FRET Better

New developments in short-range distance sensing technology.

Biology ultimately comes down to chemistry and structure, usually of molecules that are rather small. Seeing them has been a big challenge through the decades, and successful visualization has led to significant advances, such as the original structure of DNA, to take one example. The premier method has been X-ray crystallography, more recently superceded by electron cryomicroscopy. Both of these methods use powerful, ultra-short-wave radiation and mathematical methods to reconstruct complete structures of static molecules. In each case, the subjects have to keep very still in order to have their picture taken. While it is often possible to lock proteins of interest in more than one static conformation for these analyses, such as bound to a substrate, and then without, dynamics have to be inferred or guessed from the further application of math in the form of molecular dynamics.

NMR has been a supplementary method for small molecules, which allows some dynamic analysis, but there have also been a large number of more ad-hoc methods to gain structural insight when full structures or dynamic behavior is inaccessible, such as cross-linking, immunolabeling, complex purification, and systematic genetic mutation. One of the most magical of these non-comprehensive structure methods is Förster resonance energy transfer (FRET) between pairs of fluorescent elements. Such elements can communicate directly, via their light emissions, how close they are, and thus can give rather direct information on specific structural aspects of a molecular system in an immediate, dynamic, and convenient way.

At top, a structural schematic of light coming into one fluorescent compound (which will be the donor, on left), with the two-ring structure. This is named L-Anap, and its absorbance spectrum is shown at bottom, receiving shorter (more energetic) wavelengths. Its emission spectrum is closely related, and peaks at 494 nm. Then FRET takes place, over to the acceptor compound on a different area of the protein on the right (either HH, for the two histidines, which coordinate a copper ion, or a cysteine-tethered TETAC, which also coordinates a copper ion in a small ring. The acceptor spectrum is also shown below, with significantly lower energy absorbance- just the right gap to be an acceptor for resonant electronic excitation from the donor.

If two fluorescent molecules are close to each other, and the radiation absorbance spectrum of the acceptor is at a slightly lower energy than the emission spectrum of the donor, then instead of fluorescing away a photon, there is a good chance that the donor will transfer its electronic excitation directly, via resonance through the mediating electric field structures, to the acceptor molecule, which may (or may not) then emit the energy in its own emission wavelenght, somewhat longer than that of the donor. Obviously, this is very distance-dependant, and the distance at which the chances of resonant transfer are 50% is termed R0. This distance is surprisingly far for many pairs of robustly fluorescing molecules- on the order of 60 or 70 Ångstroms (Å), or tenths of a nanometer.

This is obviously great for some things. Photosynthesis, for instance, relies on the rapid and quantitative transfer of this kind of resonance energy from the various light-gathering antenna complexes to the photocenter where chemical reactions can take place. A recent direction in this structure field, (paper 1, 2), however, is to recognize that for detailed structure work, these distances are too far, and a finer ruler is needed. Additionally, two other issues have come up. Typical fluorophores are very direction-dependent, with large organic rings that gain excitation and generate emission preferentially in certain directions. Secondly, they are typically mounted on long tethers. Both of these properties reduce the ability to infer distances in any confident way from FRET measurements.

So the recent improvements amount to using worse fluorophores, specifically metals like copper, cobalt, and nickel, which reduce the working distance of FRET to 10 - 20 Å, and have a much more isotropic excitation profile, which is to say that they are direction-neutral, due to their simple, single-atom nature. This allows finer working distances and more accurate inferences about distance, when the intended span can be engineered to under 20 Å. For comparison, a lipid bilayer membrane is 100 Å across, and a protein alpha helix is 5.4 Å per turn, making 20 Å about 3.7 turns. One drawback to the new method is that the metal acceptors do not in turn fluoresce at a longer wavelength- they only quench the donor's fluorescence. That makes the structure professionals happy, reducing stray signals, but at the cost of some extra certainty of what is going on, not to mention some of the magic of this method.

Maltose binding protein, with maltose in pink at the center. The binding of maltose causes a well-studied structural shift from open to closed, with the top of this structure closing like a clam. Locations of studied donor and acceptor sites that were engineered into the protein are marked (black) by their amino acid position on the protein sequence.

The model system most researchers use to guage new methods is maltose binding protein, (MBP), which closes like a clam when binding the sugar maltose (pink). The amino acid positions noted 237 and 295 are about 13 Å apart in the bound state, as shown, and separate to 21 Å in the naked state. There are additional innovations in how fluorescence probes are engineered into the protein and managed, that won't be discussed. The new paper shows that, when everything is placed properly, fluorescence from the donor is cut in half as maltose is added, and if they plug all this into appropriate mathematical models of the system, they get an implied distance estimate within a couple of Ångstroms of the true values- a significant advance in accuracy for this kind of method.

Example of a result. The Y axis is fluorescence of the donor, normalized to a control case where there is no acceptor compound at all (it is tethered to a cysteine residue [cys] on the protein). When copper is added to the solution, filling the acceptor TETAC ring with its fluorescence acceptor, the signal goes to 0.6 for protein without maltose, but to 0.2 when maltose is added as well. This difference is the FRET signal: fluorescence that is lost to the acceptor by direct excitation transfer. Then DTT is added, which breaks (reduces) the cysteine bond which holds TETAC to the protein, and the donor fluorescence goes back to its original value. The X-axis is time.

While the major (comprehensive) structural methods are gaining convenience and accuracy, these extra methods of structure estimation can be lifesavers in special situations where some dynamic aspect of a system is in question. For example, another paper from this group looked at a cyclic nucleotide-gated cation channel that functions in smell, vision, and the central nervous system, being directly activated by key second messengers like cAMP. They positioned one probe on the membrane surface and another in the protein domain nearby which is a key hinge conducting the cAMP/cGMP binding signal to the channel. They found a close correlation between activity of the channels and how close their probe, and thus the hinge region, is to the membrane, thus giving a little more structural insight into this protein family.

• Global heating is an emergency.
• A few thoughts on Buddhism.
• Buffoon does foreign policy.

Work-a-Day Addiction

We are all addicted to the normal hormones of motivation.

I am watching the World Cup from time to time, and wonder- why? Why do we get so involved in competition, why are men particularly motivated to participate and watch, why do whole nations believe themselves to be "represented" by a sporting team, and feel emotional loss or gain by their fate? It is all very odd, from logical perspective- even a grand waste of effort, money and time, second only to that wasted on religion!

Naturally, one has to look at our biology and evolutionary history. A recent article in Salon outlined an interesting contrast between hormones that drive men to their characteristic activities- testosterone and oxytocin. Success gives us a testosterone boost, while social bonding gives us an oxytocin boost. Both are powerful drugs that give us highly conditional, precise motivation. If one's success serves the group, such as a successful hunt, (or war), both systems reinforce, and we are maximally happy. If the two systems are in conflict, such as a bar brawl, civil war, or domestic intrigue, we take our bonding resources were we can- from whichever group will have us, or do without, becoming loners or outcasts living on testosterone alone, if that. That really isn't much fun, and one gets the distinct impression that oxytocin is ultimately the more significant motivator. Winning only works if you have someone to share it with.

