New Phone, 2 Weeks On

Jul. 21st, 2017 02:21 pm
lil_m_moses: (phone)
[personal profile] lil_m_moses
Liking the new phone!

Good Stuff:
- Having a reliable GPS when playing Pokemon Go is a revelation! No more auto-wandering of the neighborhood while at home with my wifi off, though, shucks.
- I like some of the new little features in Nougat, including split-screen dual app use, and native call blocking (had it in my LG phone on Lollipop, didn't realize it wasn't a stock Android feature).
- The extra horsepower is a boon to Pokemon Go, along with everything else.
- The rounded edges and lack of magnetic charge port make it more comfortable to hold and easier to slip in/out of my pocket.
- I like not having glass on the back as well as the front (and it consequently doesn't try to slither off horizontal surfaces, either).
- I LOVE my new LoveHandle, which is firmly stuck to the back of my phone and lets me loop a finger through an elastic strap and keep the phone attached to my hand while I'm fumbling other stuff or just walking about and randomly klutzing. Should have gotten that years ago, though it wouldn't have helped in the ultimate demise of the previous phone (fell on it while it was in my pocket), and wouldn't have stuck to that glass back anyway. I still don't have a case, but I think the LoveHandle will preclude the need for one and I don't especially want one.
- Getting a new device inspired me to reevaluate and revamp my home screens' layouts for the better.
- I haven't yet had opportunity to take advantage of the additional LTE band (maybe this weekend?), but I'm sure that'll be primo.
- The built-in calculator knows order of operations now! But I still don't use it because I prefer/need a scientific calculator (I use the one in Android Army Knife, or a Graphing Calculator Pro app if I want something even more robust). EDIT: Oh hey, stock now has a little slide-out panel with some extra operations on it! Still pretty minimal, though.

The Less Good Stuff:
- The USB-C port means I'm having to get new adapters and cables, and those have some other minor issues, but it'll be fine.
- The wifi doesn't seem as capable all over my office buliding, but there could be a local router not working right.
- The lowest screen brightness is an irritating amount higher than the old phone, particularly in a dark room. (I'm also trying out the adaptive brightness again, but it's not reactive enough - too dim in bright sun, too bright in dim rooms.)
- The new version of the preloaded AccuWeather app sucks - it doesn't include the (omnipresent in Houston) heat index (except randomly sometimes), no longer shows me the expected weather for the current day/night in its widget view, and its background pictures aren't even useful for that either.
- They took away the jump-to-letter navigation in Contacts (though scrolling is better now) and the long-press save phone number option in Phone, both of which I used a lot.
- All the icons are a little bit smaller than they used to be. Somehow restoring my old profile made the folders go to a square shape instead of the default round shape, at least. No idea how to deliberately change that if I want to, but I'm sure the internet knows.

Rise of the Electron Beams

Jul. 21st, 2017 01:29 pm
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

There was apparently a very impressive talk from Sriram Subramaniam on cryo-electron microscopy (cryo-EM) at the Computer-Assisted Drug Design Gordon Conference, and I can well believe it. That field has grown tremendously in capabilities in recent years, and is producing some startling results – and those results are coming faster all the time. Just recently, we’ve had a structure of the vascular protein sorting 4 complex, the Hrd1 channel, tau filaments from Alzheimer’s tissue, an entire 70S ribosome from a mycobacterium, Type I CRISPR enzymes in action, DNA protein kinase, and more. These are at varying resolutions, to be sure, but those resolutions are getting finer and finer, and the best cryo-EM structures are excellent.

One big advantage of this technique over traditional X-ray crystallography is, of course, that you don’t need to crystallize anything. Pure protein, frozen on a surface, is enough. Now there’s a lot of work contained in that last sentence – the various techniques for sample preparation, data collection, and data analysis are nontrivial, particularly for really high-resolution structures, but not very long ago they couldn’t even be described as that (and they’re improving constantly). Structures that were once the domain of the cutting-edge labs are being produced at more and more institutions, and the cutting-edge stuff is moving on to even more impressive results. This has been due to improvements both in electron sources and on the detector end, with direct electron detection being the big change in the latter. New techniques such as the Volta phase plate are in active development to improve contrast and resolution. The ability to handle large amounts of data has also been crucial, since cryo-EM structures are produced from a great number of particles that have landed in all sorts of orientations.

Another big advantage is that electron microscopy doesn’t have the “phase problem” that X-ray does. X-ray detectors can give you the amplitude of the scattered X-ray beam, wherever the spots show up, but they can’t tell you the phase – that’s been lost. The problem is that the phases are very important to the structure determination, so a number of ingenious methods have been worked out to deal with this. It’s really not a problem for small molecules, in general, and hasn’t been for a long time thanks to “direct methods“, but it’s definitely a pain for large proteins. That’s why (for example) you see X-ray crystallographers working heavy atoms into their proteins – it’s a particularly direct way (anomalous dispersion) to get a handle on reconstructing the phase information, if you pick the right X-ray wavelengths for the heavy atom you’re using. (Fortunately, synchrotron X-ray sources allow you to do just that). This lets you determine the position of the heavy atoms using the sorts of direct methods that can be used on small molecule crystals, and that often allows the rest of the protein structure to start falling into place rapidly, with modern software. The electron beam information, though, has the amplitudes with the phases still available, an advantage first realized by electron crystallography pioneer Aaron Klug. Those amplitudes, in general, still can’t be determined as precisely as they can in X-ray work, but having the phase information available up front more than makes up for that. It allows for that processing of all the different orientations, mentioned above – without phase information that would be a nightmare in all directions.

