ScienceWeek

ScienceWeek - May 17, 2002 Vol. 6 Number 20

An Online Research Digest Published Weekly Since 1997

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Aristotle has said that the sweetest of all things is knowledge.
And he is right. But if you were to suppose that the publication
of a new view were productive of unbounded sweetness, you would
be mightily mistaken. No one who disturbs his fellow men with a
new view remains unpunished.
-- Ernst Mach (1838-1916)

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Top Graphic:
Portrait of Beatrice Hastings -- Amadeo Modigliani (1884-1920)

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Section 1

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Contents of this Issue (Full reports in Section 2):

Basic Sciences:

1. On Nonequilibrium Molecular Dynamics 

2. On Solvated Electrons in Clusters of Polar Molecules 

3. Proton Diffusion in Phospholipid Assemblies 

4. On the End of the Cosmic Dark Age 

5. On the Effective Mass of Composite Fermions 

6. Biomass Burning, Cumulus Clouds, and Stratospheric Moisture 

7. In Vitro Development of Malaria Mosquito 

8. On Chemotaxis in Bacteria 

9. Complexity, Proteins, and the Energy Landscape 

10. Ecology: Population Dynamics of Solitary Birds 

11. On the Mobility of Large Dinosaurs 

12. On Fluid Balance in the Lung 

Praxis:

13. A Mesoscopic Superconductor as a Ballistic Quantum Switch 

14. On Charge Carriers in Conjugated Polymers 

15. Applications of Neutron Beams 

16. Improving Substrate Specificity of Small Catalytic Peptides 

17. On Reaction Interfaces in Chaotic Flows 

18. A Robust DNA Mechanical Device 

19. An Assessment of For-Profit vs. Nonprofit HMOs 

20.On Epithelial-Tumor-Metastatic Cells in Bone Marrow 

21. Selective Binding of Gold Nanoparticles to Bacteria 

22. Alcohol Use in the US Among Women of Child-Bearing Age 

23. On Survival of Blacks vs. Whites After a Cancer Diagnosis 

24. Smallpox: Virology and Pathogenesis

Miscellany:

25. In Focus: On Einstein, Planck, and Bose 

26. ScienceWeek Notices and Subscription Information

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Section 2

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1. ON NONEQUILIBRIUM MOLECULAR DYNAMICS

Contemporary molecular dynamics simulations, which are
extrapolations of statistical mechanics and which originate in
the work of Alder and Wainright in the 1960s, are computer
simulations of molecular systems typically involving hundreds or
sometimes thousands of idealized particles interacting with
physically realistic potentials. Such molecular dynamics
simulations can provide time-dependent properties of a liquid,
but most commonly they are used to produce a set of
configurations and forces which can be averaged to give
equilibrium properties of the system.

S. Bair et al (Georgia Institute of Technology, US) discuss
nonequilbrium dynamics, the authors making the following points:

1) Nonequilibrium molecular dynamics (NEMD) is a powerful method
for the molecular-based study of transport phenomena.(1) The
essence of the NEMD method is to create a nonequilibrium steady
state in a molecular simulation by application of an appropriate
external field (F). The applied external field produces a
conjugate flux (J), and the constitutive relation between the
field and the flux, J = - FX , defines a transport coefficient
(X). NEMD methods date to the 1970s; however, it was not until
the mid 1980s that the development of linear and nonlinear
response theory made it possible to rigorously derive correct
homogeneous algorithms consistent with periodic boundary
conditions, and to prove that in the zero-field (linear regime)
limit, a properly defined transport property (X) reduces to its
corresponding equilibrium system value. One caveat in the theory
of NEMD is that the existence of a nonlinear steady state is
predicated on the ability to thermostat the system (i.e., remove
heat generated dissipatively by the application of the external
field) in a physically meaningful way.

2) NEMD is a particularly useful technique for studying
rheological properties, since the key algorithm is a direct
implementation of the experimental method for measuring
viscosity, and because it can also be used to probe the
non-Newtonian regime, common to polymers and other high
molecular weight systems, in which the transport properties are
nonlinear in the applied field.

3) The authors report a study comparing nonequilibrium molecular
dynamics of a low-molecular-weight fluid (squalane) with
experimental measurements in both the linear (Newtonian) and
nonlinear (non-Newtonian) regimes. The experimental and
simulation data are demonstrated to follow the same
time-temperature superposition master curve. The authors suggest
this represents the first comparison of the nonlinear rheology
predicted by nonequilibrium molecular dynamics with experiment,
and is thus the first experimental test of nonequilibrium
molecular dynamics simulations in the nonlinear regime.(19,20)

References (abridged):

1. D.J. Evans and G.P. Morriss, Statistical Mechanics of
Nonequilibrium Liquids (Academic Press, New York, 1990)

19. R.B. Bird et al, Dynamics of Polymeric Liquids: Fluid
Mechanics (John Wiley and Sons, New York, 1987)

20. R.B. Bird et al, Dynamics of Polymeric Liquids: Kinetic
Theory (John Wiley and Sons, New York, 1987)

Phys. Rev. Lett. 2002 88:058302

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2. ON SOLVATED ELECTRONS IN CLUSTERS OF POLAR MOLECULES

In general, the term "solvation" refers to the association or
combination of a solute unit (e.g., ionic, molecular, or
particulate) with solvent molecules. This association may
involve chemical or physical interactions or both, and may vary
in degree from a loose and indefinite complex to the formation
of a distinct chemical compound, with such an entity containing
a definite number of solvent molecules per solute molecule.
Solvation occurring in aqueous solutions is referred to as
"hydration". In general, solvation is often the key process in
the phenomenon of solubility, since the interaction energy of
solute with solvent must be greater than the interaction energy
of solute molecules with themselves in order for the solute to
dissolve in the solvent. Some textbooks consider solvation to
signify hydration, but this is an error: when a piece of
paraffin, for example, dissolves in benzene, the dissolution of
the paraffin results from the solvation of paraffin molecules by
benzene molecules, the solvation in this case involving only van
der Waals interactions. Hydration is merely a specific type of
solvation, one that involves water molecules as solvent. 

M. Gutowski et al (Pacific Northwest National Laboratory, US)
discuss solvated electrons, the authors making the following
points:

1) A cluster of polar molecules can host an excess electron in
at least two ways. First, the excess electron can be tethered to
the cluster by its interaction with the cluster’s dipole moment.
Second, the electron can localize inside the cluster, bulk
analogs being the hydrated and ammoniated electrons.(3) While
the structural reorganization of the cluster, due to attachment
of an excess electron, is typically small for dipole-bound
electrons, it is usually quite significant for “solvated
electrons”, since the solvation occurs at the expense of
breaking of preexisting hydrogen bonds. The solvated electron
structures, however, provide more contact interactions between
the polar molecules and the excess electron. For these reasons,
it is often assumed that dipole-bound electrons dominate for
small polar clusters, whereas large clusters form solvated
electrons.

2) Low energy electrons are of paramount importance in
radiation-induced chemical processes, and negatively charged
clusters of polar molecules have been extensively studied, both
experimentally and theoretically. The isolated ten-electron
molecules, HF, H(sub2)O, and NH(sub3) , are closed-shell
species, which are not known to form stable associations with an
excess electron, i.e., stable anions. However, their
hydrogen-bonded assemblies, even as small as dimers, are known
to trap excess electrons and to form stable anions in the gas
phase]. Early studies of small anionic clusters composed of
intact polar molecules concentrated on dipole-bound electrons,
also known as surface electron states, in which the cluster’s
dipole moment is fortified by coalignment of the dipoles of the
monomers forming the cluster. On the other hand, solvated
electrons (sometimes referred to as internal electron states)
were considered inherent to large clusters of polar molecules.
Recently, however, theoretical studies have contradicted these
classical views.

3) The authors demonstrate that dipole-bound electrons and
solvated electrons coexist in as small a cluster as
(HF)(sub3)(--), and they suggest that the stability of these
anions with respect to the neutral cluster results not only from
the excess electron binding energy, but also from favorable
entropic effects, which reflect the greater “floppiness” of the
anionic structures.

References (abridged):

3. E.J. Hart and M. Anbar, The Hydrated Electron
(Wiley-Interscience, New York, 1970)

Phys. Rev. Lett. 2002 88:143001

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3. PROTON DIFFUSION IN PHOSPHOLIPID ASSEMBLIES

A "Langmuir trough" is an apparatus for measuring the dependence
of the surface force exerted by a film on the area of the film,
the film a substrate floating on a liquid with which it is
immiscible. The apparatus consists of a rectangular tank
containing the subnatant liquid (e.g., water) on which a known
amount of the immiscible substance (e.g., an oil of a higher
fatty acid) is introduced (e.g., a small quantity dropped on the
surface), with the oil spread between two parallel barriers to
form a film. One of the barriers is fixed, while the other
barrier may be moved to compress the film. The force exerted on
the film to achieve any given area is measured by a system of
levers and a torsion wire or balancing mass. With an appropriate
oil and the proper amount of oil delivered to the surface, a
monolayer of oil on the surface can be achieved. This apparatus,
since its invention by Irving Langmuir (1881-1957), has been
used in research not only in chemistry to analyze the physical
properties of various comounds, but also in biophysics and
biochemistry to analyze the various properties of the
amphipathic molecules comprising biological membranes. 

J. Zhang and P.R. Unwin (University of Warwick, UK) discuss
phospholipid membranes, the authors making the following points:

1) Proton conduction is important in a wide range of areas,
including photosynthesis in green plants, the production of
electricity in hydrogen fuel cells, electrochemical sensors,
electrochemical reactors, and electrochromic devices. In
biological systems, proton migration between source and sink
sites is a key step in bioenergetic processes in cellular
membranes. Such processes are controlled by pH gradients, which
couple, for example, electron transfer and ATP synthesis in
mitochondria, chloroplasts, and bacteria.(2) Lateral diffusion
has been proposed as a mechanism for proton transport, but it
has proved difficult to measure the rate of this process with
conventional techniques.

2) Langmuir monolayers of phospholipids at the air-water
interface are attractive models for physicochemical studies of
cellular membranes, because the composition of these
self-assembled systems is readily controlled and varied. Lateral
proton diffusion in monolayers has previously been investigated
by time-of-flight fluorescence measurements and by conductivity
over centimeter length scales. Facilitated lateral proton
conductance has been advocated for pure phospholipids (both
zwitterionic and acidic), phospholipid mixtures, and pure
protein monolayers. In contrast, laser pulse measurements of
proton dwell times in vesicles have found no evidence for
unusually high lateral proton mobility.

3) Scanning electrochemical microscopy (SECM) allows interfacial
dynamics and diffusion to be studied on small length and time
scales approaching those relevant to cellular membranes. In
recent applications to assemblies at the air-water interface,
SECM has been used to study lateral proton diffusion along a
stearic acid monolayer, the effect of a 1-octadecanol monolayer
on oxygen transfer across the air-water interface, and lateral
conductivity in assemblies of metal nanoparticles. In these
studies, the response of a probe ultramicroelectrode either
translated toward or held close to a spot at a target interface
was used to obtain quantitative data on a local scale.

