Software developer, cyclist, photographer, hiker, reader.I work for the Library of Congress but all opinions are my own.Email: chris@improbable.org
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Alzheimer’s and Infectious Disease: For Real

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I’ve written a couple of times over the years about the idea that Alzheimer’s disease might have an infectious component to it. That’s been proposed many times, but it’s fair to say that it’s never caught on. For one thing, the amyloid hypothesis has always had a lot more going for it. I realize that I’ve poured scorn on that one in recent years, but that’s after a string of massive clinical failures based on it being right. It started out as by far the most plausible mechanism around, and even now, any further explanation of the disease is going to have to include an amyloid component, in much the same way that Einstein’s relativity also included an explanation of why Newtonian mechanics was so workable so much of the time.

A new paper in Neuron, though, looks to be the most unignorable one yet with evidence that there’s some sort of viral/bacteial/fungal component to the disease. A team led out of a Mt. Sinai research group has gone over a pretty large sample of Alzheimer’s brain tissue (622 patients who died with the disease, and over three hundred control brains as well), sequencing infectious organism DNA, looking for changes in the proteome, etc. They find that aging brains in normal patients display plenty of viral signatures (as indeed is probably the case in many other tissues). But the AD samples were particularly enriched in herpesviruses 6A and 7, a result that repeated across three independent cohorts from different geographical locations (the brain tissue collections were from more than one previous effort). According to Stat, there’s a paper coming out next month from another group entirely that also implicates HHV6.

But are these viruses a cause of the disease, or are they something that shows up later? That is, do HHV 6A/7 give you Alzheimer’s, or does having Alzheimer’s bring on those viral infections? This has been the problem with many previous proposals for an infectious agent, and it’s a very difficult objection to overcome. I think that this is the first study, though, that has made it over that hurdle. The paper shows that viral DNA is, in fact, incorporated into neurons from the affected regions of the brain. What’s more, analysis of both protein and mRNA levels suggest that such infection produces changes in several transcriptional regulators (specifically, a set of zinc-finger transcription factors and G-quadraplex-associated proteins) that in turn affect expression of a number of very suggestive proteins downstream:

We found that multiple viruses interact with AD risk genes. HHV-6A stood out as notable with significant overlap (FDR < 3e-3) between the set of host genes it collectively induces across all tissues and AD-associated genes (Figure 5D, Table S7). This includes several regulators of APP processing and AD risk-associated genes, including gamma-secretase subunit presenilin-1 (PSEN1), BACE1, amyloid beta precursor protein binding family B member 2 (APBB2), Clusterin (CLU), Bridging Integrator 1 (BIN1), and Phosphatidylinositol Binding Clathrin Assembly Protein (PICALM). We also found that several other viruses regulate, or are regulated by, AD risk genes, including: (1) HAdV-C-induced expression of Complement Receptor 1 (CR1), and inhibition of Solute Carrier Family 24 Member 4 (SLC24A4), (2) inhibition of KSHV by Fermitin Family Member 2 (FERMT2), and (3) inhibition of HSV-2 by Translocase of Outer Mitochondrial Membrane 40 (TOMM40). These findings indicate multiple points of overlap between virus-host interactions and AD risk genes.

There’s also an association with neuronal loss, and this and other pathways seem to converge on miR-155 as an important factor (HHV6A inhibits its expression). The team then crossed a mouse strain that’s knocked out for this microRNA with one of the APP/presenilin mutant mouse lines that is susceptible to amyloid problems. And indeed, the resulting mice  show significantly more amyloid plague formation at four months, and significantly more amyloid 1-42 in the brain.

This gets right at what I mentioned above: any alternate theory of Alzheimer’s will have to explain why there are so many apparent connections to amyloid handling. So this might well be real, and if it is, it really does open up a whole new set of mechanistic (and even therapeutic) possibilities. Although I don’t keep up with the literature in this field as well as I would were I still working in it, I think that this is one of the most significant Alzheimer’s papers I’ve seen in years. A mechanism through viral disturbance of transcription factors, miRNAs, and other such gene-expression pathways would fit well with the variations seen in the incidence and severity of the disease, because that lands you right into the mess of environmental factors, immune system variations, and so on.

The integrated findings of this study suggest that AD biology is impacted by a complex constellation of viral and host factors acting across different timescales and physiological systems (Figure 8B). This includes host mucosal defense and modulation of innate immune response by virus and host. It also includes disturbance of core biological processes, including some that are well described in AD (e.g., APP processing, cytoskeletal organization, mitochondrial respiration, protein synthesis, and cell-cycle control) and some that are less well characterized (e.g., widespread shifts in G4 activity and C2H2-TF regulatory programs). We note potential mechanisms (and candidate molecular mediators) that we find perturbed by viral species and that have known impacts on these altered processes, for instance, virally driven changes in protein synthesis machinery, tRNA synthetase activity, and nucleotide pool maintenance, which collectively exert complex effects on G4 regulation and C2H2-TF activity.