All this makes a person wonder if eventually this technique could take over from macromolecular X-ray crystallography in general – and if so, what definition we’re using for “eventually”. I know that many X-ray specialists in that field have, in recent years, been vigorously brushing up on their electron microscopy skills, with just that thought in mind. The problem that X-ray has with proteins is what’s it’s always been: growing crystals. It’s a black art, if ever there was such a thing, and a glance through the catalogs that supply workers in the field will confirm that. You can buy collection after collection of buffers and additives to try to convince recalcitrant proteins to grow crystals, and a look into any lab working in the area will show you stacks and stacks of 96-well plates trying these combinations out one after the other. Miniaturization and automation have certainly helped that process, but they’re still in the service of making the trial-and-error process run faster. Getting rid of the trial and error entirely has been beyond human capability, so far.

Cryo-EM has its own trial-and-error thing going, but it already seems to be in better shape in that department that crystal growing is, and it’s improving much more rapidly (from what I can see). Add in the number of proteins that have just never yielded to crystallization at all, and the opportunities for multiprotein complexes, etc., and the future looks pretty bright on the electron side of things. Is my outsider’s view of things accurate – are the electrons overtaking the X-rays? Or are there factors I haven’t considered? Comments welcome. . .

Update: added a bit more on the phase problem, etc.

(no subject)

Jul. 20th, 2017 08:46 pm
randomdreams: riding up mini slickrock (Default)
[personal profile] randomdreams
apologies for TMI but I keep injuring myself in ways that leave scabs like Lake Baikal and within a few days the edges are all ready to be done but the center is still very strongly attached.
Maybe I need body armor.

(no subject)

Jul. 20th, 2017 09:14 pm
lil_m_moses: (crafty)
[personal profile] lil_m_moses
This is my family-free evening (little one's at her grandparents', Josh is at tai chi), so I ran personal errands.

- I signed up for a hula class at the NASA rec center for late Sept to late Oct; I've been wanting to learn hula for years, so am very excited.
- I discovered that a delightful local pizza by the slice place closed, which was disappointing because I really wanted a slice of their mac & cheese pizza for dinner. Instead I tried the 3rd of 3 new Subway-style pizza joints in the area. It was definitely the least interesting of the 3, so...the most like Subway, I guess. ;)
- Picked up some icing tips and gel colors for the Bulbasaur cake. Decided I'm going to try the frozen buttercream transfer; I'll have to practice next weekend. Whle also quilting. Or something.
- Went to Jo-Ann and got more materials and tools for my quilt. I found a fun mottled navy fabric with constellations printed all over for the backer, and a light blue with little white stars for the framing and binding. I liked another fabric print better, but it wasn't so thematically appropriate and the color didn't coordinate quite as well. I think I'm going to quilt with a dark teal color that coordinates well but stands out a little, after doing all the piecing with a purple that blends well with all the fabrics. They only had one spool of that color, though, so I might have to find more later. I did find a square ruler in the right size to help me easily trim down my wonky star blocks to a uniform size, yay, though pricey! I found a 1/4" presser foot for my machine to help me make my seams that little bit narrower they should have been, but then they wouldn't sell me the foot because it was from a sewing machine store within Jo-Ann or something, and the sub-store was closed? Super lame - don't display it if you won't sell it to me. Amazon will take my money at any hour, I'm quite sure.
lil_m_moses: (avatar)
[personal profile] lil_m_moses
I feel like expectations of parents are becoming increasingly insane. I just read an article about 2 toddlers driving their Mom's car in an effort to get to their grandfather's house down the road. Supposedly the kids found the keys under the floor mat; I wouldn't personally put them there, but I also live in a large metropolis. Regardless of that, though, the kicker for me was that "the sheriff's office is working with the county prosecutor and Child Protective Services to determine if the mother should be charged with any crime."

It seems like it's getting to the point that one can't even let your kids play in the yard while you're inside doing some work or having a moment of peace or going to the bathroom, much less let them walk down the street to a friend's house, without being at risk of child endangerment or abandonment charges. When I was 5 I would walk alone the half mile to my friend's house (tiny town) to play with her. Mom knew where I was going and would have heard from the friend's mom if I didn't show up. Third (or 4th?) graders and up at Lillian's school are allowed to walk themselves to school, but if it's raining, parents are required to go pick them up. For _rain_. And even if you choose not to drive the average half mile between neighborhood homes and the school to pick them up on those rainy days, you still have to bring your car pickup pass as if you were driving. *eye roll* I was left alone sleeping in the car while Mom ran in to buy something (but with windows down, and it wasn't a billionty degrees), but that's a no-no now too. Bah. I have more feelings on this, but they're not yet coherent. It all just amps up the parenting anxiety.

Glioblastoma Is Bad News, Period

Jul. 20th, 2017 02:18 pm
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

Everyone keeping up with the news will have heard about Sen. McCain’s diagnosis of glioblastoma multiformae (GBM). This is not good news at all; GBM is a very aggressive tumor type for which treatment options are poor. The contrast to ex-President Jimmy Carter’s brain cancer experience is stark, and many people outside the biomedical field must be wondering why the two are so different.