Another recent experience was going to a concert. It was transporting, highly socially bonding, and its happy effects lasted long, long after, surely involving something like a surge of oxytocin. One might even call it "religious", a related activity carefully engineered to bring people together to get positive hits of social bonding, though with a veneer of pompous folderol. These are in some ways the poles of our culture- the incessant competition in sports, business, and politics, which divide us, versus bonding experiences that bring us back together. The latter are getting, perhaps, pushed to the margins as live music becomes rarer, religion dies a slow death, and our arts turn into violent superhero extravaganzas. Granted, that in competitive situations, we bond with our team, our party, our religion versus their religion. But the mixture of testosterone-fueled competitiveness makes such group-i-ness a mixed blessing, easily turning to mean, if not violent ends. Just look at our political system, where civility has turned into blood sport. We need to find a more consistently positive and unifying way to be.

The drugs we abuse follow a similar pattern. Cocaine is probably a fair testosterone analog, making one feel invincible- ready to take wing. On the other hand, there are downers like alcohol and opioids- what's up with them? One can speculate that they give an oxytocin kind of buzz- the comfortable, disinhibited state of reduced social anxiety, which melts barriers to some degree, though quickly becomes destructive in excess. The opioid epidemic is, as many have observed, a direct index of social malaise and atomization. One might add that 12-step programs to treat alcoholism attempt (mostly unsuccessfully) to supply the missing social bonding with a sort of regimented friendship. Most people, with robust lives and brain chemistry, don't fall for the fake pleasures of either drug, but get their fix from actual accomplishments and actual social connections, which generate the internal rewards which are just as chemical, but much more subtly, finely, and productively regulated.

(All this is terribly reductive, of course, and misses all kinds of details of how our motivation systems work. Yet it is clear that in a broad brush way, positive and negative feelings are strongly influenced by these and other chemicals that form the internal motivation and reward systems, for which drugs of abuse and recreation are blunderbuss versions. Whether we add in serotonin, dopamine, and others, to make more accurate models of the internal workings does not alter this picture. There is also no law that cognition can not generate emotions. But it seems to make sense that our general emotional tenor is shifted in rather gross ways, over many cognitive (and bodily) systems at once, which dictates the use of hormones and hormone-like neurotransmitters to create such wide-spread regulatory effects.)

But many forces are set against our happiness and bonding, sending us toward competition instead. Traditionally, the (testosterone-addled) patriarchy has been a major culprit, as we have experienced so clearly in the traditional setting of the society of Afghanistan. Scarcity in general, of course, generates warfare and competition, to which primitive cultures are far more prone than our own, despite their otherwise idyllic nature.

But our current version of modernity may be even worse. Society-wide bonding experiences, like patriotism, universal religion, and traditions in the very general sense, are all being corroded. Some of the corrosion comes from competitive market forces, which are invading every aspect of our lives with the retreat of public services, civic responsibility, and family structure. Some comes from our very prosperity, which allows us each more independence and freedom- which is to say, an escape from close, maybe suffocating, social ties. Some of it comes from sheer population growth, which makes everything more competitive, particularly space- the space to live, to not be homeless, to find a country in which one can make a future, instead of being crushed under poverty and corruption. And some of it comes from environmenal degradation, another consequence of population growth and rampant capitalism, which makes agriculture and subsistance more difficult in already-poor areas and degrades the spiritual balms of nature. The internet, which was supposed to bring us all together, has instead balkanized us into ever-smaller tribes, enabled anonymous flame-throwing and rampant bullying, including from the highest offices. And into the bargain, it has grievously wounded the music industry- that keystone of positive social bonding.

What is going to put all this together again? How will we re-establish healthy lives and communities against all these forces? Clearly, Scandinavian countries, which have followed a less strictly capitalistic model, with less testosterone and more social awareness and conscience, have succeeded in building happier societies. It takes a change in emphasis, and a renunciation of the imbalanced invasion of competition in every nook and cranny of our lives, where few win and most lose. Otherwise our only recourse is the artificial versions of social bonding reward.

• A depressing withdrawal from opioids.
• Trump is a bad drug.
• Remember that 81% of evangelicals support Trump. Because they are white and pure.
• The supreme court is the next domino to fall for our creeping Nazi-ism.
• Death of the middle class, cont.
• And the decline is gathering speed.
• Science takes a theory, and sometimes a little PR.
• Love ...

Now You See it

Rapid-fire visual processing analysis shows how things work in the brain.

We now know what Kant only deduced- that the human mind is full of patterns and templates that shape our perceptions, not to mention our conceptions, unconsciously. There is no blank slate, and questions always come before answers. Yet at the same time, there must be a method to the madness- a way to disentangle reality from our preconceptions of it, so as to distinguish the insane from the merely mad.

The most advanced model we have for perception in the brain is the visual system, which commandeers so much of it, and whose functions reside right next to the consciousness hot-spot. From this system we have learned about the step-wise process of visual scene interpretation, which starts with the simplest orientation, color, movement, and edge finding, and goes up, in ramifying and parallel processes, to identifying faces and cognition. But how and when do these systems work with retrograde patterns from other areas of the brain- focusing attention, or associating stray bits of knowlege with the visual scene?

A recent paper takes a step in this direction by developing a method to stroboscopically time-step through the visual perception process. They find that it involves a process of upwards processing prior to downwards inference / regulation. Present an image for only 17 milliseconds, and the visual system does not have a lot of conflicting information. A single wave of processing makes its way up the chain, though it has quite scant information. This gives an opportunity to look for downward chains of activity, (called "recurrent"), also with reduced interference from simlutaneous activities. The subjects were able to categorize the type of scene (barely over random chance) when presented images for this very brief time, surprisingly, enough.

The researchers used a combination of magnetoencephalography (MEG), which responds directly to electrical activity in the brain and has very high time resolution, but not so great depth or spatial resolution, with functional magentic resonance imaging (fMRI), which responds to blood flow changes in the brain, and has complementary characteristics. Their main experiments measured how accurately people categorized pictues, between faces and other objects, as the time of image presentation was reduced, down from half a second to 34, then 17 milliseconds, and as they were presented faster, with fewer breaks in between. The effect this had on task performance was, naturally, that accuracy degraded, and also that what recognition was achieved was slowed down, even while the initial sweep of visual processing came up slightly faster. The theory was that this kind of categorization needs downward information flow from the highest cognitive levels, so this experimental setup might lower the noise around other images and perception and thus provide a way to time the perception process and dissect its parts, whether feed-forward to feed-back.

Total time to categorization of images presented at different speeds. The speediest presentation (17 milliseconds) gives the last accurate discernment (Y-axis), but also the fastest processing, presumably dispensing with at least some of the complexities that come up later in the system with feedbacks, etc., which may play an important role in accuracy.

