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ScienceWeek
SCIENCEWEEK
ScienceWeek October 18, 2002 Vol. 6 Number 42
An Online Research Digest Published Weekly Since 1997
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It is because science is sure of nothing that it is always
advancing. -- Emile Duclaux (1840-1904)
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Section 1
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1. On Predictions of Electronic Structures of Organic Molecules
2. On Nitrogenase
3. Quantum Dots and Quantum Computers
4. On Gene Patents
5. Cage Rearrangements and the Colloidal Glass Transition
6. On Voltage-Gated Potassium Channels
7. On Hydrogen as an Energy Source
8. Decline in Physical Activity in Adolescent Girls
9. A New 20-Kilometer Impact Structure in the North Sea
10. On Neuronal Migration in Development
11. History of Quantum Tunneling
12. On the Addicted Brain
13. ScienceWeek Notices and Subscription Information
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Section 2
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1. ON PREDICTIONS OF ELECTRONIC STRUCTURES OF ORGANIC MOLECULES
S. Tretiak and S. Mukamel (Los Alamos National Laboratory, US)
discuss theoretical predictions of electronic structures of
organic molecules, the authors making the following points:
1) Predicting the electronic structure of extended organic
molecules constitutes an important fundamental task of modern
chemistry. Studies of electronic excitations, charge-transfer,
energy-transfer, and isomerization of conjugated systems form
the basis for our understanding of the photophysics and
photochemistry of complex molecules(1-3) as well as organic
nanostructures and supramolecular assemblies.(4,5)
Photosynthesis and other photochemical biological processes that
constitute the basis of life on Earth involve assemblies of
conjugated chromophores such as porphyrins, chlorophylls, and
carotenoids. Apart from the fundamental interest, these studies
are also closely connected to numerous important technological
applications. Conjugated polymers are primary candidates for new
organic optical materials with large nonlinear polarizabilities.
Potential applications include electroluminescence, light
emitting diodes, ultrafast switches, photodetectors, biosensors,
and optical limiting materials.
2) Optical spectroscopy, which allows chemists and physicists to
probe the dynamics of vibrations and electronic excitations of
molecules and solids, is a powerful tool for the study of
molecular electronic structure. The theoretical techniques used
for describing spectra of isolated small molecules are usually
quite different from those of molecular crystals, and many
intermediate size systems, such as clusters and polymers, are
not readily described by the methods developed for either of
these limiting cases. Solving the many-electron problem required
for the prediction and interpretation of spectroscopic signals
involves an extensive numerical effort that grows very fast with
molecular size.
3) Two broad classes of techniques are generally employed in the
calculation of molecular response functions. Off-resonant
optical polarizabilities can be calculated most readily by a
variational/perturbative treatment of the ground state in the
presence of a static electric field by expanding the Stark
energy in powers of electric field. The coupled perturbed
Hartree-Fock (CPHF) procedure computes the polarizabilities by
evaluating energy derivatives of the molecular Hamiltonian. It
usually involves expensive ab initio calculations with basis
sets including diffuse and polarized functions, that are
substantially larger than those necessary for computing
ground-state properties.
4) The second approach starts with exact expressions for optical
response functions derived using time-dependent perturbation
theory, which relate the optical response to the properties of
the excited states. It applies to resonant as well as
off-resonant response. Its implementation involves calculations
of both the ground state and excited-state wave functions and
the transition dipole moments between them.
References (abridged):
1. Birks, J. B. Photophysics of Aromatic Molecules; Wiley: New
York, 1970.
2. Michl, J.; Bonacic-Koutecky, V. Electronic Aspects Of Organic
Photochemistry; Wiley: New York, 1990.
3. Klessinger, M.; Michl, J. Excited States and Photochemistry
of Organic Molecules; VCH: New York, 1995.
4. Forrest, S. R. Chem. Rev. 1997, 97, 1793.
5. McBranch, D. W.; Sinclair, M. B. In The Nature of the
Photoexcitations in Conjugated Polymers; Sariciftci, N. S., Ed.;
Word Scientific Publishing: Singapore, 1997.
Chem. Rev. 2002 102:3171
Web Links: calculation of molecular structure
Related Background Brief:
DESIGN OF ORGANIC MOLECULES WITH LARGE TWO-PHOTON ABSORPTION
CROSS SECTIONS. The authors report that a strategy for the
design of molecules with large two-photon absorption cross
sections (delta) was developed on the basis of the concept that
symmetric charge transfer, from the ends of a conjugated system
to the middle, or vice versa, upon excitation is correlated to
enhanced values of delta. Synthesized bis(styryl)benzene
derivatives with donor-pi-donor, donor-acceptor-donor, and
acceptor-donor-acceptor structural motifs exhibit exceptionally
large values of delta, up to about 400 times that of
trans-stilbene. Quantum chemical calculations performed on these
molecules indicate that substantial symmetric charge
redistribution occurs upon excitation and provide delta values
in good agreement with experimental values. The authors suggest
that the combination of large delta and high fluorescence
quantum yield or triplet yield exhibited by molecules developed
in the study offers potential for unprecedented brightness in
two-photon fluorescent imaging or enhanced photosensitivity in
two-photon sensitization, respectively. M. Albota et al: Science
1998 281:1653.
Related Background Brief:
ELECTRON-OPTICAL PROPERTIES OF ATOMIC FIELDS. A unified
discussion and illustrations are presented of the
electron-optical aspects of electron penetration into, or escape
from, the inner region of atoms. Both processes may focus or
defocus the amplitudes of wave functions and shift their phases,
as manifested in countless phenomena ranging from level shifts
to b-decay rates. A background survey begins by discussing the
Fermi-Segre formula for hyperfine splittings and emphasizes the
interplay of hydrogenic and WKB approximations. The
Phase-Amplitude Method, which detects amplitude ratios and phase
shifts directly, proves useful for interpreting the systematics
of these parameters along the Periodic System. Results are
presented of survey calculations carried through the Periodic
System using Hartree-Slater potential fields. A broad mapping is
provided of certain fundamental parameters based on rather crude
but realistic calculations. The authors suggest these results
are meant to serve as a bench mark in surveying problems and in
checking new results, while standard methods are preferable for
working out specific applications accurately. U. Fano et al:
Rev. Mod. Phys. 1976 48:49.
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2. ON NITROGENASE
Barry E. Smith (John Innes Center, UK) discusses nitrogenase,
the author making the following points:
1) Given sufficient water, plant growth and therefore
agricultural productivity is usually limited by the amount of
bioavailable (fixed) nitrogen. Biological nitrogen fixation
still contributes about half of the total nitrogen input to
global agriculture, the rest principally coming from nitrogenous
fertilizer produced chemically from the Haber-Bosch synthesis of
ammonia. To produce the hydrogen gas together with the high
temperatures and pressures needed for this chemical process,
about 1% of the world's total annual energy supply has to be
consumed. In marked contrast, a similar chemical process
requiring only atmospheric temperature and pressure is carried
out by nitrogen-fixing bacteria, many of which live in symbiotic
association with legume plants. The secret of their success is
the enzyme nitrogenase, which transforms atmospheric nitrogen
gas (dinitrogen) into ammonia that plants can then use for
growth. Many groups have tried for decades to determine how
nitrogenase catalyzes this essential process.
2) Nitrogenase (2) consists of two essential metalloproteins:
one, the iron (Fe) protein, is a very specific ATP-activated
electron donor to the other, the molybdenum-iron (MoFe) protein.
The MoFe protein contains two unique metallosulfur clusters: the
P cluster [8Fe-7S] and the [Mo:7Fe:9S]:homocitrate
iron-molybdenum (FeMo) cofactor cluster. About a decade ago, the
first and relatively low-resolution (2.8 angstroms) crystal
structure of the MoFe protein was reported (3). At this level of
resolution, there were still some uncertainties about the
structures of the metalloclusters. However, subsequent
improvements in resolution to 2.0 angstroms (4) and then to 1.6
angstroms (5) yielded what seemed to be the accurate structure
of the FeMo cofactor. The FeMo cofactor is bound to the MoFe
protein through both a cysteine sulfur ligand (binding to the
terminal tetrahedral iron atom) and a histidine ligand (binding
to the molybdenum atom, which also binds to the homocitrate
through its hydroxyl group and one carboxyl group). One of the
features of the structure that has excited considerable interest
is the trigonal nature of the other six iron atoms, which appear
to be coordinately bound to only three atoms instead of the
usual four or more atoms.
3) A high-resolution structure of part of bacterial nitrogenase
reported by Einsle et al (1) yields some surprises about the
biosynthesis and catalytic activity of this crucial
metalloenzyme. Einsle et al. report the structure of the MoFe
protein of bacterial nitrogenase at an improved resolution of
1.16 angstrom (1). This is a major achievement with a protein of
this molecular size (~240,000 daltons).
References (abridged):
1. O. Einsle et al., Science 297, 1696 (2002).
2. B. E. Smith, in Advances in Inorganic Chemistry, A. G. Sykes,
R. Cammack, Eds. (Academic Press, London, 1999), vol. 47, pp.
159-218.
3. J. S. Kim, D. C. Rees, Science 257, 1677 (1992).
4. J. W. Peters et al., Biochemistry 36, 1181 (1997).
5. S. M. Mayer, D. M. Lawson, C. A. Gormal, S. M. Roe, B. E.
Smith, J. Mol. Biol. 292, 871 (1999).
Science 2002 297:1654
Web Links: nitrogenase
Related Background Brief:
NITROGENASE MOFE-PROTEIN AT 1.16 Å RESOLUTION: A CENTRAL LIGAND
IN THE FEMO-COFACTOR. A high-resolution crystallographic
analysis of the nitrogenase MoFe-protein reveals a previously
unrecognized ligand coordinated to six iron atoms in the center
of the catalytically essential FeMo-cofactor. The electron
density for this ligand is masked in structures with resolutions
lower than 1.55 angstroms, owing to Fourier series termination
ripples from the surrounding iron and sulfur atoms in the
cofactor. The central atom completes an approximate tetrahedral
coordination for the six iron atoms, instead of the trigonal
coordination proposed on the basis of lower resolution
structures. The crystallographic refinement at 1.16 angstrom
resolution is consistent with this newly detected component
being a light element, most plausibly nitrogen. The presence of
a nitrogen atom in the cofactor would have important
implications for the mechanism of dinitrogen reduction by
nitrogenase. O. Einsle et al: Science 2002 297:1696.
