The Alan Sondheim Mail Archive

May 16, 2010


intake

contraption, now partly invisible, o protection, trying to land
on a planet, slipping out, from under it, sliding away from the
diegetic, blade and surface thickness molecular, atomic, quark,
no language but the same old tale, everyone's caught in the flat,

of intake, ingesting from beyond
of outtake, what, present, would have been removed

this intake from transformed calculations, this intake asks,
of where would this have been, if it were there, what are the
named surfaces, coordinates, physics, dynamics,
never mind the motives

http://www.alansondheim.org/intake.mp4

Hatsune Miku Visits

http://www.alansondheim.org/hmmmiku.mp4
http://www.alansondheim.org/miku.mov

---------- Forwarded message ----------
Date: Sun, 16 May 2010 22:06:15
From: moderator@PORTSIDE.ORG
To: PORTSIDE@LISTS.PORTSIDE.ORG
Subject: Fink or Fungus - They're All Among Us

I, Mold
Conquering the rising tide of infection is hindered
by the many similarities between humans and fungi
By Laura Beil
Science News
May 22, 2010
http://www.sciencenews.org/view/feature/id/58915/title/I%2C_Mold

In the germ world, fungi usually lack the flair of
viruses or bacteria. To people with normal, healthy
immune systems, a fungus will rarely show itself - even
though you carry around a microscopic film of fungus on
your hair and skin, and take in invisible clouds of
fungal spores with each breath. While many other
microbes prefer to make a living through disease and
death, a fungus is often content to wait for its host to
die of something else.

In fact, throughout the history of civilization fungi
have mostly been humans' friends, providing the bounty
of bread and beer, recycling trash and enabling plants
to extract nutrients from the soil. Scientists estimate
that roughly 1.5 million species of fungus inhabit the
Earth, but only a handful are capable of causing human
disease.

Problem is, when they do, fungi can be remarkably
lethal: For example, about half the patients who develop
serious infections from the fungus Aspergillus will not
survive. The mortality rate for the most common fungal
infection in hospitals, candidiasis, has been reported
to be just as high - and though numbers are hard to come
by, reports suggest overall fungal infection rates have
been on the rise. Doctors have also recently become
concerned about a once-rare infection from the
Cryptococcus fungus spreading in the Pacific Northwest
(SN Online: 4/22/10).

Understanding what transforms a fungus from pal to
pathogen has occupied researchers for more than a
century. Yet scientists have only recently discovered
some key principles that govern how fungi operate, and
that allow a normally peaceful fungus to turn against
people. In trying to decode the molecular conversation
between microbe and human host, fungus explorers have
also found some surprising secrets about the human
immune system.

"We're now starting to see studies that rival anything
else done before them," says William E. Goldman, a
microbiologist at the University of North Carolina at
Chapel Hill. Since 2004, when the complete genetic
blueprint of Candida albicans was published, researchers
have cataloged the genomes of about a dozen species of
fungus that cause disease. Studies of these genomes may
soon reveal how fungi survive in people's bodies - and
suggest new ways to extinguish the germs. Scientists
have also recently discovered families of molecules on
human immune cells that alert the body to the presence
of fungi and other invaders, as well as mechanisms that
allow a fungus to evade those cells.

Taken together, these findings may soon solve one of the
most challenging aspects of treating fungal infection:
how to get rid of the germ that is your closest
relative.

In old biology classes, fungi were lumped with plants,
presumably because both forms of life could sprout from
dirt. Today, fungi are recognized as their own kingdom,
a diverse group of organisms that live in the inky
depths of the ocean, the sub-zero snows of Antarctica
and the forgotten apple in the refrigerator.

Fungi include mold, yeast, mushrooms and other growths
that don't make energy from chlorophyll and light. To
reproduce, many fungi shed microscopic spores, each one
capable of propagating. Even if you don't see fungi, you
live with them daily. A 2005 study found that about a
million spores are nestled in your pillow alone.

On a cellular level, fungi have more in common with
humans than they do with bacteria. A thick cell wall and
beta-glucan molecules are two features that fungal cells
(a yeast cell, reproducing by budding, is shown) possess
that human cells don't.Nicolle Rager Fuller

Fungi are usually the vultures of the ecosystem,
preferring food that is almost or already dead.
(Aspergillus, for example, usually hangs around rotting
leaves and compost piles, feasting on decaying matter.)
But sometimes, when conditions are right, a fungus
starts to germinate while its host is still among the
living. In people, this generally leads to troublesome,
but not fatal, infections of the skin and nails.

"Most fungal pathogens are pretty wimpy," Goldman says.
"They are not very good at causing disease in normal
hosts with normal immune systems."

