Saturday, December 26, 2015

A Gentle Touch at Metaphase

Dynamic modeling of the metaphase chromosomes as microtubules push them about.

One of the more magical phenomena of biology is the orchestrated congregation and division of chromosomes at the midline of a eukaryotic cell at mitosis, or cell division. One has to keep reminding oneself that there is no central brain organizing the process- it is driven by a network of molecules regulating each other and conjuring collective organization and action out of blind chemistry.

What are the mechanics involved? The main force comes from the microtubules originating at the spindle poles, which connect in somewhat noisy fashion to the chromosomes, especially to the kinetochores that are located at the middle of each chromosome at its centromere. About 10 to 30 microtubule plus ends are stuck into each kinetochore, when everything is working properly. Microtubules are fascinating structures in themselves- they can exert force in either direction, either (+) growing by polymerizing more of their subunits, or (-) by shrinking and losing subunits. This is quite apart from the various cargo carriers that use the motor kinesin to travel along stable microtubules to ferry materials around cells.

Electron microscopy of microtubule ends (bottom), and as stuck into
a kinetochore (at right). When splayed out, the end is de-polymerizing
and retreating. When straight, the end is advancing by polymerization.

The strongest forces come from the microtubules docked successfully to kinetochores. Having all the kinetochores docked is a key prerequisite for proceeding with cell division, to insure that each daughter cell gets a full set of chromosome copies. But there is another, weaker force, which comes from microtubules touching other areas of the chromosomes, away from the kinetochores. These attachments (called the polar ejection force, or PEF) are much simpler, and only push in one direction, away from the spindle and towards the midline of the cell. They connect to chromokinesins distributed all over the chromosome arms. A recent paper modeled what is known about these forces, and concluded that it is the PEF that gives the key nudge to line all the chromosomes up properly at the midline, while the kinetochore-attached forces swing rather wildly back and forth, causing the chromosomes to oscillate as they gradually find their equilibrium position.

A still from a video that shows the typical oscillation
of chromosomes being tugged back and forth by
their attached microtubules. The chromosomes are
the dark globules beneath the labelled molecules (red
is the microtubules, green is the kinetochores and
spindle poles).

A third force or factor is the attachment strength between the two copied chromosomes, the two partnered kinetochores. This is trivial, however, as it acts like a rather stiff spring which can not be broken until the signal is given for the cell actually divide and the paired chromosomes part to opposite sides.

The researchers use video recordings of labelled human HeLa cells to document the back-and-forthings of the mitotic chromosomes, and using a basic model of the forces involved develop a more detailed model of the dynamics they are seeing. The upshot is that while the strong kinetochore forces are switching back and forth, (and forms another story about how the kinetochore-microtubule connections are made and regulated), insuring capture of each kinetochore, the PEF, which is about 1/3 as strong, consistently pushes each chromosome towards the center, thus biassing the net force to line everyone up at the midline. These two processes are collaborative, since alignment in a single row / plate at the center also helps to insure that all the kinetochores are captured, on both sides. There is an additional consideration, which is that each kinetochore needs to associate with only one spindle, not with both. This is probably helped by the stochastic push-pull process, where microtubules, which are relatively stiff themselves, rapidly attach and detach from the kinetochore, which has a rigid, single orientation.

Schema and results from the cited paper. On left are the forces at work,
including a spring force between the paired kinetochores (green). The other
graphs show the deduced forces for individual kinetochore excursions,
with the PEF and inter-kinetochore spring force (right) much weaker than
the main kinetochore microtubules, which show much more dramatic
directional switching.

Once each kinetochore has successfully docked with microtubules from the opposite spindle pole, how are their motions coordinated? The researchers find that switches in direction are led 4/5 of the time by the side that is shorter and pulling towards its pole. The stiff connection between the two chromosomes then quickly transmits this switch in motion to induce the partner kinetochore+microtubules to follow suit, after which the pair is once again heading together in the opposite, direction. The bias in the tendency to switch directions also helps keep the chromosomes centrally postioned. But why does this bias happen? That remains unanswered, and likely is also due to the gentle, but persistent, PEF.

All this is a prelude, once the spindle checkpoint is passed and the paired chromosomes fire their release rockets, to when the kinetochore-associated microtubules pull hard and in unison toward the poles. This transition orchestrated by other molecular signals which have been well-studied, particularly the anaphase promoting complex. Life is a process, and a network, which knows no end and few boundaries.

