Shoulder Rehab for Desk Jockeys

Repair your shoulder and keep it healthy.

This is an unusual post, on self-help. It has been revelatory for me to go through this program, and it might be useful for others who experience shoulder pain, weakness, and lack of mobility. What presents as bursitis, impingement, bicep tendonitis, or even frozen shoulder is often a deeper and more common issue of mis-alignment and weakness in the whole shoulder, with chronic cramping of various muscles, brought on by years of hunching in our modern posture of always-forward attention to computers, phones - even books! In my case it was a lab bench that started the process.

It is hard to get a straight answer or analysis about shoulder problems, since it is a complicated and unusual joint. Small issues in the anatomy can cause big issues with soft-tissue irritation and pain, which may take years to develop, but present as sudden pain and debility. But one key concept is scapular rhythym- the fluid rising motion that the scapula should be following when you reach overhead. That can't happen if the scapula is not properly aligned. Which is to say, it should be flat against the back. When sitting in a chair with a solid back, do your shoulder blades lie flat against it? Or do they stick out against it, or even align to the side, not touching the chair back at all? When standing straight with your hands falling loosely to the side, do your hands face backwards? They shouldn't. They should be facing inwards, to your hips. Bad shoulder alignment affects your whole posture, and correcting it takes time, but yields wide-ranging benefits.

The syndrome is well-described here. Knowing shoulder anatomy is somewhat helpful, but not essential, really. The basic idea of the rehab program is to strengthen the back muscles that pull the shoulder blades back into proper position, after they have been stretched and weakened for so long by the hunched posture that over-weights the front-pulling muscles. The first step is to restore mobility and range of motion to all the muscles around the shoulder. So start with a series of stretches. Older people especially need lots of stretching to keep muscles working properly. Both the stretching and the strengthening would then be a life-long program, given that activities with forward posture tend to also be a life-long love affair.

• Door stretch: with arms up and elbows half-way up, like a stick-up, lay them against a door frame and push through forward with your body/chest to open up the shoulder and chest.
• Do the same thing with each arm singly, stretching each arm to 45 degrees back from the plane of the body.
• Facing against a wall, with one arm, reach straight up, then work the arm back through a full circle, turning sideways and stretching against the wall as you go around. Finish with a cross-stretch with the arm going in the front across your chest.
• With a broom handle, place it straight up behind one shoulder with the opposite hand, and reach back to it over the top with the same hand. Then pull forward and up with the opposite hand till you feel a stretch in the subscapularis.
• Brachiation: from a pullup bar, just hang for a few seconds with as much weight as possible.
• During the day, remember to stand and open up your shoulders periodically. Sometimes you can even get a crack out of your sternum, if you have been hunched for a while. A phone app reminder every 10 minutes may be helpful. 
• Against a shelf or seat about waist high, lay the front of your arms on it, and lower your trunk till you feel a thorough stretch, then lift about half your weight with your arms- repeat 6 times.
• Hitch arms together behind your back, grasping each opposite elbow. Bend trunk to the sides, stretching the obliques, bend forward and back. Turn neck to each side as far as possible, holding stretch.
• With your back towards a shelf or bar about shoulder-high, grab with your hands, and lower your body to stretch the front of the shoulder. The aim should be to get about horizontal with the arms going straight back, or slightly lower. Next, using the same shelf and position, bend each elbow in turn and lay it/forearm on the shelf behind you, lowering the body again. This is a more intense stretch with the same goal.
• On the floor, on a mat or carpet, make sure your scapula is flat against the ground. Then make angels, swinging arms through full range from sides to overhead, 10X; alternate arms, 10X more.

The next step is strengthening, to counteract the typically forward- directed actions we take all day, and make the posture changes permanent. There are many helpful videos and other instructions on the internet.

• With face down, on a support like a weight-lifting bench or table, lift the arms straight out and up to the sides, as far as possible. Start with no weights, then add weights as possible. 3X 12 repetitions.
• Same posture, but with elbows out and arms pointed forward. 3X 12 repetitions
• Rowing against resistance- using a rowing machine, or resistance band, or rope, pull about 1/2 your weight, 10 times at least. Start slowly with this exercise, as it can cause pain at first.
• With a relatively heavy resistance band, stretch between your hands in front, about shoulder-wide. While stretching apart as much as you can, work your hands up and down a wall, from arms fully up to fully down, 12X. Start slowly with this one as well.
• With a relatively light resistance band, extend arms straight forward and pull wide to the sides, out as far as possible, 12X. While you are at it, while extended, swing your arms back over your head and down to your lower back, for a good stretch.
• With a resistance band anchored to a pole or wall to the side, hold your elbows down at your side with hands straight forward. Pull the resistance band 90 degrees sideways, 20X each direction, strengthening both arms in the rotatory cuff.
• When all that is working OK, raise weights from the side, standing position, to fully overhead, about 10 pounds each side, 10X, strengthening deltoids.
• When all that is working OK, add push-ups and pull-ups.

