Saturday, January 25, 2020

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.

Saturday, January 18, 2020

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.

Saturday, January 11, 2020

Shoulder Rehab for Desk Jockeys

Repair your shoulder and keep it healthy.

This is an unusual post, on self-help. It has been revelatory for me to go through this program, and it might be useful for others who experience shoulder pain, weakness, and lack of mobility. What presents as bursitis, impingement, bicep tendonitis, or even frozen shoulder is often a deeper and more common issue of mis-alignment and weakness in the whole shoulder, with chronic cramping of various muscles, brought on by years of hunching in our modern posture of always-forward attention to computers, phones - even books! In my case it was a lab bench that started the process.

It is hard to get a straight answer or analysis about shoulder problems, since it is a complicated and unusual joint. Small issues in the anatomy can cause big issues with soft-tissue irritation and pain, which may take years to develop, but present as sudden pain and debility. But one key concept is scapular rhythym- the fluid rising motion that the scapula should be following when you reach overhead. That can't happen if the scapula is not properly aligned. Which is to say, it should be flat against the back. When sitting in a chair with a solid back, do your shoulder blades lie flat against it? Or do they stick out against it, or even align to the side, not touching the chair back at all? When standing straight with your hands falling loosely to the side, do your hands face backwards? They shouldn't. They should be facing inwards, to your hips. Bad shoulder alignment affects your whole posture, and correcting it takes time, but yields wide-ranging benefits.

The syndrome is well-described here. Knowing shoulder anatomy is somewhat helpful, but not essential, really. The basic idea of the rehab program is to strengthen the back muscles that pull the shoulder blades back into proper position, after they have been stretched and weakened for so long by the hunched posture that over-weights the front-pulling muscles. The first step is to restore mobility and range of motion to all the muscles around the shoulder. So start with a series of stretches. Older people especially need lots of stretching to keep muscles working properly. Both the stretching and the strengthening would then be a life-long program, given that activities with forward posture tend to also be a life-long love affair.
  • Door stretch: with arms up and elbows half-way up, like a stick-up, lay them against a door frame and push through forward with your body/chest to open up the shoulder and chest.
  • Do the same thing with each arm singly, stretching each arm to 45 degrees back from the plane of the body.
  • Facing against a wall, with one arm, reach straight up, then work the arm back through a full circle, turning sideways and stretching against the wall as you go around. Finish with a cross-stretch with the arm going in the front across your chest.
  • With a broom handle, place it straight up behind one shoulder with the opposite hand, and reach back to it over the top with the same hand. Then pull forward and up with the opposite hand till you feel a stretch in the subscapularis.
  • Brachiation: from a pullup bar, just hang for a few seconds with as much weight as possible.
  • During the day, remember to stand and open up your shoulders periodically. Sometimes you can even get a crack out of your sternum, if you have been hunched for a while. A phone app reminder every 10 minutes may be helpful. 
  • Against a shelf or seat about waist high, lay the front of your arms on it, and lower your trunk till you feel a thorough stretch, then lift about half your weight with your arms- repeat 6 times.
  • Hitch arms together behind your back, grasping each opposite elbow. Bend trunk to the sides, stretching the obliques, bend forward and back. Turn neck to each side as far as possible, holding stretch.
  • With your back towards a shelf or bar about shoulder-high, grab with your hands, and lower your body to stretch the front of the shoulder. The aim should be to get about horizontal with the arms going straight back, or slightly lower. Next, using the same shelf and position, bend each elbow in turn and lay it/forearm on the shelf behind you, lowering the body again. This is a more intense stretch with the same goal.
  • On the floor, on a mat or carpet, make sure your scapula is flat against the ground. Then make angels, swinging arms through full range from sides to overhead, 10X; alternate arms, 10X more.

The next step is strengthening, to counteract the typically forward- directed actions we take all day, and make the posture changes permanent. There are many helpful videos and other instructions on the internet.
  • With face down, on a support like a weight-lifting bench or table, lift the arms straight out and up to the sides, as far as possible. Start with no weights, then add weights as possible. 3X 12 repetitions.
  • Same posture, but with elbows out and arms pointed forward. 3X 12 repetitions
  • Rowing against resistance- using a rowing machine, or resistance band, or rope, pull about 1/2 your weight, 10 times at least. Start slowly with this exercise, as it can cause pain at first.
  • With a relatively heavy resistance band, stretch between your hands in front, about shoulder-wide. While stretching apart as much as you can, work your hands up and down a wall, from arms fully up to fully down, 12X. Start slowly with this one as well.
  • With a relatively light resistance band, extend arms straight forward and pull wide to the sides, out as far as possible, 12X. While you are at it, while extended, swing your arms back over your head and down to your lower back, for a good stretch.
  • With a resistance band anchored to a pole or wall to the side, hold your elbows down at your side with hands straight forward. Pull the resistance band 90 degrees sideways, 20X each direction, strengthening both arms in the rotatory cuff.
  • When all that is working OK, raise weights from the side, standing position, to fully overhead, about 10 pounds each side, 10X, strengthening deltoids.
  • When all that is working OK, add push-ups and pull-ups.

