Trees Look Serene, But Operate Under Very High Pressure

Xylem, phloem, turgor ... what the heck is going on in tall plants so they can drink from dizzying heights?

Atmospheric pressure is 76 cm of mercury, or 10.3 meters of water, or 0.1 MPa. That means that even a vacuum can't pull water up higher than 10 meters from the earth's surface. Yet Redwoods grow to 115 meters. How does that happen? There are two problems- where does the pulling force come from, and even with the requisite force, how can anything conduct water to far greater heights than a vacuum on bulk water would allow?

The answer to the second issue is capillary action. Plants have a circulatory system somewhat analogous to ours, with two parts going in opposite directions connected by tiny selective membranes. But there is no heart- no pump. Fluid is moved around by high pressure differentials, driven by osmotic differentials, strong cellular architecture, and active molecular transport at the sub-microscopic level.

One part (phloem, maybe analogous to arteries) is for the sugars produced by the leaves, called sap. The second is xylem, (maybe analogous to veins), conducting water and minerals up from the roots. Xylem is a dead, porous tissue inside the cambium. Using tiny, hydrophilic vessels allows water tension to "hold it all together", while the negative pressure at the top of a plant pulls continuously upwards. How much pressure is needed at the top of a plant? Well, about 19 atmospheres of negative pressure for a hundred-meter tall tree, or ~2MPa. (Compared to this, our blood pressure is negligible, at 0.015 MPa.) The xylem is carefully constructed to prevent bubbles from forming, and from spreading if they do form, helping the natural cohesion of water (which causes the phenomena of capillary action and surface tension) to keep the water column intact under such intense pressures.

Xylem, full of small conducting pores, and carefully isolated within the plant to sustain high negative pressures. The pores  also stand ready to break the spread of air, if any is introduced.

Just as interesting, however, is the phloem system, which generates high positive pressures and is integral to the whole circulatory regime. Phloem is living tissue- just outside the cambium (in trees) and specialized to conduct sugar fluid to sites that need it, like fruits and roots, all over the plant. The xylem and phloem systems are selectively interconnected. The key "capillary" point in the leaves where xylem fluid is drawn towards the phloem fluid, due to the osmotic pressure from a low-solute (xylem) to a high solute (sugary phloem) fluid, forms the pressure differential that makes the whole system work, by what is called the Münch hypothesis.

It has taken decades to test this hypothesis, since it was proposed almost a century ago, for technical reasons- the second you cut into a plant to look at its phloem, the pressure drops in that region. A recent paper (review) used fluorescence tracers and microneedle probes as new methods to observe pressures and flow rates in living, whole plants- the morning glory vine.

Phloem, while largely empty space, has a complex internal surface, including walls (and companion cells) which contain the selective ionic barriers that keep sugars in while letting water and minerals from the xylem fluid enter, at least in locations like the leaves where that is useful. They also have open pores (sieve plate pores) between successive cells (called sieve tubes) that allow flow, but can quickly restrict it in case of injury. Sieve tubes even have their own type of plastid, whose function is entirely unknown.

Phloem sieve tube plates, aligned with a plant and locations from which they were sampled. The lower plates are more tilted to allow more flow. Their pores are also larger, though that is not so apparent here.

The morning glory vine was used for obvious reasons. It is highly accessible, easy to grow, grows to great heights, is easily manipulated, and has a thin stem that is easily dissected. In its stem, it has phloem both inside and outside of a xylem zone, which reinforces the idea that the xylem needs to be carefully protected from the atmosphere.

A stem section taken at four meters height. Phloem- dashed arrows, xylem- yellow and green arrows.

The researchers calculated the sap viscosity, its flow rate, and the phloem volume and cell structural characteristics, to come up with the pressures and other parameters required to achieve it. They also used micro-pressure guage needles and fluorescent dyes in the sap to attempt direct measurements on the phloem channels. Results where that the sap had a sugar concentration of 18%, and about 0.2MPa are needed per meter to drive sap flow. Over a seven meter plant, which was what they were studying at first, this amounts to about +1.4 MPa overall at the leaves, to drive fluid movement to the roots, which was indeed observed overall.

Next, they grew the plants to 17 meters high, removed the lower leaves to simplify the analysis, and measured again. The phloem pressure at the top was +2.2 MPa, which is high, but not enough by their prior analysis to get the fluid all the way to the roots. So they took a second look at the anatomy, and found that the plant had instituted structural changes to ease sap flow. The lower you are on the plant, the larger the pores between successive phloem cells, the larger and more tilted the pore plates themselves, and the higher the sap conductivity, up to six-fold. They conclude that the phloem system is pressure-driven, with the pressure carefully raised, along with other physiological parameters, to adapt to longer lengths of transport.

This leads to a unified picture of plant fluid transport, where very high pressures, both positive and negative, and clever anatomy, allow the transport of both key fluids- the water from the roots, and the precious photosythesized food from the leaves. Osmotic pressure is key at both ends, since not only does the high sugar content of the phloem sap drive root water towards it and supply its pressurization, but in the roots, a modest level of sugar and/or other concentrated ions drives water from the surrounding soils into the root, the pressure of which varies in different plants.

• Another evil lobby & product, in the grand tradition of guns, tobacco and oil: sugar.
• The banks are worse, not better.
• Indeed, our economy is ridden with bigger and more entrenched companies than ever.
• Why do we keep paying for this moral travesty?
• Equality- do we want it or not?
• Actually, the Fed should cut rates.
• Insurrection, treason, and terrorism has its partisans, and a loving US memorial.
• A race to the bottom, in Tennessee.
• A gene involved in the folding of hominid brains.
• When Obama pulled the veil of colorblindness. There was a black America and a white America, after all.
• A key tool to address inequality: the estate tax. Guess what the Trump position is?

The Desktop is Dead

Stick computers like the Chromebit are part of our future- tiny, portable, cheap.

As someone who consults frequently on personal computer issues, it was interesting to hear about a new form factor- the stick computer. The leading example is the Chromebit. Chrome books are better known- petite laptops that give you a Google Chrome browser that is a portal to the whole web, including a series of web apps and soon, android apps as well. The Chromecast product is also better known, as a tiny computer that lets you channel WiFi streams into your TV, using a phone as a remote controller.

