Way Too Much Dopamine

Schizophrenia and associated delusions/hallucinations as a Bayesian logic defect of putting priors over observations, partly due to excess dopamine or sensitivity to dopamine.

It goes without saying that our brains are highly tuned systems, both through evolution and through development. They are constantly active, with dynamic coalitions of oscillatory synchrony and active anatomical connection that appear to create our mental phenomena, conscious and unconscious. Neurotransmitters have long been talismanic keys to this kingdom, there being relatively few of them, with somewhat distinct functions. GABA, dopamine, serotonin, glutamate, acetylcholine are perhaps the best known, but there are dozens of others. Each transmitter tends to have a theme associated with it, like GABA being characteristic of inhibitory neurons, and glutamate the most common excitatory neurotransmitter. Each tends to have drugs associated with it as well, often from natural sources. Psilocybin stimulates serotonin receptors, for instance. Dopamine is central to reward pathways, making us feel good. Cocaine raises dopamine levels, making us feel great without having done anything particularly noteworthy.

As is typical, scientists thought they had found the secret to the brain when they found neurotransmitters and the variety of drugs that affect them. New classes of drugs like serotonin uptake inhibitors (imipramine, prozac) and dopamine receptor antagonists (haloperidol) took the world by storm. But they didn't turn out to have the surgical effects that were touted. Neurotransmitters function all over the brain, and while some have major themes in one area or another, they might be doing very different things elsewhere, and not overlap very productively with a particular syndrome such as depression or schizophrenia. Which is to say that such major syndromes are not simply tuning problems of one neurotransmitter or other. Messing with transmitters turned out to be a rather blunt medical instrument, if a helpful one.

All this comes to mind with a recent report of the connection between dopamine and hallucinations. As noted above, dopamine antagonists are widely used as antipsychotics (following the dopamine hypothesis of schizophrenia), but the premier hallucinogens are serotonin activators, such as Psilocybin and LSD, though their mode of action remains not fully worked out. (Indeed, ketamine, another hallucinogen, inhibits glutamine receptors.) There is nothing neat here, except that nature, and the occasional chemical accident, have uncovered amazing ways to affect our minds. Insofar as schizophrenia is characterized by over-active dopamine activity in some areas, (though with a curious lack of joy, so the reward circuitry seems to have been left out), and involves hallucinations which are reduced by dopamine antagonists, a connection between dopamine and hallucinations makes sense. 

"... there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical." - Wiki

So what do they propose? These researchers came up with a complex system to fool mice into pressing a lever based on uncertain (auditory) stimuli. If the mouse really thought the sound had happened, it would wait around longer for the reward, giving researchers a measure of its internal confidence in a signal which may have never been actually presented. The researchers thus presented a joint image and sound, but sometimes left out the sound, causing what they claim to be an hallucinated perception of the sound. Thus the mice, amid all this confusion, generated some hallucinations in the form of positive thinking that something good was coming their way. Ketamine increased this presumed hallucination rate, suggestively. The experiment was then to squirt some extra dopamine into their brains (via new-fangled optogenetic methods, which can be highly controllable in time and space) at a key area known to be involved in schizophrenia, the striatum, which is a key interface between the cortex and lower/inner areas of the brain involved in motion, emotion, reward, and cognition.

Normal perception is composed of a balance of bottom up observation and top-down organization. Too much of either one is problematic, sometimes hallucinatory.

This exercise did indeed mimick the action of a general dose of ketamine, increasing false assumptions, aka hallucinations, and confirming that dopamine is involved there. The work relates to a very abstract body of work on Bayesian logic in cognition, recognizing that perception rests on modeling. We need to have some model of the world before we can fit new observations into it, and we continually update this model by "noticing" salient "news" which differs from our current model. In the parlance, we use observation to update our priors to more accurate posterior probability distributions. The idea is that, in the case of hallucination, the top-down model is out-weighing (or making up for a lack of) bottom-up observation, running amok, and thus exposing errors in this otherwise carefully tuned Bayesian system. One aspect of the logic is that some evaluation needs to be made of the salience of a new bit of news. How much does it differ from what is current in the model? How reliable is the observation? How reliable is the model? The systems gone awry in schizophrenia appear to mess with all these key functions, awarding salience to unimportant things and great reliability to shaky models of reality. 

Putting neurotransmitters together with much finer anatomical specification is surely a positive step towards figuring out what is going on, even if this mouse model of hallucination is rather sketchy. So this new work constitutes a tiny step in the direction of boring, anatomically and chemically, into one tiny aspect of this vast syndrome, and into the interesting area of mental construction of perceptions.

• Another crisis of overpopulation.
• And another one.
• Getting China to decarbonize will take a stiff carbon price, about $500 to $1000/ton.

Various policy scenarios of decarbonization in China, put into a common cost framework of carbon pricing (y-axis). Some policies are a lot more efficient than others. 

Zooming In On The Genome

Better sequencing methods bring the human genome to higher resolution and accuracy.

Most of the progress in DNA sequencing over the last two decades has come in what is known as "short read" sequencing. The dominant company, Illumina, produces massive machines that crank out huge amounts of data, but in the form of tiny individual reads, only about 90 bases long. That means that there is a lot of work on the back end for data analysis to piece everything together. And given the frequent occurence in our genomes of repeats and repetitive sequences in many forms and sizes, these reads are simply too short to fully make sense of it. No amount of assembly magic can make up for a lack of long-range information.

So there has been a second movement of "next generation" sequencing methods, pursuing long reads, of tens of thousands of bases. Several methods exist, but the leader is Pacific Biosciences, (PacBio), whose method tacks down a single polymerase into a special optical well and then uses fluorescence to detect each individual nucleobase incorporation as the polymerase chugs away at the given template. This is not a fool-proof process, being at the single molecule level. While the Illumina system greatly amplifies the DNA and thus raises the signal (which is also ultimately fluorescence-based) to a high and reliable level, these long-read methods tend to have lower reliability. A recent paper described a way around this, featuring a long read system which was used to analyze 34 human genomes to collect new information about large scale structure and variation.

