Saturday, July 29, 2017

Prophetic Diagnosis

Using MRI to detect brain damage that leads to temporal lobe epilepsy.

Magnetic resonance imaging has been an amazing and flexible technology. It has been tailored to varying chemical targets and environments, so that both chemical and anatomical details can be visualized. A recent paper (review) deployed tractology, which uses MRI to trace water diffusion in lengthy neurons and related cells, to vizualize detailed brain organization.

They were looking for traces of damage or change that could predict or correlate with epilepsy. Their model was mice, whom they injected with kainate in their hippocampi. Kainate over-excites and rapidly kills neurons, and this particular injection is known to induce temporal lobe epilepsy, a syndrome that can be brought on by genetics or trauma in humans, and is known to cause not only seizures, but also other problems such as memory loss, depression, personality changes, and hyper-religiosity. Whether the mice start propounding new religions is naturally unknown.

Time course after injecting damaging chemicals into the hippocampus of mice, and then tracing the growth of new glia oriented cross-wise (green, in box) versus the native neural tracts.

What they did find is that they can track damage in the mice quite easily, and this brain damage takes the form, in part, of new tracts of (glial) cells that grow cross-wise versus the native neural pathways. This helps to rationalize what may be causing the epilepsy, and was supported by finding similarly deranged tracts of glia in the brains of humans suffering from temporal lobe epilepsy and hippocampal sclerosis, which is the main physiological finding associated with such epilepsy, especially forms that can not be treated by drugs. And the severity of the lesion, which in the mouse system is traceable from very early times, prior to the onset of epilepsy, correlates in both systems with the severity of the eventual epilepsy.
Our study demonstrates for the first time that the extent of epileptogenesis-associated tissue alterations in the hippocampus directly mirrors the ensuing severity of intractable mTLE [mesial temporal lobe epilepsy].
This may provide and early way to check out brain damage that may lead to this syndrome, though what to do about it is a separate question, typically answered in these cases by surgically removing the mis-grown scar tissue that was studied here.

Saturday, July 15, 2017

What if Coal Were All We Had?

What if there was no renewable energy, or sustainable options to keep advanced civilization afloat?

I was reading an article about coal country, and the tradeoffs, dreams and delusions surrounding it, when it struck me what a different position we would be in if coal was all we had. Our civilization floats on a miasma of oil, gas, and coal, with some nuclear and hydropower thrown in. Wind and solar are growing, but fossil fuels make up 80% of energy resources, and will for years to come, especially as India and China continue to commit to more coal-based power. For all the oil we guzzle in transportation, heating, chemicals, and other uses, we use more than twice as much coal, to the tune of roughly ten billion tons per year.

But what if we lived in an alternate world where we did not have fracked natural gas, or renewables, or even oil? What if coal were all we had? Our industrial development would be a different place, clearly. Though World War 2 demonstrated that one can make practically anything from coal that can be made from oil, the processes are quite a bit more difficult. We would have more trains and streetcars, and fewer automobiles. More importantly, though, we would be facing much different choices in global warming, and pollution generally.

We would be in a world more like Victorian England, and contemporary China, where coal pollution is choking. The irony is that installing scrubbers to take out the most noxious pollutants, not to mention sequestering the CO2, is very expensive, not only in financial terms, but in energy terms, wasting even more of the fuel that in this world would be so precious. Coal would still be a limited resource, with a time horizon of maybe 200 to 300 years in all. Foresightful planning would regard this as an extremely precious resource, if not substitute were available, ever.

So from both the foresight and the pollution standpoints, we would be forced to conserve energy- that would be the solution to such a noxious resource. We would be much farther along in taxing carbon/coal to reduce usage to amounts consistent with local human health and future global health, even if strip-mining it were cheap and its many local costs acceptable. Hopefully, natural beauty would not be a distant memory in such a world, if we made these decisions in time- a time much earlier than we have the luxury of doing today. Would the human population be as high as currently? Given that the poorest areas of the world typically have the highest population and population density, that is quite likely. We would just all be poorer, crimped by a resource base that would be dirtier and scarcer than the one we have today.

Thankfully, we have a much brighter future in reality. In the developed world, pollution is not an in-your-face threat to human existence, but rather an invisible, subtle menace that needs to be met with responsibility and foresight if we wish to preserve much of the natural world that we evolved in, and have known in our own lifetimes, intact.