4) The authors report they have developed a new scanning
electrochemical microscopy proton feedback method for
investigating lateral proton diffusion at phospholipid
assemblies: specifically Langmuir monolayers at the air-water
interface. In this approach, a base is electrogenerated by the
reduction of a weak acid (producing hydrogen) at a "submarine"
ultramicroelectrode placed in the aqueous sub-phase of a
Langmuir trough close to a monolayer. The electrogenerated base
diffuses to and titrates monolayer-bound protons and is
converted back to its initial form, so enhancing the current
response at the ultramicroelectrode. Local deprotonation of the
monolayer creates a concentration gradient for lateral proton
diffusion. A numerical model has been developed, taking into
account the potential-dependent association/dissociation
constant of the interfacial acid groups. A comparison is made of
monolayers comprising either acidic
DL-alpha-phosphatidyl-L-serine (DPPS) dipalmitoyl, or
zwitterionic L-alpha-phosphatidylcholine dipalmitoyl (DPPC)
monolayers at a range of surface pressures. It is demonstrated
that lateral proton fluxes at DPPS are significant, but the
lateral proton diffusion coefficient is lower than in bulk
solution. In contrast, lateral proton diffusion cannot be
detected at DPPC, suggesting that the acid/base character of the
phospholipid is important in determining the magnitude of
interfacial proton fluxes.

References (abridged):

2. R.B. Gennis, Biomembranes: Molecular Structure and Function;
Springer-Verlag, New York, 1989

J. Am. Chem. Soc. 2002 124:2379

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4. ON THE END OF THE COSMIC DARK AGE

Martin J. Rees (University of Cambridge, UK) discuss the cosmic
dark age, the author making the following points:

1) Our universe started off intensely hot, bright, and dense,
cooling down as it expanded. After about half a million years,
the temperature fell below 3000 kelvins. Thereafter, the
primordial black-body radiation shifted into the infrared, and
the cosmos became utterly dark. The dark age was over by the
time the universe was a billion years old. By then, the first
quasars observed today had lit up. These quasars are probably
powered by massive black holes in the centers of galaxies. Their
presence thus implies that some galaxy-scale structures had
formed by then. But cosmic structures seem to develop in a
hierarchical way: Small-scale structures form first and then
agglomerate into larger systems. So the stars that provided the
very first cosmic light could have formed earlier, in units
smaller than present-day galaxies. But how much earlier? And
what were these first stars like?

2) Theorists are now deploying elaborate computer codes to
address these questions. At first sight, these projects may seem
overambitious -- after all, present-day star formation is still
poorly understood. We can map the dusty giant molecular clouds
where stars are now forming in our galaxy, but even with that
information we still cannot accurately model the rate at which
stars condense nor their distribution of masses. The first stars
formed in a very different environment, to which theory is our
only guide. The physical conditions were, however, simpler than
today, and the starting conditions are well defined.

3) Matter was initially distributed fairly smoothly, but gravity
enhances density contrasts in an expanding universe: Overdense
regions are decelerated by an excess gravitational force, so
that they expand progressively slower than their surroundings
and eventually condense out. According to the standard "hot big
bang" model, the primordial gas consisted of 77 percent by
weight of hydrogen and 23 percent of helium, with traces of
deuterium and lithium. The main coolant in this mixture was
molecular hydrogen, which is inefficient below 200 kelvins; the
gas therefore could not get as cool as 10 kelvins, the
prevailing temperature in giant molecular clouds. Also, magnetic
fields, thought to be important in present-day star formation,
were probably absent.

4) Recent computer simulations by Abel et al (2001) demonstrate
that by the time the universe was 100 million years old, the
dark matter had developed an intricate filamentary structure. At
the density peaks where filaments intersect, gravitationally
bound concentrations of dark matter condense out. The gas
"feels" the gravitational pull of these irregular clumps of dark
matter. Gas pressure tends to smooth its small-scale
distribution, but clumps with masses exceeding a few times 105
solar masses provide a deep enough potential well to overwhelm
the pressure of the gas and pull it inward. Moreover, the
infalling gas gets hot enough (a few hundred kelvins) for
collisional excitation of H(sub2), followed by photon emission,
to carry energy away, thereby allowing further contraction and
compression. This sets the stage for the formation of the first
stars.

Science 2002 295:51

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5. ON THE EFFECTIVE MASS OF COMPOSITE FERMIONS

Fermions (electrons, protons, neutrons) are particles that obey
the Pauli exclusion principle: i.e., no two fermions of the same
kind can occupy the same quantum state.

The term "quasiparticle" refers to a propagated perturbation in
a medium (or field) that behaves as a particle, with energy
(mass) and momentum, and that can be treated as such
theoretically.

In classical physics, the Hall effect is the development of a
transverse voltage across a current-carrying conductor in a
magnetic field, the voltage being perpendicular to both the
direction of the current and the direction of the magnetic
field. In quantum physics, there are two other Hall effects, an
integer charge quantum Hall effect, and a fractional charge
quantum Hall effect, these quantum Hall effects being observed
at extremely low temperatures (a few degrees Kelvin) and
extremely intense magnetic fields (at least several tesla). Both
quantum Hall effects were first noted in the 1980s, and the
fractional quantum Hall effect, although experimentally
observed, has not been theoretically resolved.

L.V. Kukushkin et al (Max Planck Institute for Solid-State
Physics Stuttgart, DE) discuss composite fermions, the authors
making the following points:

1) It is occasionally possible to interpret strongly interacting
many-body systems within a single-particle framework by
introducing suitable fictitious entities, or "quasi-particles".
A notable recent example of the successful application of such
an approach is for a two-dimensional electron system that is
exposed to a strong perpendicular magnetic field. The conduction
properties of the system are governed by electron–electron
interactions, which cause the fractional quantum Hall effect.(1)
Composite fermions, electrons that are dressed with magnetic
flux quanta pointing opposite to the applied magnetic field,
were identified as apposite quasi-particles that simplify our
understanding of the fractional quantum Hall effect. They
precess, like electrons, along circular cyclotron orbits, but
with a diameter determined by a reduced effective magnetic
field.(5) The frequency of their cyclotron motion has hitherto
remained enigmatic, as the effective mass is no longer related
to the band mass of the original electrons and is entirely
generated from electron–electron interactions.

2) The authors experimentally demonstrate enhanced absorption of
a microwave field in the composite fermion regime, and interpret
it as a resonance with the frequency of composite fermion
circular motion. From this inferred cyclotron resonance, the
authors derive a composite fermion effective mass that varies
from 0.7 to 1.2 times that of the electron mass in vacuum as
their density is tuned from 0.6 x 10^(11) cm^(-2) to 1.2 x
10^(11) cm^(-2).

References (abridged):

1. Das Sarma, S. and Pinczuk, A. (eds.) Perspectives on Quantum
Hall Effects (Wiley, New York, 1996)

5. Heinomen, O. (ed.) Composite Fermions (World Scientific,
Singapore, 1998)

Nature 2002 415:409

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6. BIOMASS BURNING, CUMULUS CLOUDS, AND STRATOSPHERIC MOISTURE

The atmosphere of Earth is divisible into several layers, each
layer having a characteristic temperature range, pressure range,
and composition. The layers, from the surface of Earth, are
(with thicknesses varying at different latitudes): troposphere
(0 to approximately 10 kilometers), stratosphere (from
approximately 10 to 50 kilometers), mesosphere (approximately 50
to 80 kilometers), thermosphere (approximately 80 to 500
kilometers), and exosphere (above approximately 500 kilometers.
Other layers, essentially meta-layers, are also recognized: a)
the "chemosphere" is the region between approximately 32 and 92
kilometers where many important chemical reactions occur; b) the
"ionosphere", above approximately 80 kilometers, is a shell of
high electron concentration resulting from very short wavelength
sunlight stripping electrons from atoms and molecules (mainly
oxygen and nitrogen) to create an ionized layer; c) the
magnetosphere is the constantly changing magnetic field
generated by the Earth's dynamo, this magnetic field influencing
the behavior of electrically charged particles and the field
extending approximately 10 Earth radii (64,000) kilometers into
space on the sunward side.


Steven Sherwood (Yale University, US) discusses stratospheric
moisture, the author making the following points

1) Data collected during the last half-century appear to
indicate an approximate doubling of stratospheric water vapor
during this period, of which approximately half can be accounted
for by increases in stratospheric production of water vapor by
methane oxidation.(1) The other half presumably results from
increases in the moisture content of air entering the
stratosphere through the tropical tropopause. However,
temperatures near this entry point, which were thought to
regulate stratospheric moisture levels, have not increased
during recent decades.(2,3) This implies that either relative
humidity near the tropopause has substantially increased, or
other pathways exist whereby moisture can enter the
stratosphere. The importance of this problem is underscored by
recent findings that stratospheric moisture increases may be a
significant contributor to global temperature trends(4) and may
also interfere with the recovery of polar ozone by exacerbating
destruction mechanisms.(5)

2) The author demonstrates that fluctuations in stratospheric
humidity can indeed be caused by fluctuations in relative
humidity just below the tropical tropopause, which in turn are
governed by the sizes of ice crystals lofted in deep convective
updrafts. The moisture content of air entering the stratosphere
is thought to be controlled by condensation of vapor to the ice
phase in transient lifting events outside of convective cells
and/or phase changes within intense convective cells themselves.
The relative importance of these two controlling factors is
unknown. Convective moistening or drying should depend not only
on temperature but also on the propensity of lofted ice to
evaporate at a level high enough ( > 14 to 15 kilometers) so
that the vapor will enter the stratosphere rather than subsiding
back into the troposphere. It has been widely assumed that
condensation outside of convection resets the water vapor to a
lower value independent of convective influence, but the
evidence presented by the author argues against this assumption.

3) In summary: The author establishes a likely causal chain that
connects humidity in the stratosphere, relative humidity near
the tropical tropopause, ice crystal size in towering cumulus
clouds, and aerosols associated with tropical biomass burning.
The connections are revealed in satellite-observed fluctuations
of each quantity on monthly to yearly time scales. More aerosols
lead to smaller ice crystals and more water vapor entering the
stratosphere. The connections are consistent with physical
reasoning, probably hold on longer time scales, and may help to
explain why stratospheric water vapor appears to have been
increasing for the past five decades.