The "weird trick" that PacBio uses is to circularize templates of about 15,000 bases, and then drive the polymerase reaction described above around those circles upwards of fifty times. This allows multiple passes around the same DNA to make up (in volume/repetition) for the inherent error rate of each individual pass. Reads of this size are big enough to surround most forms of repetition and low complexity in our genomes, or at least cover enough landmarks/variants that one repeat can be distinguished from others. Indeed, these researchers could even figure out, based on allelic variants peppered through the genome, which parent each sequence came from, assembling each of the subject's two copies of each chromosome separately. All this makes it possible to assemble whole genomes with unprecedented accuracy, (~1 error in a half-million bases), especially in terms of long-range features and variations.

And that has been a growing area of interest in human genetics- variations in structure that lead to extra copies of genes, insertions, deletions, and altered regulatory contexts.  It is a frontier that has had to wait for these new techniques, while millions of single nucleotide variants have been piling up. Cancers are notorious, for instance, for being caused by accidental fusions of two distant genes whereby some developmental or cell cycle gene function is put under novel and (usually) high activation by some other gene regulatory region. Down Syndrome is caused by a whole-chromosome duplication to trisomy. Smaller deletions and duplications have significant effects as well, naturally.

The new paper digs up twice as many structural variants as previous analyses (and does so from only 37 human genomes, compared to the >2000 genomes used by other analyses) - 107,590 insertion/ deletions over 50 bp in size; 316 inversions, 2.3 million insertions/deletions under 50 bp in size; and 15.8 million single nucleotide variants. Many of these count as normal alleles, of long-standing in the human genome, just difficult to piece together previously. In non-gene regions, these variants may have little effect. Per individual, and in comparison to the current reference human genome, they claim to see 24,653 large structural variants, 794,406 small insertions/deletions under 50 bases, and 3,895,274 single nucleotide variants. This is quite a lot in a genome of 3 billion bases, amounting to about 0.1% of all individual positions that are varying in the population, and almost a million other re-arrangements, deletions, etc.

An example of one transposon (top) that the current paper discovered has jumped several times in succession, from chromosome 3 to chromosome 1, then from that landing spot to two other locations on chromosome 1 and one spot on chromosome 17. Each jump brought along a bit of extra DNA from the originating locus.

The vast majority of these mutations arose from repair events, where the DNA broke and was then fixed either by repair using the other homolog sequence for reference (~65% of cases), or simple blunt end rejoining, with a few percent coming from errors that happen during replication, particularly of repetitive sequences. Another source of mutation is the movement of mobile genetic elements, which encode their own apparatus of transposition to new locations. These researchers found ~ 10,000 that were not present or not identified in the human reference genome (because this is what is generally called "junk"). Their detailed data, in comparison to outside references like the chimpanzee genome, allowed them to assess the ages and relationships of these mobile elements. Most are old fossils and no longer active due to mutation. But others have clear and recent lineages, and are still giving rise to mutations, even causing cancers. One can imagine that genome editing could eventually turn these off permanently, reducing one source of cancer and birth defect risk.

Close-up view of one part of chromosome 3, cytological band q29. Even in this small population sample (individual haplotypes listed down the left side, bottom), there is a flurry of structural variations, including inversions and duplications. (CNP = copy number polymorphism.) At top left is a map of genes located here in the reference sequence (hg38). The light arrow shows the direction of transcription, and the heavy vertical lines are the exons. For example. TNK2 is a protein kinase that relays signals inside cells, is active during brain development, and can be an oncogene when activated or overexpressed, as well as having a role in cell entry by some viruses.

An additional analysis was for trait loci associated with the newly found structural variants. As can be surmised from the sample genomic location diagrammed above, this kind of jumbling of the genome is likely to have functional consequences, either by breaking genes apart, joining them to foreign regulatory regions, or by duplicating or deleting them, in part or whole. The researchers found that roughly half of structural variants that map to known trait loci (called quantitative trait loci, or QTLs), were newly found in this study. So while the accuracy increase may not seem like a lot, it can have profound consequences.

The count of structural variants that differ by population. Superpopulation (region) count in light color, and population-specific in dark color.

Lastly, this new fund of variation data allows another look at human ancestry. As we know, the bulk of human variation remains in Africa, and that is reflected in structural variation as well as other forms of variation. Populations elsewhere are far less diverse, due to the small groups that founded those populations from the mother-continent, and perhaps also through the new selective pressures that swept those populations, either positively or negatively. Twenty years after the original human genome was published, it continues to be a clinical and research goldmine, but also requires ongoing work to bring to complete accuracy- something this work gets us much closer to.

• Power sharing is not on the table.
• Amazon as an employer.
• Back to Wuhan ...
• On coinbase- Sorry, but limited access tokens are not currencies.
• Which side were the Capitol police on?
• Yes, collusion.

We Are Still Poisoning the World

Anthropogenic environmental poisonings, intentional or not.

We have an EPA and long-standing bureaucracies of environmental review, so our environment should be clean, right? Well, rivers may not be burning anymore, but that doesn't mean things are as tidy as they may look. Humanity has proven capable of inventing and selling innumerable chemicals, creating a situation that is far more complex than any kind of precautionary testing or policy making can address. Shocking issues have arisen in recent years that remind us that there is a great deal more to do if we are serious about caring for the biosphere.

6PPD is engineered to react with ozone to become 6PPD-quinone. That protects tire rubber, but kills salmon.

A recent paper showed that the decline of salmon all over the Western US is attributable to a completely unanticipated source. An obscure chemical from automobile and truck tires, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), reacts with ozone to form an incredibly toxic compound, which is killing salmon exposed to roadway runoff. This chemical makes up about 1% of tire formulas, and is meant to react with ozone to protect the rest of the rubber in the tire from degradation. The yearly rate of tire rubber degradation and emission is about a pound per person, leaving a great deal of this poison in the environment. So ... does anyone care? A web search for 6PPD yields very little news, despite this being a clear environmental crisis.

Putting the tire problem in perspective. LC50 is the lethal concentration where half of organisms die.

An even more complicated story came up recently from the southeast of the US, where eagles are dying from a mysterious neurological syndrome. It turns out that an invasive water weed, hydrilla, responds vigorously to agricultural nutrient runoff pollution, and accumulates bromine, of all things. This in turn leads to a bloom of an algal parasite, Aetokthanos hydrillicola which grows on the hydrilla, and produces, as cyanobacteria are wont to do, various toxins, in this case a highly brominated amino acid derivative which causes the eagles' lethal neurological disease.