When walking, attend to posture, leading with the feet, not the shoulders. When sitting, attend to posture, laying scapula flat against the seat.

That is the full program, though many other exercises and stretches can be added. Much of the damage and pain from this syndrome can be assigned to the anterior of the rotator cuff, (supraspinatus, subscapularis, and bicep tendon), and this program will not reverse the damage, but it will prevent further damage and allow effective operation of the shoulder without relying on, and irritating, the front of the rotator cuff so much. I think this issue is endemic and under-recognized. Much of the enthusiasm for muscle "trigger points" and deep massage comes from cramped muscles in the shoulder, neck and back regions. But typically, regular stretching is a better and longer-term solution, even if trigger point release provides rapid relief from pain. Every muscle can be stretched, so when you notice one giving pain or limiting range of motion, do some research on how to loosen it up, and add that to your program.

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We Are All Special

A study in yeast finds that rare mutations have outsize influence on traits.

The word "mutation" is frowned upon in these politically correct days. While we may have a human reference genome sequence derived from some guy from Buffalo, New York, all genomes are equal, and thus differences between them and the reference are now termed "variations" rather than mutations.

After the first human genome was cranked out, the natural question was- How do we differ, and what do those differences say about our medical futures and our evolutionary past? This led to the 1000 genomes project, and much more, to the point that whole genome sequencing is creeping into normal medical practice, along with even more common panels of a smattering of genes analyzed for specific issues, principally cancers. Well, we differ a lot, and this data has been richly rewarding, especially in forensic and evolutionary terms, but only somewhat in medical terms. The ambition for medical studies has been extremely high- to interpret from our code why exactly we are the way we are, and what our medical fate will be. And this ambition remains unfulfilled. It will take decades to get there, and our code is far from controlling everything- even complete knowledge of our sequences and their impact on our development and medical issues will leave a great deal to accidents of fate.

The first approach to mining the new genomic information, especially variations among humans, for medically useful information was the GWAS study. These put the 1000 genomes (or some other laboriously accumulated set of sequences, which came tagged with medical information) into a blender and asked which variations between people's sequences correlated with variations in their diseases. Did diabetes correlate with particular genes being defective or altered? Despite huge resources and high hopes, these studies yielded very little.

The reason was that the notion of variation (or mutation) and especially the intricate field of evolutionary population genetics, was, among these researchers, in a somewhat primitive state. They only accepted variations that occurred a few times, so that they could be sure they were not just random sequencing mistakes. In a population of, say, 1000, any variation that occurs a few times has a particular nature, which is to say that it must be somewhat stable in the population and have a long history, to allow it to rise to such a (modest, but significant) level of prevalence. This in turn means that it can not have a severe effect, in evolutionary terms, which would otherwise have cut its history in the population rather short. So it turned out that these researchers were studying the variations least likely to have any effect, and for all the powerful statistics they brought to bear, little fruit turned up. It was a very frustrating experience for all concerned.

A recent paper recapitulated some of these arguments in the setting of yeast genetics. The topic remains difficult to approach in humans, because rare variations are, by definition, rare, and hard to link to diseases or traits. Doing so in a clinical study requires statistical power, which arises from the number of times the linkage is seen- a catch-22 unless one can find an obscure family pedigree or a Turkish village where such a trait is rampant. In yeast, one can generate lineages of infinite size at will, and the sequencing is a breeze, with a genome 1/250 the size of ours. The only problem is that the phenotypic range of yeast is slightly impoverished compared to ours(!) Yet what variety they can display is often quantifiable, via growth assays. The researchers used 16 yeast strains from diverse backgrounds as parents, (presumably containing a wide variety of distinctive variations), generated and sequenced 28,000 progeny, and subjected them to 38 growth conditions to elicit various phenotypes.

The major result, graphing the frequency of variations against their phenotypic effect. The effect goes up quite strongly as the frequency goes down.

These researchers claim that they can account for 73% of phenotypic variation from their genetic studies- far higher the rate seen for any complex human trait. They see on average 120 loci affecting each trait across the study, and 12 loci affecting each trait in any one mating. Based on past work with libraries of yeast strains, they could also classify the mutations, er, variations they saw coming from these diverse parents as either common (similar to what was analyzed in the classic GWAS experiments in humans, occurring at 1% or more) or rare. Sure enough, the rarer the allele, the bigger its effect on phenotype, as shown below. In rough terms, the rare variants accounted for half the phenotypic variation, despite comprising only a quarter of the genetic variation.

