ScienceWeek

SCIENCEWEEK

ScienceWeek
December 13, 2002
Vol. 6 Number 50

An Online Research Digest Published Weekly Since 1997

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The verb "to theorize" is now conjugated as follows:
"I built a model, you formulated a hypothesis, he made a
conjecture."
-- John Ziman

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Section 1

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1. ON DARK GAMMA RAY BURSTS.
Astronomers once thought that GRBs occurred within our Galaxy,
but in the early 1990s it was realized that these explosive
events actually occur at cosmological distances of the order of
15 billion light years away. New observations suggest that the
seeming lack of optical emission from dark bursts is in fact a
result of insufficiently prompt and sensitive observations.

2. ON CARBON ELECTRONICS.
Diamond is a semiconductor with physical properties that make it
the ideal material for electronic devices. The major barrier to
realizing this potential of diamond to date has been the
difficulty in synthesizing it in a form that is pure and perfect
enough for electronics.

3. ON MYELIN PROTEINS AND NERVE REGENERATION.
Unlike peripheral nervous system (PNS) axons, severed central
nervous system (CNS) axons are unable to regenerate. Why do CNS
and PNS axons differ so dramatically in their regenerative
abilities? Differences in CNS and PNS glial cells appear to be
crucial, as some CNS axons are able to regenerate through a
peripheral nerve graft.

4. ON PERINATAL TESTOSTERONE, STRESS, AND ADULT LEARNING.
The presence of sex hormones during gestation and development
organizes whether and how acute stressful experience will affect
the ability to acquire new information in adulthood. These
cognitive responses to stress appear to be masculinized by
exposure to testosterone and feminized by its absence during very
early development.

5. A NANOSCALE OPTICAL BIOSENSOR.
Triangular silver nanoparticles (~100 nm wide and 50 nm high)
have remarkable optical properties. In particular, the peak
extinction wavelength of their localized surface plasmon
resonance spectrum is unexpectedly sensitive to nanoparticle
size, shape, and local (~10-30 nm) external dielectric
environment.

6. ON RADIATION IN THE TREATMENT OF CANCER.
At present, the most common radiotherapy treatment uses high-
energy x- rays. Shaped beams of x- rays are directed toward the
patient. The beams pass through the patient, undergoing near-
exponential attenuation as they interact with tissues, and
deposit dose along the way.

7. SUSCEPTIBILITY GENES FOR MENTAL DISORDERS.
Research on the genetic basis of mental disorders has crossed a
major watershed. For the first time, specific genes have been
discovered that apparently influence susceptibility to
schizophrenia, a psychosis that affects nearly 1% of people
throughout the world and accounts for about 2.5% of health-care
costs.

8. ON MOTOR FUNCTION IN CEREBRAL PALSY.
Cerebral palsy, which occurs in every to 2/1000 to 2.5/1000 live
births, is an umbrella term covering a group of non-progressive,
but often changing, motor impairment syndromes secondary to
lesions or anomalies of the brain arising in the early stages of
development.

9. ScienceWeek Notices and Subscription Information

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Section 2

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1. ON DARK GAMMA RAY BURSTS.

Gerald J. Fishman (NASA Marshall Space Flight Center, US)
discusses gamma ray bursts, the author making the following
points:

1) Gamma-ray bursts (GRBs) are intense flashes of radiation that
originate in the furthest reaches of the Universe. The bursts are
expected to be followed by an afterglow of radiation at optical
wavelengths. But for many GRBs (approximately 60% of the total
sample of less than 40 bursts that have now been followed up),
this afterglow seems to be missing. Hence, they have become known
as "dark" bursts. Berger et al(1) have reported data from an
armada of telescopes that reveal a faint optical afterglow from a
GRB that would otherwise have been classed as "dark", and their
observations suggest that the seeming lack of optical emission
from dark bursts is in fact a result of insufficiently prompt and
sensitive observations.

2) Astronomers once thought that GRBs occurred within our Galaxy,
but in the early 1990s it was realized that these explosive
events actually occur at cosmological (extra-galactic) distances,
of the order of 15 billion light years away. The distance issue
was settled by an observational breakthrough -- the accurate and
rapid location of GRBs by the Italian Dutch spacecraft Beppo SAX.
Following the initial detection and accurate location of gamma-
rays by Beppo SAX, the optical-radiation counterpart could be
determined by other telescopes. This also makes it possible to
measure the distance of the burst from the Earth. More
importantly, detailed follow-up observations could then be made
of the burst afterglow and of its host galaxy at other
wavelengths by some of the most powerful telescopes in the world,
both ground-based and space-based (in particular, the Hubble
Space Telescope and the Chandra X-ray Observatory).

3) The field of prompt GRB follow-up observations has burgeoned
in the past four years, in both the observational and the
theoretical areas. Afterglow observations are being made at X-
ray, optical, microwave, infrared and radio wavelengths. In each
observational band, and by combining data from different bands,
astronomers can make clever use of the data, such as providing a
measure of the angular size of the emitting region by observing
radio variability(2-5).

References (abridged):

1. Berger, E. et al. Astrophys. J. (in the press); Preprint
astro-ph/ 0207320, http://arXiv.org

2. Waxman, E., Kulkarni, S. & Frail, D. Astrophys. J. 497, 288-
293 (1998).

3. Hurley, K. et al. Astrophys. J. Suppl. 122, 497-501 (1999).

4. http://www.swift.psu.edu

5. http://www-glast.sonoma.edu

Nature 2002 419:259

Related Background:

A REASSESSMENT OF GAMMA RAY BURSTS

Gamma ray bursts are intense flashes of gamma rays detected at
energies up to 10^(6) *electronvolts. They were discovered by US
Air Force satellites in 1967 but not declassified until 1973. The
detection of these bursts averages about 1 per day, and
measurements indicate the distribution of bursts is isotropic,
i.e., they are uniformly distributed across the sky. Recent views
are that gamma ray bursts are produced by the merger of two
neutron stars, or a neutron star with a black hole, or a massive
star with a black hole. Up to this point, the bursts that have
been noted apparently originate outside our own galaxy.

Gamma rays are radiation of high energy, from about 10^(5)
*electronvolts to more than 10^(14) electronvolts -- radiation
with the shortest wavelengths and highest frequencies, the gamma
ray region of the electromagnetic spectrum merging into the
adjacent lower energy x-ray region.

Stan Woosley (University of California Santa Cruz, US) discusses
gamma ray bursts, the author making the following points:

1) Though sometimes touted as the largest explosions since the
Big Bang, gamma ray bursts are now seeming less energetic than
they did just two years ago, and recent observations suggest that
the energy required to produce these bursts may not be much more
than that of an ordinary supernova in which emitted energy is
somehow focused into a narrow jet moving very close to the speed
of light and pointing directly towards Earth. New evidence, based
on measurements of the size of the jets, suggests that all gamma
ray bursts release approximately the same amount of energy.

2) The energies inferred from gamma ray burst observations are
enormous, amounting in some cases to the mass of the Sun being
converted directly into gamma rays within a few seconds. In the
late 1990s, model builders struggled to reproduce these sorts of
burst energies in computer simulations, and wondered whether the
energies were really that large. In particular, would a gamma ray
burst be just as bright if it were seen from some other angle?

3) In the past decade, theoretical astrophysicists began
suggesting that much less energy would be needed to produce the
same brightness if gamma ray bursts broadcast their energy in a
narrow cone or jet. Most models of gamma ray burst formation
involve either the cataclysmic collapse of a massive rotating
star into a black hole, or a neutron star merging with a black
hole. Because the material accreting into the black hole forms a
rotating disk, it blocks the outflow of mass, so any material
that does escape [before being swallowed up by the black hole] is
forced into two narrow and oppositely directed jets. Other
astronomical phenomena thought to be powered by accreting black
holes, such as quasars, are also known to produce jets, so why
not gamma ray bursts? Recent experimental estimates of the
angular size of gamma ray bursts, based on observations of their
afterglows, suggests that even if we assume that the original
emission is spherical, matter released by a gamma ray burst is
accelerated close to the speed of light and so emits radiation in
a narrow beam along its path.

Nature 2001 414:853

Related Background:

GAMMA RAY BURSTS: THE LARGEST EXPLOSIONS IN THE UNIVERSE

Gamma rays are extremely high energy electromagnetic radiation
with wavelengths of less than approximately 0.01 nanometers. X-
rays are radiation of wavelengths approximately 0.01 to 10
nanometers, shorter than ultraviolet radiation but longer than
gamma rays. Gamma ray bursts are intense flashes of gamma rays
and x-rays detected at energies up to 10^(6) *electron volts.
They were discovered by US Air Force satellites in 1967 but not
declassified until 1973. The detection of these bursts averages
approximately 1 per day, and measurements indicate the
distribution of bursts is isotropic, i.e., they are uniformly
distributed across the sky. The nature of gamma ray bursts
remains mysterious. Astronomers have obtained rigorous distance
estimates only recently, placing gamma ray bursts definitely in
the realm of cosmology. *Redshift measurements suggest extremely
large distances, making gamma ray bursts the most powerful
catastrophic energy releases known to mankind.