AETX, a heavily bromimated derivative of the amino acid tryptophan. This is a toxin, causing myelinopathy in eagles after it bio-accumulates in the food chain from ducks and other aquatic browsers that eat the cyanobacterial-infested hydrilla. 

But this is just the tip of the iceberg, based on incredibly painstaking work by chemists newly armed with today's analytical chemistry tools to look at particularly dramatic cases of dead wildlife. What about the lead in firearm ammunition, which litters the countryside and shatters into poisonous shrapnel in its targets? What of the intentional poisonings by farmers and ranchers, that are killing condors in the Andes? What of the landfills and coal ash heaps, and whatever leaches out of them? And what of the mountains of plastic that are increasingly filling the planet's waterways and oceans? They are not just physical nuisances but leach out an uncountable array of obscure chemicals. 

These are slow-motion Chernobyls, which need to be taken seriously and mitigated by a more precautionary approach to new products, a life-cycle approach to collecting and reprocessing existing products, and more investment in cleaning and protecting the environment.

• Not quite alive, not quite dead ... what happens after you get that RNA vaccine injection. 
• Bach, slow and easy.
• Notes on antitrust.
• Are we heading towards a "managed" democracy?
• Carbon tax, now! Or maybe carbon neutral products at slightly higher prices?

Gears Within Gears Within Gears

What the Antikythera mechanism says about the technology and culture of Western antiquity.

A recent paper has laid out a complete reconstruction of the Antikythera mechanism, which was an astronomical computer made around 50 to 200 BCE. It is a machine of breathtaking scope and ambition, far beyond what the ancient world was thought capable of- a detailed model of the motions of all the planets of the day, sun, moon (with phases), plus on the back, detailed predictions of solar eclipses and, in true sports page fashion, schedules for the most popular panhellenic games. All this was available decades in advance, though a true modeling computer that the user could wind through at will, forward or back. As a bonus, an instruction manual was inscribed on the back.

An artist's rendition of the current researcher's proposals about the front face of the Antikythera computer. The moon (black and white) revolves around the earth at center, with phases reflected in its rotation. Outer rings and pointers successively portray the Sun, Mercury, Venus, Earth date, Mars, Jupiter, and Saturn. A knob at the side would have allowed the user to run it.

To understand the detailed mechanisms and proposals of this research group, watch their video. No one would have known about this technology had not some sponge divers found a ~75 BCE wreck off the coast of Antikythera in 1900. One of the many artifacts was a lump of bronze, with a clearly mechanism-like structure but heavily corroded. Indeed only a third of the original was ever found, and it has taken all this time, including recent intensive X-ray examinations of its inner workings and inscriptions, to figure out its full splendor.

A partial rendition of the computer's inner workings, with gears noted with their numbers of gear teeth. Eccentric motions were provided by bars connected to gear-mounted pins off-set from the gear's pivot center.

One of the more puzzling aspects of this device, on a purely technological level, is how the precise machining was done, all in bronze. The front face displays at least nine separately moving dials or pointers, each driven by one of a set of nested tubes making up the central shaft of the computer. Could the Hellenistic Greeks cast bronze to this kind of uniformity and thinness? Or did they have lathes with such precision? What can be assumed is that this mechanism is not alone, and must have been the product of an ongoing tradition of precision device manufacture- a long technological evolution that accumulated the numerous ingenious solutions and remarkable miniaturization evident in this device. How could such a tradition have otherwise so thoroughly evaded historians and archeologists? And what became of this tradition into Roman times?

The astronomy that this device is based on has its roots with the Babylonians, who were avid readers of the skys and its many cycles. The gears within accord with various grand cycles with which key events, like the position of the moon or planets, recur with regularity. For example, the Saros cycle is when the Earth, Moon, and Sun line up for an eclipse, and recurs every 18 years, 11 1/3 days. The gearing in the Antikythera mechanism goes through five different pairings to come up with the 940/4237 ratio that approximates the 18 year cycle every four turns of the crank. The Greeks naturally contributed their own astronomical theories, such as a conviction in the regularity / sphericity of the planetary orbits, despite their wayward motion.

All this tells us strongly that these ancient people were every bit as inventive and thoughtful as we are. But they had very different cultural conceptions and resources to work with. The most frustrating aspect to this amazing story is why this inventiveness did not lead to a more general technological revolution, instead sputtering out with the fall of Rome and the fallow Dark Ages, before technological development resumed at a high level during the later Middle Ages.

I think the answer needs to be put down to the class relations and nature of work in the ancient world. Capitalism certainly was not lacking. Antiquity was just as capitalistic as modern times, with an extremely free business sector able to finance wide-ranging trade and manufacturing operations, and merchants occupying the pride of place in Greek and Roman fora- the malls of their time. The story of Crassus extorting Romans of their burning properties in return for fighting the fire tells you all you need to know about the nature of capitalism in these times. It was red in tooth and claw. But that was not enough to foster technological development on a broad basis.

Rather, slavery and vast inequality made work a degraded, mean affair, beneath the dignity of aristocrats. Their minds were on government, law, military conquest, art, and philosophy. Anything but practical affairs of efficiency, improved production, and technological advancement. Work was secondary to power relations- the essence of a slave society. We have seen this in the Southern culture of the US under slavery. It was obsessed with pursuit of "refinements" and honor. Even though labor was expensive in the form of slaves, and its management a social imperative of the highest order, the idea of supplementing it or replacing it via technology does not seem to have been a high priority. The cotton gin was invented, not by a Southerner, but by Eli Whitney of Massachusetts.

It is a general problem of highly unequal societies, that the maintenance (and defense) of inequality takes on a large part of the mental space of the society, (particularly its educated elite), overtaking the motivations that in a more egalitarian society- where all participate in work and all are eager to adopt improved methods in the work they all share in- that promote the development and propagation of technological advancements. (Think of the revolutions in mechanized agriculture in midwestern America in the late 1800's.) In scholarship as well, the segregation of abstract philosophy and other written forms / stores of knowledge into ivory towers, as was common in Hellenistic culture, reflected the same cultural stratification and lack of concern with the day-to-day drudgery that formed the rather static basis of economic existence.

• Heat pumps.
• Anonymous member of Biden administration speaks out.
• Forests are falling.
• Marine ecosystems, dying.