They did not just use the subject reports, though. They also used the fMRI and MEG signals to categorize what the brains were doing, separately from what they were saying. The point was to see things happening much faster- in real time- rather than to wait for the subjects to process the images, form a categorical decision, generate speech, etc. etc. They fed this MEG data through some sort of classifier, (SVM), getting reliable categorizations of what the subjects would later report- whether they saw a face or another type of object. They also focused on two key areas of the image processing stream- the early visual cortex, and the inferior temporal cortex, which is a much later part of the process, in the ventral stream, which does object classification.

The key finding was that, once all the imaging and correlation was done, the early visual cortex recorded a "rebound" bit of electrical activity as a distinct peak from the initial processing activity. The brevity of picture presentation (34 ms and 17 ms) allowed them to see (see figure below) what longer presentation of images hides in a clutter of other activity. The second peak in the early visual cortex corresponds quite tightly to one just slightly prior in the inferior temporal cortex. While this is all very low signal data and the product of a great deal of processing and massaging, it suggests that decisions about what something is not only happen in the inferior temporal cortex, but impinge right back on the earlier parts of the processing stream to change perceptions at an earlier stage. The point of this is not entirely clear, really, but perhaps the most basic aspects of object recognition can be improved and tuned by altering early aspects of scene perception. This is another step in our increasingly networked models of how the brain works- the difference between a reality modeling engine and a video camera.

Echoes of categorization. The red trace is from the early visual processing system, and the green is from the much later inferior temporal cortex (IT), known to be involved in object categorization / identification. The method of very brief image presentation (center) allows an echo signal that is evidently a feedback (recession) from the IT to come back into the early visual cortex- to what purpose is not really known. Note that overall, it takes about 100 milliseconds for forward processing to happen in the visual system, before anything else can be seen.

• Yes, someone got shafted by the FBI.
• We are becoming an economy of feudal monoliths.
• Annals of feudalism, cont. Workers are now serfs.
• Promoting truth, not lies.
• At the court: better cowardly and right wing, than bold and right wing.
• Coal needs to be banned.
• Trickle down not working... the poor are getting poorer.

Hitler and Donald Trump

With apologies to "God and Donald Trump". An authoritarian comparison.

Hitler did not pounce on Germany suddenly and unannounced. His rise was a lengthy story of norms broken, lies told, prejudices nurtured, institutions destroyed, brilliant propaganda, judicious bullying, and the age-old scapegoating alchemy of victimization and hate. We are in the midst of a similar process, with the worser angels of our natures being seduced and exemplified by the current president. Trump loves authoritarian leaders, pines for authoritarian methods, (reads authoritarian speeches), and, overall, seems to use a playbook from one of the greatest authoritarians of all time. Maybe it is worth counting up the similarities. One of the best books on this remains William Shirer's Rise and Fall of the Third Reich.

Propaganda
Trump had a few difficulties with FOX at first, as they had a few components still beholden to the old GOP, or with principles otherwise. But nothing succeeds like success, and FOX could not deny the beast they themselves had created through years of alternative reality and hate-filled programming. It is now a fully consumated marriage, with daily hate, direct policy integration, and personnel going back and forth. Joseph Goebbels would have been proud, though he would have criticized us for still allowing free media to exist. Trump has been doing his best to discredit all responsible media, and is getting a sympathetic hearing from those in his camp. Whether this infection of corrupt media values spreads into the rest of the culture is one of the biggest questions of our time.

Novel modes of communication
The Nazis used film, radio, graphics, and other media in very innovative ways, still admired today in some instances. Mass communication was still young, and they made great use of it for their propaganda. Now we have the first twitter president, marrying his lack of self-control and need to bully and  lash out at every source of anxiety with the new media of our time which narrow-casts and broadcasts simultaneously and instantly. These new media themselves are not the problem, rather it is the content, obviously. The issue is whether we neglect to take a longer view and are able to maintain our intellects and moral values while marinating involuntarily in this cesspool of Newspeak.

Scapegoats and concentration camps
Immigrants are the current administration's scapegoats and objects of hatred. No insult is too vile, no policy too harsh. Walls are to be built, detention centers filled, children ruined. Germany never had organized and nation-wide resistance to the antisemitism of the Nazis, so we are slightly ahead there. But in Germany too, the concentration camp system started slowly, first only holding communists and political opponents, and only gradually developing into the slaughterhouses found by the allies in the end. Immigrants are right now an easy target, not being citizens, with nebulous rights, if any.

Bullying
Trump's bullying is instinctive, relentless, and always personal. (Just ask Stormy Daniels!) If there is policy involved, it is decades out of date, and uninformed. The Nazis were obviously bullies as well, with far more lattitude, given their paramilitary organizations and eventual totalitarian control. Hitler's temper tantrums were evidently very Trumpian. But in foreign policy, they directed their bullying more sensibly- against their enemies rather than their friends. First Austria, then Czechoslovakia, were crushed by propaganda and threats. England was cowed from interfering, Russia was subborned and bribed, before being turned on later. There was method to the madness, where with Trump, we have daily lashing out without much sense let alone long term strategy. China is our friend, then our enemy. Russia is complemented on one hand, and sanctioned with the other. Canada is turned from our best friend to a bitter spouse. The authoritarian instinct is obviously the same, but with Trump, the point gets lost in personal narcissim, short attention span, and poor judgement.

Narcissism
Was Hitler a narcissist? Perhaps not as flagrantly as Trump, but anyone who starts a world war and ends up incinerating his own country in the pyre of his ambition probably gets the nod. There was also the personality cult, Führer, etc. So yes, he and Trump are cut from the same cloth there. Trump has tried mightily to identify himself with the nation and its wounds and salvation- just listen to his clunky inauguration speech. He is the only one who can fix what is wrong with the nation! The instincts are there, and the charismatic connection to at least some of his base. But he is far, far, from closing the deal with the country at large, and also has such appalling lack of judgement, intellect, and self-control that the whole project simply falls flat on purely operational grounds.

Economic policy
Here we get to a big constrast between the two. Trump has talked alot about infrastructure spending and beautiful airports and roads. But he has not lifted a finger to get there. His version of deficit spending is to give a lot more money to the rich- he's no national socialist! Hitler, on the other hand, really built the autobahn, the Beetle and other infrastructure. His Keynesian policies put everyone to work, as well as re-arming the nation. Of course all this led to tears, but it illustrates the difference between someone who really wants to rebuild the nation, and someone who only wants to get a feeling from a crowd of believers, while selling them down the river to his rich friends.

Crony capitalism
Yes, Hitler's economics put the big companies in control. But the program was obviously derigiste- under the state, and secondly, with the ultimate goals, successfully achieved, of rebuilding both the economy and the armed forces. Trump, in contrast, is spending all his efforts in strightforward Republican projects of favoring the corporate class generally over the wroking class. The tarriffs, the death of consumer protection, the death of the EPA, the corporate tax cuts- none of that is making America as a whole better let alone great. The nationalist rhetoric expresses Trump's authoritarian instincts, but his heart and whatever else passes for his head is with his corporate cronies, not with workers, or the nation at large.

