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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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acdha
87 days ago
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Washington, DC
petrilli
87 days ago
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Arlington, VA
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glenn
87 days 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

Trump on Jeff Bezos: ‘How Can I Fuck With Him?’

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Gabriel Sherman, writing for Vanity Fair:

Now, according to four sources close to the White House, Trump is discussing ways to escalate his Twitter attacks on Amazon to further damage the company. “He’s off the hook on this. It’s war,” one source told me. “He gets obsessed with something, and now he’s obsessed with Bezos,” said another source. “Trump is like, how can I fuck with him?” […]

Even Trump’s allies acknowledge that much of what’s fueling Trump’s rage toward Amazon is that Amazon C.E.O. Jeff Bezos owns The Washington Post, sources said. “Trump doesn’t like The New York Times, but he reveres it because it’s his hometown paper. The Washington Post, he has zero respect for,” the Republican close to the White House said. While the Post says that Bezos has no involvement in newsroom decisions, Trump has told advisers he believes Bezos uses the paper as a political weapon. One former White House official said Trump looks at the Post the same way he looks at the National Enquirer. “When Bezos says he has no involvement, Trump doesn’t believe him. His experience is with the David Peckers of the world. Whether it’s right or wrong, he knows it can be done.”

Josh Marshall, earlier this week, in an excellent column at Talking Points Memo:

Having a sitting President launching scathing personal attacks on a federal law enforcement officer and demanding his firing or imprisonment for personal and political motives is wildly outside the norms that govern the American system. Similarly, a President who routinely threatens prosecutorial or regulatory vengeance against private companies because they are not sufficiently politically subservient to him personally is entirely outside of our system of governance. At present, Donald Trump is an autocrat without an autocracy.

Can you even imagine the reaction from Republicans if Barack Obama had gone after, say, Rupert Murdoch in this way? And of course, Trump’s main beef with Amazon, that the U.S. Post Office is losing $1.47 on every package they deliver for Amazon, is complete bullshit. How anyone supports this president at this point is beyond my comprehension.

Amazon’s stock is taking a hit as a result of Trump’s rhetoric, but if I were an Amazon investor, I wouldn’t worry. Jeff Bezos is very, very smart. Donald Trump is not.

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petrilli
166 days ago
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Trump believes Bezos uses it as a political weapon because HE would use it as a political weapon, and he's incapable of imagining that anyone could possibly make better decisions.
Arlington, VA
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Vulture interviews Quincy Jones

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every line of this interview is unreal, a man who truly has no fucks to give

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petrilli
222 days ago
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*head spinning*
Arlington, VA
rosskarchner
223 days ago
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whut
DC-ish
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Just watch this

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It’s a good, no, great talk about principles of leadership by Bryan Cantrill. At turns hilarious, angry, and poignant, it is quite simply one of the best talks I have ever seen about what we’re building in tech and why and how to do better. We need to move forward, take responsibility and begin to tear down a culture in which “always be hustlin'” is a leadership principle. A frank, harsh look at Amazon, Uber, and techbro thinking, with some eulogy to Sun baked in. It’s a great talk. Please watch it.

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petrilli
283 days ago
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Worth a watch.
Arlington, VA
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jonwreed
282 days ago
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could be good
Northampton, MA

Why Didn’t Twitter Delete the Anti-Muslim Tweets Promoted by Trump?

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Ivana Kottasová, reporting for CNN:

The anti-Muslim videos were first posted by Jayda Fransen, deputy leader of the far-right party Britain First. They depict violent assaults and the destruction of a statue of the Virgin Mary.

They also appear to violate the terms of use published by Twitter. It warns users: “You may not promote violence against, threaten, or harass other people on the basis of race, ethnicity, national origin, sexual orientation, gender, gender identity, religious affiliation, age, disability, or serious disease.”

Asked why the original tweets have not been deleted, a Twitter spokesperson said:

“To help ensure people have an opportunity to see every side of an issue, there may be the rare occasion when we allow controversial content or behavior which may otherwise violate our rules to remain on our service because we believe there is a legitimate public interest in its availability.”

Translation from PR Weasel-ese to English: Twitter is afraid of pissing off Trump.

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petrilli
288 days ago
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I wish Twitter would be more honest about the fact that what keeps it from deleting Trump's account is the (very real) fear that the sociipathic narcissistc in chief would use his cadre of incompetent criminals and hangers-on to persecute Twitter constantly and likely would bankrupt the company.

Be honest.
Arlington, VA
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rtreborb
285 days ago
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Translation: it drives revenue
martinbaum
291 days ago
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Maybe, but more like Twitter is still relevant because Trump's the best traffic driver their platform has ever had.

Intel Performance Libraries and Python Distribution enhance performance and scaling of Intel® Xeon® Scalable (‘Skylake’) processors on GCP

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Google was pleased to be the first cloud vendor to offer the latest-generation Intel® Xeon® Scalable (‘Skylake’) processors in February 2017. With their higher core counts, improved on-chip interconnect with the new Intel® Mesh Architecture, enhanced memory subsystems and Intel® Advanced Vector Extensions-512 (AVX-512) functional units, these processors are a great fit for demanding HPC applications that need high floating-point operation rates (FLOPS) and the operand bandwidth to feed the processing pipelines.
New Intel® Mesh Architecture for Xeon Scalable Processors

Skylake raises the performance bar significantly, but a processor is only as powerful as the software that runs on it. So today we're announcing that the Intel Performance Libraries are now freely available for Google Cloud Platform (GCP) Compute Engine. These libraries, which include the Intel® Math Kernel Library, Intel® Data Analytics Acceleration Library, Intel® Performance Primitives, Intel® Threading Building Blocks, and Intel® MPI Library, integrate key communication and computation kernels that have been tuned and optimized for this latest Intel processor family, in terms of both sequential pipeline flow and parallel execution. These components are useful across all the Intel Xeon processor families in GCP, but they're of particular interest for applications that can use them to fully exploit the scale of 96 vCPU instances on Skylake-based servers.

Scaling out to Skylake can result in dramatic performance improvements. This parallel SGEMM matrix multiplication benchmark result, run by Intel engineers on GCP, shows the advantage obtained by going from a 64 vCPU GCP instance on an Intel® Xeon processor E5 (“Broadwell”) system to an instance with 96 vCPUs on Intel Xeon Scalable (“Skylake”) processors, using the Intel® MKL on GCP. Using half or fewer of the available vCPUs reduces hyper-thread sharing of AVX-512 functional units and leads to higher efficiency.
In addition to pre-compiled performance libraries, GCP users now have free access to the Intel® Distribution for Python, a distribution of both python2 and python3, which uses the Intel instruction features and pipelines for maximum effect.

The following chart shows example performance improvements delivered by the optimized scikit-learn K-means functions in the Intel® Distribution for Python over the stock open source Python distribution.
We’re delighted that Google Cloud Platform users will experience the best of Intel® Xeon® Scalable processors using the Intel® Distribution for Python and the Intel performance libraries Intel® MKL, Intel® DAAL, Intel® TBB, Intel® IPP and Intel® MPI. These software tools are carefully tuned to deliver the workload-optimized performance benefits of the advanced processors that Google has deployed, including 96 vCPUs and workload-optimized vector capabilities provided by Intel® AVX-512.”  
Sanjiv Shah, VP and GM, Software Development tools for technical, enterprise, and cloud computing at Intel
For more information about Intel and GCP, or to access the installation instructions for the Intel Performance Library and Python packages, visit the Intel and Google Cloud Platform page.
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petrilli
305 days ago
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The improvements on scikit-learn are pretty staggering.
Arlington, VA
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