. Another fix for an addicted economy, like switching from heroine to oxycontin. We need to break this addiction, and as fast as possible, with strong policy that takes the problem seriously. Elizabeth Warren aims her policy at decarbonization by 2030. Bernie Sanders aims at 2050. Donald Trump says to hell with us all.

• January sets another heat record.
• Bumble bees are dying.
• Quote of the week: "Here, then, is a discovery of new evils, I said, against which the guardians will have to watch, or they will creep into the city unobserved. What evils? Wealth, I said, and poverty; the one is the parent of luxury and indolence, and the other of meanness and viciousness, and both of discontent." - Plato's Republic

Hyperdemocracy or Oligarchy?

What can China teach the US about governance? Does it point to more democracy or less? A double book/essay review.

We are at a low point in the US democracy, with the Senate having covered itself in shame over the last week, and sure to do so again next week, courtesy of one party that is in thrall to its president. But the whole world is headed in the same direction, as rightist, "strong" leaders pop up all over, from Brazil to China. The whole idea of democracy is under threat world-wide from the a new authoritarianism, which has evolved out of the old communism and more traditional feudal arrangements. And from the lust for power generally. The US misadventures in Iraq and Afghanistan, trying so blindly to implant democracy in societies woefully traumatized and unprepared for it, followed by the appalling handling and aftermath of the Arab spring, seem to have cancelled any hope of an end to history in the form of democracy triumphant across the globe.

Two decades ago, Hugh Helco wrote a prescient jeremiad titled "Hyperdemocracy" diagnosing the ills of a shallow and ill-educated democracy in the US, titillated with constant "news" (fake and otherwise) and oversharing, but lacking true deliberation and veering towards ungovernability. One ironic consequence of everyone, every corporation, and interest group having their say is that no one can be trusted. Eventually government is bereft of the basic civic faith and common narrative that the social contract relies on. His critique was acute, but his suggested treatments were afterthoughts and the problem has amplified dramatically in recent years, with foreign countries like Russia weaponizing so-called "free speech" against us.

"For the making of public policy, hyperdemocracy presents three general problems. Policy debate occurs without deliberation. Public mobilization occurs without a public. And the public tends to distrust everything that is said. " "... good policy argumentation is bad political management"

A book relevant to the question came out in 2013, from billionarie Nicolas Berggruen, who argues in Intelligent Governance for the 21st Century that some sort of convergence between the non-democratic methods of China and our rather chaotic and hyperdemocratic methods is called for, to merge China's effectiveness in public management with our respect (such as it still is) for individual rights and democratic legitimacy. Berggruen has set up a series of vanity foundations and Davos-like talk shops to solve the problems of Europe, the world, and California. The solutions focus on meritocracy- trying to insulate decision makers from the political winds by appointing Berggruen's friends to influential commissions and special bodies that would advise the politicians who may not benefit from proper think-tank training. For California, his solutions ended up recommending taxing the poor more and the rich less- which says alot about his version of meritocracy.

Nevertheless, these arguments raise interesting questions at this perilous time. Does being in a hyperdemocracy mean that we have too much democracy and deserve less? Or do we really live in a hyperdemocracy at all? And does China have some kind of secret sauce for public management and institutional far-sightedness and continuity that we could learn from, seeing as they are a rising power with confidence and in some cases, outstanding public services? I think hyperdemocracy is a bit of a misnomer, since it is hardly an acceleration of democracy to replace reasoned discourse with propaganda and corporate interests, and to give up our politicians to utter corruption. The lack of a civil and civic discourse formed around truth and mutual respect is an unmitigated disaster, not some hyper form of democracy. The fact that Facebook allows those with money and psychological skills of a nefarious or pathological nature to implant viral falsities into our body politic is not "democracy", or "free speech", but is abdication of the most basic role of publishing- that of standing behind what you publish and standing for a level of discourse that befits our culture.