Dieter H. Hartmann (Clemson University, US) presents a review of
current
research concerning gamma ray bursts, the author making the
following points:

1) Gamma ray bursts are short flashes of almost pure high- energy
emission (x-rays and gamma rays) that occur randomly on the sky,
and from loci which apparently do not emit more than once.
Typical durations are of the order of seconds, but can range from
a few milliseconds to over 1000 seconds. The bursts are extremely
bright, outshining all other objects on the gamma ray sky, but
their spectra are featureless and reveal little about the
underlying physical processes. Integrating burst spectra over
energy and time yields large fluences (received energy per unit
area), but does not determine the total burst energy until the
distance is known.

2) Although the statistical properties of gamma ray bursts long
supported the idea that bursts occur at cosmological distances,
this distance scale was finally established by a burst on 8 May
1997, for which a faint extended object was optically identified
as the host, the object showing clear evidence of absorption
lines that indicated a lower redshift limit of z = 0.835. On 14
December 1997, another burst showed absorption lines at z = 3.42,
and then a third burst on 3 July 1998 had associated absorption
lines at z = 0.966 -- all of this indicating that gamma ray
bursts, along with *quasars, are the most distant objects in the
Universe. Such large distances imply large energies, and in fact
the assumption of isotropic emission implies burst energies in
excess of 10^(53) ergs, comparable to *supernova energies but
released predominantly in the gamma ray band. The optical
afterglows of gamma ray bursts are much brighter than supernova,
hence the name "hypernova" has been proposed.

3) Studies of gamma ray burst host galaxies suggest they are
normal star-forming galaxies, and not galaxies with *active
nuclei. The estimated star formation rates in these hosts,
together with other evidence from x-ray spectra and photometry of
the gamma ray burst afterglows suggests that gamma ray bursts may
be directly associated with star-forming regions. If that turns
out to be correct, astronomers would have a powerful new tool for
the study of structure formation in the Universe, a tool that
could reach further back in time than quasars.

4) Despite recent breakthroughs in gamma ray burst observations,
many questions remain about the nature of the underlying
processes and the evolutionary sequences leading up to the
creation of the central engine driving these outbursts. The
ultimate goal of understanding this engine may be accomplished
through simultaneous optical observations, and such is the
objective of dedicated experiments under development throughout
the world.

Proc. Nat. Acad. Sci. 1999 96:4752

 Notes:

 ... ... *electron volts: An electronvolt is defined as the
energy acquired by an electron falling freely through a potential
difference of one volt, and is equal to 1.6022 x 10^(-19) joule.

 ... ... *Redshift: Redshift (symbol: z) is a lengthening of the
wavelengths of
electromagnetic radiation from a source caused either by the
movement of the source (Doppler effect) or by the expansion of
the universe (cosmological redshift). Redshift is defined as the
change in wavelength of a particular spectral line divided by the
unshifted wavelength of that line. Large redshifts imply large
radial velocities (which imply large distances, according to
current cosmological theory), but at redshifts greater than about
0.2 there is a relativistic divergence from a linear relation. A
redshift of 4.0 corresponds to an object receding with a radial
velocity 92% that of the velocity of light. The largest
astrophysical redshifts so far observed are of the order of z =
5.

... ... *quasars: (quasi-stellar objects) Extremely luminous
sources radiating energy over the entire spectrum from x-rays to
radio waves, and which are apparently among oldest and most
distant objects in the universe.

... ... *supernova: A violent explosion in which certain stars
end their lives. The star may become more than 10^(9) times as
bright as the Sun and may outshine its host galaxy for weeks.

... ... *active nuclei: (active galactic nuclei) Central regions
of galaxies in which considerable energy is generated by
processes other than those operating in ordinary stars. The
energy may result from the accretion of material into a massive
black hole situated at the core of the galaxy.

ScienceWeek http://www.scienceweek.com

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2. ON CARBON ELECTRONICS.

Gehan A.J. Amaratunga (Cambridge University, UK) discusses carbon
electronics, the author making the following points:

1) Pure carbon naturally forms two different crystalline
materials: diamond, in which all bonds between carbon atoms are
the same, and graphite, with two different types of bonds between
the atoms. Because diamond is the higher energy form of the two,
its natural occurrence is rare compared with that of graphite. In
contrast, the lowest energy form of related elements such as
silicon (Si) and germanium (Ge) has the same crystal structure as
diamond, but no naturally occurring form like graphite.

2) The quirk of nature that makes graphite the lowest energy form
of carbon is the main reason it has not been used in electronic
devices, in stark contrast to its neighbor in the periodic table,
Si. A material suitable for an electronic device must not conduct
electrical current in its pure state at room temperature.
However, it should be possible to tune its conductivity in a
controllable manner by introducing trace amounts of impurity
atoms (dopants). Such materials are termed "semiconductors."
Graphitic carbon conducts electricity at room temperature. In
contrast, diamond is a semiconductor with physical properties
(such as maximum electric field, saturation velocity, thermal
conductivity and band-gap) that make it the ideal material for
electronic devices (1-3). The major barrier to realizing this
potential of diamond to date has been the difficulty in
synthesizing it in a form that is pure and perfect enough for
electronics.

3) Natural diamonds have too many defects and impurities for use
as semiconductors, regardless of the cost associated with their
rarity. Only manufactured semiconductor materials are of the
appropriate quality for electronics. Crystalline Si wafers used
for electronics have impurity and crystalline defect densities
that are lower than the atomic density by a factor of 10^(-11) to
10^(-12). Electronic-grade Si is the purest bulk material known.
The first artificial synthesis of diamond [HN7] was reported in
1955 (4). It was achieved by subjecting graphite to high pressure
and high temperature (HPHT) in the presence of a transition-metal
catalyst. This method is now a standard industrial process. It
yields diamonds with submicrometer to submillimeter dimensions
that are used as grit in mechanical applications such as
polishing. These applications exploit the extremely high hardness
and chemical inertness of diamond. But until recently, the
impurities and defects in HPHT-synthesized diamonds and their
small size precluded their use in electronics.(5)

References (abridged):

1. J. Isberg et al., Science 297, 1670 (2002).

2. M. W. Geis, N. N. Efremow, D. D. Rathman, J. Vac. Sci. A6,
1953 (1988).

3. K. Shenai, R. S. Scott, B. J. Baliga, IEEE Trans. Electron.
Devices 36, 1811 (1989).

4. F. P. Bundy et al., Nature 176, 51 (1955).

5. J. C. Angus, H. A. Will, W. S. Stanko, J. Appl. Phys. 39, 2915
(1968).

Science 2002 297:1657

Related Background Brief:

HIGH CARRIER MOBILITY IN SINGLE-CRYSTAL PLASMA-DEPOSITED DIAMOND.
Room-temperature drift mobilities of 4500 square centimeters per
volt second for electrons and 3800 square centimeters per volt
second for holes have been measured in high-purity single-crystal
diamond grown using a chemical vapor deposition process. The low-
field drift mobility values were determined by using the time-of-
flight technique on thick, intrinsic, freestanding diamond plates
and were verified by current-voltage measurements on p-i junction
diodes. The improvement of the electronic properties of single-
crystal diamond and the reproducibility of those properties are
encouraging for research on, and development of, high-performance
diamond electronics. J. Isberg et al: Science 2002 297:1670.

Related Background:

POLYMORPHISM IN CRYSTALS

In general, in this context, the term "polymorphism"
(pleomorphism) refers to the crystallization of a chemical
substance into two or more forms having different structures, for
example, diamond and graphite.

H. Liu et al (North Carolina State University, US) discuss
polymorphism in crystals. Understanding the factors that control
polymorphism is important for the rational design and synthesis
of crystalline materials that exhibit targeted physical
properties, just as control of isomerism, for example, is
critical in natural product synthesis. In biology, only L-amino
acids are used in protein synthesis, and the enzymes that
catalyze the reactions do not recognize the D-enantiomers.
Similarly, in solid-state chemistry, two polymorphs of a material
frequently exhibit dramatically different properties. For
example, silicon carbide crystallizes in numerous polymorphs, the
most common polymorph widely utilized as the abrasive called
carborundum, whereas another polymorph is suitable for blue-light
emitting diodes. In the absence of a mechanistic understanding,
reaction design to achieve desired products is only an empirical
endeavor. While a detailed understanding of organic reaction
mechanisms is of fundamental importance to the modern
pharmaceutical industry, a mechanistic understanding of solid-
state chemistry is still in its infancy. Increasingly,
measurements of the kinetics and thermodynamics of solid-state
phase transitions in bulk solids and nanoparticles have been
reported, but microscopic descriptions of the atomic motions
involved, particularly where bonds are broken or formed, are
rarely presented.