Carter’s diagnosis was metastatic melanoma, which until very recently was just about as bad an answer to get as GBM. Surgery and radiation have been the standard combination for melanoma, but the metastatic form of the disease is much harder to deal with, since it has, of course, spread to other organs at that point. But immunotherapy has been added to that in recent years, and that’s what tipped the balance in President Carter’s case. Many metastatic melanomas are particularly dependent on PD-1 as a mechanism to keep T cells from recognizing and attacking them, and the antibodies targeting that protein have shown themselves to be quite effective. Unfortunately, GBM is another thing entirely, and illustrates the problem that cancer is really a collection of thousands of different diseases.

Glioblastomas are characterized by extreme genomic instability, even by the standards of cancer cells, meaning that what appears to be a single tumor is almost certainly a large collection of different cell types using different mechanisms to grow and survive. That explains why no single therapy has had much success in the field. The standard treatment is temolozomide, which is really a brain-penetrating prodrug that produces the same species as another chemotherapy agent, dacarbazine. That’s a DNA alkylating agent, so we’re now back into the classic (and brutal) form of chemotherapy, where you’re damaging dividing cells in general, but damaging the rapidly dividing ones even more (dacarbazine is, in fact, used to treat metastatic melanoma as well). It’s also a prodrug itself, and organic chemists will be alarmed to find out that it breaks down to diazomethane, which is what does the actual methylation of guanine bases in DNA. Cancer therapy with a systemically dosed diazomethane precursor sounds pretty primitive, and it is. But that’s the best we have for GBM.

Many attempts have been made at improving this situation, and one of the most notable was the idea of placing slowly dissolving wafers containing the chemotherapy agent carmustine at the site of the tumor directly after surgical resection. This makes a lot of sense, as the recurrence of GBM after surgery makes it clear that it’s impossible to do a clean-margin removal of the cancer tissue. Carmustine is a really rough compound, a combination of a nitrogen mustard and a nitrosourea (which is a diazomethane precursor, as those who have made the reagent in the lab well know). Unfortunately, the wafer (brand name Gliadel) has not seemed to demonstrate any advantage in survival compared to regular temozolomide treatment, at least not in randomized trials (cohort studies have looked better). So it’s not clear if there’s a real advantage in using it.

As you would figure, all sorts of approaches have been tried against GBM, with a conspicuous lack of success. One that remains to be tested is the use of a GSK3 kinase inhibitor along with radiation, which has shown promise in model studies. Let’s hope that this translates into efficacy in humans, because something efficacious is badly needed in this field. It’s a really tough one.

Space Station Virtual Tour

Jul. 20th, 2017 09:24 am
lil_m_moses: (NASA meatball)
[personal profile] lil_m_moses
Holy crap, this is SO COOL. Google did a Street View of the International Space Station. Check it out here:

You can drag your mouse around to look around (and remember, there's stuff on the "ceilings" and "floors" too, because there's no true up and down in space!), and if you click on the little up-arrow at the bottom, you can move to different modules. In the Lab module, look for a fat orange hose along one corner (standoff), then look for a funny-shaped aluminum box sticking out over it (just left and down of where the view starts), and that's my payload (and the stuff it's attached to above and behind it)!

You can also look at this in Google Maps format:,-95.0853914,3a,75y,214.46h,90t/data=!3m6!1e1!3m4!1szChzPIAn4RIAAAQvxgbyEg!3e5!7i10000!8i5000 and the resolution seems a bit better. However, I had trouble getting it to move between modules.

Insectile Invaders

Jul. 19th, 2017 06:21 pm
lil_m_moses: (A is for Amy)
[personal profile] lil_m_moses
Oh hey! I think I finally I identified our blue-black waspy friends, who are particularly abundant inside the house this year. They're blue mud wasps, or blue mud daubers. Not aggressive, which we inferred (particularly when one tried to fly into my ear the other day, then down my shirt in its disorientation and I was none the worse for the experience), and they eat black widow spiders (YAY).

Ignoring the Literature, Selectively

Jul. 18th, 2017 02:06 pm
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

Very little time for blogging today (travel), but I wanted to pass on some words of wisdom from Kevan Shokat, from a recent Perspectives piece in Nature Reviews Cancer. Talking about chemical probes, and how to know if they’re valid enough to work with, he suggests that you need to see dose-response data (for one thing), and he’s much, much happier when there’s a crystal structure of the proposed probe with the target protein (hey, who isn’t?) But then there’s this point:

The third criteria is proof that the first drug can be modified and its biochemical and cellular activity improved in a manner consistent with the structural model. Note that I do not include a requirement that the molecule work in an animal model. In my opinion, too many first reports describe animal efficacy data, long before the first three criteria are established, leading to false-positive proof of target inhibition. Something to look for if the report was published more than a year ago, is whether a follow-up study has appeared showing an improved version of the molecule and further proof of target engagement. If nothing appears after several years in the peer-reviewed literature, bioRxiv, or published patent applications, you can bet the molecule was an artefact and the target remains undrugged.

I endorse both of those – the too-fast animal model problem and the lack of follow-up criterion. When the answer to “Whatever happened to. . .?” is “Nothing, apparently”, then it’s a bad sign. The only mitigating factor might be if the report was from a more obscure source or published in a more obscure journal. That gives you a possible out, in that other people may not have noticed it, but that could also be offset by the possibility that the group reporting it may not have had the resources or experience to do adequate characterization themselves.

