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stone baby

#dark souls #everlasting dragon

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#shitpost #$2 for big boom

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#art #circuit board #want

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What's the current status of Tumblr alternatives, either for the whole experience or just for blogging? Last time we thought this place might go under I tried Instagram (didn't last long, lol) and went to a bunch of effort to start cleaning up my more serious science posts and hosting them on WordPress since at the time that seemed like a much more stable place with less chance of either users getting nuked at random or the owner suddenly deciding to burn the place to the ground. However, considering recent displays of calm and intelligent behavior from their/our CEO, that may not be an accurate assessment anymore so I'm looking for a new backup plan.

Anyone have favorites? I've heard of fediverse stuff, Dreamwidth, Neocities, and some others that mostly seem to fall into the "Twitter knockoff" bucket.

#tumblr

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I never remember century things, so I'm tagging @jackironsides and @vincentbriggs because you MUST SEE IT

#BAGTRACHIANS #frog purse

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I saw some mentions of rabies going around again and have no clue what's set it off this time, but given recent scientific developments I want to revisit the idea of curing symptomatic rabies.

First things first: there is still no practical way to do this. The famous Milwaukee Protocol fails far more frequently than it succeeds, and even the successes are not making it out in anything like a normal state. It's been argued that it should no longer be considered a valid treatment [1] due to these issues; any continued use is because there's literally nothing else on the table.

However. There are now two separate studies showing it's possible to cure rabies in mice after the onset of symptoms. The lengths you have to go to in order to pull this off are drastic, to put it mildly, and couldn't really be adapted to humans even if you wanted to. But proof of concept is now on the board.

long post under the cut, warnings for animal experimentation and animal death. full bibliography at the end and first mention of each source links to paper.

Quick recap - rabies is a viral disease of mammals usually transmitted through the saliva of an infected animal. From a contaminated bite wound, it propagates slowly for anywhere from days to months until it reaches the central nervous system (CNS). Post-exposure vaccination can head it off during this phase, but once it reaches the CNS and neurological symptoms appear it's game over. There will typically be a prodromal phase where the animal doesn't act right - out at the wrong time of day, disoriented, abnormally friendly, etc. This will then progress to the furious (stereotypical "mad dog" disease) and/or paralytic phases, with death eventually caused by either seizures or paralysis of the muscles needed for breathing.

That's the course we're familiar with in larger animals. Mice, though, are fragile little creatures with fast metabolisms.

In the first study's rabies infection model, lab mice show rabies virus in the spinal cord by day 4 after infection and in the brain by day 5. Weight loss and slower movement start by day 7, paralysis starting from the hind limbs from day 8 on, and if not euthanized first they're dead by day 10-13. [2]

This study (fittingly conducted at the Institut Pasteur) had two human monoclonal antibodies, and wanted to see if there was any possibility they could be used to cure rabies after what we think of as the point of no return.

Injecting the antibodies into muscle saved some mice if done at days 2 or 4, and none if done later, even at high doses of 20 milligrams per kilogram of body weight of each. Conclusion: targeting the virus out in the rest of the body is no use if it's already replicating in the CNS.

Getting a drug past the blood-brain barrier is, to use a highly technical term, really fucking hard. It's the sort of problem that even the best-funded labs and biggest companies in the world routinely fail at. And that's for small molecule drugs, which are puny compared to antibodies.

But this isn't drug development for a clinical trial. This is a very, very early proof-of-concept attempt, which means you're willing to ignore practicality to see if this idea is even remotely workable. So you can do things like brute force the issue by cutting through the skull to implant a microinfusion pump, which lets you deliver the antibodies directly into the normally-protected space around the brain. Combine this with the normal injections, and you can treat both the CNS and the rest of the body at the same time. Here's a survival graph of treated mice. X axis is days, Y axis is percentage of mice in that group still alive.

