ScienceWeek

SCIENCEWEEK

ScienceWeek - July 26, 2002 Vol. 6 Number 30

An Online Research Digest Published Weekly Since 1997

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We must never conceal from ourselves that our concepts are
creations of the human mind which we impose on the facts of
nature, that they are derived from incomplete knowledge and
therefore will never _exactly_ fit the facts, and will require
constant revision as knowledge increases.
-- A.G. Tansley (1871-1955)

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Section 1

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1. On the Composition of the Earth

2. An Observation of Chiral Recognition

3. On Sonoluminescing Bubbles

4. On Plant Cytokinesis

5. On Chromatin Dynamics

6. Enzymes and Global Change

7. On Electrolytic Actuators

8. Lanthanide Complexes and Asymmetric Catalysis

9. On a Large-Scale Ion-Trap Quantum Computer

10. On Atrial Fibrillation

11. On Vitamins for Chronic Disease Prevention in Adults

12. On Protein Misfolding Diseases

13. In Focus: On the Physics of Diffusion

14. New Books

15. Position Open: University of California Davis, US

16. Fellowship Open: National Institutes of Health

17. ScienceWeek Notices and Subscription Information

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Section 2

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1. ON THE COMPOSITION OF THE EARTH

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)

"Planetesimals" 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. As the mass of the agglomerate
increases, so does the rate of accretion, and this accretion
process is believed to generally occur in the form of a disk. A
stellar accretion disk is a swarm of dust grains that evolve
into planetesimals and then planets.

Meteorites are divided roughly into 3 main classes according to
their composition. "Iron meteorites" consist of an alloy of iron
and nickel; "stony meteorites" consist of silicate minerals; and
"iron-stony meteorites" are a mixture of the two previous types.
The stony meteorites are further divided into "chondrites" and
"achondrites". Chondrites contain small spherules of
high-temperature silicates ("chondrules") and constitute more
than 85 percent of recovered meteorites. The achondrites (which
contain no chondrules) range in composition from rocks made up
essentially of single minerals (e.g., olivine) to rocks
resembling basaltic lava. Each category is further subdivided on
the basis of chemical composition. (The olivines are a group of
metal-silicate minerals, with the metal as magnesium, iron,
manganese, and calcium, with minor amounts of nickel. The most
common form is a solid solution of magnesium silicate and iron
silicate.)

M.J. Drake and K. Righter (University of Arizona, US) discuss
the composition of the Earth and make the following points:

1) Most researchers assume implicitly that the Earth is made of
some sort of extant primitive material delivered to the Earth as
meteorites and probably originating in the asteroid belt.
Indeed, much has been learned from meteorites about the
materials present and processes occurring in the accretion disk
as the planets grew. However, confusion is caused by the
convenient reference of terrestrial rock abundances to CI
chondrites or just 'chondrites', leading to an unintended
perception that the Earth must be made of such materials.

2) The formation of the Earth has been debated in terms of
heterogeneous accretion versus homogeneous accretion, with the
former holding sway for the last 25 years or so. Heterogeneous
accretion, as most prominently championed by Waenke(1),
envisioned the material accreting to the Earth changing in
composition and oxidation state with time. Driven by the
"stair-step" distribution of siderophile (metal-seeking)
elements in the terrestrial upper mantle, Waenke(1) suggested
that the first 80% to 90% of the Earth accreted from very
reducing materials. All elements except the refractory
lithophile elements such as Sc and the rare earth elements would
be quantitatively extracted into the core, and the mantle would
be devoid of Fe2+. The next 20% to 10% or so of material
accreting to the Earth would be more oxidizing, and all but the
highly siderophile elements (Ir, Os, Au and so on) would remain
stranded in the mantle. The highly siderophile elements were
again quantitatively extracted into the core. The last roughly
1% added (the "late veneer"(2)) was so oxidizing that metallic
Fe did not exist (note that CI chondrites(3) and Tagish Lake(4)
are the only chondrites containing no metal(3), and all
siderophile elements delivered by the "late veneer" were forced
to remain in the mantle, where they were very efficiently
homogenized at the hand-specimen (centimeter) scale on a global
basis. The stair-step pattern of siderophile elements is thus
explained. We note that the term "late veneer" is unfortunate,
as the last dregs of material accreted to Earth are well mixed
into at least the upper mantle, rather than veneering the
surface. The term is, however, entrenched in the literature.

3) The heterogeneous accretion hypothesis makes dynamical sense
in that the "feeding zone" of the Earth must have extended
further out from the Sun as the growth of planets, particularly
Jupiter, increased the relative velocities and hence the
eccentricities of the accreting material. However, there is a
general consensus5 that the Earth developed one or more magma
oceans late in its accretion, effectively homogenizing any
pre-existing material. Thus, there is unlikely to be any record
of heterogeneous accretion remaining, with the possible
exception of the "late veneer". The bulk geochemical properties
of the Earth were probably established by magmatic processes in
a high-pressure and high-temperature magma ocean environment.

4) In summary: A long-standing question in the planetary
sciences asks what the Earth is made of. For historical reasons,
volatile-depleted primitive materials similar to current
chondritic meteorites were long considered to provide the
"building blocks" of the terrestrial planets. But material from
the Earth, Mars, comets and various meteorites have Mg/Si and
Al/Si ratios, oxygen-isotope ratios, osmium-isotope ratios and
D/H, Ar/H2O and Kr/Xe ratios such that no primitive material
similar to the Earth's mantle is currently represented in our
meteorite collections. The "building blocks" of the Earth must
instead be composed of unsampled "Earth chondrite" or "Earth
achondrite".(5)

References (abridged):

1. Waenke, H. Constitution of terrestrial planets. Phil. Trans.
R. Soc. Lond. 303, 287-302 (1981)

2. Chou, C.-L. Fractionation of siderophile elements in the
Earth's upper mantle. Proc. Lunar Planet. Sci. Conf. 9, 219-230
(1978)

3. Brearley, A. J. & Jones, R. H. in Planetary Materials.
Reviews in Mineralogy Vol. 36 (ed. Papike, J. J.) 3-1-3-398 (The
Mineralogical Society of America, Washington DC, 1998)

4. Brown, P. G. et al. The fall, recovery, orbit, and
composition of the Tagish Lake meteorite: a new type of
carbonaceous chondrite. Science 290, 320-325 (2000)

5. Drake, M. J. Accretion and primary differentiation of the
Earth: a personal journey. Geochim. Cosmochim. Acta 64,
2363-2370 (2000)

Nature 2002 416:39

Web Links: Earth formation

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2. AN OBSERVATION OF CHIRAL RECOGNITION

In general, chirality is a property of certain asymmetric
objects such that the object and its mirror image cannot be
superimposed one on the other while both objects are restricted
to the same plane (e.g., a left- and right-handed glove). In
chemistry, chiral molecules are optically active, a phase of
each form rotating the plane of incident polarized light. The
two possible forms are called "optical isomers", and each form
is called an "enantiomer". An equal mixture of the two forms is
called a "racemic mixture". "Homochirality" is the preference of
a process or system for a single optical isomer in a pair of
isomers. Optically active substances are termed "dextrorotatory"
(the D- form; the + form) or "levorotatory" (the L- form; the -
form) according to whether the plane of polarization of the
incident polarized light is rotated to the right or to the left
with respect to the direction of incidence of the light. In
biology, one of the great puzzles is that nearly all amino acids
in biological systems are of the L- form, while nearly all
sugars are of the D- form (glycine is the only biological amino
acid that is not chiral), and the puzzle is how did this arise?

First available in the early 1980s, the technique of "scanning
tunneling microscopy" involves an atomically sharp metal tip
brought in atomic proximity (e.g., 0.5 to 1 nanometer) to a flat
surface so that electrons can "tunnel" between the two systems.
Recording the atomic modulation of the atomic structure which
scanning the tip across the surface allows one to image adsorbed
species and surface morphologies. "Tunneling" is a quantum
mechanical phenomenon involving an effective penetration of an
energy barrier resulting from the width of the barrier being
less than the wavelength of the particle. "Scanning probe
microscopy" is a general term comprising all atomic-level probe
techniques.

For atomic force calculations on solids, the current method of
choice is "density functional theory", due to Kohn, Hohenberg,
and Sham. Its name comes from its predicted connection between
the total ground state electronic energy of a system and the
electronic charge density. The theory was first proposed in
1964, and has since been useful as a simplifying alternative to
more rigorous but intractable many-electron wavefunction
calculations. In general, in density functional theory, it is
the electron density which is the fundamental variable: the
ground state of a system is defined by that electron density
distribution which minimizes the total energy. In this approach,
once the ground state electron density is known, all other
ground state properties (lattice constants, cohesive energies,
etc.) follow, at least in principle. In mathematics, a
"functional" is a function whose value depends on the set of all
values of another function. In density functional theory, the
ground state properties of a system are functionals of the
ground state electron density function.

A. Kuehnle et al (University of Aarhus, DK) discuss chiral
recognition and make the following points:

1) Stereochemistry plays a central role in controlling molecular
recognition and interaction: the chemical and biological
properties of molecules depend not only on the nature of their
constituent atoms but also on how these atoms are positioned in
space. Chiral specificity is consequently fundamental in
chemical biology and pharmacology(1, 2) and has accordingly been
widely studied. Advances in scanning probe microscopy now make
it possible to probe chiral phenomena at surfaces at the
molecular level. These methods have been used to determine the
chirality of adsorbed molecules(3-5), and to provide direct
evidence for chiral discrimination in molecular interactions and
the spontaneous resolution of adsorbates into extended
enantiomerically pure overlayers(3).