This is not a mandate to ignore the literature wholesale. If you do that, you’ll end up stuck pretty quickly in this field. Richard Feynman was famous among colleagues, when he moved into a field of research, for deliberately not reading the literature and trying to work his way up from first principles. That, though (as one of those colleagues remarked in James Gleick’s biography) only worked if you were as smart as Feynman. And at any rate, it doesn’t work at all in biology, where there are no first principles, at least by the standards of physics. No, we’re stuck with the literature, and we have to keep up with it, but we also have to remember that a reasonable percentage of it is wrong, and be prepared to ignore parts of it as needed, and with cause. If you try the opposite, and decide that every report you read is completely correct, you will end up stuck as firmly in the mire as if you don’t read the literature at all. It ain’t easy.

[personal profile] mjg59
In measured boot, each component of the boot process is "measured" (ie, hashed and that hash recorded) in a register in the Trusted Platform Module (TPM) build into the system. The TPM has several different registers (Platform Configuration Registers, or PCRs) which are typically used for different purposes - for instance, PCR0 contains measurements of various system firmware components, PCR2 contains any option ROMs, PCR4 contains information about the partition table and the bootloader. The allocation of these is defined by the PC Client working group of the Trusted Computing Group. However, once the boot loader takes over, we're outside the spec[1].

One important thing to note here is that the TPM doesn't actually have any ability to directly interfere with the boot process. If you try to boot modified code on a system, the TPM will contain different measurements but boot will still succeed. What the TPM can do is refuse to hand over secrets unless the measurements are correct. This allows for configurations where your disk encryption key can be stored in the TPM and then handed over automatically if the measurements are unaltered. If anybody interferes with your boot process then the measurements will be different, the TPM will refuse to hand over the key, your disk will remain encrypted and whoever's trying to compromise your machine will be sad.

The problem here is that a lot of things can affect the measurements. Upgrading your bootloader or kernel will do so. At that point if you reboot your disk fails to unlock and you become unhappy. To get around this your update system needs to notice that a new component is about to be installed, generate the new expected hashes and re-seal the secret to the TPM using the new hashes. If there are several different points in the update where this can happen, this can quite easily go wrong. And if it goes wrong, you're back to being unhappy.

Is there a way to improve this? Surprisingly, the answer is "yes" and the people to thank are Microsoft. Appendix A of a basically entirely unrelated spec defines a mechanism for storing the UEFI Secure Boot policy and used keys in PCR 7 of the TPM. The idea here is that you trust your OS vendor (since otherwise they could just backdoor your system anyway), so anything signed by your OS vendor is acceptable. If someone tries to boot something signed by a different vendor then PCR 7 will be different. If someone disables secure boot, PCR 7 will be different. If you upgrade your bootloader or kernel, PCR 7 will be the same. This simplifies things significantly.

I've put together a (not well-tested) patchset for Shim that adds support for including Shim's measurements in PCR 7. In conjunction with appropriate firmware, it should then be straightforward to seal secrets to PCR 7 and not worry about things breaking over system updates. This makes tying things like disk encryption keys to the TPM much more reasonable.

However, there's still one pretty major problem, which is that the initramfs (ie, the component responsible for setting up the disk encryption in the first place) isn't signed and isn't included in PCR 7[2]. An attacker can simply modify it to stash any TPM-backed secrets or mount the encrypted filesystem and then drop to a root prompt. This, uh, reduces the utility of the entire exercise.

The simplest solution to this that I've come up with depends on how Linux implements initramfs files. In its simplest form, an initramfs is just a cpio archive. In its slightly more complicated form, it's a compressed cpio archive. And in its peak form of evolution, it's a series of compressed cpio archives concatenated together. As the kernel reads each one in turn, it extracts it over the previous ones. That means that any files in the final archive will overwrite files of the same name in previous archives.

My proposal is to generate a small initramfs whose sole job is to get secrets from the TPM and stash them in the kernel keyring, and then measure an additional value into PCR 7 in order to ensure that the secrets can't be obtained again. Later disk encryption setup will then be able to set up dm-crypt using the secret already stored within the kernel. This small initramfs will be built into the signed kernel image, and the bootloader will be responsible for appending it to the end of any user-provided initramfs. This means that the TPM will only grant access to the secrets while trustworthy code is running - once the secret is in the kernel it will only be available for in-kernel use, and once PCR 7 has been modified the TPM won't give it to anyone else. A similar approach for some kernel command-line arguments (the kernel, module-init-tools and systemd all interpret the kernel command line left-to-right, with later arguments overriding earlier ones) would make it possible to ensure that certain kernel configuration options (such as the iommu) weren't overridable by an attacker.

There's obviously a few things that have to be done here (standardise how to embed such an initramfs in the kernel image, ensure that luks knows how to use the kernel keyring, teach all relevant bootloaders how to handle these images), but overall this should make it practical to use PCR 7 as a mechanism for supporting TPM-backed disk encryption secrets on Linux without introducing a hug support burden in the process.

[1] The patchset I've posted to add measured boot support to Grub use PCRs 8 and 9 to measure various components during the boot process, but other bootloaders may have different policies.

[2] This is because most Linux systems generate the initramfs locally rather than shipping it pre-built. It may also get rebuilt on various userspace updates, even if the kernel hasn't changed. Including it in PCR 7 would entirely break the fragility guarantees and defeat the point of all of this.