When walking, attend to posture, leading with the feet, not the shoulders. When sitting, attend to posture, laying scapula flat against the seat.

That is the full program, though many other exercises and stretches can be added. Much of the damage and pain from this syndrome can be assigned to the anterior of the rotator cuff, (supraspinatus, subscapularis, and bicep tendon), and this program will not reverse the damage, but it will prevent further damage and allow effective operation of the shoulder without relying on, and irritating, the front of the rotator cuff so much. I think this issue is endemic and under-recognized. Much of the enthusiasm for muscle "trigger points" and deep massage comes from cramped muscles in the shoulder, neck and back regions. But typically, regular stretching is a better and longer-term solution, even if trigger point release provides rapid relief from pain. Every muscle can be stretched, so when you notice one giving pain or limiting range of motion, do some research on how to loosen it up, and add that to your program.

Saturday, January 4, 2020

Russia and its Sphere of Influence

What happens if no one wants to be in your club? Review of "Putin's World: Russia against the West and with the rest", by Angela Stent.

History plods on, despite our pride in having achieved "modernity", so that everything can now stop and rest at our state of perfection. Nowhere is that more apparent than in Russia, where the past weighs heavily, affecting attitudes and policy in substantial contrast to interests and current conditions. Russia has been an imperial power for centuries, gradually beating most of its neighbors into submission and incorporating them into a multi-ethnic but hardly socially equal empire. This process was capped by the Great Patriotic War, aka World War 2, which ended with the USSR in control of new territories inside Europe, and others inside Japan, and with ideological friends in many other lands. It was not a happy empire, but it was a huge one, and the Russians were and remain proud of its achievement.

Then everything fell apart, and since the end of the Cold War, Russia has been trying to get it back. That would be a brief synopsis of Stent's book, which goes in very professional fashion through Russia's history, current relations, conflicts, and friendships all over the world. On the whole, Russia has over the last couple of decades managed its relations quite well, leveraging what little strength it has (lots of oil and gas, a ruthless attitude towards politics near and far, and a prodigious ability to suffer) into substantial strides back to relevance on the world stage.

But what should the West think and do about it? We came in for a great deal of criticism for our cavalier attitude during the breakup of the USSR. We advocated "shock therapy", and boy were they shocked! Without effective state control or cultural traditions of capitalism, what was a rotten system of communism turned into a laissez-faire wild west of rampant economic and political corruption. State control has now been re-asserted, but the patterns that formed in those days, which frankly reflect a long history of "informal" political relations throughout the region, persist to this day, despite verying formalities of democracy and rule of law. There remains a fundamental misunderstanding (and mistrust) of what political and economic liberalism means and how the West has gotten to its dominant position, despite centuries of study, copying, inferiority complexes, and deep economic and political relations. Russia remains instinctively authoritarian, not only due to the cleverness of Vladimir Putin, but apparently as a general cultural default. Maybe this did not have to be, maybe there was an opening in the early days of Yeltsin's rule, but our thoughtless and disastrous prescriptions at the time helped sow a bitter harvest. Now Russia equates democracy with weakness, and has decided to demonstrate that principle by deploying its most expert propaganda into our free media spaces.

It is generally realized now that China, in contrast, did things correctly, becoming a booming capitalist state while keeping absolute political control. That is how an properly authoritarian state manages things, (as previously modeled by various Asian tigers, particularly Singapore), and is now a model for Russia among many others. Unlike the Russian breakdown, China's ability to change its spots from communism to capitalism raises deep questions of whether liberalism and democracy are the best system, not only in human rights terms, but in their ability to manage capitalism. For it is clear, from both the Russian debacle and from the Chinese success, that capitalism is not self-perpetuating or self-managing. It relies inextricably on a strong state and legal system that sets rules by which competition among oligarchs, firms, workers, and other actors remains on the economic level, not on the military, political, or criminal levels. Democracy can be responsive to these issues, but we are, in the US, currently in the grip of a very destructive ideology that denigrates the state, is restoring corruption at all levels, and appears heedless of the future in economic, political, and planetary terms. The outcomes of this ideology became frighteningly apparent in our chaotic occupations of Iraq and Afghanistan, yet the lesson may still not have been learned.