  • Our war on fish.
  • Mars is not a backup planet.
  • Yes, we can, and must, do a carbon tax.
  • Brains have male and female traits, but no one is pure here.
  • Islam has a branding problem, and a self-fulfilling isolation problem.
  • Or perhaps we have the branding problem.
  • Sandra Bland aftermath: everything is OK!
  • What is lithium used for?
  • Judging the Federal Reserve. Good, but it could have been so much better.
  • Bill Mitchell on the core problems of the EU:
"The French drove the process of integration and became increasingly influenced by the Monetarist thinking, which pushed them closer to the German emphasis on monetary control and fiscal thrift. What the French didn’t appreciate was that this emphasis could not deliver effective outcomes to its own economy much less the broader European Member States, given the fact that German manufacturing and its trade capacity was superior in every way."

Saturday, December 19, 2015

We Just Found the Outrage

The GOP reaches a new low in incivility and untruthfulness.

The recent Republican debate struck a new low for our body politic. Not much remarked, but striking to anyone suffering through it, was a new tone of empty vitriol directed especially at President Obama. The Republicans have been consumed with hate since he was elected, but I have never seen decorum drop to quite such a low level.

"America has been betrayed. We've been betrayed by the leadership that Barack Obama and Hilary Clinton have provided to this country over the last number of years." - Governor Chris Christie.
"This is why -- this is what I said at the beginning that this administration, Barack Obama and Hillary Clinton through their foreign policy, have betrayed the American people, because the weakness they've displayed has led to Putin's incursions in the Middle East and in eastern Europe, and has led -- has led to significant problems in the Middle East as well, and the death and murder of lots of folks." - Governor Chris Christie
"As far as other people like in the migration, where they're going, tens of thousands of people having cell phones with ISIS flags on them? I don't think so, Wolf. They're not coming to this country. And if I'm president and if Obama has brought some to this country, they are leaving. They're going. They're gone." - Donald Trump
"One of the things I would immediately do, in addition to defeating them here at home, is bring back the warrior class -- Petraeus, McChrystal, Mattis, Keane, Flynn. Every single one of these generals I know. Every one was retired early because they told President Obama things that he didn't want to hear." - Carly Fiorina
"This president and this is what the focus ought to be, it's not the differences between us, it's Barack Obama does not believe America's leadership in the world is a force for good. He does not believe that our strength is a place where security can take place." - Former Governor Jeb Bush
"And let us remember one other thing. Hillary Clinton and Barack Obama are responsible for the growth of ISIS because they precipitously withdrew from Iraq in 2011 against the advice of every single general and for political expediency. It's not these people up here. It's Hillary Clinton." - Carly Fiorina
"Well, Wolf, I'll tell you what reckless is. What reckless is is calling Assad a reformer. What reckless is allowing Russia to come into Crimea and Ukraine. What reckless is is inviting Russia into Syria to team with Iran. That is reckless. And the reckless people are the folks in the White House right now. Barack Obama and Hillary Clinton are the reckless people." - Governor Chris Christie
"Barack Obama has said he doesn't believe in American leadership or America winning -- he is wrong." - Senator Ted Cruz
  • The word "kill" came up 26 times in the debate
"I would certainly be open to closing areas where we are at war with somebody. I sure as hell don't want to let people that want to kill us and kill our nation use our Internet. Yes, sir, I am." - Donald Trump
  • Then there was the bizarre over-inflation of ISIS as a threat.
"Regarding national security, we need to restore the defense cuts of Barack Obama to rebuild our military, to destroy ISIS before it destroys us." - Former Governor Jeb Bush

The "reckless" charge is particularly ironic in light of Barack Obama's predecessor, who sort of defines the term, including the "killing of lots of folks" part. At any rate, extreme competition among a very crowded field of mediocre candidates has lowered the level of rhetoric, to what I would regard as unconscionable levels. How do they expect to be treated in office, and how do they expect the office to maintain its value if they as public officials make of it such a pig-sty?

This is not even to delve into Mr. Trump's ugly past rhetoric. In this debate, he continued to expound on his "strength", as shown by his willingness to kill relatives of terrorists, and to prohibit Muslims from immigrating to the US. From a left perspective, the GOP is a motley circus, but that doesn't excuse us from paying some attention and noting that we all share in the national discussion and need to draw some lines of basic decency if our politics is not to descend to the level of farce, and worse.

