ScienceWeek

SCIENCE-WEEK - Part 1/3

A Free Weekly Digest of the News of Science

January 30, 1998
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"There is no national science just as there is
no national multiplication table; what is national
is no longer science." -- Anton Chekhov

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Contents of This Issue:

Part 1:
1. On the Future of US Science Policy
2. On the Birth of Star Clusters
3. On Stellar Planetary Systems
4. Evidence that Martian Meteorite Amino Acids are Contaminants
5. An Explanation for Mercury-Glass Contact Light Discharge
6. Rapid Determination of Molecular Charge Density Distributions
7. On 75 Years of Chemistry

Part 2:
8. Engineered Mutation of New Catalytic Activity in an Enzyme
9. Structural Analysis of DNA-Polymerase Activity
10. Extension of Mitotic Limits by Telomerase Expression
11. Neurobiology: An Argument Against Strong Visual Loops
12. A Proposal for Memory Suppressor Genes
13. Secretion of Glutamate by Brain Astrocytes
14. On the Mechanism of Pain Modulation by Cannabinoids

Part 3:
15. Postsynaptic Membrane Fusion and Long-Term Potentiation
16. Circadian Rhythms in Humans: Extra-Visual Phototransduction
17. On the Respiratory Function of Hemoglobin
18. Cancer Treatment by Targeting Tumor Blood Vessels
19. A Potassium Channel Mutation in Neonatal Human Epilepsy
20. Fatal Human Respiratory Illness Caused by an Avian Virus

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1. ON THE FUTURE OF US SCIENCE POLICY
The expenses of scientific research in the US, as in other
places, are largely paid for from government funds, and so the
public attitudes of the government and legislators are of
potential consequence. In an editorial in the journal Science,
Vernon J. Ehlers, Republican congressman from the state of
Michigan and vice chairman of the House Science Committee,
discussing the future of US science policy, notes that the end of
the Cold War has brought with it "a vacuum in terms of a national
imperative to justify research funding." Ehler says that since
the federal government cannot fund every worthwhile scientific
project, a policy for determining priorities is essential, and
that "it is time to wipe the slate clean and decide on a future-
based vision of where science can and should take the nation."
Representative Ehlers would like the scientific community to
announce "what should our scientific and technological enterprise
strive to be 10, 20, or 50 years from now?" But many working
scientists might demur, reflecting that science is a human
enterprise with an evolution far from planned. Broad financial
support of research is desirable, but a narrow focus on specific
"missions" may be counterproductive. Perhaps the words of
physicist Neils Bohr, often quoted in this publication and in
other places, are apt: "What is the path? There is no path." QY:
Vernon J. Ehlers, US House of Representatives, Washington, DC US
(Science 16 Jan 98)


2. ON THE BIRTH OF STAR CLUSTERS
A star cluster is a group of stars whose members are close enough
to each other to be physically associated, and the current
consensus is that the stars in a cluster formed together. A
globular cluster is a spherically symmetrical and compact cluster
of stars, the cluster containing from several tens of thousands
to perhaps a million stars, and as in clusters in general, these
stars are thought to share a common origin. The Hubble Space
Telescope, named after the astronomer Edwin Hubble (1889-1953),
was launched from a space shuttle in 1990 into a 600-kilometer
low-Earth orbit and has been providing extensive imaging and
spectroscopic observations critical for the development of
astronomy and astrophysics. The new information has concerned hot
stars, stellar chromospheres and coronas, the interstellar
medium, galaxies and galactic clusters, quasars, etc. -- all of
it information uncorrupted by the Earth's atmosphere, which is
the problem for ground based telescopes. ... ... Meylan and
Brandl (2 installations, DE US), in a review of the birth of star
clusters, focus on the nebula NGC 2070 (also known as 30 Doradus
or the "Tarantula Nebula"), and note that it is now known that
this nebula in the nearby galaxy called the Large Magellanic
Cloud is an exceptionally massive and luminous concentration of
ionized hydrogen (showing an "H II" region in the spectrum) where
thousands of stars are in the process of being born, and that
recent observations by the Hubble Space Telescope indicate that
in NGC 2070 the birth of a globular star cluster may be
occurring. QY: Georges Meylan, European Southern Observatory,
Garching DE (Sky & Telescope March 1998)


3. ON STELLAR PLANETARY SYSTEMS
Extrasolar planetary systems are planetary systems involving one
or more planets in orbit around stars other than our own Sun, and
there is growing evidence that such systems do indeed exist.
The term "Doppler-shift" refers to an observed change in spectrum
frequencies when the source of the spectrum or the observer move
toward or away from each other, and certain perturbations in
Doppler-shifts can be interpreted as indicating the presence of
dark massive objects orbiting stars. The Keck telescopes are a
pair of twin telescopes at the W.M. Keck Observatory on Mauna
Kea, HI US, each with 10 meter mirrors, the pair constructed
1992-1996. The installation is managed by the University of
California (US) and the California Institute of Technology (US).
An optical interferometer is a system involving separate but
linked telescopes whose collection of optical waves is combined
to improve spatial resolution, the resolving power becoming
equivalent to that of a single instrument with an aperture equal
to the largest distance separating the component telescopes.
... ... Marcy and Butler (2 installations, US AU), in a review of
extrasolar planetary systems, note that within the next 5 years
Doppler surveys of nearly a thousand stars will be undertaken,
that the two Keck telescopes will be linked as an optical
interferometer with sufficient precision to detect extrasolar
planets by stellar positional perturbations, and that the US
National and Aeronautics Space Agency's space-borne interfero-
meter, if funded, should be able to obtain actual images of
extrasolar orbiting planets. The authors suggest that by the year
2010 we should have completed the first true census of planets of
nearby stars. QY: Geoffrey Marcy, San Francisco State Univ. 415-
338-2017 (Sky & Telescope March 1998)


