India’s Disgrace

Feb. 15th, 2019 02:11 pm
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

I’ve written here about what I referred to as “nationalist science”, in that case actions by the Hungarian government against its own universities and the Chinese government’s vigorous promotion of traditional medicine. Now we can (unfortunately) add another one to the list. The Hindu nationalist movement in India has been moving into science and medicine in recent years, making claims about ancient discoveries and remedies that are completely unfounded but appeal to their supporters.

This article at Science will get you up to speed, most unenjoyably. There was an incident last month at the Indian Science Congress where a chemist, vice-chancellor of Andhra University yet, made the claim that ancient Hindus has been doing research in stem cell technology based on a tale from the Mahabharata. You know, back in 1972 I was more skeptical as a ten-year-old reading those Erich von Däniken paperbacks which made similar claims, so it’s not very encouraging to see this stuff showing up in 2019. In fact, from the looks of it, some of these folks are citing the exact same verses in the ancient epics, and why the hell not, I guess.

Problem is, this is not some lone crank:

Some blame the rapid rise at least in part on Vijnana Bharati (VIBHA), the science wing of Rashtriya Swayamsewak Sangh (RSS), a massive conservative movement that aims to turn India into a Hindu nation and is the ideological parent of Modi’s Bharatiya Janata Party. VIBHA aims to educate the masses about science and technology and harness research to stimulate India’s development, but it also promotes “Swadeshi” (indigenous) science and tries to connect modern science to traditional knowledge and Hindu spirituality.

VIBHA receives generous government funding and is active in 23 of India’s 29 states, organizing huge science fairs and other events; it has 20,000 so-called “team members” to spread its ideas and 100,000 volunteers—including many in the highest echelons of Indian science.

The former head of Indian defense research, for example, says that he firmly believes in the powers of gemstones to influence human health. Narenda Modi himself claimed a few years ago that the transplantation of the god Ganesh’s elephant head onto a human was an example of outstanding ancient Hindu surgical techniques. And if that sort of thing doesn’t make you want to bury your head in your hands, try this:

Critics say pseudoscience is creeping into science funding and education. In 2017, Vardhan decided to fund research at the prestigious Indian Institute of Technology here to validate claims that panchagavya, a concoction that includes cow urine and dung, is a remedy for a wide array of ailments—a notion many scientists dismiss. And in January 2018, higher education minister Satya Pal Singh dismissed Charles Darwin’s evolution theory and threatened to remove it from school and college curricula. “Nobody, including our ancestors, in written or oral [texts], has said that they ever saw an ape turning into a human being,” Singh said.

Excellent. The first time I remember hearing that one was from Mr. Smith, an elderly man who lived next door to us in my small Arkansas town in the late 1960s. He had the exact same line about apes and humans, and went on to inform me that moon landing program was a hoax and that dinosaurs never existed (“Just a bunch of old bones they stuck together”) As a six-year-old fan of NASA and defender of the honor of dinosaurs, these claims did not go over well with me. My 1968 visions of what the world would be like in fifty years tended towards space travel and flying cars, and most definitely did not include national ministers of science taking the side of Mr. Smith.

Needless to say, India has produced great scientists (Hindu and otherwise) who have done great work: Bose, Raman, Chandrasekhar, Ramanujan, Khorana and many more. But the country’s scientific record is dishonored and mocked by this sort of thing. There are many prominent Indian researchers speaking out against these idiotic statements, and I support them wholeheartedly. Science in general is dishonored by attempting to impose nationalist or religious criteria on top of its underlying principles. Those principles? To find out the truth about the natural world, to validate it by careful and repeated experiment, to build on that knowledge wherever it may lead. To understand physical reality, in other words, to work with it as it is and not to play games by believing only what it makes us feel good to believe.

Woo, Convergence!

Feb. 14th, 2019 04:50 pm
lil_m_moses: (convergence)
[personal profile] lil_m_moses
Just got ourselves set up for Convergence _25_ in Boston!