In an additional analysis, they compared all these variants to their relatives in a close relative of this yeast species, in order to judge which allele (variant / mutant or the reference / normal version) was ancestral, i.e. older. As expected, the rare variations that led to phenotypic effects were mostly of recent origin, and more so the stronger their effect.

"Strikingly, no ancient variant decreased fitness by more than 0.5 SD units, whereas 41 recent variants did."

The upshot is that to learn about the connection between genotype and phenotype, one needs significant (and typically deleterious) mutations, as geneticists have known since the time of Mendel and Morgan. Thus the use of common variants (with small effects) to analyze human syndromes and diseases has yielded very little, either medically or scientifically, while the study of rare variants has been a gold mine. And we all have numerous rare variants- they come up all the time, and are likewise selected out of existence all the time, due to their significant effects.

The scale of the experiments done here in yeast allow high precision genetic mapping. Here, one trait (growth in caffeine) is mapped against correlating genomic variations. The correlations home in on variations in the TOR1 gene, a known target of caffeine and a master regulator of cell growth and metabolism.

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Addiction, Exorcism, and the American Dream

Review of Beautiful Boy.

Why is drug addiction such a widespread and dangerous scourge? A lot has been made of the despair of the working class especially in declining rural areas- a crisis of meaning and survival at the short end of the capitalist system. But there is higher anxiety everywhere in our unequal, precarious, and atomized system. Even in wealthy Marin, where the story of this movie originates, parents are in what seems like fight to the death to get their offspring into colleges to fulfil an overwhelming set of competitive expectations. No wonder young adults, even when well-to-do, already feel themselves in a rat race which it would be pleasant to check out of, momentarily. Then add in the viciousness of modern drugs like crystal meth and fentanyl, and you have a lethal witches' brew.

Still from the movie. Timothee Chalamet playing Nic Sheff, and Steve Carrel playing David Sheff.

We used to regard Russia as a demographic basket case, with declining population riven with alcoholism in the wake of the Soviet collapse. Now we are facing a similar downward dynamic- a social rot punctuated by self-destruction through drugs and suicide. The ultimate source seems to be broad insecurity, which was precisely the point of the economic and cultural reforms of the recent Republican epoch, starting with Ronald Reagan. The benefits of competition and division were trumpeted, and the rich were feted as job creators and entrepreneurs, and given absurd benefits like a tax rate on investment profits half as high as the rate on labor income. Companies developed an ideology of serving profits to the exclusion of all other goals, which meant the destruction of stable life schedules, stable jobs, and stable communities. The Reagan era gave rise to wide-spread homelessness, the ultimate warning to labor to keep its head down. And a broad reduction of safety nets of all sorts, from corporate pensions to onerous rules for welfare, which was divided into a puzzle of ungenerous programs.

How ironic, then, that Donald Trump offered to fix all this for workers, restoring the greatness and jobs of America. Who suspected that he came from a Republican tradition whose first order of business, when given power, has been to hand money to the rich? Who suspected that his policy ideas came more from the tabloid headlines of the 80's and 90's (not to say his fascist forebears in the 30's) than from the issues the working class face today? Who suspected that the greatest epoch in American history, after World War 2, was actually our period of highest taxation, culminating in, not coincidentally, the Apollo space program, which was hardly a capitalist venture?

Reagan, George W. Bush, and Trump each cloaked themselves as shamans for an anxious society, ready to exorcise the demons of economic malaise and insecurity, as well as those of Vietnam. While Democrats offered laundry lists of melioration, Republicans could do no such thing, their object being to strengthen hierarchy and help the better-off. They have instead lighted on a more tribally / religiously tinged approach, offering a broad ideology of conservatism (however radical the implementation, and departure from the existing system) and order, which would by some mystery of compassionate conservatism redound to the benefit of all after generous payouts to the few.

On the military front, they authored a series of military misadventures that climaxed with the criminal debacle in Iraq. On the economic front, they pushed hard-line capitalism as the cure-all to bring economic growth, starving the state with deregulation, outsourcing, and bitter budget / deficit battles as a purgatorial nostrum that would rejuvenate an ailing system. Curiously, however, the treatment never worked for the middle class and poor, keeping them economically static and ever more insecure, while the rich and super-rich pocketed all the proceeds.