2) The mercapto or thiol group -SH binds to gold with high
affinity, and a rich literature on the adsorption of
self-assembled thiol monolayers on gold surfaces exists. Of the
20 naturally occurring amino acids, only cysteine
(HS-CH2-CH(NH2)-COOH) contains a mercapto substituent, making
this chiral amino acid interesting for studying adsorption on
gold surfaces.

3) The authors report scanning tunneling microscopy studies of
cysteine adsorbed to a (110) gold surface, which show that
molecular pairs formed from a racemic mixture of this naturally
occurring amino acid are exclusively homochiral, and that their
binding to the gold surface is associated with local surface
restructuring. Density-functional theory calculations indicate
that the chiral specificity of the dimer formation process is
driven by the optimization of three bonds on each cysteine
molecule. The authors suggest these findings provide a clear
molecular-level illustration of the well known three-point
contact model for chiral recognition in a simple bimolecular
system.

References (abridged):

1. Sheldon, R. A. Chirotechnology 39-72 (Dekker, New York/Basel,
1993).

2. Cline, D. B. Physical Origin of Homochirality in Life 17-49
(AIP Press, Woodbury, New York, 1996).

3. Fang, H., Giancarlo, L. C. & Flynn, G. W. Direct
determination of the chirality of organic molecules by scanning
tunneling microscopy. J. Phys. Chem. 102, 7311-7315 (1998).

4. Lopinski, G. P., Moffatt, D. J., Wayner, D. D. M. & Wolkow,
R. A. Determination of the absolute chirality of individual
adsorbed molecules using the scanning tunneling microscope.
Nature 392, 909-911 (1998).

5. Böhringer, M., Morgenstern, K., Schneider, W.-D. & Berndt, R.
Separation of a racemic mixture of two-dimensional molecular
clusters by scanning tunneling microscopy. Angew. Chem. Int. Edn
38, 821-823 (1999).

Nature 2002 415:891

Web Links: chiral recognition

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3. ON SONOLUMINESCING BUBBLES

R. Toegel et al (University of Twente, NL) discuss
sonoluminescing bubbles and make the following points:

1) A violently collapsing gas bubble can emit short flashes of
light so intense as to be visible to the naked eye. Stable
clocklike light emission from an isolated gas bubble known as
single-bubble sonoluminescence was first reported in 1990 [1]
and has been studied extensively since [2-4]. The probable
origin of single-bubble sonoluminescence light emission has been
identified as thermal bremsstrahlung and recombination radiation
from the optically thin bubble heated to a few 10^(4) K peak
temperature [5]. Recently, it has been pointed out that water
vapor may significantly reduce the heating at collapse of the
bubble. Water vapor invades and escapes the bubble as it expands
and collapses. However, the final phase of collapse is so fast
that vapor cannot readily diffuse to the bubble wall to maintain
the equilibrium composition. Thus, a considerable portion of
vapor is trapped, which acts to reduce heating in two ways: (a)
As the rest of the bubble consists largely of noble gas, the
presence of water reduces the effective adiabatic exponent of
the mixture, restricting the maximum temperature of the bubble
to about 15 000-20 000 K. These temperatures are nevertheless
sufficiently high for thermal bremsstrahlung emission. (b)
Taking chemical reactions of the water vapor into account
drastically decreases the temperature since most of the
reactions are endothermic and hence consume a major part of the
thermal energy of the bubble. At the residual temperature of
6000-8000 K, hardly any thermal bremsstrahlung or recombination
radiation would occur. These temperature calculations rely on
chemical reaction rates and chemical equilibrium data that were
taken under conditions much less extreme than those in a
collapsed single-bubble sonoluminescence bubble, where the gas
reaches almost solid state density. There is therefore some
uncertainty about the quantitative results.

2) The authors report an attempt at a more fundamental approach
to obtain reaction rates for high-density gases. They find
significant suppression of chemical reactions under typical
sonoluminescence conditions, resulting in sufficiently high peak
temperatures for light emission. Qualitatively, the mechanism at
work is Le Chatelier's principle applied to a reactive van der
Waals gas: dissociated water vapor molecules in the bubble take
up more space than undissociated molecules. When the bubble
volume becomes comparable to the excluded volume of the gas
molecules, little free space remains, favoring the undissociated
state.

References (abridged):

1. D. F. Gaitan, Ph.D. thesis, University of Mississippi, 1990.

2. L.A. Crum, Phys. Today 47, No. X, 22 (1994).

3. B. P. Barber, R. A. Hiller, R. Lofstedt, S. J. Putterman, and
K.R. Weninger, Phys. Rep. 281, 65 (1997).

4. D. Hammer and L. Frommhold, J. Mod. Opt. 48, 239 (2001).

5. B. Gompf, R. Gunther, G. Nick, R. Pecha, and W. Eisenmenger,
Phys. Rev. Lett. 79, 1405 (1997).

Phys. Rev. Lett. 2002 88:034301

Web Links: sonoluminescence

Related Background:

EVIDENCE FOR NUCLEAR EMISSIONS DURING ACOUSTIC CAVITATION

In general, the term "cavitation" refers to the formation of
gas- or vapor-filled cavities in liquids in motion when the
pressure is reduced to a critical value while the ambient
temperature remains constant.

R.P. Taleyarkhan et al (Oak Ridge National Laboratory, US
discuss acoustic cavitation, the authors making the following
points:

1) The intense implosive collapse of gas or vapor bubbles,
including acoustically forced cavitation bubbles, can lead to
ultrahigh compressions and temperatures and to the generation of
light flashes attributed to sonoluminescence. The authors report
a study of ultrahigh compression and temperatures in bubbles
nucleated by means of fast neutrons, whereby bubble nucleation
centers with an initial radius of 10 to 100 nanometers are
created, and the bubbles grow in an acoustic field to a maximum
radius of approximately 1 millimeter before an implosive
collapse. This report builds on observations that increasing the
maximum radius modestly (e.g., by 50 percent), or increasing the
rate of collapse, can result in very large increases in peak gas
temperatures and produce light emission during implosions. In
contrast to single-bubble experiments, in which the initial
bubble radius typically increases to the maximum bubble radius
by a factor of only approximately 10 (e.g., from 10 microns to
100 microns), the neutron-induced nucleation technique used by
the authors results in bubble-radius increases of approximately
10^(5). For a spherical bubble, a radius-ratio increase by a
factor of 10^(4) implies a related volumetric-ratio increase of
10^(12) over that produced by conventional cavitation
techniques. The authors state their expectation was that such an
approach, with its vastly increased energy concentration
potential during implosions, should give rise to significant
increases in the peak temperatures within the imploding bubbles,
leading to fusion and detectable levels of nuclear particle
emissions in suitable fluids.

2) The authors report that in such cavitation experiments with
deuterated acetone, tritium decay activity above background
levels was detected. In addition, evidence for neutron emission
near 2.5 million eV was also observed, as would be expected by
deuterium-deuterium fusion. Control experiments with normal
acetone did not result in tritium activity or neutron emissions.
Hydrodynamic shock code simulations supported the observed data
and indicated highly compressed and hot (10^(6) to 10^(7)
kelvins) bubble implosion conditions, as required for nuclear
fusion reactions.

Science 2002 295:1868

Editor's note: This paper has caused considerable controversy in
the physics community, including reported pressure against the
journal _Science_ not to publish the paper. In an editorial on
the paper, the editor of the journal, Donald Kennedy, states:
"We see no good reason for abandoning our plans to publish the
paper, and we can see no merit whatsoever in the efforts to
discredit it in advance. Both the premature critics and those
who believe in the result would do well to wait for the
scientific process to do its work." ScienceWeek fully concurs,
particularly since the experimental results reported above were
already theoretically predicted nearly 5 years ago, as indicated
below.

Related Background:

SONOLUMINESCENCE MODEL SUGGESTS THERMONUCLEAR FUSION POSSIBILITY

Sonoluminescence is an energy transduction phenomenon associated
with the nucleation, growth, and collapse of small gas-filled
bubbles in a liquid, the transduction involving the conversion
of sound (mechanical) energy to light energy, which means the
conversion of energy of motion to light energy. The luminescence
is extremely short in duration, =< 50 picoseconds [10^(-12)
seconds], and synchronous with the periodic acoustic driving
field. Experimental measurements of the spectra of the emitted
light pulses reveal interior gas temperatures as great as the
surface of the sun and maybe as much as a million degrees
centigrade. There is no question about the experimental
observations: the luminescence occurs, it can be measured, it
can be altered by doping the bubbles with various noble gases.
Experiments can also be done with a single levitated bubble,
rather than with a population of bubbles, and in this case the
experimental observations are quantitatively but not
qualitatively different. The problem for physicists has been to
explain the phenomenon, and there are half a dozen different
theories ranging from the sonoluminescing bubble as a
macroscopic demonstration of quantum vacuum radiation to the
idea that the sonoluminescing bubble is a microscopic high
temperature reaction chamber. This week William C. Moss et al
(Lawrence Livermore National Laboratory, Livermore CA US)
presented a mathematical model of the single sonoluminescing
bubble as a thermally conducting, partially ionized,
two-component plasma, and the calculations from this model
appear to be consistent with the idea that the sonoluminescent
bubble may indeed be a high temperature reaction chamber in
which temperatures as high as a million degrees centigrade may
be achieved, at which temperatures thermonuclear fusion would be
possible. The result has caused excitement in the physics
community.