This paper immediately suggests several lines of research. HHV6A needs to be studied in more detail (and distinguished from HHV6B, which current tests don’t always do). Viral mechanisms of transcriptional disruption have already been investigated in other contexts, but there’s a lot to be done in the Alzheimer’s territory. We need to see if miR-155 is a real node in the system, and so on. And it wouldn’t do any harm to look at the effects of existing antiviral drugs on these HHV strains, would it? After years of writing about amyloid-centric disappointments, I think it’s great to have some new hypotheses to test!

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glenn
7 hours ago
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As a layman, the article referenced here was helpful as well.

https://www.statnews.com/2018/06/21/herpes-viruses-alzheimers-disease-role/

Also mentions a Taiwan study that a herpes-infected group was 2.6 times as likely to develop dementia. But in people treated with antiviral drugs, that risk was reduced by 90 percent!

Waterloo, Canada
petrilli
18 hours ago
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Arlington, VA
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DEA Asks for Help Laundering Money

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As Justin Rohrlich reports this week for the Daily Beast, the Drug Enforcement Administration recently expressed a concern that currency it seizes in drug busts could be covered in deadly chemicals, and has asked potential vendors for information about helping it clean up the dangerous bills.

There is good reason to believe that this is ridiculous.

In a Request for Information posted on June 14, the DEA said it was “interested in learning more about available capability in cleaning and decontaminating currency tainted with drugs and other unknown substances.” Some of these substances, it explained, “may be extremely harmful to human health and potentially result in death,” which can also be extremely harmful to human health. “As such,” the DEA continued, “the currency must be decontaminated to ensure safety.” It invited interested vendors to respond by June 26.

There is a lot wrong with this, even beyond the glaring misuse of the phrase “as such” to mean “therefore” and to refer to “substances” in one sentence but “currency” in the other. I mean, that is certainly appalling and something we need to address, it’s just not the biggest problem here.

Here are two bigger ones.

First, according to multiple sources quoted in the article, while one could not describe currency in circulation as “clean,” and drug residue of some kind is not rare, there seems to be little if any evidence that the levels involved could be harmful in any way, much less deadly. I say this only partly because the “hazardous substances” listed by the DEA for potential “decontamination” include marijuana/THC. (I’m not a doctor, but I haven’t exactly seen any headlines about emergency rooms being choked with cases of marijuana poisoning, and I live in San Francisco.) But what did the actual experts quoted in the article say? Here’s a summary:

  • Former FBI special agent for 22 years: this is all news to me.
  • Forensic toxicologist: “absurd at best,” also “ludicrous.”
  • Med-school professor: “quite odd, given the lack of scientific support.”
  • Former detective: no … but maybe for fentanyl?
  • Forensic toxicologist again: no, not fentanyl either, unless maybe you eat the bills.

The question therefore seems to be: Are DEA agents or administrators eating any of the currency they seize?

And this brings us to the second problem: if they are eating it, how would we know? Because the most interesting thing in the RFI is the DEA’s statement that, because the seized drug money is so dangerous that they will not be able to count it before turning it over to the vendor for cleaning:

Contaminated Currency Packaging Requirements and Delivery. The vendor shall indicate to DEA how contaminated currency should be packaged. DEA will not count the contaminated currency (due to inherent safety issues) prior to packaging the contaminated currency, but will have a general indication of the amount that has been packaged for the vendor. The vendor shall also indicate whether they provide pick up services for DEA, if DEA should deliver the contaminated currency, or both. It is preferred that DEA have a service where the contaminated currency can be double-bagged and provided directly to the vendor….

Emphasis added.

***

“Hi, guys, Steve over at DEA again. Hey, so we got another truckload or so of contaminated currency here that we need to ship over for you to laun— to decontaminate.”

“Whoops! You almost said it, Steve!”

“No, I said ‘decontaminate.’ Like in the proposal. Anyway, we’ve got, like, a truckload of hundreds here. What do you think?”

“Will Friday work?”

“Yes. Oh, and don’t forget—we need to get a truckload back, too.”

“Oh, absolutely. You will get a truckload back.” <is making air quotes with fingers>

“Okay … You’re not making air quotes, are you?”

“No.”

“Okay. Because we talked about that.”

“Absolutely. Oh, and Steve?”

“What?”

“Don’t forget to double-bag the cash. You know, so some of the bags don’t break and spill the money out all over the road, never to be seen again.”