Size and Consciousness

Are flies conscious? Are neurons conscious? How many neurons make up a thought?

Are animals conscious? Descartes thought not, consigning them to mere mechanism. But obviously, he was wrong, as the evidence of feeling and consciousness is all around, in the animals we can see frantically trying to get into our bird feeders, chasing each other around for play and sex, and raising their young with exquisite care. If they are mere mechanism, then so are we. Now, we consign only plants and invisible microbes to the zone of no-consciousness, though we could be mistaken there as well. Consciousness seems to be defined by some mental and emotional engagement with the world that is responsive, built around modeling of how things are and are wished to be, networked in a way that puts the emotions and the models in close relation with each other. Bacteria have desires too, but they do not have the apparatus of feeling about them and planning around them that would suggest that they are conscious.

Flies, however, are a different story. They hunt for food, victims, mates, avoid pain and escape danger, and in most cases have visual, tactile, and olfactory worlds of substantial complexity. Flies have become leading model systems for neurobiology, even up to studies of consciousness. A recent paper asked whether one of the leading theories of consciousness, integrated information theory, could be applied to flies. This theory posits that consciousness is not a single thing or location of mental processing, but the network flexibly binding together many mental modes such as feelings, sensations, memory, planning, and analysis to form that shifting, yet durable, sense of a self at the center of our being. Specifically, it posits that reductions of consciousness, such as induced by anaethesia or sleep, can be analytically, even quantitatively, characterized by reductions of network size that should be commensurate with the reduction of subjective consciousness. This idea has started to inform the quite practical problem of evaluating levels of anaesthesia in humans, as well as rare neurological conditions such as "locked-in" states, using scanning technologies and network analyses of remaining brain function.

The default hypothesis, of low complexity and no consciousness for a fly brain, would postulate a fully one-directional processing system, going from visual inputs to action outputs, with little networking or complexity in between. The rapid, and often stereotypical, reflexes of flies might support this kind of view. But we now know, after decades of trying to make video cameras smarter, that that is no way to build a visual system, let alone a generally intelligent brain. These researchers obviously find something quite different- complex feedback and integrated information systems, detectable with their electrodes which are mercilessly plugged into their subject's tiny brains.

"In stark contrast to a view which assumes feedforward architecture for insect brains, especially fly visual systems, we found rich information structures, which cannot arise from purely feedforward systems, occurred across the fly brain. Further, these information structures collapsed uniformly across the brain during anesthesia. Our results speak to the potential utility of the novel concept of an “informational structure” as a measure for level of consciousness."

Collapse of larger information structures on anaesthesia, in flies.

Flies have about 100,000 neurons, a far cry from the ~100 billion neurons we have. But as recent work has claimed, it only takes about 14 neurons to constitute a distinct thought or response, so flies have plenty of brains for thought, and quite possibly consciousness. The current workers do not, in the end, pronouce on the capability of flies to have consciousness, or have it in a way that resembles ours. But in addition to finding clear markers of integrated information networks that decline on anaesthesia, they cite past literature that shows that flies share molecular, cellular, and structural themes with mammalian brains, and show attention, memory, feature integration, and long term planning. So I think it is fair to assume that they are a good model for some modest level of consciousness, and perhaps we should regard them as more than nuisances.

• We all need to get on board, on climate change, and other biosphere issues.
• The evangelical toxic stew, etc.
• Liberals hate god.
• Thoughts on the Wuhan lab.
• Fossil companies will stop at nothing. Or do anything.
• Some Texas payback.

Worker Exploitation at the Krusty Krab

What does SpongeBob have to tell us about capitalism?

Capitalism is a total cultural system, not just an economic mode or principle. It encompasses class relations, media and consumer culture, and views on the importance of most aspects of life. That includes movies made for children, who are taught how to take their places, and stay in them, in this reigning system.  While SpongeBob SquarePants may have started out as a marine organism, he was animated into a loving friend and happy worker, getting into various scrapes and adventures with his octopus, starfish, and squirrel friends. Positivity is the main theme, since SpongeBob bounces back from every reverse and challenge with renewed enthusiasm, everything works out, and all adventures end happily.

The boss is Mr. Krabs. SpongeBob is the short-order cook, creating the Krabby Patties that draw the entire population of Bikini Bottom to their restaurant, the Krusty Krab. Especially, the patrons are drawn away from the other establishment, Sheldon Plankton's Chum Bucket. We may note at the outset that only one regular character in the series is accorded an honorary title- Mr. Krabs. Like Mr. Potter and other bosses of film lore, the boss position is not just an economic function, but a social pedestal. SpongeBob is the epitome of an exploited worker, happily filling orders, then scrubbing the whole kitchen down at the end of the day, while oblivious to his true value to the establishment. Is he paid fairly? Of course not. He is barely paid at all, and children are taught the lesson of complete abandonment of any hint of whining, disgruntlement, or entitlement to fair treatment in this workplace.

Archetypal capitalist, Mr. Krabs.

This pattern is, incidentally, painfully evident this weekend, as the NCAA tournament exhibits a billion dollar entertainment and gambling enterprise built on the unpaid labor of enthusiastic young athletes trapped in an exploitative system. Only when they join unions in the pro leagues will a few of them be paid fairly. Exploiting youth is still remarkably common, from the fast food industry to the research establishment.

In the current movie, SpongeBob does take some time off, for the important matter of tracking down his pet snail. The Krusty Krab promptly goes down the drain, and Mr. Krabs even goes so far as to join the crew in tracking down SpongeBob and friends to haul them back to Bikini Bottom. He even evinces some feelings. But any recognition of the business value, and monetary value of SpongeBob, in any way that leads to better pay, conditions, or partnership? Not on your life. Not in this ecosystem.

• Review of bad boss behavior.
• US policy in Afghanistan peddles fantasies.
• Happy Easter! 
• And more guns!
• Religion was the basic problem, not sex or race.

Transmission of SARS-CoV2

Reflections on viral spread.

This is a brief update based on studies of SARS-CoV2 transmission over the course of the pandemic. They mostly nail down features that we already know, and offer a comparison with influenza, which has interesting differences in its transmission. One observation is that influenza has been eradicated to an astonishing degree by our efforts to prevent SARS-CoV2 transmission, a testament not only to the lower transmissibility of influenza, but also to the regular round of death and illness that we have been putting up with for millennia without much complaint.