Economic vitality needs some dynamism and destruction. But people and communities need stability and a basic level of egalitarianism to feel human and have basic freedoms. The founders foresaw that rising wealth and inequality might make of America the same class-ridden culture they had fled in Europe. Their hopes were tied not just to the new republican structure they were building, but also, in economic terms, to the frontier- the jobs-for-all program of its day- which would continue to offer all Americans (and immigrants from all over the world) the option of a decent and hard-working living, preventing excessive inequality.

Now the frontier is gone, the population continues to rise, and the only solution from the "conservative" right is to squeeze the middle class and poor relentlessly in a spiral of anxiety that drives everyone to work and live under ever less humane conditions. We need a better balance that builds more unifying social structures and public goods, reels back the excesses of extreme capitalism, and gives people breathing space and freedom to dream of being more than cogs in a machine.

Chromosomes Blown to Smithereens

Where do cancers and cancer relapses come from?

DNA is a treasure trove that keeps on giving. The human genome sequence was a milestone that may not have been self-interpreting, but has provided grist for leaps of technical advancement and knowledge. Ancestry studies are one example, but disease studies are of more immediate interest. Cancer is now understood to be a molecular disease where the DNA suffers mutations that release various brakes on cell proliferation. One of the most influential types of mutations are gene fusions, where one gene that has roles in proliferation is broken from its normal regulatory controls, either within its coding sequence (such as a repressing protein domain) or its upstream expression controls, and hooked up with some other gene that drives its expression in new places and high levels. A recent paper studied several cancers in detail, sequencing samples from various time points and locations, coming up with very interesting findings about the origins of these mutations and the nature of metastasis.

One example of a genome blow-up, called "chromoplexy". A few regions of the genome got caught in some kind of spindle, and came out with several breaks which then were repaired to form re-joined fusions. In this diagram (right) of one resulting fusion, of genes BCLAF1 and GRM1, the chromosome 6 parts on the outside have rejoined, while the broken parts between the rejoined ends have fused to each other and then to chromosome 16, with one small bit unassigned and perhaps ending up somewhere else. The diagram seems to indicate that GRM1 ends up upstream of BCLAF1, (these are divergently transcribed in the native chromosome), which I think is an error.

Chromoplexy is one form of a genome blowup, one that is restricted in scope (at least compared with the even more destructive chromothripsis). The best theory about its origin posits that the affected portion of the genome (typically an early-replicating and transcriptionally active region) gets caught outside the normal nucleus, forming a temporary mini-nucleus which is cut off from normal controls, causing the trapped DNA to break up. The cell has strong controls against free DNA ends, and uses end-joining DNA repair to patch things up, pasting ends together essentially at random. This is obviously quite dangerous, and leads to unexpected gene fusions, of which hundreds of different examples are now known that drive various cancers. One such fusion, diagrammed above, is between genes BCLAF1 (upstream) and GRM1 (downstream).  GRM1 is a receptor for glutamate, the most prevalent excitatory neurotransmitter. While most highly expressed in the brain, glutamate receptors act throughout the body, and malfunctions are connected with a variety of diseases. Increased expression and activation can drive cell proliferation. The other fusion partner, BCLAF1, is a promoter of cell suicide, or apoptosis. That function will be lost in the fusion, which might have some importance to the disease (though a second copy presumably remains intact elsewhere). The important part is that it is very widely expressed, especially in bone marrow. An earlier paper describing this fusion states:

"The GRM1 coding region remains intact, and 18 of 20 CMFs (90%) showed a more than 100-fold and up to 1,400-fold increase in GRM1 expression levels compared to control tissues. Our findings unequivocally demonstrate that direct targeting of GRM1 is a necessary and highly specific driver event for CMF [bone tumor chondromyxoid fibroma] development."

This pattern of mutation, and the specific fusions that resulted, became apparent due to the deep sequencing the researchers did, taking samples from the patient's tumors and from normal tissues. An important concept here is of mutational signatures. Each mechanism of mutation has its characteristic pattern of mutations left in the genome. Exposure to UV light, which causes C->T mutations, will leave a much different pattern in the genome than the localized chromoplexy blowup mentioned above. So a forensic analysis of the patient's DNA can tell what happened, in some mechanistic detail. For example, the various fusions seen in these samples were not part of extensive copy number variations- reduplications that are common in cancerous cells, which indicated that this blowup took place once as a discrete event, not repeatedly or slowly over a long period of time.