Science 1997 30 May

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4. ON PLANT CYTOKINESIS

Laurie G. Smith (University of California San Diego, US)
discusses plant cytokinesis and makes the following points:

1) Cytokinesis in most plant tissues is achieved through the
formation of a new cell wall between the daughter nuclei from a
recently completed mitosis [1] . A cytoskeletal structure called
a phragmoplast acts as a scaffold to guide the movement of
Golgi-derived vesicles containing cell-wall components to its
equator, where fusion of the vesicles initiates the formation of
a new cell wall (called a cell plate while under construction).
Each half of the barrel-shaped phragmoplast contains a dense
array of short, parallel microtubules oriented with their "plus"
ends interdigitating at the phragmoplast equator. It has long
been thought that vesicles are driven along phragmoplast
microtubules to the site of cell plate formation by a
plus-end-directed motor protein. A number of kinesins have been
localized to phragmoplasts, but until recently no good
candidates for a vesicle-translocating motor had been identified
[2] . Two recent studies have now identified candidates for such
a motor, which may be one and the same protein [3,4].

2) To complete cytokinesis, the phragmoplast expands laterally
until the cell plate reaches the parental wall and plasma
membrane, while microtubules disappear from the center of the
phragmoplast where the cell plate was initiated earlier. A
recent study shows that another kinesin-like protein is required
for the proper completion of cytokinesis, and implicates this
kinesin in the coordination of cell-plate formation with removal
of microtubules from the center of the expanding phragmoplast.

3) Ultrastructural analysis of cell-plate formation in the
developing endosperm (part of the seed) reported by Otegui et
al. [3] has provided new evidence for the involvement of a
kinesin in vesicle transport to the cell plate. In the
endosperm, multiple rounds of mitosis without cytokinesis
initially create a syncitium, which is later cellularized as
cytokinesis almost simultaneously partitions each nucleus into a
separate cell . Syncitial-type cell-plate formation in the
endosperm is initiated by "mini phragmoplasts" of microtubules
that radiate from the surfaces of neighboring nuclei. Otegui et
al. [3] used dual-axis high-voltage electron tomography to
analyze high pressure-frozen freeze-substituted samples of
developing Arabidopsis endosperm, which permitted the
construction of high-resolution, three-dimensional images
revealing features of cell-plate formation that had not been
seen previously. One such feature is the linkage of most
vesicles in the phragmoplast to microtubules via a pair of
kinked, rod-shaped structures. These connecting elements
resemble the kinesin molecules seen in earlier studies linking
latex beads incubated with kinesin to microtubules, and linking
membrane-bounded organelles to microtubules in neurons .

References (abridged):

1. Verma D.P.S. (2001) Cytokinesis and building of the cell
plate in plants. Annu. Rev. Plant Physiol. Plant Mol. Biol.,
52:751-784.

2. Liu B. and Lee Y.R.J. (2001) Kinesin-related proteins in
plant cytokinesis. J. Plant Growth Regul., 20:141-150.

3. Otegui M.S., Mastronarde D.N., Kang B.-H., Bednarek S.Y. and
Staehelin L.A. (2001) Three-dimensional analysis of
syncitial-type cell plates during endosperm cellularization
visualized by high resolution electron tomography. Plant Cell,
13:2033-2051.

4. Lee Y.-R. J., Giang H.M. and Liu B. (2001) A novel plant
kinesin-related protein specifically associates with the
phragmoplast organelles. Plant Cell, 13:2427-2439.

5. Strompen G., El Kasmi F., Richter S., Lukowitz W., Assaad
F.F., Jürgens G. and Mayer U. (2002) The Arabidopsis HINKEL gene
encodes a kinesin-related protein involved in cytokinesis and is
expressed in a cell cycle-dependent manner. Curr. Biol.,
12:153-158.

Current Biology 2002 12:R206

Web Links: plant cytokinesis

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5. ON CHROMATIN DYNAMICS

Susan M. Gasser (University of Geneva, CH) discusses chromatin
dynamics and makes the following points:

1) The visualization of chromatin in living cells has long
challenged cell biologists. In contrast to its successful
application to metaphase chromosome structure, electron
microscopy revealed little about the functional organization of
interphase chromatin. However, thanks to a bacterial
repressor/operator interaction and naturally fluorescing
proteins [e.g., green fluorescent protein (GFP)], recent
breakthroughs in high-resolution analysis of nuclear
organization have been possible. The genomic integration of lac
operator arrays in eukaryotic cells that express a GFP-lac
repressor fusion permits the tracking of specific chromosomal
sites by real-time fluorescence microscopy (1). The integrated
binding sites can cover as little as 2 kb in a yeast chromosome
(2), and both nuclease and functional analyses suggest that the
inserts do not substantially alter local chromatin structure
(3). By combining these chromosomal tags with a GFP-labeled
nuclear pore protein, one can obtain high-resolution information
on the movement of a given locus in relation to the nuclear
envelope.

2) The initial surprise from this approach was the extremely
dynamic behavior that chromatin exhibits in both yeast and
Drosophila nuclei (4,5). The characterization of these rapid
movements required high-speed image acquisition by either
charge-coupled device-based deconvolution or scanning confocal
microscopy. In the model systems explored to date, fluorescence
and transmission imaging were combined to characterize the
tagged cell with respect to its division cycle or
differentiation pathway. In the first example of high-resolution
tracking, a tagged site inserted near the telomere of the X
chromosome was examined in Drosophila spermatocytes (5). These
nuclei expanded markedly in size as the cells progressed through
a prolonged G2 phase, before the first prophase of their meiotic
division. A second system made use of mitotically dividing
budding yeast, in which multiple loci (including a centromere, a
telomere, and two internal chromatin sites) were tagged in
different strains. In yeast, large rapid movements (>0.5 microns
in a 10-sec interval) were observed for the internal chromosomal
loci in G1- and S-phase nuclei. Smaller, saltatory movements
(<0.2 microns) occur throughout interphase in both yeast and
flies, whereas the large rapid movements are most frequent in
the G1 phase, occurring on average once per minute in yeast.
Given that the size of the GFP signal and the focal resolution
of fluorescence microscopy both range from 0.2 to 0.3 microns,
these shorter distances are difficult to characterize by light
microscopy. In contrast, the half-micron movements were
striking, representing movement across half the radius of a
yeast nucleus, a distance equivalent to roughly 100 kb of folded
chromatin [based on a linear compaction ratio of approximately
70-fold].

3) What is the importance of this unexpected chromatin mobility?
Is the motion a result of an active process -- energy-dependent
or motor-driven? Does it reflect the impact of the cytoskeleton
or other cytoplasmic structures on the nucleus? Are the
movements directed, or is the DNA on a random, diffusive walk?
Most importantly, can such motion be linked to specific nuclear
activities? The initial studies have provided nearly as many
questions as answers and reveal the need for new models for
nuclear organization that accommodate rapid and large-scale
chromatin dynamics.

4) In summary: Real-time fluorescence microscopy has emerged as
a powerful tool for examining chromatin dynamics. The initial
lesson is that much of the genome, particularly in yeast, is
highly dynamic. Its movement within the interphase nucleus is
correlated with metabolic activity. Nonetheless, the nucleus is
an organelle with conserved rules of organization. Determining
the distribution and regulation of mobile domains in interphase
chromosomes, and characterizing sites of anchorage, will
undoubtedly shed new light on the function of nuclear order.

References (abridged):

1. A. S. Belmont, Trends Cell Biol. 11, 250 (2001)

2. D. A. Thrower and K. Bloom, Mol. Biol. Cell 12, 2800 (2001)

3. P. Heun, T. Laroche, M. K. Raghuraman, S. M. Gasser, J. Cell
Biol. 152, 385 (2001)

4. W. F. Marshall, et al., Curr. Biol. 7, 930 (1997)

5. J. Vazquez, A. S. Belmont, J. W. Sedat, Curr. Biol. 11, 1227
(2001)

Science 2002 296:1412

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6. ENZYMES AND GLOBAL CHANGE

Dan Yakir (Weizmann Institute of Science, IL) discusses enzymes
and makes the following points:

1) The realization that enzyme-driven molecular discrimination
can be detected at the global level induces a sense of vertigo
at the immensity of the scale shifts involved. Some enzymes are
so central in nature that their discrimination signals are
indicators of global changes. Yet, remarkably, these
global-scale signals can be recreated with a few cells in a
sealed test tube, or with a leaf in a bell jar.

2) Each element has different isotopes, most of which are stable
and can be distinguished by their mass. Enzymes catalyze
chemical reactions that are sensitive to differences in the
dissociation energies of molecules. It is usually easier to
form, or break, bonds of molecules that contain the lighter
isotope of a given element, because the vibrational frequency of
such bonds tends to be higher. Consequently, molecules
containing lighter isotopes are preferentially incorporated into
the products of incomplete reactions, whereas heavier isotopes
become enriched in unreacted residues. These simple,
mass-dependent traits give rise to useful signals -- stable
isotopes can be thought of as natural labels on all
environmental processes, allowing us to see a dynamic universe
that is normally hidden from view.