But a growing population of people have not-so normal
immune systems. Fungal infections are so deadly in part
because most patients who become seriously ill are
already weakened by AIDS, cancer, transplants or
medications that handicap the body's ability to mount a
strong defense. More and more of these patients have
taken high doses of anti-biotics to prevent other
infections, fundamentally changing the body's ecology
and allowing unnatural fungal growths to take over. More
patients are also undergoing medical procedures that
breach normal immune barriers with catheters and other
devices.

While relatively rare a generation ago, candidiasis - a
blood infection from the fungal genus Candida, which
normally lives on the skin - has become the fourth most
common infection acquired in hospitals. Although
infections from Aspergillus are not carefully tracked,
studies suggest that the number of deaths quadrupled
during the 1980s and '90s.

Drugs to treat fungal infections have been difficult to
develop because fungi share many properties with people;
from an evolutionary standpoint, fungi are closer to the
animal kingdom than any other form of life. If you put
mushrooms on your pizza, the mushrooms have more in
common with you than with the tomato sauce. Fungi are
also much more closely related to humans than are
viruses and bacteria, which makes attacking fungal
infection a tricky business.

Unlike other kinds of germs, both people and fungi are
eukaryotes - among other commonalities, their cells have
a nucleus, and the nucleus has its own membrane. In
fact, fungal cells are so much like animal cells that
much about the basics of human life has been gleaned
from studies of baker's yeast.

To fight infection, antimicrobial drugs often exploit
some molecular difference between an invading organism's
cells and human cells. But with fungal treatment, human
tissue is more likely to find itself in the line of
fire. Although more modern antifungal drugs are less
harsh than their predecessors, one of the first widely
used antifungals - amphotericin B - had a reputation for
being highly toxic.

"When we are evolutionarily so similar, it's hard to get
drugs that target fungi alone," says Bruce Klein of the
University of Wisconsin-Madison. Drugs that treat
bacterial infections often aim for molecules in the
bacterial membrane. However, if drugs attack fungal
membranes, the treatments often hit human cells too.

Fungal targets

There are, however, distinctions between human and mold.
Most notably, fungal cells enclose themselves in a tough
outer wall that shields them from abrupt changes in
moisture and temperature.

"The fungal cell wall is the major difference between us
and them," says Stuart Levitz of the University of
Massachusetts Medical School in Worcester. "But it can
be their Achilles' heel. It's what protects them in the
environment, but also what flags them as being
different."

The most important building blocks of this wall, at
least to the immune system, are large glucose-based
molecules called beta-glucans. In recent years,
researchers have begun to compile a laundry list of
receptor molecules on the surfaces of human immune cells
that recognize and interact with the beta-glucan
molecules from fungi. Receptors act as gatekeepers,
linking the outside of a cell to its internal workings.
By examining these receptors, researchers can eavesdrop
on the molecular crosstalk between fungi and people.

Studies have found that just after fungi enter the body,
defense relies mostly on "innate immunity" - a general,
shotgun-like immune response that enlists certain types
of white blood cells to find and destroy invaders. The
other type of immunity, "adaptive immunity," takes
longer to kick in, involving specialized infection-
fighting white blood cells known as T cells and the
production of antibodies that confer long-lasting
protection against a specific target.

While humans produce plenty of antifungal antibodies,
innate immunity is thought to be the first responder
against a fungus. This basic defense mechanism is found
throughout the animal kingdom; even horseshoe crabs
protect themselves from fungi using innate immunity.

Scientists speculate that one reason fungi don't cause
as much human disease as other microbes is because "our
innate immunity has evolved very, very well so we're
able to recognize and respond to fungi by a variety of
different mechanisms," says Levitz. "Possibly as a
consequence of that, the fungi have not evolved to
become significant human pathogens to the extent that
bacteria, parasites and viruses have." (Plants have not
been so fortunate; despite plants and fungi's long and
close interaction, fungi are significant plant pathogens
that spoil about 10 percent of the world's harvests each
year.)

Among the most important type of proteins that recognize
fungi are the toll-like receptors, so named because they
resemble a similar fruit fly molecule called toll. As
receptors, they switch on when they encounter proteins
from fungi and bacteria, setting off other reactions
inside the cell. A team of French researchers reported
in 1996 in the journal Cell that flies with mutations in
the gene for a toll receptor were unusually vulnerable
to infection with Aspergillus. In human white blood
cells, two toll-like receptors in particular - TLR2 and
TLR4 - appear to be involved in the body's fungus-
fighting ability.

In 2008, scientists from the Fred Hutchinson Cancer
Research Center in Seattle helped demonstrate the
fungus-fighting role of TLR4 in a study in the New
England Journal of Medicine. The researchers examined
patients who had received bone marrow transplants and
later developed Aspergillus infections. In general,
about 10 to 15 percent of transplant patients will
develop the life-threatening condition aspergillosis,
but it's not clear why the other 85 to 90 percent of
patients escape unscathed.