It can also tell when it happened, and here we get to a particularly interesting message from this paper. When they sequenced primary and relapsed tumors, (with comparisons to normal tissue), such tumors shared some key mutations, those which drove the overall cancer. But they failed to share many others. Indeed, the metastatic tumors carried none of several mutations that were uniformly present in the primary tumor. This says that metastases or relapse cancers, (this part of the study was specific only to Ewing's sarcoma, a bone cancer typically arising around ages 1-20), typically do not develop from the primary tumor, but from cells that carry the same driver mutation, but diverged before primary tumor formation. They are independent events, and metastatic prognosis has little to do with the fate of the primary tumor.

The author's proposed time course of Ewing's sarcoma evolution, placing the origin of metastatic and relapsing tumors well before and outside of the primary tumor at the time of diagnosis.

Whether this observation about metastisis applies to other tumors is naturally important to follow up. It would alter significantly how we deal with primary tumors, and informs the kind of conservative treatments (lump-ectomies, for instance) that are becoming more common. As sequencing becomes cheaper and more common for all kinds of tumors, the particular drivers, from whatever mutational source, can be identified and used to direct specific, (buzzword: "precision") treatments. GRM1 can be targeted by direct or indirect means. But if one has Ewing's sarcoma, typically associated with a fusion of EWSR1-FLI1, where FLI1 is a transcription factor that drives growth factor production and hence cell proliferation, a different set of therapies would be indicated.

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Screwy Locomotion: the Spirochete

How do spirochete bacteria move?

Getting around isn't easy. Some of our greatest technological advancements have been in locomotion. Taming, then riding, horses; railroads, automobiles, airplanes. Microorganisms have been around for a long time, and while flying may be easy for them, getting through thicker media is not, nor is steering. The classic form of bacterial motion is with an outboard motor- the flagellum. The prototypical bacterium E. coli has several flagella sprinkled around its surface. Each flagellum is slightly helical, thus forming a languid sort of propeller, which if turned along its helical axis, (at roughly 6,000 rpm), can propel the bacterium through watery media. Turning multiple flagella in this same direction (counter-clockwise) encourages them all to entangle coherently and unite into a bundle. It turns out, however, that bacteria can easily switch their motors to the opposite direction, which causes the flagella to separate, and also to flail about, (since for a left-handed helix, this is the "wrong" direction), sending the cell in random directions.

A typical bacterium with multiple flagella, which will cooperate in forming a bundle when all turned in the same direction, consonant with their helicity (i.e. counter-clockwise).

These are the two steering options for most bacteria- forward or flop about. And this choice is made all the time by typical bacteria, which can sense good things in front (keep swimming forward), or sense bad things in front / good things elsewhere (flail about for a second, before resuming swimming). The flagellar base, where the motor resides, uses both ATP and the proton motive force (i.e. protons that were pumped out by cellular respiration, or the breakdown of food). The protons drive the motor, and ATP drives the construction of the flagellum, which is itself a very complicated dance of self-organization, built on the foundation of an extrusion/injection system also used by pathogenic bacteria to inject things into their targets.

Animated video describing how the flagellum and its base are constructed.

But sometimes a bacterium really needs to get somewhere badly, and is faced with viscous fluids, perhaps inside other organisms, or put out by them to defend themselves. One human defense mechanism is a DNA net thrown out by neutrophils, a type of white blood cell. Spirochetes have come up with an ingenious (by evolution, anyway!) solution- the inboard motor. This is not a motor sticking out of the bottom, but a motor fully enclosed within the cell wall of the bacterium.

Choice of directions (small forward or back arrows) that are dictated by the rotation of the flagella (blue). One set of flagella originate at the rear, and a second set originates at the front. Only if they turn in opposite directions (top two panels) does the spirochete swim coherently, either forward or back. 

How can that work? It is an interesting story. Spirochetes, as their name implies, are corkscrews in shape. In mutants lacking flagella, they instead relax to a normal bacterial rod shape. So they have flagella, but these are positioned inside the cell wall, in the periplasmic space. Indeed they form the central axis around which the corkscrew rotates, with one set of (approximately ten) flagella coming from the rear and another set from the front, each ending up around the middle. If each set rotates as hard as it can, they drive their respective ends to counter-rotate, in reaction. If the front motors (of which there are several) turn their flagella counterclockwise, as viewed from the back, they will, in reaction, drive (and bend) the nose into a clockwise orientation. If the back set of motors run clockwise, driving their flagella counterclockwise (also as seen from the back), then the rear part of the bacterium counter-rotates in clockwise fashion, and the coordinate action drives spiral bending and an overall drilling motion forward.

Video of a non-spirochete bacterium with its flagellum stick to the slide, causing the tail to wag the dog.

Video of spirochete bacteria in motion.