“Very funny. You guys are a real hoot.”

“Hey, it’s a good joke.” <is making air quotes again> “Okay, we’ll try to make some room in the hundreds bin.”

“Okay, thanks.”

***

The phrase you’re looking for, I think, is “what could go wrong?” We have a federal agency pursuing a “war on drugs” that is basically pointless to begin with; an agency that (like many others) has a record of seizing assets before any conviction has taken place and without any discernible connection to law enforcement (see Report: Many DEA Cash Seizures Have ‘No Discernible Connection’ to Law Enforcement” (Apr. 6, 2017); and here it is saying it’s going to ship money back and forth for “decontamination,” on a questionable basis, without even counting it.

What could go wrong?

See also DEA Agent: If You Legalize Pot, Rabbits Will Get High” (May 4, 2015) (discussing another really stupid argument a DEA agent made once).

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acdha
16 hours ago
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The better question is which administration buddy this contract will be steered to. The Trump Org is too obvious but has anyone checked Erik Prince’s business filings recently?
Washington, DC
aranth
2 days ago
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🤔

Those grainy Moon photos from the 60s? The actual high-res images looked so much better.

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In 1966 and 1967, NASA sent five spacecraft to orbit the Moon to take high-resolution photos to aid in finding a good landing spot for the Apollo missions. NASA released some photos to the public and they were extremely grainy and low resolution because they didn’t want the Soviet Union to know the capabilities of US spy satellites. Here’s a comparison to what the public saw at the time versus how the photos actually looked:

Old Moon New Moon

The Lunar Orbiters never returned to Earth with the imagery. Instead, the Orbiter developed the 70mm film (yes film) and then raster scanned the negatives with a 5 micron spot (200 lines/mm resolution) and beamed the data back to Earth using lossless analog compression, which was yet to actually be patented by anyone. Three ground stations on earth, one of which was in Madrid, another in Australia and the other in California recieved the signals and recorded them. The transmissions were recorded on to magnetic tape. The tapes needed Ampex FR-900 drives to read them, a refrigerator sized device that cost $300,000 to buy new in the 1960’s.

The high-res photos were only revealed in 2008, after a volunteer restoration effort undertaken in an abandoned McDonald’s nicknamed McMoon.

They were huge files, even by today’s standards. One of the later images can be as big as 2GB on a modern PC, with photos on top resolution DSLRs only being in the region of 10MB you can see how big these images are. One engineer said you could blow the images up to the size of a billboard without losing any quality. When the initial NASA engineers printed off these images, they had to hang them in a church because they were so big. The below images show some idea of the scale of these images. Each individual image when printed out was 1.58m by 0.4m.

You can view a collection of some of the images here.

Tags: Moon   NASA   photography   space
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hannahdraper
15 hours ago
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Washington, DC
dianaschnuth
16 hours ago
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Toledo OH
schnuth
12 hours ago
OK, that's pretty amazing.
zwol
17 hours ago
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Mountain View, CA
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Just Following Orders

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“In a democracy people get the leaders they deserve.” (Joseph de Maistre)

The President recently reversed his own decision to separate children from their parents after crossing into the United States, an action that the United Nations office of human rights condemned as a violation of basic human rights of children. They weren’t alone. The Pope spoke out citing such a disgraceful policy as contrary to Catholic values, and immoral. The Methodist Church called it child abuse and racism. Other religious leaders echoed this sentiment. Business leaders spoke out publicly condemning it. All five living first ladies spoke out against it. It was clear to the world that the United States, under the direction of the Donald Trump administration, was committing violations of human rights of children. Yes, it was disgusting and disgraceful, and the world was ashamed of us. Yes, I blame the Trump administration as the root cause of it. I also blame the people that carried it out, who all too often get away with no accountability for “just following orders”.

Such a mandate to violate human rights should have never gotten past the terrible leadership call; the orders should have been outright refused by the people who were tasked with handing them down, and ultimately by those carrying them out. Refusing inhumane orders is what separates us from a history of atrocities. Why didn’t these orders get refused on a large scale? We should consider this very seriously. There are only two possibilities: either the agents who carried these orders out didn’t realize they were abusing the children as they were ripping them from parents and putting them in cages, or they were willing to commit acts they knew to be immoral and inhumane (for any variety of reasons). In either case, we are dealing with defective human beings who should not be in a position of authority.

Most of the time, agents that are just following orders are rarely ever prosecuted, and it’s unlikely there will be any disciplinary action over this. Digging deeper, though, we also need to look in the mirror and ask what we’ve done lately to better our society. At the end of the day, a government is a reflection of society. In America and other democratic nations, it is society that shapes the government. We are all guilty to some degree for the acts that were committed. The racism, the hate, and the ignorance that we see happening in this country trickles up just as much into government as it does any other working group. You cannot answer the question, “what is wrong with our government”, without also asking, “what is wrong with society?” We should be wearing sackcloth and ashes as a nation over this.