J. Am. Chem. Soc. 123:7564

Related Background:

ON THE NATURAL OCCURRENCES OF DIAMOND

In general, in this context, the term "metamorphism" refers to
the mineralogical and structural changes of solid rock in
response to environmental conditions at depth in the Earth's
*crust. Diamond is a good example of the metamorphic formation of
a rock crystal. The most common naturally occurring forms of pure
carbon are graphite and diamond. If diamond is heated to
approximately 1200 degrees centigrade, it slowly transforms to
graphite, the rate of transformation increasing with temperature.
At 2000 degrees centigrade the transformation is extremely rapid
and the crystal shatters into a heap of graphite powder. It has
been found, however, that diamond can survive these high
temperatures if it is subjected to a pressure of several thousand
atmospheres. Conversely, diamond can be produced by heating
graphite to approximately 2500 degrees centigrade under a
pressure in excess of 100,000 atmospheres, and it is this process
that is responsible for the production of diamonds in nature.
Before the middle of the 19th century, virtually all diamonds
were found in or near surface streams, and most of these diamonds
were discovered either in India or Brazil. In the year 1866, the
children of a Boer farmer, Daniel Jakobs, while playing on the
bank of the Orange River at Hopetown near Kimberley in South
Africa, found a diamond weighing 21.25 *carats (slightly more
than 4 grams). Subsequent exploration in the area demonstrated
that the diamond-bearing deposit was a roughly circular region a
few hundred meters in diameter, effectively a cylindrical "pipe"
that had been pushed upwards from a region deep in the Earth's
crust. Such a geological feature is now known as a "Kimberlite
pipe". At present, the main source of diamonds is the *igneous
rock "kimberlite", in which diamonds are found as scattered
crystals. Kimberlite pipes are believed to be the remains of
magma plugs that have been forced up to the Earth's surface, and
there are known Kimberlite pipes with diameters up to a
kilometer. There is evidence that in some cases the magma plugs
may derive from *mantle plumes. The largest gem quality diamond
ever found was the 621-gram (3106 carats) Cullinan crystal
discovered in 1905. Diamonds have also been found in meteorites
as microcrystalline clumps up to approximately a millimeter in
size, the meteoritic diamonds evidently formed from graphite
nodules as *iron meteorites were subjected to intense high
pressures by the shock of impact on the surface of the Earth
(shock metamorphism). Concerning the use of diamond in industry,
diamond is the hardest substance available. In addition, diamond
has the highest thermal conductivity of any known substance (five
times the thermal conductivity of copper at room temperature),
which means that a diamond cutting tool transfers heat quickly
and does not become hot while in use.

Stephen E. Haggerty (University of Massachusetts Amherst, US)
presents a review of the natural occurrences of diamond and the
implications of diamond for our knowledge of Earth and Solar
System processes. The author makes the following points:

1) Carbon is the fourth most abundant element in the Solar System
after hydrogen, helium, and oxygen. As a nucleosynthetic bridge
to the heavy elements, to stellar evolution, and to biosynthesis,
carbon holds an interesting position in the periodic system of
elements. Diamond is pure carbon and is an impervious time
capsule: Some diamonds are pre-Solar and have recorded such
extraordinary astrophysical events as *supernovae explosions;
other diamonds bear witness to Solar System formation; and
diamonds from our planet are a window to the geodynamic evolution
of Earth's deep interior.

2) The study of diamond and its various crystal forms
(polymorphs) (e.g., *lonsdaleite, *fullerene, and graphite) has
seen a recent burst of activity in geochemistry and geophysics,
in novel methods of synthesis, and in the development of useful
applications that take advantage of its covalent bonding,
clarity, extreme hardness, high thermal conductivity, and high
electrical resistance.

3) Diamond is now recognized as an extraordinary recorder of
astrophysical and geodynamic events that extend from the far
reaches of space to Earth's deep interior. Many diamonds are
natural antiques that formed a) in presolar supernovae by carbon
vapor deposition, b) in asteroidal impacts and meteorite craters
by shock metamorphism, and c) from fluids and melts in Earth's
mantle 1 to 2 billion years after *planetary accretion. The
carbon in diamond is primordial, but there are unexplained
isotopic fractionations and uncertainties in heterogeneity.

cience 1999 285:851

Text Notes:

... ... *crust: The crust is the outermost of the 3 major layers
of the planet (core, mantle, crust), its depth varying from
approximately 5 kilometers to as much as 60 to 80 kilometers.

... ... *carats: 1 carat = 0.2 grams

... ... *igneous rock: Igneous rocks are rocks that have
congealed from a molten mass.

... ... *mantle plumes: Mantle plumes are thin vertical conduits
of molten rock material from the core-mantle boundary to the
crust. Seismic studies indicate the interior of the Earth
consists of three parts: a metallic core, a dense rocky mantle,
and a thin low-density crust. The central part of the core is
solid, but the outer part of the core is evidently liquid.  The
mantle, the layer of dense rock and metal oxides between the
molten part of the core and the surface, has plastic properties
(i.e., it is a solid capable of flow under pressure).

... ... *iron meteorites: Meteorites composed mostly of iron,
with less than 30 percent nickel, and with only a small
proportion of silicate minerals. They form only a few percent of
meteorite falls.

... ... *supernovae explosions: Supernovae are stellar explosions
in which virtually an entire star is disrupted. The estimate is
that in our own Galaxy approximately 1 supernova occurs every 30
years, with most of the supernovae obscured by galactic dust.

... ... *lonsdaleite: A form of carbon found in meteorites. It
can also be formed synthetically by ballistically accelerating
metal projectiles into carbon targets.

... ... *fullerene: Fullerenes are large molecules composed
entirely of carbon, with the chemical formula C(n), where n is
any even number from 32 to over 100. They apparently have the
structure of a hollow spheroidal cage with a surface network of
carbon atoms connected in hexagonal and pentagonal rings.

... ... *planetary accretion: Planetesimals, present in the
vicinity of a young star, are bodies with dimensions of 10^(-3)
to 10^(3) meters that are believed to form planets by a process
of accretion. The term "accretion" refers to an aggregation, an
increase in the mass of a body by the addition of smaller bodies
that collide and adhere to it, provided the relative velocities
are low enough for coalescence.

ScienceWeek http://www.scienceweek.com

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3. ON MYELIN PROTEINS AND NERVE REGENERATION

T.A. Watkins and B.A. Barres (Stanford University, US) discuss
nerve regeneration, the authors making the following points:

1) Unlike peripheral nervous system (PNS) axons, severed central
nervous system (CNS) axons are unable to regenerate. Why do CNS
and PNS axons differ so dramatically in their regenerative
abilities? Differences in CNS and PNS glial cells appear to be
crucial, as some CNS axons are able to regenerate through a
peripheral nerve graft [1] . Axons are tightly wrapped by myelin
membrane produced by oligodendrocytes in the CNS and Schwann
cells in the PNS. Following axonal injury in the PNS, myelin is
rapidly cleared by macrophages as the axons degenerate in a
process known as Wallerian degeneration. In contrast, myelin is
cleared much more slowly after CNS injury. This difference
suggests that CNS myelin strongly inhibits regenerating axons, a
possibility that was directly confirmed in elegant experiments by
Martin Schwab and his colleagues [2].

2) An important first step towards identifying myelin inhibitors
of axon regeneration was taken many years ago with the
development of an anti-CNS myelin monoclonal antibody, IN-1,
which promotes CNS regeneration and a limited degree of
functional recovery in animal models [2] . Only in the last few
years, however, have researchers begun to elucidate the key
inhibitors and their receptors, uncovering a few surprises along
the way. The target of the IN-1 antibody turned out to be Nogo, a
reticulon homolog with three isoforms: Nogo-A is expressed
primarily in oligodendrocytes, and the other two isoforms are
more widely distributed (3). Interestingly, Nogo-A has two
separate domains that can inhibit growing axons: the amino-
terminal portion (Amino-Nogo), which is unique to Nogo-A, and a
66 amino acid peptide (Nogo-66) located between the two
transmembrane regions, which is common to all isoforms.

3) How does Nogo inhibit regenerating axons? The functional
receptor for Nogo-66, NgR, is a 473 amino acid protein with an
attached glycosylphosphatidylinositol (GPI) lipid. This GPI
linkage serves to anchor the protein to the outer surface of the
cell membrane, where it can interact with its ligand. Binding
studies and the effects of ectopic expression both confirmed that
this protein is the functional receptor for Nogo-66 [4] . The
expression patterns of Nogo and NgR are consistent with the
interactions of these proteins at points of contact between axons
and myelin, as well as at synapses [5] . It is unlikely, however,
that NgR works alone: its lack of a transmembrane region implies
the presence of an as yet unidentified transmembrane co-receptor
that transduces the inhibitory signal.

4) In summary: Three different myelin proteins, Nogo, MAG, and
OMgp, inhibit regenerating axons after CNS injury. New work
reveals that they all share a common receptor and that blockade
of this receptor promotes CNS repair and functional recovery.