3) Take Rubisco (ribulose 1,5-bisphosphate
carboxylase–oxygenase), the most common enzyme on Earth and the
primary enzyme in photosynthesis, which fixes carbon dioxide
from the air to form sugars. Essentially, all carbon dioxide
assimilated by photosynthesis passes through this single enzyme.
Because of the mass-dependent effects described above, Rubisco
discriminates against carbon dioxide containing C-13 (around 1%
of carbon in nature), producing sugars that are depleted in this
isotope. Because of the staggering quantities of carbon dioxide
processed by Rubisco on the global scale, there is a marked
accumulation of C-13 in atmospheric carbon dioxide.

4) Photosynthesis on land consumes approximately 350 billion
tons of carbon dioxide every year (about one-seventh of all the
carbon dioxide in the atmosphere), all of which ultimately
returns to the atmosphere through respiration and combustion. On
land, photosynthesis increases and decreases with the seasons,
so changes in C-13 concentration in the atmosphere can be
observed. In the ocean, carbon dioxide is taken up by
dissolution with little discrimination. This makes atmospheric
C-13 useful in distinguishing carbon dioxide uptake by
photosynthesis on land and by dissolution in the ocean, a
critical point in tracing the fate of carbon dioxide from spent
fossil fuel.(1-3)

References (abridged):

1. Bigeleisen, J. Science 147, 463–471 (1965).

2. Griffith, H. (ed.) Stable Isotopes and the Integration of
Biological, Ecological and Geochemical Processes (Bios
Scientific, Oxford, 1998).

3. Berry, J. A. in Primary Productivity and Biogeochemical
Cycles in the Sea (eds Falkowski, P. G. & Woodhead, A. D.)
411–454 (Plenum, New York, 1992).

Nature 2002 416:795

Web Links: rubisco

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7. ON ELECTROLYTIC ACTUATORS

C.G. Cameron and M.S. Freund (California Institute of
Technology, US) discuss electrolytic actuators and make the
following points:

1) There has been considerable recent interest in the
development of materials to convert electrical energy directly
to mechanical energy, and a number of new actuating materials
are being developed to this end. These include electrochemically
responsive conducting polymers (1, 2), capacitance-driven carbon
nanotube actuators (3), pH-responsive hydrogels (4), ionic
polymer metal composites (5), electric field responsive
elastomers, and field electrostrictive polymers. The impetus
behind this development is the need to create more efficient
transduction that can be scaled to size or weight demands that
cannot be fulfilled by conventional electric motors, pumps, and
switches. These constraints are particularly relevant to the
emerging fields of microfluidics, microelectromechanical
systems, and robotics. Although many of the new materials under
investigation exhibit useful specific properties, e.g., large
stresses, sizable strains, or fast cycling time, they commonly
suffer from inherent limitations that severely restrict their
general applicability.

2) Although a significant amount of work has been directed
toward developing new materials for actuation and pumping, the
use of established, scalable electrochemical phase
transformations has been largely overlooked. Although faradaic
and nonfaradaic processes that lead to swelling and/or
conformational changes within a material constitute an
interesting approach to simple actuators (1-5), there are
considerable advantages to pursuing processes that result in
reversible phase transitions, particularly between liquid and
gas. The greatest benefit of this particular transformation is
the enormous volume and pressure changes that are obtainable.
There are a few examples in the literature of electrolysis being
used as the basis for microvalves, switches), dispensing
systems, and dosing systems. However, these reports focus on the
design of highly specialized microelectromechanical systems
prototypes and do not explore the nature of the electrochemical
reactions or their implications on design and performance of
actuators in general. Consequently, they do not indicate the
tremendous potential of this strategy relative to current
state-of-the-art approaches to actuation.

3) In summary: The emerging field of materials-based actuation
continues to be the focus of considerable research because of
its inherent scalability and its promise to drive
micromechanical devices that cannot be realized with
conventional mechanical actuator strategies. The electrolytic
phase transformation actuator offers a new broad-spectrum
solution to the problem of direct conversion of electrical to
mechanical energy. Strains of 136,000% and unoptimized work
cycle efficiencies near 50% are demonstrated in a prototype
device. Conceivably capable of generating stress beyond 200 MPa,
this new approach promises performance orders of magnitude
beyond other novel actuation strategies.

References (abridged):

1. Jager, E. W. H. , Smela, E. & Inganäs, O. (2000) Science
290, 1540-1545

2. Baughman, R. H. (1996) Synth. Met. 78, 339-353

3. Baughman, R. H. , Cui, C. , Zakhidov, A. A. , Iqbal, Z. ,
Barisci, J. N. , Spinks, G. M. , Wallace, G. G. , Mazzoldi, A. ,
Rossi, D. D. , Rinzler, A. G. , et al. (1999) Science 284,
1340-1344

4. Shibayama, M. & Tanaka, T. (1993) Adv. Polym. Sci. 109, 1-62

5. Shahinpoor, M. & Kim, K. J. (2001) Smart Mater. Struct. 10,
819-833

Proc. Nat. Acad. Sci. 2002 99:7827

Web Links: electrolytic actuators

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8. LANTHANIDE COMPLEXES AND ASYMMETRIC CATALYSIS

The term "asymmetric catalysis" refers to the use of of
homogeneous catalysts for the synthesis of chiral compounds. In
general, the major goal of this field in synthetic organic
chemistry is the development of highly stereoselective and
efficient catalysts for the synthesis of enantiomerically pure
compounds.

M. Shibasaki and N. Yoshikawa (University of Tokyo, JP) discuss
asymmetric catalysis and make the following points:

1) Asymmetric catalysis has received considerable attention over
the past few decades, and its contribution toward organic
synthesis has become increasingly significant.(1) A wide variety
of enantioselective chemical transformations are now performed
with only catalytic amounts of chiral promoters, providing
highly economic access to optically active compounds. Some of
these enantioselective transformations can be applied to
industrial production. Nonetheless, the performance of most
artificial catalysts is still far from satisfactory in terms of
generality and reactivity. On the other hand, enzymes catalyze a
broad range of organic transformations under rather mild
conditions, even though they are often specific for certain
substrates. An advantage of enzymes over most artificial
catalysts is that they often contain two or more active sites
for catalysis. The synergistic functions of the active sites
make substrates more reactive in the transition state and
control their positions so that the functional groups are
proximal to each other. This concept of multifunctional
catalysis is key to increasing the scope of natural and
artificial catalysts.(2)

2) The development of asymmetric catalysis to date has been
accomplished by employing various metal elements on the basis of
the type of reaction targeted. While asymmetric catalysts
containing p-block metal elements or d-block elements have been
studied extensively,(1) the use of f-block elements (lanthanides
and actinides) as metal components for asymmetric catalysts has
not been studied until recently.(3) The utility of lanthanides
for asymmetric catalysis was first demonstrated by Danishefsky
et al.(4) These authors reported promotion of hetero Diels-Alder
reactions by Eu(hfc)3 with moderate enantiomeric excess (up to
58%). Several groups reported other examples of enantioselective
catalytic cycloaddition.(5) Other lanthanide complexes were
reported as catalysts in other enantioselective reactions such
as Meerwein-Ponndorf-Verley reductions, hydrogenations,
hydrosilylations, hydroaminations, polymerizations, and
Mukaiyama aldol reactions. These studies demonstrate the
exceptional capability of lanthanides as Lewis acids.

3) Since the first report of a catalytic asymmetric nitroaldol
reaction in 1992, Shibasaki et al. continued to develop the
concept of multifunctional catalysis, wherein the catalysts
exhibit both Lewis acidity and Bronsted basicity using
lanthanide complexes. The synergistic effects of the two
functions enable transformations that have never been possible
using conventional catalysts employing only Lewis acidity.
Furthermore, a variety of enantioselective transformations has
been realized by carefully choosing the metal elements according
to the type of the reaction, consistent with the above-mentioned
concept. In particular, the development of heterobimetallic
complexes that contain a lanthanide and alkali metal offer a
versatile framework for asymmetric catalysts, because the
property of the catalyst can be tuned dramatically according to
the choice of alkali metal and further refined by choosing the
proper lanthanide.

References (abridged):

1. For recent reviews, see: (a) Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999. (b) Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000.

2. For recent reviews of artificial enzymes, see: (a) Kirby, A.
J. Angew. Chem., Int. Ed. Engl. 1996, 35, 707. (b) Breslow, R.;
Dong, S. D. Chem. Rev. 1998, 98, 1997. (c) Williams, N. H.;
Takasaki, B.; Wall, M.; Chin, J. Acc. Chem. Res. 1999, 32, 485.
(d) Molenveld, P.; Engbersen, J. F. J.; Reinhoudt, D. N. Chem.
Soc. Rev. 2000, 29, 75.

3. For a review of asymmetric catalysis by lanthanide Lewis
acids, see: Shibasaki, M.; Yamada, K.-i.; Yoshikawa, N. In Lewis
Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH:
Weinheim, Germany, 2000; Vol. 2, Chapter 20.

4. Bednarski, M.; Maring, C.; Danishefsky, S. Tetrahedron Lett.
1983, 24, 3451.

5. (a) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M.
Tetrahedron Lett. 1993, 34, 4535. (b) Kobayashi, S.; Ishitani,
H.; Hachiya, I.; Araki, M. Tetrahedron 1994, 50, 11623. (c)
Kobayashi, S.; Ishitani, H. J. Am. Chem. Soc. 1994, 116, 4083.
(d) Kobayashi, S.; Ishitani, H.; Araki, M.; Hachiya, I.
Tetrahedron Lett. 1994, 35, 6325. (e) Ishitani, H.; Kobayashi,
S. Tetrahedron Lett. 1996, 37, 7357. (f) Kobayashi, S.;
Kawamura, M. J. Am. Chem. Soc. 1998, 120, 5840. (g) Kawamura,
M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 3213.