Saturday, July 8, 2017

Who Are the Real Wealth Creators?

Technologists, of course.

Of the various indignities of the campaign last year, the economic ignorance displayed and accepted was particularly galling. The Trump voters of the hinterlands, supposedly angry about their compromised economic position, elected a party and person whose avowed goal is to take more money from our public institutions, the poor, and the middle class, and give it to the rich. This after a near-decade of total intransigence by the same party against restarting an economy that was floored in the banking meltdown and has been limping since. It has taken a decade to get back to more or less normal conditions- time lost to economic growth in general and to countless individual traumas.

Who and what creates economic growth? Is it the "job creators"? Is it Goldman Sachs? Is it the 1%? That is a big question facing the nation, both politically and in straight economic policy. The new administration says yes, yes, yes, arguing that giving the rich hefty tax breaks, not to mention reducing regulations of all sorts in financial and environmental sectors, will help economic growth. Will it? Obviously we have been through all this before, under G. W. Bush and Reagan as well. And the answer is no, it does not increase economic growth. Money going to the rich is money that is, largely, invested in low-risk assets like bonds and real estate.

More generally, does the managerial class create wealth by their organizational prowess? Is Amazon better than Staples, which is better than Pat's Stationery store down the street? Organizational differences make only minor advances in overall wealth, and seem mostly to facilitate the redistribution of labor earnings to ever fewer and richer capitalists. As previously discussed, the power of capital is that it always wins, through good times and bad, in every negotiation, since versus labor, it is always taking less risk.

What Amazon has that Pat's establishment does not is, mostly, new technology. The internet came along and showed that everyone could be connected, instantly. How about using that connection to sell things on a nationwide scale, especially things that are easy to ship? Sears would have been the natural founder of this franchise, based in their nationwide catalog roots, but they had become too invested in their stores to pay attention. Capitalists only deploy the technology that exists. They do very little to generate new technology- that is left to academics and the government. It is technology that keeps revolutionizing our lives and raising our standards of living- our collective wealth. And when it comes to distributing new technology, sometimes the market does a worse job than the government, such as with roads. We could have much better internet infrastructure if it were managed in the public interest as a utility.

Where would the "job creators" be without their cell phones? Where would they be without databases and spreadsheets? Where would they be without electricity? They would doubtless be riding herd over an estate of serfs. They would be just as wealth-creating in relative terms, but all in a much poorer society. The dark ages were dark not because entrepreneurs had lost their will to manage others, but because technological, scholarly, and governing instututional development ground to a halt with the dissipation of the Western Roman Empire. It took centuries of slow, accreting technological progress to make cities as large as they were in Roman times, and make societies as wealthy. By that point, the process took on a life of its own in the West as an ideology of Enlightenment and material and moral progress took hold, maintaining support for learning and innovation which reached unimaginable heights in the twentieth century.

Looking back, we can rue that the fuel of all this transformative progress and wealth creation has been buried reduced carbon, which as our waste product, CO2, is now befouling the biosphere. Our collective wealth has also begotten a vast and completely unsustainable increase in human population, whose many appetites are destroying much else of the biosphere. These are the problems of prosperity, and are, if we are morally responsible, now foremost in our public and private intentions and actions to transition to a sustainable as well as prosperous future.

  • Who needs clean water?
  • Who will sue on behalf of the public interest?
  • Free? We are not free. We are under the feudal thumb of corporations. "Likewise, the origin and success of the factory lay not in technological superiority, but in the substitution of the capitalist’s for the worker’s control of the work process and the quantity of output, in the change in the workman’s choice from one of how much to work and produce, based on his relative preferences for leisure and goods, to one of whether or not to work at all, which of course is hardly much of a choice."
  • Trump is the weakling.

Saturday, July 1, 2017

A Cleanser For Tau Clumps

Alzheimer's disease is caused in part by protein clumps including amyloids and tau fibrils. We have an enzyme for that!

The iPhone appeared a decade ago, and gained ground so definitively because it provided a general platform (and large screen) for which others could develop rich applications. The ramifying copying, diversification, and specialization of those apps is reminiscent of evolution in general, and particularly of the "apps" present in every cell. Proteins are based on a generic/genetic platform of DNA coding and RNA translation, and self- assemble into countless shapes and sizes, complexes and pathways, to do all sorts of tasks to make life better for the organism. Where once there must have been very few or even none (in the RNA world), proteins have diversified over evolutionary time by endless rounds of copying, stealing, mutating, and specializing to constitute our current biospherical profusion.