We went to NOLA for 22, but I was pregnant at the time and it was an odd weekend. Hopefully this one will be smoother, and it'll be great to return to the site of my first Convergence, 24 years later (holy crap!). Josh's folks are going to stay at our house with Lillian for the weekend (she's still in school and TX absence policies are draconian (family vacations don't count as excused)).

Odd Peroxides Indeed

Feb. 14th, 2019 03:01 pm
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

You know, normally when you start combining interesting or reactive functional groups in the same molecule, you end up with something that’s worse than before. Would I pick up a flask containing a compound that has both a perchloryl ester and a geminal di-azide? I would not, and neither should you, should someone ever be foolhardy enough to prepare such a thing. Those are only for lobbing at hostile monsters in video games. So I was interested to see a recent paper on perfluoroalkyl peroxides. Changing the electronics of that group would surely have an effect, but of what kind? (And perfluoroalkyls want all the electron density, so you know that something is going to change).

Well, to my surprise, the result is the friendliest batch of alkyl peroxides that you’re ever going to see. There was some foreshadowing, though. It turns out that the only member of this compound class that had really been characterized in the literature to date was the bis-trifluoromethylperoxide, which dates back to 1933. It was found to be weirdly stable, as in up to 200 degrees C. Do not, under any circumstances, try heating up a regular dialkyl peroxide in such a manner – you’re not going to get very far, although the pieces of the reaction vessel will.

Preparing these things is worse than handling them once they’re made, by far. As this paper shows, the previous syntheses relied on rather spirited reagents like chlorine trifluoride, and when your prep calls for that one, it’s time to re-examine the life choices that have brought you to that point. That’s what this Berlin group did, clearly, coming up with a route that involves some generally unappealing chemistry, such the treatment of silver wool with elemental fluorine gas at 100 degrees. OK, you don’t start at that temperature, no matter how much of a buckaroo you are – they introduce “small portions” of fluorine to the silver in a sealed metal apparatus at RT “until the pressure remains constant”, that is to say, until it stops whooping and hollering in there, and then they raise the temperature. You also have to prepare hypofluorites of the alkyl groups, which you do from the alcohol and cesium fluoride, introducing (yet again) elemental fluorine in portions until all the overpressures stop spiking, and then do trap-to-trap distillation at -150C. Treating the hypofluorite with that silver fluoride/silver wool, followed by another trap-to-trap purification, gives you the desired perfluoroalkyl peroxide.

None of this am I lining up to perform. Straight fluorine has long been on my “Things I Won’t Work With” list, although if I had to choose, I would go for that over using chlorine trifluoride, albeit with profound unhappiness and thoughts of chucking the whole business and opening a taco truck instead.But at the end of all this, the compounds you get out are, as mentioned, surprisingly tame. The bis(perfluoro-t-butyl) peroxide, for example, melts at about 18C, so at most room temperatures it’s colorless liquid that just sits there, bizarrely. It’s insensitive to shock, insensitive to friction, and you can even get a boiling point on it (99C), albeit with decomposition.

You cannot say any of that about the plain bis-alkylperoxides, that’s for damned sure, except for the decomposition part, which unfortunately can happen with fearsome speed when you so much as look at them funny. So what’s going on? The paper notes that the O-O bond energy isn’t that different in the two sorts of compounds. What changes, though, is the energetics of the alkoxy radicals that form when that bond cleaves. The reactions of the perfluoroalkoxy species are slow and endothermic; the reactions of the regular alkyls, definitely not. The paper goes into a number of structural and computational details – there have been some longstanding arguments about peroxide conformations and bond angles versus theoretical predictions, and these compounds have some bearing on that.

So there you have it: if you’re willing to walk through the valley of elemental fluorine, you can arrive at these odd compounds. It’s be interesting to see what sort of reactivity they have as selective oxidants. Who knows, they may turn into familiar reagents if they do something useful, or they may just remain as chemical curiosities. They’ll always be that!