Chem. Rev. 2002 102:2187

Web Links: asymmetric catalysis

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9. ON A LARGE-SCALE ION-TRAP QUANTUM COMPUTER

D. Kielpinski et al (Massachusetts Institute of Technology, US)
discuss quantum computers and make the following points:

1) A quantum computer is a device that prepares and manipulates
quantum states in a controlled way, offering significant
advantages over classical computers in tasks such as factoring
large numbers(1) and searching large databases(2). The power of
quantum computing derives from its scaling properties: as the
size of these problems grows, the resources required to solve
them grow in a manageable way. Hence a useful quantum computing
technology must allow control of large quantum systems, composed
of thousands or millions of qubits.

2) The first proposal for ion-trap quantum computation involved
confining a string of ions in a single trap, using their
electronic states as qubit logic levels, and transferring
quantum information between ions through their mutual Coulomb
interaction(3). All the elementary requirements for quantum
computation4 -- including efficient quantum state
preparation(5), manipulation, and read-out -- have been
demonstrated in this system. But manipulating a large number of
ions in a single trap presents immense technical difficulties,
and scaling arguments suggest that this scheme is limited to
computations on tens of ions. One way to escape this limitation
involves quantum communication between a number of small
ion-trap quantum registers. Recent proposals along these lines
that use photon coupling and spin-dependent Coulomb interactions
have not yet been tested in the laboratory.

3) To build up a large-scale quantum computer, the authors have
proposed a "quantum charge-coupled device" (QCCD) architecture
consisting of a large number of interconnected ion traps. By
changing the operating voltages of these traps, one can confine
a few ions in each trap or shuttle ions from trap to trap. In
any particular trap, one can manipulate a few ions using the
methods already demonstrated, while the connections between
traps allow communication between sets of ions. Because both the
speed of quantum logic gates and the shuttling speed are limited
by the trap strength, shuttling ions between memory and
interaction regions should consume an acceptably small fraction
of a clock cycle.

4) In summary: Among the numerous types of architecture being
explored for quantum computers are systems utilizing ion traps,
in which quantum bits (qubits) are formed from the electronic
states of trapped ions and coupled through the Coulomb
interaction. Although the elementary requirements for quantum
computation have been demonstrated in this system, there exist
theoretical and technical obstacles to scaling up the approach
to large numbers of qubits. Therefore, recent efforts have been
concentrated on using quantum communication to link a number of
small ion-trap quantum systems. Developing the array-based
approach, the authors demonstrate how to achieve massively
parallel gate operation in a large-scale quantum computer, based
on techniques already demonstrated for manipulating small
quantum registers. The use of decoherence-free subspaces
significantly reduces decoherence during ion transport, and
removes the requirement of clock synchronization between the
interaction regions.

References (abridged):

1. Shor, P. W. in Proc. 35th Annu. Symp. on the Foundations of
Computer Science (ed. Goldwasser, S.) 124-134 (IEEE Computer
Society, Los Alamitos, 1994)

2. Grover, L. K. Quantum mechanics helps in searching for a
needle in a haystack. Phys. Rev. Lett. 79, 325-328 (1997)

3. Cirac, J. I. & Zoller, P. Quantum computations with cold
trapped ions. Phys. Rev. Lett. 74, 4091-4094 (1995)

4. DiVincenzo, D. P. in Scalable Quantum Computers (eds
Braunstein, S. L. & Lo, H. K.) 1-14 (Wiley-VCH, Berlin, 2001)

5. Monroe, C. et al. Resolved-sideband Raman cooling of a bound
atom to the 3D zero-point energy. Phys. Rev. Lett. 75, 4011-4014
(1995)

Nature 2002 417:709

Web Links: ion-trap quantum computers

Related Background:

ON MESOSCOPIC ELECTRONIC CIRCUITS AND QUANTUM COMPUTING

In general, the term "quantum computing" refers to the use of
quantum mechanical effects as the basis of computer processors.
One way to engage these effects is at the level of mesoscopic
physics, the physics of nanoscale and microscale interactions.

Jan van Ruitenbeek (University of Leiden, NL) presents a
commentary on current research on mesoscopic electronic circuits
and quantum computing, the author making the following points:

1) The author points out that mesoscopic electronics is the
study of the movement of electrons in extremely small circuits,
circuits composed of conductors, capacitors, and inductors but
on the order of hundreds of nanometers to several microns in
scale. At these dimensions, and at low temperatures, quantum
mechanics dominates all of the properties of circuit elements,
so the common laws used by engineers in the design and analysis
of electronic circuits are useless. An apparently complete
quantum field theory of mesoscopic circuits has recently been
proposed, but the theory is so complicated that it can only be
applied to simple systems.

2) The author (van Ruitenbeek) points out that properties of
electrons cause three complications at mesoscopic scales:

... ... a) The motion of electrons at such scales must be
described in terms of quantum waves. Like light waves, quantum
waves are scattered by objects such as the edge of the metallic
conductor and defects or impurities present in its interior.
This scattering results in an interference pattern, making
properties such as resistance extremely sensitive to variations
in the circuit geometry.

... ... b) Another complication arises from the charge of the
electron, which results in a repulsive force between all of the
electrons in the circuit. For example, for very small
capacitors, adding a single electron to the many electrons
already inside the capacitor plates may be sufficient to raise
the capacitor energy to a level high enough to prevent the next
electron from entering. In general, the motion of any electron
in a mesoscopic circuit can influence all other electrons in the
circuit, making the calculations complicated.

... ... c) Finally, one must account for the correlations in the
motion of the electrons, correlations that give rise to
phenomena such as superconductivity. 3) The author points out
that one attractive application of mesoscopic circuit analysis
is quantum computing. The quest to create a quantum computer has
spread into many areas of physics, including quantum optics and
atomic physics, but the mesoscopic physics approach has the
advantage that one can design and fabricate circuits consisting
of many individual elements with various properties. The author
concludes: "The challenge of developing a full-size quantum
computer puts our ability to fabricate circuits and our
understanding of these systems to an extreme test. It is
becoming increasingly likely that to make a quantum computer we
will have to integrate the knowledge and techniques from many
fields, combining tools from mesoscopic physics with those from
quantum optics and molecular physics."

Nature 2001 410:424

Related Background:

APPLIED SCIENCE: ON PHYSICS AND THE INFORMATION REVOLUTION

Since the dawn of the modern computer era, physicists and
computer technologists have been involved in a symbiosis
--physicists active in research in the fundamental science
underlying computer technology, and computer technologists
designing the high-speed machines that physicists use to solve
quantitative problems previously off-limits to physicists when
such machines were not available. Of course, this symbiosis is a
particular instance of the general interaction between science
and technology, but the interaction between physicists and
computer technologists is perhaps more direct and clear than any
other, and it continues to be mutually vital. Many people, both
physicists and computer technologists, believe that because of
intrinsic limitations in current computer technology, a new
phase in the "information revolution" will soon be required if
advances in computing power are to occur, and that this new
phase will depend on new contributions of fundamental physics,
particularly quantum physics.

J. Birnbaum and R.S. Williams (Hewlett-Packard, US) review the
current state of computer technology and what must be done to
sustain the momentum of the past few decades. The authors make
the following points:

1) The first stored-program electronic computer was ENIAC
(Electronic Numerical Integrator and Computer), built in 1946.
This was a vacuum-tube machine that could 5000 numbers in one
second. ENIAC could calculate the trajectory of an artillery
shell in only 30 seconds, compared to 40 hours required by a
human with a mechanical calculator. The machine contained 17,468
vacuum tubes, weighed 60,000 pounds, occupied 16,200 cubic feet,
and consumed 174 kilowatts (233 horsepower). The authors point
out that the amount of energy expended by ENIAC to compute a
single shell trajectory was comparable to that of the explosive
discharge required to actually fire the shell. In 1954, nine
years later, ENIAC was still the fastest computer on Earth, when
it was turned off because the US Army could no longer justify
the expense of running and maintaining it. In 1949, a panel of
experts confidently predicted that the future of computer
technology would involve a machine such as ENIAC with only 1500
vacuum tubes, weighing only 3000 pounds, requiring only 10
kilowatts of power, and about the size of an automobile. So much
for the experts: at the present time, a palmtop computer is
thousands of times more powerful than ENIAC.

2) The authors point out that the reason for the now-laughable
error of the experts in 1949 was that their prediction was based
on the wrong foundation: reasonable extrapolation of the
in-place vacuum-tube technology. Although the transistor, which
represented a "disruptive technology" (i.e., a technology that
could replace vacuum tubes in computers), had already been
invented, the transistor was completely ignored. The authors
point out that even though transistors as discrete devices had
significant advantages over vacuum tubes and progress on
transistors was steady during the 1950s, the directors of many
large electronic companies believed that the vacuum tube held an
unassailable competitive position. These companies were
eventually eclipsed by companies that invested heavily in
transistor research and development and were thus poised to
exploit new advances. The authors state: "There are eerie
parallels with the situation today."