References (abridged):

1. K. H. Rosenlof, et al., Geophys. Res. Lett. 28:1195 (2001).

2. D. J. Seidel et al, J. Geophys. Res. 106:7857 (2001).

3. X. L. Zhou et al, J. Geophys. Res. 106:1511 (2001).

4. P. M. D. Forster and K. P. Shine, Geophys. Res. Lett. 26:3309
(1999).

5. D. B. Kirk-Davidoff et al, Nature 402:399 (1999)

Science 2002 295:1272

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7. IN VITRO DEVELOPMENT OF MALARIA MOSQUITO

The disease malaria is caused by a type of protozoan with the
general name Plasmodium, an organism characterized by a sequence
of life cycles involving different organismic forms. The asexual
cycle occurs in the liver and red blood cells of vertebrates
(including humans), and the sexual cycle occurs in mosquitoes.
Essentially, the asexual form is ingested by blood-sucking
mosquitoes, and in the mosquito the asexual form is induced to
produce the sexual form necessary to complete the total life
cycle. The details of the process are as follows: Plasmodium
cells called "gametocytes" (precursors of gametes) in human
blood are ingested by the mosquito, and in the mosquito,
apparently within seconds, gametocytes are induced into
"gametogenesis", producing gametes. These gametes produce a
cell-type called "sporozoites", which accumulate in the salivary
gland of the mosquito, from where they are injected into the
vertebrate blood stream when the mosquito feeds on vertebrate
blood. The sporozoites accumulate in the vertebrate liver, where
they multiply and produce a form (merozoites) that invades red
blood cells, replicates, destroys red blood cells, and so on,
with an eventual decline in this asexual replication. However,
after invasion of red blood cells, some merozoites produce
gametocytes, which have the genomic potential for restarting the
total life cycle. These gametocytes cannot self-replicate, and
they die unless ingested by a mosquito, but once in the
mosquito, the total life cycle begins again. There are
apparently 2 inducers of gametogenesis in vivo (i.e., in the
mosquito): one inducer is a pH of 7.5 to 7.6, and the other
inducer has been thought to be an unknown mosquito-derived
gametocyte-activating factor.

E.M. Al-Olayan et al (Keele University, UK) discuss the complete
development of the malaria parasite in vitro, the authors making
the following points:

1) For over a century, a major objective of malaria control
programs has been to block parasite transmission by mosquitoes.
Such approaches would clearly benefit from a better
understanding of parasite development within the vector,
initiated when gametocytes are taken up in a blood meal.
Fertilization of macrogametes within the mosquito midgut
produces zygotes that transform into motile and invasive
ookinetes. These penetrate and traverse the midgut epithelium
and become sessile vegetative oocysts lying beneath the midgut
basement lamina, each potentially producing 2 to 8000
sporozoites. Knowledge of the mosquito-related factors
regulating these processes is improving, but it is difficult to
determine the specific and separate effects of these factors in
vivo. Early events associated with midgut invasion have recently
been studied in vitro with the use of midgut preparations or
co-cultured mosquito cells, but these systems do not sustain
long-term development or simulate oocyst interaction with the
basal lamina and do not permit investigation of sporozoite
differentiation.

2) Fertilization and ookinete development can be achieved in
vitro for many malaria parasite species, including Plasmodium
berghei, a parasite of rodents. These culture systems have
facilitated the study of ookinete molecules that may be targeted
by antibodies induced by transmission-blocking vaccines or
drugs. After many pioneering attempts, it is only recently that
in vitro transformation of Plasmodium gallinaceum and Plasmodium
falciparum ookinetes into oocysts and sporozoites has been
achieved, but the numbers of oocysts produced are low and, more
importantly, the infectivity of these sporozoites has not been
demonstrated.

3) The authors report they have cultured gametocytes of
Plasmodium berghei through to infectious sporozoites with
efficiencies similar to those recorded in vivo and without the
need for salivary gland invasion. Oocysts developed
extracellularly in a system whose essential elements include
co-cultured Drosophila S2 cells, basement membrane matrix, and
insect tissue culture medium. Sporozoite production required the
presence of para-aminobenzoic acid. Thus the entire life cycle
of P. berghei, a useful model malaria parasite, can now be
achieved in vitro, and the authors suggest this immediately
opens up important new areas of investigation.

References (abridged):

1. P. F. Billingsley and R. E. Sinden, Parasitol. Today 13:297
(1997).

2. A. Ghosh, M. J. Edwards, M. Jacobs-Lorena, Parasitol. Today
16:196 (2000)

3. R. E Sinden and P. F. Billingsley, Trends Parasitol. 17:209
(2001).

4. M. Shahabuddin and P. F. Pimenta, Proc. Nat. Acad. Sci.
95:3385 (1998).

5. H. Zieler and J. A. Dvorak, Proc. Nat. Acad. Sci. 97:11516
2000).

Science 2002 295:677

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8. ON CHEMOTAXIS IN BACTERIA

In general, the term "chemotaxis" refers to any movement of an
organism in response to chemical concentration gradients, and
such movements are of extreme importance in maintaining the
viability of microorganisms such as bacteria. In general,
chemotaxis allows the bacterium to adjust its swimming behavior
so that it can sense and migrate toward increasing levels of an
attractant chemical or away from a repellent one.

J.E. Gestwicki and L.L. Kiessling (University of Wisconsin
Madison, US) discuss bacterial chemotaxis, the authors making
the following points:

1) The sensing mechanisms of chemotactic bacteria allow them to
respond sensitively to stimuli. Escherichia coli, for example,
respond to changes in chemoattractant concentration of less than
10 percent over a range spanning six orders of magnitude.(1,2)
Sensitivity over this range depends on a nonlinear relationship
between ligand concentration and output response.(3) At low
ligand concentrations, substantial amplification of the
chemotactic signal is required, but the mechanism responsible
for this amplification remains unclear.

2) A family of at least four chemoreceptors (methyl-accepting
chemotaxis proteins; MCPs) mediates metabolism-independent
chemotactic responses in E. coli6. The high-abundance
chemoreceptors of this family (Tsr and Tar) mediate responses to
serine and aspartate, respectively; the low-abundance
chemoreceptors (Tap and Trg) are present at only 10 percent of
the concentration of Tsr. Responses to dipeptides are
transmitted through Tap. Trg mediates responses to galactose and
ribose by means of their respective periplasmic binding proteins.

3) The authors report a demonstration that inter-receptor
communication within a lattice(4,5) acts to amplify and
integrate sensory information. Synthetic multivalent ligands
that interact through the low-abundance, galactose-sensing
receptor Trg stabilize large clusters of chemoreceptors and
markedly enhance signal output from these enforced clusters. On
treatment with multivalent ligands, the response to the
attractant serine is amplified by at least 100-fold. This
amplification requires a full complement of chemoreceptors;
deletion of the aspartate (Tar) or dipeptide (Tap) receptors
diminishes the amplification of the serine response. The authors
suggest that these results demonstrate that the entire array is
involved in sensing, and that this mode of information exchange
has general implications for the processing of signals by
cellular receptors.

References (abridged):

1. Mesibov, R., Ordal, G. W. & Adler, J. The range of attractant
concentrations for bacterial chemotaxis and the threshold and
size over this range. J. Gen. Physiol. 62:203-223 (1973).

2. Adler, J., Hazelbauer, G. L. & Dahl, M. M. Chemotaxis towards
sugars in Escherichia coli. J. Bacteriol. 115:824-847 (1973).

3. Jasuja, R., Yu-Lin,, Trentham, D. R. & Khan, S. Response
tuning in bacterial chemotaxis. Proc. Nat. Acad. Sci.
96:11346-11351 (1999).

4. Duke, T. A. J. & Bray, D. Heightened sensitivity of a lattice
of membrane receptors. Proc. Nat. Acad. Sci. 96:10104-10108
(1999).

5. Bray, D., Levin, M. D. & Morton-Firth, C. J. Receptor
clustering as a cellular mechanism to control sensitivity.
Nature 393:85-88 (1998).

Nature 2002 415:81

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9. COMPLEXITY, PROTEINS, AND THE ENERGY LANDSCAPE

The term "complexity" is fashionable in science these days, the
interest presumed to indicate a movement away from reductionism,
away from the idea that the behavior of a system is best
understood in terms of how the components of the system behave
and interact. A focus on "complexity", however, is not perforce
anti-reductionist. Indeed, in practice, with real systems, the
behavior of a system is often not predictable from knowledge of
the behavior of its components, but most often this is simply
because that knowledge is incomplete, and not because of any
_principle_ barring prediction of the behavior of the system
from knowledge of its parts. Even systems exhibiting *chaotic
fluctuations are not necessarily non-reductionist, since such
systems are mathematically deterministic. In any case, faced
with an apparent unpredictability of a system given available
information about its parts, one looks for predictive global
methods to understand the system, methods that do not depend
upon a detailed knowledge of the behavior of the components of
the system. Thermodynamics is exactly such a global method of
great utility in chemistry and physics, and since thermodynamics
is a method of analysis that goes back to its originator Carnot
in 1824, one can safely say that the idea of special methods to
deal with "complexity" is quite old. In our time, at least for
ideal systems, we can derive the equations of thermodynamics
from statistical mechanics, i.e., derive the global equations
from equations for the behavior of components. But Nicolas Sadi
Carnot (1796-1832) never heard of statistical mechanics, which
was introduced by Boltzmann (1844-1906) in 1871; Carnot founded
thermodynamics as a predictive global method to deal with an
important "complex" system of his time -- the steam engine.

Hans Frauenfelder (Los Alamos National Laboratory, US) discusses
proteins and complexity, the author making the following points:

1) What is complexity? Which systems are complex? What are the
crucial concepts in complex systems? A system can be called
complex if it can assume a large number of states or
conformations and if it can carry information. One often hears
even biologists talk about "astronomically large numbers."
Astronomically large numbers are actually very small compared
with biological numbers. They are of the order of 10^(200) or
log n(subastro) of approximately 200. Consider now DNA. It is
built from four different units (bases) and may contain 10^(9)
bases. The number of conceivable DNAs is therefore log n(subbio)
of approximately 10^(8), which is much greater than log
n(subastro). The number of possible proteins is of the order of
log n(subprot) >> 200. Even the number of states that an
individual protein can assume is very large. Biological systems
clearly also carry information. Hence proteins, and in general
biological systems, are complex.

2) Proteins are built from 20 different amino acids (1, 2).
Directed by the DNA, of the order of a few hundred of these
building blocks are linked together into a linear polypeptide
chain. The order in which the different amino acids are inserted
determines structure, function, and dynamics. In the proper
solvent, the chain folds into a compact structure that is often
globular and that has linear dimensions of a few nanometers.
Proteins perform essentially all functions in biological
systems. The textbook picture of a protein is clear: The folded
structure is unique; each atom is in its proper place. The
pictures obtained by x-ray diffraction techniques appear to
support this -- at first sight -- appealing situation. Such
proteins would be aptly characterized by Schroedinger's words,
"aperiodic crystals" (3). Reality, however, is different.
Proteins are dynamic and not static systems, and they must
perform motions to execute their functions. Motions are possible
only if a given protein can assume a large number of somewhat
different conformations, for instance with open and closed
channels. Actually, the motions involve the atoms not just of
the protein itself but also of the hydration shell, a layer of
water surrounding the protein. The structure and dynamics of the
protein and the hydration shell can be characterized by the
energy or conformation landscape.