Related Background Brief:
STRUCTURAL MODELS FOR THE METAL CENTERS IN THE NITROGENASE
MOLYBDENUM-IRON PROTEIN. Structural models for the nitrogenase
FeMo-cofactor and P-clusters are proposed based on
crystallographic analysis of the nitrogenase molybdenum-iron
(MoFe)-protein from Azotobacter vinelandii at 2.7 angstrom
resolution. Each center consists of two bridged clusters; the
FeMo-cofactor has 4Fe:3S and 1Mo:3Fe:3S clusters bridged by
three non-protein ligands, and the P-clusters contain two 4Fe:4S
clusters bridged by two cysteine thiol ligands. Six of the seven
Fe sites in the FeMo-cofactor appear to have trigonal
coordination geometry, including one ligand provided by a
bridging group. The remaining Fe site has tetrahedral geometry
and is liganded to the side chain of Cys alpha 275. The Mo site
exhibits approximate octahedral coordination geometry and is
liganded by three sulfurs in the cofactor, two oxygens from
homocitrate, and the imidazole side chain of His alpha 442. The
P-clusters are liganded by six cysteine thiol groups, two which
bridge the two clusters, alpha 88 and beta 95, and four which
singly coordinate the remaining Fe sites, alpha 62, alpha 154,
beta 70, and beta 153. The side chain of Ser beta 188 may also
coordinate one iron. The polypeptide folds of the homologous
alpha and beta subunits surrounding the P-clusters are
approximately related by a twofold rotation that may be utilized
in the binding interactions between the MoFe-protein and the
nitrogenase Fe-protein. Neither the FeMo-cofactor nor the
P-clusters are exposed to the surface, suggesting that substrate
entry, electron transfer, and product release must involve a
carefully regulated sequence of interactions between the
MoFe-protein and Fe-protein of nitrogenase. J. Kim and D.C. Rees
et al: Science. 1992 257:1624.
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3. QUANTUM DOTS AND QUANTUM COMPUTERS
A. Zrenner et al (Technical University of Munich, DE) discusses
quantum computers, the authors making the following points:
1) Physicists are actively seeking to transfer the weird
phenomena of the quantum world from their laboratories to the
real world. In particular, the prospect of quantum-information
processing has attracted considerable attention for its
potential to improve the speed and reliability of data
handling(1). Information would be encoded in "quantum bits", and
the search is on for a physical system that could form a
reliable, controllable quantum bit.
2) In contrast to classical bits, which can be in either state 0
or state 1, quantum bits exist as a combination (a linear
superposition) of two quantum logic states, represented as "0"
and "1". In a quantum computer, the quantum bits first have to
be controlled individually in order to initialize the quantum
register in which information is stored. Then a controllable
interaction between the quantum bits must be established so that
the quantum states become entangled. It is this "entanglement"
that is the key to a quantum computer's power: in effect, a
rigid coupling is introduced between the quantum bits, which can
then no longer be considered individually but are affected
simultaneously by a calculational operation. It is thanks to
this capacity for parallel processing that a quantum computer
should be able to perform calculations much faster than a
classical computer.
3) The original proposals for quantum computers were based on
atomic systems(1), such as atoms held in traps, where the
quantum bit is formed by two energy levels between which an
atomic electron can make transitions. Now that semiconductor
quantum dots have been synthesized, it opens up the possibility
of mimicking these approaches in a solid-state environment.
Quantum dots, tiny clusters of semiconductor material, are often
called "artificial atoms", because the charge carriers in these
systems (electrons or holes) can only occupy a restricted set of
energy levels, just like the electrons in an atom. In fact,
quantum dots offer a variety of two-level systems, based on
charge or spin (or both). One such two-level system is a coupled
electron–hole pair -- an exciton. The absence (equivalent to the
state "0") and presence (state "1") of an exciton in a
semiconductor quantum dot could represent the two levels of a
quantum bit.(2-5)
References:
1. Bouwmeester, D., Ekert, A. & Zeilinger, A. (eds) The Physics
of Quantum Information (Springer, Berlin, 2000).
2. Zrenner, A. et al. Nature 418, 612-614 (2002).
3. Stievater, T. H. et al. Phys. Rev. Lett. 87, 133603 (2000).
4. Kamada, H. et al. Phys. Rev. Lett. 87, 246401 (2001).
5. Htoon, H. et al. Phys. Rev. Lett. 88, 087401 (2002).
Nature 2002 418:597
Web Links: quantum dots quantum computers
Related Background Brief:
COHERENT PROPERTIES OF A TWO-LEVEL SYSTEM BASED ON A QUANTUM-DOT
PHOTODIODE. Present-day information technology is based mainly
on incoherent processes in conventional semiconductor devices.
To realize concepts for future quantum information technologies,
which are based on coherent phenomena, a new type of "hardware"
is required. Semiconductor quantum dots are promising candidates
for the basic device units for quantum information processing.
One approach is to exploit optical excitations (excitons) in
quantum dots. It has already been demonstrated that coherent
manipulation between two excitonic energy levels -- via
so-called Rabi oscillations -- can be achieved in single quantum
dots by applying electromagnetic fields. The authors report they
make use of this effect by placing an InGaAs quantum dot in a
photodiode, which essentially connects it to an electric
circuit. The authors demonstrate that coherent optical
excitations in the quantum-dot two-level system can be converted
into deterministic photocurrents. For optical excitation with
so-called pi-pulses, which completely invert the two-level
system, the current is given by I = fe, where f is the
repetition frequency of the experiment and e is the elementary
charge. The authors report that this device can function as an
optically triggered single-electron turnstile. A. Zrenner et al:
Nature 2002 418:612.
Related Background:
ON THE OPTICAL ACTIVITY OF QUANTUM DOTS
One of the most significant developments in physics during the
past several decades has been the introduction of techniques for
manipulating small populations of electrons, and the
ramifications of this technology for both basic and applied
science have excited many physicists. At the present time, the
central player in this field is the so-called "quantum dot",
which essentially is an artificial atom. Quantum dots are small
isolated electrically conducting regions, typically less than 1
micron in diameter, that contain from one to a few thousand
electrons. Because of the small volume, the electron energies
within the dot are quantized, and the behavior of the quantum
dot is intermediate between that of an atom and that of a
classical macroscopic object.
Daniel Gammon (Naval Research Laboratory, US) presents a
commentary on current research on electrons in artificial atoms,
the author making the following points:
1) An electron in a quantum dot can be described by a quantum
wavefunction that is similar to that used for an electron in a
single atom, although the energy of the electron in the quantum
dot is spread in a coordinated way (spread "coherently") over
the lattice of atomic nuclei. The electronic wave functions of
quantum dots are often labeled with atomic notation, but quantum
dots are very much solid-state nanostructures that can be
tailored into different shapes. Recent studies (M. Bayer et al:
Nature 405:923 2000; R.J. Warburton et al: Nature 405:926 2000)
describe the optical behavior of individual quantum dots and
quantum rings, and such behavior is of considerable interest
because quantum dots that emit light are expected to form the
basis of a new generation of lasers.
2) In these optical studies of quantum dots, the semiconductor
dots and rings are made from indium arsenide embedded in gallium
arsenide, and the structures were grown using techniques
developed within the past decade that allow much smaller
nanostructures to be created than were previously possible. In
these new experiments, electrons are introduced one by one into
individual quantum dots while the optical emission of the dots
is measured with great precision. These studies provide new
perspectives on the internal quantum-mechanical workings of
quantum dots; the ultimate goal is to create useful electronic
and optical nanomaterials that have been quantum-mechanically
engineered by tailoring the shape, size, composition, and
position of various quantum dots.
3) Concerning the physics of quantum dots, adding even a single
electron to such a system requires a significant amount of extra
energy because of the repulsion between the negatively charged
electrons as they are forced into a smaller volume. One result
of this, called the "Coulomb blockade", is to make possible a
greater laboratory control of the number of electrons in a
quantum dot, i.e., researchers can tune the number of electrons
by manipulating input energy.
4) In general, optical excitation of a semiconductor leads to
the creation of a quasi-particle known as an "exciton" -- a
negatively charged electron bound together with a positively
charged "hole". In contrast to the Coulomb blockade resulting
from electrical injection of electrons into a quantum dot, such
dots remain neutrally charged following optical excitation, and
the quantum dot exciton has been studied in detail by measuring
the light emitted when the hole and electron recombine.
5) The author concludes: "Quantum dots have great flexibility
because their properties can be artificially engineered, but
this comes at a price. Nature has given us atoms; scientists
must make quantum dots. Further advances in this exciting field
of science and technology will depend heavily on the creativity
of physicists, chemists, and materials scientists who make these
tiny structures."
Nature 2000 405:899
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4. ON GENE PATENTS
Nigel Williams (Current Biology, UK) discusses gene patents, the
author making the following points:
1) The filing of patents containing DNA sequences has been
contentious since it was first attempted two decades or so ago.
The issue has often been polarized with companies sometimes
seeking to patent broadly and others, notably funders of public
research and some key scientists, wishing to make all sequence
data fully available to all researchers. But the climate of free
access is under increasing pressure as universities around the
world are now setting up offices to encourage and facilitate
patent protection of as much of their staff's research as
possible to generate potentially lucrative royalty income.
2) A new report by the Nuffield Council of Bioethics in London
is therefore timely in its efforts to try to find a defendable
and pragmatic middle ground. It hopes that the report might help
pave the way to the patenting of genes in a way that the
research community would find acceptable while preserving access
to key data for researchers and protecting the investment needed
for the development of new medicines based on genetic data. The
new report does not say that patenting genes is wrong in
principle. What it concludes is that far too many gene patents
are being granted by a system that is failing to apply the rules
strictly enough. The purpose of patents is to stimulate
innovation for the public good and reward people for new
inventions. "But many new patents for human DNA are likely to
impede innovation and create powerful monopolies capable of
charging high prices for tests and drugs based on human genes,"
says Sandy Thomas, director of the council. "Patents involving
human DNA should be granted only in rare cases. They should be
the exception rather than the norm."