The researchers discovered an inherited gene that causes
a malfunctioning TLR4 in the patients who had become
ill. Without a normal TLR4, the scientists proposed,
these patients' immune responses may have been weakened.
Genetic testing for this mutation among blood stem cell
donors may one day identify patients who need special
care or attention following a transplant, the authors
pointed out.

Two other reports in the New England Journal of Medicine
last year described genetic flaws that caused increased
susceptibility to fungal disease, confirming the role of
other receptors in fungal protection. One involved
dectin-1, a receptor first recognized as key to fungal
defense in 2001. Dectin-1 partners with the TLR
receptors to produce substances that both attack fungi
and deploy other white blood cells to help fight
infection.

Last October, an international team of researchers
described genetic studies of one family in which
otherwise healthy women seemed particularly prone to
chronic Candida ("yeast") infections of the vagina,
fingers and toes. The researchers found an inherited
genetic alteration that led to a defect in dectin-1.

A second team investigated another family whose members
were prone to recurrent, and sometimes fatal, infections
of Candida. A team led by University College London
researchers found a different inherited mutation that
made a person vulnerable to fungal infection. When
dectin-1 detects the fungus, it sets off a chain
reaction that gets immune cells in battle mode. A
mutation can interfere with one link in that chain, a
molecule called CARD9, the researchers found. In this
case, dectin-1 was triggered correctly, but the
mechanism jammed farther down the line.

While these and other discoveries have brought new
understanding to how immunity works, much about how the
human body handles its relationship with fungi remains
unclear.

"The thing that's most on my mind is how these organisms
can manage to survive and proliferate in such a close
relationship with host cells without triggering alarms,"
Goldman says.

Stealth spores

Goldman's work focuses largely on Histoplasma, which can
cause lung infections. These fungal spores grow inside
white blood cells called macrophages - innate immunity
cells assigned the job of destroying invading organisms
like fungi. "Here is an organism that gets inside the
very cell that's supposed to be destroying them," he
says.

While the stealth tactics deployed by Histoplasma remain
largely a mystery, scientists recently reported that
Aspergillus may dodge the immune system by borrowing a
tool from Harry Potter: a cloak of invisibility.

Though each cubic meter of inhaled air may contain a
thousand or more Aspergillus spores, the immune system
doesn't seem to notice. Scientists had been unclear why.
Then, writing in August 2009 in Nature, researchers from
the Pasteur Institute and elsewhere offered an
explanation: The body's immune system can't react to the
spores because the immune system doesn't know they are
there. Normally, the spores are coated with a thatching
of small fibers called the "rodlet layer." In
experiments with mice, the researchers found that the
fibers alone do not excite the immune system. However,
when researchers stripped the rodlets from the outside
of the cells, the exposed spores invoked a robust immune
response.

It appears that the rodlet layer may allow the fungal
spores to hide in the body, waiting until conditions are
favorable to germinate (such as death). The researchers
also noted that when Aspergillus spores start to grow,
the outer coating disintegrates and the immune system
kicks in.

Scientists have recently discovered other deceptive
feats. In the March 18 Nature, researchers revealed that
members of a fungus genus that attacks plants are
capable of passing off genes to one another - a lateral
handoff thought to occur almost exclusively in bacteria.
The discovery means fungi that develop genetic
resistance to a drug treatment could theoretically share
that secret with neighboring organisms.

The shocking thing, says study co-author Michael Freitag
of Oregon State University in Corvallis, was the ease
with which fungi traded genes. Freitag and his
colleagues simply put genetically distinct samples of
the fungi side by side on a petri dish, incubated them
together and tracked genetic movement. "It's not that
far removed from what would occur in natural
conditions," Freitag says. "I was surprised it would
work that well."

While no one knows whether other species of fungus are
capable of sharing genes so readily, the findings
reinforce the idea that nothing about fungi should be
underestimated. To succeed in conquering infections, the
next generation of treatment will need to hit several
targets at once.

Freitag likens current antifungal treatments to the
cancer treatments of the '60s and '70s, most of which
were designed to target cells that grew rapidly, and not
cancer cells specifically. Today, doctors have a number
of drugs that can zero in on the specific defects of a
malignant cell, and physicians prescribe drug cocktails
that try to disable several mechanisms simultaneously.
Fungal infections appear to have similar complexity,
including sharing properties with nontargeted cells, and
will require treatment just as sophisticated, Freitag
says. "Just like now we can attack very specific targets
in cancer," he says, "we are going to have to do that
with fungi."

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