References (abridged):

1. David S. and Aguayo A.J. (1981) Axonal elongation into
peripheral nervous system 'bridges' after central nervous system
injury in adult rats. Science, 214:931-933.

2. Caroni P. and Schwab M.E. (1988) Antibody against myelin-
associated inhibitor of neurite growth neutralizes nonpermissive
substrate properties of CNS white matter. Neuron, 1:85-96.

3. Goldberg J.L. and Barres B.A. (2000) Nogo in nerve
regeneration. Nature, 403:369-370.

4. Fournier A.E., GrandPre T. and Strittmatter S.M. (2001)
Identification of a receptor mediating Nogo-66 inhibition of
axonal regeneration. Nature, 409:341-346.

5. Wang X., Chun S.J., Treloar H., Vartanian T., Greer C.A. and
Strittmatter S.M. (2002) Localization of Nogo-A and Nogo-66
receptor proteins at sites of axon-myelin and synaptic contact.
J. Neurosci., 22:5505-5515.

Current Biology 2002 12:R654

Related Background Brief:

AXONAL ELONGATION INTO PERIPHERAL NERVOUS SYSTEM "BRIDGES" AFTER
CENTRAL NERVOUS SYSTEM INJURY IN ADULT RATS. The authors report
that the origin, termination, and length of axonal growth after
focal central nervous system injury was examined in adult rats by
means of a new experimental model. When peripheral nerve segments
were used as "bridges" between the medulla and spinal cord, axons
from neurons at both these levels grew approximately 30
millimeters. The regenerative potential of these central neurons
seems to be expressed when the central nervous system glial
environment is changed to that of the peripheral nervous system.
S. David and A.J. Aguayo: Science 1981 214:931.

Related Background Brief:

ANTIBODY AGAINST MYELIN-ASSOCIATED INHIBITOR OF NEURITE GROWTH
NEUTRALIZES NONPERMISSIVE SUBSTRATE PROPERTIES OF CNS WHITE
MATTER. CNS white matter from higher vertebrates and cultured
differentiated oligodendrocytes are nonpermissive substrates for
neurite growth and fibroblast spreading. The authors report that
membrane proteins of 35 kd and 250 kd with highly nonpermissive
substrate properties could be extracted from CNS myelin
fractions. Monoclonal antibodies were raised against these
proteins: IN-1 and IN-2 bound both to the 35 kd and 250 kd
inhibitors and to the surface to differentiated cultured
oligodendrocytes. Adsorption of nonpermissive CNS myelin or
nonpermissive oligodendrocytes with either antibody markedly
improved their substrate properties. Optic nerve explants
injected with IN-1 or IN-2 allowed axon ingrowth of co-cultured
sensory and sympathetic neurons. The authors conclude that the
nonpermissive substrate properties of CNS white matter are due to
these membrane proteins on the surface of differentiated
oligodendrocytes and to their in vivo product, myelin. P. Caroni
and M.E. Schwab: Neuron 1988 1:85.

Related Background Brief:

IDENTIFICATION OF A RECEPTOR MEDIATING NOGO-66 INHIBITION OF
AXONAL REGENERATION. Nogo has been identified as a component of
the central nervous system (CNS) myelin that prevents axonal
regeneration in the adult vertebrate CNS. Analysis of Nogo-A has
shown that an axon-inhibiting domain of 66 amino acids is
expressed at the extracellular surface and at the endoplasmic
reticulum lumen of transfected cells and oligodendrocytes. The
acidic amino terminus of Nogo-A is detected at the cytosolic face
of cellular membranes and may contribute to inhibition of axon
regeneration at sites of oligodendrocyte injury. The authors
demonstrate that the extracellular domain of Nogo (Nogo-66)
inhibits axonal extension, but does not alter non-neuronal cell
morphology. In contrast, a multivalent form of the N terminus of
Nogo-A affects the morphology of both neurons and other cell
types. The authors identify a brain-specific, leucine-rich-repeat
protein with high affinity for soluble Nogo-66. Cleavage of the
Nogo-66 receptor and other glycophosphatidylinositol-linked
proteins from axonal surfaces renders neurons insensitive to
Nogo-66. Nogo-66 receptor expression is sufficient to impart
Nogo-66 axonal inhibition to unresponsive neurons. Disruption of
the interaction between Nogo-66 and its receptor provides the
potential for enhanced recovery after human CNS injury. A.E.
Fournier et al: Nature 2001 409:341.

Related Background Brief:

LOCALIZATION OF NOGO-A AND NOGO-66 RECEPTOR PROTEINS AT SITES OF
AXON-MYELIN AND SYNAPTIC CONTACT. Axon regeneration in the adult
CNS is limited by the presence of inhibitory proteins. An
interaction of Nogo on the oligodendrocyte surface with Nogo-66
Receptor (NgR) on axons has been suggested to play an important
role in limiting axonal growth. The authors compare the
localization of these two proteins immunohistochemically as a
test of this hypothesis. Throughout much of the adult CNS, Nogo-A
is detected on oligodendrocyte processes surrounding myelinated
axons, including areas of axon-oligodendrocyte contact. The NgR
protein is detected selectively in neurons and is present
throughout axons, indicating that Nogo-A and its receptor are
juxtaposed along the course of myelinated fibers. NgR protein
expression is restricted to postnatal neurons and their axons. In
contrast, Nogo-A is observed in myelinating oligodendrocytes,
embryonic muscle, and neurons, suggesting that Nogo-A has
additional physiologic roles unrelated to NgR binding. After
spinal cord injury, Nogo-A is upregulated to a moderate degree,
whereas NgR levels are maintained at constant levels. The authors
suggest that taken together these data confirm the apposition of
Nogo ligand and NgR receptor in situations of limited axonal
regeneration and support the hypothesis that this system
regulates CNS axonal plasticity and recovery from injury. X. Wang
et al: J Neurosci 2002 22:5505.

Related Background Brief:

NOGO-66 RECEPTOR ANTAGONIST PEPTIDE PROMOTES AXONAL REGENERATION.
Myelin-derived axon outgrowth inhibitors, such as Nogo, may
account for the lack of axonal regeneration in the central
nervous system (CNS) after trauma in adult mammals. A 66-residue
domain of Nogo (Nogo-66) is expressed on the surface of
oligodendrocytes and can inhibit axonal outgrowth through an
axonal Nogo-66 receptor (NgR). The IN-1 monoclonal antibody
recognizes Nogo-A and promotes corticospinal tract regeneration
and locomotor recovery; however, the undefined nature of the IN-1
epitope in Nogo, the limited specificity of IN-1 for Nogo, and
nonspecific anti-myelin effects have prevented a firm conclusion
about the role of Nogo-66 or NgR. Here, we identify competitive
antagonists of NgR derived from amino-terminal peptide fragments
of Nogo-66. The Nogo-66(1 40) antagonist peptide (NEP1 40) blocks
Nogo-66 or CNS myelin inhibition of axonal outgrowth in vitro,
demonstrating that NgR mediates a significant portion of axonal
outgrowth inhibition by myelin. Intrathecal administration of
NEP1 40 to rats with mid-thoracic spinal cord hemisection results
in significant axon growth of the corticospinal tract, and
improves functional recovery. Thus, Nogo-66 and NgR have central
roles in limiting axonal regeneration after CNS injury, and NEP1-
40 provides a potential therapeutic agent. T. GrandPre et al:
Nature 2002 417:547.

Related Background Brief:

GANGLIOSIDES ARE FUNCTIONAL NERVE CELL LIGANDS FOR MYELIN-
ASSOCIATED GLYCOPROTEIN (MAG), AN INHIBITOR OF NERVE
REGENERATION. Myelin-associated glycoprotein (MAG) binds to the
nerve cell surface and inhibits nerve regeneration. The nerve
cell surface ligand(s) for MAG are not established, although
sialic acid-bearing glycans have been implicated. The authors
identify the nerve cell surface gangliosides GD1a and GT1b as
specific functional ligands for MAG-mediated inhibition of
neurite outgrowth from primary rat cerebellar granule neurons.
MAG-mediated neurite outgrowth inhibition is attenuated by (i)
neuraminidase treatment of the neurons; (ii) blocking neuronal
ganglioside biosynthesis; (iii) genetically modifying the
terminal structures of nerve cell surface gangliosides; and (iv)
adding highly specific IgG-class antiganglioside mAbs.
Furthermore, neurite outgrowth inhibition is mimicked by highly
multivalent clustering of GD1a or GT1b by using precomplexed
antiganglioside Abs. The authors suggest these data implicate the
nerve cell surface gangliosides GD1a and GT1b as functional MAG
ligands and suggest that the first step in MAG inhibition is
multivalent ganglioside clustering. A.A. Vyas et al: Proc. Nat.
Acad. Sci. 2002 99:8412.