The Chromebit is a bit of each, with a small size of the Chromecast, a bargain basement price of $85, and the computer capabilities of a Chrome computer. Like the Chromecast, it plugs into an HDMI port on any TV or monitor. But it turns that screen into a computer, given that web apps such as mail, docs, and storage now allow one to work entirely online, including cloud printing. Storage is negligible, so everything has to go to Google drive or some similar online service. Likewise, connectivity is minimal, with one USB 2.0 port- enough for connecting a camera in a pinch, or a keyboard or mouse, though these should be bluetooth. Naturally, you have to be online to do anything with this device.

Intel and Android also offer stick computers. At $150, the Intel stick is a fully stocked Windows 10 computer, though with only 32G of storage. Android sticks do not offer full computer capability, being restricted to apps, like a tablet, but these capabilities obviously run quite a gamut, from skype to web browsing, voice control, and millions of other programs.

For a person on a tight budget, these computers are an impressive way to get online with minimal expense, and one can use an existing TV to save even more. A full system would run something like...

$85 - computer
$15 - bluetooth mouse
$30 - bluetooth keyboard
$70 - cloud-compatible printer (optional)
$100- monitor with HDMI (or use existing TV)
=====
$300

This is impressive from a budget perspective, but it also indicates something about the future. One can imagine a world where our phones act as the computers behind everthing we do, which we can plug into dumb screens wherever we want, turing them into secure, full computers. Whether the applications also reside in the cloud as Google is working towards, reducing reliance on any local computing power, is uncertain. This depends only on slightly faster network connections than most of us have today to make fully animated clients driven almost entirely from distant sources. How much we can trust those corporate, centralized sources in an always-connected ecosystem to serve us faithfully is, naturally, another question.

---

Meanwhile, while we are on tech issues, to power all these bluetooth devices, rechargeable batteries are the sustainable and cost-effective solution. Charging such batteries can be tricky. It pays to use a smart charger that operates not just on a timer as most chargers do, but by sensing the status of the battery.

• Gerrymandering has brought us a crazy, unrepresentative House. There ought to be a law, right?
• Both retrograde forces in the Arab world have more power (and arms) than the progressives.
• Crime pays.
• It's not easy being the only super-power.
• Republicans fight in the gutter. Then they call others "crooked".
• A lesson in psychological projection.
• Bill Moyers and the Housewive's Rebellion.
• People with a modicum of compassion, vs Trump.
• What's going on in Puerto Rico?
• Over a 1 million-mile lifetime on the roads, you have a 1 in 90 risk of dying in a crash. That is not good enough.
• Annals of waste, pork, and fraud.
• Health care markets still don't work very well.
• Recidivism from Guantanamo.

Association, Attention, and Gamma Waves

Associative memory gets broken down by frequency band and location.

Do you have your own madelaine? A place, song, taste, or feel that transports you into the past? That is associative memory, retrieving a more complete set of experiences based on a relatively simple, (if uncannily specific) cue. It may seem effortless, but under the hood, a great deal is obviously going on. Memory is associated with the hippocampus structure deep within the brain. Missing that structure blocks formation of new memories or retrieval memories by association. (Though some older memories may still be available- it is not clear yet whether memories are stored exclusively in the hippocampus, or are only staged there for eventual transfer to other parts of the cortex for long-term storage.)

"Specifically, dense recurrent connections among CA3 pyramidal cells [in the hippocampus] are thought to allow, after a single exposure, for auto-associative reinstatement of a previous learning pattern upon receiving a retrieval cue. Consistent with a role for pattern completion, selective knock-out of the CA3 NMDA receptor was shown to result in impaired memory on a Morris water maze when only partial environmental cues were available, i.e. when performance presumably relied more strongly on successful pattern completion."

A recent paper makes use of direct recording in the brains of surgical patients to observe neural activity and rhythyms as they learn and recall events. Given enough analysis, one can "fingerprint" particular experiences, and see that they are represented similarly when they first occur, and again when they are remembered. The acuity of being able to put electrodes directly into the hippocampus is far higher than the non-invasive methods of fMRI.

The test was to present patients with words and pictures to make an association. Then later, the word alone was presented and the patient asked to remember the full scene. Or a control word with no association was presented. The latter was called item recognition, which involves others types of recall, while the former was called associative recognition.

Correlation between the first presentation and the recall event, in activity from the hippocampus electrodes. For associative recall, (vs item recall) the correlation is clearly higher and more complex. The AR surrogate data comes from the average of the original readings during the presentation of the AR stimulus/scenes, rather than their recall, as an additional control similar to the item recall.

It is clear that associative recall generates a richer experience and richer readings from the hippocampus. That is not news, really. What was interesting was that the researchers had access to far more activity detail and could especially look at the rhythmic effects of this recall.

A dramatic increase in gamma waves as recall happens. Concurrently, alpha waves decline.

That is basically it for this rather short paper. They make the key points that recall involves re-representation of the original stimulus, in some form that is detected by these electrode readings, though far from being understood or decoded by them. And secondly that this recall is accompanied, on this very local basis, by a big increase in gamma wave activity and a decrease in alpha wave activity. This all agrees with the developing paradigm, which is that alpha wave patterns correlate with default / resting brain activity, while gamma waves happen during attention and intense thought. Gamma waves are not carriers of information the way radio waves are, but seem to represent the coordination of select areas of the brain as they form ad-hoc coalitions to attend to some thing- the spotlight of attention, and of consciousness.

• Capitalism is going to the dogs.
• And ends up sabotaging our infrastructure and lives, if there's a profit.
• A philosophy and culture of non-accountability.
• Yes, a right-wing conspiracy. And love of innuendo.
• Trump puts it out there for all to see.
• But who is really paying attention?
• Certainly not his own party.
• Please, please don't pay us any taxes!
• Good thing she's not governor.
• Climate apathy is bad too.
• Sometimes, math is just a curtain to hide intuition and bias.
• Gazprom: corruption, bloat, and decline.

Living on the Spectrum

Of sexuality, and other existential dimensions.

It is common now to refer to people diagnosed with autism as being "on the spectrum". The disorder is unusual for the number of genes whose mutation can contribute to it, estimated at about 100 to 400. Thus it is easy to see why affected people turn up with a wide spectrum of phenotypes, and indeed why that spectrum extends well into the "normal" range- people who may be only slightly odd, but never formally diagnosed.