After all the hand-wringing about hand-washing, we gradually learned that this new virus is almost exclusively passed by aerosols through the air, with limited range in space and time. Also that, despite the infinitesimal size of the virus, that face masks of many kinds are effective in knocking down both emission and reception of viral innocula by several-fold. This is doubtless because both the viruses with their lipid coats, and the moist aerosols they reside in, are quite sticky, prone to capture by even rough cloth filters with channels many times the size of a viral particle. The notorious superspreader events are characterized by 

• indoors, close physical proximity to others
• limited air circulation
• an infected person, typically asymptomatic, engaging in
• vocal activity, like singing or loud talking
• with no mask

Scale drawing of surgical mask fibers, against viral and aerosol particle sizes.

Meditation is not conducive to transmission, nor do most infected people transmit their infection. Superspreaders seem to have a very high viral load in key areas of their vocal or respiratory tracts that leads to abundant aerosol emissions with high viral counts. For recipients, it takes numerous viruses to establish an infection- something like 300 for influenza, and something similar for SARS-CoV2. This is a live virus count, not counting inactive viruses, which are always part of the produced and transmitted population of particles. The reason is probably due to our various innate clearance mechanisms, both physical and molecular, meaning that only one virus may get through to successfully infect someone, out of a population of thousands that that person breathed in. 

SARS-CoV2 transmission vs influenza. SARS-CoV2 seems to survive longer in air, leading to more infections in enclosed spaces. Being outdoors subjects the aerosols to getting blown away, and to purifying UV light. This graph does not show it, but SARS-CoV2 also differs in having high viral loads prior to symptom onset, or sometimes without any symptoms, making isolation and contact tracing very difficult.

Additionally, infection by one or few viruses may present a speed problem, where they can not grow an infection fast enough relative to the ability of the immune system to respond and put out small fires. Only if the inoculum immediately generates a large conflagration (think Molotov cocktail) is the fire department overwhelmed, at least for a few days. This leads in turn to the fascinating prospect of mass inoculation with small doses of the virus. Understandably, this is not a popular idea, with its similarity to playing roulette. It resembles the old-fashioned method of small pox inoculation, which used to be done with small doses of actual small pox, not cow pox as was later introduced by Jenner. 

But it may be a significant explanation behind the enormous conundrum of the low impact of Covid-19 on tropical and low-income countries. These countries (India, Central America, Nigeria) show quite high seropositive rates, indicating wide-spread infection. But their death rates and hospitalization rates are very low, and they have escaped this pandemic with relative ease. While reporting issues and pre-existing immune exposure are possible explanations, so is a possible warmer outdoor culture with lower innocula and lower-severity infections. An interesting aspect of inoculum size is that it can have far-reaching consequences, with lower-level infections leading to smaller viral counts in the aerosols emitted, thereby causing smaller, less-severe infections in the next recipients.

The study of viral transmission and infectivity could have profound effects on how we deal with this and similar diseases, and one has to say that it has been frustrating that our knowledge of it remains haphazard, and has been so slow in coming, with such mediocre experiments, false starts and poor messaging.

• Restaurants? Don't do it.
• Reclining on an airplane? Don't bet on it.
• Future nuclear power.

Prospects for Hydrogen

What are the prospects for hydrogen as part of a sustainable, green economy?

Hydrogen is perennially spoken of as a fuel of the future- clean, renewable, light. It is particularly appealing in an environment (like that of California) where solar energy is having a huge impact on the grid and causing rising portions of solar production to be "curtailed". That is, turned off. But even in California, solar power has hardly scratched the surface. Only few roofs have solar and the potential for more power production is prodigious. Over time, as more renewable sources of energy come on line, the availability of excess power at peak times will rise dramatically, prompting a huge need for storage, or other ancillary uses for excess power. Many storage schemes exist or are under development, from traditional water pumping to batteries, flywheels, gravitational weights, etc. Hydrogen is one of them, spoken of as a versatile storage and fuel medium, which can be burned, or even more efficiently put through fuel cells, to return electrical power.

A typical day on California's electrical grid. The top teal line is total demand, and the purple zone is power not supplied by renewables like wind, hydropower, and solar. During the mid-day, most power now comes from solar, an amazing accomplishment. Roughly 2 GW are even turned off at the highest peak time, due to oversupply, either locally or regionally. How could that energy be put to use?

Unfortunately, as a fuel, hydrogen leaves much to be desired. We have flirted with hydrogen-powered cars over the last couple of decades, and they have been a disaster. Hydrogen is such an awkward fuel to store that battery-powered electric vehicles have completely taken over the green vehicle market, despite their slowness in refueling. The difficulties begin with hydrogen's ultra-low density. The Sun has the gravitational wherewithal to compress hydrogen to useful proportions, at the equivalent of 100,000 earth atmospheres and up. But we on Earth do not, and struggle with getting hydrogen in small enough packages to be useful for applications such as transport. The prospect of Hinden-cars is also unappealing. Lastly, hydrogen is corrosive, working its way into metals and weakening them. Transforming our natural gas system to use green hydrogen would require replacing it, essentially.

The awkwardness, yet usefulness, of (reduced) hydrogen as an energy currency in an oxygenated atmosphere is incidentally what led life during its early evolution to devise more compact storage forms, i.e. hydro-carbons like fats, starches and sugars. And these are what we dug up again from the earth to fuel our industrial, technological, and population revolutions.

But how useful is hydrogen for strictly in-place storage applications, like load balancing and temporary grid storage? Unfortunately, the news there is not good either. Physical storage remains an enormous problem, so unless you have a handy sealed underground cavern, storage at large scales is impractical. Second, the round-trip efficiency of making hydrogen from water by electrolysis and then getting electricity back by fuel cell (both rather expensive technologies) is roughly 35 to 40%. This compares unfavorably to the ~95% efficiency of electrical batteries like Li ion, and the 80% efficiency of pumped water/gravity systems. Hydrogen here is simply not a leading option.