3) The energy landscape is a construct in 3N dimensions, where N
is the number of atoms in the protein and the hydration shell.
The energy landscape contains valleys and saddle points between
valleys. We call each valley a conformational substate. A
substate describes the structure of the entire protein, because
it characterizes the positions of all atoms. Transitions between
substates correspond to protein motions. Unfortunately, it is
difficult to visualize the landscape, because it lives in a
hyperspace. One- or two-dimensional cross sections can give a
misleading impression. One difference between such a
representation and the complete landscape is the path between
two substates. In the low-dimensional cross section, it may
appear that the protein has to overcome many saddles, whereas in
reality only one or two steps may be necessary. One goal of the
physics approach to proteins is the exploration of the energy
landscape. In no protein is the entire landscape known. This
state is not surprising if one contemplates how many years it
took to determine the energy levels of complex nuclei or
atomssystems that are far simpler than proteins. 

References:

1. Stryer, L. (1995) Biochemistry (Freeman, New York).

2. Fersht, A. (1999) Structure and Mechanism in Protein Science
(Freeman, New York).

3. Schroedinger, E. (1944) What Is Life? (Cambridge Univ. Press,
Cambridge, U.K.). 

Proc. Nat. Acad. Sci. 2002 99:2479

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10. ECOLOGY: POPULATION DYNAMICS OF SOLITARY BIRDS

B.E. Saether et al (Norwegian University of Science and
Technology, NO) discuss population dynamics of birds, the
authors making the following points:

1) One of the challenges in ecology is to identify
characteristics that can be used to predict interspecific
differences in patterns of population fluctuations. Comparisons
covering a wide range of taxa have shown a strong pattern of
covariation of life history traits that divide species along a
"slow-fast continuum".(2,5) Life history characteristics such as
early onset of reproduction, rapid ontogenetic development, and
large litter sizes are typical for species at one end of this
continuum, whereas species with low reproductive rates, but
longer life expectancies, are found at the other end. Several
hypotheses have been proposed to explain this covariation among
life history traits, e.g., density-dependent r-K selection,
adaptive life history responses to differences in extrinsic
mortality, or adaptations to variation in predictability or
variability of the habitats. Few studies have, however,
quantitatively examined how characteristics of the population
dynamics are related to the species' position along this
continuum of life history variation; an exception was Fowler,
who showed that the pattern of density regulation was related to
the rate of increase per generation. The presence of such
patterns will enable characterization of patterns in population
fluctuations from knowledge of basic demography or life history
characteristics.

2) The authors report a study using time-series data on
populations of solitary bird species. The authors report they
found that fluctuations in population size of solitary birds
were affected by deterministic characteristics of the population
dynamics as well as stochastic factors. In species with highly
variable populations, annual variation in recruitment was
positively related to the return rate of adults between
successive breeding seasons. In stable populations, more
recruits were found in years with low return rates of breeding
adults. This identifies a gradient, associated with the position
of the species along a "slow-fast" continuum of life history
variation, from highly variable populations with a
recruitment-driven demography to stable, strongly
density-regulated populations with a survival-restricted
demography. The authors suggest these results indicate that
patterns in avian population fluctuations can be predicted from
a knowledge of life-history characteristics and/or temporal
variation in certain demographic traits.

References (abridged):

2. R. C. Lewontin, in The Genetics of Colonizing Species, H. G.
Baker, G. L. Stebbins, Eds. (Academic Press, New York, 1965),
pp. 77-91.

5. E. L. Charnov, Life History Invariants (Oxford Univ. Press,
Oxford, 1993).

Science 2002 295:2070

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11. ON THE MOBILITY OF LARGE DINOSAURS

The term "Theropoda" (theropods) refers to a suborder of
dinosaurs, all of which were carnivorous, that ranged in size
from that of a chicken to the huge Tyrannosaurus, which weighed
6 tons or more. Theropod fossils have been recovered from the
late Triassic through the late Cretaceous periods (from 230 to
66.4 million years ago), and from all continents except
Antarctica. All the theropods were bipeds, with strong hind legs
designed for support and locomotion, and with short forelimbs
and mobile hands apparently adapted for grasping and tearing
prey. Theropod feet usually resembled the feet of birds, and
many researchers believe that all modern birds are descended
from one lineage of small theropods.

Tyrannosaurus was the largest of the theropods. It was a massive
two-legged animal with a powerful tail, large head and tiny
arms. Its primary weapon was its mouth, with a 1.2 meter-long
jaw and a 1 meter gape. Curved serrated teeth, longer than a
human hand, could be used to puncture an animal's organs. The
first reasonably complete Tyrannosaurus skeleton was discovered
by Barnum Brown in Hell Creek, Montana in 1902.

Andrew A. Biewener (Harvard University, US) discusses the
mobility of large dinosaurs, the author making the following
points:

1) Over the course of history, vertebrates have evolved an
enormous range of sizes, spanning well over six orders of
magnitude in body mass. The largest and most captivating
terrestrial giants were the dinosaurs, and Tyrannosaurus —
although not the largest at around 6000 kilograms — is perhaps
the most famous and terrifying representative of this group.
Some workers(1) have argued that bipedal tyrannosaurs and other
huge dinosaurs could not move fast because their size would have
imposed severe constraints on physiological and mechanical
functions. But others claim that these creatures were much more
athletic.(3,4)

2) The skeletal muscles in all animals are made of the same
contractile proteins, so their intrinsic capacity for generating
force is very nearly the same. The force that can be produced
depends on the cross-sectional area of a muscle's fibres. But as
body size increases, the geometrical effects of scale mean that
muscle capability does not increase proportionately. The force
that a muscle can generate increases less rapidly than body
weight, so, despite their greater volume, the muscles of larger
animals generate less force per unit weight. In addition, the
ability of an animal's skeleton to support mechanical loads
decreases with size because bone area does not increase nearly
as fast as an animal's weight. Living terrestrial mammals can
accommodate these problems of scale by altering their limb
posture when they run: larger animals run on more erect limbs
than much smaller animals, which gives their muscles greater
mechanical advantage6 and allows them to maintain similar
capacities of force generation and bone loading. But this only
applies to animals as large as 300 kilograms or so. Above this
weight, further changes in muscle mechanical advantage are
probably limited, and sustaining force capacity for movement at
greater speeds becomes a problem.

3) An obvious difficulty in resolving the problem is that
dinosaurs have been extinct for a long time, so reconstructing
how they moved is a challenge. But Hutchinson and Garcia (2002)
recently introduced a new biomechanical approach to the problem,
applying an analysis of living animals to their ancient dinosaur
relative. They show that Tyrannosaurus simply did not have large
enough leg muscles to produce the forces required for an animal
of such size to run.

References (abridged):

1. Alexander, R. McN. Dynamics of Dinosaurs and Other Extinct
Giants (Columbia Univ. Press, New York, 1989.

3. Bakker, R. T. Dinosaur Heresies (Willam Morrow, New York,
1986.

4. Paul, G. S. Predatory Dinosaurs of the World (Simon &
Schuster, New York, 1988.

Nature 2002 415:971

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12. ON FLUID BALANCE IN THE LUNG

The term "homeostasis" refers to a physiological equilibrium
necessary in general for the viability of an organism, and in
particular for the operation of many cellular functions.
Homeostatic mechanisms in biological systems usually involve an
element of negative feedback signaling. In vertebrates, for
example, when blood temperature is too high, temperature
receptors provoke a sequence of events involving many pathways
that ultimately results in a lowering of body temperature.
Similar homeostatic mechanisms operate at cellular levels.

M.D. Johnson et al (University of California San Francisco, US)
discuss fluid balance in the lung, the authors making the
following points:

1) How the lung establishes and maintains homeostasis of
airspace fluid is of major clinical importance. At birth, the
respiratory epithelium must rapidly resorb large amounts of
fluid as the fetal lung converts from fluid secretion to fluid
reabsorption to survive in an air environment. After birth,
establishment and maintenance of an appropriate thin fluid
subphase in the alveoli is essential for gas exchange. Mass
transfer of gases between the air and blood compartments in the
alveoli is rapid because both the cellular anatomic barrier and
the liquid alveolar lining layer are very thin and the alveolar
surface area is large. Pulmonary edema, an abnormal accumulation
of fluid in the air spaces that impairs gas exchange, may occur
in a variety of different pathologic states, including cardiac
failure, trauma, sepsis, and pneumonia. This disturbance of
normal lung fluid balance can impair gas exchange and lead to
morbidity and mortality. Precise regulation of lung fluid
balance is therefore crucial for gas exchange, and, ultimately,
for survival.

2) Fluid balance is driven by osmotic gradients created by
active solute transport (1). It is thought that the alveolar
epithelium maintains the airspace relatively free of liquid via
active transport of solutes (2), with Na+ influx occurring via
movement through apical epithelial Na+ channels in response to
an electrochemical gradient created by basolateral Na+-,
K+-ATPase. The resulting osmotic gradient leads to fluid
reabsorption from the alveolar space (reviewed in refs. 3 and 4).

3) The surface area available for gas exchange and fluid
reabsorption in the lung is large, approximately 100 to 150
square meters in human lung (5). The alveolar epithelium,
comprised of alveolar type I (TI) and type II (TII) cells, lines
more than 99 percent of the internal surface area. TII cells,
which cover 2 to 5 percent of the surface area, produce,
secrete, and recycle pulmonary surfactant. TII cells, which
contain both Na+-, K+-ATPase, and amiloride-sensitive epithelial
Na+ channels, actively transport Na+ in culture. Very little is
known about TI cells because this cell type is difficult to
isolate. Current concepts about TI cells are that they are
"inert" cells that provide solely a barrier function, rather
than having active functions.

4) The authors report a study that demonstrates that TI cells
not only contain molecular machinery necessary for active ion
transport, but also transport ions. The authors suggest these
results modify some basic concepts about lung liquid transport
and indicate that TI cells may contribute significantly in
maintaining alveolar fluid balance and in resolving airspace
edema.

References (abridged):

1. Diamond, J. M. (1979) J. Membr. Biol. 51, 195-216

2. Saumon, G. & Basset, G. (1993) J. Appl. Physiol. 74, 1-15

3. Matalon, S. , Benos, D. J. & Jackson, R. M. (1996) Am. J.
Physiol. 271, L1-L22

4. Matalon, S. & O'Brodovich, H. (1999) Annu. Rev. Physiol. 61,
627-66

5. Weibel, E. R. (1963) Morphometry of the Human Lung (Springer,
Berlin).

Proc. Nat. Acad. Sci. 2002 99:1966

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13. A MESOSCOPIC SUPERCONDUCTOR AS A BALLISTIC QUANTUM SWITCH

In this context, the term "ballistic" (as opposed to the term
"diffusive") refers to the passage of electrons through a
conductor whose length is less than the mean free path of
electrons in the conductor, with the result that most of the
electrons pass through the conductor without scattering.