But we live on many other spectra of talent, capability, being. Indeed everything about us is variable. Height, color, sociability, musical ability, extraversion, intelligence are common examples. A recent story in the New Yorker profiled a London police unit of specialists who recognize faces. It turns out that people occupy a wide spectrum of facial recognition talent, from those who can not recognize themselves in a mirror, to those who never forget a face, no matter how briefly glimpsed. It is a capability that is so private and obscure that people typically do not realize what the normal range is and where they fall in its spectrum. So it is only with the burgeoning video surveillance carried out in Britain that high levels of this talent became belatedly recognized as relatively common as well as useful.

One of the most interesting spectra is that of gender. The Olympics reminded us (among many other forms of diversity) that diversity among humans extends to a spectrum of gender. Indeed, one's biological gender, and the gender one feels oneself to be, and the gender one is sexually attracted to, each seem to lie on spectra that, while usually correlated with the "normal" axes and occupying a bimodal distribution, can range spectacularly, and independently, to far reaches.

This is particularly interesting in light of the tight and binary social construction that has traditionally been put on gender. Why is that? Why enforce uniformity where there is variability? An interesting book about the philosophy of the Matrix series of films poses a similar question, in the context of Zion, which tries to be a gender-neutral society, as opposed to the Matrix, which is conventionally normed. Can we escape binary thinking? Should we?

I can think of three general hypotheses. First is pure patriarchy and power. The clear delineation of gender, as also happens in white/black racism with the one-drop rule, eliminates ambiguity when power is being divided up, with all power going to one group, and not the other. Oppression is much harder to institutionalize (and tribalize) without simple rules about who is in, and who is out. Setting the "normal" standard for each class is also a form of social power, as everyone in junior high school learns. When power and attractiveness are properties by definition of the "typical" and "normal", the social system maintains itself in a consistent, conservative way.

A second reason is simply our way of thinking. We are habitually reductionistic, thinking in cartoons and schematics. Cars are reduced to metaphorical "wheels", men and women are objectified mutually to their most basic aspects and organs. With a natural bimodal distribution of gender, it is natural to schematize them as two clear classes, declare those as "normal" and then be made uncomfortable by deviation from that simple mental model. Perhaps, conceptually, humans do not "do" diversity terribly well, since our understanding of the world depends so strongly on our capacity to make "sense", i.e. rules and schemata, out of the welter of reality.

Thirdly, one might turn to deeper psychology, seeing that our models for existence come from complex, unconscious archetypes. The mother/female and father/male archetypes are probably the most powerful we have. Whole religions have been founded on each, with the father especially blowing up to cosmic, infinite, and omnipotent proportions. Conversely, the Catholic church has a difficult time controlling the growth of the mother archetype in the person of the Madonna, which in some regions such as Mexico can even put Jesus in the shade.

So we have to fight on numerious psychological fronts to deal with reality in an honest way, especially to interact with the reality and psychology of others fairly.

• Almost a decade on, monetary policy makers start thinking about fiscal assistance for recovery.
• Not yet post-racial.
• Are we heading into a spiral of stagnation and inequality?
• Interdicting North Korea.
• Gene Wilder.
• Trumpism, for his peers.
• A sad day for Brazil.
• Our feudal system continues getting worse.
• Wimps- popular, but shy.
• A bad Mexican performance.

What Does it Mean to be Supernatural?

What was once a reasonable hypothesis has become an epistemological trash heap. And, if something "points beyond itself" does anyone know where it is pointing?

After having exhausted the possibilities of "discernment" as a theological buzzword, philosophical believers have moved on to a new expression, that anything real "points beyond itself" to whatever they think animates the world's workings beneath the surface. Which is to say, god. It is an empty expression, reflecting an indoctrinated mindset more than an analysis of anything outside the theological system.

This is not to say that there are not hidden realities that we have inferred with some, even great, warrant. We have a universe flooded with neutrinos which we can only barely detect. There is dark enery and dark matter that eludes any detection at all, but still is inferred to be there. And the origin of the universe itself is far from being explained.

Back in the day, before humanity discovered evolution, electricity, atoms, uniform force fields, and all the other apparatus by which so much of reality is now reasonably and mechanically explained, the sheer number of wonders in the world that required explanation was truly prodigious. Invoking magic, in the form of heroic or father-beings, was reasonable enough, though already faintly ridiculous. Some ancient philosophers may have dabbled in atomic theory and evolution-like ideas, but even they had hardly more going for their theories, in actual content, observation, and detail, than the mythicists did.

A trinity, with cherubim. A theory of reality, or something else entirely?

Now things are quite different, and it is significant to note that in the intervening time, none of the newly found mechanisms of reality have had anything to do with gods or other supernatural mechanisms. Plenty of odd things have been found, but none with any theological character. So the batting average of what was, a priori, an attractive hypothesis, is now zero, with a lot of scientific "discernment" under our belts. Yet theological theorists and believers press on with their trinities, spirits, and gods, invoking supernatural realms of which our puny science knows nothing.

A more modern trinity, participating in another archetypal savior story.

But what does it mean to be supernatural? Nothing positive, that's for sure. It is void of knowledge filled with whatever is unknown or imagined, yet for which reasonable, testable models of reality have no place. A place for the archetypal father-gods, the prayers that don't work, the grace and hope that saves one person in an airplane crash while killing all the others, the creator who nudges evolution to make one being in god's image- us. How obvious. Yet human psychology is so reliable and flawed, and the slick supernatural dreams of theology so well-honed over the millennia, that people skilled in the arts of pursuasion and confidence gain converts still at this very late date.

• De-institutionalizing security on an internet of value, and also, meanwhile, killing the banks.
• On the other hand, if we leave it to Amazon, music will die.
• Trump- hero or antihero?
• Health care still costs too much.
• Due to lack of competition, and lack of a public option.
• Class, capitalism, and pay-for-performance, cont.
• Fighting dirty, in energy.
• Accountability or secrecy? Secret settlements are wrong.
• Good news from the Philippines.
• Lack of competition makes productivity look worse.

Donuts and Zippers for DNA Repair

How the protein RAD52 conducts homologous search and rescue of damaged DNA. And what we can do with that knowledge.

