The Alan Sondheim Mail Archive

April 4, 2010


platos cave illuminated by sound


recording 8 minute oud solo with eyes closed. i suppose this is easy for
bowed-string players in general; most plucked-string players i know watch
- at least on occasion - what they're doing. certainly it helps intona-
tion, especially when leaps are involved. of course there are many blind
musicians who move effortlessly on their instruments. (without glasses, my
eyesight is miserable; i can't read the big E on the chart; sometimes i
don't even see the chart.) but i watch what i do. then i noticed, playing
oud, i had to develop some sort of muscle memory - watching doesn't quite
work when the fingerboard is featureless. i can judge the neighborhood,
but not the house. so i find i can play with my eyes closed, which brings
up, plato's cave: for the cave itself is an acoustic instrument, one that
responds to aural registers, one whose depth is revealed by echo and
resonance, by the playing-out of harmonics, by what goes on in the
interior of someone's mind, someone listening, or someone playing, for
examples, in a closed space, perhaps the space of an infinite ocarina,
perhaps a universal sonic map. and here is the space of visual darkness,
the space of sound projecting, messing up ideal forms with taylor series
stretched to the limit, with a hollowness that neither knows its name nor
note. so one, i muse, might in such a space play a world, one might world
a world. so i made sure to inhabit the forms, the pulse and flow of music,
if such be music, i made through being there, present, playing, within
such an infinitude illuminated by sound.

http://www.alansondheim.org/platoscave.mp3

(apologies for length)


archive: all my now zero work or my work is zero

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==

---------- Forwarded message ----------
Date: Sun, 4 Apr 2010 21:58:27 -0400
From: moderator@PORTSIDE.ORG
To: PORTSIDE@LISTS.PORTSIDE.ORG
Subject: Finding a Medical "Silver Bullet" to Disable Many of the World's
     Deadliest Viruses

Thinking on the Envelope: Finding a Medical "Silver
Bullet" to Disable Many of the World's Deadliest Viruses

A series of promising compounds can cripple all
enveloped viruses' ability to invade cells as well as
circumvent any resistance that hobbles traditional
antiviral drugs. But will they work outside the lab?

By Bob Roehr
Scientific American
March 29, 2010
http://www.scientificamerican.com/article.cfm?id=broad-spectrum-anti-viral

Benhur Lee may have discovered a medical silver bullet
that can disable pandemic HIV, exotic Ebola, the common
flu and possibly every kind of enveloped virus on the
planet. An added bonus is that those viruses likely are
unable to develop resistance to the compound.

If this sounds too good to be true, you are not alone.
Lee was skeptical himself, and that is why it took four
years of detailed work by his lab at the University of
California, Los Angeles, (U.C.L.A.), along with
collaborators spread across the country before the first
paper was published on the potentially revolutionary
discovery, on February 16 in Proceedings of the National
Academy of Sciences.

Lee is an expert on the viral envelope, the dynamic
outside surface of a virus that latches onto a cell,
then changes its shape to let the virus enter and infect
the cell. This work began as part of a biodefense grant
from the National Institutes of Health, screening a
library of 30,000 compounds for activity against the
envelope of Nipah virus, an emerging infection first
identified in 1999 in Malaysia.

Nipah is so deadly that work with the virus itself can
only be done in biosafety level 4 (BSL-4) labs where
researchers wear tightly sealed hazmat suits with
internal oxygen supplies. The labs themselves are
strongly secured. There are only four in the U.S.

Lee got around that by creating a hybrid virus. He
striped off the envelope covering the relatively benign
vesicular stomatitis virus (VSV) and added the Nipah
envelope to that core. This allowed him to screen the
compounds in his lab at the university using much lower
BLS-2 safety standards, to see if they inhibited viral
entry into the cell.

"One compound (LJ001) looked really good, it had an IC50
of one micromolar [meaning that it inhibited the
pathogen at a low concentration], which for an initial
read is okay. Most importantly, it wasn't toxic" to cell
cultures, Lee explained.

Mike Wolf, a grad student in the lab, wanted to make
sure the compound was specific to Nipah, so he screened
it against VSV. When the inhibition curves came back
identical, he originally was disappointed because the
study's funding was based on exploring potential
therapeutics for Nipah.

Lee, however, encouraged him to be more persistent, and
curious. After a series of studies confirmed the
activity and lack of toxicity, Lee sent double-blinded
samples of the compound and control to a colleague at
the BSL-4 lab at the University of Texas Medical Branch
at Galveston who tested it against Nipah, Ebola and
other viruses. They were shocked when LJ001 inhibited
viral entry to all of them.

So Lee pitted it against HIV, a pathogen he had worked
with extensively-it worked there, too. "That didn't make
any sense at all to a virologist, because retroviruses
have nothing to do with these negative-strand RNA
viruses" like Nipah and Ebola, he says.

"We started going through a list of 20-plus viruses,"
and it inhibited entry of all of them. "I had no idea of
what was going on, I couldn't find anything common about
them." Finally, when he ran the compound against
adenovirus, it came back negative. Only then did he
recognize the commonality: LJ001 worked against lipid
envelope viruses only. It took a few years to rule out
possibilities that the compound might be inhibiting the
binding or fusion processes by which such viruses enter
cells.

Lee demonstrated that the compound binds to lipids in
the envelope of both the virus and the invaded cell.
Eventually he came to realize that it causes damage to
both organisms. The difference is that the larger cell
is equipped to repair all sorts of regularly occurring
insults. The more primitive virus, however, carries no
repair mechanisms; a new virion (complete virus)
acquires lipids for its envelope by literally ripping
them off of the cellular membrane as it buds off from
the infected cell. Once the viral lipids were disabled
by LJ001 they stayed that way.

Current antiviral drugs target encoded proteins
essential to the viral life cycle, and which vary so
much among virus types that a specifically tailored drug
seldom is effective against more than one of them.
Furthermore, active processes allow viruses to
inevitably develop resistance to such compounds. To
compensate for this shortcoming, combination therapy
attempts to hit a virus at so many places simultaneously
that it cannot develop resistance to them all.

But viruses do not have genetic control of their lipids
like they do with proteins. So, Lee is optimistic about
the potential for resistance to drugs like LJ001. He
says, "I can't imagine how the virus can develop
resistance to it."

When U.C.L.A. lawyers searched the patent database, they
found that a company already had filed a patent on LJ001
claiming antiviral activity but describing little else.
Lee is not concerned; his colleague Michael Jung, a
medicinal chemist at U.C.L.A., had tinkered with the
original compound and found a series of variations that
are 100-fold more potent. The university is filing claim
to those.

Lee says it is important to demonstrate in vivo efficacy
of these compounds. He is working to try to overcome a
few barriers they have identified, and he readily
concedes that it will take teams of experts with
specialized knowledge to bring a product to market. His
primary focus is on basic research, and he already is
thinking about those next challenges.

Warner Greene, director of the Gladstone Institute of
Virology and Immunology at the University of California,
San Francisco, congratulated Lee and his collaborators
on "a fascinating piece of work on an unexpected
finding." But, he cautions, "from a therapeutic point of
view it is a very, very early finding."

"The breadth of antiviral activity is fascinating but I
fear that with the underlying mechanism of membrane
disruption, there might be a lot more toxicity than is
currently appreciated. Primary cells often are much more
sensitive than laboratory-adapted cells," Greene says.

He adds: "With this type of drug you are always going to
be operating in a window of whether or not the cell can
catch up and keep the cell alive while the drug is still
being effective against the virus. It will be a race."
That is the same principle behind many current therapies
for cancer.

_____________________________________________

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