Figure 2A from reference 2, accessed February 2024

The fact that the blue, green, and purple lines did anything other than sink horribly to zero is unheard of. When the combination treatment was started at day 6, 100% of the mice survived. Started at day 7 (prodromal phase), 5 out of 9 mice recovered and survived. Started at day 8 (solidly symptomatic, paralysis already starting to set in), 5 of 15 mice recovered and survived. And when they say "survived", they kept these mice all the way to day 100 to make sure. Some of them had permanent minor paralysis but largely they were back to being normal mice doing normal mouse things. So, success, but by pretty extreme means.

Enter the second paper [3]. This was a different approach using a single human monoclonal antibody against Australian bat lyssavirus (ABLV - closely related to rabies, similar symptoms in humans) to try for a cure without needing to deliver treatments directly into the CNS. They also made a luminescent version of ABLV that let them directly image viral activity, so they could see both where the virus was replicating and how much there was in a live mouse.

Figure 1 from reference 3, accessed February 2024

Mice infected with ABLV start showing symptoms around day 8. You can see in the figure that at day 3 there's viral replication in the foot at the site of infection, which has shifted into the spine and brain by day 10. So what happens if you give one of these doomed mice one single injection of the antibody into the body?

Done at day 3, the virus doesn't make it to the brain until day 14, and while disease does set in after that around 30% of the mice survive. Days 5 and 7 are much more interesting. Those mice still develop symptoms at day 8, but the imaging shows the amount of virus in their spines and brains never gets anywhere near the levels seen in untreated controls, and within days it starts to decrease. Around 80% of day 5 and 100% of day 7 mice survive.

Okay, sure, you can stop another lyssavirus, but technically you did start treatment before symptoms appeared. What about symptomatic rabies?

The rodent-adapted rabies strain CVS-11 starts causing symptoms as early as day 3 after infection, and untreated mice die between days 8 and 11. The same single dose of antibody saved 67% of mice treated on day 5 and 50% of mice treated on day 7. Without making the luminescent version of the virus there's no real-time imaging of the infection, but you can still track symptoms.

Figure 2 from reference 3, accessed February 2024. CVS-11 is the name of the rodent rabies strain and F11 is the name of the antibody.

Disease score is a combination of several metrics including things like whether the mice are behaving normally and whether they show signs of paralysis. In untreated mice it goes up and up, and then they die. If one of those lines starts coming back down and continues past day 10 or so, that's a mouse that recovered. The success rate isn't as good as against ABLV, but again, this is a rabies strain specifically adapted to rodents and treatment wasn't started until it was well-established in the CNS.

So how on earth is this happening? The antibody neutralizes both ABLV and rabies really well in a test tube, but we've already established that there's no way a huge lumbering antibody is making it past the blood-brain barrier without serious help. Something about the immune response is clearly making it in there though. And it turns out that if you start trying this cure in mice missing various parts of their immune systems, mice without CD4+ T cells don't survive even with the treatment. By contrast mice without CD8+ T cells take longer to work through the infection, but they eventually manage it and are immune to reinfection afterwards.

To grossly oversimplify the immune system here, CD4+ are mature helper T cells, which work mostly by activating other immune cells like macrophages (white blood cells) and CD8+ T cells (killer T cells) against a threat.

Normally, T cells are also kept out by the blood-brain barrier, but we know that in certain specific cases including viral infection they can pass it to migrate into the brain. In the brains of the infected mice for which antibody treatment either wasn't given or didn't work, you can find a roughly even mix of CD8+ and CD4+ T cells along with a whole lot of viral RNA. But in the brains of those successfully fighting off the infection, there's less viral RNA and the cells are almost exclusively CD4+. So the antibody doesn't work by neutralizing the virus directly - something about it is activating the animal's own immune system in a way that gives it a fighting chance.

Again, neither of these proof of concept treatments is really workable yet as a real world cure. The first one is almost hilariously overkill and still has a pretty good chance of failure. The second is less invasive but careful sequencing still shows both low-level viral replication and signs of immune response in the brains of the survivors even at day 139, so it may not be truly clearing the virus so much as trading a death sentence for life with a low-level chronic infection. But now we know that 1. curing rabies after symptoms begin is at least theoretically possible, and 2. we have some clues as to mechanisms to investigate further.

Not today. Not tomorrow. But maybe not never, either.