3) The most common objection to the patents on gene sequences is
that genes occur naturally: they are there to be discovered and
not invented. The draft map of the human genome published last
year described an estimate of 30,000 to 40,000 genes. But the
council found this argument unpersuasive, arguing that isolated
DNA does not occur naturally, and without isolating and cloning
a gene, you cannot decipher its sequence. Moreover, the patent
system has long recognised useful applications of discoveries as
inventions.
Current Biology 2002 12:R577
Web Links: gene patents
Related Background:
DNA PATENTS AND DNA RESEARCH
For the past 200 years, the fundamental paradigm underlying
industrial progress in the US has been the free flow of basic
scientific information coupled with the practical applications
of science (inventions) as protectable intellectual property.
The intactness of this fundamental paradigm essentially came to
an end two decades ago with the introduction of governmental
patent protection for identification of actual or putative DNA
gene sequences. There has been much controversy surround this
change in attitude toward scientific intellectual property, and
the full social and economic consequences of the change are not
yet apparent.
The essential issue is as follows: A research group, academic or
commercial, identifies the DNA sequence for a particular gene.
The research group applies for a patent on this sequence, is
issued such a patent by the US Patent Office, and once the
patent is issued, the research group requires that anyone who
applies _knowledge_ of that sequence for any use -- medical,
commercial, or whatever -- must pay royalties to the
patent-holder.
From the viewpoint of the physical sciences, this is certainly a
strange situation: In the physical sciences, if a research group
identifies the molecular constituents and molecular formula for,
let us say, a found mineral, it is certainly not possible to
obtain a patent on the _knowledge_ of the constituents of the
mineral and require payment of royalties for use of that
knowledge in any application, commercial or noncommercial. So
something is brewing here, and lest anyone think there is only a
_potential_ for problems, it should be realized that in the US
alone many thousands of patents on human genes are now pending
in the Patent Office. As of the year 2000, the top 10 human gene
patent-holders (patents already awarded) were as follows:
Incyte Genomics...................397 patents
University of California..........253
Glaxo SmithKline..................248
US Dept. Health & Human Services.....205
Novo Nordisk......................196
Genentech.........................165
Isis Pharmaceuticals..............146
Chiron............................135
American Home Products............130
Novartis..........................128
Human Genome Sciences holds patents on 103 human genes,
including those believed to be involved in osteoporosis and
arthritis, and the company has pending patents on another 7500
genes. Celera, which only began decoding DNA in 1999, has
already filed patent claims on at least 6500 human gene
sequences.
In an article on the situation last year, Antonio Regalado
pointed out that no US Congressional vote or Supreme Court
decision has ever directly addressed the question of whether
human genes should be patentable at all. Many scientists and lay
people believe the knowledge of human genes and how they work
ought to be public property. Physicians and scientists are
complaining that the thicket of patent rights is already
stifling biomedical research, and even interfering with the care
of patients. Even those in the pharmaceutical and biotechnology
industries who readily embrace intellectual property protections
are confronting the question: Is today's deluge of patents on
human genes really good for innovation?
As an example of the current situation, Regalado noted that in
April 2000, the University of Rochester (US) was granted a
patent on the human gene Cox-2. University officials immediately
filed a lawsuit against G.D. Searle, a subsidiary of Pharmacia.
The basis of the lawsuit: Searle markets the highly lucrative
pain-killer (analgesic) called "Celebrex" which acts by blocking
the enzyme encoded by the Cox-2 gene. The University of
Rochester claimed that Searle's drug infringed its patent, which
describes not just the DNA letters of the gene, but also the
"general idea" of using a drug that blocks Cox-2 as a way to
alleviate pain. In 1999, the first year on the market, Celebrex
sales amounted to US$1.5 billion. A University of Rochester
press release last year stated the university's patent is
"likely to be the most lucrative in US history."
Another example cited by Regalado: A research group at the Miami
Children's Hospital (Florida, US) helped discover (and then
patented) the mutations that cause Canavan disease, an inherited
neurological disorder. Knowledge of the mutation allows
physicians to test patients who fear they might be carriers of
the defect by taking blood samples and checking for specific DNA
mutations on chromosome 17, where the Canavan gene is located.
Miami Children's Hospital requires a royalty payment of US$12.50
for every test performed, even though the test procedure itself
is not covered by the patent. A similar situation exists with
companies that have patents on genes that can predict the onset
of breast cancer or Alzheimer's disease. Royalties are demanded
for use of _knowledge_ of the genes.
Regalado concluded: "Although gene patenting has been going on
for years, as far as the man and woman on the street are
concerned, the debate has just begun. And if it follows the
course of other recent biomedical controversies over cloning and
stem cell research, it may be one argument that politicians and
ordinary citizens will not be content to leave in the hands of
scientists, pharmaceutical companies, or patent lawyers."
In 1998, John J. Doll, Director of Biotechnology Examination at
the US Patent and Trademark Office presented a number of points
concerning this issue, with Doll stating:
1) Just as the issuing of broad product claims at the early
stages of polymer technology did not deter development of other
new vulcanizable copolymers, the issuing of relatively broad
claims in genomic technology should not deter inventions in
genomics.
2) The same patent-ability analysis is conducted for every
patent application, regardless of whether the application is for
a computer chip, a mechanical apparatus, a pharmaceutical, or a
piece of DNA. In every field of technology -- whether emerging,
complex, or competitive -- all the conditions for patentability
(such as statutory subject matter utility, enablement, written
description, novelty, and non-obviousness) must be met before a
claim is allowed.
3) In order for DNA sequences to be distinguished from their
naturally occurring counterparts, which cannot be patented, the
patent application must state that the invention has been
purified or isolated or is part of a recombinant molecule or is
now part of a vector.
4) Once a product is patented, that patent extends to any use,
even those that have not been disclosed in the patent. A future
non-obvious method of using that product may be patentable, but
the first patent will be dominant and a license for the use of
the product may be required.
5) Without the incentive of patents, there would be less
investment in DNA research, and scientists might not disclose
their new DNA products to the public. It is only with the
patenting of DNA technology that some companies, particularly
small ones, can raise sufficient venture capital to bring
beneficial products to the marketplace or fund further research.
6) A strong US patent system is critical for the continued
development and dissemination to the public of information on
DNA sequence elements.
Thus the case for DNA patents, at least from the standpoint of
the US Patent Office.
In a commentary on the subject last month, R. Cook-Deegan and
S.J. McCormack pointed out that more than 25,000 DNA-based
patents were issued by the end of 2000, covering purified and
cloned gene fragments and full-length genes, regulatory
sequences, sequencing and diagnostic methods, and many other
inventions. Cook-Deegan and McCormack suggested that the
expectation of patents being granted is one reason that 73
publicly-traded genomics firms were collectively valued at $96
billion at the end of the year 2000. Cook-Deegan and McCormack
stated: "No other sector of the economy depends as much on
strong patent protection or on the flow of information from
academic science as pharmaceuticals and biotechnology."
Technology Review 2000 September/October
Science 1998 280:689
Science 2001 293:217
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5. CAGE REARRANGEMENTS AND THE COLLOIDAL GLASS TRANSITION
E.R. Weeks and D.A. Weitz (Emory University, US) discuss cage
rearrangements, the authors making the following points:
1) Many liquids undergo a glass transition when rapidly cooled,
where their viscosity grows by orders of magnitude for only
modest decreases in temperature. This drastic increase in
viscosity is unaccompanied by significant structural changes;
instead, the dynamics slow dramatically. Physically, this
slowing of the dynamics reflects the confinement of any given
particle by a "cage" formed by its neighbors; it is the
rearrangement of the cage which leads to the final structural
relaxation, allowing the particle to diffuse through the sample
[1]. The dynamics of cages have been studied with scattering
measurements, which probe a spatial and temporal average of
their behavior, and with computer simulations; however, in real
systems, the actual motion of the individual particles involved
in cage dynamics and breakup are still poorly understood [1-5].
2) The authors report a study of the motion of the individual
particles and their neighbors during cage breakup, and provide
the first direct experimental visualization of this process. The
authors use confocal microscopy to study the motion of colloidal
particles in a dense suspension, an excellent model for the
glass transition. The authors use sterically stabilized
poly-methylmethacrylate) particles with a radius of 1.18
microns. The rearrangement of cages involves the cooperative
motion of neighboring particles [2-5]. While most neighboring
particles move in similar directions, a significant minority
move in opposite directions, resulting in local changes in
topology. The authors also find that the more mobile particles
are located in regions with a lower local volume fraction, and
higher disorder. The authors suggest these measurements provide
a direct, quantitative physical picture of the nature of cage
rearrangements.
References (abridged):
1. M.D. Ediger, C. A. Angell, S.R. Nagel, J. Phys. Chem. 100, 13
200 (1996); C. A. Angell, J. Phys. Condens. Matter 12, 6463
(2000).
2. W.K. Kegel and A. van Blaaderen, Science 287, 290 (2000).
3. E. R. Weeks, J. C. Crocker, A. C. Levitt, A. Schofield, and
D. A. Weitz, Science 287, 627 (2000).
4. W. Kob, C. Donati, S.J. Plimpton, P.H. Poole, S.C. Glotzer,
Phys. Rev. Lett. 79, 2827 (1997).
5. C. Donati et ai, Phys. Rev. Lett. 80, 2338 (1998).
Phys. Rev. Lett. 2002 89:095704
Web Links: glass transition colloids
Related Background:
PHYSICAL CHEMISTRY: THE GLASS TRANSITION OF WATER
Dennis D. Klug (National Research Council, CA) discusses phase
transitions of water, the author making the following points:
1) Few known simple molecular systems can rival the complexity
of the water phase diagram. Water boasts numerous solid phases
and may even form two different liquid phases at low
temperatures. But pinning down the exact nature of the different
phases and the transitions between them has proved difficult.
2) One of the intractable properties of water is the temperature
at which water changes from a liquid to a glassy state. The
glass transition temperature is usually defined as the
temperature at which the liquid becomes very viscous and
essentially a quenched liquid upon cooling, or as the
temperature at which the solid-like glass transforms to a liquid
upon heating. This is an operational rather than a thermodynamic
definition, because the glass transition temperature depends,
for example, on the rate at which the liquid is cooled. On
timescales of a picosecond, even liquid water at room
temperature is quite hard.