Our bodies are full of wonders. Despite being about fifty years into the age of molecular biology, we are still only scratching the surface of the complexity that lies within. Remember that when you hear that someone has found a gene "for" a disease. That gene and the protein it encodes have a lengthy and intricate story to tell about what it does in the normal organism, how it got to that point in evolution, and maybe a multitude of ways in which mutations might drive it off track. Linking it to one disease is only a small part of a much larger tale.

BRCA2 is an example of this: a pre-eminent gene "for" breast cancer. But what does it do? The point of its existence is hardly to make us miserable. No, it participates in DNA repair, and thus some mutations in its sequence, or full deletions, can leave cells open to a cascade of further mutations, which can lead to cancer.

Recent work has shown that BRCA2 is synthetically lethal with a better understood protein called RAD52. Being synthetically lethal (in mice in this case, where genetics can be done) means that a mutation or deletion of either one of the genes is not lethal by itself, but the combination of both *is lethal. Such an observation implies that the two proteins participate in the same process, at least partially. One can "cover" for defects in the other one, in a pinch. But take away both, and the organism can not survive.

So BRCA2 and RAD52 do similar things, which is helpful to know, since RAD52 is actually better understood. Yeast cells, which are even easier to study than mice, have RAD52 but no BRCA2, which seems to have arisen more recently in evolution. We'll get back to BRCA2 briefly below, but I will focus on RAD52- a protein that conducts that amazing process that is homology-driven DNA repair.

Homologous DNA repair happens when a mutation is detected, such as a double-strand break, a missing nucleotide (and consequent single strand break), or even just where a mis-matching nucleotide was inserted by the DNA polymerase by mistake. Perhaps the sequence goes CAGCT on one strand, and GGTTG on the other, antiparallel strand. There is a G:T pair in here that is an error- not part of the official Watson-Crick regime!

A mismatch happens (orange).

What was the right sequence? The sequence of this duplex does not tell you, unfortunately, anymore. In some cases, there are chemical marks like methylation that can be used to tell the difference between the newly synthesized strand and the other one that has been around the block, and this is used in some forms of post-replication repair. But if the mutation slipped through that process, or happened at a different time, again we would not know where to turn for the right way to correct such an error.

But there is one place to turn ... another copy of that DNA, if the organism has one. Diploid organisms always have another copy of every gene lying around, and other organisms, even bacteria, do as well, if they have already replicated their DNA but not divided the cell, quite yet. This is called homologous DNA repair, because the other copy is called a homolog of the first. Organisms have developed ornate methods of homology detection, strand invasion, copying, and repair to use the information from a good version to repair a defective one. And one of the key actors is RAD52, or its colleague, BRCA2.

Structure of RAD52. The ring is composed of multiple subunits of the same protein, each colored differently here. DNA, in single stranded form, can wind around the outside.

RAD52 looks like a big donut. Well, in relation to DNA, at least. The DNA doesn't thread though the middle, as it does in some other important machinery, but rather winds around the outside, in single-stranded form. That way, RAD52 can expose the single stranded DNA to other donuts with their respective single stranded DNA, and figure out which ones match. It is evident that the energetics of DNA-DNA binding and DNA-RAD52 binding are engineered to be very similar, so that DNA engaged in mismatches does not get tangled up in unproductive knots, but prefers to wrap around these massive protein donuts. But then on the other hand, when a true DNA-DNA duplex match is found, it smoothly zippers up, out of the Rad52-wrapped state.

Model of the energetics of SS DNA binding to RAD52, with subtle transitions from SS and protein-bound, to double-stranded if a proper match is found (pink).

This is the mechanistic secret of homology search between DNA stands, at least in principle. How this happens at the scale of full super-coiled duplex genomes, in the crowded milieu of the cell, with the DNA studded with countless other proteins and complexes, plus a few chemical alterations, remains a bit hard to understand, however. And the rest of the repair story, of directing a large invasion of homologous DNA into the defective duplex, editing out the defective strand, re-duplicating the donor DNA, flushing the ends, and all the other odds and ends, are of course another story entirely.

In the current paper, the researchers looked for inhibitors of RAD52, intended for breast cancer treatment. On of the traditional treatments is to break the patient's DNA with toxic chemicals, because the cancer cells typically are missing the function of some DNA repair proteins like BRCA2, or BRCA1 which acts in the same pathway. Missing this repair function has generated the cancer in the first place by creating new mutations, but there can be too much of a good thing. That is, an excess of DNA damage causes cells- even cancer cells- to kill themselves or to die outright. So it would be helpful in this mode of therapy to be able to turn off what turns out to be, for humans, a backup DNA repair pathway- RAD52.

"RAD52 forms an oligomeric ring, where the primary ssDNA binding site is located in the narrow groove spanning the ring circumference. We designated this ssDNA-binding groove as the feature to be targeted by small molecule inhibitors. While disrupting the protein-ssDNA interaction with small molecules presents a formidable challenge that has only been overcome in a handful of cases, the ssDNA binding groove of RAD52 is a promising target and is distinct from the ssDNA binding sites of other ssDNA binding proteins."

The technique to screen for RAD52 inhibitors used fluorescence energy transfer. Donor and acceptor fluorophores were put on opposite ends of 30-nucleotide DNA strands. This happens to be exactly the length that fits around one RAD52 donut, so when the DNA binds to RAD52, the ends meet and the acceptor efficiently absorbs fluorescent photons from the donor, and re-emits at its own characteristic wavelength. Wow!

Compound found by screening for impaired fluorescence energy transfer between ends of DNA wrapped around RAD52 protein complexes.

Example of screening data, showing that binding of double-stranded DNA (gray) is unaffected by the compound "1", while the binding of single-stranded DNA is strongly impaired, at very low concentrations. The assay (Y axis) is fluorescence by the red fluorophore, which is excited by the green fluorophore only when the green fluorophore is nearby and also excited by the researchers shining appropriate (green) wavelength light onto the experiment.

After screening a bunch of chemicals, they came up with one that really works well, at low concentration. It clearly inhibits single strand DNA winding around RAD52. It also, in other work, interacts directly with RAD52, indicating that, as it looks quite a bit like a couple of DNA bases, it probably just binds better than DNA itself. By computational modelling they find that this compound binds into the single-stand DNA binding groove of RAD52, very snugly positioned in a way that is tightly bound and will keep anything else at bay.