The fact is the America is hardly even a democracy at this point. The public routinely stands behind significant public policy advances that are as routinely stymied by a minority that is funded by rich ideologues, both directly through political corruption and through myriad propaganda outlets. Far from a hyperdemocracy, we live in a oligarchy, one that is slowly morphing into an even more concentrated fascist regime before our eyes. The convergence is taking place, but not in a good or intended way.

A high-speed train to nowhere. California's rail plan is in crisis.

So the prescriptions that Berggruen touts, allowing that they were authored before our current administration, hardly meet the crisis of our times. Yes, we need more competent public administration. Just look at California's high speed train fiasco, and its public pensions crisis. Yes, we need longer-term strategic thinking. But the elites that have been serving us over the last couple of decades have not done such a good job, particularly from Republican administrations. Where have the truly momentous foreign policy disasters come from? Where has the denial of climate change come from? From one region in our political spectrum. And that is no accident, being the region that has antidemocratic tendencies, and seems dedicated to some sort of aristocracy of class and money. Replacing it with a slightly more centrist aristocracy of class and money, with an intellectual patina, is not likely to alter our course very much.

Berggruen proposes an ideal republic that is extremely indirect, such that a small community of a few thousand people elect ten representatives, and then those representatives elect a next level that represents about 100,000 people, and they elect another body, and so forth until the top layer of some kind of president or council is elected in a pyramid of representation that is four levels deep. This hearkens back to what the American founders were trying to accomplish with their indirect elections of Senators, and the electoral collage for the Presidential election. But then later in the book, he bemoans the out-of-touch-ness of the European administration in Brussels, which has so little democratic legitimacy. It is a curious conflict in a book full of them, and of airy ideas.

Nevertheless, the idea of a more vibrant local politics is a very important one. We are overly focused on national politics, about which the average person can do nothing but get upset. Voting is great, but participation is better, in face-to-face settings. One way to enable this is to mandate one day per month holiday for political functions. This could include voting, but also encompass neighborhood meetings, town council events, etc. The way our culture values work over civic obligations and participation is extremely unbalanced. Participation would not be manadatory, but all levels of government would obligated to open their doors, hold relevant meetings on these days, and foster public participation.

Secondly, the idea of some insulation from the political winds is also important, for many policy makers, particularly those oriented towards the long-term. Berggruen points to institutions like the Federal Reserve, the civil service, and many other regulatory bodies, which have purposefully been separated from the political fray in a way that balances accountability with the freedom to think calmly and for the long-term. We should have more such bodies, even perhaps modeled on the 5-year plan system of China, to think carefully about our future infrastructure, our future social policies, and our future politics. The state of California could certainly use a bit more organized foresight, which used to be provided by business leaders like Leland Stanford, but now is more likely to be corrupted by business than served by it.

Berggruen bemoans the state of the California referendum system, originally a gem of democracy, which has been captured by business interests which regularly compete against each other in offering rival propositions which are engineered to sound as anodyne and contrary to their actual intent as possible. Here there is an easy solution, which is to outlaw paying people to collect signatures. The currency of the referendum system is signatures, and collecting them is arduous. No one would do so unless they either cared a great deal about the issue or were well paid.

Lastly, there is the media (leaving out general corruption, which can be addressed by public financing of elections and prohibitions on corporate meddling in political affairs). Here we get to the to a truly difficult issue- how to re-establish a shared culture of truth and civic pride from our dispirited current state of Twitted discourse. Here we could learn a few lessons, not from China, but from Europe, which carefully, but legally, disables some extreme forms of speech to set guardrails on the society. We might consider making false claims grounds for suit and penalty, (proportionate to the audience), not only in commercial speech where this is already the case, but in political and policy speech. Propaganda outlets like FOX are a cancer on the Republic, that trade in lies as the foundation of their bizarre narratives. Block the lies, and the narratives are much more difficult to maintain. This is very fraught policy to propose, as our largely free speech standard has served the US quite well most of our history, (excepting several phases of extremely partisan presses), and any kind of censorship can be twisted to nafarious purposes. But this legal standard would not be enforced in some star chamber, rather in open court, presumably with evidence, experts, scholarly apparatus, etc. There is far more to do to re-establish a productive fourth estate, which is such a crucial participant in a functioning democracy, but the truth is one place to start.