Tastelessness
Here, Trump is almost in a class of his own. Hitler was a notoriously bad painter, but not entirely talent-less, and led a party that innovated in media, graphics, public displays, and architecture (if of an oppressively bombastic and brutalist style). Trump's style is more classic mobster and nouveau-riche. Both cases betray a lack of empathy and human feeling. As the Greeks and many after them maintained, aethetics are moral. We express ourselves and our vision of humanity through the art we make, support, and appreciate. It is a window into the soul or lack thereof of our leaders to see what they are capable of appreciating. Trump's case is one of edifice complex with a slather of gilt.

Fighting the last war
Hitler took a great deal of his ultimate program from America. We shamelessly swept Native Americans from our fertile prairies. We had slavery. We supported eugenics. He thought that the Ukrainian and Russian breadbasket could be the great fertile frontier for Germany. Too bad that the people already living there had airplanes and tanks! In this case, Hitler was several decades, if not centuries out of date, and paid grievously for it. For all his prowess in harnessing modern technology and economics to a program of national rebuilding and totalitarian control, Hitler was additionally obsessed with the the defeat by France in World War 1. It was all very backward-looking. Trump's errors of history are smaller-bore, but analogous, in that his conceptions, such as they are, are generally decades out of date. Is coal going to come back? That is absurd, not to mention environmentally suicidal. Is manufacturing coming back? Only with robots. He is harping on the nefarious trade policies of China (and Canada!). Well, that ship has mostly sailed. China has developed with our implicit help and support (not to mention funding our prodigious deficits). The remaking of a poverty-stricken communist basket case into a prosperous capitalist nation over the recent decades is the strongest possible compliment to our ideology and generous guidance of the international system. (Though further work remains to make our democracy functional and attractive as an alternative to China and Russia's new model of authoritarian capitalism). We should concentrate on fostering an increasingly rule-based and legitimate international system that keeps China on a responsible and lawful path, rather than introducing instability that only diminishes our current and future standing.

Love for fellow authoritarians
Whether there is a compromising Russian dossier on Trump or not, his love for Putin is unfeigned. G. W. Bush looking into Putin's eyes was bad enough, but this is revolting. Whether Duterte, Jinping, bin Salman, or Jong Un, Trump seems to love them all. Naked power is his elixir and dream. How sad that America's power has been built over the last century on more subtle foundations- the attractiveness of a properous, lawful, and respectful system that other peoples and nations can aspire to rather than cow before. Making America great used to involve opposing dictatorships rather then trying to emulate them.

• A linguistic emergency.
• State of the border. 
• Turning the international order upside down.. on Putin's orders?
• Mental illness.
• Remember the dust bowl? 
• Empathy is not weakness.

Why no Russian Renaissance?

Russia was much closer to Byzantium than Western Europe. So why didn't it feed from the scholarship of the East on the fall of Constantinople, as the West did? Books by John Lawrence and Martin Sixsmith.

OK, this is an unfair question. But if one's closeness to the learning and culture of Byzantium is supposed to be related to one's ability to assimilate it and recover the riches of antiquity that supposedly fed so much of the Western European Renaissance, then Russia was far better positioned than Florence. Russia had long-standing trade relationships and routes to Constantinople, and shared the same Orthodox Christianity. Indeed it still sees itself as the last inheritor of Byzantine culture. Some of the largest cities in Europe in 1000's were Novgorod and Kiev, of the early Rus period after Viking/Varangian invasion of the nascent Slavic areas.

But there were countless hindrances. When the scholars of Byzantium fled the Muslim takeover in the 1400's, did they want to go to Russia? Not likely. Western Europe had already gone through a mini-renaissance in the 1200's, and was incomparably more diverse, academically advanced, and wealthy than Russia at the time. Also, the Mongols invaded Russia in 1237, ruling with a slowly loosening grip till 1480. This would obviously put a serious crimp into any renaissance.

Poland, next-door, had its own mini-renaissance, roughly through the 1500's. Even in this most distant province of Europe, Italian architecture, arts, and science penetrated, and yielded the brilliant response of Copernicus, among others. It turned out that exposure to Byzantium was only a small part of the recipe- a spark, but far from the most important ingredient. Poland's great period was based on riches from trade with the Baltics, and dominion over a great deal of what is Ukraine, Belarus, and Russia today, plus quite a bit of travel to Italy. Prosperity and its consequent cosmopolitanism was perhaps more imporant than contact with Byzantium alone.

Holy investiture

One could also imagine getting too much of a good thing. Byzantium itself was Orthodox Christian, and inheritor of Greek and Roman learning, but had itself nothing we would call a renaissance. There was something about Greek Orthodox Christianity that seems to have been, and still is, stultifying to free thought and scholarship.

Was Islam an influence? In the West, Islam was a transmitter of ancient texts and a source of independent scholarship, via the lengthy occupation of al-Andalus, as well as trade throughout the Mediterranian. This was at least as influential as the recovered treasures of Byzantium. But, being present at the very gates of Constantinople, and as a significant part of the Mongol empire, the Islamic influences must have been at least as strong in Byzantium itself as well as in Russia- but to little avail.

It is not a big point, but the historical irony is that Russia inherited the strong ruler model, the love of ornate ceremony, iconography, architecture, and the deeply entwined church-state model of Byzantium- some of which were rather retrograde characteristics- leaving the West to gain from some of its other, more positive achievements, or perhaps rather, transmissions from a deeper past.

• Taliban poised for success. Despite hearts and minds operation... while the American military seems delusional, like in Vietnam.
• Librarians- on the front lines of homelessness and drug addiction, and community.
• Lawless organization ... our border system.
• Fake news / warfare from Russia. Or Trump. Or Fox.
• Some problems with Bill Clinton.
• "As much as 54% of present high-seas fishing grounds would be unprofitable without large government subsidies."
• Who really owns the jobs issue?

How Big is Your Working Memory?

Evanescent working memory may be defined by gamma brain waves, whose number is limited by the capacity of theta waves containing them.

Human working memory is sadly minuscule. We can keep only a handful of things in immediate mind at a time, like a new telephone number. How luxurious it is, in comparison, to program a computer with its gigabytes of ram, which can be consulted instantaneously! Humans have lots of intermediate and long-term memory, which are accessible quite rapidly. But working memory is a special class, happening (as far as we know) without any neural cell alterations, rather purely on the electro-chemical level. A recent paper pursued the theory that working memory is mechanistically constituted by the encoding of gamma electrochemical rhythms within the theta rhythm cycle, a bit like AM radio carries sound amplitudes encoded in its carrier wave.