We’ll likely never see the individuals that carried out these orders prosecuted, jailed, or even named, and with the President’s executive order to reverse this policy, the bleeding is beginning to stop, although there is a lot left to fix this. This series of events has given us opportunity to examine the moral compass of our government, but also our society. There are many great people working in our government. There are clearly also others willing to violate human rights.  It begs the question of what other crimes against human rights are they willing to commit if given the order? These are not faceless robots, they are our neighbors; people living down the street.

The child separation policy was a test of our grit as Americans. I’m very proud that so many stood up against it, and I am sure that there are many good men and women in law enforcement who did too – many we will probably never hear about. It was, however, also clear feedback to certain government agencies about whether or not such orders would be followed. Those that did not refuse such orders failed an important test of their character, and have no business serving the people. Next time, the orders may be even more inhumane. Agents that follow such orders and keep telling themselves, “next time” will always follow those orders: the line just keeps moving until it is no longer visible.

Over my time working with government, I’ve come to know many amazing human beings who do good work, believe in human rights, and keep us safe. The people who forcefully ripped children away from their parents and locked them in cages were not deserving of the badge. Those people should, in my opinion, be charged and prosecuted for crimes against children, to set an example that America won’t stand for this kind of behavior. We should all take this as a serious warning that there are those in our society who are capable of such things, and rectify the situation before it gets worse. America should not be capable of this. Yet we have been, historically. We should be better than this. If left unchecked and unrepentant, we may one day find ourselves not far from repeating the atrocities of history.

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jimwise
1 day ago
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...

Today in Uber Autonomous Murderbot News

jwz
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"Safety driver" of fatal self-driving Uber crash was watching Hulu at time of accident:

Police obtained records from Hulu, an online service for streaming TV shows and movies, which showed Vasquez's account was playing the TV talent show "The Voice" for about 42 minutes on the night of the crash, ending at 9:59 p.m., which "coincides with the approximate time of the collision," the report said. [...]

The Uber car was in autonomous mode at the time of the crash, but the company, like other self-driving car developers, requires a back-up driver inside to intervene when the autonomous system fails or a tricky driving situation occurs.

WHICH WILL NEVER WORK!

Vasquez looked up just 0.5 seconds before the crash, after keeping her head down for 5.3 seconds, the Tempe police report said. Uber's self-driving Volvo SUV was traveling at just under 44 miles per hour. [...] Police said a review of video from inside the Volvo showed Vasquez was looking down during the trip, and her face "appears to react and show a smirk or laugh at various points during the times that she is looking down." The report found that Vasquez "was distracted and looking down" for close to seven of the nearly 22 minutes prior to the collision. [...]

According to a report last month by the National Transportation Safety Board, which is also investigating the crash, Vasquez told federal investigators she had been monitoring the self-driving interface in the car and that neither her personal nor business phones were in use until after the crash. That report showed Uber had disabled the emergency braking system in the Volvo, and Vasquez began braking less than a second after hitting Herzberg. [...]

In addition to the report, police released a slew of audio files of 911 calls made by Vasquez, who waited at the scene for police, and bystanders; photographs of Herzberg's damaged bicycle and the Uber car; and videos from police officers' body cameras that capture the minutes after the crash, including harrowing screams in the background.

I repeat myself, but:

  1. The Uber executives who put this software on the public roadways need to be in jail. They disabled safety features because they made testing harder. They disabled safety features because they made the ride rougher.

  2. This notion that having a "safety driver" in the passenger seat will allow a distracted human to take over at the last minute is completely insane. You think driving-while-texting is dangerous? This is so much worse. When people aren't engaged in the task of driving, their minds wander. They cannot re-engage fast enough. This is obvious on its face, we don't need studies to prove it. Oh, but we have them anyway.

  3. I would still like to know the answer to the question of who gets charged with vehicular homicide when one of these machines kills someone. Even if they are ultimately ruled to be not at fault, what name goes on the court docket? Is it:

    • The Uber employee "non-employee independent contractor" in the passenger seat?
    • Their shift lead?
    • Travis Kalanick?
    • The author(s) of the (proprietary, un-auditable) software?
    • The "corporate person" known as Uber?

Previously, previously, previously, previously, previously, previously, previously, previously, previously.

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Opinion | A Jury May Have Sentenced a Man to Death Because He’s Gay. And the Justices Don’t Care.

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On Monday, the Supreme Court announced it would not stop South Dakota from killing a man who may have been sentenced to death because he is gay. Some of the…
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