Our problems cry out for reform, not revolution. Our democracy is under extreme pressure, but has not yet broken down completely. It is an index of our problems that Democrats need typically to find the perfect candidate, pristine in speech and spotless in record and demeanor, in order to have any hope of winning, while Republicans can put up virtually any grifter or mysogyinst with a fair chance of success. It is a reflection of the unfairness of our current system, ridden as it is with dark money in the service of extreme and retrograde ideologies. But there is hope, especially in demographic change, that California, dysfunctional though it may be in many ways, represents the imploded future of the Republican party, which would unleash enormous energies for national reform, towards a democratic, not an oligarchic, future.

• Delete everything: the new normal in corporate obstruction of justice.
• An update from Mr. Sloth.
• Oh, the perils of crime.
• When grifters are in charge.
• Guess who cashes in on climate change?

Toxoplasma: What's Eating Your Brain?

A large proportion of the US population is chronically infected with a psychoactive pathogen.

Do you love cats? There may be a reason, quite beyond their noble indifference to your affection. Toxoplasma gondii is a parasitic microbe that passes from cats to other animals in their environment, including humans, and is notorious for causing mental disturbances in them. For example, rats infected with Toxoplasma switch from avoiding cat urine to being attracted by it. The evolutionary logic of this phenomenon is as obvious as it is macabre, but how does it happen? A recent paper presented a small step towards understanding this pathogen, by finding one transcription factor that runs a large portion of its program of differentiation into the brain-cyst form, the bradyzoite.

Toxoplasma is a complex one-celled eukaryote, in the same family as the malaria parasite, plasmodium vivax. These pathogens lead far more interesting lives than your average bacterium and come with larger genetic repertoires. Toxoplasma generates several different cell types, starting with sperm and egg cells, which form in the cat hosts. These mate and form oocysts which are incredibly tough- they survive defecation by the cat and survive thereafter in the environment for months. When picked up by another unsuspecting mammal, (we can ingest them either as contaminating oocysts from the environment, or from undercooked pork that was infected), they proliferate in an asexual stage, and can invade any cell or tissue, causing toxoplasmosis, which can be fatal. But usually it isn't, and the immune system fights these tiny cells to a draw, prompting some to hunker down in a specially dormant form, the bradyzoite, that forms cysts full of toxoplasma cells in muscle and brain tissue. These cysts are completely impervious, not only to immune system attack, but to any drug or vaccine yet devised.

A Toxoplasma cyst in a brain, full of pathogen cells, courtesy of the USDA.

Somewhere between a quarter and half of the US population is chronically infected with this pathogen, and it would be nice to know what effects it is having. Chronic toxoplasma infection is known to positively associate with schizophrenia, pose special dangers to pregnant women, and even contribute to traffic accidents, not to mention to the proliferation of cats. While we do not yet know quite what the bradyzoites are doing in our brains, their formation is more amenable to scientific study. It is stress factors from immune pressure, specifically chemical attack from cells like neutrophils and macrophages that cause Toxoplasma to respond by differentiating, in a program that involves hundreds of genes, (of its genome of roughly 8,000 genes), to the bradyzoite cell type, which is slow-growing and communal, with special protective surface features. The current authors have finally found one gene that, when knocked out, completely abolishes differentiation into the bradyzoite state, and also, they show, is a critical part of the normal program that generates it. They call this gene BFD1, for bradyzoite formation deficient.