3) Experimental studies of the liquid and amorphous phases of
water indicate a highly complex behavior. Several theories
suggest the possible existence of two distinct liquid water
phases, a liquid-liquid phase transition upon cooling, and a
liquid-liquid critical point in the low-temperature region of
the phase diagram. The glass transition may occur in one of
these liquid forms of water if the theories are correct. The
location of the glass transition defines the region where one
can search for the low-temperature liquid, the liquid-liquid
transition, and the proposed second critical point. The glass
transition of water is also of interest in the context of
cryoprotection processes and biological organisms at low
temperature.
Science 2001 294:2305
Related Background:
ON THE DYNAMIC GLASS TRANSITION
T.S. Grigera et al (University of Rome, IT) discuss the dynamic
glass transition, the authors making the following points:
1) Despite a large number of investigations, there is still much
to understand about the dynamic glass transition in supercooled
liquids. The basic problem is that, strictly speaking, there is
no dynamic transition at all. In systems known as fragile
liquids, experiment reveals a sharp rise of the viscosity in a
very narrow interval of temperature upon cooling. The shear
relaxation time increases by several orders of magnitude within
a few degrees, and it becomes impossible to perform an
equilibrium experiment. Nevertheless, sharp as this behavior may
be, it is not a genuine dynamic singularity. At the other
extreme of the experimental spectrum, one finds strong liquids
that experience a gentle increase of the relaxation time, often
according to the Arrhenius law. Even in such systems, however,
when the viscosity becomes too large, equilibrium can no longer
be achieved on experimental timescales.
2) The glass transition temperature is conventionally defined as
that temperature at which the value of the viscosity is 10^(13)
poise. Below the glass transition temperature, equilibrium
experiments become difficult to perform and a sample can be
considered to be in its glass phase. However, the glass
transition temperature is merely a conventional experimental
temperature defined out of the need to mark the onset of glassy
dynamics. The attempt to give a theoretical description of such
an ill-defined “transition” may therefore seem pointless. On the
one hand, this conclusion is correct for the strongest liquids:
here nothing peculiar happens close to the glass transition
temperature , and the glass transition fully displays its purely
conventional nature. On the other hand, the most fragile systems
resist such an objection, simply by virtue of the extremely
steep increase of relaxation time within a small interval of
temperature around the glass transition temperature. This fact
suggests that some kind of new physical mechanism is indeed
responsible for the onset of the glassy phase in fragile
supercooled liquids.
3) The authors report they numerically studied the potential
energy landscape of a fragile glassy system and found that the
dynamic crossover corresponding to the glass transition is
actually the effect of an underlying geometric transition caused
by the vanishing of the instability index of saddle points of
the potential energy. Furthermore, the authors demonstrate that
the potential energy barriers connecting local glassy minima
increase with decreasing energy of the minima, and they relate
this behavior to the fragility of the system. Finally, the
authors analyze the real space structure of activated processes
by studying the distribution of particle displacements for local
minima connected by simple saddles.
References (abridged):
1. C. A. Angell, J. Phys. Chem. Solids 49, 863 (1988).
2. M. Goldstein, J. Chem. Phys. 51, 3728 (1969).
3. F.H. Stillinger and T.A. Weber, Phys. Rev. A 25, 978 (1982).
4. A. Cavagna, Europhys. Lett. 53, 490 (2001).
5. J. Kurchan and L. Laloux, J. Phys. A 29, 1929 (1996).
Phys. Rev. Lett. 2002 88:055502
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6. ON VOLTAGE-GATED POTASSIUM CHANNELS
Gary Yellen (Harvard University, US) discusses voltage-gated
potassium channels, the author making the following points:
1) The voltage-gated K+ channels are the prototypical
voltage-gated channels. At their simplest, they are
homotetrameric channels, with each subunit containing a voltage
sensor and contributing to the central pore. The standard K+
channel subunit contains six transmembrane regions, with both
amino and carboxy termini on the intracellular side of the
membrane (a tetrameric "6TM architecture"). The pore-forming
subunits of voltage-gated Na+ and Ca2+ channels contain four
non-identical repeats of this motif, strung together on a single
polypeptide. There is enormous variety within each of these
channel families: voltage-gated K+ channels alone are made by at
least 22 different genes in mammals, with additional variety
produced by alternative splicing and heteromultimerization.
2) Some close relatives of the voltage-gated K+ channels share
the tetrameric 6TM architecture but differ in key functional
features. These include the sensory channels of the
photoreceptors and olfactory neurons, which are non-selective
(Na+ and K+) channels that are cyclic-nucleotide-gated (the "CNG
channels") and insensitive to voltage, and the pacemaker
channels found in heart muscle and neurons (the "HCN channels")
that are controlled by both cyclic nucleotides and voltage.
3) Each of these signaling proteins performs three main
functions. Ion permeation is the central function, and the
movement of ions through the pore must be fast and
ion-selective. This permeation is then regulated by opening and
closing of the pore -- a set of conformational changes called
"gating". Finally, the gating is coupled to a sensing mechanism,
which detects transmembrane voltage in the core members of the
family, but can also be geared to sense Ca2+, cyclic
nucleotides, and perhaps other cellular signals. From
approximately 40 years of electrophysiology and biophysics, a
little over a decade of cloning followed by mutagenesis and
physiology on cloned channels, and from a few important crystal
structures of some bacterial relatives of these channels, we now
have a relatively clear picture of how these functions are
accomplished.(1-5)
References (abridged):
1. Hodgkin, A. L. & Huxley, A. F. A quantitative description of
membrane current and its application to conduction and
excitation in nerve. J. Physiol. (Lond.) 117, 500-544 (1952)
2. Latorre, R. & Miller, C. Conduction and selectivity in
potassium channels. J. Membr. Biol. 71, 11-30 (1983)
3. Doyle, D. A. et al. The structure of the potassium channel:
molecular basis of potassium conduction and selectivity. Science
280, 69-77 (1998)
4. Zhou, Y., Morais Cabral, J. H., Kaufman, A. & MacKinnon, R.
Chemistry of ion hydration and coordination revealed by a K+
channel-Fab complex at 2.0 Å resolution. Nature 414, 43-48 (2001)
5. Morais-Cabral, J. H., Zhou, Y. & MacKinnon, R. Energetic
optimization of ion conduction rate by the K+ selectivity
filter. Nature 414, 37-42 (2001)
Nature 2002 419:35
Web Links: potassium ion channels
Related Background Brief:
THE STRUCTURE OF THE POTASSIUM CHANNEL: MOLECULAR BASIS OF K+
CONDUCTION AND SELECTIVITY. The potassium channel from
Streptomyces lividans is an integral membrane protein with
sequence similarity to all known K+ channels, particularly in
the pore region. The authors report that x-ray analysis with
data to 3.2 angstroms reveals that four identical subunits
create an inverted teepee, or cone, cradling the selectivity
filter of the pore in its outer end. The narrow selectivity
filter is only 12 angstroms long, whereas the remainder of the
pore is wider and lined with hydrophobic amino acids. A large
water-filled cavity and helix dipoles are positioned so as to
overcome electrostatic destabilization of an ion in the pore at
the center of the bilayer. Main chain carbonyl oxygen atoms from
the K+ channel signature sequence line the selectivity filter,
which is held open by structural constraints to coordinate K+
ions but not smaller Na+ ions. The selectivity filter contains
two K+ ions about 7.5 angstroms apart. This configuration
promotes ion conduction by exploiting electrostatic repulsive
forces to overcome attractive forces between K+ ions and the
selectivity filter. The architecture of the pore establishes the
physical principles underlying selective K+ conduction. D.A.
Doyle et al: Science 1998 280:69.
Related Background Brief:
CHEMISTRY OF ION COORDINATION AND HYDRATION REVEALED BY A K+
CHANNEL-FAB COMPLEX AT 2.0 A RESOLUTION. Ion transport proteins
must remove an ion's hydration shell to coordinate the ion
selectively on the basis of its size and charge. To discover how
the K+ channel solves this fundamental aspect of ion conduction,
the authors report they solved the structure of the KcsA K+
channel in complex with a monoclonal Fab antibody fragment at
2.0 A resolution. The authors demonstrate how the K+ channel
displaces water molecules around an ion at its extracellular
entryway, and how it holds a K+ ion in a square antiprism of
water molecules in a cavity near its intracellular entryway.
Carbonyl oxygen atoms within the selectivity filter form a very
similar square antiprism around each K+ binding site, as if to
mimic the waters of hydration. The selectivity filter changes
its ion coordination structure in low K+ solutions. This
structural change is crucial to the operation of the selectivity
filter in the cellular context, where the K+ ion concentration
near the selectivity filter varies in response to channel
gating. Y. Zhou et al: Nature 2001 Nov 1;414(6859):43.
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7. ON HYDROGEN AS AN ENERGY SOURCE
R.D. Cortwright et al (University of Wisconsin, US) discuss
hydrogen as an alternate fuel, the authors making the following
points:
1) Concerns about the depletion of fossil fuel reserves and the
pollution caused by continuously increasing energy demands make
hydrogen an attractive alternative energy source. Hydrogen is
currently derived from nonrenewable natural gas and
petroleum(1), but could in principle be generated from renewable
resources such as biomass or water. However, efficient hydrogen
production from water remains difficult and technologies for
generating hydrogen from biomass, such as enzymatic
decomposition of sugars(2-5), steam-reforming of bio-oils, and
gasification, suffer from low hydrogen production rates and/or
complex processing requirements.
2) The authors report a demonstration that hydrogen can be
produced from sugars and alcohols at temperatures near 500 K in
a single-reactor aqueous-phase reforming process using a
platinum-based catalyst. The authors report they are able to
convert glucose -- which makes up the major energy reserves in
plants and animals -- to hydrogen and gaseous alkanes, with
hydrogen constituting 50% of the products. The authors find that
the selectivity for hydrogen production increases when they use
molecules that are more reduced than sugars, with ethylene
glycol and methanol being almost completely converted into
hydrogen and carbon dioxide. The authors suggest these findings
indicate that catalytic aqueous-phase reforming might prove
useful for the generation of hydrogen-rich fuel gas from
carbohydrates extracted from renewable biomass and biomass waste
streams.