This theory (more generally reviewed here) would imply that gamma waves individually mark different bits of content, which is somewhat difficult to understand, really. Neural oscillations have come to be seen as entraining selected networks across the brain, allowing attentive synchronization and binding of content from various anatomical regions. The waves do not carry the content, rather the anatomy does. But each network actuated by separate peaks of the gamma oscillation could be different, thus "carrying" different information, though the wave is simply a timing and separation device. This mechanism of enclosing a set of distinct gamma patterns (typically running at roughly 40 Hz) within a theta wave (typically running at a much slower 5 Hz, but ranging from 3 to 8 Hz) is already understood in the case of place cell firing/encoding in the hippocampus, so it is not a stretch to think, as many seem to, that it is also responsible for working memory in many different subsytems of the brain. In that place cell system, the encoding is not only differentiated by gamma cycle, but time-compressed, such that a physical traversal of a space that takes a second may be encoded by gamma peaks only tens of milliseconds apart. So there is true encoding of information going on here.

Experimental protocol. Subjects where asked to memorize a pattern of colored dots for roughly a second. They were randomly directed to memorize the left side set (experiment) or the right side set (control). The number of dots that they successfully recalled as staying the same or changing was the measured outcome.

A recent paper (review) sought to support this hypothesis by using transcranial AC current stimulation (TACS) to entrain the theta rhythm in the visual cortex to faster or slower pace than normal, and asking subjects to memorize visual features. TACS is a very interesting technique, different from the transcranial magnetic stimulation you may have heard of before. These AC currents are specifically designed to alter neural oscillations, not general activity. The authors found that slowing down the theta rhythm allowed for a slightly increased memory capacity, consistent with the theory that the slower theta wave could fit in more gamma waves. Conversely, speeding up the theta rhythm significantly cut the subject's memory capacity. Amazing! Control experiments that sent the TACS current over a more superficial path from the left visual field, or, even better, which asked for memorization in the right visual field rather the left one that was being stimulated, showed no significant effect.

Theory of the experiment. If the theta rhythm is slowed down (left), more gamma waves, and thus distinct working memory engrams, could be enclosed within each theta wave, increasing effective memory capacity.

The authors mention that the difference in induced theta rates (between 4 and 7 Hz), would have theoretically have allowed two more or less gamma cycles to be enclosed, thus two more items memorized in working memory at 4 Hz than at 7 Hz. The effect size was very small, (about 0.8 items more or less were memorizable), but the experimental intervention was rather diffuse and blunt as well. This kind of work helps gives specific shape to our models of what oscillations do- how they can organize information transfer and binding within the brain, while not themselves really carrying anything in their waves/waveforms.

Data. Memory retention (in terms of items remembered, vs average) is plotted on the right vs the induced theta current. See the paper for controls.

• Yes, to a job guarantee. And a detractor, making as though GDP growth were the point.
• Science? Not broken.
• Bernie on foreign policy.
• The meritocracy that devours itself. By not sharing the wealth.
• Millennials are depressed, and no wonder.
• Mainstream, supply-side economics remains wrong. We need to go back to the Keynesian model.
• The ECB saves the day, but Europe's reckoning will come nevertheless.
• More on Europe's enormous imbalances.
• Down syndrome, or no Down syndrome?
• When California's primary is too much of a good thing.
• We are seeing obstruction of justice in public, on a daily basis.

Philosophy of Science, or Philosophy vs Science?

A review of "Theory and Reality", by Peter Godfrey Smith, touching on a few criticisms and issues in the philosophy of science.

The philosophy "of" science has been fraught for decades, if not centuries. The usurpation of the theological explanation certainly rubbed many religious thinkers the wrong way, and modern philosophy has, perhaps unconsciously, carried on that rather adversarial tradition. A 2003 book by Stanford professor Peter G. Smith recounts the more recent back and forths in a judicious fashion. The modern story starts with the logical positivists of the inter-war Vienna Circle. They wanted to put science on a firmer footing by describing a logical basis for the scientific method. While scientists were groping in the dark, they, with their logical powers as philosophers, were going to straighten out the whole field. Never mind that, at the very same time, Gödel and others were showing that even logical systems have their limits, quite apart from the details of how they are applied to what we (so naively!) call reality.

A logical positivist.

The logical positivists were a little like the behaviorists- they tried their best to ignore invisible abstractions and hidden causes. They were obsessed by language and clarity, attempting to make of scientific language something purely empirical, linked at every point to directly observable entities and tests. This language was also supposed to be comprehensive and simple, hopefully mathematical in nature. And everything "scientific" would then end up being proven and lock-tight. However there were many problems, some inspired by the arch-skeptic, David Hume.

One was the problem of induction. While the sun has come up over 4 billion times, and reliably in our personal observation, there is still no guarantee that it will rise tomorrow. Such a prediction, premised on the inductive logic that since the sun has always come up, it will ever do so, can never be "proven". It can only be a matter of probability, confounded by the next black hole to come sailing through the solar system. The positivists and others trying to put the routine scientific logic of explanation and induction on a footing of certainty could not do so, however hard they tried. Even calling our most regular and elegant findings "natural laws" doesn't help. They remain founded on the clay of repeated observation and probabalistic extrapolation, not gold-plated logic (except for relations that are actually mathematical, like the symmetry laws of Emmy Noether; yet these rely on other observables for their premises, so ultimately rest on contingent properties of the universe). There was a sort of mathematics envy going on, as philosophers obsessed with making sense of physics yearned to make everything provable.

But that is not possible. Our findings about the world, however carefully observed, elegantly abstracted, and powerfully predictive, are necessarily probabilistic generalizations. Late in Smith's book, he delves into Bayesian logic and its stong attractions to philosophers as a way to represent probabilistic representations of the claims of science. Smith is dubious, and hopes for another solution, but it is important to point out that Bayes' theorem is not just a technical innovation to parameterize our belief and doubt. It is a solution for the whole problem of induction, which is to say that our expectations for certainty (whereby it is called inductive logic) need to be fundamentally tempered. An earlier breakthrough along these lines happened from Karl Popper, who offered disproof as the coin of the scientific realm. Perhaps, since nothing could be inductively proven, scientists could just work in disproving bad hypotheses, and leave it at that. But that is not how science works either. More on that below.

There were many other problems with the logical positivist program, such as an inability to make of language a pure, clean, perfectly observation-based mode of expression. No, languages of any kind presuppose large networks of meaning that have to be learned, and imply ontologies (unseen and abstract, no less) which model some version of reality, including hidden aspects. The whole positivist program is now a historical curiosity, (though its empiricist aspects are far from dead), but it paved the way for other, sometimes even more extreme approaches.

The most devastating critique was a social one. The 60's and 70's brought philosophers who looked more closely at what scientists did, and found that, far from following the dictates of the logical positivists, or at least those of Popper, they were behaving a lot like humans, with pet theories, a mania to prove themselves right, and petty squabbles over elaborate theories and the credit for them. Thomas Kuhn led the way, with an altogether nuanced and sophisticated picutre of the scientific process. Kuhn is probably the hero of Smith's book, and is rehabilitated in several respects. Kuhn devoted most of his main work to the process of "normal science", which goes forth within an over-arching paradigm that is largely uncontested, is inculcated by lengthy training (not to say indoctrination!), and digs ever deeper into the secrets of its field. Kuhn then followed with a description of the crisis phase of science. This is when paradigms change, and old verities no longer hold. He noted dryly that this is when scientists tend to become interested in philosophy! The clearest example is the quantum and relativistic revolutions in physics, which upended the stable, indeed Euclidean, Newtonian world.