(no subject)

Jul. 16th, 2017 10:34 pm
randomdreams: riding up mini slickrock (Default)
[personal profile] randomdreams
So let me tell you...
No, there is too much. Let me sum up.
Today was my grandmother's 100th birthday party.
N was feeling awful so I did some cleaning around the house, pulled fistfuls of hair out of the tub drain and grape-sized clots out of the sink drain, and then headed down to the middle of nowhere, where my aunt and uncle live in a very expensive house in a gated community, and my grandmother lives in their basement.
She was really together. She's been getting foggy the last couple of years, but she and I got to have a couple long conversations that stayed on topic. She gets a bit aphoristic if I don't lead the conversation, but I think that's because she hangs out with my aunt way too much.
My very conservative but pleasant uncle got into another long intense conversation with my very liberal aunt (from the other side), which seems to happen every time everyone gets together. He's conservative as in his brother made a half million dollars writing Left Behind imitations and his family disowned another brother who announced he was gay but going to spend his life celibate so as to not sin. Apparently celibacy wasn't good enough. My aunt is liberal as in got a degree in Chinese history in 1970 at UC Berkeley. Again: no idea why the two of them talk so much.
I got to see my cousin's ex-wife for the first time since the divorce four years ago, as she brought their kids over to drop them off. She's looking like a tired redhed-going-grey housewife, which is an improvement over last time I saw her, when she had jet-black hair, a very short skirt, and knee-high combat boots, as part of her effort to keep the marriage together. (Which must have driven her crazy: literally her entire immediate family works for James Dobson/Focus On The Family.) She took off pretty quickly when my cousin showed up with his new girlfriend, who has jet-black hair, a very short skirt, and knee-high bright green leather boots.
anyway. Grammy was okay. We talked. I talked a bunch to my cousin's kids, who are all really cool.
I drove home and went out to the shop to start working on machining a test fixture for a new product for Mad Scientist Hut. I set up the thousand-dollar sprinkler while I was doing that. (You know those old sprinklers like tractors that drive across the lawn, following the hose? I found one in an alley, brought it home, we used it, then we had one of those springs where it's 35C and the grass is all brown and dying so I water it and the next day we get a knee deep snowstorm and while walking the compost out to the pit I managed to step on the free trash sprinkler and break one of the arms off, so I went and bought a metal lathe and fixed the free trash sprinkler, so it's the thousand dollar sprinkler, yo.)
So the sprinkler's running and I stick my head out to make sure it hasn't gotten stuck and there are three kids half-running through the yard, sobbing, which means a dog has gotten away and they are trying to catch it. This is a regular event.
Of course I join in. These kids are really young. Well, everyone less than 18 looks like they should be wearing diapers, pretty much. But I think these kids were really young since they couldn't jump off the retaining wall between my house and Ray's, and it's only a meter and change high.
We all piled through that and headed towards the church, where I saw the dog.
It's a huge german shepard. Huge. I think I could have put two of these kids on it.
I can't outrun a german shepard.
I tried, though.
And I'm a lot more canny than it, because I've caught 30-something dogs over the last few years.
It of course ran straight to the main road where all the traffic is and started running down the side of the road. I crossed the road and started running along behind/beside it, because it was definitely scared of me. That way, it wasn't going to run INTO the road.
I paralleled it until it got distracted by a smell, then got ahead of it and started moving back towards it, so it reversed course. My thought was either I'd chase it back to its kids or up the hill away from the road. We did both at various points. Eventually the three kids, two joggers, and I managed to corral it in someone's yard and one kid got her hands on its collar and we all headed back to the church.
Where we found kid number four lying in the grass making horrible noises.
She claimed she was having an asthma attack.
As a long-term asthma person, I'm pretty sure what she was having was a panic attack.
But not the time to screw around.
So I chucked it back into high gear and ran home, got the car, and drove back, at which point other family members were there, but she couldn't walk and nobody in her family had the oomph to do much about it.
I picked her up and carried her to her mom's car, and they drove off.
About ten minutes later, the first three kids showed up again. One of them had lost her cellphone in the shenanigans and they were retracing their steps.
As we were looking around my yard, another kid said "what do you have in that weird little barn?"
I said "a bunch of broken bikes."
She said "huh. Can I have one?"
I had to explain they were all 40 year old bikes, too large for her, with no wheels or seats.

Then I finished the test fixture, went grocery shopping, made dinner (Marcella Hazan's chicken breast sauteed in butter/lemon/parsley) and am just right now finishing it, sitting down while not driving for the first time since about 11AM.

Too Big to Be True

Jul. 17th, 2017 02:36 am
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

I recently wrote a column for Chemistry World on the concept of effect size – the readership there is from all sorts of chemistry, so it’s perhaps not as familiar a concept, and I thought it worth highlighting. (Briefly, effect size is the difference between the means of your treatment group and control group, divided by the standard deviation – it’s a “corrected” difference between the two. A small clinical trial is likely to only reach statistical significance for things that have a rather large effect size, while a large trial, on the other hand, can at times still reach significance for things that are small enough to make no real-world difference).