References (abridged):
1. Rostrup-Nielsen, J. Conversion of hydrocarbons and alcohols
for fuel cells. Phys. Chem. Chem. Phys. 3, 283-288 (2001)
2. Kumar, N. & Das, D. Enhancement of hydrogen production by
enterobacter cloacae IIT-BT 08. Process Biochem. 35, 589-593
(2000)
3. Woodward, J. et al. Enzymatic hydrogen production: Conversion
of renewable resources for energy production. Energy Fuels 14,
197-201 (2000)
4. Yokoi, H. et al. Microbial hydrogen production from sweet
potato starch residue. J. Biosci. Bioeng. 91, 58-63 (2001)
5. Woodward, J., Orr, M., Cordray, K. & Greenbaum, E. Enzymatic
production of biohydrogen. Nature 405, 1014 (2000)
Nature 2002 418:964
Web Links: hydrogen as an alternate fuel
Related Background Brief:
CONVERSION OF HYDROCARBONS AND ALCOHOLS FOR FUEL CELLS. Fuel
conversion to hydrogen is an important part of most fuel cell
systems. The author describes the available technologies for
conversion of hydrocarbons and alcohols. The endothermic steam
reforming catalysts and processes as well as autothermal
reforming are proven technologies. Recent developments include
catalytic partial oxidation. The integration of the fuel
processing with the fuel cell represents a task with
requirements depending on each type of fuel cell and
application. The automotive use of fuel cells is at present a
special challenge. The optimum fuel for stationary plants is
natural gas (if available), whereas light naphtha appears to be
the choice for automotive use. J.R Rostrup-Nielsen: Phys Chem
Chem Phys 2001 3:283.
Related Background Brief:
ENHANCEMENT OF HYDROGEN PRODUCTION BY ENTEROBACTER CLOACAE
IIT-BT 08. A gram negative hydrogen producing facultative
anaerobe was isolated and characterized as Enterobacter cloacae
IIT-BT 08. Hydrogen yields by using this microorganism varied
from substrate to substrate (2.2 mol/mol glucose, 6 mol/mol of
sucrose and 5.4 mol/mol cellobiose considering 1% w/v substrate
in MY medium). The maximum rate of hydrogen production achieved
was at 36 degrees C and initial pH 6.0. The maximum rate was
29.63 mmol/(g dry cell per h). The pH profiles of the
fermentation broth under aerobic and anaerobic conditions were
monitored and found to differ from each other particularly
beyond the pH of 4.8. About 28% of substrate energy were
recovered in the form of hydrogen using sucrose as a substrate.
N. Kumar and D. Das Process Biochemistry 2000 35:589.
Related Background Brief:
ENZYMATIC HYDROGEN PRODUCTION: CONVERSION OF RENEWABLE RESOURCES
FOR ENERGY PRODUCTION. Using the enzymes glucose dehydrogenase
(GDH) and hydrogenase, the authors report a demonstration that a
variety of sugars that are components of renewable resources can
be enzymatically converted to molecular hydrogen. The rates at
which hydrogen was evolved paralleled the substrate specificity
of GDH. The highest rate of hydrogen production measured was
97.8 mu mol/h, and the stoichiometric yield of hydrogen was 98%
with 50 mM glucose as the substrate. Lactose, sucrose,
cellulose, xylan, steam-exploded aspen wood, and starch also
served as substrates for hydrogen production when the
corresponding enzymes were included in the reaction mixture to
generate the appropriate monosaccharide for which GDH has
specificity. The data obtained are discussed in the context of
the rate-limiting steps of hydrogen production from renewable
sugar and the possible applications of enzymatic hydrogen
production. J. Woodward et al: Energy & Fuels 2000 14:197.
Related Background:
ON PHOTOCATALYSIS AND MOLECULAR HYDROGEN FUEL SOURCES
James K. McCusker (Michigan State University, US) discusses
photocatalysis. The laws of thermodynamics are rigid and
unforgiving: if you want energy, you must pay for it. From a
scientific perspective, this simply means that to get energy out
of a system, at least that amount of energy will collectively
have to be spent. By far the most abundant and arguably the most
environmentally friendly currency at our disposal for paying
this cost is sunlight. It has been estimated that the amount of
solar energy reaching the surface of the Earth every day is more
than mankind could use in 30 years. Nature recognized the wisdom
of tapping into this resource billions of years ago, when it
came up with the photosynthetic apparatus for converting
sunlight into usable chemical and/or mechanical energy. But the
scientific community has yet to develop artificial methods for
efficient solar energy conversion that can compete, economically
or otherwise, with other sources of energy such as fossil fuels
and nuclear fission. One resource that might be generated by
solar energy is molecular hydrogen. The notion of molecular
hydrogen as a fuel source has already had the attention of the
industrial community, and it plays a key role in current US
policy concerning alternative fuels. The targeting of molecular
hydrogen in photoconversion schemes is as old as the idea of
solar energy conversion itself, and it was obvious early on that
acids provide an almost ideal source for the protons needed.
Catalytic production of hydrogen -- one of the most important
considerations -- was achieved more slowly but can now be
accomplished under a variety of conditions. The most successful
approaches involve heterogeneous reactions, i.e., reactions in
which the reactant species are in different phases (such as
solid and gas).
Science 2001 293:1599
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8. DECLINE IN PHYSICAL ACTIVITY IN ADOLESCENT GIRLS
S.Y. Kimm et al (University of Pittsburgh, US) discuss physical
activity in adolescent girls, the authors making the following
points:
1) Since the early 1960s, the prevalence of obesity in female
children and adolescents in the United States has more than
doubled, with the greatest increase among black girls.(1)
Periodic surveys show no concomitant increase in food
intake.(2,3) Analogous information on trends in activity level
in this population is not available. It has been conjectured
that adolescents have become less active in recent years, and
that this trend may be responsible for the increased prevalence
of obesity.(4,5)
2) In cross-sectional studies, activity levels have been
reported to drop by as much as 50 percent during adolescence.
Although white girls tend to be more active than black girls,
both groups become increasingly sedentary with age, beginning as
early as the age of 10 years. However, the factors associated
with the decline in activity during adolescence remain largely
unknown.
3) The authors report they examined longitudinal changes in
physical activity in a large, biracial cohort of adolescent
girls and examined racial differences and other factors
associated with these changes. The authors prospectively
followed 1213 black girls and 1166 white girls enrolled in the
National Heart, Lung, and Blood Institute Growth and Health
Study from the ages of 9 or 10 to the ages of 18 or 19 years.
The authors used a validated questionnaire to measure
leisure-time physical activity on the basis of metabolic
equivalents (MET) for reported activities and their frequency in
MET-times per week; a higher score indicated greater activity.
The respective median activity scores for black girls and white
girls were 27.3 and 30.8 MET-times per week at base line and
declined to 0 and 11.0 by year 10 of the study (a 100 percent
decline for black girls and a 64 percent decline for white
girls, P<0.001). By the age of 16 or 17 years, 56 percent of the
black girls and 31 percent of the white girls reported no
habitual leisure-time activity. Lower levels of parental
education were associated with greater decline in activity for
white girls at both younger ages (P<0.001) and older ages
(P=0.005); for black girls, this association was seen only at
the older ages (P=0.04). Pregnancy was associated with decline
in activity among black girls (P<0.001) but not among white
girls, whereas cigarette smoking was associated with decline in
activity among white girls (P<0.001). A higher body-mass index
was associated with greater decline in activity among girls of
both races (P0.05).
4) The authors conclude: Substantial declines in physical
activity occur during adolescence in girls and are greater in
black girls than in white girls. The authors suggest that some
determinants of this decline, such as higher body-mass index,
pregnancy, and smoking, may be modifiable.
References (abridged):
1. Troiano RP, Flegal KM, Kuczmarski RJ, Campbell SM, Johnson
CL. Overweight prevalence and trends for children and
adolescents: the National Health and Nutrition Examination
Surveys, 1963 to 1991. Arch Pediatr Adolesc Med
1995;149:1085-1091.
2. Carroll MD, Abraham S, Dresser CM. Dietary intake source
data: United States, 1976-80. Advance data from vital and health
statistics. No. 231. Hyattsville, Md.: National Center for
Health Statistics, 1983. (DHHS publication no. [PHS] 83-1681.)
3. McDowell MA, Briefel RR, Alaimo K, et al. Energy and
macronutrient intakes of persons ages 2 months and over in the
United States: Third National Health and Nutrition Examination
Survey, Phase 1, 1988-91. Advance data from vital and health
statistics. No. 255. Hyattsville, Md.: National Center for
Health Statistics, 1994:1-24. (DHHS publication no. [PHS] 94.)
4. Kann L, Kinchen SA, Williams BI, et al. Youth risk behavior
surveillance — United States, 1997. MMWR Morb Mortal Wkly Rep
CDC Surveill Summ 1998;47:SS-3:1-89.
5. Sallis JF, Simons-Morton BG, Stone EJ, et al. Determinants of
physical activity and interventions in youth. Med Sci Sports
Exerc 1992;24:Suppl 6:S248-S257.
New Engl. J. Med. 2002 347:709
Web Links: adolescent obesity
Related Background Brief:
OVERWEIGHT PREVALENCE AND TRENDS FOR CHILDREN AND ADOLESCENTS.
THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEYS, 1963 TO
1991. The authors report a study to examine the prevalence of
overweight and trends in overweight for children and adolescents
in the US population. The study involved nationally
representative cross-sectional surveys with an in-person
interview and a medical examination, including measurement of
height and weight. Between 3000 and 14,000 youths aged 6 through
17 years were examined in each of five separate national surveys
during 1963 to 1965, 1966 to 1970, 1971 to 1974, 1976 to 1980,
and 1988 to 1991 (Cycles II and III of the National Health
Examination Survey, and the first, second, and third National
Health and Nutrition Examination Surveys, respectively). The
main outcome measures: Prevalence of overweight based on body
mass index and 85th or 95th percentile cutoff points from Cycles
II and III of the National Health Examination Survey. RESULTS:
From 1988 to 1991, the prevalence of overweight was 10.9% based
on the 95th percentile and 22% based on the 85th percentile.