Does that mean we are out of luck? Not quite. It turns out that there already is a hydrogen economy, as feedstock for key chemical processes, especially ammonia and fertilizer production, and fossil fuel cracking, among much else. Global demand is 80 million tons per year, which in electrical terms is 3-4 tera watt hours. That is a lot of energy, on the order of total demand on the US electric grid, and could easily keep excess power generator's hands full for the foreseeable future. Virtually all current hydrogen is made from natural gas or coal, so the green implications of reforming this sector are obvious. It already has storage and pipeline systems in place, though not necessarily at locations where green energy is available. So that seems to be the true future of hydrogen, not as a practical fuel for the economy in general, but as a central green commodity for a more sustainable chemical industry.

• Unions
• Afghanistan, inexorably going back to the Taliban.

The Autism of Politics

Our politics is an inarticulate communal search for expression of emotion.

I recently saw "A Brilliant Young Mind", a British take on growing up with autism. It is one of the most beautiful movies I have ever seen, exploring themes of family, loss, and love with wrenching sensitivity. The challenge of expressing, even feeling, one's own emotions is at the heart, naturally enough, for people on the spectrum. There is a fight by family members to crack that shell, to establish communication that expresses the love they know is there, and which will build warmth and confidence.

One theme is the power of speech- the bullying in school, the words of love from a parent. We may have recited the saying about sticks and stones, but it isn't true. Humans feel and use speech as touch, like Chimpanzees use grooming, to soothe each other. Music functions similarly, to touch others with shared emotions, strengthening essential bonds of trust and empathy. We also use speech also to attack each other, and climb the social hierarchy on the bodies of those cut down by words. 

Well, politics is a natural extension. We feel strongly that there should be someone in charge of each political unit- one person who embodies and expresses our feelings about the whole. It is not just a job, or an executive position, but a strongly archetypal role, which includes the work of binding us together through speech, or not, as our collective mood dictates. We have just been through an administration dedicated to the destructive power of speech, firing off tweets to cut down friends and enemies, formulating cryptic messages supporting inequality, tribalism, and racism. 

But political speech is hobbled by the vast population it addresses. The movie above spoke to me, perhaps because I felt familiar with many of its themes and dilemmas, or happened to appreciate its artistic approach. But it may not speak to you. Politics is about finding the largest possible audience, using the vaguest possible formulations to which listeners can impute their feelings about the body politic. It is thus necessarily painfully awkward, smothered in platitudes, and minimally communicative. In short, a little autistic. 

A still from the movie, with the main character and his mother in a typical pose.

So we as citizens are all in the position of wanting the collective to satisfy a some very deep needs for connection, security, and self-realization and expression. But we are reading a cryptic body politic and leadership for clues of true intention, hidden beneath what may be a voluble exterior of near-meaningless speech, and at the same time confounded by a lack of transparency and radical lack of personal access to those people who are the leaders. Conversely, those leaders are sequestered in their security and network bubbles, wanting (ideally) to understand and share the feelings of their constituents, but unable, simply by the scale of the enterprise, to do so. And anyhow, seeking the average feeling or attitude in a democracy ends inevitably in a muddled middle. Thus leaders are confined to rhetoric that in recent inaugurations, state of the union addresses, and so forth has been bland and weak, as uninspired as it is uninspiring. 

Our political / psychological needs seem to differ along temperamental / party lines, with Democrats forever searching for the healing leader who can reach out across the divide to bring a larger coalition together to accomplish empathetic ends, for the downtrodden, for the environment, and for the future. On the other hand, Republicans seem, since at least the time of Goldwater, to be unhopeful about change, and the future in general, indeed motivated by fear. Their quest is for a leader who will advocate for the hard truths of the inherent and useful infairnesses of life to restore the social hierarchical order, keep out aliens, and keep down the restive and poorly paid masses. The last administration was unusually forthright about the whole program, thus speaking into an intense rapport with its "base", while foresaking the traditional mincing "compassionate conservative" or "city on a hill" gestures that have in the past served to sugar-coat that message.

But speaking to the base turned out to be a disastrous political strategy, losing the House, Senate, and Presidency in turn. However powerful in expressing, even generating, rare emotional responses in that base, it failed to follow the most basic principle of political math. So we are back now to the anodyne stylings of a new Democratic administration, back to a normal relationship, which is to say not much of a relationship, between the leader and the led. Which is a great relief on the national level, even if it would be maddening and unsatisfying on any personal level.

• Are you on the spectrum?
• That music in our heads.
• The true nature of conservative jurisprudence.
• Myths, magic, and gods- right or wrong?
• Hamsterkauf?
• Bill Mitchell on inflation and other historical matters.
• Some delightful piano.

There Are no Natural Rights

Rights are always a political construct, which we devise and grant each other.

American politics is drenched with "rights". The Bill of Rights, natural rights, god-given rights, human rights. Both right and left use "rights" language to claim victimization and seek restitution. But the history goes back much farther, to the Magna Carta and beyond, into the heart of being a social species. Sociality means compromise, giving up some powers in return for other things, some of which are called rights. Good civilized behavior and diligent work entitles us to membership in the group, and benefits such as collective defense and shared resources. Since there can be long time lags between service and repayment, even extending over a lifetime or even multiple generations, a way is needed to keep track of such obligations. One way is to proclaim rights, such as a right to communal fields and pastures for members of the group, in perpetuity.

Thus rights are generally keenly felt as obligations and matters of long-standing, even eternal, usage. But all are social agreements, as our proclivity to murder and execute each other makes clear. If one does not even have an inalienable right to life, what are the others worth? They are neither natural nor god-given, but entirely human-given. They are rhetorical constructs meant to structure our communal relations, hopefully for good of all and the durable continuance of the system, but sometimes, not so much. Indeed, rights can be brutally oppressive, such as those of Brahmins in the Indian caste system, among many others.

Gun nuts frequently make a fetish of their rights- to guns, self defense, and in various convoluted ways to religious rights and duties. When rights have been written into the law, such as our constitution, that moves them into another rhetorical level- the legal system. But that just expresses and codifies agreements that exist elsewhere in the social system, and which the social system can, through its evolution, change. Gay rights have been an outstanding example, of the destruction of one rights system- that of normative sexuality and marriage rights- and the rise of a new set of rights oriented to personal freedom in the expression and practice of sexuality. Where in ancient times, fecundity was of paramount importance, that need has naturally fallen away as a societal imperative as our societies and planet creak under loads of overpopulation.