4. EVIDENCE THAT MARTIAN METEORITE AMINO ACIDS ARE CONTAMINANTS
As the subunits that compose protein polymers in living systems,
the detection of certain amino acids in a material is often
interpreted as indicating a possible biological origin. The
meteorite ALH84001, along with a number of other discovered
meteorites, has a composition that suggests it was apparently
ejected from the surface of Mars, and during the past year it has
been proposed that microanalysis of this meteorite indicates the
possible presence of bio-organics and biogenic fossils. This
proposal, however, has met with considerable controversy, and the
controversy is still in full force. ... ... Bada et al (4 authors
at 3 installations, US) now report that the amino acids present
in a sample of the ALH84001 meteorite appear to be terrestrial in
origin and similar to those found in the ice where the meteorite
was discovered, although the possibility remains that minute
amounts of endogenous amino acids are preserved in the meteorite.
The authors suggest that radiocarbon studies (cf. contiguous
report: Jull et al, Science 279:366 1998), coupled with their own
amino acid results, indicate that major and minor organic
constituents in the Martian meteorites are contaminants. QY:
Jeffrey L. Bada  (Science 16 Jan 98)

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Related Background:

AN ARGUMENT FOR RELIC LIFE ON MARS
In 1984, a 1.9 kilogram meteorite the size of a potato (desig-
nated ALH84001) was found in Antarctica, and because of its
chemical composition the consensus is that this meteorite (and a
dozen similar meteorites) originated from the planet Mars. The
basis for the consensus is the detailed quantitative correspond-
ence of the trapped gases in the meteorites to Martian atmosph-
eric gases, and the specific distributions of oxygen isotopes. In
1996 a group of researchers, McKay et al (National Aeronautics
and Space Administration Johnson Space Center, US; Stanford
University, US) reported they had concluded that unusual charact-
eristics of the meteorite ALH84001 can be most reasonably
interpreted as vestiges of ancient Martian bacterial life. In
particular, the authors noted the presence of tubules 20 to 40
nanometers in diameter (called by some "nannobacteria"), and they
proposed these structures were fossilized bacteria or parts of
microorganisms. The report provoked considerable controversy when
it appeared, and the controversy continues, with many biologists
objecting to the interpretation of the rock data, and partic-
ularly to the idea of "bacteria" 20 to 40 nanometers in diameter.
Now Gibson et al (National Aeronautics and Space Administration
Houston, US; University of Georgia, US), this group including
some of the authors of the 1996 report, in a review of the
evidence for relic life on Mars, consider the ALH84001 meteorite
not only the strongest evidence for Martian relic life, but also
for the possibility of present Martian microbial life. The
authors are hopeful that in 2005 a "sample return" mission will
be launched to robotically collect Martian rocks and soil and
return them to Earth.
QY: Everett K. Gibson 
(Scientific American December 1997)

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EVIDENCE AGAINST NANOFOSSILS IN MARTIAN METEORITE
The term "nanofossils" (originally spelled "nannofossils" by the
group that introduced the term) refers to elongated microscopic
forms found in the Martian meteorite ALH84001. Several groups in
the space and geology communities have proposed these forms are
fossilized bacteria, but most biologists have rejected the idea
on the basis that the forms are too small to be bacteria and
should not be classified as such. Bradley et al (3 installations,
US) now report that new analysis of material from the ALH84001
meteorite indicates the majority of the elongated microscopic
forms can be resolved as either emergent substrate layers or
magnetite whiskers, rather than biogenic nanofossils. Their
report is followed by a response from McKay et al (3 install-
ations, US CA), some of the original proponents of the nanofossil
idea, and in their response McKay et al say the artifact
possibilities mentioned by Bradley et al are already known to
them, but are not related to their own observations. They add
that living bacteria as small as 70 nanometers in diameter have
been observed in mammalian blood, and that soil bacteria as small
as 80 nanometers have also been observed. The references for
these bacterial forms are one unpublished paper and two recently
published papers in Proc. Soc. Photo-Opt. Instrum. Eng.
3111:420,429 (1997). It is evident that the nanofossil contro-
versy has not yet been resolved.
QY: J. P. Bradley, Georgia Inst. Technol. 404-894-2000; David S.
McKay  (Nature 4 Dec 97)

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A CONTROVERSY CONCERNING MINIMUM POSSIBLE DIMENSIONS OF BACTERIA
Apart from their heuristic significance, scientific controversies
can be either amusing or irritating. In recent months, a
controversy between some geologists and many biologists has
developed, and it is apparently irritating the biologists. The
issue concerns the minimum possible dimensions of bacteria. The
geologists are led by Robert L. Folk (University of Texas, Austin
TX US), and they have proposed that certain microscopic entities
found in the Martian meteorite ALH84001 are fossils of what they
term "nannobacteria" (their own unique spelling of the prefix
nano-), which they say are similar to those found in Earth
travertine and limestone rocks, and which have dimensions of 30
to 50 nanometers. This has caused a furor among biologists, whose
understanding of bacteria and life forms in general is that the
smallest dimensions possible for a life form with a bounding
plasma membrane is about 200 nanometers (see Focus Report in this
issue). In fact no membrane-bound bacterium with dimensions less
than 340 nanometers has ever been identified, and one can make
simple calculations that a 50 nanometer bacterium would not have
enough internal volume to sustain its chemistry. Folk published
papers on the subject in several geological journals in 1996,
starting the debate, and in the Letters section of the 20 June
1997 issue of Science the debate continues, and this week it is
being reported in the popular media as a "debate about life on
earth". What evidently irritates biologists is the apparent
misunderstanding by these geologists of experimental methods in
biology. Characterizations of "living" vs. "non-living" by
biologists are made on the basis of experimental laboratory
replicability of an organism, and not on the basis of the visible
structure of an entity. Which means the geologists involved need
to attempt to culture their Earth-rock entities, and which means
decisions that the Martian meteorite's so-called "nannobacteria
fossils" are actually such will require demonstration of cultured
entities with those dimensions. Biologists are not unwilling to
admit the existence of new species of life forms, of which they
have already recognized several million entities, but they argue
that one does not classify pieces of rock as a life form on the
basis of structure alone. (New York Times 29 Jul 1997)