To step out of the story briefly, it is imporatant to note here that, while Kuhn's story has given us the impression that such paradigm shifts are a necessary and continuing part of science, thus that nothing we know now is really stable or "true", that would be misleading. The Newtonian world lives on as a first approximation of reality- it was not discarded in any complete way. Equally important, some fields have really come to a final picture of their subjects. Molecular biology is an example. New things continue to be found and we have very far to go to unravel all the molecular networks that touch on health, not to mention consciousness, but the basic picture of DNA and its core processes are not going to change. Biology after Darwin could have been upended by the new technologies of genetics, microscopy, crystallography, and then of DNA. But it has not been- far from. Each innovation has only provided deeper and more detailed explanations of the theory of natural selection, in all its ramifications.

While Kuhn was very measured in his portrayal, his successors in social constructivist and postmodern philosophy let it all hang out, generating a decades-long body of work that, at its fringes, claimed that science was entirely socially constructed, and had no more say about the nature of reality than did the science of voodoo, which was at least the province of an oppressed and thus virtuous and authentic society. This fed on the age-old obsession of philosophy- what is reality? If observation is theory-driven, which everyone now agrees on, (in contrast to the logical positivists), how does reality enter our models of it? Obviously, there is a cycle (one might even call it a dialectic!) going on, of hypothesis, observation, evaluation, problem, and re-hypothesis. Our minds excel in making models, which then inform our observations, which then feed back (if we are paying attention) to those models. But a sufficiently motivated philosopher with a sufficiently narrow and uncharitable view of what is going on in science can come to a different conclusion. Smith provides a valedictory about this phase of his field:

"A lot of work in these fields has been organized around the desire to oppose a particular Bad View that is seen as completely wrong. The Bad View holds that reality determines thought by stamping itself on a passive mind; reality acts on scientific belief with 'unmediated compulsory force'. That picture is to be avoided at all costs; it is often seen as not only false but even politically harmful, because it suggests a passive, inactive view of human thought. Many traditional philosophical theories are interpreted as implicitly committed to this Bad View. This is one source for descriptions of logical positivism as reactionary, helpful to oppressors, and so on. 

What results from this is a tendency for people to go as far as possible away from the Bad View. This encourages people to asset simple reversals of the Bad View's realtionship between the mind and world. Thus we reach the idea that theories construct reality. 

Some explicitly embrace the idea of an 'inversion' of the traditional picture, while others leave things more ambiguous. But there is little pressure within the field [Science studies, particularly] to discourage people from going too far in these statements. Indeed, those who express more moderate denials of the Bad View leave themselves vulnerable to criticism from within the field. The result is a literature in which one error - the veiw that reality stamps itself on the passive mind - is exchanged for another error, the view that thought or theory constructs reality."

One author comes in for extra discussion- Paul Feyerabend:

 "Feyerabend was not, as he is sometimes portrayed, an 'enemy of science'. He was an enemy of some kinds of science. In the seventeenth century, according to Feyerabend, science was the friend of freedom and creativity, and was heroically opposed to the stultifying grip of the Catholic church. ... But the science of Galileo is nto the science of today. Science, for Feyerabend, has gone from being an ally of freedom to being an enemy. Scientists are turning into 'human ants', entirely unable to think outside of their training. And the dominance of science in society threatens to turn man into a 'miserable, unfriendly, self-righteous mechanism without charm or humor.' In the closing pages of Againt Method, he delcares that society now has to be freed from the strangling hold of a domineering scientific establishment, just as it once had to be freed from the grip of the One True Religion."

One can see how this ties in with the anti-intellectualism of the current Trumpian moment, and how the Evangelical movement sees its deepest interests in the construction and maintenance of an alternate reality that has been comprehensively threatened by intellect salvaged by a man like Trump, who shares their postmodern view about things like reality and its moral implications.

Smith spends the later parts of the book not on historical review, but on an effort to synthesize a more mature view of the field, taking a pluralistic view of what counts as evidence in science, and how the interaction with reality operates, ending up with a very reasonable view of the matter:

".. we might think of science as something like a strategy. In this sense science is the strategy of subjecting even the biggest theoretical ideas, questions, and disputes to testing by means of observation. This strategy is not dictated to us by the nature of human language, the fundamental rules of thought, or our biology; it is more like a choice. The choice can be made by an individual or a culture. The scientific strategy is to construe ideas, to embed them in surrounding frameworks, and to develop them, in such a way that exposure to experience is sought even in the case of the most general and ambitious hypotheses about the universe. That view of science is a kind of empiricism."

There are a couple more points that I would add to what Smith presents. First is about the role of criticism in science. This gets somewhat short shrift, I think, in favor of citation credit as the primary mode of motivation, yet plays a central role. Everyone is a critic- that is true in all walks of life and work. There is great power that accrues to scientists who brilliantly point out the flaws in others' work. This is why thesis committees exist, and peer review, grant review, group meetings, conferences, and much of the social apparatus of science, such as it is. Criticism, especially in public, inspires fear, which in turn inspires enormous efforts to address weaknesses in one's work. It is one of the primary motivations for scientists to make extra mental effort step outside their pet theories and obsessions- to strain to be "objective".

A second point is about another motivation in science, the ultimate one. This is not social at all, whether social approbation, credit, or fear, but is rather more spiritual: personal contact with reality. There really are eureka moments, in science as elsewhere, and they are tremendously fulfilling. All the care about details, the straining to be objective, and the acceptance of criticism, all function in the service of making contact with some new truth about the real world. Scientists are not Marines. They do not live and die for their band of brothers. They dedicate their lives to truth ... the pursuit we all share in some portion in our native curiosity to learn ever more about our world, but which, taken seriously, morally, and systematically, turns into the privilege of working full time to push forward knowledge about topics more or less obscure and useful, aka science.

It is an implicit recognition of the philosophical difficulties of dealing with and knowing about reality- this shadow world that we study incessantly, through our mental powers of modeling, but can never directly know. This is why students are given laboratory exercises, rote as they may be- to show that what seems so inert on the pages of their textbooks was once alive as a question which was answered by nature via a theory-driven and carefully constructed test. That the sought-after truth may be imperfect, tentative, and probabilistic is no matter. Any progress is better than none. And touching a new truth about how things work, which no one has witnessed before, after a lifetime spent feeding on the regurgitated knowledge of others, is truly addictive.

Smith's book finally shows a significant retreat from the glorious early aims of the queen of the sciences to rule over her dronish brethren. Philosophy may deal in big questions, but it is not very adept at answering them, or even posing them very constructively. Its lack of empirical engagement leaves it prone to the kind of appalling group-think that led the French constructivists and science studies acolytes so thoroughly off the rails. Its attitude towards science has been remarkably patronizing and counterproductive, not to say politicized and naive. Smith retreats to a far more humble descriptive, rather than normative, program of accepting pluralism in the methods and criteria of various sciences, and working, (one might say almost scientifically), to sort through and make sense of each of them in turn.