In this context, the term "quasiparticle" refers to a propagated
perturbation in a medium (or field) that behaves as a particle,
with energy (mass) and momentum, and that can be treated as such
theoretically. Quasiparticles are important conceptions in
condensed-matter physics and nuclear physics. Any traveling
energy perturbation can be treated as a traveling quasiparticle,
and in certain cases such treatment yields new insights into the
behavior of various systems. Some physicists, in fact, have
proposed that since every so-called "actual particle" can be
considered a traveling mass-energy perturbation of a field,
every particle is a quasiparticle and the prefix "quasi-" is
superfluous.

A.S. Mel'nikov and V.M. Vinokur (Argonne National Laboratory,
US) discuss superconductors, the authors making the following
points:

1) Several key experiments(1-3) have revealed a rich variety of
vortex structures in mesoscopic superconductors, structures in
which only a few quanta of magnetic flux are trapped: these
structures are polygon-like vortex "molecules" and multi-quanta
giant vortices. Ginzburg–Landau calculations(4) confirmed
second-order phase transitions between the giant vortex states
and stable molecule-like configurations(5).

2) The authors report a theoretical study of the electronic
structure and the related phase-coherent transport properties of
such mesoscopic superconductor systems. The quasiparticle
excitations in the vortices form coherent quantum-mechanical
states that offer the possibility of controlling phase-coherent
transport through the sample by changing the number and
configuration of trapped flux quanta. The sample conductance
measured in the direction of the applied magnetic field is
determined by the transparency of multi-vortex configurations,
which form a set of quantum channels. The transmission
coefficient for each channel is controlled by multiple Andreev
reflections within the vortex cores and at the sample edge.
These interference phenomena result in a stepwise behaviour of
the conductance as a function of the applied magnetic field, and
the authors state they propose to exploit this effect to realize
a vortex-based quantum switch where the magnetic field plays the
role of the gate voltage.

3) The authors point out that Giaever (1969) was the first to
notice that when magnetic flux gets trapped in a superconductor,
the small normal areas that appear in parallel with
superconducting areas influence transport characteristics. The
authors report they find that phase-coherent transport mediated
by the quasiparticle Andreev states associated with these normal
domains enables one to tune the probability of tunnelling
through a superconductor by changing the external magnetic
field. The authors demonstrate that owing to a peculiar parity
effect in the spatial distribution of the quasiparticle density
of states, the ballistic conductance of a thin superconducting
disk squeezed between very sharp contacts placed at the very
center of the disk can alternate between finite and near-zero
values as a function of magnetic field. In this regime, the
mesoscopic superconductor realizes a quantum vortex switch where
the external magnetic field plays the role of gate voltage.

References (abridged):

1. Boato, G. et al. Direct evidence for quantized flux threads
in type II superconductors. Solid State Commun. 3, 173-176
(1965). 

2. McLachlan, D. S. Quantum oscillations and the order of the
phase charge in a low k type II superconducting microcylinder.
Solid State Commun. 8, 1589-1593 (1970).

3. Geim, A. K. et al. Fine structure in magnetization of
individual fluxoid states. Phys. Rev. Lett. 85, 1528-1531 (2000).

4. Schweigert, V. A., Peeters, F. M. & Deo, P. S. Vortex phase
diagram for mesoscopic superconducting disks. Phys. Rev. Lett.
81, 2783-2786 (1998).

5. Chibotaru, L. F. et al. Symmetry-induced formation of
antivortices in mesoscopic superconductors. Nature 408, 833-835
(2000).

Nature 2002 415:60

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14. ON CHARGE CARRIERS IN CONJUGATED POLYMERS

An "exciton" is a quasiparticle, a combination of an electron
and a positive hole, the exciton free to move through a
nonmetallic crystal as a unit. Although it transports energy,
the exciton has no net electrical charge. When an electron in an
exciton recombines with a hole, the original atom is restored
and the exciton vanishes. When this occurs, the energy of the
exciton may be converted into light, or the energy may be
transferred to an electron of a neighboring atom with the
production of a new translocatable exciton.

The term "polaron" also refers to a quasiparticle, an electron
moving through constituent atoms in a solid, with the electron
causing neighboring positive charges to shift toward it and
neighboring negative charges to shift away. Thus, a polaron is
essentially a propagated polarization. In general, a polaron
behaves as a negatively charged particle with a mass greater
than that of an isolated electron, the increased mass due to the
energy of interaction with the surrounding atoms of the solid.
Polaron phenomena are most pronounced in ionic solids.

J.G. Mueller et al (Ludwig-Maximilians University, DE) discuss
charge carriers in conjugated polymers, the authors making the
following points:

1) The transition from a neutral excited state to a pair of
charge carriers and the reverse process determine the operation
of organic photodetectors and organic light emitting diodes. In
the field of conjugated polymers, the interplay between emissive
and nonemissive neutral states and charged quasiparticles has
been a subject of intense research during the past few years
(1,2). Apart from singlet and triplet intrachain excitons, pairs
of oppositely charged excitations have been invoked to explain
the experimental observations. Among those are spatially
indirect excitons (3), intrachain and interchain polaron pairs
(4), as well as geminate pairs (5). Such excitations are
expected to be particularly important in the presence of a
strong electric field lowering the energy of states with charge
transfer character.

2) Although experiments have clearly proven the existence of
such intermediate states, not much is known about the yield for
the formation of such states, their dynamics and mutual
interplay with singlet intrachain excitons, and their role in
photocurrent generation. Recently, Arkhipov et al (1999)
discussed the idea that ultrafast formation of intrachain
polaron pairs due to hot exciton dissociation during vibrational
relaxation is the main source for intrinsic photocarrier
generation in conjugated polymers.

3) The authors report photocurrent experiments using two
femtosecond laser pulses on a photodiode with a ladder-type
conjugated polymer as the active layer. With a photon energy of
3.1 eV, the first pulse excites singlet excitons. A time-delayed
second pulse with a photon energy of 2.49 eV leads to a decrease
of the photocurrent by exciton depletion due to stimulated
emission. S(sub1) excitons dissociated during their entire
lifetime are identified as the only relevant channel for charge
carrier generation. Intrachain polaron pairs are also formed on
an ultrafast time scale with a yield of approximately 10 percent
. They can be efficiently dissociated by reexcitation with
photons with an energy of 1.9 eV.

References (abridged):

1. N. S. Sariciftci (ed.) Primary Photoexcitations in Conjugated
Polymers: Molecular Exciton versus Semiconductor Band Model
(World Scientific, Singapore, 1997).

2. M. Wohlgenannt et al., Phys. Rev. Lett. 82, 3344 (1999).

3. M. Yan et al., Phys. Rev. Lett. 72, 1104 (1994).

4. E. L. Frankevich et al., Phys. Rev. B 46, 9320 (1992).

5. U. Albrecht and H. Bässler, Chem. Phys. Lett. 235, 389 (1995).

Phys. Rev. Lett. 2002 88:147401

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15. APPLICATIONS OF NEUTRON BEAMS

F. Pfeiffer et al (Laue-Langevin Institute Grenoble, FR) discuss
neutron beams, the authors making the following points:

1) Neutron diffraction, spectroscopy, and imaging using beam
sizes in the submicrometer range are rapidly evolving fields of
research. Progress is fueled not only by the availability of
novel neutron optics, such as microcollimators, supermirrors, or
focusing monochromators, but also by the urgent need for
characterization tools that meet the demands of the advances in
biochemical and semiconductor nanoscience. During recent years,
planar thin-film x-ray waveguide structures have been developed
and have been proved to deliver coherent beams efficiently with
cross sections in the submicrometer range and with precisely
defined properties of divergence and coherence (1–5). They have
been used for submicrometer resolved one-dimensional projection
phase-contrast microscopy, microdiffraction, enhanced diffuse
scattering, depth profiling of incorporated nanocomposites, and
for providing complex far-field diffraction patterns.

2) However, for many applications, the achieved x-ray based
results (in particular for effects related to magnetism) are
limited by the x-ray optical properties of materials. Thus the
use of appropriate neutron investigation techniques combined
with neutron optical devices with the ability to prepare
submicrometer beam sizes would be desirable or even
indispensable. The simple use of slits to define a submicrometer
neutron beam width in the range of 100–5000 angstroms is,
however, both difficult and inefficient for various reasons.

3) The authors report an experimental demonstration that planar
neutron waveguides can be used as resonant beam couplers to
efficiently produce a coherent neutron line source with cross
sections in the submicrometer range. The Fraunhofer far-field
diffraction pattern of the first three resonance modes was
measured and found to be in excellent agreement with the
theoretical model. The authors report their measurements confirm
that an excited exiting mode is fully coherent in the direction
perpendicular to the surface of the thin-film coupler and may
therefore be used for applications of interest to a broad user
community in biochemical and semiconductor nanosciences, such as
static and time-resolved coherent speckle experiments or
phase-contrast imaging.

References (abridged):

1. Y. P. Feng, H. W. Deckmann, and S. K. Sinha, Appl. Phys.
Lett. 64, 1 (1993)

2. Y. P. Feng et al., Phys. Rev. Lett. 71, 537 (1993)

3. M. J. Zwanenburg et al., Phys. Rev. Lett. 82, 1696 (1999)

4. W. Jark, A. Cedola, S. Di Fonzo, and M. Fiordelisi, Appl.
Phys. Lett. 78, 1192 (2001)

5. F. Pfeiffer, T. Salditt, P. Høghøj, I. Anderson, and C.
David, SPIE Int. Soc. Opt. Eng. 4145, 193 (2001)

Phys. Rev. Lett. 2002 88:055507

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16. IMPROVING SUBSTRATE SPECIFICITY OF SMALL CATALYTIC PEPTIDES

F. Tanaka and C.F. Barbas III (Scripps Research Institute, US)
discuss small catalytic peptides, the authors making the
following points:

1) Substrate specificity is one of the hallmarks of enzymes.
Substrate specificity allows an enzyme to catalyze a reaction
involving substrate molecules found within a complex mixture of
compounds possessing the same functional groups. Generation of
designer protein catalysts that possess substrate specificity
has been demonstrated by modification of nature's enzymes(1) and
by the preparation of catalytic antibodies.(2) In contrast to
large proteins, small peptide catalysts have demonstrated
limited specificity for small-molecule substrates.(3) This is
presumably a result of the limited opportunities small peptides
have to fold in a manner that provides for the formation of an
isolated reaction vessel that effectively binds and sequesters
substrates from bulk solvent while at the same time catalyzing
their transformation.

2) The authors report that to explore routes for the preparation
of small peptide enzymes that possess improved substrate
specificity, they have examined a modular assembly strategy. The
authors report a demonstration of the potential of this strategy
with the construction of a small 35-amino acid residue aldolase
peptide with improved substrate specificity. The design strategy
attempts to recruit a substrate-specific module for providing
substrate specificity to an otherwise promiscuous catalyst.
Covalent combination of binding- and catalytic-domain modules
might improve the substrate specificity of the catalyst. When
the binding site is in close proximity to the catalytic site,
the catalytic site would receive the benefit of a higher local
substrate concentration provided by sequestering the substrate
in close proximity to the catalytic site. The potential
advantages of this approach are that it reduces the demand on
the functionalization of the catalytic site, which is limited in
small peptides, and it is modular, therefore making its
adaptation to a variety of specificities rapid.