5. AN EXPLANATION FOR MERCURY-GLASS CONTACT LIGHT DISCHARGE
The term "barometer light" refers to an optical discharge
discovered in 1670 by Picard, the discharge being produced by the
swirling of liquid mercury in an evacuated glass flask. In
mechanics, "stick-slip" motion is motion involving two surfaces
that are alternately at rest and in motion with respect to each
other. ... ... Budakian et al (4 authors at Univ. California Los
Angeles, US) revisit the "barometer light" phenomenon, and report
that repetitive emission of light from mercury moving over glass
is accompanied by the collective picosecond transfer of large
numbers of electrons, the glass acquiring a net charge. The
electrical interaction can drag mercury against gravity, and when
the mercury slips relative to the glass, a picosecond electrical
discharge and flash of light are produced. The repetitive build-
up and discharge of static electricity thus gives rise to stick-
slip motion. QY: S.J. Putterman, Univ. of Calif. Los Angeles,
Dept. Physics 310-825-3164 (Nature 15 Jan 98)


6. RAPID DETERMINATION OF MOLECULAR CHARGE DENSITY DISTRIBUTIONS
Molecular charge density distribution is the distribution of
electric charge in a molecule, and since the interaction between
molecules is greatly governed by the topology of their respective
charge density distributions, it is of some importance to deter-
mine those distributions for molecules of interest. X-ray
diffraction is a method of studying atomic and molecular struct-
ure based on spatial differences in the scattering of x-rays due
to atomic structure within a material. A synchrotron is a device
for accelerating electrons or protons in closed orbits in which
the frequency of the accelerating voltage and the strength of an
applied magnetic field are simultaneously varied to keep the
orbit radius constant, and synchrotron radiation is electro-
magnetic radiation generated by the acceleration of charged
relativistic particles in a synchrotron (or in any magnetic
field). A charge-coupled device (CCD) is a semiconductor device
in which charge stored in a surface layer can be moved about the
surface by applied fields or impacting radiation, and such
devices are now in common use as electromagnetic radiation
sensors. ... ... Koritsanszky et al (6 authors at 3 install-
ations, DE) report a 1-day x-ray diffraction experiment on DL-
proline monohydrate with synchrotron radiation and a charge-
coupled device area detection technique. The authors suggest the
accuracy of the charge density distribution and related
electronic properties extracted from the data is comparable or
even superior to that obtained from a 6-week experiment with
conventional x-ray diffraction methods, and the technique renders
larger molecular systems of biological importance accessible to
charge density experiments. QY: P. Luger  (Science 16 Jan 98)


7. ON 75 YEARS OF CHEMISTRY
Commemorating its 75th year, Chemical & Engineering News, the
news magazine of the American Chemical Society, observes that 80%
of what is interesting in chemical science today was not
understood to exist in 1923, when Linus Pauling was a graduate
student. In a lengthy and detailed article, C & N News notes
developments of the following branches of chemistry during the
past 75 years: chemical synthesis, drug discovery, polymers,
zeolites, superconductors and fullerenes, lasers, NMR spectro-
scopy, x-ray crystallography, chromatography, mass spectrometry,
electroanalytical chemistry, atomic and molecular spectroscopy,
theory of the chemical bond, valence-bond theory, the molecular-
orbital approach, crystal and ligand field theories, quantum
theory of chemical reactions, electron-transfer reactions, the
meeting of chemistry and biology, DNA structure, biochemical
pathways, the origin of life. The authors of the article quote
Arnold Thackray, a historian of chemistry: "Concepts that we now
take as self-evident were once at least debatable, if not clearly
ridiculous." QY: Stuart A. Borman, Chem. & Eng. News 202-872-
4405 (Chem. & Eng. News 12 Jan 98)


(continued in Part 2)

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SCIENCE-WEEK - Part 2/3

A Free Weekly Digest of the News of Science

January 30, 1998

Contents of Part 2:

8. Engineered Mutation of New Catalytic Activity in an Enzyme
9. Structural Analysis of DNA-Polymerase Activity
10. Extension of Mitotic Limits by Telomerase Expression
11. Neurobiology: An Argument Against Strong Visual Loops
12. A Proposal for Memory Suppressor Genes
13. Secretion of Glutamate by Brain Astrocytes
14. On the Mechanism of Pain Modulation by Cannabinoids

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8. ENGINEERED MUTATION OF NEW CATALYTIC ACTIVITY IN AN ENZYME
Enzymes are among the most important entities in biological
systems, with a high degree of specificity and the ability to
increase the rates of certain chemical reactions by factors of as
much as 10^(5) or 10^(6). In all cases, this action by enzymes is
apparently based on a specific site of the enzyme polymer cata-
lyzing an intermediate transition state in a chemical reaction.
Cyclosporins, produced by fungi, are a group of nonpolar cyclic
oligopeptide antibiotics, and cyclophilin is a protein with
strong binding affinity for cyclosporin. A protease is any enzyme
that cleaves proteins by catalyzing the hydrolysis of the peptide
bonds that link the amino acids in the protein polymer, and
serine protease is a protease that contains an essential serine
residue (subunit) in the active site. ... ... Quemeneur et al (4
authors at CEA Saclay, FR) report the engineering of new cata-
lytic activity into a bacterial (Escherichia coli) cyclophilin by
mutating 3 amino acids close to the peptide-binding cleft to form
a catalytic triad similar to that found in serine proteases. The
authors suggest their results indicate a strategy based on modif-
ication of pre-existing enzymatic sites may lead to the design of
efficient and new protease activities. QY: Eric Quemeneur
 (Nature 15 Jan 98)