3) "Moore's Law", first formulated by Gordon Moore of Intel
Corporation, states that the number of transistors that can be
built on a chip increases exponentially with time. During the
past 28 years, computer technology has exhibited a
factor-of-four increase every 3.4 years in the number of bits
that can be stored on a memory chip. But there is also "Moore's
Second Law": the cost of building fabrication facilities to
manufacture chips has also been increasing exponentially. Thus
the cost of manufacturing chips is increasing significantly
faster than the market is expanding. In 1995, to build a single
fabrication facility required approximately US$1 billion, or
approximately 1 percent of the entire annual chip market. By the
year 2010, a fabrication facility could cost US$30 billion to
US$50 billion, or approximately 10 percent of the total annual
market at that time.

4) The authors point out that by 2010 the individual transistors
in computer circuits will be turned on or off by the addition or
removal of only 8 electrons on the gate of a transistor,
compared to approximately 1000 electrons today. The statistics
of small numbers will become a significant factor, and the
ability to distinguish between zero and one in a digital circuit
will be severely compromised. By 2020, the continuation of
geometric scaling would mean that less than one electron would
be available to switch the transistor. The authors state: "That
would require getting around a fundamental physical limitation,
and not just an engineering obstacle. Yet, many researchers and
corporate executives seem to have a blind optimism that somehow
that will happen... If there is to be any hope of sustaining the
economic benefits to the national economy that come from
containing Moore's Law, then we have no choice but to develop
quantum switches and the means to interconnect them."

5) Concerning nanostructured devices, the authors suggest that
perhaps the search for a way to make such devices should
concentrate on wires and switches, because those are the
components that will allow high-defect-tolerant systems to be
built. The most desirable types of wires would be those that
could conduct information without having to conduct electric
current (e.g., information conducted in the form of the phase of
a charge density wave). The switches should be a form of
nonvolatile memory that requires the expenditure of power only
to open or close a circuit, but not to maintain the state of the
switch.

6) The authors conclude: "Today, we have the silicon
field-effect transistor, but we speculate that a quantum-state
switch could be better. Many laboratories are now engaged in
basic research on fabricating materials into arbitrary shapes
and sizes. They are searching for the device concept that will
lead to a disruptive new technology. Breakthroughs will
significant advances in the understanding of fundamental issues
and will undoubtedly act as the foundation for new mathematical
and scientific disciplines. Those companies that convert the
breakthroughs into a new manufacturable technology will be the
survivors of the quantum age of information processing."

PhysicsToday January 2000)

Related Background:

ON THE FUTURE OF QUANTUM COMPUTING

The superposition principle in quantum mechanics derives from
the superposition principle in pure mathematics, which states
that for a linear homogenous differential equation, if
y(sub1)(x) and y(sub2)(x) are solutions, then so is y(sub1)(x) +
y(sub2)(x). In other words, for such a differential equation,
the sum of solutions is itself a solution. A corollary is that
any physical system which can be described by a linear
homogeneous differential equation (or a set of such equations)
will obey the superposition principle. This principle produces
various applications and formulations in the physics of
oscillating systems. In quantum mechanics, where the
time-independent Schroedinger equation is a linear homogenous
differential equation and systems are described by oscillating
probability amplitudes, the principle of superposition results
in the postulate that any state function of a given quantum
mechanical system corresponding to a given observable (e.g.,
energy) can be expressed as a linear expansion of the
eigenstates of the system for the same observable, with the term
"eigenstate" referring to any one of the wave function solutions
(probability amplitude function solutions) to the Schroedinger
equation for the given boundary conditions. Another way to state
the quantum mechanical principle of superposition is as follows:
If a physical state of a system can be realized in a number of
different but unknown distinct ways, then the actual state of
the system is a superposition for each distinct way, and there
is a distinct probability amplitude for each way in which the
physical state can be realized. This is essentially a
restatement of Feynman's rule: The probability amplitude of an
event that can occur in two or more indistinguishable ways is
the sum of the probability amplitude for each considered
separately. And Feynman's rule, in turn, is an analog of Bayes'
rule in classical probability theory: The probability of an
event which can occur in two indistinguishable ways is the sum
of the probabilities for each way considered separately. The
quantum mechanical principle of superposition is of major
importance in considerations of quantum computing, particularly
in connection with "decoherence". In this context, the term
"decoherence" refers to the observed destruction of the
superposition of pure quantum states, the destruction due to
interactions with uncontrolled or unknown physical effects
(e.g., interactions with the environment of the system). It is
currently believed that quantum computers, which manipulate
quantum states rather than classical "bits", may someday be able
to perform tasks that would be inconceivable with conventional
digital technology.

John Preskill (California Institute of Technology, US) presents
a review of current problems in the development of quantum
computers, the author making the following points:

1) Formidable obstacles must be overcome before large-scale
quantum computers can become a reality. A major difficulty is
that quantum computers are highly susceptible to making errors.
The considerable theoretical power of a quantum computer derives
from its ability to process *coherent quantum states (i.e.,
quantum states obeying the principle of superposition), but the
coherence of such quantum states is very easily damaged by
uncontrolled interactions with the environment (decoherence).

2) The indivisible unit of classical information is the "bit",
which takes one of two possible values, 0 or 1. Any amount of
classical information can be expressed as a sequence of bits. A
classical computer executes a series of simple operations
("gates"), each of which acts upon a single bit or pair of bits.
By executing many gates in succession, the computer can evaluate
any *Boolean function of a set of input bits.

3) Quantum information can also be reduced to elementary units,
called quantum bits or "qubits". A qubit is a two-level quantum
system (e.g., the spin of an electron). A quantum computer
executes a series of elementary quantum gates, each of which is
a *unitary transformation that acts on a single qubit or pair of
qubits. By executing many such gates in succession, the quantum
computer can apply a complicated unitary transformation to a
particular initial state of a set of qubits. Finally, the qubits
can be measured, the measurement outcome the final result of a
quantum computation.

4) It was Richard Feynman (1982) who suggested that using a
quantum computer might enormously speed up finding solutions to
certain difficult computational problems. David Deutsch (1985),
developing the idea further, observed that a quantum computer
can invoke the equivalent of a massive parallelism by operating
on a coherent superposition of a vast number of classical
states. In fact, a single computation acting on just 300 qubits
can achieve the same effect as 2^(300) simultaneous computations
acting on classical bits, more than the number of atoms in the
visible Universe. It is not possible to build a conventional
computer with that many processors.

5) There is, however, a problem of principle that is potentially
very serious for the future of quantum computers --namely,
decoherence. Unavoidable interactions with the environment will
cause the quantum information stored in a quantum computer to
decay, thus inducing errors in the computation. Decoherence
occurs very rapidly in complex quantum systems, which is the
reason we never observe macroscopic superpositions. If quantum
computers are ever to be capable of solving difficult problems,
a method must be found to control decoherence and other
potential sources of error.

6) At present, quantum information technology remains in the
pioneering stage. It is currently possible to do experiments
involving a few qubits and a few quantum gates. For a quantum
computer to compete with a state-of-the-art classical computer,
we will need machines with hundreds or thousands of qubits
capable of performing millions or billions of operations. The
technology clearly has far to go before quantum computers can
assume their rightful place as the world's fastest machines. But
recent advances in the theory of quantum error correction
suggest there are no insurmountable obstacles, and quantum
computers of the 21st century may indeed unleash the vast
computational power woven into the fundamental laws of physics.

PhysicsToday June 1999

Text Notes:

... ... *coherent quantum states: In order for a system to be
used to process and transfer information, the system must be
"coherent" in its parts. In quantum physics, coherence is a
matter of locking of phase differences between wave functions.
The wave functions of two or more particles are said to be
coherent if the phase difference between their wave functions
remains constant. So if new quantum electrodynamic information
processing devices are to be developed, methods must be found to
keep the quantum states of the parts of the system coherent long
enough for information to be processed and transferred from one
place to another.

... ... *Boolean function: In general, a "Boolean function" is
any function assembled by the application of the operations AND,
OR, NOT to a set of variables and elements whose common domain
is a "Boolean algebra". The term "Boolean algebra" refers to a
form of symbolic logic devised by George Boole (1815-1864), such
an algebra providing a mathematical procedure for manipulating
logical relationships in symbolic form. In the realm of
computers, Boolean algebra is an important tool enabling the
bits 0 and 1 to be related to logical functions of the computer.

... ... *unitary transformation: In this context, the term
"unitary transformation" refers to a linear operator whose
adjoint is equal to its inverse. The "adjoint" A* of an operator
A is an operator such that for all f and g in the domain of A:
(Af,g) = (f,A*g). If A* = A, then A is said to be self-adjoint.

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10. ON ATRIAL FIBRILLATION

J.M. Cooper et al (Brigham and Women's Hospital Boston, US)
discuss atrial fibrillation and make the following points:

1) Atrial fibrillation is a common arrhythmia that causes
symptoms such as palpitations and dyspnea but is also associated
with stroke, heart failure, and an increased risk of
hospitalization and death.(1,2) The incidence of atrial
fibrillation increases markedly with age. As the average age of
the general population increases, the overall prevalence of
atrial fibrillation is also increasing. Among the most common
approaches to management are rate control plus anticoagulation
and rhythm control with antiarrhythmic medications. Neither of
these two strategies is ideal. Anticoagulation does not
eliminate the risk of stroke, and the antiarrhythmic drugs often
do not maintain sinus rhythm.(3,4) Both approaches also entail a
risk of side effects and complications. In some cases,
antiarrhythmic drugs appear to have led to life-threatening
ventricular arrhythmias.(5) One new therapeutic option --
pacemakers and defibrillators -- is beginning to influence the
management of atrial fibrillation.