  • Some are uncomfortable with this language.
  • A few more lies.
  • Is ISIS going to kill us all?
  • Which side are the Saudis on, really? What a change from the 60's, when a Muslim military alliance was forged against Israel. And how did that work out?
  • And they don't just imprison political protesters, they behead them.
  • A look back at the Arab spring. Note especially (and in connection with the new Saudi "coalition") how the social and economic dominance of the military in Muslim countries like Egypt, Syria, and Pakistan has no relationship to its effectiveness. It is empty, political, patriarchal machismo writ large.
"If Islamic fundamentalist forces managed to become dominant among the organized forces in those uprisings, with no exception, it is surely due, on the one hand, to the practical and/or political weakness of the Left, but, on the other hand, it is also and above all a product of decades of rule by the despotic regimes. No one should miss that. The Syrian regime was not a shield against Islamic fundamentalism, nor were Mubarak or Ben Ali, and nor are Assad and Sisi today." 
Islam as a religion and ideology, of course, seems to go unnoticed. Time and again in this discussion, it come up in passing as the most powerful regional ideology, by far. What does modern liberalism have to offer in its place?
"Add to this the very active involvement of the regional counterrevolutionary stronghold represented by the Gulf oil monarchies, which did their best to strengthen the Islamic fundamentalist component of the Syrian opposition at the expense of anything else. Because, a real democratic uprising is the major threat to them like it is for Assad. In a sense, they concurred with the Assad regime in promoting the Islamic fundamentalist component of the opposition at the detriment of the secular democratic."

Saturday, December 12, 2015

Odysseus Among the Stars

Star Trek as an Odyssey retold.

Star Trek is one of the great narratives of our time, burrowing into the cultural unconscious with its optimism, classic storylines, inexhaustable fund of aliens, and dash of humor. What other story is equally classic, with a hero who commands his ship through a long series of adventures, who meets aliens of many descriptions, and gets out of one bizarre scrape after another? Why Odysseus, of course!

Realizing this clarified to me the staying power and deep resonance of this new myth. Odysseus wasn't big on preaching the benefits of a peaceful Federation, (though that may have been an implicit lesson to its original listeners, binding together a Greek world constantly at war), but on the other hand, he had heard of most of the monsters and gods he meets, getting more of a head start than Kirk has. Like Odysseus, Kirk is a winner, happy to seduce a woman if that will save his ship, using deception and every wile to get what he wants. Or to go in with guns blazing if that is needed. While Odysseus had a home to go back to, Star Trek dispenses with that bit of plot, concentrating on the voyage exclusively, the far more engaging part of the story.

One big difference is the role of Spock. Odysseus has no significantly characterized companions from what I recall, none whom one would call a number two. While a soldier and coming back from war, the military organization of his ships is hardly mentioned and seems rather lax. Odysseus keeps his own counsel and gets little help from his sailors, who die right and left in various misadventures. Nor are aliens brought along on his voyage. Time after time, he flees as fast as he can from each monster in turn.

A medical officer with a shamanic touch, like McCoy, might not have been unknown to the Greek world, but Spock is another matter. He exemplifies the classical philosophical position of Stoicism, but this hardly had much place in the original tale, outside of mundane forbearance of disasters which rain down constantly. Odysseus doesn't involve himself in much philosophical discussion, or introspection, which becomes such an important part of Greek culture only later. The Odyssey is a tale of action, not thought. Spock introduces both an element of diversity and philosophical perspective, (especially an occasional check on senseless violence), which is sorely needed in what is also, among its other themes, a pean to what was at the time a growing US federation of democratic and peaceful planets, er nations.

Modern, contemporary, retro, or classic?

  • We are on the ISIS side, in Yemen, along with Saudi Arabia.. why? Why take sides in the Sunni-Shia showdown?
  • Narratives and theories of anorexia.
  • New US jobs are heavily low-wage.
  • Hope, belief, and con games large and small.
  • Why are bitter, fundamentalist losers messing everything up?
  • Bill Mitchell on basic income.
  • Is quietist Dawa fundamentalism better than militant Wahabi and Salafi fundamentalism?
  • Trump is blowing up the code. FOX/GOP can not wash its hands of what it has wrought.

Sunday, December 6, 2015

Raising Consciousness

New methods to detect and characterize consciousness in the brain. AKA, going beyond Granger causality to understand brain dynamics.

Neuroscience and the study of consciousness has to date peeked at the living human brain via MRI, and analyzed it by correlation, trying to join slight activity signatures to various mental tasks and subjective experiences. There has been a great deal of speculation about what the neural correlates of consciousness are, complete with fanciful mathematical theories (phi, critique of phi, gamma waves, etc.) But none has been convincing, though there has been a general coalescence around some ideas- that consciousness involves fleeting coalitions among many brain areas coordinated to some degree by anatomical connection and rhythmic oscillation in the gamma band.

Getting beyond that, to a more detailed theory of consciousness, will take not only better techniques of looking at the brain, with higher time and space resolution, but also better analytical methods & theories to make sense of the vast amount of activity we see and data we already gather.