This mutability and social basis of rights leads to a lot of one-upmanship in rights discourse, like the attempts to found abortion rights in presumptively more universal or fundamental rights like privacy, autonomy, or women's rights, versus competing formulations of rights to fetal life with related arguments about the legal and life-like status of embryos and fetuses. All this speaks to the fact that rights are not discovered on tablets handed down by either god or Darwin, but are continually developed out of our feelings about our communities- what is fair based on what is required from each of us to live in them, and what they can reasonably demand and give in return.

• Let's hear it for the neurodivergent.
• Cattle are unsustainable.
• Good riddance.

Squeezing Those Electrons For All They've Got

How respiratory complex I harnesses electron transfer from NADH to quinone to power the mitochondrial battery.

Energy- we can't live without it, we can't make it ourselves, and we use all sorts of complex technologies to harvest and store it. Solar power is reaching a crisis as we realize that it isn't going to work without storage. Life faced similar crises billions of years ago, and came up with core solutions that we know now as the chemical transformations of photosynthesis and metabolism. Plants make storage compounds from sunlight, which we in turn eat for energy, transforming them into a series of currencies from short- to long-lived, such as NADH, protons, ATP, glucose, and finally, fat.

Within us, the mitochondrion is the engine, not making energy, but burning it from the food we eat. The core citric acid cycle disassembles the reduced carbon compounds that serve as our food and longer-term storage compounds into oxidized CO2 and energy carriers NADH, FADH. While used widely in the cell for specialized needs, these compounds are not our core energy stores, and are generally sent to the electron transport chain for transmutation into a proton gradient that serves as the battery of the mitochondrion, which is in turn used to synthesize our general energy currency, ATP. ATP is used all over the cell for general needs, including the synthesis of glucose, glycogen, and fat as needed for longer term storage.

The discovery of the proton battery was one of the signal achievements of 20th century biochemistry, explaining how mitochondria, and bacteria generally, (from which they evolved), handle the energy harvested via the electron transport chain from food oxidation in an organized and efficient way, without any direct coupling to the ATP synthesis machinery. The electron transport chain is a series of protein complexes embedded in the innermost mitochondrial membrane that receive high-energy electrons from NADH / FADH made in the matrix through the citric acid cycle and use them to pump protons outwards. Then the ATP synthetase enzyme, which is another highly specialized and interesting story, uses the energy of those protons, flowing back in through its rotary structure, to synthesize ATP. The proton gradient is short-lived, a bit like our lithium batteries, continually needing to be recharged- a key form of storage, but just one part of a larger energy transformation system.

A recent pair of papers from the same lab, capitalizing on the new technologies of atomic structure determination, describe in new detail the structure of respiratory complex I, which is a huge complex of 45 proteins that receives NADH, conducts its two electrons to ubiquinone, and uses that energy to pump out four protons from the mitochondrial matrix. Not all questions are answered in these papers, but it is a fascinating look into the maw of this engine. Ubiquinone (often abbreviated as Q) is then later taken up by another respiratory complex that squeezes out a few more protons, while transferring the electrons to cytochrome C, which goes to yet another respiratory complex that squeezes out a final few protons.  Like in our macroscopic world, a lot of complicated machinery is needed to keep a power system humming. 

The complex hinges literally on the Q binding site, which is at the elbow between the intracellular portion that binds NADH, and the series of proteins that all sit in the membrane. When Q binds, the bend is larger, (called the closed form), and when it leaves, the bend is smaller (called the open form). The electron path through the paddle is reasonably well understood, going through several iron-sulfur and flavin mononucleotide complexes that have special overlapping quantum tuning to allow extremely efficient electron transport. The key to the whole system is how the transfer of electrons from NADH through the paddle domain down to Q, which protonates it to QH2 and makes it leave to travel through the membrane to its other destinations, is coupled with a long-range physical and electrostatic shift through the rest of the complex to run the proton pump cycle. 

Structure of complex I, emphasizing the electron path in the paddle (upper right) and the many possible proton conduction paths in the membrane-resident part of the complex (bottom). The Q binding site is shown in brown at the elbow. Each protein subunit is named and given a distinct color. A conductive "wire" through the middle of the membrane components is isolated from the solvent, but connected to each membrane side with dynamically gated pathways. Whether these gates have more of a physical character or an electrostatic character, or both, remains uncertain.

The membrane domain, made up of several similar proteins all side-by-side, seems to have a sort of wire running through the middle, made up of charged amino acid side chains and water molecules, capable of conducting protons parallel to the membrane. It also has specific proton conduction paths within each subunit that provide the possible entry and exit paths for protons getting pumped from the interior outwards. The authors propose that there is a sort of hokey-pokey going on, where one bent form (the open form, with Q ejected) of the machine exposes the matrix-side proton channels, while the other bent form (closed form, with Q present) closes those channels and opens a corresponding set of four channels on the other side that let those same protons out to the cell. The internal wire, they propose, may possibly redistribute the protons to buffer the input channels. Or it might even allow all four to exit on the last, fourth pump complex. In any case, this in essence is the core of biological pump designs, opening channels in one direction to capture protons from one side, (by diffusion), and then executing a switch that closes those and opens ports to the other side, again using diffusion to let them go, but in a new direction. It is the physical cycle that translates energy into chemical directionality, aka pumping.

Proposed mechanism, with the insertion or ejection of Ubiquinone Q dictating the  proton channel accessibility along the membrane proton pump subunits of complex I. Protons enter from the mitochondrial matrix in the blue structures (closed), and exit via the other side in the green structures (open).

Closeup of one of the membrane proton pump segments, showing the dynamic formation of one proton conduction channel in the "open" state (left) vs the closed state (right, circled). The somewhat dramatic turning of the center protein helix carrying residues M64 and F68 opens the way

• Astronomical de-twinkling.
• New SARS-CoV-2 spike variant is twice as good at getting into human cells.
• What the future of Covid looks like: decreasingly lethal, and more cold-like.
• A political poem.
• Rough breakdown of residential CO2 emission sources.
• Table of the week.. Are we as free as China? Are we great yet? A comparison of the US and China in key Covid measures, taken Feb 9.