Here’s an excellent blog post on the idea, illustrated by an example that you may have heard about. There was a study a few years ago that seemed to show that judges handed down stiffer sentences right before lunch. The authors ascribed this to hunger, irritability, a desire to wrap things up, etc. But as that post shows the effect size that the paper found is impossibly huge, for a psychological effect:

If hunger had an effect on our mental resources of this magnitude, our society would fall into minor chaos every day at 11:45. Or at the very least, our society would have organized itself around this incredibly strong effect of mental depletion. Just like manufacturers take size differences between men and women into account when producing items such as golf clubs or watches, we would stop teaching in the time before lunch, doctors would not schedule surgery, and driving before lunch would be illegal. If a psychological effect is this big, we don’t need to discover it and publish it in a scientific journal – you would already know it exists.

There are other good examples given, along with links to papers that have tried to refute the “hungry judges” story in general. To not enough avail – it still gets trotted out as an example of the interesting and surprising findings that social science and psychology can provide. The point here, though, is that we should be wary of things that look too interesting and surprising, and also look for other causes when we find them. (In this case, one possibility is courtroom scheduling, where complicated cases are scheduled early, while plea bargains, mandatory sentences, and other more open-and-shut items get fitted in before lunch as time allows).

The more startling the result (positive or negative), the more it needs to be interrogated. We have better chances, in biomedical research trials, of producing profound effects, but we still need to be open to all sorts of possible explanations for them. . .


Planning the Birthday Party

Jul. 16th, 2017 05:25 pm
lil_m_moses: (cooking)
[personal profile] lil_m_moses

She's still big on Pokemon, and loves Bulbasaur, so I'm looking at cake design ideas that aren't wildly over my very limited skill level. Here's some inspiration(s), along with the semi-profile and face-on reference pics above:

Bulbasaur mostly-round:
Homemade Pikachu (at my level of amateurness):
Flat Bulbasaur that I can't find an actual source for
Minimalist Pikachu (could do similar for Bulbasaur): (oh, and here's a tutorial:
A cool frozen buttercream applique thing I could try (though I don't have icing tools):
Cut-out Pikachu w/ buttercream star frosting:
This square Squirtle looks a lot like Bulbasaur:

I like buttercream better than fondant, but the fondant could look nicer and might hold together better for a Texas summer BBQ party that we have to drive an hour to get to. Hrm.

And related to none of this, I just think it's cool: galaxy mirror cake by a girl with a very odd affect:

One of these days I should take a cake decorating class, 'cause I'm pretty bad at it.

Future changes at Disney World

Jul. 16th, 2017 08:59 am
mmcirvin: (Default)
[personal profile] mmcirvin
 So, apparently a lot of rumors about future stuff were confirmed at Disney's big fan expo (and some weren't):

  • There's going to be a duplicate of Shanghai's awesome Tron light-cycle coaster in the Magic Kingdom's Tomorrowland. The big surprise: it's not replacing the Tomorrowland Speedway, as most rumors had it. It'll be in the back of Tomorrowland, outside the railroad tracks, to the left of Space Mountain. Tomorrowland Speedway apparently lives on for a while yet.
  • Similarly, they're duplicating the Ratatouille ride from Paris at Epcot's France pavilion.
  • The Universe of Energy pavilion at Epcot is going to be gutted and used in a Guardians of the Galaxy-themed ride of some sort. There's a nice fourth-wall-breaking conceit that the gang is at Epcot because Peter Quill went there as a kid, which might allow them to at least give a nod to what Epcot is supposed to be about. The Guardians are one of the few Marvel properties that Disney is allowed to use in Florida, because Universal isn't using those characters. There's going to be a larger Marvel-superhero-themed land at California Adventure, but they can't do that at WDW. (This also suggests that Florida's Tower of Terror is probably not going to get the Guardians-themed conversion.)
  • Some kind of complete makeover of the non-centrifuge half of Mission: Space, and an immersively space-themed restaurant nearby (I don't think I'd even heard rumors about this--I wonder if the restaurant is going to replace the old Wonders of Life paviliion).
  • Big cosmetic updates to Epcot's whole Future World area, particularly the entrance.
  • Cable skyways connecting some of the hotels and parks around the Epcot/Hollywood Studios area. I imagine they'd consider expanding the network if it works out; this is probably cheaper than building out the monorail.
  • The Great Movie Ride at Hollywood Studios will be replaced by a Mickey Mouse ride based on the recent, very wacky cartoon shorts. Looks like it will make heavy use of projection mapping. Maybe the most controversial change, since that ride was basically the centerpiece of "Disney/MGM" when it first opened. We'll see, I guess.
  • Probably the single wildest thing: a Star Wars-themed hotel with a multi-day immersive guest experience, to go with the new Star Wars land at Hollywood Studios. Sounds expensive, and probably not my thing (it might entirely replace rather than supplementing a traditional Disney World visit), but I admire the audacity.

The one thing I wonder is whether the general slump in international tourism is going to affect these plans. Disney may figure they're doing all right with domestic traffic in the US and they're internationally diversified enough that it won't kill them in general. I get the impression that they consider Universal's parks to be their main threat, and competing means stepping up their game. Animal Kingdom got their splashy new land built already; Hollywood Studios is in the throes of massive construction; clearly Epcot is next on the list to get the love.

Nothing yet about new Epcot country pavilions, or Imagination with Figment becoming an Inside Out ride, or a conversion of Rock 'n' Roller Coaster, or Zootopia at Animal Kingdom, or a Moana ride in MK's Adventureland (other rumors I'd heard). I suspect those are either not happening or are more blue-sky future things.