Shutdown Season

Feb. 13th, 2019 12:17 pm
lil_m_moses: (NASA meatball)
[personal profile] lil_m_moses
We're preparing for 2019 Government Shutdown Mark II. This time it seems they're leaning toward no unexcepted workers on site, more like what they did in October 2013. Our contract got paid in the last couple weeks of ops, so we're good into April, though it sounds like they may not be able to keep everyone working if we're restricted from being on site (I imagine this will principally affect technicians, which is extra unfortunate), and while some folks may be able to bring work off site, they'll likely be stashed whereever there's spare room (conf rooms, etc.). Last time we were in a shrinking mode and had spare desks available, but this time we've been growing fast and most of our building space is occupied.

Hopefully the Legislative and Executive Branches can work it out before Saturday (or at least before Tuesday), but I am dubious.

Vibrating Proteins, Resolved

Feb. 13th, 2019 04:39 pm
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

Here’s something that many of us don’t tend to think about when we think about enzymes: vibrational energy. But it’s long been thought that anisotropic vibrational energy transfer (VET) plays a role in both enzyme active sites and in things like coupling to allosteric sites. Getting a handle on that, though, has not been easy – how would you pick out one particular part of a protein and suddenly increase just its vibrational energy?

Well, this new paper has found an ingenious way of doing just that. The group (a multinational effort from Germany, Canada, and Denmark) used an unnatural amino acid, the azulene analog of phenylalanine. Azulene is beloved by those who know it for its striking blue color and odd spectroscopic behavior, and that’s what’s being taken advantage of here. When the molecule is excited by 600nm light, it undergoes an unusual conversion from the singlet excited state, shedding all that energy into vibrational modes. In effect, when you do this to an AzAla-containing protein, you are quickly and selectively heating up that particular side chain, which you have placed wherever you choose in the protein’s structure.

Of course, to realize that last part isn’t necessarily trivial, and in this case the team used a genetic code expansion, evolving a new aminoacyl-tRNA synthetase enzyme to handle the unnatural amino acid. They were able to use this system to put the AzAla residue into a model protein for allostery (PDZ3) and see what happens when vibrational energy gets suddenly injected. As a sensor for that, they also incorporated azido-homoalanine (Aha) residues, whose side chains can be monitored by IR spectroscopy, into the peptide ligand for the protein.

When the team irradiated systems of this kind with 613nm light, monitoring the azide group by IR, they did indeed see an instant VET signal. The azide absorption shifted to a lower wavenumber in two different experiments, one where the AzAla was relatively buried and one when it was on the surface. The latter showed less of an effect, though, because some of the vibrational energy got transferred out into the water instead. It appears that the vibrational energy transfer happens on the order of picoseconds, which is what you’d expect.

So now that this technique is feasible, the next step will be to incorporate this donor/sensor pair into a wider variety of positions and proteins. Eventually, this will allow a map of vibrational energy transfer for a given protein – we’ll be able to see how this propagates, through what parts of the protein structure, and at what speeds. A key part of protein behavior, one that we’ve been fairly blind to, is now opening up – this and new spectroscopic techniques in the area are going to tell us a lot that we’ve never known.

(no subject)

Feb. 12th, 2019 11:02 pm
randomdreams: riding up mini slickrock (Default)
[personal profile] randomdreams
I'm taking an electrical engineering course through the engineering department of CU Boulder and it is kicking my butt. He says second order differential equations so casually.
Today I left work early, came home, watched a nice man haul off my poor old Subaru, drove the Triumph down to the credit union and paid off my new Subaru, then drove over to get a crown replaced. On the way home, the seatbelt retract mechanism on the Triumph failed. This isn't the original one, it's one I put in 5 years ago when I replaced the original belts. I think seatbelts should be replaced periodically, but I don't think 5 years is a suitable replacement period. Nevertheless, that's what I get. There is a plastic hat-shaped bit that engages a spiral spring on one side, and engages the reel on the other, and it broke in the middle. I could mend it or 3d print a replacement, or best of all machine one out of aluminum. But I could also just buy another.