References:

Zeiler, F. A., & Jackson, A. C. (2016). Critical appraisal of the Milwaukee protocol for rabies: this failed approach should be abandoned. Canadian Journal of Neurological Sciences, 43(1), 44-51.

de Melo, G. D., Sonthonnax, F., Lepousez, G., Jouvion, G., Minola, A., Zatta, F., ... & Bourhy, H. (2020). A combination of two human monoclonal antibodies cures symptomatic rabies. EMBO molecular medicine, 12(11), e12628.

Mastraccio, K. E., Huaman, C., Coggins, S. A. A., Clouse, C., Rader, M., Yan, L., ... & Schaefer, B. C. (2023). mAb therapy controls CNS‐resident lyssavirus infection via a CD4 T cell‐dependent mechanism. EMBO Molecular Medicine, 15(10), e16394.

#rabies #biology #long post #animal death #medicine #original content

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reblog to be eaten by this thing

#gif #dinosaur #velociraptor

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Hydra!

#hydra

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anyways CATCH THESE BEANS

#cat #boop

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I finished a big science post late last night and nearly posted it completely unaware of what day today is... bullet dodged

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#cat #boop

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The people have spoken; dorsal view it is!

On one hand I spent a lot of time finding molts with the undercarriage intact, and I do think it's really cool. On the other, if I'm hanging it on the wall I don't want to spook maintenance or the landlord. I do have a second, slightly larger one, so one day maybe I'll find or make a bigger shadowbox and do that one with the leggies showing.

Will try and update when I finish putting everything together.

I have a smallish horseshoe crab molt and finally found a shadowbox that (barely) fits it. However this now presents a question: which side should be on display? Dorsal (back shell, stereotypical image of a horseshoe crab) or ventral (underside, many legs)?

I can't decide and also I'm not sure if the legs are too far into creepy crawly territory. My plan is to have the crab as the main item and add a few small fossils from the same beach around it.

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I have a smallish horseshoe crab molt and finally found a shadowbox that (barely) fits it. However this now presents a question: which side should be on display? Dorsal (back shell, stereotypical image of a horseshoe crab) or ventral (underside, many legs)?

I can't decide and also I'm not sure if the legs are too far into creepy crawly territory. My plan is to have the crab as the main item and add a few small fossils from the same beach around it.

#poll #horseshoe crab

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Intersections of Boston.

by @barelymaps

#boston #driven through several of these

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Me to postdoc: hey, any advice for getting through this paper?

Her: have you tried tequila?

#grad school

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Serratia marcescens possibly? That's one of the few contaminants you can identify by eye when it gets in your plates because the colonies are obnoxiously red-pink.

there's a bacteria that turns water pink, and it was one of the coolest things I've ever gotten to see, and I must share it with you all

#bacteria

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Hi, Tumblr. It’s Tumblr. We’re working on some things that we want to share with you. 

AI companies are acquiring content across the internet for a variety of purposes in all sorts of ways. There are currently very few regulations giving individuals control over how their content is used by AI platforms. Proposed regulations around the world, like the European Union’s AI Act, would give individuals more control over whether and how their content is utilized by this emerging technology. We support this right regardless of geographic location, so we’re releasing a toggle to opt out of sharing content from your public blogs with third parties, including AI platforms that use this content for model training. We’re also working with partners to ensure you have as much control as possible regarding what content is used.

Here are the important details:

We already discourage AI crawlers from gathering content from Tumblr and will continue to do so, save for those with which we partner. 

We want to represent all of you on Tumblr and ensure that protections are in place for how your content is used. We are committed to making sure our partners respect those decisions.

To opt out of sharing your public blogs’ content with third parties, visit each of your public blogs’ blog settings via the web interface and toggle on the “Prevent third-party sharing” option. 

For instructions on how to opt out using the latest version of the app, please visit this Help Center doc. 

Please note: If you’ve already chosen to discourage search crawling of your blog in your settings, we’ve automatically enabled the “Prevent third-party sharing” option.

If you have concerns, please read through the Help Center doc linked above and contact us via Support if you still have questions.

#tumblr