But getting back to Russia ... The nations of the former USSR have developed in almost linear relation to how closely they are positioned to Europe, geographically and culturally. The Baltic states turned relatively easily and completely to the European model. The middle area of Romania and Bulgaria, among others, have turned more slowly, but are also firmly in the pro-Europe camp. But those bordering Russia, like Belarus out east to Kazakstan, remain authoritarian and mired in "informal relations". Ukraine has tried to buck this trend and is deeply divided. Partly this is due to the large number of expatriate Russians living in these areas. But in any case, each has its own nationalism, and no one wants to re-unite with Russia to remake the old empire. Recent news stories show that even Belarus, Russia's most reliable and sycophantic ally, draws a line.
"Ultimately, Russia, China, and the states of Central Asia share fundamental ideas of what stability in the region looks like and how to maintain it. They are a group of authoritarian states dedicated to maintaining themselves in power and ensuring no Islamist or color revolutions threaten their rule. Whereas they view with great suspicion any Western attempts to open up their societies, Central Asian elites welcome Russian and Chinese support of the status quo."

So Russia is determined to have a club that few want to join. The ex-Soviet republics may share many cultural, political, and economic patterns, and cooperate to some extent in organizations like the Shanghai Cooperation Organization, but Russia's dreams of expansion and re-integration are generally rebuffed. It has turned to invasions like the takeover of Crimea, South Ossetia, and the creeping war in Eastern Ukraine, treating its neighbors like piñatas to be whacked at will and bullied with fossil fuel subsidies and threats. It is reminiscent of the spoiler role Pakistan maintains in its region, fomenting unrest in Afghanistan lest that country ever have peace and positive economic development.

And then Russia demands that we all respect its "sphere of influence", as though we were still in Victorian times, playing some sort of great game on a map of the world, and heading in to World War 1. But this supposed sphere is entirely composed of unwilling and oppressed neighbors- not quite as badly treated as in Soviet times, but uniformly uninterested in recreating those glory days. Russia has no intrinsic or deserved "rights" in this respect, despite its vaunting desires- we need to keep offering self-determination and choice to its neighbors, as we do to all other countries around the world. Russia is armed to the teeth, and really needs no defensive buffer of this kind, nor is its cultural influence so positive that its bullying should be regarded as a family matter. Quite the opposite.

NATO countries of Europe, in blue.

Which brings us to NATO. We did not think through its fate very carefully when the cold war ended. NATO stood during the cold war as a defense against the USSR, pure and simple, plus a way to keep Germany pacified and integrated in Europe. When the USSR collapsed (foremost because its captive nationalities and "republics" wanted out), and the Warsaw pact dissolved, we half-heartedly offered coordination to Russia. But never really thought through what our military posture should be towards this new friend, or offered a comprehensive and durable peace. We were, however, eager to integrate as many of the newly ex-Soviet states as wanted to join, such as Poland, Bulgaria, Romania, the Baltic states, Hungary, the Czech Republic, and Slovakia, not to mention various members of the former Yugoslavia. That makes it look like a rather offensive affair, from Russia's perspective. And then Ukraine wanted to join as well. Integrating all these countries into a modern mutual defence organization was certainly positive for them, as one more element of their cultural headlong run away from Russia and communism.

But what is it really defending? One gets the distinct sense that, like in the post-WW2 era, NATO's purpose has become keeping the principal adversary of the latest war at bay. But whereas Germany was integrated into NATO, subject to continued occupation, though of a relatively friendly sort, now the enemy, i.e. Russia, is outside, and is not being killed with kindness, but rather being provoked by encirclement. All this is relatively obvious and not terribly objectionable now, now that Russia has become increasingly anti-Western, but that did not have to be the outcome. (Though Stent is dubious- she maintains that Russia's historical attitude strongly re-asserted itself after the breakup, and it would be chimerical to think that Russia would ever align fully with the West, such as joining NATO and allowing extensive occupation / collaboration by foreign forces- see the quote below) We drifted into it by inertia- by lazy thinking in our foreign policy and military establishments, not to say simple gloating. Would Russia have responded more positively if we had given them a better deal? Only if we had matched it with more effective economic reconstruction assistance as well. But neither of these things happened, and attitudes in Russia quickly hardened and became, understandably, rather bitter. Nevertheless, this does not justify an undeserved sphere of influence or renascent empire on Russia's part. Does Britain demand a sphere over France? Does Germany over Denmark? No. Did we invade Cuba when it turned to communism? Well, sort of and half-heartedly(!)
"As Putin consolidated his rule, it became clear to much of the world that a main reason for Russian's rejection of Western-style economic and political programs was because they are Russians, not because they were communists. Seventy years ago, George Kennan understood that communist ideology reinforced and exacerbated, but did not contradict, the characteristics of traditional tsarist rule. Communism had been superimposed on centuries of Russian autocracy and personalistic rule, and had, if anything, strengthened those traditions. The ideology was a means to consolidate the Bolsheviks' rule, mobilize society, and, with great pain, drag Russian peasants into modernity. ... The minority who supported Gorbachev and Yeltsin and believed that Russia should become more like the West both politically and economically, were outnumbered from the outset."