9. STRUCTURAL ANALYSIS OF DNA-POLYMERASE ACTIVITY
DNA polymerases, of which there are several types, are enzymes
that specifically assemble deoxyribonucleoside triphosphates (DNA
nucleotides) into DNA strands in the order dictated by a temp-
late. In addition to the template, a fragment of RNA or DNA must
be annealed to the template as a primer, the catalyzed polymer
synthesis then consisting of additions to one end of that primer.
A critical aspect of DNA polymerase activity is that the template
is copied with high fidelity, but the precise mechanism by which
nucleotides are in sequence correctly incorporated in the copy is
not yet known. ... ... Kiefer et al (4 authors at 2 installat-
ions, US) report high resolution crystal structures (1.8 ang-
stroms) of a thermostable bacterial (Bacillus stearothermophilus)
DNA polymerase (type I) fragment, the fragment bound with DNA
primer templates at the active polymerase site, and the complex
retaining catalytic activity and allowing direct observation of
the products of several rounds of nucleotide incorporation. The
polymerase also retains its ability to discriminate between
correctly and incorrectly paired nucleotides in the crystal. The
authors suggest their procedure makes possible snapshots of
successive polymerase complexes, and that the structures provide
the most detailed view of any polymerase DNA complexes yet
determined. QY: Lorena S. Beese 
(Nature 15 Jan 98)


10. EXTENSION OF MITOTIC LIMITS BY TELOMERASE EXPRESSION
Somatic cells are all cells other than germline cells such as egg
cells and sperm cells, and the term "cellular replicative
senescence" refers to the observation that somatic cells, in
contrast to germline cells, can proliferate (divide) only a fixed
number of times, the actual number dependent on the organism from
which the somatic cells derive. Since there is a general correl-
ation between cellular replicative senescence in vitro and the
average life-spans of various animals (including humans),
cellular replicative senescence has been implicated in aging and
age-related pathologies. Telomeres are regions at the ends of
chromosomes consisting of repeats of particular nucleotide
sequences, and with each somatic cell division a small part of
the telomere is ordinarily lost. What has been observed is that
in germline cells the lengths of telomeres are maintained
constant by repair, while in somatic cells this repair does not
occur, and this difference has led to the idea that the finite
proliferative capacity of somatic cells is related to the
ultimate depletion of telomere lengths. The enzyme telomerase is
the enzyme that causes repair of telomeres, and this enzyme is
active in germline cells, but it is not expressed in most somatic
cells. In animals, epithelial cells compose the cell layers that
form the interface between a tissue and the external environment,
for example, the cells of the skin, the lining of the intestinal
tract, and the lung airway passages, and fibroblasts are a type
of connective tissue cell that secret structured proteins such as
collagen. Transfection is the uptake of exogenous (foreign) DNA
fragments in solution directly into animals cells in laboratory
culture, and is one method of introducing foreign genes into
cells. The term "vector", in the context of DNA cloning, is any
DNA fragment used in a transfection process. ... ... Bodnar et al
(10 authors at 2 installations, US) now report that two normal
human cell types (retinal pigment epithelial cells and foreskin
fibroblasts) that do not ordinarily express telomerase, can be
transfected with vectors encoding the human telomerase catalytic
subunit, the transfected cells (as opposed to controls) then
exhibiting elongated telomeres, dividing vigorously and exceeding
their normal life-span by at least 20 doublings. The authors
suggest their results establish a causal relationship between
telomere shortening and in vitro cellular replicative senescence,
and that the ability to maintain normal human cells in a youthful
state can have important applications in research and medicine.
QY: Serge Lichtsteiner  (Science 16 Jan 98)


11. NEUROBIOLOGY: AN ARGUMENT AGAINST STRONG VISUAL LOOPS
The thalamus is a deep part of the brain consisting of nuclei
(groups of nerve cells) that project to various other areas,
particularly the cerebral cortex. The thalamus acts as a relay
station for the various sensory modalities, including vision, and
the linkages between the thalamus and the parts of the cerebral
cortex concerned with vision are essential in primates for the
processing of visual information. During most of this century,
neurobiologists have recognized the importance of feedback
mechanisms in the functioning of neural networks, in particular
the significance of positive feedback and negative feedback
paradigms known to all engineers. In general, as has long been
recognized in the analysis of engineering systems, negative
feedback can produce control of the response of a system, while
positive feedback can produce the opposite, namely a runaway
response. ... ... Now Crick and Koch (2 installations, US), in a
discussion of interconnections between visual areas in the
primate brain, suggest that connections between cortical areas
never form strong directed loops, and that for connections
between the visual cortex and certain thalamic nuclei, strong
directed loops will not be found because their existence would
result in uncontrolled oscillations. QY: Francis Crick, Salk
Institute, 10010 N. Torrey Pines Road, La Jolla, CA 92037 US
(Nature 15 Jan 98)


12. A PROPOSAL FOR MEMORY SUPPRESSOR GENES
One of the central problems in neurobiology is to delineate the
mechanisms involved in information storage -- in the human
context, memory storage. How do neurons and neural circuits and
neural systems retain information about their past history, and
how does the past history influence present activity? When we
evoke a memory, a visual image of a rose, for example, where and
how is this image stored in the brain, and how is it evoked into
consciousness? Most neurobiologists believe that important
aspects of the memory/information storage process involve changes
in synaptic connections, the connections between neurons, and the
term "synaptic plasticity" refers to the changeability of neur-
onal synaptic connections, usually as a result of ongoing neural
activity. Tumor suppressor genes are sequences of DNA that code
for proteins that prevent or inhibit the growth of tumors.... ...
Now Abel et al (4 authors at Columbia Univ., US), in a review of
the relation between synaptic plasticity and memory storage,
propose that by analogy to tumor suppressor genes, the restraint
of synaptic growth involved in inhibitory restraints on memory
storage should be termed "memory suppressor genes". The authors
suggest that because these suppressor genes modulate or gate
other signaling pathways rather than directly activate them,
drugs targeted at memory suppressor gene products may prove to be
more therapeutically precise than those targeted at positive
regulators of memory storage. QY: Eric R. Kandel, Columbia Univ.
212-854-1754 (Science 16 Jan 98)