Technical Hand-Waving

Jul. 15th, 2017 06:05 pm
lil_m_moses: (phone)
[personal profile] lil_m_moses
Hm. I got the new screen installed on the old phone (well, it's at least taped onto the frame and electrically connected to the rest of the stuff which I stuck back into the slightly broken frame), and it's working now (huzzah!), though I broke apart and then gave up on the earpiece, which was glued to shards of broken glass on the back of the old screen. I'm just going to sell it for parts when I'm done cleaning it off, so completeness is not important. Seems the battery (which is the bent part - eek!) isn't talking to the motherboard, either, as it's stuck at 50% and not showing charging when the cable's connected, though I'm getting the connection bing. I was able to recharge it a few days ago, before I took it apart, and it's been off since shortly after that, so the charge should be sufficient to do this activity even if it's not charging now.

I'm trying to transfer the data between the two phones via wifi and the Xperia transfer app, but it lost connection once, and then seemed to stall out on the second attempt and then said it lost connection while I was poking through its help file (and it had switched to the other wifi band when I looked; I consequently made it forget that one). I'm trying a third time now (maybe it hadn't been stalled, since it got through the current piece fast this time?), but if this doesn't work I'll just dump what I can via computer, and if that's not enough, I'll go get a USB OTG cable (which might be handy to have anyway) and try it that way instead of over wifi.

EDIT 1:30 AM: Ended up doing a backup of the old phone onto the SD card and then doing a restore from that onto the new phone. Then took FOREVER trying to figure out how to get my calendar data transferred. Annoyed that I bought an upgrade to my calendar program and it wasn't able to do what I needed. Did finally find a separate app that could make it work, though I'll be damned if I understand what it did and why none of the other stuff that was supposed to work did. Not sure I'll be able to import my cross stitch floss list (think I did it manually last transfer). I had a few files in a secure notes app, the app was crashing in the new phone and I needed to reinstall it, but I very foolishly did that _before_ trying to switch the SD card back to the old phone and export the files first, and now they're gone. *facepalm* If I have to recreate the files anyway *whimper* maybe I'll check Google Play for something better. I think I have everything else that contained data I care about transferred, thank goodness.

EDIT 8:45 AM: Victory! After sleeping on it, I tried another restore from the backup file, of just the apps, and it recovered my data for both those apps! I'm still fighting with the calendar a bit, though. Again.

30 Stars

Jul. 15th, 2017 12:44 pm
lil_m_moses: (crafty)
[personal profile] lil_m_moses
30 Stars

Finished my 30 star blocks for the quilt. Next is the star borders, or sashing, which will help hide the unevenness of my star edges. This is all I need before the next class, though.

Not super happy with one that's reverse contrast and another that's negligible contrast, but whatever. This is my newbie quilt. Trying really hard not to make any star/sashing combo changes, though. I'm terrible at randomization, but feel like I did OK at randomizing these initially.

Model This?

Jul. 14th, 2017 03:03 pm
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

Via Ash Jogalekar on Twitter, I came across this new paper from researchers at AstraZeneca (and collaborators in Sweden, the UK, and Denmark) on the synthesis and activity of some plasmin inhibitors. Plasmin is an anticoagulation target, and has a lysine-binding site in its Kringle-1 domain (yeah, that’s the real name) that is the site of action for tranexamic acid. The AZ team had discovered some small piperdinyl heterocycles that hit the same binding site, and you can easily see how they might (TXA is at the left, and the prototype AZ compound is at the right).

They produced a set of 16 simple analogs of that first isoxazolone/hydroxyisoxazole, adding methyls, changing the ring size of the piperidine or putting a double bond into it, moving the heteroatoms around, adding a nitrogen or swapping the oxygen for a sulfur, and so on – classic medicinal chemistry on a small scaffold, and perfectly reasonable stuff. The efficacy in the clotting assay matched very well with the Kringle-1 binding affinity, so everything holds together just fine (three or four of them had similar or better potency to the lead, and the others were slightly to noticeably worse). The interesting part is when they went back with this set of compounds and used all the computational tools at their disposal to try to see if anything could predict their affinities or rank-order them well.

They went after it with classic QSAR descriptors, three-dimensional similarity scores, ligand geometries from protein-bound crystallographic data, docking programs, FEP (free energy perturbation), and MM/GBSA. Here’s how all these techniques performed: the QSAR models using simple descriptors, with or without principle components analysis, were of no use at all. Ligand-centric QSAR using molecular shape scoring was equally worthless. The structure-based QSAR calculations also failed, because everything came out as too similar in shape and electrostatic potential. Moving on to the docking programs, the poses for the various compound all came out very similar, but the scoring functions (that try to determine the effect of hydrogen bonds, electrostatic effects, and so on) gave very poor results across the board. The FEP calculations likewise gave an extremely poor fit, as did the MM/GBSA calculations, which gave a very small trend in the wrong direction entirely.

This is not an impressive set of outcomes, clearly, and these are not large or complex molecules. That in itself might be part of the problem, since relatively high ligand efficiency means that most parts of the structure are important. But still. The authors believe that part of the problem is the heteroaromatic group, and the charged/zwitterionic nature of the compounds. But we certainly make an awful lot of heterocycles in this business, and charged interactions are some of the bread-and-butter of medicinal chemistry (and biology!) It may be that some of the techniques in this paper have been applied suboptimally, and I’m sure that if this is the case (or many even if it isn’t) we’ll hear about it. But for now: one would hope for better.