Overweight prevalence increased during the period examined among
all sex and age groups. The increase was greatest since 1976 to
1980, similar to findings previously reported for adults in the
US. The authors conclude: Increasing overweight among youths
implies a need to focus on primary prevention. Attempts to
increase physical activity may provide a means to address this
important public health problem. R.P. Troiano et al: Arch
Pediatr Adolesc Med 1995 149:1085.
Related Background Brief:
PHYSICAL ACTIVITY PATTERNS IN AMERICAN HIGH SCHOOL STUDENTS.
RESULTS FROM THE 1990 YOUTH RISK BEHAVIOR SURVEY. The authors
report a study to assess by self-reported participation in
vigorous physical activity, the quantity and quality of school
physical education, team sports, and television watching among
11,631 American high school students. RESULTS: Of all students
in grades 9 through 12, 37% reported engaging in 20 minutes of
vigorous physical activity three or more times per week.
Participation in vigorous physical activity was higher among
boys than girls (P < .01) and higher among white students than
among those of other races and ethnic groups (P < .01). Overall,
43.7% of boys and 52% of girls reported that they were not
enrolled in physical education classes. Of the students who
reported attending physical education class during the past 2
weeks, 33.2% reported exercising 20 minutes or more in physical
education class three to five times per week. In contrast, rates
of participation in varsity and junior varsity sports remained
constant across grade levels, but participation in recreational
physical activity programs showed a lesser magnitude and also
decreased with advancing grade. More than 70% of students
reported spending at least 1 hour watching television each
school day, and more than 35% reported watching television 3
hours or more each school day. The authors conclude:
Participation in vigorous physical activity and physical
education class time devoted to physical activity are
substantially below the goals set in Healthy People 2000. As
students move toward graduation, the authors observed disturbing
declines in participation in community recreation programs and
overall vigorous activity. Students appear to spend considerably
more time watching television than participating in physical
activity. The authors suggest that public health efforts should
focus on increasing the physical activity levels of our youth to
enhance their current well-being and to reduce the risks of
future chronic disease. G.W. Heath et al: Arch Pediatr Adolesc
Med 1994 148:1131.
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9. A NEW 20-KILOMETER IMPACT STRUCTURE IN THE NORTH SEA
S.A. Stewart and P.J. Allen (British Petroleum Ltd., UK) discuss
a new impact structure, the authors making the following points:
1) Most craters found on Earth are highly eroded, poorly
preserved and only exposed on land(1,2). The authors describe a
multi-ringed impact structure discovered in the North Sea from
the analysis of three-dimensional seismic reflection data. The
structure is 20 km in diameter, and has at least ten distinctive
concentric rings located between 2 and 10 km from the crater
center. The structure affects Cretaceous chalk and Jurassic
shales, and is well preserved below several hundred meters of
post-impact Tertiary strata, which constrains its age to be
60–65 Myr old. The formation of concentric ringed impact
structures at this relatively small scale had not previously
been thought possible, especially on the terrestrial
planets(1,3,4).
2) The authors report they have mapped the ring structures at a
resolution of tens of meters both laterally and in depth, and
demonstrate that the rings are fault-bounded graben structures,
similar to fault arrays formed in low-strain-rate detachment
tectonic settings(5). Strata deeper than 500 m palaeodepth
appear unfaulted, and the authors infer that the concentric ring
structures may have accommodated post-impact extension towards
the excavated crater, through detachment on weak layers within
the chalk.
3) The authors term the structure "Silverpit crater" after a
nearby sea-floor channel. The structure was gently folded by
late Tertiary regional tectonics, and now lies at a depth range
spanning 300 m to 1,500 m below the sea bed. Present-day water
depth is 40 m. The seismic data reveal a number of distinctive
aspects of the structure, such as a conical central peak buried
inside a 3-km-diameter crater that is in turn bounded by a set
of several inward-facing fault scarps. But the most striking
aspect of this structure is the plan-view pattern of concentric
rings forming the outer parts of the structure, mapped at the
top of the Cretaceous.
References (abridged):
1. Grieve, R. A. F. & Pesonen, L. J. The terrestrial impact
cratering record. Tectonophysics 216, 1-30 (1992)
2. Grieve, R. A. F. Extraterrestrial impacts on earth: the
evidence and the consequences. Geol. Soc. Lond. Spec. Publ. 140,
105-131 (1998)
3. Melosh, H. J. Impact Cratering: A Geological Process (Oxford
Univ. Press, New York, 1989)
4. Moore, J. M. et al. Large impact features on Europa: Results
of the Galileo nominal mission. Icarus 135, 127-145 (1998)
5. Schultz-Ela, D. D. & Walsh, P. Modeling of grabens extending
above evaporites in Canyonlands National Park, Utah. J. Struct.
Geol. 24, 247-275 (2002)
Nature 2002 418:520
Web Links: impact craters
Related Background Brief:
THE TERRESTRIAL IMPACT CRATERING RECORD. Approximately 130
terrestrial hypervelocity impact craters are currently known.
Due to variations in preservation and in geologic knowledge,
this sample is biased towards young (< 200 Ma), large (> 20 km)
craters on the cratons of Australia, Europe (including the
former USSR) and North America. The rate of discovery of new
craters is 3-5 craters per year. Although modified by erosion,
terrestrial impact craters exhibit the range of morphologies
observed for craters on other terrestrial planetary bodies, such
as the Moon. Terrestrial craters provide essential ground truth
data on the geologic effects of impact and the subsurface
structure of impact craters, which can be used to constrain
interpretations of lunar samples and models of crater formation.
Due to erosion and its effects on form, terrestrial craters are
recognized primarily by the occurrence of shock metamorphic
effects. These include: shatter cones, microscopic planar
deformation features, solid-state and fusion glasses, high
pressure polymorphs and whole rock melting and Vaporization.
Shock recovery experiments indicate that these features occur
over shock pressures of greater-than-or-equal-to 5 GPa to > 100
GPa. Terrestrial craters have a set of geophysical
characteristics which are largely the result of the passage of a
shock wave and impact-induced fracturing. They include gravity
and magnetic lows and reductions in seismic velocity. The
gravity anomalies are seldom greater than approximately 30 mGal,
due to the limiting effects of lithostatic pressure on
fracturing. At large complex craters, the gravity signature may
include a central relative gravity high, due to uplift, and
short wavelength central magnetic anomalies, due to a variety of
processes. Much current work is focused on the effects of impact
on earth evolution. Previous work on shock metamorphism and the
contamination of impact melt rocks by meteoritic siderophile
elements provides a basis for the interpretation of the physical
and chemical evidence from Cretaceous-Tertiary boundary sites as
resulting from a major impact. Suggestions that other biological
boundaries in the Stratigraphic record are due to periodic
impacts are not supported by time series analysis of the
terrestrial cratering record. By analogy with the lunar record
and modeling of the effects of very large impacts, it has been
proposed that biological and atmospheric evolution of the Earth
could not stabilize before the end of the late heavy bombardment
approximately 3.8 Ga ago. The present terrestrial cratering rate
is 5.4 +/- 2.7 x 10^(-15) km^(-2) per year for a diameter >= 20
km. This represents a local threat on historic time scales. On a
global scale, a major impact sufficient to cripple human
civilization severely will occur on time scales of approximately
10^(6) years. R. Grieve and L.J. Pesonen: Tectonophysics 1992
216:1.
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10. ON NEURONAL MIGRATION IN DEVELOPMENT
Mary E. Hatten (Rockefeller University, US) discuss neuronal
migration during development, the author making the following
points:
1) The migration of immature neurons from germinal zones to
specific positions where axon-target interactions occur is a
critical step in the development of the synaptic circuitry of
the brain. During development of the worm Caenorhabditis
elegans, very few cells move from the positions where they are
generated. Only 12 cell populations migrate, including three
classes of neurons (HSN, CAN, and Q neuroblasts), somatic gonad
precursors, and sex myoblasts (1-3). The more complex body plan
of the fruit fly Drosophila is reflected in more widespread cell
migration (3). In vertebrates, many cells undergo remarkable
cell migrations, including the cells of the gonads, kidney, and
the immune and nervous systems. Neuronal migration culminates in
the formation of layered cortical structures in mammals where a
novel form of migration, across the radial plane of the neural
tube, develops.
2) Studies on neuronal migration in C. elegans have identified
numerous genes that encode chemoattractants or receptors
important for neuroblast migration along the body axis, either
along the dorsoventral (DV) axis or anterior-posterior (AP)
axis. The most studied of these is unc-6 (also called
unc-6/Netrin1), which is required for DV but not AP migrations
in C. elegans. unc-6 encodes a protein secreted by ventral
midline cells, which guides the migration of cells in the dorsal
direction via the receptor UNC5 and ventrally via the receptor
UNC40 (4). UNC-6/Netrin1 and its receptors are critical for
early cell migrations along the DV axis of vertebrates as well.
With regard to the AP axis of C. elegans, MIG13 is a
transmembrane protein that acts nonautonomously in anterior
migrations of Q neurons (5) The expression of MIG13 is regulated
by Hox gene activity, such that increasing doses of MIG13 causes
cells to migrate further anterior. In C. elegans, vab-8
functions in posterior migrations (6). The vab-8 locus encodes
two isoforms of an intracellular protein, one of which contains
a kinesin-like motor domain. The general schema seen in C.
elegans, of migrations along the central axes of the embryo via
global positioning system genes, is now appreciated in
vertebrate embryos.
3) In summary: Over the past decade, genetic analyses have
yielded a more molecular view of neuronal migration and its role
in central nervous system development. We now realize that many
of the molecular mechanisms that guide migrations in
invertebrates are recapitulated in the vertebrate nervous
system. These mechanisms guide dorsoventral and
anterior-posterior migrations and merge with radial migratory
pathways that are prominent in the development of the mammalian
cortex. The author discusses the choreography of these different
migratory mechanisms within the context of genetic approaches
that have defined their molecular mechanisms.