13. SECRETION OF GLUTAMATE BY BRAIN ASTROCYTES
Glial cells are more numerous than neurons in the brain, but
their function has been generally characterized as "metabolic" or
"supportive", without much discussion of details, and more is
known about peripheral glial cells than glial cells in the
central nervous system. Astrocytes are the largest glial cells,
with many extensions radiating outward like a starburst, and at
least one of their functions is apparently to maintain the so-
called "blood-brain barrier" effectively separating neural tissue
from blood. L-glutamate (derived from the amino acid, glutamic
acid) is considered the principal excitatory neurotransmitter in
the vertebrate central nervous system, and is one of the neuro-
transmitter substances that interact with ligand-gated ion
channels. Kainic acid, an algal neurotoxin, is a structural
analogue of glutamate, and it has been extensively used in
research, since at high concentrations it selectively destroys
glutamate receptor neurons (glutaminergic neurons). Glutamate is
known to act on 3 classes of receptors, one of them called the
kainate receptor because at low concentrations of kainic acid the
action of glutamate on this receptor is enhanced. The chemistry
of this kainate receptor is not yet well-characterized, mainly
because selective ligands for it are not known. Another class of
glutamate receptor is the AMPA receptor [AMPA = (RS)-alpha-amino-
3-hydroxy-5-methyl-4-isoxazoleproprionic acid], and the third is
NMDA (N-methyl-D-aspartate). These 3 receptors are ionotropic,
i.e., their activation produces changes in membrane ion permeab-
ility. According to another and more recent scheme of glutamate
receptor classification, one receptor type is AMPA/kainate
(ionotropic), another receptor type is NMDA (ionotropic), and a
third receptor type is a slow-acting receptor type coupled to G-
proteins and called metabotropic receptors. (The G-proteins are
membrane-bound proteins that act as transducers between messenger
molecules interacting with the cell surface and the intracellular
messenger system). Prostaglandins are fatty acids secreted by
cells that have hormone-like actions in the immediate vicinity,
and one circumstance that produces their release is tissue
injury. ... ... Bezzi et al (8 authors at 2 installations, IT)
report that coactivation of the AMPA/kainate and metabotropic
glutamate receptors on astrocytes stimulates these cells to
release glutamate through a calcium-dependent process mediated by
prostaglandins. The authors suggest their results reveal a new
pathway of regulated transmitter release from astrocytes, and
that interactions between neurons and astrocytes may play a
critical role in synaptic plasticity and neurotoxicity. They also
suggest that the prostaglandin-mediated glutamate release from
astrocytes may be involved in the pathophysiology of various
brain diseases and injuries.
QY: Andrea Volterra  (Nature 15 Jan 98)


14. ON THE MECHANISM OF PAIN MODULATION BY CANNABINOIDS
In general, the clinical entity "hyperalgesia" (sometimes known
as "hyperalgia") is a heightened sensitivity to painful stimuli.
Cannabinoids are derivatives or preparations from the plant
Cannabis sativa (the marijuana plant), a group of a dozen
compounds chemically related to cannabinol, including delta-9-
tetrahydrocannabinol (THC), and the cannabinoid receptor is the
binding site for the psychoactive component of marijuana, as well
as for anandamide, the endogenous physiological ligand. Anand-
amide is known to modulate the pain pathway, but the mechanisms
are not clear. ... ... Richardson et al (3 authors at Univ. of
Minnesota Minneapolis, US) now report studies in animal models
that indicate that hyperalgesia may be linked to a faulty
cannabinoid system in the spinal cord. The authors suggest that
endogenous cannabinoids attenuate pain by preventing the release
of glutamate from presynaptic terminals of neurons that transmit
pain messages to the spinal cord. QY: Jenelle D. Richardson,
Harvard Univ. Medical School, Dept. Neurobiology 617-432-1550
(Chem. & Eng. News 19 Jan 98)


(continued in Part 3)

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

SCIENCE-WEEK - Part 3/3

A Free Weekly Digest of the News of Science

January 30, 1998

Contents of Part 3:

15. Postsynaptic Membrane Fusion and Long-Term Potentiation
16. Circadian Rhythms in Humans: Extra-Visual Phototransduction
17. On the Respiratory Function of Hemoglobin
18. Cancer Treatment by Targeting Tumor Blood Vessels
19. A Potassium Channel Mutation in Neonatal Human Epilepsy
20. Fatal Human Respiratory Illness Caused by an Avian Virus