References (abridged):

1. Petrounia, I. P.; Arnold, F. H. Curr. Opin. Biotechnol. 2000,
11, 325. Cedrone, F.; Menez, A.; Quemeneur, E. Curr. Opin.
Struct. Biol. 2000, 10, 405.

2. Reymond, J.-L. Top. Curr. Chem. 1999, 200, 59. Barbas, C. F.,
III; Rader, C.; Segal, D. J.; List, B.; Turner, J. M. Adv.
Protein Chem. 2000, 55, 317. Schultz, P. G.; Lerner, R. A.
Science 1995, 269, 1835. Tanaka, F.; Lerner, R. A.; Barbas, C.
F., III. J. Am. Chem. Soc. 2000, 122, 4835.

3. Broo, K. S.; Nilsson, H.; Nilsson, J.; Baltzer, L. J. Am.
Chem. Soc. 1998, 120, 10287. Broo, K. S.; Brive, L.; Ahlberg,
P.; Baltzer, L. J. Am. Chem. Soc. 1997, 119, 11362. Johnsson,
K.; Allemann, R. K.; Widmer, H.; Benner, S. A. Nature 1993, 365,
530. Peptide ligases operate via template-assisted catalysis and
demonstrate good substrate specificity: Kennan, A. K.; Haridas,
V.; Severin, K.; Lee, D. H.; Ghadiri, M. R. J. Am. Chem. Soc.
2001, 123, 1797. Yao, S.; Ghosh, I.; Zutshi, R.; Chmielewski, J.
Nature 1998, 396, 447.

J. Am. Chem. Soc. 2002 124:3510

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17. ON REACTION INTERFACES IN CHAOTIC FLOWS

In this context, the term "advection" refers to horizontal
transport parallel to a aurface.

M. Giona et al (University of Rome, IT) discuss reaction
interfaces in chaotic flows, the authors making the following
points:

1) The response of a physical process occurring in a stirred
fluid system depends significantly upon the interaction between
diffusion and convective stirring. Well-known examples include
heat and mass transport with or without chemical reactions (1,2)
as well as the growth of magnetic-field seeds in chaotic flows
(the so-called fast dynamo problem) (3). Several different
approaches have been used to describe and quantify the interplay
between stirring effects induced by a chaotic flow and
diffusion: statistical analysis of mean square displacement (4);
methods based on Melnikov theorem (5) and shadowing techniques;
time splitting between diffusion and convection (pulsed systems)
(3); analysis of diffusing-reacting systems for which the
nonlocal effects of diffusion can be neglected; analysis of
premixed lamellar systems under diffusion; numerical simulations
of advecting-diffusing-reacting systems.

2) There is, however, one important feature that has not been
addressed: namely, the question of how the geometry of partially
mixed structures — with specific reference to the dynamics of
interfaces undergoing chaotic advection — is modified by
molecular diffusion. Besides, the knowledge of pattern dynamics,
under stirring, diffusion, and, possibly, chemical reactions,
provides important phenomenological information useful to build
up models of industrial reacting flows(1), dispersion of solid
and liquid pollutants, growth of microorganisms in flowing
media, etc.

3) The natural physical framework to approach the dynamics of
segregation patterns is given by transport-controlled
bimolecular chemical reactions A + B --> P , on the assumption
of equal molecular diffusivity and stoichiometric loading of the
reactants. Beyond its practical relevance (mixing-controlled
reactions), the assumption of transport-controlled kinetics is
crucial in that it implies that the species A and B remain
segregated at all times, as they cannot coexist at one and the
same spatial location. The intermaterial contact area can
therefore be identified as the reaction interface between the
two segregated reactants, and the system considered provides a
simple physical framework for a well-posed comparison between
the evolution of partially mixed structures with and without
molecular diffusion.

4) The authors analyze the geometry and dynamics of reaction
interfaces and of the corresponding mixing patterns for
transport-controlled reactions in chaotic flows in the presence
of diffusion. The authors report that the dynamics of the
intermaterial contact area undergoes a crossover from
kinematics-dominated exponential growth to a persistent
oscillatory regime resulting from the intertwined action of
advection and diffusion.

References (abridged):

1. J. Baldyga and J. R. Bourne, Turbulent Mixing and Chemical
Reactions (Wiley, New York, 1999).

2. A. Mokrani, C. Catelain, and H. Peerhossaini, Int. J. Heat
Mass Transf. 40, 3089 (1997); D. R. Sawyers, M. Sen, and H.-C.
Chang, Int. J. Heat Mass Transf. 41, 3559 (1998).

3. S. Childress and A. D. Gilbert, Stretch, Twist, Fold: The
Fast Dynamo (Springer Verlag, Berlin, 1995); V. I. Arnold and B.
A. Khesin, Topological Methods in Hydrodynamics
(Springer-Verlag, Berlin, 1998).

4. S. W. Jones, Phys. Fluids A 3, 1081 (1991); S. Benkadda, S.
Kassibrakis, R. B. White, and G. M. Zaslavsky, Phys. Rev. E 55,
4909 (1997); M. Clueck, A. R. Kolovsky, and H. J. Korsch,
Physica (Amsterdam) 116D, 283 (1998).

5. V. Rom-Kedar and A. C. Poje, Phys. Fluids 11, 2044 (1999).

Phys. Rev. Lett. 2002 88:024501

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18. A ROBUST DNA MECHANICAL DEVICE

H. Yan et al (New York University, US) discuss a DNA mechanical
device, the authors making the following points:

1) Controlled mechanical movement in molecular-scale devices has
been realized in a variety of systems—catenanes and
rotaxanes(1-3), chiroptical molecular switches(4), molecular
ratchets(5) and DNA(6) — by exploiting conformational changes
triggered by changes in redox potential or temperature,
reversible binding of small molecules or ions, or irradiation.
The incorporation of such devices into arrays could in principle
lead to complex structural states suitable for nano-robotic
applications, provided that individual devices can be addressed
separately. But because the triggers commonly used tend to act
equally on all the devices that are present, they will need to
be localized very tightly. This could be readily achieved with
devices that are controlled individually by separate and
device-specific reagents. A trigger mechanism that allows such
specific control is the reversible binding of DNA strands,
thereby "fuelling" conformational changes in a DNA machine.

2) The authors report an improvement upon the initial prototype
system that uses this mechanism but generates by-products, their
study demonstrating a robust sequence-dependent rotary DNA
device operating in a four-step cycle. The authors show that DNA
strands control and fuel their device cycle by inducing the
interconversion between two robust topological motifs, paranemic
crossover and its topoisomer, in which one strand end is rotated
relative to the other by 180°. The authors suggest that a wide
range of analogous yet distinct rotary devices can be created by
changing the control strands and the device sequences to which
they bind.

References (abridged):

1. Pease, A. R. et al. Switching devices based on interlocked
molecules. Acc. Chem. Res. 34, 433-444 (2001)

2. Jimenez, M. C., Dietrich-Buchecker, C. & Sauvage, J.-P.
Towards synthetic molecular muscles: Contraction and stretching
of a linear-rotaxane dimer. Angew. Chem. Int. (Engl.) 39,
3284-3287 (2000)

3. Brouwer, A. M. et al. Photoinduction of fast, reversible
translational motion in a hydrogen-bonded molecular shuttle.
Science 291, 2124-2128 (2001)

4. Koumura, N., Zijlstra, R. W. J., van Delden, R. A., Harada,
N. & Feringa, B. L. Light-driven monodirectional molecular
rotor. Nature 401, 152-155 (1999)

5. Kelly, T. R., De Silva, H. & Silva, R. A. Unidirectional
rotary motion in a molecular system. Nature 401, 150-152 (1999)

6. Mao, C., Sun, W., Shen, Z. & Seeman, N. C. A DNA
nanomechanical device based on the B-Z transition. Nature 397,
144-146 (1999)

Nature 2002 415:62

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19. AN ASSESSMENT OF FOR-PROFIT VS. NONPROFIT HMOS

H.T. Tu and J.D. Reschovsky (Center for Studying Health System
Change, US) discuss HMOs, the authors making the following
points:

1) Investor-owned, for-profit companies have a major role in the
health maintenance organization (HMO) industry. Thanks to the
widespread conversion of nonprofit health plans to for-profit
status and the aggressive expansion of large for-profit
companies, the market share of for-profit plans increased from
one quarter of HMO enrollment in the mid-1980s to approximately
two thirds by the late 1990s.(1)

2) This trend has aroused concern that the delivery and quality
of health care are being compromised.(2,3) Critics of for-profit
plans contend that accountability to profit-seeking shareholders
can lead to incentives to withhold needed care.(4) This concern
is especially acute for people in poor health, who consume a
disproportionate share of the medical budgets of health plans.
At the same time, this group of patients is most vulnerable to
adverse outcomes if care is inadequate. Others argue, however,
that whatever differences may have distinguished nonprofit from
for-profit health plans in the past, all plans now face similar
market pressures and economic constraints, which have resulted
in greater similarity of incentives and behavior by the two
types of plans.(5) 

3) Empirical evidence regarding the effect of profit status on
patient care is limited and inconclusive. The authors report
they used data from large, nationally representative surveys of
consumers and insurers to analyze the relation between the
profit status of commercial HMOs and consumers' assessments of
the care they receive. The authors conclude that although there
are few overall differences in assessments of medical care
between enrollees in for-profit and nonprofit HMOs, for-profit
HMOs are rated less favorably than nonprofit HMOs by patients
who have self-reported fair or poor health.

References (abridged):

1. The InterStudy HMO trend report, 1987-1997. Bloomington,
Minn.: InterStudy, 1998

2. Kuttner R. Must good HMOs go bad? The commercialization of
prepaid group health care. N Engl J Med 1998;338:1558-1563

3.Nelson H. Nonprofit and for-profit HMOs: converging practices
but different goals? New York: Milbank Memorial Fund, 1997

4. Nudelman PM, Andrews LM. The "value added" of not-for-profit
health plans. N Engl J Med 1996;334:1057-1059

5. Wynn P. Making heads or tails of for-profit health care.
Manag Care 1996;5:23-30

New Engl. J. Med. 2002 346:1288

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20. ON EPITHELIAL-TUMOR-METASTATIC CELLS IN BONE MARROW

In animals and humans, epithelial cells compose the cell layers
that form the interface between a tissue and the external
environment, for example, the cells of the skin, the lining of
the intestinal tract, and the lung airway passages. An
"epithelial tumor" is a tumor involving such cells.

The term "cytoskeleton" refers quasi-rigid matrix that among
other things determines cell shape and acts as a scaffold for
various intracellular translocations.