Our bodies are filled with protein apps that generally keep their heads down and do their work without complaint. But a few can make trouble. Most notorious are the prions, which, as bizarrely misfolded versions of natural, functional proteins, can encourage other proteins to join them on the dark side, and even infect other organisms, causing unusual brain diseases and panics over epidemic transmission. Less notorious, but far more devastating, are various dementias such as Alzheimer's. These appear to be caused by the accumulation of junky proteins which clog cellular processes, and eventually kill brain cells, destroying the organ from within. The exact cause of this accumulation and how, or even whether, it kills cells are both still under study, but deposits of this junk (amyloid plaques and tau tangles/fibrils) are universally diagnostic of these dementias and prime candidates for research and treatment.

Proteins are constantly growing old and getting sent to the garbage, in all cells. The problem with the Alzheimer's-related proteins seems to be that they escape this disposal process, either because they accumulate too rapidly, or because they condense into crystalline entities that can no longer be pried apart by the various chaperones and other proteins that constitute our sanitary services. A recent paper discusses one human protein that seems able to clean up junk composed of the tau protein, even at its worst, and might be the kind of thing that could be injected or increased by genetic therapy to treat such syndromes.

Proline, the only amino acid that cyclizes back to the peptide chain, creating kinks in protein structures. The bond that Cyclophilins wrench back and forth is resonance-stabilized, making this trick a bit harder than it looks.

Cyclophilins are a class of protein chaperone (which are proteins that assist the folding of other proteins) that catalyze the switching of proline peptide bonds from cis to trans (see above). Proline is the stiffest amino acid, and plays a major role in generating kinks, turns, and other rigid aspects of protein structure. So cyclophilins help loosen up such structures and get proteins back on track if they have gone down a tangled path. That seems to be the case with tau, which is the crystallized conformation of fragments of a protein that in its normal state is a membrane protein thought to participate in synapse formation. Naturally, the accident of causing dementia in old age is, in evolutionary terms, a minor issue as it takes place well after reproduction has occurred, allowing such evident genetic defects to persist in our population.

The authors diagram how the tau protein (red and gray) might get its turns loosened up by CyP40, (black), allowing the tight beta-sheet structure to dissolve.

The authors run through a series of experiments to show that one cyclophilin, CyP40, is particularly effective in dissolving tau fibrils, one form of protein aggregation seen in Alzheimer's. It dissolves them in the test tube, it dissolves them when infected via a virus into the brains of mice, and it reduces neuron damage and cognitive decline that happens in these mice, which are engineered with extra human tau protein expression, and exhibit a rapid dementia-like progression.

When CyP40 is added (red), tau fibers can be dissolved in the test tube. FKB51 and -52 are other cycophilins that do not have this particular activity, serving as controls.

Engineered tau-expressing mice (red) can have their cognitive abilities improved after a virus carrying the CyP40 expressing gene was injected into their brains. The Y-axis is rate of errors in a water maze test, done at 3 months, which is relatively late in life for these mice.

It is an impressive and promising piece of work, to go from molecular structure to medically significant function, though it took 19 authors to get there. One notable aspect of this protein is that it does not require ATP- its mechanism is very efficient and the protein is relatively small- properties that are helpful when the targeted protein clump is outside of cells or in dying or dead cells. It is also part of family of 41 such proline isomerase enzymes in humans, so others may be found that operate on the other major culprit in Alzheimers, amyloid beta protein. On the other hand, we already encode and make Cy40 and it relatives. Why are they not being turned on and expressed in our brains where and when they are so desperately needed? The authors are silent on that score, and have taken out a patent for the therapeutic possibilities of the exogenously supplied version.

  • Ignorance is strength.
  • And isn't going to prevent some illogical hypocrisy.
  • Or cruel policy
  • Where is it all headed? To a new and permanent feudalism / authoritarianism.
  • Much ignorance is due to corporate media, whose interests are not ... the public interest.
  • Fake logic finds a home at the Supreme Court.
  • What is to become of the next Afghanistan surge?
  • The Russia story goes deeper.