2) During atrial fibrillation, the atrioventricular node is
bombarded with electrical impulses, which typically result in
rapid ventricular rates. The rate at which signals are
transmitted to the ventricles depends on the electrical
properties of the conduction system; these properties can be
influenced by medications and autonomic input. The ventricular
response may be slow in patients with intrinsic
conduction-system disease, in those who are taking
rate-controlling pharmacologic agents, or in patients with a
high vagal tone. Permanent pacemakers have long been used to
treat symptomatic bradycardia caused by any of these factors.

3) If rapid ventricular rates persist after pharmacologic
therapies for atrial fibrillation have proved unsuccessful or
intolerable to the patient, permanent ablation of the
atrioventricular node is an effective therapy. An ablation
catheter is introduced through a femoral vein and positioned at
the atrioventricular node under fluoroscopic and
electrocardiographic guidance. Radio-frequency energy is
delivered to this site, destroying the underlying conduction
tissue and thus producing permanent heart block and eliminating
tachycardia. This procedure is irreversible and typically leaves
the patient with only a slow escape rhythm, necessitating the
implantation of a permanent pacemaker. In patients with atrial
fibrillation that is refractory to drug therapy,
atrioventricular-node ablation decreases the incidence of
palpitations, dyspnea, and fatigue by controlling the
ventricular rate and also increases exercise tolerance. This
approach eliminates the need for rate-controlling medications.
The restoration of a regular ventricular rhythm with pacing may
also have an important role, since cardiovascular hemodynamics
are impaired by an irregular ventricular rhythm.

References (abridged):

1. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel
WB, Levy D. Impact of atrial fibrillation on the risk of death:
the Framingham Heart Study. Circulation 1998;98:946-952.

2. Wolf PA, Mitchell JB, Baker CS, Kannel WB, D'Agostino RB.
Impact of atrial fibrillation on mortality, stroke, and medical
costs. Ann Intern Med 1998;158:229-234.

3. Nattel S, Hadjis T, Talajic M. The treatment of atrial
fibrillation: an evaluation of drug therapy, electrical
modalities and therapeutic considerations. Drugs 1994;48:345-371.

4.Ganz LI, Antman EM. Antiarrhythmic drug therapy in the
management of atrial fibrillation. J Cardiovasc Electrophysiol
1997;8:1175-1189.

5. Prystowsky EN. Proarrhythmia during drug treatment of
supraventricular tachycardia: paradoxical risk of sinus rhythm
for sudden death. Am J Cardiol 1996;78:35-41.

New Engl. J. Med. 2002 346:2062

Web Links: atrial fibrillation

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11. ON VITAMINS FOR CHRONIC DISEASE PREVENTION IN ADULTS

K.M. Fairfield and R.H. Fletcher (Harvard Medical School, US)
discuss vitamins for disease prevention and make the following
points:

1) Vitamins are organic compounds that cannot be synthesized by
humans and therefore must be ingested to prevent metabolic
disorders. Although classic vitamin deficiency syndromes such as
scurvy, beriberi, and pellagra are now uncommon in Western
societies, specific clinical subgroups remain at risk. For
example, elderly patients are particularly at risk for vitamins
B12 and D deficiency, alcohol-dependent individuals are at risk
for folate, B6, B12, and thiamin deficiency, and hospitalized
patients are at risk for deficiencies of folate and other
water-soluble vitamins. Inadequate intake or subtle deficiencies
in several vitamins are risk factors for chronic diseases such
as cardiovascular disease, cancer, and osteoporosis. In
addition, pregnancy or alcohol use may increase vitamin
requirements. At least 30% of US residents use vitamin
supplements regularly, suggesting that physicians need to be
informed about available preparations and prepared to counsel
patients in this regard.(1) At a minimum, patients should be
queried about their usual diet and use of vitamin supplements.

2) The authors searched MEDLINE for English-language articles
published from 1966 through January 11, 2002, about vitamins,
vitamin deficiencies and toxicity, and specific vitamins in
relation to chronic diseases. Review of 9 vitamins showed that
elderly people, vegans, alcohol-dependent individuals, and
patients with malabsorption are at higher risk of inadequate
intake or absorption of several vitamins. Excessive doses of
vitamin A during early pregnancy and fat-soluble vitamins taken
anytime may result in adverse outcomes. Inadequate folate status
is associated with neural tube defect and some cancers. Folate
and vitamins B6 and B12 are required for homocysteine metabolism
and are associated with coronary heart disease risk. Vitamin E
and lycopene may decrease the risk of prostate cancer. Vitamin D
is associated with decreased occurrence of fractures when taken
with calcium.

3) The authors conclude: Some groups of patients are at higher
risk for vitamin deficiency and suboptimal vitamin status. Many
physicians may be unaware of common food sources of vitamins or
unsure which vitamins they should recommend for their patients.
Vitamin excess is possible with supplementation, particularly
for fat-soluble vitamins. Inadequate intake of several vitamins
has been linked to chronic diseases, including coronary heart
disease, cancer, and osteoporosis.(2-5)

References (abridged):

1. Balluz LS, Kieszak SM, Philen RM, Mulinare J. Vitamin and
mineral supplement use in the United States: results fro m the
third National Health and Nutrition Examination Survey. Arch Fam
Med. 2000;9:258-262.

2. Morrison HI, Schaubel D, Desmeules M, Wigle DT. Serum folate
and risk of fatal coronary heart disease. JAMA.
1996;275:1893-1896.

3. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from
diet and supplements in relation to risk of coronary heart
disease among women. JAMA. 1998;279:359-364.

4. Homocysteine Lowering Trialists' Collaboration. Lowering
blood homocysteine with folic acid based supplements:
meta-analysis of randomised trials. BMJ. 1998;316:894-898.

5. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S.
Homocyst(e)ine and cardiovascular disease: a critical review of
the epidemiologic evidence. Ann Intern Med. 1999;131:363-375.

J. Am. Med. Assoc. 2002 287:3116

Web Links: vitamin supplements and disease

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12. ON PROTEIN MISFOLDING DISEASES

M. Bucciantini et al (University of Firenze, IT) discuss protein
misfolding diseases and make the following points:

1) An increasing body of evidence suggests that amyloid
formation is the fundamental cause of protein deposition
diseases(1, 2). The nature of the pathogenic species and the
mechanism by which the aggregation process results in cell
damage are, however, the subject of intense debate(3-5). In
systemic non-neurological diseases the accumulation of large
quantities (sometimes kilograms) of aggregated species within a
variety of organs and tissues may itself be the major cause of
clinical symptoms. In other cases, particularly the degenerative
neurological diseases, it appears likely that impairment of
cellular function is directly linked to the interaction of
protein aggregates with cellular components.

2) One specific indicator of the significance of aggregate
formation in pathological conditions is the evidence for a high
variability in the age of disease onset, an observation that has
recently been linked to the evidence that aggregates form by
nucleation. Further clues to the molecular basis of amyloid
diseases and the biological significance of protein aggregation
have been provided by recent observations that a range of
proteins not associated with amyloid diseases are able to
aggregate in vitro into fibrils indistinguishable from those
found in pathologic conditions. This finding has led to the
proposal that aggregation can be viewed as a general property of
polypeptide chains rather than one restricted to a small number
of sequences.(2)

3) The authors report they have examined the effects on cell
viability of aggregated species produced in vitro from two
proteins not associated with amyloid diseases. The authors
demonstrate that species formed early in the aggregation of
these non-disease-associated proteins can be inherently highly
cytotoxic. The authors suggest this finding provides added
evidence that avoidance of protein aggregation is crucial for
the preservation of biological function and suggests common
features in the origins of this family of protein deposition
diseases.

4) The authors suggest that the present findings, that early
aggregates formed by a wider range of proteins than those known
to be associated with neurological diseases can be cytotoxic,
provide new opportunities to define the nature of amyloid
diseases and the mechanism of amyloid toxicity at the molecular
level. They also raise the possibility that trace amounts of
aggregates of a variety of proteins might occur spontaneously,
particularly during ageing, and that such aggregates could
account for subtle impairments of cellular function in the
absence of an evident amyloid phenotype.

References (abridged):

1. Kelly, J. W. The alternative conformations of amyloidogenic
proteins and their multi-step assembly pathways. Curr. Opin.
Struct. Biol. 8, 101-106 (1998).

2. Dobson, C. M. The structural basis of protein folding and its
links with human disease. Phil. Trans. R. Soc. Lond. B 356,
133-145 (2001).

3. Lambert, M. P. et al. Diffusible, nonfibrillar ligands
derived from A-42 are potent central nervous system neurotoxins.
Proc. Natl Acad. Sci. USA 95, 6448-6453 (1998).

4. Hartley, D. M. et al. Protofibrillar intermediates of amyloid
beta-protein induce acute electrophysiological changes and
progressive neurotoxicity in cortical neurons. J. Neurosci. 19,
8876-8884 (1999).

5. Pillot, T. et al. The nonfibrillar amyloid -peptide induces
apoptotic neuronal cell death: involvement of its C-terminal
fusogenic domain. J. Neurochem. 73, 1626-1634 (1999).