• Errol Morris blames Kuhn for postmodernism and scientific faith-ism ... which is unfair.
• Coming to terms with reality.
• Trumpire Putinesca. "Sater is the one who famously sent Cohen the email in 2015 that said 'I will get Putin on this program, and we will get Donald elected.'"
• Comey v McCabe.
• Pigs on Twitter.

mm-Hmmm ...

The critical elements of conversation that somehow didn't make it into the "language". A review of How We Talk, by N. J. Enfield.

Written language is a record of elision. The first written languages were hardly more than accounting symbols, and many early forms of writing lacked basic things like vowels and punctuation. The written forms are a shorthand, for those practiced in the art of spoken language to fill in the blanks, and they still hide a great deal today. For example, the same letter, such as "a" can stand for several vowel sounds, as in ate, art, ahh, am, awe. Another rich part of the language left on the editing room floor are completely unrecorded (except by authors of dialog looking for unusual verisimilitude) sounds, like um, ah, huh, mm-hmmm and the like. N. J. Enfield makes the case that, far from being uncouth interjections, these are critical parts of the language, indeed, part of an elaborate "conversation machine" which is one behavior that distinguishes humans from other animals.

Arabic, a language commonly written without vowels.

When we are in conversation, time is of the essence. We expect attentiveness and quick responses. It is a relationship with moral aspects- with obligations on each side. The speaker should repeat things when asked, not take up too much of the floor, provide clear endings to turns. Enfield describes a very disciplined timing system, where, at least in Japan, responses begin before the first speaker has stopped. Other cultures vary, but everyone responds within half a second. Otherwise, something is discernably wrong. One thing this schedule indicates is that there is a sing-song pattern within the speaker's production that signals the ending of a speaking turn well before it happens. The other is that there is an serious obligation to respond. Not doing so will draw a followup or even rebuke from the speaker. Waiting more time to respond is itself a signal, that the response is not what is desired.. perhaps a "no". It can also be softened by an "uh" or "er" kind of filler that again signals that the responder is 1. having some difficulty processing, and 2. paving the way for a negative response.

Likewise, "mm-Hmm" is a fully functional and honorable part of the language- the real one used in conversation. It is the encouraging sign that the listener is holding up her part of the bargain, paying attention to the speaker continuously. Failing to provide such signs leads the speaker to miss a necessary interaction, and interject.. "Are you listening?".

Finally, Enfield deals with "Huh?", a mechanism listeners use to seek repair of speech that was unclear or unexpected. When a response runs late, it may switch to "Huh?", in a bid to say that processing is incapable of making sense of what the speaker said, please repeat or clarify. But at the same time, if something of the original speech can be salvaged, listeners are much more likely to ask for specific missing information, like "Who?", or "where was that?" or the like. This again shows the moral engine at work, with each participant working as hard as they can to minimize the load on the other, and move the conversation forward in timely fashion.

Huh is also a human universal, one that Enfield supposes came about by functional, convergent evolution, due to its great ease of expression. When we are in a relaxed, listening state, this is the sound we can most easily throw out with a simple breath ... to tell the speaker that something went off track, and needs to be repeated. It is, aside from clearly onomatopoeic expressions, the only truly universal word among humans.

A conversation without words.

It is a more slender book than it seems, devoted to little more than the expressions "uh", "mmm-Hmmm", and "Huh?". Yet it is very interesting to regard conversation from this perspective as a cooperation machine, much more complex than those of other species, even those who are quite vocal, like birds and other apes. But it still leaves huge amounts of our face-to-face conversational engine in the unconscious shadows. For we talk with our hands, faces, and whole bodies as well. Even with clothes. And even more interesting is the nature of music in relation to all this. It is in speech and in our related vocal intimacies and performances that music first happens. Think of a story narration- it involves not only poetry of language, but richly modulated vocal performance that draws listeners along and, among much else, signals beginnings, climaxes, endings, sadness and happiness. This seems to be the language of tone that humans have lately transposed into the free-er realms of instrumental music and other music genres. Analyzing that language remains something of an uncharted frontier.

• Machines can do it too.
• Varieties of technoreligion.
• Monopoly is a thing.
• Appalling display of religious fundamentalism: The US ambassador to Israel refers to old testament and 3,000 year old rights of Israel. If other 3,000 year old land claims were to be honored, the US would be in substantial peril!
• In praise of Jimmy Carter.
• Collapse or innovation.. can we outrun the Malthusian treadmill?
• Truth and Rex Tillerson.
• Sunlight makes us feel better.
• We still have a public sector pension crisis.
• Economic graph of the week. Worker quit rates are slowly rising. Will that affect pay?

The Biology of Fluoride

Fluoride has no biological functions, other than the need to get rid of it.

Fluorine is the smallest and most reactive halogen, a relative of chlorine, bromine, and iodine. Chloride is ubiquitous in salts and in the ionic milieu of our bodies, and iodine has found a central role in metabolism in virtually all species. Even bromine has various biological roles, though mostly in microorganisms. Fluorine, however, has found no role at all, despite being relatively common- more abundant in rocks than chlorine, let alone bromine or iodine. Its only part to play is as a noxious ion to get rid of. And all organisms have ways to get rid of it, via both active and passive trasporters. More on that below.

Humans, in their wisdom, however, have found some remarkable uses for fluorine. Modern chemistry uses it a great deal, to make very tough chemicals like Teflon, Lipitor, and Lexapro. Virtually nothing displaces fluorine from carbon bonds, so its compounds, while very useful, also end up as rather persistent waste products. More interesting, however, is our practice of ingesting fluoride (the ionic form of fluorine) in small amounts for oral health. This has been a subject of tremendous controversy and conspiracy theorizing for decades. But the benefits couldn't be more clear- teeth are much tougher from trace topical exposure to fluorine, which works its way into the crystal structure of enamel.

However, ingesting fluoride is another matter. It is reputed to cause kidney problems at higher concentrations, but there is very little epidemiology to support claims that these risks start at low concentrations.. anywhere near the levels used in drinking water supplementation. Similar to observations of bone deformities and tooth fluorosis, the syndrome of too much fluoride common in geologic regions with excess fluoride, there would have been observations of rampant kidney or other disorders. But that doesn't seem to be the case, other than very sketchy reports. At any rate, the therapeutic dose of fluoride put in water supplies is about 30 micromolar, while the newest regulations in the US establish a conservative cap of about 100 micromolar, in light of the lack of any use for higher concentrations, and the occasional problems from higher natural exposure, top which the artificial amount adds.