Related Background Brief:

MYELIN-ASSOCIATED GLYCOPROTEIN INTERACTS WITH GANGLIOSIDE GT1B. A
MECHANISM FOR NEURITE OUTGROWTH INHIBITION. Myelin-associated
glycoprotein (MAG) is expressed on myelinating glia and inhibits
neurite outgrowth from post-natal neurons. MAG has a sialic acid
binding site in its N-terminal domain and binds to specific
sialylated glycans and gangliosides present on the surface of
neurons, but the significance of these interactions in the effect
of MAG on neurite outgrowth is unclear. The authors present
evidence to suggest that recognition of sialylated glycans is
essential for inhibition of neurite outgrowth by MAG. Arginine
118 on MAG is known to make a key contact with sialic acid. The
authors demonstrate that mutation of this residue reduces the
potency of MAG inhibitory activity but that residual activity is
also a result of carbohydrate recognition. The authors
investigated gangliosides GT1b and GD1a as candidate MAG
receptors, and demonstrate that MAG specifically binds both
gangliosides and that both are expressed on the surface of MAG-
responsive neurons. Furthermore, antibody cross-linking of cell
surface GT1b, but not GD1a, mimics the effect of MAG, in that
neurite outgrowth is inhibited through activation of Rho kinase.
The authors suggest these data strongly indicate that interaction
with GT1b on the neuronal cell surface is a potential mechanism
for inhibition of neurite outgrowth by MAG. M. Vinson et al: J
Biol Chem 2001 276:20280.

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4. ON PERINATAL TESTOSTERONE, STRESS, AND ADULT LEARNING.

T.J. Shors and G. Miesegaes (Rutgers University, US) discuss
perinatal testosterone, the authors making the following points:

1) Exposure to sex hormones prenatally and early in development
organizes the brain for many behavior patterns that manifest
throughout adulthood (1-5). Reported changes in behavior tend to
be sexual in nature; i.e., in the presence of ovarian hormones,
adult males castrated at birth will exhibit a posture known as
lordosis that normally occurs in sexually receptive females. In
contrast, females that are briefly exposed to testosterone at
birth do not ovulate or exhibit lordosis but will exhibit male
sexual behaviors such as mounting in response to testosterone
exposure. From these studies, it is generally considered that the
background or default condition for reproductive behavior is
feminine and the presence of testosterone in the female converts
the behavior to a masculine one.

2) The authors have reported that the exposure to a stressful and
traumatic event greatly enhances new learning in adult male rats,
whereas exposure to the same stressful experience impairs
performance in adult female rats. The stressful event is acute,
consisting of <30 min of inescapable swimming or exposure to
brief intermittent tail stimulations. The learning paradigm is an
associative task in which a conditioned stimulus (CS) of white
noise predicts the occurrence of a periorbital eyelid stimulus,
which elicits an eyeblink as an unconditioned stimulus (US). As
the animal learns that the CS predicts the occurrence of the US,
it elicits a conditioned eyeblink response (CR) in response to
the CS. The opposite effects of stress on performance are evident
during several paradigms, including trace conditioning, a
hippocampal-dependent task in which the stimuli are discontiguous
in time. Moreover, these opposite effects of stress are dependent
on differing hormonal substrates. In males, the enhancement of
learning in response to stress is dependent on the presence of
the adrenal hormone, corticosterone, whereas in females, the
impaired performance is dependent on the presence of the sex
hormone estrogen. Thus, exposure to a stressful traumatic event
can have opposite effects on an animal's ability to learn simply
by virtue of its sex and these effects are mediated by different
hormonal systems, at least as manipulated in adulthood.

3) In summary: Exposure to an acute stressful event can enhance
learning in male rats, whereas exposure to the same event
dramatically impairs performance in females. The authors report
they tested whether the presence of sex hormones during early
development organizes these opposite effects of stress on
learning in males vs. females. In the first experiment, males
were castrated at birth whereas females were injected with
testosterone. Rats were trained as adults on the hippocampal-
dependent learning task of trace eyeblink conditioning.
Performance in adult males that had been castrated at birth was
still enhanced by exposure to an acute stressful experience.
However, adult females injected with testosterone at birth
responded in the opposite direction, i.e., exposure to the
stressor that typically reduces performance instead enhanced
their levels of conditioning. In the second experiment, exposure
to testosterone was manipulated in utero by injecting pregnant
females with a testosterone antagonist. After foster rearing,
adult offspring were exposed to the stressor and trained on the
hippocampal-dependent learning task of trace conditioning.
Although performance in adult females was unaffected by
antagonizing testosterone in utero, i.e., stress still reduced
performance, the enhancement of conditioning after stress in
adult males was prevented. Thus, the presence of sex hormones
during gestation and development organizes whether and how acute
stressful experience will affect the ability to acquire new
information in adulthood. The authors suggest that as with many
sexual behaviors, these cognitive responses to stress appear to
be masculinized by exposure to testosterone and feminized by its
absence during very early development.

References (abridged):

1. Arnold, A. P. & Breedlove, S. M. (1985) Horm. Behav. 19, 469-
498.

2. Balthazart, J. , Tlemcani, O. & Ball, G. F. (1996) Horm.
Behav. 30, 627-661.

3.  Arnold, A. (1996) Horm. Behav. 30, 495-505.

4.  Kendrick, A. M. & Schlinger, B. A. (2000) Horm. Behav. 30,
600-610.

5.  Williams, C. L. , Barnett, A. M. & Meck, W. H. (1990) Behav.
Neurosci. 104, 84-97.

Proc. Nat. Acad. Sci. 2002 99:13955

Related Background Brief:

ORGANIZATIONAL AND ACTIVATIONAL EFFECTS OF SEX STEROIDS ON BRAIN
AND BEHAVIOR: A REANALYSIS. The actions of sex steroids on brain
and behavior traditionally have been divided into organizational
and activational effects. Organizational effects are permanent
and occur early in development; activational effects are
transient and occur throughout life. Over the past decade,
experimental results have accumulated which do not fit such a
simple two-process theory. Specifically, the characteristics said
to distinguish organizational and activational effects on
behavior are sometimes mixed, as when permanent effects occur in
adulthood. The authors suggest that attempts to determine whether
specific cellular processes are uniquely associated with either
organizational or activational effects are unsuccessful. These
considerations blur the organizational-activational distinction
sufficiently to suggest that a rigid dichotomy is no longer
tenable. A.P. Arnold and S.M. Breedlove: Horm Behav 1985 19:469.

Related Background Brief:

DO SEX DIFFERENCES IN THE BRAIN EXPLAIN SEX DIFFERENCES IN THE
HORMONAL INDUCTION OF REPRODUCTIVE BEHAVIOR? WHAT 25 YEARS OF
RESEARCH ON THE JAPANESE QUAIL TELLS US. Early workers interested
in the mechanisms mediating sex differences in morphology and
behavior assumed that differences in behavior that are commonly
observed between males and females result from the sex
specificity of androgens and estrogens. Androgens were thought to
facilitate male-typical traits, and estrogens were thought to
facilitate female-typical traits. By the mid-20th century,
however, it was apparent that administering androgens to females
or estrogens to males was not always effective in sex-reversing
behavior and that in some cases a "female" hormone such as an
estrogen could produce male-typical behavior and an androgen
could induce female-typical behavior. These conceptual
difficulties were resolved to a large extent by the seminal paper
of C. H. Phoenix, R. W. Goy, A. A. Gerall, and W. C. Young in
(1959, Endocrinology 65, 369-382) that illustrated that several
aspects of sexual behavior are different between males and
females because the sexes have been exposed during their
perinatal life to a different endocrine milieu that has
irreversibly modified their response to steroids in adulthood.
Phoenix et al. (1959) therefore formalized a clear dichotomy
between the organizational and activational effects of sex
steroid hormones. Since this paper, a substantial amount of
research has been carried out in an attempt to identify the
aspects of brain morphology or neurochemistry that differentiate
under the embryonic/neonatal effects of steroids and are
responsible for the different behavioral response of males and
females to the activation by steroids in adulthood. During the
past 25 years, research in behavioral neuroendocrinology has
identified many sex differences in brain morphology or
neurochemistry; however many of these sex differences disappear
when male and female subjects are placed in similar endocrine
conditions (e.g., are gonadectomized and treated with the same
amount of steroids) so that these differences appear to be of an
activational nature and cannot therefore explain sex differences
in behavior that are still present in gonadectomized steroid-
treated adults. This research has also revealed many aspects of
brain morphology and chemistry that are markedly affected by
steroids in adulthood and are thought to mediate the activation
of behavior at the central level. It has been explicitly, or in
some cases, implicitly assumed that the sexual differentiation of
brain and behavior driven by early exposure to steroids concerns
primarily those neuroanatomical/neurochemical characteristics
that are altered by steroids in adulthood and presumably mediate
the activation of behavior. Extensive efforts to identify these
sexually differentiated brain characteristics over the past 20
years has only met with limited success, however. As regards
reproductive behavior, in all model species that have been
studied it is still impossible to identify satisfactorily brain
characteristics that differentiate under early steroid action and
explain the sex differences in behavioral activating effects of
steroids. This problem is illustrated by research conducted on
Japanese quail (Coturnix japonica), an avian model system that
displays prominent sex differences in the sexual behavioral
response to testosterone, and in which the endocrine mechanisms
that control sexual differentiation of behavior have been clearly
identified so that subjects with a fully sex-reversed behavioral
phenotype can be easily produced. In this species, studies of sex
differences in the neural substrate mediating the action of
steroids in the brain, including the activity of the enzymes that
metabolize steroids such as aromatase and the distribution of
steroid hormone receptors as well as related neurotransmitter
systems, did not result in a satisfactory explanation of sex
differences in the behavioral effectiveness of testosterone. J.
Balthazart et al: Horm Behav 1996 30:627.