Tuesday List

Feb. 12th, 2019 03:35 pm
lil_m_moses: (lists)
[personal profile] lil_m_moses
- do 2 pushups, 10 air squats, and 15 situps
- evening Lillian supervision
- clear off desk chair and desk space
- clear off futon and pick sewing stuff up off office floor
- figure out where to pick up with my bathtub shelf tiling project and make a plan (realistically, the tub replacement is not on the _need_ list, and I already have most of the stuff to finish the fix I started years ago)
- put dirty dishes in dishwasher, and quickly wipe down kitchen counters, stove, & sink before bed
- lights out by 10:30

The FDA and the Dietary Supplements

Feb. 12th, 2019 01:25 pm
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

I’ve been complaining for years on this blog about the “dietary supplement” industry, which exists in its present form thanks to Sen. Orrin Hatch. That’s the 1994 “Dietary Supplement Health and Education Act”, which like many a federal bill has a name that is somewhat detached from reality. I would suggest the “Sell Any Damn Pill You Want Act” , with the proviso that you include words “dietary supplement” in 8-point font on the label, and have someone quickly mutter “These statements have not been evaluated by the FDA” at the end of your TV ads. Then you can sell any damn pill you want, apparently. When someone takes the time to analyze many of these preparations, all too often the herbal goodies turn out to be weeds and unknown material, although there are times when active ingredients get thrown in there, too – just not the ones on the label.

I’m glad to report that the FDA seems to be devoting more scrutiny to this issue. To be fair, the agency doesn’t have much freedom to operate thanks to that 1994 law, but they’re trying to implement an NDI framework (New Dietary Ingredient) that manufacturers would need to comply with, and trying to communicate potential problems with marketed supplements much more quickly. The announcement coincides with letters to 17 companies pointing out that their dietary supplement are not, in fact, therapies for Alzheimer’s disease, no matter what their ads say. Here’s an example of such a letter – the medical claims go all the way down the page. Known to treat this, clinically proven for that, counteracts the symptoms of the other, safe and highly effective, prevents Alzheimer’s, prevents cancer, prevents Parkinson’s, prevents diabetes, on and on and on. This is crap, of course.

The US supplement industry has grown at least tenfold since the 1994 legislation, and why wouldn’t it? While there are legitimate things one can add to one’s diet, the big problem is that the law as written is an invitation to sell snake oil. Find something that no one knows how to treat and tell people that you can treat it; it’s not a difficult business model to understand, and the money most certainly does roll in. The sorts of claims made above are a disgrace, and should in fact be a crime, but they’re very profitable indeed. If the FDA can turn a hose on this sort of thing, then good for them. Let’s see what happens. . .

Too Many Ideas, Not Enough Money

Feb. 11th, 2019 02:58 pm
lil_m_moses: (The Party Pad)
[personal profile] lil_m_moses
Argh. I keep getting new ideas for ways to improve the house, but of course, they'll all cost $$$. Today's idea is to put a bank of shallow cabinets on the (currently mirrored) end of the dining room: solid doors bottom, glass doors top, counter space between, wine fridge space on end. The idea would be a replacement for the bar space, plus space for most of the stuff that's currently in a glass-front barrister bookcase. We could store our booze, tea, table linens, party glassware, maybe some games, etc. there, and have drink prep and serving dish overflow space on the countertop. (I'm totally blanking on the name of this sort of feature. The little file clerk in my head will find it later today. Aha - I finally googled the right thing. Sideboard or buffet is the word I want. Except with uppers. And built in. %) Dry bar, really.)
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

This new paper on “ultra-large” virtual screening is well worth a look in detail. We find a great many lead compounds in this business by random screening of compound libraries, and virtual screening is (as the name implies) the technique of doing this computationally instead of with hundreds (thousands) of sample plates and tireless robot arms. All of that takes time and effort and money – accumulating such a compound collection, making sure that those compounds are (or are still) what you think they are, dispensing them in a useful form, coming up with an assay that’s strong enough to run in automated fashion and actually getting it done, etc. The idea of doing all this computationally by docking mathematical representations of molecules into mathematical representations of your target has always been appealing, and it gets more so every year as the hardware gets ever more capable.  Even if you can’t predict de novo the compounds that will do the job, and we can’t, you can still run huge numbers of them, all varieties, and see which ones come out on top.