BFD1 is a transcription regulator, from a well-known (Myb) family, which bind DNA and frequently participate in development and proliferation, some of which are also oncogenes. In this case, not only is BFD1 itself induced during such stress and able to completely block differentiation when absent, but it can also drive differentiation all by itself, in the absence of stress. This is shown by arranging overexpression under control of the experimenter rather than by the normal stresses, which leads to cell differentiation and formation of the characteristic bradyzoite cysts. It is a rare demonstration of a true master controller of a developmental process.

Toxoplasma gene BFD1 is driven by the experimenters by adding a chemical (called Shield-1, lower panels) that releases a destruction system over an engineered and over-expressed BFD1, and leads, after 6 days, to cyst formation. The control infection (upper panels) leads instead to the obliteration of the infected cells. This demonstrates that even in the absence of normal differentiating signals, BFD1 will initiate the full differentiation program all by itself.

This is a landmark achievement in the study of this pathogen, and will open up a lot of future work on its encystment differentiation program, on how these cells defend themselves in a hostile environment, and what they are doing in our and to our brains. For example, these researchers found 509 genes to which BFD1 binds, among which are itself (for a positive feedback loop), and other genes known as markers for the bradyzoite state. Is some unusual chemical or protein being expressed that causes neural alterations, or is it the locations the bradyzoites choose for their cyst formation? Or is it the occasional release from encystement, and the ensuing immune reaction, that generates these effects? It is an area of some public health concern, and another area slowly yielding to the advance of scientific inquiry.

• More on Russia, nascent capitalism, and the botched transition.
• Where are we at in Afghanistan?
• Guantanamo- part of the slide towards state lawlessness.
• Poem of the week.

Cellular IM by GPCR

Looking into the mechanism of action of one our primary internal communication devices.

Cells need to protect themselves from the outside world, but they also need to interact with it and know what is going on. Bacteria have a lot of sensing mechanisms, primarily for food and toxins, but eukaryotes took this project to a whole new level, especially with the advent of multicellularity. While a few of the things cells sense come right through the cell membrane, like steroid hormones or fatty vitamins A and D, most things are blocked. This leads to the need for a large collection of proteins (receptors) that sit in the membrane and face both sides, with a ligand-binding face outside, and an effector face inside, which typically interacts with a series of other proteins that transmit signals, by phosphorylating other proteins, or modifying them with lipids, or just binding with a series of other proteins to form new complexes and activities.

A couple of GPCRs (red and orange) portrayed in a schematic membrane (black lines), bound by a couple of their primary intracellular targets and signaling partners, a G-protein (left, teal) and an arrestin (right, purple).

Human DNA encodes upwards of 800 receptors of one class, the G-protein coupled receptor (GPCR), which arose early in eukaryotic evolution, and duplicated / diversified profusely due to their effectiveness as a platform for binding all sorts of different molecules on the exterior face. They dominate our sense of smell as olfactory receptors, respond to 1/3 of all drugs ever approved, such as the opioids, and also conduct our sense of vision. Rhodopsin, which detects the photon-induced conformational flip-flop of retinal, is a GPCR receptor in the photoreceptor cell membrane. The fact that photons, which could have been detected anywhere, by many sorts of mechanisms, are detected by a membrane-bound GPCR receptor illustrates just how successful and dominant this mechanism of sensing became during evolution. More GPCRs are still being found all the time, and even after receptor genes are deciphered from the genome, figuring out what they bind and respond to is another challenge. Thus over 150 of our GPCR receptors remain orphans, with unknown ligands and functions.