As David Eagleman illustrated in his excellent PBS show on the brain, there is a storm of activity taking place all the time, associated, as usual, with the words "billions" and "trillions". Somehow, it gets the job done, but figuring all this out from the outside requires another order of analysis. A recent paper describes new mathematical methods that appear very promising, for determining causality within a complex network like the brain.
"A dilemma is that overly realistic and detailed simulations often require a number of unknown parameters and can obscure physiological principles. It is, therefore, not straightforward to instantiate an appropriate reductive model that capture dynamical complexity and diversity across multiple brain areas. "

The problem, for a complex dynamic system, is that correlation methods alone are extremely crude. Imagine probing a computer's internal circuits with a correlation meter, and expecting to figure out its logic and mechanisms- it would be impossible. The system is non-linear, which means that a signal here can lead to negative signals there, or to vastly amplified signals, or altered patterns of waves, etc., so that simple correlations among points of activity have very limited analytical power. Then there is feedback and other network behavior that can obscure the directionality of causation.

The next step of analysis has been Granger causality, which is an extension of correlation analysis to a time series. Compare two time series of events, and if changes in one series routinely predict changes in the other, (i.e. correlate with a time lag), that supports a hypothesis of causality from one series to the other. But this method relies on the two variables being independent, and also struggles with non-linear effects, as other correlation methods do.

The new method, called convergent cross-correlation mapping (CCM) or cross-embedding, arrives from a recent ecology paper that asked what causes the unusual cycles of anchovies and sardines, each of which go through boom and bust cycles which seem anti-correlated with each other. Do they compete with each other's food sources? Is there a predator cycle that determines their abundance? The authors conclude that each population is driven by sea surface temperature, independently of the other. The causality went precisely from temperature to each species' abundance, not from either species to the other. The new method uses correlation, but through some higher-level math that better accommodates non-linear systems with feedback characteristics.

This paper showed a nice example of the method, analyzing the predator-prey relationship of the classic protists, Didinium and Paramecium. The dynamic cyclicity is very clear (in A), but what causes what? The Granger method could call it either way, depending on how you set the lag time. The cross-embedding method (rho, on the Y-axis of B) finds a higher amount of information provided by the Paramecium graph against the Didinium graph, suggesting that the predator exerts stronger top-down control of Paramecium than the reverse. In other words, the subject variable (Paramecium in this case) is more dependent on, and thus directly informative about, the driving variable (Didinium) than the reverse. A feature of this method is that it provides stronger results (suggesting true causality) the longer the time series, whence the "convergent" in its name.

A Didinium eating a Paramecium.
Population dynamic between the predator Didinium and its prey, Paramecium. 

Getting back to humans, (or thereabouts), another recent paper used this method to look at neural correlates of consciousness in macaque monkeys. They used electrodes applied directly to the exposed brain surface, getting much higher signal and resolution than when they only applied to the scalp. The monkeys were either anesthetized or conscious and behaving in various ways to test visual and other forms of perception / consciousness. The question was whether, over large distances in the whole brain, correlates of consciousness can be detected. (They also have prior work, using Granger methods.)

Electrode map and anatomical codes, top. At bottom, an example of one electrode pair and its analysis shows directionality of signaling, from #118 (red, visual cortex) to #41, (green, motor and somatosensory cortex).

The answer is that they can get significant signals from awake and behaving brains that are not only different from anestheized brains, but also reflective of an expected hierarchy of directionality and complexity, for instance that the visual system is causal towards signals in the frontal cortex during visual perception, and that the frontal areas overall have significantly higher complexity than the primary sensory processing areas at the rear of the brain.

Complexity and directionality measures among major brain areas in macaque brains under different conditions, using cross-embedding analysis. Consciousness is easily detectable, among other significant characteristics.
"Based on this method, we simultaneously characterized the large-scale cortical interaction and the dynamical complexities embedded in individual area activities. It revealed that the awake brain has a hierarchical structure of the dynamical complexity, where the frontoparietal areas had more complex dynamics than visual areas. Intriguingly, this hierarchy was linked to the directed cross-area interaction from visual to frontoparietal areas. To our best knowledge, this is the first study reporting clear cortical hierarchy in terms of dynamical complexity, as well as its relationship to the global cortical interaction. Moreover, we found that this hierarchy was universal across different behavioral/sensory conditions and disappeared after the loss-of-consciousness induced by either of two different anesthetization methods. These results indicate that this hierarchical structure is correlated with the level of consciousness rather than its specific contents reflecting perception or action."

This work is not unique in finding distinctions between conscious and unconscious states, but the improved data analysis is a significant step forward in teasing out reliable correlates of consciousness as observed from (sort-of) outside. Of course it is still a long, long way from telling what the content of that conscious state is, let alone sharing it in any rich way. And, being based on naked brain EEG, it is not clinically useful either.

  • Who is subsidizing the coal industry? You are.
  • One party is at fault.
  • And is also wrong. I mean really, really wrong.
  • And is also corrupt.
  • Update from the god & gun nuts. Update two.
  • Other things that are wrong...
  • What is your anti-capitalist stance?
  • Using dispersants on oil spills does no good.
  • This week in the WSJ: corruption at the Afghan anti-corruption committee.