This paper (a large multi-center academic collaboration) reports what I believe is the largest publicly disclosed effort of this type. It takes as its starting point 70,000 commercially available building block compounds, and elaborates those using a set of 130 known reactions. This gives you what should be a “make-on-demand” library whose actual synthesis has a good chance of being reasonable. The paper itself screens 99 million compounds against one target (the AmpC enzyme) and 138 million against another (the D4 receptor), and the library has grown much larger since then. Less than 3% of that library is itself commercially available; there are a lot of compounds to make in this world.

The computational screening of this set is not a trivial exercise – to their credit, the authors did a pretty thorough job. You could play the game of run-a-quick-minimization-and-dock-that-as-if-were-rigid on these things, and you’d get through them pretty quickly, but to what end? Reality is more various than that. So for each compound, an average of around 4,000 orientations was checked (basically, which part of the molecule approaches the protein target and a what angle) and for each of those, 280 conformations of the molecule were sampled. That adds up to a number of possibilities in the ten to the thirteenth range, scored with DOCK3.7, which will take you tens of thousands of core hours to chew through on typical hardware. Compounds resembling known ligands for these targets were deliberately filtered out in a search for new chemical matter.

Now we get to some interesting numbers. From the AmpC hits, the team picked out 51 top-ranking molecules (each from a different scaffold class) to synthesize, and 44 of those efforts were successful. (These molecules, as with the D4 example coming up next, were selected both by docking scores and by human inspection – see below!) Of those 44, only five showed any activity in the enzyme assay (ranging from about 1 micromolar to about 400 micromolar). The best of that list represents a very good starting point indeed for this enzyme, and synthesizing analogs of its structure led to a 77 nM compound, which appears to be among the most potent non-covalent inhibitors reported for it. A crystal structure of the inhibitor/enzyme complex confirmed the predicting docking pose, which is always good to see.

As for the dopamine D4 effort, this one went a bit more in-depth. The team selected 589 structures, and not just from the top rank of the docking scores, but from the middle and lower parts of the list as well. 549 of these could be synthesized, and 122 of these showed more than 50% radioligand displacement at 10 micromolar. 81 of these were dose-responsed, and showed Ki values of 18 nanomolar to 8 micromolar. Not bad! Most of the potent compounds were full or partial agonists, but there were two antagonists in there as well. One of the potent agonists was synthesized as its four separate diastereomers, and one of those was down to 180 picomolar activity, 2500x selective against the related dopamine receptor subtypes, which is about as good as you’re ever going to get.

There are a lot of interesting take-aways from this work. For one thing, as the authors mention, it would be tempting to just dock representative members of each structural type/cluster, rather than having to do them all. But trying that really demolished the effectiveness of the screen, shedding active hits at an alarming rate. The current docking/scoring technology can get you as far as “compounds that look kind of like this”, but definitely cannot reach in and pick out the best representative of any given class. And even that level of discrimination comes with a lot of effort – note the number of hit compounds in both the examples above that turned out to be completely inactive on synthesis. That definitely argues for setting up these virtual libraries according to expected ease of synthesis, because otherwise you could spend a lot of time making tough compounds that don’t do anything. People have.

This also speaks to the importance of size. The D4 receptor has been the subject of virtual screening before, but not at this scale, and the best compounds here were (of course) not found in those efforts. Nor were any that were as potent as the best ones here. Size matters, and since we can’t zero in on the best compounds, we’d better be prepared to evaluate as many of them as we can stand.

Another point is that high-middle-low effort on the D4 case. The binding assay results compared to the docking scores are shown at right. You can see that the number of potent compounds (better than 50% displacement, below that dashed line) decreases as the scores get worse; the lowest bin doesn’t have any at all. But at the same time, there are a few false-negative outliers with binding activity at pretty low scores, and at the other end of the scale, the top three bins look basically undistinguishable. So the broad strokes are there, but the details are of course smeared out a bit.