Reading this book reinforces that it is the US and the West in general that is the revolutionary agent afoot in the world. We are the ones fomenting color revolutions. We are the ones planting thoughts of human rights, rule of law, justice, and prosperity around the world. We think that all this is obvious, progressive, and unexceptional, but democracies are still the minority, and the other countries, notably including Russia and China, have developed a countervailing authoritarian bloc who studiously refrain from criticizing each other's miserable internal politics, and complain ceaselessly about those who do.

Democracy Index, with darker green denoting greater democracy. Note how China rates slightly higher than Russia, due to its better governance and more functional political culture, despite lacking any electoral process.

Are we right to do so? The issue of self-determination is perhaps the thorniest area where this ideology hits the real world- not everyone can or should have their own country. The USSR broke up over the failure of the center to, in the face of countless failures, justify holding on to its huge empire, and has now turned into 15 successor states, most with an ethnic character. Several of those successor states have experienced civil wars and separatist movements of their own. The fact is that few large countries have ever become large by voluntary means. Given generally peaceful conditions, most peoples with any kind of distinct culture want their own country, as is being expressed in such places as Catalonia, Scotland, Quebec, Kurdistan, and even 150 years ago in our own Confederate South. As Stent acidly points out, separatism is Russia's (and China's) bête noir, leading to its brutal repression of Chechnya, among many other places ... until it comes to Ukraine and Georgia, where Russia uses separatism in the most cynical way.
"Russia will push to jettison the post-Cold War, liberal, rules-based international order driven by the US and Europe in favor of a post-West order. For Russia, this order would resemble the nineteenth-century concert of powers, with China, Russia, and the United States dividing the worlds into spheres of influence."

But there was one place that had a "velvet divorce". Slovakia and the Czech Republic parted ways without bloodshed, because they were oriented to the European model, and negotiated their differences. As a foreign policy stance, we should not encourage separatism generally, but should always support peaceful resolutions and reasonable accommodations. One might add in passing that, if one holds an election to validate a minority breaking away, referendums of this sort should have a high bar, such as 75% , rather than the typical 50%. At any rate, this episode illustrates a key point- that the Western model is good, and tends to lead to peaceful and durable outcomes, because it is not repressive and takes people's interests and rights seriously. Repression can keep the peace for a while, but durable, prosperous peace (and good governance) is best kept with respect, moderation, and truthful communication.

So the order of preference, from all these historical lessons, is as follows. The worst government is none, representing chaos and unleashing the worst forms of power- criminal and informal military. The next best is authoritarian, which can range from brutally repressive, like Stalinist Russia, to repressive and even quite functional, if not benevolent, like China, Turkey, and Russia today. And the best is liberal (and functional!) democracy, which respects its citizens while maintaining a strong state. Unfortunately, democracies are difficult to run, have various inefficiencies, and are perpetually at risk of turning to authoritarianism, particularly when new technologies of propaganda arise that can hypnotize and misinform the populace, as happened during the fascist era, and is happening again today.

Does this mean that we should agitate for democracy everywhere and all the time? Yes, in short, it does. We can and must work with all governments as they exist, to manage what interests we have in common. But we should never mistake our instrumental relations with countries like Saudi Arabia, Russia, and China for true friendship and ideological compatibility. We need to keep our eyes on the interests of people across the world now and into the future, which are uniformly best served by freedom and democracy, with strong and effective states founded on the active participation and decisive decision-making by their citizens. Authoritarianism can be an effective form of government, and sometimes a stepping stone to better conditions. But it is not a desirable end-point, and nor is its correlate, a spheres-of-influence world. And who knows? Maybe one of the democracies that we encourage will someday be in a position to save us in turn.