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5. A NANOSCALE OPTICAL BIOSENSOR.

A.J. Haes and R.P. Van Duyne (Northwestern University, US)
discuss biosensors, the authors making the following points:

1) The development of biosensors for the diagnosis and monitoring
of diseases, drug discovery, proteomics, and environmental
detection of biological agents is an extremely significant
problem.(1) Fundamentally, a biosensor is derived from the
coupling of a ligand-receptor binding reaction(2) to a signal
transducer. Much biosensor research has been devoted to the
evaluation of the relative merits of various signal transduction
methods including optical,(3,4) radioactive,(5) electrochemical,
piezoelectric, magnetic, micromechanical, and mass spectrometric.
Although each of these methods has its individual strengths and
weaknesses, a strong case has been made that optical sensors, in
particular those based on evanescent electromagnetic fields such
as propagating surface plasmon polaritons (SPP) at planar gold
surfaces, are fast becoming the methods of choice in many
affinity biosensing applications.(4)

2) SPP, or more commonly, surface plasmon resonance (SPR)
spectroscopy has been widely used to monitor a broad range of
analyte-surface binding interactions including the adsorption of
small molecules, ligand-receptor binding, protein adsorption on
self-assembled monolayers, antibody-antigen binding, DNA and RNA
hybridization, and protein-DNA interactions. The sensing
mechanism of SPR spectroscopy is based on the measurement of
small changes in refractive index that occur in response to
analyte binding at or near the surface of a noble metal (Au, Ag,
Cu) thin film. The development of large-scale biosensor arrays
composed of highly miniaturized signal transducer elements that
enable the real-time, parallel monitoring of multiple species is
an important driving force in biosensor research. This is
particularly significant in high-throughput screening
applications such as drug discovery and proteomics research where
many thousands of ligand-receptor or protein-protein interactions
must be rapidly examined.

3) In summary: The authors report that triangular silver
nanoparticles (~100 nm wide and 50 nm high) have remarkable
optical properties. In particular, the peak extinction
wavelength, lambda-max, of their localized surface plasmon
resonance (LSPR) spectrum is unexpectedly sensitive to
nanoparticle size, shape, and local (~10-30 nm) external
dielectric environment. This sensitivity of the LSPR lambda-max
to the nanoenvironment has allowed the authors to develop a new
class of nanoscale affinity biosensors. The authors suggest that
the LSPR nanobiosensor provides a pathway to ultrasensitive
biodetection experiments with extremely simple, small, light,
robust, low-cost instrumentation that will greatly facilitate
field-portable environmental or point-of-service medical
diagnostic applications.

References (abridged):

1. Turner, A. P. F. Science 2000, 290, 1315-1317.

2. Klotz, I. M. Ligand-Receptor Energetics: A Guide for the
Perplexed; Wiley: New York, 1997.

3. Lee, H. J.; Goodrich, T. T.; Corn, R. M. Anal. Chem. 2001, 73,
5525-5531.

4. Hall, D. Anal. Biochem. 2001, 288, 109-125.

5. Wang, J.; Cai, X.; Rivas, G.; Shiraishi, H.; Farias, P. A. M.;
Dontha, N. Anal. Chem. 1996, 68, 2629-2634.

J. Am. Chem. Soc. 2002 124:10596

Related Background Brief:

SPR IMAGING MEASUREMENTS OF 1-D AND 2-D DNA MICROARRAYS CREATED
FROM MICROFLUIDIC CHANNELS ON GOLD THIN FILMS. The authors report
that microfluidic channels fabricated from poly(dimethylsiloxane)
(PDMS) are employed in surface plasmon resonance imaging
experiments for the detection of DNA and RNA adsorption onto
chemically modified gold surfaces. The PDMS microchannels are
used to (i) fabricate "1D" single-stranded DNA (ssDNA) line
arrays that are used in SPR imaging experiments of
oligonucleotide hybridization adsorption and (ii) create "2D" DNA
hybridization arrays in which a second set of PDMS microchannels
are placed perpendicular to a 1D line array in order to deliver
target oligonucleotide solutions. In the 1D line array
experiments, the total sample volume is 500 mL; in the 2D DNA
array experiments, this volume is reduced to 1 mL. As a
demonstration of the utility of these microfluidic arrays, a 2D
DNA array is used to detect a 20-fmol sample of in vitro
transcribed RNA from the uidA gene of a transgenic Arabidopsis
thaliana plant. The authors also show that this array fabrication
method can be used for fluorescence measurements on chemically
modified gold surfaces. H.J. Lee et al: Analytical Chemistry 2001
73:5525.

Related Background Brief:

DNA ELECTROCHEMICAL BIOSENSOR FOR THE DETECTION OF SHORT DNA
SEQUENCES RELATED TO THE HUMAN IMMUNODEFICIENCY VIRUS. The
authors describe an electrochemical biosensor for the detection
of short DNA sequences related to the human immunodeficiency
virus type 1 (HIV-1). The sensor relies on the immobilization and
hybridization of the 21- or 42-mer single-stranded
oligonucleotide from the HIV-1 U5 long terminal repeat (LTR)
sequence at carbon paste or strip electrodes. The extent of
hybridization between the complementary sequences is determined
by the enhancement of the chronopotentiometric peak of the
Co(phen)3(3+) indicator. Numerous factors affecting the probe
immobilization, target hybridization, and indicator binding
reactions are optimized to maximize the sensitivity and speed the
assay time. A detection limit of 4 x 10^(-9) M HIV-1 U5 LTR
segment is reported following a 30 min hybridization. The
hybridization biosensor format obviates the use of radioisotopes
common in radioactive methods for the detection of HIV-1 DNA. The
authors also report on the direct adsorptive chronopotentiometric
stripping measurements of trace levels of various HIV-1 DNAs. J.
Wang et al: Anal Chem 1996 68:2629.

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6. ON RADIATION IN THE TREATMENT OF CANCER.

A.L. Boyer et al (Stanford University, US) discuss radiation
treatment, the authors making the following points:

1) Research in physics has contributed directly and indirectly to
cancer therapy over the past century. Only months after their
discovery, x-rays were used to treat a patient with breast
cancer. The use of protons in radiation therapy is another
dividend from physics research. Other heavy particles, such as
neutrons, light ions (particularly carbon and neon), and pi
mesons have also been used for radiation therapy: With the
exception of pi mesons, which did not live up to their promise,
heavy particles continue to be investigated for their clinical
potential. These particles all have somewhat different biological
effects on cells.

2) At present, the most common radiotherapy treatment uses high-
energy x- rays. Shaped beams of x-rays are directed toward the
patient. The beams pass through the patient, undergoing near-
exponential attenuation as they interact with tissues, and
deposit dose along the way. (The strength or dose of radiation is
characterized by the energy imparted per unit mass. The unit of
dose is the gray; 1 Gy = 1 J/kg.) It is the interactions of
secondary electrons set loose by the primary interactions of the
x-rays that are the dominant cause of the molecular disruptions
that eventually lead to cell death.

3) Protons differ from high-energy x-rays in that they can
deliver radiation dose up to an energy-dependent depth, and
virtually none beyond it, whereas x-rays continue to penetrate
with near-exponentially decreasing intensity. One noteworthy
feature is the low x-ray dose in the first few millimeters due to
the lack of secondary electron buildup. The resulting skin
sparing can have beneficial clinical consequences not shared by
protons, particularly for shallow targets.

4) Radiation can cause lethal damage to cells. Secondary
electrons create highly reactive radicals in the intracellular
material. The radicals can chemically break bonds in the cellular
DNA, causing cells -- both the malignant cells one is trying to
render inactive and cells in the normal tissues that one wishes
to spare -- to lose their ability to reproduce. The higher the
dose, the greater the probability of killing cells.

Physics Today 2002 September

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7. SUSCEPTIBILITY GENES FOR MENTAL DISORDERS.