 Model, using the known structure of both RAD52 and compound "1", of how they fit together. The chemical fits tightly in a groove that would otherwise bind single stranded DNA.

Finally, they ask whether this candidate drug works in cells. In tissue culture cells, the very low concentration of 500nM makes the cells behave as though they had no RAD52 at all, which is very promising indeed. Indeed, it kills cells lacking BRCA2, if treated with a chemotherapy regime, validating the idea of the work. How all this will work in whole animals and in humans is, of course another story entirely, in a long road to drug development. But this is an example of beautiful work with its origins in studies in model organisms (yeast) and structures in basic molecular biology.

"We also show that [compound] ‘1’ selectively kills cells depleted of BRCA2, further supporting the importance of the RAD52-ssDNA interaction in BRCA deficient cells and the potential therapeutic value of RAD52 inhibition."

• It is OK to be just OK?
• Religion as fully imaginary... and for some, that is OK. "Secret knowledge that everyone else was too blind to see" "God is the ultimate transitional object".
• The decades of lies and meanness that led to this.
• Who are you gonna believe?
• Of ~400 districts in Afghanistan, the Taliban controls 40 and is actively fighting to control 44 more.
• Costa Rica- a beautiful, just, peaceful, and low-carbon country... "Traffic is offensive."
• Is there a problem with the sources of Islam, and our understanding of its history?
• Our friends the Saudis, cont... balkanizing the Balkans.
• Krugman detects evil and greed on the GOP side.
• In return, one of the steps of grief ... denial and lashing out.
• Is America breaking bad?
• Obama leaves a great deal undone.

I Like Looking at Westerns, Not Being In One

Where are the gun nuts taking us?

I admit it.. I love Westerns. The classics channels have my number. When you carry the law on your hip, drama is liable to break out at any moment. For a family show, Bonanza sure stacked 'em up. For dramatic purposes and moral edification, the Western is one of the finest genres, right up there with medieval-ish science fiction-ish power-drama. If our love of drama (like our experience of dreams, in part) is about social play and modelling, focused on training to face tough choices that come up rarely in real life, but have extraordinary consequences when they do, the payoff from Westerns is obvious.

But watching is one thing. Being in the middle of it is something else. The point of our communal "real" life, politics, law, etc., as opposed to our dramatic alter-lives, is to make horrible choices, compelling a they are dramatically, as rare as possible, not more common. I get it that you as a gun-toting open-carry-ist are the last hero standing between my precious bodily fluids and that cold-blooded robber. Or worse yet, a Hillar-ized jack-booted federal agent. But the reality is quite different.

The reality is that guns make us less safe, not more. The police are going into conniptions about facing an ever increasing tide of guns. They don't want the "help" from all those open-carry-ists. The Republican convention is a no-gun zone. Why? Not because crime won't happen. It is because guns are dangerous to everyone around them, even to the very well-trained. Western towns set up gun controls as soon as they could- as soon as the law became stronger than the outlaws. Why? Because guns are unsafe, and if everyone has one, someone with less training and dedication to the constitution than the dedicated, well-trained, and articulate gun nut is going to come stumbling out of a saloon and shoot up the town for whatever purpose, or none. Look at Afghanistan, a country awash with guns, and a sort of contemporary wild west. Is that a safer place to live? A better place to live?

Unfortunately, addressing the fantasy life of gun nuts is easier said than done. Apparently statistics and reason doesn't make you stop wanting to buy, clean, stroke, and carry your gun around. And this fantasy extends to insurrection and terrorism. A blog I follow regularly issues threats, both veiled and explicit, against the "gun-grabbers". Unique among grievances in our country, the gun nuts think the very power they are guarding so zealously is the means of its and their defense, leading naturally to revolutionary rhetoric- the kind of thing that would be unconscionable in any other community or venue:

"Yea, Hopkins just went from being a stooge to being an enemy.  Understand, Hopkins, that universal background checks will bring out the guns, and not in a good way, if you know what I mean.  That is a line that cannot be crossed by anyone.  It won’t happen, and your willing adultery with the Bloomberg position is most disappointing."

"Finally, it gives me amusement and pleasure to point out the obvious.  You can never effect this outcome because we have the guns.  Understand?  You can’t take them from us because you eschew them and we don’t.  What?  You didn’t really think we’d give them up, did you?  And you didn’t really think those cops would want to be gunned down as they try to confiscate weapons, did you?"

"God grants me the right (and even duty) to go armed and conduct myself in a manner consistent with self defense.  Not you, and not the constitution, and not black robed tyrants.  That means that whatever the outcome of this “day in court” to which you refer, the right to self defense is still present because God said so."

"But it’s not over with.  Know who your local police are.  Make sure to let them know in no uncertain terms, without them knowing who you are, that it is all just beginning.  Make your points in the shadows, not in the light of day.  Make it clear to them that you will not tolerate infringements on your God-given rights. ... Make your points until the police no longer want to wage war on otherwise peaceable citizens.  Make your points in the shadows. That’s how this should go down.  Do you understand?"

And this is not to mention Donald Trump's recent casual incitement of the assassination of his opponent.

So we are faced with a heady macho-psycho-Freudian-theological brew of perceived potency, with strong ties to American history and heritage, but also to much more deeply seated emotional issues.  Other countries have been able to lower the temperature around guns. Why not us?

• Guns cause murder.
• Trump and the mob.
• Protectionism the way the pros do it.
• Software development, time, and scrum.
• Marxist take on Chavismo: not socialist enough!
• Life: we are killing it.
• On the triumph of Bayes, of induction and of guessing generally.
• IBM fail.
• Leotard watch.
• Essential curriculum: empathy.
• The Afghan hinterlands count too.
• Yet another market failure.
• Is Italy next-it?
• Human memory is very bad.

No, I do Not Really Feel Your Pain

Where is pain in the brain, and is empathic pain in the same domain?