Nature 2002 416:507

Web Links: protein misfolding

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13. IN FOCUS: ON THE PHYSICS OF DIFFUSION

O.S. Vaulina et al (Russian Academy of Sciences, RU) discuss
diffusion and make the following points:

1) Problems associated with transport processes in dissipative
systems of interacting particles are under discussion in the
varied fields such as plasma physics, molecular biophysics,
thermodynamics, physics and chemistry of polymers, etc. [1-4].
One basic transport phenomena is diffusion. Diffusion is a
nonequilibrium mass transfer process caused by thermal motion of
particles, which leads to a steady state of distribution of
their concentrations and is one basic source of energy loss in
real physical systems. Diffusion occurs in various regimes, for
example, the Brownian diffusion of macroparticles suspended in a
background gas, or the self-diffusion of particles. For clouds
consisting of positive ions and electrons, the joint diffusion
transport of oppositely charged particles (ambipolar diffusion)
may appreciably influence the dynamic properties of the system.

2) The case of ambipolar diffusion of low-ionized plasma in the
absence of a magnetic field was surveyed by Shottky in 1924. The
experimental observations of ambipolar diffusion without the
attendant processes such as ionization or vortex currents are
missing at the present time [3,5]. It should be noted also that
direct measurements of diffusion constants based on an analysis
of concentrations or mean-square displacements of particles
exist only for specific cases (Brownian motion, the diffusion of
thermalized electrons in the absence of an electric field) [2,3].

3) Most of the techniques for experimental determination of
diffusion constants for ions, or electrons, are based on
indirect measurements of a mobility of particles in the external
electrical fields [3]. These techniques are unsuitable for
diagnostics in plasma samples, as they contribute the
significant perturbations in the studied systems. For diffusion
measurements of weakly interacting macroparticles (molecules,
colloidal solutions, viruses), photon correlation methods are
widely used [2]. Application of these methods is restricted by
the short-range order of the interparticle interaction, as the
usual hydrodynamic and thermodynamic descriptions give a
successful explanation for a diffusion of particles only in this
case. When the forces of interaction are not so small, as in
gases, the construction of correct kinetic equations fails.
Thus, the basic problem is determining values of the
interparticle interaction for which these approaches are valid.

References (abridged):

1. J. Crank, The Mathematics a/Diffusion (Clarendon, Oxford,
1975).

2. Photon Correlation and Light Beating Spectroscopy, edited by
H.Z. Cummins and E.R. Pike (Plenum, New York, 1974).

3. Y.P. Raizer, The Physics of Gas Discharge (Springer-Verlag,
Berlin, 1991).

4. H. Lowen, T. Palberg, and R. Simon, Phys. Rev. Lett. 70,1557
(1993).

5. A. P. Jilinsky and L.D. Tsendlin, Phys. Usp. 131, 343 (1980).

Phys. Rev. Lett. 2002 88:035001

Web Links: diffusion

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14. NEW BOOKS:

The Bacterial Phosphotransferase System. JMMB Symposium Series,
vol. 5. Milton H. Saier Jr., Ed. Horizon Scientific, Wymondham,
Norfolk, UK, 2002 Hardback: 301 pp., illus. $149. ISBN
1898486352

Cell Biology. Thomas D. Pollard and William C. Earnshaw.
Saunders (Elsevier Science), Philadelphia, 2002 Hardback: 819
pp., illus. $55. ISBN: 0721639976

The Fate of Knowledge. Helen E. Longino. Princeton University
Press, Princeton, NJ, 2002. 245pp. $49.50 ISBN: 0691088756

Imaginal Discs. The Genetic and Cellular Logic of Pattern
Formation. Lewis I. Held Jr. Cambridge University Press, New
York, 2002 Hardback: 476 pp., illus. $140. ISBN: 0521584450

International Tables for Crystallography. Vol. A, Space-Group
Symmetry. 5th ed. Theo Hahn, Ed. Kluwer Academic, Norwell, MA,
2002 Hardback: 931 pp., illus. $225, EUR 242, £142. ISBN:
0792365909

International Tables for Crystallography. Brief Teaching Edition
of Vol. A, Space-Group Symmetry. 5th ed. Theo Hahn, Ed. Kluwer
Academic, Norwell, MA, 2002 Paperback: 172 pp., illus. $25, EUR
27, £16. ISBN: 0792365917

Mad in America: Bad Science, Bad Medicine, and the Enduring
Mistreatment of the Mentally Ill. Robert Whitaker. 334pp. New
York, Perseus, 2002.$27 ISBN: 0738203858

Medicinal and Aromatic Plants XII. T. Nagata and Y. Ebizuka,
Eds. Springer, New York, 2002 Hardback: 366 pp., illus. $199. 
ISBN: 3540416862

Methods for Affinity-Based Separations of Enzymes and Proteins
Munishwar Nath Gupta, Ed. Birkhaeuser, Basel, Switzerland, 2002
Hardback: 235 pp., illus. $119. ISBN: 3764363061

Nonlinear Photonics. Nonlinearities in Optics, Optoelectronics
and Fiber Communications Y. Guo et al. Springer, New York, 2002
Hardback: 432 pp., illus. $89.95. ISBN: 3540431233

Ocean Acoustic Interference Phenomena and Signal Processing San
Francisco, California, 1-3 May 2001 William A. Kuperman and
Gerald L. D'Spain, Eds. American Institute of Physics, Melville,
NY, 2002 Hardback: 285 pp., illus. $140. ISBN: 0735400709

Practical Amateur Spectroscopy. Stephen F. Tonkin, Ed. Springer,
New York, 2002 Paperback: 220 pp., illus. $39.95. ISBN:
1852334894

Quantitative Methods for Conservation Biology. Scott Ferson and
Mark Burgman, Eds. Springer, New York, 2002 Paperback: 334
pp., illus. $49.95. ISBN: 0387954864

Seminars in Organic Synthesis. XXVI Summer School "A. Corbella".
June 16-22, 2001, Palazzo Feltrinelli, Università degli Studi di
Milano, Gargnano (BS) Società Chimica Italiana, Rome, 2001 U. S.
distributor, Springer, New York Paperback: 695 pp., illus.
$64.95. ISBN: 8886208189

Statistical Physics. An Advanced Approach with Applications.
Web-enhanced with Problems and Solutions. 2nd ed. Josef
Honerkamp Springer, New York, 2002 Hardback: 529 pp., illus.
$64.95. ISBN: 3540430202

Techniques in Molecular Systematics and Evolution. Rob DeSalle,
Gonzalo Giribet, and Ward Wheeler, Eds. Birkhäuser, Basel,
Switzerland, 2002 Hardback: 417 pp., illus. $129. ISBN:
3764362561

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15. POSITION OPEN

POSITION IN SYSTEMS NEUROSCIENCE - CENTER FOR NEUROSCIENCE
DBS:NPB UNIVERSITY OF CALIFORNIA, DAVIS (US). The Center for
Neuroscience and the Section of Neurobiology, Physiology and
Behavior, in the Div. of Biological Sciences, University of
California, Davis, invite applications for a Systems
Neuroscientist at the assistant professor level, to begin July
1, 2003. Specialization within the areas of vision, auditory,
somatosensory, or motor systems is preferred. We are
particularly interested in faculty who can work in conjunction
with the Calif. Regional Primate Research Center, located at UC
Davis. Applicants will be expected to demonstrate leadership in
their research specialty, obtain extramural funds, and teach
systems neuroscience courses at both graduate and undergraduate
levels. Candidates must possess a Ph.D. or M.D. degree.
Applicants should send a letter describing research and teaching
interests, a curriculum vitae, copies of representative
publications, and the names of at least five persons from whom
references will be obtained to: Edward G. Jones, Director,
Center for Neuroscience, 1544 Newton Court, University of
California, Davis, CA, 95616-8659. All materials must be
received by November 30, 2002, to be assured consideration. The
search will continue until this position is filled. The
University of California is an Affirmative Action/Equal
Opportunity Employer.

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16. FELLOWSHIP OPEN:

POSTDOCTORAL POSITION. Genome Technology Branch. National Human
Genome Research Institute. National Institutes of Health. A
Postdoctoral research position is available immediately for an
individual interested in vertebrate genetics and genome analysis
at the National Human Genome Research Institute (NHGRI).
Establishing technologies for using microarrays as a tool to
study vertebrate development. This position is a collaboration
between two labs in the NHGRI and will utilize a recently
developed and comprehensive microarray of zebrafish genes to
study aspects of vertebrate development on a genome-wide scale.
Particular research areas include establishment of the blood
lineages and development of the vertebrate ear and hearing.
Funding is for 3 years initially with the possibility of
extending for 2 years more. The National Human Genome Research
Institute at the National Institutes of Health in Bethesda
provides and exciting scientific environment in one of the
largest biomedical research facilities in the world. Candidates
should possess an MD and/or PhD and have less than five years of
postdoctoral experience. Applications will be accepted until the
position is filled. Please send a letter, CV, and three letters
of reference to: Dr. Shawn Burgess c/o Ms. Erika Schwab,
NHGRI/NIH, 50 South Dr., Bidg. 50, Rm.5531, Bethesda, MD
20892-8004 (or dgsapply@nhgri.nih.gov). The NIH is an Equal
Opportunity Employer and applications by women and minorities
are strongly encouraged.

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17. NOTICES

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