On the other hand, if the motors on the opposite ends of the bacterium go in the same direction, then the flagella induce opposite, instead of coordinate, counter-rotations, and the bacterium doesn't tumble randomly, as normal bacteria do, but contorts and flexes in the middle, with a similar re-orienting effect. This ability incidentally shows the remarkable toughness of these bacteria, considering the lipid bilayer nature of their key protective membranes. These bacteria can also easily reverse direction, by sending both sets of motors in reverse, operating very much like little drills. How this exquisite coordination works has not yet been worked out, however.

Reconstruction, drawn from electron microscopy, of one end of a spirochete, showing the motor orientations, the sharp hook/base of the flagellum, the membrane and cell wall structure, and one of the signaling proteins (MCP), which transmits  a sensory signal to dictate the direction of motor rotation.

One thing that is known, however, is that spirochete motors are massive- almost twice the size of E. coli motors, with special outside hooks to propagate power through the tight turn inside the periplasmic space. It is interesting that these motors can be scaled up in size, with more subunits, and more proton ports for power, as if they were just getting more cylinders in a (fossil fuel-burning) car engine.

Structure of the Borrelia flagellar motor, showing the stator (blue), which is attached to the membrane and stabilized against rotation; the rotor (yellow spokes and teal C-ring), and the gateway ATPase complex which unfolds and transmits the structural components (proteins) into the central channel from which they build the machine.

All this is in service of getting through messy, gelatinous material. The model for most of this work is the spirochete responsible for Lyme disease. The characteristic red ring seen in that infection is thought to track the progress of the spirochete outward and away from the original tick bite site, in relation to the immune system catching up via inflammation. But such viscous environments are quite common in the organic muck of the biosphere, including biofilms established by other bacteria. So the evolutionary rationale for the superpowers of spirochetes is probably quite ancient.

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Striptease by HIV

How the virus disrobes is an important part of its life cycle, secrets of which are still being uncovered.

For such a tiny entity, HIV-1 has a very complicated life. Its study has generated numerous drugs that interfere with key life events, and have brought it under control in most developed areas of the world. But there is a lot left to learn. While its fusion with target cell membranes and eventual replication have received the most study, less is known about what happens in between.

The layers of HIV. Outside is a membrane, which features proteins like gp120 that binds to T-cell receptors.

The virus has several layers. On the outside is a membrane coat, designed to protect the virus in moist environments, but more imporantly to expose surface proteins that seek out T-cells specifically, and then to fuse with their membranes, thus entering them. Inside the lipid membrane and its supporting proteins is the capsid, a protein coat that protects the HIV genome from attack by internal T-cell defenses like RNases, helicases, RNA sensing proteins, interferons, and their various downstream effects. This capsid finally lets go if its cargo at the nucleus, where the viral genome, now transformed into double stranded DNA, integrates itself into the cell's genome.

Electron micrograph of HIV particles. The capsid sits inside the membrane coat, all of which is about 120 nm in diameter.

Innermost is the genome, composed of RNA, not DNA. Packaged alongside it are key enzymes integrase, RNase H, and reverse transcriptase. Once HIV enters the cell, and meets the rich mother-lode of ATP and other nucleotides, including deoxy-ribonucleotides that are the building blocks of DNA, the reverse transcriptase can begin its work. It copies the  genome in a complex sequence of starts within the linear RNA, hops to the other end of the RNA, continuation, and finally termination. All the while, the RNase digests the original RNA genome, in a remarkable process of self-transmutation. It is thought that synthesis of the complementary DNA strand only begins after the virus rides the cell's light rail system (microtubules) to the nucleus, where it leaves its capsid behind.

Some recent papers shed a bit of light on the nature of the HIV capsid, which is more interesting than previously understood. It was not previously clear whether the capsid uncoats at the membrane during original entry, or only at the nucleus, or even inside the nucleus. But one paper shows quite definitively that the capsid remains intact through the first strand of DNA synthesis, thus through most or all of the virus's trip from the outside membrane the nucleus. This work required rather difficult assays for capsid integrity, judged by the inclusion of fluorescent protein GFP into the viral genome. Most of this protein escaped during viral fusion with the membrane, since most of the free volume of the virus is outside the capsid. But a small portion remained visible as long as the capsid remained intact.

One hexamer of the capsid protein CA. At the center is pore, accommodating a very small molecule of ATP, in yellow/orange. The surrounding blue parts of the protein are positively charged, ideally suited to attract nucleotides and the IP6 stabilizing molecule.