So we can't do much with fluorine, biologically speaking. Indeed it is generally toxic, messing with the phosphate chemistry that is central to all life. How do we get rid of it? There are three mechanisms, overall. In animals, our kidneys take care of it, using clever ion transport to excrete excess fluoride. (Recall that the first step of the kidney's work is to remove all the small solutes from blood plasma, and then later to selectively bring back the important things we want, like sugar, some salts, lactate, water, etc. The remainder that is not actively re-absorbed includes such oddities as fluoride.)

But other organisms that live directly in the soup, i.e. microorganisms, all need to take specific and active measures on the cellular level against fluoride. An important point in this chemistry is that fluoride has a significant acid-base preference. HF forms at relatively high pH (pKa of 3.4, much higher than HCl, which stays ionic to pH 1 and below, an oddity of fluoride's chemistry), which means that in moderately acidic environments, external HF can easily form and diffuse into cells as an uncharged entity, and there, under more neutral conditions, dissociate and be trapped as F- ions. This leads to chronic over-loading of cells with F-, (up to 30X over external levels), which can be remedied by a protein channel (second mechanism) that lets these ions back out passively, while not letting out other ions such as the closely related chloride. The third mechanism, exclusively used by bacteria, is active antiport, (H+/F-), using the stored energy of the proton gradient (high outside, low inside) to drive F- excretion.

 

Structure of two copies of E. coli-derived Fluc, a passive fluoride channel/exporter. The proteins are blue and yellow, respectively, the membrane represented by black lines, and the fluoride ions are modeled as gray or red balls. Given the symmetry of the proteins and their passive role, the orientation (up/down) makes no difference. The channel is formed at the interfaces between the two proteins.

A recent paper described the simple passive transporters that are ubiquitously used for fluoride export in microbes. They are odd in that it takes two proteins to form a functional transporter. The channel through which the F- ion passes is on the surface between the two proteins, in a symmetric structure that forms two channels (above). In eukayotic microbes like yeast cells, two such genes have become fused to form one gene encoding a protein that retains dimeric symmetry, but one of whose channels has become non-functional / vestigial.

A close-up view of one of the channels, showing some of the key individual amino acids that coordinate / bind to the fluoride ion as it travels along. This close physical and electrostatic coordination insures that nothing that is not fluorine can get through. Notably, part of the job is done by uncharged phenylalanine residues, (blue and orange ring structures), which are usually regarded as hydrophobic, but have a slight face/edge polarization that can be exploited by strong ions

The channel is, understandably, very tight, with intensive coordination all along the way, particularly with uncharged phenylalanines which provide an unusual side-ways polar coordination that is proposed to make the channel particularly specific to F-, vs Cl-. And it is very selective- over 10,000-fold selective for F- vs Cl-. Replacing these phenylalanines with the hydrophobic amino acid isoleucine reduces F- transport to negligible levels. It would have been interesting to ask what a less bulky and less hydrophobic replacement like glycine or threonine does to the channel's activity, perhaps making it significantly less selective, while still functional.

• Unfit to serve on a sewer board, cont. Climate, shimate.
• Desperate US military and allies have lost ground.
• Antitrust should not be just about consumers.
• Property is monopoly.
• Tourism makes up 8% of carbon emissions.
• Lowdown on money laundering.
• Driving remains dangerous.
• Some non-profits are not so non-profitable.

Green Power

California's open political structure opens the opportunity for the Green party to create a revolution.

A recent op-ed in the local paper by a Republican party official complained about California's open primary system. This system runs primaries and general elections without regard to party affiliation. The top two finishers in the primary run against each other in the general election. In California, this has resulted in many state-wide races being contested between two Democrats. The Republican party no longer has a lock on one position on the general election ballot as they used to, and this naturally rankles. The editorialist complained pathetically about lack of diversity (of all things!), and how the choice between two Democrats was so limited. It was whining at its most exquisite.

California has frequently been in the political vanguard, whether in tax revolts or in progressive climate change policy. The 60s were headquartered here. California has put redistricting on a non-partisan basis. The open primary system has been a dramatic success, giving the best two candidates a hearing before the voters in the general election, and reducing partisanship and cronyism in the state. One side benefit is that voters can register with a minor party without the penalty of being locked out of the key primary races, which are no longer parochial, but open to all. This new political landscape (which was the beneficent and ironic gift of Arnold Schwartzenegger) could lead to another progressive advance, in the form of a revitalized Green party.

Trends in party affiliation in California. Greens come in at 0.62%- currently negligible.

The Democratic regime in California has not been a bad thing on the whole. Under Jerry Brown, who operates as a centrist, the drama surrounding budget battles and other fringe issues has been sharply reduced. Except for the pension crisis, the state has been quite well run, if inefficient. Advances in climate change regulation, marajuana legalization, gun control, and formal resistance to the Trump administration are generally appreciated. Trump is reviled. Education and infrastructure funding remain dreadful. There is little stomach in the state for a return of Republicans as the opposition, (they are now legislatively locked out of veto power), which would bring back endless bickering and corrupt dealing. There is, however, room for less corporatism and more progressivism, which is what a stronger Green party could provide.

The Green party currently is not much healthier than the Republican party, unfortunately. In California, it fields a grand total of 60 office holders, none of which are statewide. Its web sites and organization seem moribund. Due to the two-party structure at the national level, it is unthinkable to support it in presidential races, where it would be a spoiler to benefit Republicans. But with open primaries in California, the party could cultivate a state-wide program and candidates, while vowing to back the Democratic party (or whichever party is more aligned with Green objectives) in races that are significantly contested by Republicans, which is to say, effectively support the left. That would provide a solid platform for activism within the state, building the movement and the party.

Each non-presidential race would have to be carefully evaluated for whether the participation of a Green candidate would raise the chances of Republican / Conservative victory significantly. In primaries, this is likely be a negligible risk as things stand. At least one Democrat will always win in non-rural districts. For the general election, if a Green candidate is not running, Greens would support the Democratic candidate, or whichever one most agreed with the Green agenda. This would make for a sort of mature, parliamentary-style politics, where coalitions are assembled in response to conditions.

Oddly, however, the Green party is officially against the open primary system, mistakenly thinking that the loss of a coveted (though pointless) automatic spot on the general election ballot outweighs the decisive gain of flexibility for their voters and sympathizers in the primary election. They want something still better, like proportional representation, logic that to me seems maybe nice in theory, but self-defeating and irrelevant in practice. Worse, the national Green party is a disaster, indeed a toxic blight on the left, pushing its presidential candidate in the teeth of all logic and experience. That is no way to succeed.

The Republican editorialist bemoaned the lack of competing perspectives and arguments in California politics. But the voters have decisively rejected the Republican program of meanness, business cronyism, labor expoitation, environmental degradation, and xenophobia, which has only become more extreme and blatant on the national level. Maybe the discussion that voters in the state really want is one between Democrats and those who want progress to go even faster- toward single payer health care, faster de-carbonization of the economy, more effective business (and internet) regulation, and more balanced housing and transportation growth, among many other issues. The climate is shifting.

• Change your party registration right now!
• We are choking on zoning.
• CO2 is not only rising, but rising faster than ever.