O. Solakoglu et al (University Clinic Hamburg-Eppendorf, DE)
discuss metastasis of epithelial tumors, the authors making the
following points:

1) Even if a primary epithelial tumor can be removed by surgery,
a significant number of patients will postoperatively develop
blood-origin (hematogeneous) metastases. There is, in fact,
emerging evidence that epithelial tumor cells are able to
disseminate to secondary organs at an early stage of primary
tumor development (1). Bone marrow is the most important
secondary organ for the detection of these cells, and even in
cancer entities where overt skeletal metastases are rare (e.g.,
colorectal cancer), bone marrow is a prognostically relevant
indicator organ for the presence of hematogeneously disseminated
tumor cells (2-4).

2) Disseminated cancer cells in bone marrow express epithelial
cytokeratins, and are therefore immunocytochemically detectable
with monoclonal antibodies against these antigens (1). The
frequency of cytokeratin-positive cells in cytologic bone marrow
preparations from cancer patients is about 10^(-5) to 10^(-6)
(1). Cytokeratins are part of the cytoskeleton of epithelial
cells and therefore represent a unique feature of epithelial
cells. Extensive studies on large number of non-carcinoma
control patients have shown that an immunocytochemically
detectable cytokeratin expression in "normal" bone marrow cells
is a rare event (5).

3) The mere detection of cytokeratin-positive cells provides,
however, no information about the proliferative potential of
disseminated cancer cells. Whereas the prognostic significance
of the detection of cytokeratin-positive cells has been studied
in prospective clinical trials in patients afflicted with
various types of epithelial tumors, very little is known about
the biologic features and particularly the proliferative
potential of these cells. The currently available data suggest
that cytokeratin-positive cells in bone marrow aspirates of
cancer patients represent a selected but still heterogeneous
population of dormant cancer cells (1).

4) The authors report a study investigating the clinical
relevance of the in vitro proliferative potential of
cytokeratin-positive cells. The authors report their results
demonstrate a) that the majority of cancer patients without
overt metastasis harbor viable cytokeratin-positive tumor cells
in their bone marrow at the time of primary surgery, and b) that
the ability of these cells to grow in vitro is a strong
indicator of an unfavorable prognosis for these patients.

References (abridged):

1. Pantel, K. et al (1999) J. Natl. Cancer Inst. 91, 1113-1124

2. Lindemann, F. et al (1992) Lancet 340, 685-689

3. Soeth, E. et al (1997) Cancer Res. 57, 3106-3110

4. Leinung, S. et al (2000) J. Hematother. 9, 905-911

5. Pantel, K. et al (1994) J. Hematother. 3, 165-173

Proc. Nat. Acad. Sci. 2002 99:2246

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21. SELECTIVE BINDING OF GOLD NANOPARTICLES TO BACTERIA

C-C. Lin et al (Academia Sinica Taipei, TW) discuss binding of
nanoparticles, the authors making the following points:

1) Metal and semiconductor nanoparticles coupled with
biomolecules have attracted much interest recently because the
resulting materials may provide new applications in biological
systems.(1) In protein-based recognition, many current
diagnostic kits have been developed on the basis of the
interaction between antibody conjugated gold nanoparticles and
their antigens.(2) Recently, gold nanoparticles attached to DNA
have been used for the detection of target sequences via
complementary hybridization.(3) Also, functional organic ligands
have been encapsulated on gold nanoparticles for the fabrication
of new chemical probes.(4) Besides gold nanoparticles,
semiconductor nanoparticle bioconjugates as selective
fluorescent biological labels have shown great potential in
biological studies and medical applications.(5) However, the
biomolecules on functionalized nanoparticles in recent studies
are mostly DNA or protein, and very few examples have been
reported of carbohydrates. Moreover, the application of
carbohydrate conjugated nanoparticles in biological assays has
not been explored.

2) The technical advantages of applying gold nanoparticles in
biological systems have been well recognized.(2) Covalent
binding between gold nanoparticles and biomolecules can be
easily achieved by self-assembly of thiolated molecules onto the
nanoparticle surface. In addition, gold nanoparticles exhibit an
intense color in the visible region for spectroscopic detection
and also great contrast for electron microscopic imaging.
Moreover, a single nanoparticle with a large surface to volume
ratio is amenable to the covalent attachment of multiple
ligands, which provides a possibility for the enhancement of
certain biomolecular interactions. For example, ordinary
carbohydrate-protein interactions are generally characterized in
the laboratory by very low affinity, but in nature such low
affinity is often compensated by the presentation of multiple
ligands to individual receptors, and polyvalent interactions
between multi-ligands and their receptors can be collectively
much stronger than corresponding monovalent interactions.
Similar compensation can occur on large nanoparticles bearing
multiple ligands.

3) The authors report a demonstration that carbohydrate-attached
gold nanoparticles can be used as efficient labeling probes and
multiligand carriers in a biological system (the bacterium
Escherichia coli).

References (abridged):

1. Niemeyer, C. M. Angew. Chem., Int. Ed. 2001, 40, 4128-4258

2. (a) Hayat, M. A. Colloidal Gold: Principles, Methods and
Applications; Academic Press: New York, 1989. (b) Kreuter, J. In
Microcapsules and Nanoparticles in Medicine and Pharmacy;
Donbrow, M., Ed.; CRC: Boca Raton, 1992

3. (a) Alivisatos, A. et al, Nature 1996, 382, 609-611. (b)
Mirkin, C. et al, Nature 1996, 382, 607-609. (c) Taton, T. et
al, J. Am. Chem. Soc. 2001, 123, 5164-5165. (d) Taton, T. et al,
Science 2000, 289, 1757-1760.

4. (a) Boal, A. et al, Nature 2000, 404, 746-748. (b) Boal, A.
and Rotello, V., J. Am. Chem. Soc. 2000, 122, 734-735.

5. (a) Bruchez, M. et al, Science 1998, 281, 2013-2016. (b)
Chan, W. and Nie, S., Science 1998, 281, 2016-2018.

J. Am. Chem. Soc. 2002 124:3508

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22. ALCOHOL USE IN THE US AMONG WOMEN OF CHILD-BEARING AGE

The term "fetal alcohol syndrome" refers to fetal dysfunction
due to maternal alcohol abuse during pregnancy, and it is the
most common cause of drug-induced fetal dysfunction and fetal
malformations (teratogenesis). The most severe dysfunction
consequence is severe mental retardation due to impaired brain
development. In general, alcohol ingested during pregnancy can
produce a wide spectrum of defects, ranging from spontaneous
abortion to severe behavioral defects without apparent physical
anomalies. The US incidence of fetal alcohol syndrome is
approximately 2.2 per 1000 live births, which exceeds that of
Down syndrome and cerebral palsy. The critical volume of
ingested alcohol that results in fetal alcohol syndrome is
unknown.

The Morbidity and Mortality Weekly Report (Centers for Disease
Control and Prevention, US) discusses alcohol use among women of
child-bearing age, the report making the following points:

1) Prenatal exposure to alcohol is one of the leading
preventable causes of birth defects, mental retardation, and
neurodevelopmental disorders in the United States.(1) One of the
national health objectives for 2010 is to increase the
percentage of pregnant women abstaining from alcohol to 94
percent.(2) During 1991-1995, alcohol use by pregnant women
increased substantially, and alcohol use by nonpregnant women of
childbearing age increased slightly.(3) To characterize trends
in alcohol use among women of childbearing age, CDC analyzed
representative survey data from the Behavioral Risk Factor
Surveillance System (BRFSS) during 1991-1999. This report
summarizes the results of the analysis, which indicate that the
rate of any alcohol use (i.e., at least one drink) during
pregnancy has declined since 1995. However, rates of binge
drinking (i.e., 5 drinks on any one occasion) and frequent
drinking (i.e., 7 drinks per week or 5 drinks on any one
occasion) during pregnancy have not declined, and these rates
also have not declined among nonpregnant women of childbearing
age. The report suggests that health-care providers should
routinely screen women of childbearing age for alcohol use and
counsel them about the adverse effects of alcohol use during
pregnancy.

2) BRFSS is an ongoing, state-based, random-digit–dialed
telephone survey of the noninstitutionalized U.S. civilian
population aged 18 years. Data were analyzed for women aged
18-44 years in all 50 states. Women were asked about their use
of alcohol during the 30 days preceding the survey. Three
alcohol drinking patterns were examined: any use, binge
drinking, and frequent drinking. Information on alcohol use was
obtained every year through 1993 and every other year thereafter.

3) During 1995-1999, a total of 4,695 (4.3 percent) of the
107,141 women aged 18-44 years who were interviewed about their
alcohol use during the month preceding the survey reported that
they were pregnant at the time of the interview. The prevalence
of any alcohol use among pregnant women increased from 12.4
percent in 1991 to 16.3 percent in 1995.(3) Compared with 1995
data, prevalence was lower in 1997 (11.4 percent) and 1999 (12.8
percent). In contrast, the rates of binge drinking and frequent
drinking reported by pregnant women in 1995 remained
substantially unchanged in 1997 and 1999: binge drinking rates
were 2.9 percent in 1995, 1.8 percent in 1997, and 2.7 percent
in 1999, and frequent alcohol use rates were 3.5 percent in
1995, 2.1 percent in 1997, and 3.3 percent in 1999. Among
nonpregnant women who reported any alcohol use, rates remained
stable: 53.2 percent in 1995, 52.8 percent in 1997, and 53.3
percent in 1999. Binge drinking rates among this population were
11.2 percent in 1995, 10.8 percent in 1997, and 12.3 percent in
1999.

4) In comparison with other pregnant women, pregnant women who
reported any alcohol use, binge drinking, and frequent drinking
were more likely to be aged >30 years, employed, and unmarried.
Nonpregnant women who reported any alcohol use, binge drinking,
and frequent drinking had similar employment and marital status
as pregnant women. In addition, nonpregnant women reporting any
alcohol use were more likely to be white and to have higher
education levels than women who did not engage in this behavior;
nonpregnant women who reported binge drinking and frequent
drinking tended to be aged <30 years.

References (abridged):

1. Jacobs EA, Copperman SM, Jeffe A, Kulig J. Fetal alcohol
syndrome and alcohol related neurodevelopmental disorders.
Pediatrics. 2000 106:358-61.

2. US Department of Health and Human Services. Healthy People
2010 (conference ed, in 2 vols). Washington, DC: US Department
of Health and Human Services, 2000.

3. CDC. Alcohol consumption among pregnant and childbearing-aged
womenUnited States, 1991 and 1995. MMWR Morb Mortal Wkly Rep.
1997;46:346-50.

4. US Department of Health and Human Services. Summary of
findings from the 1999 National Household Survey on Drug Abuse.
Washington, DC: US Department of Health and Human Services, 2000.

5. Ebrahim SH, Diekman ST, Floyd LR, Decoufle P.
Pregnancy-related alcohol use among women in the United
States1988-95. Prenat Neonat Med. 1999 4:39-46.