Another paper took a closer look at the stability and composition of the capsid. It is known to be composed of roughly 1500 copies of the viral CA protein, in multimeric (hexameric and pentameric) rosettes. The structure above shows that at the center of these rosettes is a small pore, big enough to let in ATP- suggesting clearly that the deoxynucleotides needed for reverse transcription can enter even while the capsid is intact, providing the virus with the best of both worlds- protection from the cell's various specific antiviral defenses, but also food for its replication. In the lab, these capsids have been remarkably unstable, however, leading some to believe that the virus uncoats soon after it enters the cell. But these authors find that a chemical that is obscure, but common in cells, IP6, is shaped just right, and negatively charged just right, to sit in these rosette pores and stabilize the whole structure, extending the lifespan of capsids in the test tube to hours instead of minutes.

Two mysteries remain- first is how deoxyribonucleotides get in if IP6 is blocking the pores and stabilizing the structure. The likely answer is simply that these small molecules are not plugs. They have more stochastic behavior, jumping on and off frequently enough to allow other small molecules occasional access. The second question is what finally causes the capsid to unravel at the nucleus and release its now-DNA genome to join that of the cell. It is thought that these capsids are too large to go through the nuclear pore, so they may dock in some fashion and only transmit their contents, probably using special signals that mimick one of the many other proteins and molecules that are regularly imported into the nucleus. That process is currently unknown, and may be another avenue of viral inhibition and drug development.

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Blood Tests For Cancer

"Liquid biopsies" for cancer are coming to the clinic.

Cancer remains the winner in the war on cancer. New molecularly-driven precision treatments have improved outcomes for a few types of cancer, and the reduction in smoking has provided substantial improvements in death rates, but the overall statistics remain grim, most treatments are dreadful, and early detection is more a mirage than reality. One promising, though still experimental, area of progress is in detecting cancers using blood samples.

Cancer trends in the US, overall.

Early detection has been a holy grail, with enormous resources devoted to mammography and PSA tests, among much else, which have turned out to be of marginal utility, or far less than touted. I do not believe there is currently any cancer for which a reliable medical test of any kind provides detection before symptoms or manual / visible detection is possible. After the various reliable and unreliable methods of detection, assessment of cancers involves biopsy, which is far more invasive and disruptive than it sounds, piercing the putative site / organ with a large sampling needle which can cause permanent damage. Biopsy should be regarded as a full surgical procedure in its own right.

Both of these problems could be alleviated with effective blood tests for cancer presence, type, and progression. A significant development in the research field over the last decade or two has been the realization that cancers shed material constantly. Cells are sloughed off in live and dead form, and DNA from tumors is generally in circulation. One corollary is that metastasis is more a matter of these cells finding a congenial home than of their dispersal from their primary source. A second is that blood tests can detect these DNAs and cells on a routine basis.

The root method for doing so is PCR- that revolutionary method in molecular biology that harnesses DNA replication to amplify nucleic acids exponentially, allowing detection of infinitesimal amounts. One of the papers under review in this post claims that a single molecule of cancer cell DNA can be detected in 5 ml of blood. This is astonishing, but also puts bounds on the ultimate utility of this method, since they also say that less than half of grade 1 cancers provide even such a tiny signal. It turns out that, as one might expect, earlier and smaller cancers shed less material than later ones do.

Early stage cancers are hard to detect, but not impossible. The lowest Y-axis levels correspond to one molecule in the sample.

This landmark paper tests patients with many different types of cancer to evaluate the possibility of a relatively blood test for certain known cancer mutations. They find that brain cancers are particularly poorly represented- their shed materials are likely to be confined due to the blood-brain barrier system, plus the glymphatic system. But other cancers are quite amenable to blood testing, at least when in an advanced state. This would at least be a boon to recurrence tracking, and treatment monitoring, for which (repeated) biopsy is either impractical or impossible.

Which cancers give usable blood-born DNA samples?

"... 47% of patients with stage I cancers of any type had detectable ctDNA, whereas the fraction of patients with detectable ctDNA was 55, 69, and 82% for patients with stage II, III, and IV cancers, respectively."

For early screening, blood testing is not, as of this paper in 2014, truly reliable. On the other hand, it finds half of stage 1 cancers, which otherwise might not be found at all, raising the question of how such a cancer should diagnosed and found if a blood test finds, for example, that a common mutation (for example, in the gene TP53) is found to be afoot in a patient. Such mutations, which drive many different cancers, could come from virtually any organ. Some more sleuthing would be in order.