References (abridged):
1. R. Blelloch, C. Newman, J. Kimble, Curr. Opin. Cell Biol. 11,
608 (1999)
2. W. C. Forrester, E. Perens, J. A. Zallen, G. Garriga,
Genetics 148, 151 (1998)
3. D. Montell, Development 126, 3035 (1999)
4. E. Hedgecock, J. Culotti, D. Hall, Neuron 4, 61 (1990)
5. M. Sym, N. Robinson, C. Kenyon, Cell 98, 25 (1999)
Science 2002 297:1660
Web Links: neuronal migration in development
Related Background Brief:
IDENTIFICATION OF CAENORHABDITIS ELEGANS GENES REQUIRED FOR
NEURONAL DIFFERENTIATION AND MIGRATION. To understand the
mechanisms that guide migrating cells, the authors report they
have been studying the embryonic migrations of the C. elegans
canal-associated neurons (CANs). The authors describe two
screens used to identify genes involved in CAN migration. First,
the authors screened for mutants that died as clear larvae (Clr)
or had withered tails (Wit), phenotypes displayed by animals
lacking normal CAN function. Second, the authors screened
directly for mutants with missing or misplaced CANs. The authors
isolated and characterized 30 mutants that defined 14 genes
necessary for CAN migration. The authors report that one of the
genes, ceh-10, specifies CAN fate. ceh-10 had been defined
molecularly as encoding a homeodomain protein expressed in the
CANs. Mutations that reduce ceh-10 function result in Wit
animals with CANs that are partially defective in their
migrations. Mutations that eliminate ceh-10 function result in
Clr animals with CANs that fail to migrate or express CEH-23, a
CAN differentiation marker. Null mutants also fail to express
CEH-10, suggesting that CEH-10 regulates its own expression.
Finally, the authors report that ceh-10 is necessary for the
differentiation of AIY and RMED, two additional cells that
express CEH-10. W.C. Forrestera et al: Genetics 1998 148:151.
Related Background Brief:
THE GENETICS OF CELL MIGRATION IN DROSOPHILA MELANOGASTER AND
CAENORHABDITIS ELEGANS DEVELOPMENT. Cell migrations are found
throughout the animal kingdom and are among the most dramatic
and complex of cellular behaviors. Historically, the mechanics
of cell migration have been studied primarily in vitro, where
cells can be readily viewed and manipulated. However, genetic
approaches in relatively simple model organisms are yielding
additional insights into the molecular mechanisms underlying
cell movements and their regulation during development. The
author focuses on these simple model systems where we understand
some of the signaling and receptor molecules that stimulate and
guide cell movements. The chemotactic guidance factor encoded by
the Caenorhabditis elegans unc-6 locus, whose mammalian homolog
is Netrin, is perhaps the best known of the cell migration
guidance factors. In addition, receptor tyrosine kinases (RTKs),
and FGF receptors in particular, have emerged as key mediators
of cell migration in vivo, confirming the importance of
molecules that were initially identified and studied in cell
culture. Somewhat surprisingly, screens for mutations that
affect primordial germ cell migration in Drosophila have
revealed that enzymes involved in lipid metabolism play a role
in guiding cell migration in vivo, possibly by producing and/or
degrading lipid chemoattractants or chemorepellents. Cell
adhesion molecules, such as integrins, have been extensively
characterized with respect to their contribution to cell
migration in vitro and genetic evidence now supports a role for
these receptors in certain instances in vivo as well. The role
for non-muscle myosin in cell motility was controversial, but
has now been demonstrated genetically, at least in some cell
types. Currently the best characterized link between membrane
receptor signaling and regulation of the actin cytoskeleton is
that provided by the Rho family of small GTPases. Members of
this family are clearly essential for the migrations of some
cells; however, key questions remain concerning how
chemoattractant and chemorepellent signals are integrated within
the cell and transduced to the cytoskeleton to produce directed
cell migration. New types of genetic screens promise to fill in
some of these gaps in the near future. D.J. Montell: Development
1999 126:3035.
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11. HISTORY OF QUANTUM TUNNELING
Eugen Merzbacher (University of North Carolina, US) discusses
the history of quantum tunneling, the author making the
following points:
1) A mong all the successes of quantum mechanics as it evolved
in the third decade of the 20th century, none was more
impressive than the understanding of the tunnel effect -- the
penetration of matter waves and the transmission of particles
through a high potential barrier. Eventually, five Nobel prizes
in physics were awarded for research involving tunneling in
semiconductors and superconductors and for the invention of
scanning tunneling microscopy. Tunneling occurs in all quantum
systems. It is crucial for nucleosynthesis in stars, and it may
also have played an essential role in the evolution of the early
universe. From its beginning, quantum tunneling has remained a
hot topic, with myriad applications to this day.
2) In 1923, Louis de Broglie (1892-1987) proposed that matter
waves have a wavelength inversely proportional to their
velocity. In analogy with light waves, matter waves presumably
would also penetrate and be transmitted through classically
forbidden regions, albeit with attenuated amplitude. A
quantitative analysis of the physical implications of this
tunneling effect had to await Erwin Schroedinger's wave
mechanics and Max Bern's probability interpretation of the
quantum wavefunction. Transmission of particles through a
potential barrier through a potential
barrier of finite height and width is less easily visualized in
the Heisenberg-Bohr formulation of quantum mechanics, which
speaks of particles going over the top of the barrier with
transient violation of conservation of energy. In both
formulations, the language that permeates most descriptions of
quantum transmission through a potential barrier has the
anachronistic ring of Newtonian mechanics, with its underlying
assumption that a particle always moves in a continuous orbit.
3) By 1927, quantum mechanics was in place, and a new generation
of theoretical physicists went to work on its many applications
in the microscopic domain, from condensed matter to nuclear
physics. The history of the early days of the tunnel effect is
set in a few centers of theoretical physics --Goettingen,
Leipzig, and Berlin, Germany; Copenhagen, Denmark; Cambridge,
both England and Massachusetts; Princeton, New Jersey; and
Pasadena, California -- with most of the active participants in
their twenties or early thirties. Before tunneling became the
standard term for the nonclassical transmission of particles
through a potential barrier,(1) the quantum mechanical process,
either in German or English, was often referred to as
penetration of, or leaking through, a barrier (or sometimes a
potential hill). Friedrich Hund (1896-1997) was the first to
make use of quantum mechanical barrier penetration in discussing
the theory of molecular spectra in a series of papers in 1927.
The first of these(2) was submitted from Copenhagen in November
1926, acknowledging encouragement from Niels Bohr and Werner
Heisenberg and support from the International Education Board
(IEB), founded in 1923 by John Rockefeller Jr. The paper deals
with an outer electron (Leuchtelektron, or luminous electron, in
Hund's words) moving in an atomic potential with two or more
minima separated by classically impenetrable barriers
(Schwellen, that is, sills or ridges).(3-5)
References (abridged):
1. In a talk given in 1931 and published in Phys. Z. 32, 833
(1931), Walter Schottky referred to the wellenmechanische
Tunneleffekt (wavemechanical tunnel effect) at the
metal-semiconductor interface. The author (Merzbacher) reports
he found the first English use of the term "tunnel effect" in J.
Frenkel, Wave Mechanics, Elementary Theory, Clarendon Press,
Oxford, UK (1932). The author suggests that to this day,
Frenkel's rarely cited textbook provides one of the most
comprehensive theoretical accounts of quantum tunneling.
2. F. Hund, Z. Phys. 40, 742 (1927).
3. F. Hund, Z. Phys. 43, 805 (1927).
4. L. Nordheim, Z. Phys. 46, 833 (1927).
5. J. R. Oppenheimer, Phys. Rev. 31, 66 (1928).
Physics Today 2002 August
Web Links: quantum tunneling
Related Background:
QUANTUM PHYSICS: ON ATOMIC TUNNELING
In 1924, Louis de Broglie (1892-1987) suggested that all
particles have wave properties in addition to particle
properties, with the wave properties given by what is now called
the "de Broglie equation": l = h/(mv), where (l) is the
wavelength of the particle, (h) is Planck's constant, (m) is the
mass of the particle, and (v) is the velocity of the particle.
This relationship provided the basis for quantum mechanics as
formulated by Erwin Schroedinger (1897-1961) in 1925-1926. In
1927, the wave nature of electrons was detected experimentally.
Macroscopic objects have a computed wavelength much smaller than
that of electrons, so the wave properties of macroscopic objects
are never detected: macroscopic objects exhibit only particle
behavior.
In general, the term "quantum mechanical tunneling" refers to a
quantum mechanical phenomenon involving an effective penetration
of an energy barrier by a particle resulting from the width of
the barrier being less than the de Broglie wavelength of the
particle. Essentially, the idea is that the square of the
amplitude of the wavefunction of the particle determines the
probability distribution of the particle, and if the dimensions
of that probability distribution exceed the dimensions of the
barrier, there is a finite probability the particle will
"tunnel" through the energy barrier to the other side. In
general, for particles of known mass and velocity, if the height
and thickness of the energy barrier are known, this tunneling
probability can be calculated via quantum mechanics. The
phenomenon of quantum tunneling has many important applications,
including explanations of *alpha particle emission in
radioactive decay, and in the theory and engineering of the
*Esaki diode (tunnel diode).
The new technology of scanning probe microscopy has created a
revolution in microscopy, with applications ranging from
condensed matter physics to biology. The first scanning probe
microscope, the scanning tunneling microscope, was invented by
G. Binnig and H. Rohrer in the 1980s (they received the Nobel
Prize in Physics in 1986), and the invention has been the
catalyst of a technological revolution. Scanning probe
microscopes have no lenses. Instead, a "probe" tip is brought
very close to the specimen surface, and the interaction of the
tip with the region of the specimen immediately below it is
measured. The type of interaction measured essentially defines
the type of scanning probe microscopy. When the interaction
measured is the force between atoms at the end of the tip and
atoms in the specimen, the technique is called "atomic force
microscopy". When the quantum mechanical tunneling current is
measured, the technique is called "scanning tunneling
microscopy". These two techniques, atomic force microscopy (AFM)
and scanning tunneling microscopy (STM) have been the parents of
a variety of scanning probe microscopy techniques investigating
a number of physical properties.
In general, in scanning tunneling microscopy, electrons quantum
mechanically tunnel between the tip and the surface of the
sample. This tunneling process is sensitive to any overlap
between the electronic wave functions of the tip and sample, and
depends exponentially on their separation. The scanning
tunneling microscope makes use of this extreme sensitivity to
distance. In practice, the tip is scanned across the surface,
while a feedback circuit continuously adjusts the height of the
tip above the sample to maintain a constant tunneling current.