J. Am. Med. Assoc. 2002 287:2069

MMWR 2002 51:273

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23. ON SURVIVAL OF BLACKS VS. WHITES AFTER A CANCER DIAGNOSIS

P.B. Back et al (Memorial Sloan-Kettering Cancer Center, US)
discuss racial differences in survival after cancer diagnosis,
the authors making the following points:

1) In the United States, 5-year survival after a cancer
diagnosis is poorer for blacks than for whites -- from 1992 to
1997, the figures were 52 percent and 63 percent,
respectively.(1) Large, well-designed epidemiologic studies have
explored possible reasons for this disparity. Differences in
factors such as stage at diagnosis, socioeconomic status, and
health insurance coverage, though present, do not appear to be
entirely responsible.(2-4) For example, the National Cancer
Institute sponsored a Black-White Cancer Survival Study, which
compared survival for blacks and whites with cancer of the
colon, breast, uterus, and bladder. The poorer survival rates
that were observed for blacks with all 4 cancer types persisted
after adjustment for both clinical and socioeconomic
characteristics.(5) Because these factors do not appear to
explain the racial difference in survival, the theory that
cancers afflicting blacks may be fundamentally more aggressive
due to biological or genetic differences has gained prominence.

2) Few studies have been designed to evaluate 2 other factors,
unrelated to cancer biology, which may reduce the longevity of
blacks with cancer: lesser quality treatment and greater
mortality due to other illnesses. Because there are numerous
studies documenting differences in the quality of cancer care
received by blacks and whites, the thought that treatment
differences may ultimately underlie the discrepancies in
survival has gained many proponents. Moreover, several studies
have documented similar survival for black and white patients
with cancer who have received similar treatments. Rates of death
because of cardiovascular disease, diabetes, and other major
illnesses are also greater for blacks than whites, leading some
investigators to suggest that differences in population
mortality should be considered.

3) The authors conducted a study to determine whether there was
evidence in the literature of racial disparities in survival
between blacks and whites who had received the same treatments
for similar stages of cancer. The authors postulated that if
blacks had poorer survival than whites in this context, the
survival differences would be explained by the excess rates of
deaths due to other causes in blacks. If not, the authors
reasoned that the magnitude of the unexplained survival gap
would constitute an estimate of that which may be attributable
to differences in cancer biology.

4) From their results, the authors conclude that only modest
cancer-specific survival differences are evident for blacks and
whites treated comparably for similar-stage cancer. Therefore,
differences in cancer biology between racial groups are unlikely
to be responsible for a substantial portion of the survival
discrepancy. Differences in treatment, stage at presentation,
and mortality from other diseases should represent the primary
targets of research and interventions designed to reduce
disparities in cancer outcomes.

References (abridged):

1. Ries LAG, et al. SEER Cancer Statistics Review, 1973-1998.
Bethesda, Md: National Cancer Institute, National Institutes of
Health, 2001.

2. Marcella S and Miller JE. Racial differences in colorectal
cancer mortality: the importance of stage and socioeconomic
status. J Clin Epidemiol. 2001 54:359-366.

3. Ragland KE, et al. Black-white differences in stage-specific
cancer survival: analysis of seven selected sites. Am J
Epidemiol. 1991 133:672-682.

4. Steinhorn SC, et al.. Factors associated with survival
differences between black women and white women with cancer of
the uterine corpus. Am J Epidemiol. 1986 124:85-93.

5. Howard J, et al. A collaborative study of differences in the
survival rates of black patients and white patients with cancer.
Cancer. 1992 69:2349-2360.

J. Am. Med. Assoc. 2002 287:2106

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24. SMALLPOX: VIROLOGY AND PATHOGENESIS

J.G. Breman and D.A. Henderson (National Institutes of Health,
US) discuss smallpox, the authors making the following points:

1) The smallpox virus (variola virus) belongs to the family
Poxviridae, subfamily Chordopoxvirinae, and genus orthopoxvirus,
which includes vaccinia (smallpox vaccine), monkeypox virus, and
several other animal poxviruses that cross-react
serologically.(8,9) The poxviruses contain single, linear,
double-stranded DNA molecules of 130-to-375-kilobase pairs and
replicate in cell cytoplasm. They are shaped like bricks on
electron micrographs and measure approximately 300 by 250 by 200
nanometers.

2) Studies of mousepox, rabbitpox, and monkeypox have provided
information about the pathogenesis of poxviruses.(9,10,11,12,13)
The virus enters the respiratory tract, seeding the mucous
membranes and passing rapidly into local lymph nodes. After a
brief period of viremia, there is a latent period of 4 to 14
days, during which the virus multiplies in the
reticuloendothelial system. Another brief period of viremia
precedes the prodromal phase. During the prodromal phase, mucous
membranes in the mouth and pharynx are infected. The virus
invades the capillary epithelium of the dermal layer in skin,
leading to the development of lesions. Oropharyngeal and skin
lesions contain abundant viral particles, particularly early in
the illness. Virus is also present in urine and conjunctival
secretions, with the levels decreasing during convalescence. The
spleen, lymph nodes, liver, bone marrow, kidneys, and other
viscera may contain large quantities of virus.

3) The migration of infected macrophages to lymph nodes after
the initial infection elicits the production of cytotoxic T
cells and B cells; these responses limit the spread of
infection. Neutralizing antibodies appear during the first week
of illness but are delayed if the infection is severe;
hemagglutination-inhibition antibodies are detectable by day 16
of the infection, and complement-fixation antibodies by day 18.
Neutralizing antibodies remain present for many years, whereas
levels of hemagglutination-inhibition and complement-fixation
antibodies begin to decrease after one year. The correlation
between humoral antibodies and protection from smallpox is not
entirely clear.

References (abridged):

8. Moss B. Poxviridae: the viruses and their replication. In:
Fields BN, Knipe DM, Howley PM, eds. Fields virology. 3rd ed.
Vol. 2. Philadelphia: Lippincott-Raven, 1996:2637-71.

9. Fenner F. Poxviruses. In: Fields BN, Knipe DN, Howley PM,
eds. Fields virology. 3rd ed. Vol. 2. Philadelphia:
Lippincott-Raven, 1996:2673-83.

10. Roberts JA. Histopathogenesis of mousepox. I. Respiratory
infection. Br J Exp Pathol 1962;43:451-461.

11. Bedson HS, Duckworth MJ. Rabbit pox: an experimental study
of the pathways of infection in rabbits. J Pathol Bacteriol
1963;85:1-20.

12. Buller RM, Palumbo GJ. Poxvirus pathogenesis. Microbiol Rev
1991;55:80-122.

13. Zaucha GM, et al. The pathology of experimental aerosolized
monkeypox virus infection in Cynomolgus monkeys (Macaca
fascicularis). Lab Invest 2001;81:1581-1600.

New Engl. J. Med. 2002 346:1300

Related Background:

ON SMALLPOX

G.H. Brundtland (World Health Organization) discusses smallpox,
the author making the following points:

1) The global eradication of smallpox, certified in 1979, is one
of the greatest public health achievements in history. It marked
the end of a disease that in the past had killed 3 million
people every year and scarred or blinded millions more. It also
commemorated a decade, during the Cold War, when all countries
united behind a common humanitarian cause. The US was the
largest donor and provided major logistic and staff support. The
Soviet Union was the largest supplier of vaccine.

2) No effective treatment against smallpox was ever developed.
Vaccination, supported by surveillance and containment, was the
cornerstone of the eradication drive. And -- against
considerable odds -- it worked. When the last natural case
occurred in Somalia in 1977, one of history's longest chains of
transmission, at least 3000 years old, was broken.

3) Smallpox, with other biological agents that might be
deliberately used to cause harm, is once again in the political,
public health, and media spotlights. A single confirmed case of
smallpox would be an immediate global emergency. Although it
spreads slowly, requiring face-to-face contact, smallpox is
highly contagious. The incubation period is long: 12 to 14 days.
Immunity has waned and populations are vulnerable. The current
vaccine, though highly effective, has rare but serious and
potentially fatal complications. Let us hope that the deliberate
use of smallpox as a weapon shall never come to pass. The World
Health Organization, in cooperation with various other entities,
such as the US Centers for Disease Control and Prevention, has
instituted an intensive review of current surveillance,
containment, and response strategies to be used in the event of
an outbreak of this disease.

J. Am. Med. Assoc. 2002 287:1104

ScienceWeek http://www.scienceweek.com

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25. IN FOCUS: ON EINSTEIN, PLANCK, AND BOSE

"In June 1924 Albert Einstein received from an unknown Indian
physicist from Dacca named Satyendranath Bose a letter and a
brief manuscript, written in English. Unknown to Einstein, the
manuscript had been recently rejected by the Philosophical
Magazine of the Royal Society in London. Einstein liked the
manuscript so much that he set aside his own work and translated
it into German, arranging its publication in Zeitschrift fuer
Physik. He even added a praising note: 'In my opinion, Bose's
derivation of the Planck formula signifies an important advance.
The method used also yields the quantum theory of an ideal gas
as I will work out in detail elsewhere.' What could get
Einstein, already a Nobel prizewinner, excited enough to start
work on a new problem based on an unknown physicist's
unpublished manuscript? To fully understand this we have to go
back two decades. At the turn of the nineteenth century the
German physicist Max Planck wanted to solve a problem of much
interest to the physics community: How do objects emit light and
heat? There were two competing theories, each accounting for
different parts, but not all, of the experimental data. To date,
the many attempts to reconcile the two approaches had been
futile. Planck, in 1900, was the first to derive an expression
that perfectly fit all experiments, known today as Planck's
formula. He paid a very high price, however, as he had to
introduce the ad hoc assumption that light and heat are emitted
in small packets, or discrete quanta, an idea that disregarded
his contemporaries' view that light and electromagnetic
radiation are waves and are not made of discrete particles.
Einstein was among the first to take Planck's hypothesis
seriously. Assuming that light is indeed made of tiny particles,
called photons, he predicted the photoelectric effect, a
discovery for which he was awarded the Nobel prize in 1922.
Planck, nominated by Einstein, received a Nobel in 1919 for the
quantum hypothesis. In 1924, the quantum hypothesis of light was
still troublesome: A quantum mechanical derivation of Planck's
formula was nonexistent. While it is a straightforward problem
for undergraduate physics majors these days, at that time all
attempts to derive it were unsuccessful—until Bose offered a
bold solution. What could Bose whisper from Dacca that was
unknown to such titans of physics as Einstein and Planck? In the
nineteenth century, physicists believed that atoms could be
distinguished and numbered individually. Think of the numbered
balls bouncing in a rotating drum used to pick the winning
numbers in a lottery. If you pick a ball from the drum, millions
of ticket holders will know exactly which one has been selected,
since the numbers are painted on them. But our ability to
distinguish certain subatomic particles is an illusion borrowed
from daily life, argued Bose. Light particles are truly alike,
unnumbered, perfectly indistinguishable. Bose showed that once
statistical mechanics and thermodynamics are modified to
incorporate the fact that certain subatomic particles are truly
identical, Plank's law can be easily derived."

Albert-Laszlo Barabasi: Linked: The New Science of Networks

(Perseus Publishing, Cambridge MA 2002, p.98) (June 2002)

Source information at Amazon.Com

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