Our culture has gone through some interesting evolutions in the experience of pain. From antiquity through medieval times, inflicting pain was entertainment and justice, in forms such as gladiatorial fighting, bull-fighting, burning at the stake, trial by torture, and plain old torture. In modern times we seem to have softened to the point of respecting human rights, one of which is to not inflict gratuitous pain, even on deserving criminals. Perhaps this is due to the subjugation of pain in medical and dental settings, which has raised our expectations for an untroubled existence. Or perhaps it is due to dominance of secularism which continues to guide moral innovation and refuses to countenance twisted theistic rationalizations for our painful existence, let alone explicit theological torture. With the current election, we seem to be taking a step backward in the excruciating-ness department, but still one may hope for the best!

Despite such variation in cultural tolerance of pain, (especially that of others), our intrinsic capacities are naturally long-standing and common to most animals. In particular, pain is perhaps the most immediate and insistant instance of consciousness, and thus a particularly interesting case for investigating the nature of consciousness and its presumptive basis in the brain. One thing we have learned is that pain comes in many forms, from vague itches to excruciating burns. And in addition, we experience various abstract pains, such as bereavement, the sudden horror of devastating news, and the empathy we feel for the pain of others- at least some people, in some cutural settings(!)

So it is not a simple field. A recent paper made some new observations about empathic pain. Prior work has shown substantial overlap of self-pain and empathic pain as represented in the brain, leading to theories that it is involuntary and almost as vivid as one's own. But we know that that is not quite true- that spectators at the colosseum could, though social training and construction, view the torture and dismemberment of unfortunate gladiators with enthusiastic bloodlust rather than squeamish sympathy.

So where is it, and how do we feel pain of both types? These authors discuss various defects with the current model, particularly that brain locations that have been noted as activated during both own-pain and empathic pain are not really pain centers per se, but are activated by many non-pain events, to the point of being some of the most frequently activated areas in the brain across all fMRI studies.

"Only a small minority of dACC neurons are pain-related, and the dACC encodes emotional events, including rejection and general negative emotion, in a way that is distinct from how it encodes pain."

Indeed, the best anatomical correlate of pain perception in the brain is not found at a single anatomical location, but in a network (the Neurologic Pain Signature or NPS) that is something of an abstract, deduced entity, built up out of statistical measures of where the hurt shows up, specifically and reliably, in fMRI. The authors try to refine these anatomical claims with their own fMRI studies.

"The NPS has over 90% sensitivity and specificity in predicting somatic pain relative to several other salient states, including non-painful warmth, anticipated pain, pain recall, social rejection, and general negative emotion."

Active sites from actual, somatic heat-induced pain on the subject's arms or legs.

Their hapless subjects where seared on their forearms or feet with about 10 seconds of high temperature (46, 47, pr 48˚C, which is 115, 117, 118˚F). This doesn't sound too bad, really, perhaps just noticeable. The vicarious / empathic pain was more interesting: being shown pictures of a person putting a shovel through their foot, or cutting a finger with a knife, and asked to imagine this happenening to themselves. Trained actors were used, I assume. What they showed certainly causes a chill to go down your spine, but it does not share specific aspects with the experienced pain. The vicarious pain was not heat- better to show someone taking a blowtorch to their extremeties. Interestingly, however, the researchers claim to be able to differentiate between pain vicariously induced at the arm vs the leg. Even by this very indirect means, there are site/anatomy-specific signatures evident in the brain signals.

For exprienced pain, they validated the NPS network, seeing it reliably show up in their scans. But the vicarious / empathic pain was a different story. In fact, they found that the NPS areas were negatively correlated with empathic pain, and devised a newly calculated network to describe what was activated, which they call the vicarious pain signature, or VPS. Helpfully, however, they compared their VPS pattern with those prompted by negative affect pictures, and by romantic/social rejection and found no correlation. So evidently, fMRI is getting good enough to distinguish between several negative emotions.

Active sites from vicarious pain, i.e. from pictures of other people doing painful things to themselves. Note the quite different patterns of activation vs above.

Global correlations between experimental fMRI patterns and the modeled networks of the NPS or VPS. Note the complete lack of correlation of the somatic pain with the VPS, and conversely the vicarious pain with the NPS.

One question is how high-level the NPS network is. Does it represent the actual physical pain but not the consciousness of it, or does it represent both? In prior work, the same lab showed that they also saw complete distinction between NPS and efforts the subject might make to cognitively control that pain, seen as dampening from the frontal cortex. Insofar as the subjects of these studies could manage their pain, it did not affect the NPS intensity at all, but worked at another, higher level. So no, while the NPS correlates with some aspects of pain and its cognition, it does not seem to encompass the highest level processes of conscious pain management, and perhaps even perception.

But back to the main study. The authors observed the NPS quite consistently, and saw its intensity increasing with increasing amounts of applied pain. And as noted, the VPS was quite different. But it did overlap in very few areas- the anterior insula (aINS) and the dorsal anterior cingulate cortex (dACC). These have been previously cited as the points of overlap, thus as sites showing that we feel the pain of others. The aINS is a profound part of our brain, functioning in awareness, consciousness, sense of self, and sociality and other emotions, like the sense of importance of things- meaning. Thus it is natural that it might be activated in both these experimental regimes, without "meaning" quite the same thing.

Likewise, the dACC also functions in emotion and consciousness, as well as reward evaluation, internal conflict, and impulse control. Again, functions that might come up in both experimental scenarios without meaning quite the same thing. Whether a pain is on your own body or elsewhere, at some very high level it is just another input to evaluate for what we are going to decide to do next. In any case, the researchers give additional evidence from lack of correlation on the finest voxel-level scales within both regions to suggest that what is going on in these locations is quite different in the two pain scenarios.

So, despite our mirror neurons and the best intentions, pain is not readily shared, and counts quite a bit less when it happens in others rather than in ourselves. Which is good, since being incapacitated by someone else's pain would probably help neither person. It also points to the importance and privacy of personal consciousness. While we keep coming up with technologies to share / immerse our mental selves in other worlds (telling stories, books, movies, VR), we do so because our capacity to do so unaided is quite limited. We are naturally wired first and foremost to feel ourselves.

• If the 1% gain a lot from free trade, and many low-wage workers lose what is to them a lot, but to the 1% a little, is it a good thing?
• Growth is dead. No wonder the fight to split the pie is getting fiercer.
• We all needed someone to blow up the GOP.
• Marxists vs Trump.
• We are not a healthy country.

Animals Don't Care about Global Warming

It is entirely a human problem.