There’s also a human-versus-machine comparison in evaluating the hits. The authors took the top 1,000 compounds and selected 124 of them by eyeballing them for what looked like good interactions in the docking pose (not looking at the scoring), and took 114 molecules on the basis of docking scores alone. The hit rates for the two sets were almost identical (about 24%), but the human-selected ones were disproportionately potent – and indeed, in the two campaigns, the human-selected compounds were quite over-represented in the lists of potent compounds. So we have that going for us. But again, note that three-quarters of the compound selected, even after all this effort, were not active. That’s a huge enhancement over background, which is good news, but it’s not the magic that some outside the field think we can work, either.

One thing to note is that these two binding sites are very well characterized. There are plenty of compounds known for each, and there’s a lot of understanding about the structure of them bound to the proteins. Trying this against a blue-sky binding site that you don’t know much about is going to be a much different undertaking – but that, of course, is what we’d like to do. Ideally computational screening will eventually do even more not only with compounds that aren’t yet real, but do that against proteins that have never been physically screened before at all. Getting solid, actionable protein structures, though, is far more difficult than running through orientations and conformers for small molecules – as it stands now, screening  modeled compounds against real protein structures can (as this paper shows) give you good results, although keep in mind that this report is pretty much at the edge of what we can do with current technology. But screening modeled compounds against modeled proteins runs a substantial risk of giving you a lot of noise. We’ll get there, but we aren’t there yet.

One other sobering note: this paper, as so many virtual screening papers do, starts off by mentioning the estimate for small-molecule chemical space of perhaps 1063 compounds. There’s room to wonder about that estimate, but since it’s cited here, let’s use it against the paper’s figure of 1.2 calendar days of straight processing time on 1,500 cores to get through the 138 million compounds in the second set. Extrapolating to the Big Set of Everything That Exists, that gives us 1055 days of processor time to screen the lot. Unfortunately, it’s only been about 5 x 1012 calendar days, more or less, since the Big Bang. So even if we allow ourselves more time by turning each day since the universe began into another universe’s current age worth of time (setting off a Big Bang every morning and waiting another 13.8 billion years until counting the next day) and then take each day of that unimaginable stretch and turn every one of those into another universe’s-age worth of time, then you would only need around a quadrillion of those extra-long intervals to get through the data set. Large numbers are indeed large.

Monday List

Feb. 10th, 2019 10:58 pm
lil_m_moses: (lists)
[personal profile] lil_m_moses
- call electrician
- arrange for alternate ring delivery - took delivery this morning!
- do 2 pushups, 10 air squats, and 15 situps
- have Lillian make Valentine box
- clear off desk chair and desk space
- put dirty dishes in dishwasher, and quickly wipe down kitchen counters, stove, & sink before bed - - all hail Josh!
- lights out by 10:30

- measured rooms that are candidates for luxury vinyl flooring so we can more accurately assess potential cost of doing all of them
- swapped LoveHandle on my phone
lil_m_moses: (weekend home warrior)
[personal profile] lil_m_moses
The living room and bar are completely empty, vacuumed, and ready for the fill! I want to get an electrician in to run the circuit for and rough in the floor outlets, so as to make the concrete job a pure concrete job. I may also have him move the outlets up as long as he's here. I made the new holes and have all the parts, but I'm not sure of the best way to unstaple the electrical cables from the studs inside the wall so that they can move out of the way of and be routed into the new boxes. (Wondering if I should have just put the new boxes in the middle of the bays instead of directly above the old outlets, alongside a stud.) Don't want to hire for the ~$4-5k concrete job before I get confirmation that the government isn't shutting down again, though.

journalism and sportsball

Feb. 10th, 2019 03:21 pm
wohali: photograph of Joan (Default)
[personal profile] wohali
Even if you don't like professional sports, or televised sports, or American football in specific, I encourage you to read this ESPN article:

Bob Costas, unplugged: From NBC and broadcast icon to dropped from the Super Bowl

The article explains who Bob Costas is, if you've never heard of him - a famous sportscaster who is so eloquent and well-read that he even got a late-night talk show after Letterman's Late Night for six years. It talks about his dislike for the sport of American football, the National Football League, and their ongoing cover-up of how concussions are seriously, permanently injuring a significant percentage of its players. And it talks about how his relationship with his network, NBC, fell apart over the last couple of years, chiefly because of him espousing this viewpoint repeatedly - even when not doing so on NBC itself.