But how do they work? Due to their great importance in drug targeting, GPCRs have been studied intensely, with many crystal structures available. It is clear that they conduct their signal by way of a subtle shape change that is induced by the binding of their ligand to the external face/pocket, and conducted through the bundle of seven alpha helixes down to the other face. Here, the change of shape creates a binding site for the G-proteins with which the (active) receptor is coupled, so-named because they bind GTP in their active state and can cleave off one phosphate to form GDP. Binding to the activated receptor encourages an inactive, GDP-bound G-protein to alter its conformation to release GDP and bind a new GTP. The G-protein then runs off and do whatever signaling it can until its slow GTPase reaction takes place, turning it off. There are endless complexities to this story, such as the question of how cells can tell the difference between signals from the dozens of GPCRs they may be expressing on their surface at the same time, or how some ligands turn these receptors off instead of on, or the wide range of other participants such as kinases, GTP/GDP exchange factors, arrestins, etc., which have developed over the eons. But I will focus on the signaling mechanism within the GPCR receptor.

Rough schematic of GPCR activation. Ligands bind at the top, and a conformational shift happens that propagates a structural change to the intracellular face of the receptor, where effector signaling molecules, especially G-proteins, bind and are activated. TM refers to each trans-membrane alpha helix of the protein structure.

A recent paper purported to have condensed a large field of work and done some mutant studies to come up with a common mechanism for the activation of the main (A) class of GPCR. This extends structural concusions that many others had already drawn about this class of receptors. As shown above, the main consequence of ligand binding is that key helices, particularly helix 6, make a substantial movement to the side, allowing the G-protein (shown in the top diagram in blue) to dock and stick a finger into the receptor. This is quite idealized, however, since GPCR receptors exist in a roiling sea of motion, being at the molecular scale, and can have subtle and partial responses to their ligands- many of which have contradictory effects. Some ligands (sometimes useful as drugs) have opposite effects from the main ligand, turning the receptors off, and others can have distinct forms of "on", or partial on effects, only fleetingly allowing the activated state to occur. Also, structures from several different GPCRs have been solved, with generally similar mechanisms, but not always informative about the dynamics of action- a structure made with an activating ligand may even show the inactive conformation, since the fraction of time spent in an active state may be much less than 100%.

Closeup of one switching event during receptor activation. Orange is the inactive state, where phenylalanine 6x44 (#44 on helix 6) contacts leucine 3x40 (amino acid 40 on helix 3), but it butted out of the way, upon ligand binding and activation, by tryptophan 6x48.

These researchers analyzed 234 structures of GPCRs in various conformations to come up with an offset mechanism conducted by ~35 amino acids principally on helices 5, 6, and 7 as they conduct the tickle from the surface to the other face of the membrane. It is a classic meta-stable structure, where a small shove (by the ligand binding on the external face) causes a cascade of offsets of these amino acid side chains as they interact with each other that pushes the structure into the new, active, semi-stable conformation. A conformation that is additionally stabilized by a G-protein if one comes along, but only while in its GDP-bound state. An example of one of these individual atomic switches is shown above, where residues close to the ligand binding site undergo a dramatic shift that establishes a contact between amino acids 40 (leucine) and 48 (tryptophan), which were not close at all in the inactive state of the receptor. The larger scheme of detailed switches and shifts is shown below.

Detailed scheme of the authors for structural change propagation through the GPCR body. Each amino acid is referred to by a code, since this summarizes behavior of hundreds of different, though homologous, proteins. Contacts characteristic of the inactive state and broken or changed during activation are in orange, while those formed on activation are in green. For example, the "Na+ pocket", which contains a sodium ion in the inactive state, collapses in the active state.

So this is biology descending to the level of engineering to understand an individual protein machine. We have such machines at all points, from thousands of genes, expressed in billions of copies, all cooperating and toiling in the service of us as a larger organism, blissfully unaware, certainly until the advent of molecular biology, of the wonders at work within. GPCRs have been an amazingly successful, ever-diversifying molecular machine, alerting animal and other eukaryotic cells of phenomena happening outside. A sort of instant messaging system on the cellular and organismal scale.

• Get a 3D picture.
• Lecture on animal origins.
• Telecommuters are saving the planet.
• What is what in tech.
• A connection between racism and unemployment.
• The price of weak government.
• Word of the week: Megxit.