Global warming is the biggest problem of our time and the next one too. The icons of this problem may be the stranded polar bears, the ravaged coral reefs, the species ranges moving steadily northwards. But what do the animals think about this? Not much, really. Only we have the conscious scope and appreciation of future and past to recognize what is happening. Only we can stand back in awe and horror at what we ourselves are doing, and deem it bad.

Stranded polar bear.

So while the problem of global warming affects the biosphere, killing off species and decimating ecosystems, it is only we who can care about it. Whether our care focuses on the harm that this heating is doing to us directly, via hotter living conditions, drought, impaired agriculture, disease, war, etc., or whether our care focuses on other aspects of the biosphere that we appreciate from a more aesthetic and nature-loving perspective, it is all on us.

Back when we were killing off the North American megafauna, humans themselves probably had almost as little consciousness of what they were doing as the animals they were killing. Except, perhaps, for a twinge about hunting out one area and having to move on to the next, a process that may have encouraged the remarkably rapid settlement of the Americas clear down to Monte Verde.
https://en.wikipedia.org/wiki/Monte_Verde

But now things are different, and the cultural, political, and economic divide comes down between those who do not want to look and those who do, and who see devastating loss. The temptation of keeping our consciousness under wraps, and of denying our hard-won conception of the vast reality around us so that we can consume endlessly and reproduce geometrically, is hard to fight, when all the other side has to offer is an aesthetic, pro-nature and pro-posterity viewpoint.

• Are climate voters pivotal in this election?
• Past annals of climate change.
• Who's carrying those pitchforks?
• Gun nuttery reductio ad absurdum.
• Could central banks take over all basic banking?
• And who needs monetary policy anyhow?
• In-depth on Turkey and the Gülenists.
• But is it treason?
• Which side is Hillary on? At least she's not on Putin's side.
• Can we keep going down the capitalist road? The problem isn't capitalism per se, but the capture of the media, culture, and politics by its winners- the 1%, which leads to an unwillingness to regulate it properly.
• Tobin tax, Si!
• Our egghead in chief.

Another Go-Around With Free Will

Is free will a problem, for whom, and what does it take to solve it?

As previously noted, the problem of free will isn't much of a problem, but theists continue to be perplexed by it and horrified by the naturalist answer that there really isn't any free will. Their perplexity often results in torrents of poor philosophy and moralistic tendentiousness. This perplexed perspective is well-explained and exemplified by a recent blogger.

Towards the end of the essay, he gets to the crux, which is not whether free will exists or can be called an illusion, but how to reconcile the third person perspective (no free will) with the first person perspective (subjective free will).

"We are left with a huge problem that no philosopher has ever solved, namely, the integration of the first-person and third-person points of view. How do they cohere? No philosopher has ever explained this satisfactorily.  What can be seen with clarity, however, is that subjectivity is irreducible and ineliminable and that no solution can be had by denying that we are irreducibly conscious and irreducibly free. One cannot integrate the points of view by denying the first of them."

Philosophers may have no idea about this, but scientists do: demote the subjective perspective as the superior one that is irreducible and uneliminable. Our subjective states are notoriously variable, drug- alterable, and quite eliminable. Every sleep wake cycle is a big exercise in eliminability. They are also clearly a reducible state of their substrate- the matter of our minds and brains. Different people have subjective consciousness to different extents, varied by stroke, senility, and other physical impairments in ways that clearly show their reducibility, to the point of eliminability. So while their nature is of great interest, on personal and other levels, they are no philosophical bedrock. Quite the opposite. I think, therefore I am fortunate enough to have my wits about me still, but will not have them forever, or even through the night.

This is not to say that free will and subjectivity are "illusions". That is the wrong word, as this writer argues well (though in fairness, optical illusions are often so persistent that they also can not be shed, only understood despite their persistence). They are perspectives from inside a system. A special and unique position, but not philosophically superior to other perspectives that may have a firmer grasp of the larger context of what is going on, especially what is giving rise to precisely that subjective perspective in the first place- the physical brain. We can not shed the subjective perspective, as we might an optical illusion. But that doesn't make it a philosophically unanalyzable vantage point.

"...  All indications are that the problem of free will is simply insoluble, a genuine aporia,  and that we ought to be intellectually honest enough to face the fact.  It is no solution at all, and indeed a shabby evasion, to write off the first-person point of view as illusory."

If we take it as given that we have a perspectival problem here, such that the view from inside is different from that from outside, it seems incorrect, indeed cowardly, not to say narcissistic, to hide behind the sovereignty of the subjective perspective to say that it is irreducible and unanalyzable. When it is so clearly a product of the machinery of the brain. It is reminiscent of Ayn Rand so charmingly saying that "I will not die, the world will end". This is, sadly, another instance of theism leading people astray, as this is a theist writer, and free will is basically a theist problem- to think that there is a real "I", hidden behind and separate from the mechanism that is the neurobiology of the brain. It is the attachment to souls, to supernatural magic, and to unexamined beliefs and poor standards of evidence that get us into this particular mess, and into so many messes in philosophy and elsewhere.

It isn't just theism, though, but intutition, which is the fount of theism in the first place. It all hangs together as a perspective- I experience the world subjectively, and I feel via my intuitive consciousness to be a free, floating point- a soul, unattached to the material miasma of nature. And the only logical (and psychologically intuitive) sponsor of this kind of magic is a deity, likewise free and unattached, which has implanted this bit of divine essence into me. It hangs together with a denigration of nature as lesser and dirty compared to the Apollonian and the logos. It hangs together with all sorts of social-intuitive traditions like patriarchy, monarchy, and priestly hierarachy.

But is it true? And even if we regard these intuitions and their derived theologies as false once we wrench ourselves away from the subjective, narcissistic, intuitive perspective, might they nevertheless promote human dignity more than a naturalistic view? That remains an open question, with plenty of historical examples on both sides of the ledger. Yet the bedrock of philosophy, among many other pursuits, is that the search for and attainment of truth is not only a virtue in its own right and a part of our fundamental human purpose, but also operationally good and conducive to better individual and communal life.

• Beneath the Trumpery, the archetypes.
• Two minutes hate. Or a little more.
• Sort of hard to paint Hillary as the liar here.
• Is this the end, or not the end?
• A little in-depth on Bangladesh.
• Was California's cap and trade system too timid?
• Bill Mitchell on economic efficiency.
• God's gift of DNA molecules.
• The Taliban continues to win in the hinterlands.
• Obamacare is doing well.