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15. POSTSYNAPTIC MEMBRANE FUSION AND LONG-TERM POTENTIATION
The anatomical connections between nerve cells are called
"synapses", and in mammalian nervous systems the most important
type of connection involves the axon terminals of one neuron
(presynaptic endings) terminating on various parts of the second
neuron (postsynaptic loci). In general, electrical activity of
the first neuron causes secretion of a "neurotransmitter"
substance at its presynaptic terminals, and this neurotransmitter
may excite or inhibit the electrical activity of the second
neuron, the effect often mediated by inputs to the second neuron
from hundreds of other neurons. Prior to its release, the neuro-
transmitter substance is contained in vesicles in the presynaptic
terminals, and one of the significant events associated with
release of the neurotransmitter substance is the fusion of the
vesicle with the presynaptic membrane -- a "membrane" fusion,
since the shell of the vesicle itself is also a bilayer membrane.
In general, long-lasting enhancement of the postsynaptic response
of a neuron as a result of repetitive incoming synaptic activity
is called "long-term potentiation", and there are many varieties
of this phenomenon observed in different kinds of nerve cells,
and it is considered an example of synaptic plasticity. Since
long-term potentiation involves the behavior of a neuron relating
to its past history, the phenomenon is naturally of great
interest to neurobiologists seeking to understand neuronal
information storage. ... ... Lledo et al (5 authors at 2 install-
ations, US) report that introducing substances that block
membrane fusion into the postsynaptic cell reduces long term
potentiation. Introducing a protein (SNAP) that promotes membrane
fusion enhances synaptic transmission, but at a reduced level in
already potentiated synapses. The authors suggest that fusion
events, in addition to being important for the presynaptic
release of neurotransmitters, are also involved in some mechanism
at the postsynaptic membrane, and thus contribute to long term
potentiation. QY: Roger A. Nicoll  (Science
16 Jan 98)


16. CIRCADIAN RHYTHMS IN HUMANS: EXTRA-VISUAL PHOTOTRANSDUCTION
In biology, a circadian rhythm is a daily cyclical process, be it
biochemical, or physiological, or behavioral. The human sleep-
wake cycle is the most familiar example. Circadian rhythms are
often described in terms of endogenous "biological clocks", with
the thrust of research to reduce some particular behavioral or
physiological circadian rhythm to biochemical events. These
clocks are usually set by environmental cues such as the light-
dark cycle, and what is characteristic of an endogenous clock is
that if one removes the environmental cue, keeps the organism in
constant light, for example, the endogenous rhythm will continue,
but will tend to drift out of synch. Restoring the external
light-dark cue will reset the clock to its normal intrinsic
rhythm. ... ... Campbell and Murphy (Cornell Univ., US) report
measurements of the response of the human circadian clock to
extraocular light exposure involving light pulses presented to
the popliteal region (the area behind the knee). They report a
systematic relation between the timing of the light pulse and the
magnitude and direction of clock phase shifts. The authors
suggest their findings challenge the belief that mammals are
incapable of extraretinal circadian phototransduction, and that
the findings also have implications for the development of more
effective treatments of sleep and circadian rhythm disorders. QY:
Scott S. Campbell, Cornell Univ. Medical College 212-746-1067
(Science 16 Jan 98)

-------------------

Related Background:

... In mammals, including humans, the biological clock apparently
resides in a group of neuron clusters in a part of the brain
called the hypothalamus, a region that responds to many chemical
inputs, including the hormone melatonin, an indole derived from
the metabolism of serotonin. Melatonin is secreted by another
hypothalamic brain structure, the pineal gland, which in turn is
stimulated by neurons in a nearby cluster (the suprachiasmatic
nucleus) that receives input from the retina of the eye. So this
is the apparent pathway in mammals: light on the retina,
electrical activity in the retino-hypothalamic tract, activity in
a hypothalamic region called the suprachiasmatic nucleus,
electrical signals to the pineal gland, secretion of the hormone
melatonin, action of melatonin on other neural structures in the
hypothalamus and elsewhere. In some insects, the biological clock
may be located in the optic lobes of the brain, and biological
clocks of one sort or another have been found at nearly all
levels of organism complexity. In humans, there is some evidence
that our biological clocks can be implicated in psychiatric
entities known as mood disorders, which is not surprising, since
the hypothalamus and nearby structures are known to play a key
role in emotions. But more generally, the biological clock is
apparent to anyone who has experienced jet- lag upon travelling
long distances east or west, the jet-lag effects resulting from
the body's biological clock being out of synch with the
light-dark cycle. The key question, of course, is that if
melatonin is involved in the workings of the human biological
clock, exactly how does it function? A number of laboratories
have been concerned with this problem, and this week Steven
Reppert et al (installations in MA, CT US) report that melatonin
apparently has two receptors, a major and a minor, and that the
result of binding to the minor receptor is a lowering of activity
in the suprachiasmatic nucleus, which seems to indicate a
chemical negative feedback loop. Identification of such feed-
back loops are the key to understanding brain function. The
studies were carried out on genetically altered mice lacking the
major melatonin receptor. QY: S. Reppert, Harvard Medical School,
Boston MA US (617) 432-1000 (Neuron 25 Jul 97)  


17. ON THE RESPIRATORY FUNCTION OF HEMOGLOBIN
Hemoglobin is the respiratory protein of erythrocytes (red blood
cells), carrying oxygen from the lungs to peripheral tissues and
participating in the reverse transport of carbon dioxide. In
normal human erythrocytes, hemoglobin concentration is extremely
high (340 grams/liter), and corresponds to a 5.2 mM solution,
assuming a molecular mass of 65K grams/mole. The oxyhemoglobin
dissociation curve is a measured sigmoid-shaped quantitative
relation between oxygen saturation or content of hemoglobin and
the oxygen tension at equilibrium, and its parameters have been
intensively investigate for more than 50 years and related to
various aspects of respiratory physiology. At the present time, a
central interest is to understand the molecular mechanisms
producing conformational changes in hemoglobin and how these
changes relate to the binding of oxygen and the regulation of
respiration. ... ... C. Hsia (Univ. Texas Southwestern Medical
Center, US), in a review of the respiratory function of
hemoglobin, discusses the regulation of oxygen transport via the
oxyhemoglobin dissociation curve, and how physiologically induced
variation of oxyhemoglobin dissociation is regulated to support
the highest rate of oxygen transport in both health and disease.
QY: Connie C.W. Hsia, Univ. of Texas Southwestern Med. Sch.
214-648-2670 (New England J. Med. 22 Jan 98)