Rank	Country	Total Cases	New Cases	Total Deaths	New Deaths	Total Recovered	Active Cases	Serious, Critical	Tot Cases/1M	Deaths/1M
1	USA	27,798,163	+93,759	479,726	+3,219	17,631,858	9,686,579	21,446	83,682	1,444
83	China	89,720	+14	4,636	0	84,027	1,057	18	62	3

Competition

Balancing collaboration and competition for a healthy society.

The ongoing discussions about race and caste in America are plumbing the depths of who we want to be as a society, and of the human psychology of hierarchy and competition. As Darwin taught, competition is inherent to life. Winners don't just feel good, they live to fight another day and reproduce another generation. Competition is naturally at the core of human psychology and development as well. We only learn to know our selves against a backdrop of challenges overcome, and people to compare ourselves with. We celebrate the winners in art, music, politics, sports, business. Excellence only exists in comparison.

America was conceived from the first as a winners versus losers project. White Europeans, already sailing all parts of the known world in search of treasure and plunder in competition with each other and the other great Asian cultures, found a virgin land. At least virgin in that it hardly offered any competition, with peoples who were summarily exterminated or enslaved. That this domination was transferred to Africa as a convenient source of losers to be utterly dominated, and ultimately branded as an inferior caste in perpetuity, is at once spiritually shameful and also a natural consequence of the competive drive that inheres in all people.

Idealists then came up with a competing dream of socialism and communism, which was to be a sweeping antidote to all these racial, economic, and social injustices. But competition inexorably reared its ugly head, moving the field of play from its traditional moorings to the political and existential levels, even to the very nature of reality and truth, as seen in the Stalinist systems, and the numerous appalling dictatorial systems that copied it. There was no getting around the need to prove that some are more equal than others.

However we run our formal systems of government and economics, we live in countless competitive settings- socially, economically, sexually, in families and outside. No one loves unconditionally, or serves without reward. So the genius of civilization has been to tame and channel competitive structures and impulses to positive ends. Fairly rewarding work, or setting a standard of one sexual partner in marriage, are examples of rough attempts to forge stable, just, and positive social outcomes out of competitive instincts that if given freer license would destroy us. 

Slavery was a system that, while mostly stable and marginally productive, was also profoundly unjust. One tribe simply declared itself dominant, and used every insidious tool of indoctrination, oppression, and violence to maintain that position. Over time, the original source of the competitive superiority, (whether that was just or not), became irrelevant, and the disparity became as unearned by the oppressors as it was undeserved by the oppressed. It served in no way to expose the natural talents of either in a fair environment of self-expression and actualization through competitive effort. 

So over the history of our country, we have fitfully been waking up to this injustice and expression of erstwhile competitive success, and fighting over how to forge a new social contract. That is perhaps the main reason our political system is so bitterly divided right now. "Freedom" rings from the mouths of both sides. But for one it is typically the freedom to continue enforcing their inherited inequities and privileges. For the other, it is the quest to escape exactly those inequities, which have reified, (as they have similarly in India's caste system, over centuries), into a vast network of debilities, social dysfunctions, ingrained or instinctive attitudes, artistic modes and motifs, economic and geographic patterns.

The new social contract is obviously modeled on modern meritocracy, where all are educated as far as possible, all participate freely in the many markets that pervade our lives, from mating to consuming to job-finding and politics, and all benefit in proportion to their contributions as regulated by those markets. Historical inequities would have little influence in this world, while individual talent and character count for all. This assumes that such a meritocracy is a fair ideal, which many dispute, as the fate of the losers remains uncertain, and in our current version, unbelievably harsh.

But there is no ridding ourselves of competition, however blessed we are with countervailing instincts of empathy and cooperation. It is a rock of human nature, and of our personal development. The best we can do is to regulate it to be fair and moderate. That is, expressing the competitive success of the individual, not her forebears or tribe. And allowing enough benefits to winning to provide motivation towards excellence and success, without destroying the portion of society that necessarily will be losers in various markets. This is the perennial conflict (and competition) between right and left, Republican vs Democrat.

• What happens when the poor are concentrated on one place- East Lake Meadows.
• How long Taiwan?
• Fond memories of the Trumpers.
• What will become of our empire?
• Ten days of quarantine is plenty. Even eight would be OK.
• FOX- another reason to cut the cable cord.

On the Transition to Godhood

Kicking and screaming, humanity is being dragged into a god-like state.

We thought that harnessing electricity would make us gods. Or perhaps the steam engine, or the first rocket ship, or the atomic bomb. But each of those powerful technological leaps left us wanting- wanting more, and wanting to clean up the messes each one left behind. Next are biotechnology, gene editing, and robotics. What to do?

The fact is that we have powers that traditionally were only given to gods. Vast raw physical powers, the ability to fly, and the ability to communicate with anyone, anywhere, instantly, and to know practically anything at a touch. But the greatest of all is our power to derange the entire biosphere- destroying habitats, exterminating species, filling our geologic layer with plastic and radioactive debris, and changing the composition and physics of the atmosphere. 

We have not come to terms with all this power. Indeed half of our political system can't stand the thought of it, and lives in the fantasy that nothing has changed, humanity is not trashing its home, and we can live as profligately as we wish, if only we don't look out the window. Even more disturbingly, this demographic generally holds to a fantasy god- some bearded male archetype- who will either make magically sure that everything comes out OK, or alternately will bring on the end times in flames of wrath and salvation for the select, making any rational worry for the environment we actually live in absurd.

Judgement day is coming!

This, at a moment when we need to grow into our awesome responsibilities, is naturally disheartening. Growing up out of an infantile mind set, where our parents made everything OK, is hard. Adulthood takes courage. It takes strength to let go of fantasy comforts. But the powers of adulthood are truly god-like, especially in this age. We make and remake our environments, look deep into space, into the past and the future, know and learn prodigiously. We make new people. 

Is is clear, however, that we are not taking these powers seriously enough. Overpopulation is one example. We simply can not go on having all the children we want, taking no responsibility for the load they are putting and will put on our home, the biosphere. As nascent gods, we need to survey our domain holistically and responsibly, looking to its future. And right now, that future is rather bleak, beset by irresponsible actors resistant to their higher calling.

• What to do about all the lies?
• Another view of god.
• Don't drive everywhere.
• General breakdown.
• How did South Korea do so well? Rigorous contact tracing and quarantine enforcement.
• Greed in shorts.
• Direct air capture of CO2.