C. Robert Cloninger (Washington University St. Louis, US)
discusses mental disorders, the author making the following
points:

1) Research on the genetic basis of mental disorders recently
crossed a major watershed. For the first time, specific genes
have been discovered that influence susceptibility to
schizophrenia, a psychosis that affects nearly 1% of people
throughout the world and accounts for about 2.5% of health-care
costs (1). Chumakov et al (2) have described a new human gene,
G72, on chromosome 13q34 that interacts with the gene for D-amino
acid oxidase (DAAO) on 12q24 to regulate glutaminergic signaling
through the N-methyl-D-aspartate (NMDA) receptor pathway. Using
traditional positional cloning techniques of linkage and linkage
disequilibrium, they show that both of these genes are associated
with increased susceptibility to schizophrenia. Therefore, this
is the first discovery of a specific gene that also provides a
pathogenic molecular mechanism that can account for the major
symptoms of a psychiatric disorder. Similarly, two other groups
recently reported that the gene dysbindin on 6p22.3 (3) and the
gene neuregulin 1 on 8p (4) also influence susceptibility to
schizophrenia and may operate via the same NMDA mechanism.

2) Each of these gene discoveries came from association analysis
targeting chromosomal regions first identified by linkage
analysis. The success of groups working on three different
chromosomal regions of interest confirms the effectiveness of
traditional positional cloning techniques in complex mental
disorders. Consequently, these results justify optimism for
future progress in unraveling complex disorders in which there is
interaction among multiple genetic and environmental variables.
However, it is important to recognize both the strengths and the
limitations of the genetic and functional strategies used by
Chumakov et al (2). It is also important to recognize the
continuing significance of the prior work that laid the
foundation for these particular experiments.

3) Twin and adoption studies have demonstrated that
susceptibility to schizophrenia is strongly heritable even if
children are reared apart from their biological parents. When one
twin has schizophrenia, the risk of schizophrenia in the co-twin
is greater in monozygotic twins (45%) than in dizygotic twins
(15%). However, 40% of the monozygotic co-twins of a person with
schizophrenia are clinically normal (5). Furthermore, the risk of
illness decreases with degree of genetic relationship more
rapidly than can be explained by a single gene or the sum of
effects of several such genes. Thus, the inheritance pattern of
schizophrenia suggested that multiple genes, each of small
effect, interacted nonlinearly with one another and with
environmental factors to influence susceptibility. This
prediction has now been confirmed by more than 20 genome-wide
linkage scans in more than 1,200 families of schizophrenics.

References (abridged):

1. Meltzer, D. (1999) J. Clin. Psychiatry 60, Suppl. 3, 32-35.

2. Chumakov, I. , Blumenfeld, M. , Guerassimenko, O. , Cavarec,
L. , Palicio, M. , Abderrahim, H. , Bougueleret, L. , Barry, C. ,
Tanaka, H. , La Rosa, P. , et al. (2002) Proc. Natl. Acad. Sci.
USA 99, 13675-13680.

3. Straub, R. E. , Jing, Y. , MacLean, C. J. , Ma, Y. , Webb, B.
T. , Myakishev, M. V. , Harris-Kerr, C. , Wormley, B. , Sadek, H.
, Kadambi, B. , et al. (2002) Am. J. Hum. Genet. 71, 337-348.

4. Stefansson, H., Sigurdsson, E., Steinthorsdottir, V.,
Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J.,
Gunnarsdottir, S., Ivarsson, O., Chou, T. T., et al. (2002) Am.
J. Hum. Genet., in press.

5. Gottesman, I. I. & Shields, J. (1982) Schizophrenia: The
Epigenetic Puzzle (Cambridge Univ. Press, Cambridge, U.K.).

Proc. Nat. Acad. Sci. 2002 99:13365

Related Background Brief:

GENETIC AND PHYSIOLOGICAL DATA IMPLICATING THE NEW HUMAN GENE G72
AND THE GENE FOR D-AMINO ACID OXIDASE IN SCHIZOPHRENIA. The
authors report that a map of 191 single-nucleotide polymorphisms
(SNPs) was built across a 5-Mb segment from chromosome 13q34 that
has been genetically linked to schizophrenia. DNA from 213
schizophrenic patients and 241 normal individuals from Canada
were genotyped with this marker set. Two 1,400- and 65-kb regions
contained markers associated with the disease. Two markers from
the 65-kb region were also found to be associated to
schizophrenia in a Russian sample. Two overlapping genes G72 and
G30 transcribed in brain were experimentally annotated in this
65-kb region. Transfection experiments point to the existence of
a 153-aa protein coded by the G72 gene. This protein is rapidly
evolving in primates, is localized to endoplasmic reticulum/Golgi
in transfected cells, is able to form multimers and specifically
binds to carbohydrates. Yeast two-hybrid experiments with the G72
protein identified the enzyme D-amino acid oxidase (DAAO) as an
interacting partner. DAAO is expressed in human brain where it
oxidizes D-serine, a potent activator of N-methyl-D-aspartate
type glutamate receptor. The interaction between G72 and DAAO was
confirmed in vitro and resulted in activation of DAAO. Four SNP
markers from DAAO were found to be associated with schizophrenia
in the Canadian samples. Logistic regression revealed genetic
interaction between associated SNPs in vicinity of two genes. The
authors suggest that the association of both DAAO and a new gene
G72 from 13q34 with schizophrenia together with activation of
DAAO activity by a G72 protein product points to the involvement
of this N-methyl-D-aspartate receptor regulation pathway in
schizophrenia. Proc. Nat. Acad. Sci. 2002 99:13675.

Related Background Brief:

GENETIC VARIATION IN THE 6P22.3 GENE DTNBP1, THE HUMAN ORTHOLOG
OF THE MOUSE DYSBINDIN GENE, IS ASSOCIATED WITH SCHIZOPHRENIA.
Prior evidence has supported the existence of multiple
susceptibility genes for schizophrenia. Multipoint linkage
analysis of the 270 Irish high-density pedigrees studied by the
authors, as well as results from several other samples, suggest
that at least one such gene is located in region 6p24-21. In the
present study, family-based association analysis of 36 simple
sequence-length-polymorphism markers and of 17 SNP markers
implicated two regions, separated by approximately 7 Mb. The
first region, and the focus of this report, is 6p22.3. In this
region, single-nucleotide polymorphisms within the 140-kb gene
DTNBP1 (dystrobrevin-binding protein 1, or dysbindin) are
strongly associated with schizophrenia. Uncorrected empirical P
values produced by the program TRANSMIT were significant (P<.01)
for a number of individual SNP markers, and most remained
significant when the data were restricted to include only one
affected offspring per nuclear family per extended pedigree;
multiple three-marker haplotypes were highly significant (P=.008-
.0001) under the restricted conditions. The pattern of linkage
disequilibrium is consistent with the presence of more than one
susceptibility allele, but this important issue is unresolved.
The number of markers tested in the adjacent genes, all of which
are negative, is not sufficient to rule out the possibility that
the dysbindin gene is not the actual susceptibility gene, but
this possibility appears to be very unlikely. The authors
conclude that further investigation of dysbindin is warranted.
R.E. Straub et al: Am J Hum Genet 2002 71:337.

Related Background Brief:

MULTICENTER LINKAGE STUDY OF SCHIZOPHRENIA CANDIDATE REGIONS ON
CHROMOSOMES 5Q, 6Q, 10P, AND 13Q: SCHIZOPHRENIA LINKAGE
COLLABORATIVE GROUP III. The authors report that schizophrenia
candidate regions 33-51 cM in length on chromosomes 5q, 6q, 10p,
and 13q were investigated for genetic linkage with mapped markers
with an average spacing of 5.64 cM. The authors studied 734
informative multiplex pedigrees (824 independent affected sibling
pairs [ASPs], or 1,003 ASPs when all possible pairs are counted),
which were collected in eight centers. Cases with diagnoses of
schizophrenia or schizoaffective disorder (DSM-IIIR criteria)
were considered affected (n=1,937). Data were analyzed with
multipoint methods, including nonparametric linkage (NPL), ASP
analysis using the possible-triangle method, and logistic-
regression analysis of identity-by-descent (IBD) sharing in ASPs
with sample as a covariate, in a test for intersample
heterogeneity and for linkage with allowance for intersample
heterogeneity. The data most supportive for linkage to
schizophrenia were from chromosome 6q; logistic-regression
analysis of linkage allowing for intersample heterogeneity
produced an empirical P value <.0002 with, or P=.0004 without,
inclusion of the sample that produced the first positive report
in this region; the maximum NPL score in this region was 2.47
(P=.0046), the maximum LOD score (MLS) from ASP analysis was 3.10
(empirical P=.0036), and there was significant evidence for
intersample heterogeneity (empirical P=.0038). More-modest
support for linkage was observed for chromosome 10p, with
logistic-regression analysis of linkage producing an empirical
P=. 045 and with significant evidence for intersample
heterogeneity (empirical P=.0096). D.F. Levinson et al: Am J Hum
Genet 2000 67:652.

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8. ON MOTOR FUNCTION IN CEREBRAL PALSY.