I read it also as tragic commentary on the state of principled journalism in 2019 in North America. If even Bob Fuckin' Costas can be blacklisted in 2019, then we have a serious problem. I know Bob doesn't want to damage his relationship with his long-time associates at NBC, but I do hope that he will take this event as a moment to reflect on the bigger picture of media's role in the public sphere today. And I hope he finds a way to express those thoughts in a public forum, somewhere, on an ongoing basis.

Either way, I will definitely miss his voice.

on the bench: Old Crow's IG00153 VCO

Feb. 10th, 2019 02:38 am
wohali: photograph of Joan (Default)
[personal profile] wohali
My friend Old Crow gave me a mostly-stuffed version of his first Yamaha IG00153-clone voltage controlled oscillator (VCO) a few years ago, but without the front panel or controls. It languished in a drawer until this weekend when I took it out and hooked it up, since I want to add it to my modular synthesizer for an upcoming bit of music recording.

Details for the nerdy... )

I ordered the extra handful of parts ($3) I need to add the additional features to the board tonight, they should be here Monday. I already have all the panel controls and jacks that I need.

Once I've got the board working as I'd like, I'll design a front panel at Front Panel Express and get that sent to me. I've got a ping into Old Crow to ask him to send me the original front panel design so I can reuse his graphics. His original design is for a MOTM/5U system, but mine will be Eurorack sized. (The PCB juuuuust fits, with a little bit of filing on the edges.)


Feb. 9th, 2019 11:09 am
mmcirvin: (Default)
[personal profile] mmcirvin
Over the past few years, I gradually came to realize that I have obstructive sleep apnea. I hadn't had a really good night of sleep in years; I often woke up several times a night; Sam complained that I snored like a sawmill, and would sometimes actually hear my breathing stop entirely for a while. My symptoms generally resembled those of a whole bunch of people I know here and elsewhere who have sleep apnea, and got some relief from using a CPAP, a machine that blows air into you all night through a face mask. The idea is that the positive pressure can help keep the airway open, and the machine can even detect an apnea event and force the airway open by increasing the pressure.

So I wasn't surprised when, at my last physical, the NP quizzed me and recommended that I do a sleep study. This turned out to be, not a visit to a sleep lab, but a much cheaper at-home thing I did by borrowing a sleep monitor from Lawrence General, and sleeping with its pulse oximeter stuck on my finger and a cannula up my nose. That turned out to be kind of difficult, but I guess I got enough hours of fitful sleep that way for them to tell that there was something going on. (They also figured out that I had some pretty terrible acid reflux that needed treatment, and that's helped my sleep too, among other things.)

What followed was a month of fighting with my insurance company, who apparently thought I wasn't sick enough for them to pay out, but the sleep specialist my doctor referred me to eventually successfully badgered them into playing. So a couple of weeks ago a nice person from the CPAP dealer actually made a home visit and gave me my shiny new machine.


This is a ResMed model that has a cellular modem in it, the main purpose of which seems to be for the insurance company to spy on my sleeping habits so they can stop paying out if I'm not using it. There was a scary article about this going around recently; it's absolutely true, but the dealer did tell me the parameters up front: I have to use it at least 4 hours a night for 21 nights a month, which is not exactly onerous and would occur naturally if I'm making any effort at all to actually use it. It's a rent-to-own deal where the machine is eventually going to be mine, but it needs regular replacement masks and such. 

The CPAP itself is a surprisingly quiet machine (I'd worried there was going to be some loud fan, but it's not really audible). It's about the size of a large bedside clock radio, but heavier, with a built-in humidifier that needs to be filled with distilled water every day or two. There's a start/stop button on top, a phone-sized display screen on the front, and a dial that clicks in that's used to manipulate the menu system. I'm not allowed to mess with the air-pressure settings (these are prescription-specified), but I can adjust the temperature and humidity of the air that comes out. It turns out that these controls are worth fiddling with: I seem to do best with warmer and slightly drier air than the defaults they left me with.