Jul. 13th, 2017 02:27 pm
lil_m_moses: (Michigan)
[personal profile] lil_m_moses
We spent a lovely 9 days in Michigan last week and this. The weather was perfect (low 60s to low 80s, and felt like it!), and we soaked it up, spending as much time outdoors or with windows open as possible. Coming back to the sauna was not a joy. We're even more motivated to find a way to move north now. We were there for Cherry Festival, which is generally a thing for locals to avoid, but it was fun to show Josh & Lillian once. We went to fireworks (once right by the bay, once in the middle of my aunt's street, which has a straight-shot view to the bay (16 blocks away). We watched a pet show, with categories like best dressed and fattest cat. We watched a bit of a local native American intertribal pow-wow. Lillian and I rode some stuff at the midway (she's still too short for many things). We watched excited dogs run and jump into a big pool. We watched a parade. We ate wonderful sausages and an elephant ear and yummy local pie and ice cream and, of course, cherries. We went canoeing. We went to 2 barbecues. Josh and I went to see Spiderman. We got several large items out of my mom's basement and I cleared out a bunch of my old stuff (and shipped a little bit home). Josh exercised at the school playground a ways behind Mom's house. We went swimming in the local lake. I fixed my Mom's printer and tried to fix her computer (but its drive is pretty damaged). I had the aforementioned phone adventures. I talked (only semi-jokingly) with my uncle and cousin about starting an engineering firm up there so we can all move there: Mike is the idea man, I'll do testing, and Uncle Charlie is the business genius. We'd just have to decide _what_ we'd do - Mike has done laser range finding and ocean energy generation, and I do mostly space life support systems. Overall, it was delightfully relaxing and refreshing, and I'd like some more right now, thanks.
lil_m_moses: (to-do)
[personal profile] lil_m_moses
I was nicely productive yesterday during my bonus vacation day, between setting up new phone, haircut, car inspection, car registration renewal and title update, short bank and grocery stops, and making a few quilt stars.

Every opportunity:
- work on applications

Read more... )

- weigh myself
- 7:30 blood draw
- 8 AM minisim
- start minisim eval
- min 30 min finance work (finalize selections for Josh's benefits)
- clean the microwave and counters and misc dusting
- press star half-borders, maybe start sewing other halves

Read more... )

Sometime These 2 Weeks (ideally, tasks to be assigned to days as I go)
- pick/purchase inner frame and binding fabric, backer fabric, batting, basting pins, and a square ruler(?)
- make plans to hang out with J
- remake water bottle sling with webbing
- enroll Lillian in after care for next school year
- prep for Lillian's bday party on 5th (cake, gifts,, gift wrap, mac & cheese?, other?)
- call arborist to come prune dead stuff, raise canopy, trim side oak back from house
- get boxes to Sa
- call Mo's general contractor and the one I found an ad for, and maybe try that website again with a different need path, to arrange for hall bath remodel/plumbing fix/mold cleanup, and to arrange for living room ceiling mold remediation and rebuild
- schedule massage w/ gift cert - call to see if they'll even honor that gift cert
- get new passport photo taken
- more stuff off big list as inspiration/time dictates

Chaos at AstraZeneca

Jul. 13th, 2017 12:44 pm
[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

What on earth is going on over at AstraZeneca? The company has had plenty of wild ups and downs over the years, and managed to fight off a takeover attempt by Pfizer (and who else has managed that?) But in doing so, they made some pretty strong revenue projections (look what we’ll do if Pfizer doesn’t ruin it). The shareholders, especially the big institutional ones, took note of these markers, and management knew that they wouldn’t forget.

The company’s big push recently has been in immuno-oncology, which is certainly a field with plenty of revenue potential (and a lot of unsettled clinical science). AZN investors have been waiting for the results of the MYSTIC trial, which is testing the company’s durvalamab against non-small cell lung cancer in combination with their CTLA4 antibody. That’s the therapeutic area where Bristol-Myers Squibb’s Opdivo ran trouble, compared to Merck’s Keytruda, and the optimistic case has been that AstraZeneca, considered to be behind, has been able to benefit from all that turmoil and has positioned itself to come up with much better results that will move it (and its drugs) into the front ranks.

Nervousness about this thesis creeps up, however. Last month, CEO Pascal Soriot made some headlines when he spoke about how AstraZeneca would indeed be in trouble if MYSTIC failed to deliver. He sounded, in fact, like someone trying to prepare people for this possibility, and for the possibility that the company might find itself a takeover target again (this time, presumably, in a more disadvantaged position as well). That didn’t make anyone happy, it’s safe to say, but investors now have something to really ponder on: an Israeli newspaper reported last night that Soriot is leaving AstraZeneca entirely to become CEO of Teva. Importantly, both companies quickly came out with statements on the rumor, but importantly, those statements were. . . “No comment”.

Oops. So if Soriot really is leaving, and that sure makes it sound like he is, then what does that say about MYSTIC, and AstraZeneca’s prospects in general? The trial results have surely not been unblinded, but this does sound like a vote of no confidence in the whole effort. I can only imagine what people at the company are thinking today – it’s not going to be one of those high scientific productivity days, you can bet. Actually, there have been several days like that in the last couple of months, since Luke Miels left a high post at the company to join GSK and the dispute over his departure spilled over into the courts.

We’ll see what happens. MYSTIC might surprise, you never know. But “you never know” is not a good basis on which to run a company – and right now, we don’t know who’s going to be running this one.

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