P.L. Rosenbaum et al (McMaster University, CA) discuss cerebral
palsy, the authors making the following points:

1) Cerebral palsy occurs in every to 2/1000 to 2.5/1000 live
births.(1) It is "... an umbrella term covering a group of non-
progressive, but often changing, motor impairment syndromes
secondary to lesions or anomalies of the brain arising in the
early stages of development."(2) Thus, whatever additional
developmental difficulties individuals with cerebral palsy might
have as a result of impairment of the developing central nervous
system, the hallmark of these conditions is a disorder in the
development of gross motor function.

2) When first told that their child has cerebral palsy (generally
in the child's first 18 months of life), parents usually want to
know its severity and whether their child will ever be able to
walk. The evidence on which to base answers was, until recently,
limited to observations about the association between
constellations of reflex and early motor skills at age 2 years
and walking at a later age(3); or on motor milestones such as
sitting between the ages of 2 and 4 years and walking at a later
age. However, the findings based on even these simple markers are
conflicting.(4,5) Crude estimates of the probability of being
able to walk 10 steps unaided at or after age 5 years vary for
different clinical types of cerebral palsy. These observations
derive from clinic samples and are likely not representative of
the entire population of children with cerebral palsy.

3) Cross-sectional studies of motor behavior in children with
cerebral palsy have demonstrated characteristic patterns of motor
development according to severity of the condition, although the
descriptions of severity previously used have been crude and
unsystematic. The motor growth curves created by Palisano et al
(2000), which are based on cross-sectional population data
stratified by severity using the validated Gross Motor Function
Classification System (GMFCS) for cerebral palsy, are an
important improvement.

4) The authors report patterns of gross motor development of a
community-based sample of children with cerebral palsy followed
up prospectively. The authors used the GMFCS to longitudinally
create curves charting the rates and limits of motor function by
severity of motor impairment. The authors conclude: Evidence-
based prognostication about gross motor progress in children with
cerebral palsy is now possible, providing parents and clinicians
with a means to plan interventions and to judge progress over
time. Further work is needed to describe motor function of
adolescents with cerebral palsy.

References (abridged):

1. Stanley FJ, Blair E, Alberman E. Cerebral Palsies:
Epidemiology & Causal Pathways. London, England: Mac Keith Press;
2000:29.

2. Mutch LW, Alberman E, Hagberg B, Kodama K, Velickovic MV.
Cerebral palsy epidemiology. Dev Med Child Neurol. 1992;34:547-
555.

3. Bleck EE. Locomotor prognosis in cerebral palsy. Dev Med Child
Neurol. 1975;17:18-25.

4. Molnar GE, Gordon SV. Predictive value of clinical signs for
early prognostication of motor function in cerebral palsy. Arch
Phys Med Rehabil. 1974;57:153-158.

5. Watt JM, Robertson CM, Grace MG. Early prognosis for
ambulation of neonatal intensive care survivors with cerebral
palsy. Dev Med Child Neurol. 1989;31:766-773.

J. Am. Med. Assoc. 2002 288:1357

Related Background Brief:

EARLY PROGNOSIS FOR AMBULATION OF NEONATAL INTENSIVE CARE
SURVIVORS WITH CEREBRAL PALSY. The ambulatory status of 74
neonatal intensive care unit survivors with cerebral palsy,
excluding those with central nervous system malformations and
syndromes, was assessed at eight years of age. Detailed
examinations were completed at two and eight years of age; of the
47 who were sitting by two years, 46 became ambulatory, and a
total of 47 of the 74 children became ambulatory. The clinical
type of cerebral palsy at two years of age related significantly
to eight-year ambulation. However, between two and eight years
the diagnosis was changed for 18 children. At two years of age
the tonic labyrinthine, asymmetrical and symmetrical tonic neck
and Moro reflexes related significantly to ambulation; in five of
27 children not walking, these reflexes were absent by two years
of age. Foot placement and/or parachute reactions at two years
were found in more than one-third of children not walking.
Multivariate analysis determined that age at sitting explained 91
per cent of the variance in ambulation. No other variables,
combined with sitting, increased this prediction. J.M. Watt et
al: Dev Med Child Neurol 1989 31:766.

Related Background Brief:

OUTCOMES AFTER SELECTIVE DORSAL RHIZOTOMY FOR SPASTIC CEREBRAL
PALSY. OBJECT: The authors report a study the purpose of which
was to review the published outcomes after selective dorsal
rhizotomy (SDR) for treatment of spastic cerebral palsy. A
literature search identified all articles related to outcomes
after SDR. The outcomes were reviewed according to a paradigm
developed by the National Center for Medical Rehabilitation
Research (NCMRR). The quality of the evidence for each outcome
was assessed using Sackett's criteria and the classification
system developed by the Brain Trauma Foundation and the American
Association of Neurological Surgeons. Results: There is very
strong evidence for benefits of SDR in the impairment domain of
the NCMRR classification. SDR has been shown conclusively to
decrease lower limb spasticity and increase lower limb range of
motion. There is strong, but not as conclusive evidence that SDR
has a positive impact in the functional limitation dimension,
with improvements in motor function, and in particular the Gross
Motor Function Assessment (GMFM). There is a moderate degree of
certainty that SDR results in improvements in the disability
dimension, as evidenced particularly by improvements in the
Functional Independence Measure for Children (WeeFIM) and
Pediatric Evaluation of Disability Inventory (PEDI). There is a
moderate degree of certainty that SDR results in positive
suprasegmental effects, especially related to upper limb function
and cognition. There is weak evidence that SDR may reduce the
need for orthopedic procedures in patients with spastic cerebral
palsy, and the impact on hip subluxation relative to the natural
history of this problem is unclear. The authors conclude: This
information could help to define the role of SDR in the
management of the child with spastic cerebral palsy, in the light
of alternative therapies, such as intrathecal baclofen and
botulinum toxin, which have been introduced more recently. The
authors suggest the results also reveal the need for further
studies, particularly dealing with quality of life and economic
impact. P. Steinbok: Childs Nerv Syst 2001 17:1.

Related Background Brief:

EVALUATION OF BOTULINUM TOXIN A THERAPY IN CHILDREN WITH ADDUCTOR
SPASM BY GROSS MOTOR FUNCTION MEASURE. Intramuscular injection of
botulinum neurotoxin A is a relatively new method for treating
spastic movement disorders in children. One major goal of any
therapy for patients with movement disorders is to improve gross
motor function. In this study, 18 patients with adductor spasm
were treated with botulinum neurotoxin A. Treatment effect was
determined with the Gross Motor Function Measure, a standardized,
validated instrument designed to assist in assessment of gross
motor function. Spastic muscle hyperactivity and joint mobility
were evaluated by the modified Ashworth Scale and by range of
motion, respectively. Compared to pretreatment values,
significant improvement in gross motor function (P < .010),
decrease in the modified Ashworth Scale, and increase in the
range of motion (P < .010) were achieved. Patients with moderate
impairment of gross motor function (classed at level III and
level IV in the Gross Motor Function Classification System)
benefited most from treatment. In patients with severe handicap
(level V), only one of five treated patients showed improvement
in gross motor function. Nevertheless, all patients in this
subgroup benefited from improved ease in hygienic care. In
conclusion, we have demonstrated that for most children with
moderate functional impairment, the Gross Motor Function Measure
is a useful instrument for objective documentation of
improvements of gross motor function following treatment with
botulinum neurotoxin A. V. Mall et al: J Child Neurol 2000
15:214.

Related Background Brief:

MULTIDIMENSIONAL ASSESSMENT OF MOTOR FUNCTION IN A CHILD WITH
CEREBRAL PALSY FOLLOWING INTRATHECAL ADMINISTRATION OF BACLOFEN.
The authors present a case report describing an 11-year-old boy
with spastic diplegia whose reflex status, range of motion (ROM),
strength, and motor performance were measured before and after
implantation of an indwelling system for delivery of
intrathecally administered baclofen. Before baclofen use, the
subject experienced clonus that interfered with walking, needed
assistance with transfers, and was unable to independently put on
underwear and socks. Measures of spasticity, kinematics and
electromyographic activity during voluntary movements, ROM, Gross
Motor Function Measure (GMFM) scores, and self-reports of change
were obtained at baseline, before and after bolus baclofen
injection, during a double-blind placebo-controlled clinical
trial of baclofen administration via an indwelling pump, and
after 1 and 2 years of baclofen therapy. Spasticity, Babinski
reflexes, clonus, strength, and coactivation of antagonist
muscles during voluntary movement were decreased shortly after
baclofen administration began. Hip and ankle ROM increased,
upper-extremity movement speed increased, independence in
dressing and transfers improved, and orthoses were discarded.
After 1 and 2 years, GMFM scores were 7.8% and 6.4% above
baseline, respectively; the subject won a fitness award. After 2
years, ROM was worse than at baseline and concerns regarding hip
subluxation arose. Single-joint movement control and independence
improved and spasticity decreased during baclofen administration.
G.L. Almeida et al: Phys Ther 1997 77:751.

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