18. CANCER TREATMENT BY TARGETING TUMOR BLOOD VESSELS
Bacteriophage (phage) is a virus type that infects bacteria, and
it has been useful as a cloning vector in genetic engineering.
The phage injects its own DNA into the bacterium, effectively
assuming enough control of the bacterial genome to replicate
itself, with the ultimate disintegration of the bacterium and
liberation of the phage clones. A "phage library" is a collection
of genomic DNA fragments, each contained in a bacteriophage
cloning vector and propagated by infection of a host bacterium
(usually E. coli). The essential idea, in the context of this
report (and in many other research efforts), is to use the
genetic machinery of the phage to control the metabolic machinery
of the bacterium to produce (synthesize) particular complex
biomolecules (such as polypeptides) needed for testing. "Nude
mice" are a genetic variant of laboratory mice lacking a thymus
gland, which means they are unable to produce the T-cells
(Thymus-cells) necessary for various aspects of the mammalian
immune response. The origin and development of tumor blood
vessels (angiogenesis), is an important consideration in the
growth of cancerous tumors, since the tumor provokes directed
angiogenesis into itself with the end result that the tumor is
supplied with oxygen and nutrients. Without angiogenesis, tumors
can attain only a small size before becoming self-inhibiting.
A "xenograft" is a graft of tissue from one species into the body
of another species. ... ... Arap et al (3 authors at Burnham
Institute, US) report the use of in vivo selection of phage
libraries to isolate peptides that home specifically to tumor
blood vessels. When coupled to the anticancer drug doxorubicin,
two peptides were found that enhance the efficacy of the drug
against human breast cancer xenografts in nude mice and also
reduced the toxicity of the drug. The authors suggest their
results indicate it may be possible to develop targeted
chemotherapy strategies based on selective expression of
receptors in tumor blood vessels.
QY: Erkki Ruoslahti 
(Science 16 Jan 98)

-------------------

Related Background:

MOLECULAR TARGET OF ANTI-ANGIOGENESIS COMPOUNDS DISCOVERED
... Any clinically useful anti-angiogenesis compound is of great
interest to cancer specialists (oncologists). There are 10 or so
anti-angiogenesis agents presently undergoing clinical trials.
One of these (TNP-470) is a derivative of the natural fungal
product fumagillin, whose anti- angiogenesis activity was first
discovered in 1985. Now the cellular target of fumagillin and
TNP-470 has been discovered, a specific protein which appears to
play an important role in the proliferation of endothelial cells,
the cells that line blood vessels. The work was reported by Craig
M. Crews et al (Yale University, US), who suggests the identifi-
cation of this protein target will open new avenues of research
for the understanding of tumor-induced neo-vascularization. The
results have been independently confirmed by Jun O. Liu et al
(Massachusetts Institute of Technology, US).
(Proc. U. S. National Academy of Sciences, v94, 6099/1997)
(Chemistry & Biology June 1997)

-------------------

Related Background:

CANCER: NO ACQUIRED DRUG RESISTANCE TO ANTI-ANGIOGENIC AGENT
Angiogenesis is the generation of new blood vessels, a controlled
sequence of cell differentiation and tissue formation programmed
by the genome. It is of obvious importance during embryological
development, since new tissues need a blood supply in order to
continue macroscopic growth, and the angiogenesis process is also
of great importance during tissue trauma repair. Like new embryo-
logical tissue, a neoplasm (a tumor) also needs a blood supply,
and one of the characteristics of tumor growth is the provocation
of angiogenesis by the cancer cells so that the mass of such
cells becomes supplied with adequate vascularization. It is
known, for example, that tumors will not grow beyond a few
millimeters in diameter in the absence of a newly forming blood
supply. Cancer cells apparently provoke angiogenesis by secreting
growth factor substances, and if this is prevented, tumor growth
will be severely limited. But attempts to chemically interfere
with the secretion of growth factors by cancer cells usually fail
because the high proliferation rate of cancer cells ultimately
results in drug resistance produced by a mutational selection
process. However, the normal epithelial tissue involved in
angiogenesis is not rapidly mutating. Recently, a substance named
endostatin, a 20,000 molecular weight fragment of a type of
collagen, has been found to be a specific inhibitor of endothel-
ial cell proliferation (which means also of new blood vessel
growth), and it was found that endostatin effects only prolif-
erating endothelial cells, not resting cells, and not normal,
transformed, or neoplastic cells. It has been shown that systemic
administration of endostatin to tumor bearing mice results in the
regression of tumors to a microscopic size, and one important
question has been whether drug resistance to endostatin would
develop. Now Boehm et al (4 authors at Harvard Univ., US) report
that endostatin causes three tumor types in mice to regress
without the production of drug resistance, and that repeated
cycles of anti-angiogenic therapy are followed by prolonged tumor
dormancy without further therapy. The authors suggest that
angiogenesis inhibitors that do not induce drug resistance may be
valuable for long-term maintenance therapy. This is important
work, and one expects much will be heard about endostatin in the
future. QY: Thomas Boehm  (Nature 27
Nov 97)