The recorded trajectory of the tip creates an image that maps
the electronic wave functions at the surface, revealing the
atomic landscape in fine detail.
In this context, the term "phonon" refers to a quantum of
vibrational energy, the quantum considered a discrete particle,
and used in mathematical models to calculate thermal and
vibrational properties of solids. This idea is essentially a
reversal of the application of the de Broglie equation to
particles: In general, any propagated wave (or field
perturbation) can be considered as a particle whose momentum
(mv) is given by the de Broglie equation as mv = h/l, where (mv)
is the momentum of the particle, h is Planck's constant, and (l)
is the wavelength of the propagated perturbation.
Ali Yazdani (University of Illinois Urbana-Champaign, US)
presents a commentary on recent work (L.J. Lauhon and W. Ho:
Phys. Rev. Lett. 85:4566 2000) on tunneling of individual
hydrogen atoms on a metal surface. The author (Yazdani) makes
the following points:
1) The author points out that in condensed matter physics,
quantum tunneling of atoms is believed to play an important role
in phenomena such as the diffusion of impurities in solids and
the properties of *glasses at low temperatures. An atom can be
described as "resting" in an energy well, and it can tunnel to
another energy well if the mass of the atom is low enough and if
the energy barrier between the wells is sufficiently small.
Because the hydrogen atom is so low in mass, it is particularly
open to the possibility of quantum tunneling. On the surface of
metals, the constant movement of hydrogen has been reported down
to low temperatures, but whether this diffusion arises from
classical thermal motion or from quantum tunneling is unclear.
Some of the uncertainty can be attributed to the fact that
previous experiments measured the average behavior of a group of
atoms, and so could not resolve the role of surface defects in
the tunneling process. A localized probe, such as the tip of a
scanning tunneling microscope, sidesteps these complications.
2) Lauhon and Ho (2000) now report that they have tracked and
visualized the quantum tunneling of individual atoms for the
first time. By using a scanning tunneling microscope, they were
able to monitor the motion of individual hydrogen atoms on a
metal surface, and they found that the atoms remain mobile down
to temperatures as low as 9 kelvins. Classically, thermal
diffusion or motion is expected to fade away as the temperature
is lowered. But the constant movement of hydrogen in these
experiments implies that there is a quantum effect that allows
the atoms to tunnel along the surface of the metal. Quantum
tunneling of atoms at low temperatures has been inferred from
experiments on relatively large groups of atoms, but never
before has quantum motion been observed so directly -- one atom
at a time.
3) By detailed analysis of the scanning-tunneling-microscope
-measured diffusion rate for hydrogen, Lauhon and Ho identify
different temperature regimes in which phonon- or
electron-*scattering predominates. Most intriguing is their
observation that at the lower temperatures in the experiment,
the tunneling rate increases as the surface is cooled. This
classically impossible behavior suggests that hydrogen tunneling
improves over longer periods of time as the surface gets colder.
The author (Yazdani) suggests that perhaps reducing the
temperature by a further factor of 10 or 100 will reveal a new
regime in which hydrogen atoms can eventually tunnel over
greater distances.
Nature 25 Jan 01 409:471)
Text Notes:
... ... *alpha particle emission in radioactive decay: In
radioactive decay alpha particle emission, a nucleus emits an
alpha particle (a helium nucleus). The alpha particle has
insufficient energy as a particle to overcome the force barrier
surrounding the nucleus, but as a wave the particle can tunnel
through the barrier, i.e., the particle has a finite probability
of being found outside the nucleus. The quantum explanation of
alpha particle emission in radioactive decay was provided
independently by George Gamow (1904-1968) and by Ronald W.
Gurney (?-?) and Edward Condon (1902-1974) in 1928.
... ... *Esaki diode: A semiconductor electron-hole (p-n)
junction diode based on the tunnel effect. The device has a
current-voltage curve described by a cubic equation, with one
limited region of the curve showing a "negative resistance",
i.e., the current falling as the bias voltage is increased.
... ... *glasses: In this context, the term "glass" refers to an
amorphous solid whose atoms form a random network.
... ... *scattering: In this context, the term "scattering"
refers to the change in direction of a particle resulting from
collision with another particle.
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12. ON THE ADDICTED BRAIN
D. Goldman and C. Barr (National Institute on Alcohol Abuse and
Alcoholism, US) discuss addiction, the authors making the
following points:
1) Addictions are relapsing, remitting lifelong illnesses that
are notoriously difficult to treat. One year after they have
stopped drinking, approximately one third of patients with
alcoholism remain abstinent, one third have resumed drinking but
not at their former level of consumption, and one third have
relapsed completely. A defining problem with respect to the
treatment of addiction is that we do not know how to restore the
addicted brain to its former state, and many therapies -- for
example, methadone maintenance for opiate addiction -- do not
even attempt to do so. Because of the difficulty of treating
addictions and a lack of understanding of the benefits that
partially successful therapy convey to patients, their families,
and the community, many addicts are never identified or treated.
2) Life is complex, but many events can be defined as stress if
they are viewed from the simplistic perspective of their effect
on the brain. Behavioral, physiological, and molecular
mechanisms help the body adapt to stress. Adaptations that
return function to a previous set point may be thought of as
homeostatic.(1) However, adaptation may also result in new
physiological set points outside the normal range. This
phenomenon, which is referred to as "allostasis", is defined as
"homeostasis through change".(2)
3) The body functions through the coordinated activity of
systems evolved over millennia. Although humans are highly
resilient and capable of surviving in the most stressful
environments, it is not surprising that chronic or repeated
stress increases the risk of a variety of diseases, including
psychiatric disorders. The addictions are among the more
important sources of stress at the individual, family, and
community levels. Recently, allostatic alteration of brain
function through stress-related mechanisms has been identified
as one component of the pathway to addiction.(3) The brain
survives addiction, but in the absence of the drug, the brain
does not return to the base-line set point, and chronic
dysphoria and anxiety are present. The clinical goal is to
relieve the patient's depression and anxiety, but treatment of
depression alone rather than in combination with treatment of
addiction is often ineffective. Patients with alcoholism who are
abstinent may nevertheless have extended periods of anxiety,
depression, and sleep disturbances, predisposing them to
relapse.(4,5)
References:
1. Selye H. The stress of life. New York: McGraw-Hill, 1976.
2. McEwen BS. Stress, adaptation, and disease: allostasis and
allostatic load. Ann N Y Acad Sci 1998;840:33-44.
3. Koob GF, Le Moal M. Drug addiction, dysregulation of reward,
and allostasis. Neuropsychopharmacology 2000;24:97-129.
4. Adinoff B, Martin PR, Bone GH, et al.
Hypothalamic-pituitary-adrenal axis functioning and
cerebrospinal fluid corticotropin releasing hormone and
corticotropin levels in alcoholics after recent and long-term
abstinence. Arch Gen Psychiatry 1990;47:325-330.
5.Sillaber I, Rammes G, Zimmermann S, et al. Enhanced and
delayed stress-induced alcohol drinking in mice lacking
functional CRH1 receptors. Science 2002;296:931-933.
New Engl. J. Med. 2002 347:843
Web Links: brain and addiction
Related Background Brief:
STRESS, ADAPTATION, AND DISEASE: ALLOSTASIS AND ALLOSTATIC LOAD.
Adaptation in the face of potentially stressful challenges
involves activation of neural, neuroendocrine and
neuroendocrine-immune mechanisms. This has been called
"allostasis" or "stability through change" by Sterling and Eyer
(Fisher S., Reason J. (eds): Handbook of Life Stress, Cognition
and Health. J. Wiley Ltd. 1988, p. 631), and allostasis is an
essential component of maintaining homeostasis. When these
adaptive systems are turned on and turned off again efficiently
and not too frequently, the body is able to cope effectively
with challenges that it might not otherwise survive. However,
there are a number of circumstances in which allostatic systems
may either be overstimulated or not perform normally, and this
condition has been termed "allostatic load" or the price of
adaptation (McEwen and Stellar, Arch. Int. Med. 1993;
153:2093.). Allostatic load can lead to disease over long
periods. Types of allostatic load include (1) frequent
activation of allostatic systems; (2) failure to shut off
allostatic activity after stress; (3) inadequate response of
allostatic systems leading to elevated activity of other,
normally counter-regulated allostatic systems after stress. The
author provides examples for each type of allostatic load from
research pertaining to autonomic, CNS, neuroendocrine, and
immune system activity. The relationship of allostatic load to
genetic and developmental predispositions to disease is also
considered. B.S. McEwen: Ann New York Acad Sci 1998 840:33.
Related Background Brief:
DRUG ADDICTION, DYSREGULATION OF REWARD, AND ALLOSTASIS. The
authors review recent developments in the neurocircuitry and
neurobiology of addiction from a perspective of allostasis. A
model is proposed for brain changes that occur during the
development of addiction that explain the persistent
vulnerability to relapse long after drug-taking has ceased.
Addiction is presented as a cycle of spiraling dysregulation of
brain reward systems that progressively increases, resulting in
the compulsive use and loss of control over drug-taking. The
development of addiction recruits different sources of
reinforcement, different neuroadaptive mechanisms, and different
neurochemical changes to dysregulate the brain reward system.
Counteradaptive processes such as opponent-process that are part
of normal homeostatic limitation of reward function fail to
return within the normal homeostatic range and are hypothesized
to form an allostatic state. Allostasis from the addiction
perspective is defined as the process of maintaining apparent
reward function stability by changes in brain reward mechanisms.
The allostatic state represents a chronic deviation of reward
set point and is fueled not only by dysregulation of reward
circuits per se, but also by the activation of brain and
hormonal stress responses. The manifestation of this allostatic
state as compulsive drug-taking and loss of control over
drug-taking is hypothesized to be expressed through activation
of brain circuits involved in compulsive behavior such as the
cortico-striatal-thalamic loop. The authors suggest that the
view that addiction is the pathology that results from an
allostatic mechanism using the circuits established for natural
rewards provides a realistic approach to identifying the
neurobiological factors that produce vulnerability to addiction
and relapse. G.F. Koob and M. Le Moal: Neuropsychopharmacology
2001 24:97.
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