One such approach came up recently, in studies of regulatory markings on DNA, which some call "epigentic" marks. C nucleosides in DNA can be methylated and then derivitized from there to 5-hydroxymethyl 5-formyl, 5-carboxyl, and finally identified by the DNA repair pathway and excised / replaced. Typically, methylation is a repressive signal, part of the cellular machinery that turns off gene expression. In contrast, 5-hydroxymethy modified C residues seems to be associated with higher gene expression. At any rate, both modifications are dramatically reduced in cancer cells, and their patterns can be informative about the cancer's tissue of origin and prognosis/stage. There is even the possibility that the relative positions of 5-methyl-C and 5-hydroxymethyl-C in very small segments of DNA (detected by FRET, no less) could be informative on these issues, though that is more esoteric.

So far, these methods are plumbing the blood samples for specific DNA mutations in specific genes known to drive cancer, and thus have high specificity, but limited utility as general screening tools for patients who have not yet been diagnosed and could have any (or several) of thousands of different mutations. To do that, a far larger panel of genes needs to be assayed, possibly even whole genome sequencing, with an unbiased analysis of their mutations. But that begs the question of how to separate the cancer-derived DNA from all the other junk floating around in a blood sample. Methylation marks may be biased in cancer-derived DNA in useful ways, but they do not have categorically different characteristics usable for separating the wheat from the chaff. This is the big problem right now in cancer blood testing. On a practical level, it will start being used for already-diagnosed patients, to track their treatment and relapse. The cancer selection problem will likely be solved in a brute-force way by sequencing everything in the blood sample and sifting through that data using a growing catalog of cancer-causing mutations. But if some mark or characteristic can be found that is specific to cancer DNA, then general and convenient cancer screening via blood tests will come much sooner.

• Rules are for little people.
• Such as immigrants. Who are Christians, right?
• Does Amazon need to be split up?
• Go ahead and stretch ... every day.
• Skateboard therapy.
• More bullying and sleaze.
• Studies in groveling and sycophancy. What causes this temperament?
• Remember Martha Mitchell?
• The Taliban is winning.
• Meanwhile, Japan has a problem of not asking questions.
• Capitalism is so not working.
• Aretha on piano.
• In California, old-money landlords make out like bandits.

The Biology of Fluoride

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

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

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

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

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

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

 

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

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

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

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

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

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.

Briefly....

Just a short post, on digestion.

There was a mildly interesting paper about food choice and nutritional sensing, using the worm C. elegans. The researchers describe how these worms avoid dead bacteria as food, but like live bacteria. One of the labile elements present in live bacteria but missing in the dead bacteria is the vitamin B2, aka riboflavin. It turns out that lack of B2 down-regulates (via the key metabolic regulator TORC1, in turn via decreased levels of ATP) some key proteases in the worm's gut, which naturally impairs their digestion and appetite. Unfortunately, the paper does not go on, as promised, to explain issues of food choice and nutrient seeking, which might be mediated by general lethargy, but may also be directed by more specific neural pathways connecting the gut with the brain- an area of significant interest these days.

• Sclerosis and corruption at UC.
• Should wars be long or short?
• Can residential architecture be interesting?
•  ...  a lobbyist for Tyson Foods was injured at the Republican baseball practice.
• A freight train seems to be headed for Trump, because the feudal Putin model doesn't work here (or at least, not yet).
• In civil rights, the Federal government has been captured by the South.
• And the EPA, by industry.
• The solution, as usual, is more guns.
• Emotion, behavior and intelligence as biological traits.
• Economic graph of the week: wage share and profit share, in Australia.

Wage share vs profit share, in Australia, very similar to other economies. What would it take to make developed economies great again?

Massage and the Future of Medicine

Trigger point therapy for muscles. Brief review of "The Frozen Shoulder Workbook", by Clair Davies.

For anyone with muscle issues, trigger point therapy can be a profound experience. This is the palpation, detection, and deep massage of any muscle that has "knots" in it, which are also called trigger points. Such knots can arise from overuse or trauma, and can last for years, impairing use of the muscle, and, in the case of the shoulder, causing a cascade of impairment that comes to be known as frozen shoulder syndrome. Clair Davies' book is a thorough guide through this thicket, and brings to light issues that mainstream medicine seems to be rather slow in picking up.

Indeed, one could imagine that every general physical appointment, which now focuses on a few metrics of internal medicine, such as blood pressure and blood chemistry, might start with lengthy session of skilled massage. This would bring therapeutic massage into the medical setting, where it belongs, relax the patient while attending to key muscle issues that have been building up over the preceeding year, and also provide an entry to many other medical issues the patient may be having, like skin lesions and internal pain.  Something a little shamanic, but also holistic and integrative, changing the medical encounter for the better.

• Army life.
• A very different relationship with Russia.
• Conventional finance wisdom is wrong.
• We have a public management crisis.
• We can do single payer in one state.
• We can do spectrum and cell phone costs better, too.
• Proud to be a Californian.