19. A POTASSIUM CHANNEL MUTATION IN NEONATAL HUMAN EPILEPSY
Epilepsy is not a single disease, but a group of nervous system
disorders exhibiting similar symptoms of repeated episodes of
convulsive seizures, sensory disorders, abnormal behavior,
blackouts, etc. Apparently, all types of epilepsy involve
uncontrolled electrical discharge from neurons in the cerebral
cortex. Most epilepsy is of unknown etiology, but there are known
links to head injury, brain infection, brain tumor, blood vessel
disturbances, intoxication, chemical imbalances, etc. The term
"idiopathic" means without a known cause (e.g., idiopathic
epilepsy as opposed to epilepsy produced by brain injury), but
the term is also used for pathology of apparent genetic etiology
when the physiological consequence of the gene mutation is
unknown. In the context of studies of biological cell membranes,
the term "ion selectivity" refers to the ability of all cell
membranes, particularly nerve cell membranes, to distinguish
between various ions such as Na(+), K(+), Ca(2+), Cl(-), etc.
There is much evidence that this ion selectivity involves
specific pores or channels in the cell membrane, with certain
channels specific for certain ions, the channels capable of being
opened or closed (gated) depending on conditions and various
interactions with ligands binding to receptors. Since the
movement of ions is by definition an electric current, ion-
selective channels can be viewed as involved in "conductance"
pathways, and there are methods for measuring individual cellular
ion currents. In most neurons, potassium channel conductance is
involved in the maintenance of membrane polarization and repolar-
ization following excitation, a critical factor, since loss of
membrane polarization can result in repetitive uncontrolled
firing (production of action potentials) by the nerve cell.
Oocytes are egg cells, and frog oocytes are convenient systems
for genetic manipulation and large enough for various experi-
mental procedures. ... ... Biervert et al (7 authors at 3
installations, DE AU), investigating an age-specific human
epileptic syndrome of genetic etiology, report that an associated
potassium channel gene, when expressed in frog oocytes invest-
igated with electrophysiological methods, indicates the mutant
channel does not yield measurable potassium currents, and that
impairment of potassium-dependent repolarization produced by
mutation of the gene is the likely cause of the human age-
specific epileptic syndrome. The authors point out that no other
gene defects have yet been identified in human idiopathic
epilepsies.
QY: Thomas J. Jentsch 
(Science 16 Jan 98)

20. FATAL HUMAN RESPIRATORY ILLNESS CAUSED BY AN AVIAN VIRUS
Influenza viruses are classified as orthomyxoviruses. They are 80
to 120 nanometers in size with a core of helical RNA and a
soluble nucleoprotein that acts as an antigen. The reaction of
the nucleoprotein antigen in various tests determines the
classification of influenza viruses into types A, B, and C.
Further subtyping is based on serological reactions and various
surface antigens, the subtyping code for type A viruses usually
taking the form H(n)N(n). The virus was first isolated in 1933. A
"tracheal aspirate" is a suction yield from the windpipe.
... ... Subbarao et al (16 authors at 3 installations, US CN)
report the isolation of an avian H5N1 influenza A virus (A/Hong
Kong/156/97) from a tracheal aspirate obtained from a 3-year old
child in Hong Kong with a fatal illness consistent with influ-
enza. All 8 RNA segments were derived from an avian influenza A
virus. The virus caused nearly 100% mortality in inoculated
chickens (White Plymouth Rock and White Leghorn). The authors
suggest these results may have implications for global influenza
surveillance and planning for pandemic influenza. In a note added
in proof, the authors report 12 additional confirmed similar
human cases in Hong Kong, including 3 fatalities, with molecular
biological analysis consistent with their main report. QY: Kanta
Subbarao, Centers for Disease Control and Prevention, Atlanta, GA
30333 US (Science 16 Jan 98)

---------------------------------------------

BOOK NOTES

R.H. Abraham, L. Gardini, C. Mira:
CHAOS IN DISCRETE DYNAMICAL SYSTEMS
A Visual Introduction in 2 Dimensions
Springer-Verlag, 1997, 272p, US59.95
An undergraduate text requiring only a rudimentary background in
mathematics. Focuses on examples and visual representations.
Accompanying CDROM contains 12 full-color animations. Introduct-
ion to basic concepts of discrete chaos theory, analysis of
computer experiments, expanded mathematical treatments in append-
ices. CDROM also contains programs and programming code for 2-
dimensional chaos research. CDROM animations in AVI and Quick-
Time. The authors are mathematicians and engineers. 

F. Chung and R. Graham: ERDOS ON GRAPHS
His Legacy of Unsolved Problems
A.K. Peters, 1997, 160p, US30
A graduate text. A selection of problems in graph theory from the
recently deceased renowned mathematician. Many of the problems
have collectable monetary rewards for their solutions. Ramsey
theory, extremal graph theory, coloring theory, packing theory,
random graphs, graph enumeration, hypergraphs, infinite graphs,
etc. The authors are mathematicians.

Wen-Hsiung Li: MOLECULAR EVOLUTION
Sinauer, 1997, 502, US57.95
A comprehensive graduate text. Pre-DNA historical background,
models of evolutionary nucleotide change in DNA, methods of
computing rates of evolution, times of divergence between
species, reconstructing phylogenetic trees, molecular clock
hypothesis, evolution by gene duplication and domain shuffling,
transposition and horizontal transfer, roles of mutation and
selection. The author is a biologist.

Larry S. Liebovitch:
FRACTALS AND CHAOS SIMPLIFIED FOR THE LIFE SCIENCES
Oxford Univ., 1997, 273p, US35
An undergraduate text for non-mathematicians at about the level
of Scientific American. The author is a psychologist specializing
in brain science.

L.H. Marshall and H.W. Magoun: DISCOVERIES IN THE HUMAN BRAIN
Humana Press, 1997, 335p, US59.50
A non-technical history of the brain and the emergence of
neuroscience. Evolution, phylogeny, human brain structures,
functions of convolutions and lobes, neuron doctrine, subcortical
structures, etc. 250 illustrations. The authors are
neuroscientists.

M.L. Reaka-Kudla, D.E. Wilson, E.O. Wilson: BIODIVERSITY II
Understanding and Protecting Our Biological Resources
National Academy Press, 1997, 556p, US29.95
Explores new strategies for quantifying, understanding, and
protecting biodiversity. Integration of electronic data, species
identification and classification, Gap Analysis Program,
contributions of museum collections, etc. The authors are
zoologists.

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