The base unit is connected by a long hose to the mask, a clever Philips model made of clear silicone rubber, where the hose connects at a swiveling joint on the top of my head, the better to lie down with. The head harness consists of flattened hoses going down both sides of my face to connect at a piece that fits under my nose (all held on with a Velcro/foam rubber strap in back). I like that there isn't a big cup over my nose and/or mouth, which many CPAP masks have, but the bottom of my nose does sometimes get a bit sore and pimply from this thing pressing up on it.

I was a bit apprehensive initially about the mechanics of this: how do you breathe out? What if the machine stops working? The mask isn't completely airtight, though: aside from the hole that goes under the nostrils, the nose-piece has another little port in front for venting air, and there's also a bunch of vent holes on the hose connector. Breathing through your nose with a non-working mask on is entirely possible, though it becomes much easier when the machine is on. The machine seems to sense when you're inhaling and dials up the pressure then, at least if you take a deep breath.

Getting used to it

So... how is it to sleep with this thing? Does it work? Well... it's a process. The mask was weird and uncomfortable at first. They suggest that it might take weeks to fully acclimate to wearing the mask at night. I've had plenty of bad nights when I woke up at least as many times as before the CPAP, and didn't actually get much sleep. These aren't completely over yet. But I've noticed that on the nights when I do sleep (last night was a good one), I wake up in the morning feeling distinctly better, less kicked-in-the-head than I used to. I think the first noticeable benefit was just that I'm breathing filtered air, so whatever allergens are about at night don't bother me any more. This aspect will probably help a lot in the spring.

The strangest thing about wearing a nose-only mask is that you still can't really talk with it running: if you open your mouth for any reason, there's a bizarre sensation of air blowing out of your mouth when you try to inhale. Coughing is unpleasant unless you're sure to breathe in through your nose first.

There's an app/website where I can look at a summary of the data the machine uploads via its modem. Probably the most practical thing it does is show how badly the mask is leaking. While there are vent holes in the mask, in order to work it relies on there being a fairly good seal around the nostrils, and for the first week or so I didn't entirely have the fit worked out and could see big leaks in the numbers there. Eventually I got the hang of it.

It also shows the frequency of apnea events you're having through the night; these numbers are all over the place for me, and I don't really see a consistent trend, but presumably the machine is helping me start breathing again when I do have an event. There's a silly overall "score" it gives you, which mostly depends on whether you actually used the machine all night, but this other stuff figures into it too.

Probably the biggest issue is that my nose often gets progressively more congested over the course of the night, just from lying down, and if it's really bad the CPAP only incompletely powers past that. I may have had a mild cold when I started, which didn't help. I think I'm actually not a mouth-breather most nights (that would show up as a mask leak in the uploaded data), but I was wondering for a while if I needed to switch to a nose-and-mouth mask. Eventually I figured out that the temperature and humidity settings can help with this. But it's tricky. Some humidity helps clear out my nose; too much gives me this unpleasant situation I can only describe as "swampy nose", in which I get a powerful sensation that my nose is running like a hydrant and is going to fill the mask up with snot. When I take the mask off, this turns out to be an illusion. (I sometimes tell myself that even if it did, it wouldn't block the airflow, because of the redundant side hoses.) I suspect that with time I'll learn to discount it, but keeping the humidity right in the sweet spot helps.

A couple of nights I experimented with using Breathe Right strips to improve airflow inside my nose. I'd used those before getting a CPAP, and it actually is possible to use them with this mask, but they tend to degrade the fit, so it's a last resort.

As stated, it sometimes makes my nose kind of sore. Keeping the mask clean and using a lot of lotion there seems to help. It also takes a little fiddling to deal with my mustache, but I suspect it would actually be harder on my upper lip if I didn't have a mustache. I may end up experimenting with different kinds of masks, though I'll probably give this one some more time first.

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