Animals Use Their Genes Differently

Distal/distant enhancers really only took off in the animal lineage of eukaryotes.

Only 21,000 genes? What a paltry inheritance we have as humans. That is only twice the number of the honeybee, and three times that of yeast cells. How can a complicated, high-maintenance animal like us get by with so little genetic material? Much of the answer lies in how we use our genes, not in how many we have. There has been an explosion of regulatory complexity, even as there has been such a modest rise in the number of genes, from more humble species.

Evolutionary tree over eukaryotes, showing animals at the bottom, and Filozoa, which contain Capsaspora, nearby.

A recent paper discussed the genetic contents of a eukaryote called Capsaspora, which is thought to be sort of the last stop among the protists before we get to the multicellularity of animals. Not much is known about the filastereans, of which this species is a member, other than that in molecular terms, they are among the very closest eukaryotes to metazoans, while still being single-celled. But they are branching out, so to speak, with their filamentous processes and amoeboid form. They are parasites, (or symbionts), a bit like malaria, infecting the blood of a certain freshwater snail.

Its genome is only 28 megabases, compared to 3 gigabases for humans, so much more compact. And its count of genes is about 8,700, on par with yeast cells. The prior paper on its genome also points to a gradual increase through these lineages of new protein domains that become prominent in animals, like G-protein signalling components, cell-cell adhesion, meiosis, and developmental transcription factors. It has recently been reported to have a limited multicellular aggregation stage, when grown under agitating conditions, accounting for some of these evolutionary developments.

Capsaspora, in all its glory.

Nevertheless, these are not animals, and the authors asked what the genomic differences are that seem most relevant to the distinction. Given the large disparity of genome size, and relatively small difference in gene numbers, it seemed reasonable to look at the intergenic regions, where animals have a great deal of regulatory apparatus, not to mention junk DNA. This is where animals have enhancer cassettes that bind various transcription regulators, all of which loop around to cooperate with regulators bound at the promoter, the region directly around the transcription start site. Enhancer cassettes can come at many distances from their target gene, up to megabases away, and in many iterations, used alternately or combinatorially to drive gene expression in various developmental or inducible settings.

The authors, after having sequenced the genome of this organism previously, mapped regulatory regions all over using state-of-the-art techniques. And the upshot, as diagramed below, is that the upstream regions are indeed quite different in these organisms. Capsaspora has very little distal/distant intergenic regulatory matter (the green slice of the pie), while humans have vast amounts. Ditto for regulatory sites downstream (3' UTR) and in internal introns (intron, non-1st). Naturally, given the small genome size, coding sequences (tan or orange) take up one-third of the Capsaspora genome, but only a tiny 1% of the human genome. And the regulatory sites that Capsaspora does have are smaller, covering only 74 bases on average per gene, compared with 60 bases in humans.

Main findings, showing the dearth of distant enhancers (B; green) and the small size of regulatory elements (A) in Capsaspora, compared to its bigger relatives.

This is the evolutionary story in a nutshell. Growing new tissues and complex modes of cell-cell cooperation (and even brains!) doesn't take a lot of new material. Rather, it all uses cells- gussied up in many instances, but still basically eukaryotic cells- whose genes are put under tremendously more complex regulatory regimes so that these cells can be and do novel things in the thousands of new environments that multicellular organisms create internally.

• Krugman on group responsibility, and Republican enabling.
• Zimbabwe heading for hyperinflation again?
• 600 suicide attacks from ISIS? Is this sustainable?
• Beneath all the lies, Trump traffics in some basic truths.
• Big data and health insurance, etc.
• Notes on the homeless epidemic.
• On the line from the French revolution through Hegel to Marx, and on to the new terror.
• The wages of austerity.
• Are conventions just big sleezefests?

Religion as Science Fiction

What if theology is regarded as SciFi?

How seriously do you take science fiction? Obviously, being called "fiction", it is neither science nor any other kind of truth. Yet it is full of "truthiness"- plausible-ish technologies, settings related to our own, typically in the future, and human dramas more or less rich. It also often offers sweeping, even eschatological-scale, plots. But how can science fiction deal in human meaning if it does not deal in theology, given that the religiously inclined naturally think that meaning is given to us, not by our own ideas or efforts, but by a theos?

Obviously, one can turn that around and claim that theologies are themselves made up, and, far from scientifically observing a meaning given from on high, are exercises in making meaning, all the more effective for denying their underlying fictionality. In any case, I think science fiction is clearly the closest genre to religion, and caters to readers/viewers who have basically religious needs and temperaments.

From Jesus and Mo.

It is the science fiction fans who expect philosophical ruminations on what it means to be human, tales of a far future when humanity will have escaped the bonds of earth, often magical events and capabilities, and unimaginably powerful alien beings. Subspace, mind-melds, apocalyptic wars ... it is just a another word for supernatural.

Likewise, our ancestors clearly had the same idea(s). How better to illustrate their dreams, both bad and good, but with inflated archetypal beings and conflicts? The Ramayana reads like a Hollywood SciFi blockbuster. Why are there two versions of the Garden of Eden? It isn't because each is scientifically accurate. It is a clear statement that both are science fictions- tales of an idyll, and of an archetype.

Rama, flying in his vimana.

Why our cultures should have harbored such humorless, spiritually dead people as to take these tales seriously is beyond me. It is probably a testament to the bureaucratic mindset- the organization-alized person who clutches at tradition and order, (and certainty/explanation), over imagination and play. And over time, the original imaginative, introspective impulse is so crusted over that even the most sensitive and insightful people have no choice but to take the truth-dogma seriously as an external or historical reality, and proceed to make nonsense of what began as a wonderful work of art.

• Religion and big data.
• Groups needing to own it...
• Masons, and the convention of conventions.
• Bill Mitchell on Brexit. "Labour was advocating continued membership of an arrangement that is now broadly seen as a vehicle of the elites to suppress wages, employment and push more people into compliant poverty."
• More thoughts on Brexit.
• The financial elites are not making good policy. And not providing economic growth.
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• Can atheists and chaplains interact usefully?
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• Another theologian employed at a public university- heaven knows why.
• Fox and Friends. Or frenemies.