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ScienceWeek
SCIENCEWEEK
ScienceWeek - September 27, 2002 Vol. 6 Number 39
An Online Research Digest Published Weekly Since 1997
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Section 1
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1. On Pluripotency of Mesenchymal Stem Cells
2. On Radiation Resistance in D. radiodurans
3. On Protein Folding and Misfolding
4. On Repulsive Casimir Forces
5. On Terrestrial Planet Formation
6. Nucleotide Dangling Ends and Duplex Stability
7. On the Prion Hypothesis
8. On House Pets and Risk of Allergic Sensitization
9. Nonfinancial Conflicts of Interest in Medical Research
10. On High-Tesla Superconducting Magnets
11. On Vesicular Nanoparticles
12. On Polyacrylamides and Acrylamides
13. ScienceWeek Notices and Subscription Information
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Section 2
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1. On Pluripotency of Mesenchymal Stem Cells
Y. Jiang et al (University of Minnesota, US) discuss stem cell
pluripotency, the authors making the following points:
1) Embryonic stem (ES) cells are pluripotent cells derived from
the inner cell mass of the blastocyst that can be propagated
indefinitely in an undifferentiated state. ES cells
differentiate to all cell lineages in vivo and differentiate
into many cell types in vitro. Although ES cells have been
isolated from humans(1), their use in research as well as
therapeutics is encumbered by ethical considerations(2). Stem
cells also exist for most tissues, including haematopoietic(3),
neural(4), gastrointestinal(5), epidermal, hepatic and
mesenchymal stem cells. Compared with ES cells, tissue-specific
stem cells have less self-renewal ability and, although they
differentiate into multiple lineages, they are not pluripotent.
2) Until recently, it was thought that tissue-specific stem
cells could only differentiate into cells of the tissue of
origin; however, recent studies suggested that tissue-specific
stem cells can differentiate into lineages other than the tissue
of origin. After transplantation of bone marrow or enriched
haematopoietic stem cells (HSC), skeletal myoblasts, cardiac
myoblasts, endothelium, hepatic and biliary duct epithelium,
lung, gut and skin epithelia, and neuroectodermal cells of donor
origin have been detected. Some but not other studies
demonstrated that neural stem cells as well as muscle cells may
differentiate into haematopoietic cells. When injected into a
blastocyst, neural stem cells contribute to a number of tissues
of the chimaeric mouse embryo; however, most studies did not
conclusively demonstrate that a single tissue-specific stem cell
differentiates into functional cells of multiple tissues.
3) In summary: The authors report that cells co-purifying with
mesenchymal stem cells -- termed here "multipotent adult
progenitor cells or MAPCs -- differentiate, at the single cell
level, not only into mesenchymal cells, but also cells with
visceral mesoderm, neuroectoderm, and endoderm characteristics
in vitro. When injected into an early blastocyst, single MAPCs
contribute to most, if not all, somatic cell types. On
transplantation into a non-irradiated host, MAPCs engraft and
differentiate to the haematopoietic lineage, in addition to the
epithelium of liver, lung and gut. Engraftment in the
haematopoietic system as well as the gastrointestinal tract is
increased when MAPCs are transplanted in a minimally irradiated
host. The authors suggest that as MAPCs proliferate extensively
without obvious senescence or loss of differentiation potential,
they may be an ideal cell source for therapy of inherited or
degenerative diseases.
References (abridged):
1. Thomson, J. A. et al. Embryonic stem cell lines derived from
human blastocysts. Science 282, 1145-1147 (1998)
2. Frankel, M. S. In search of stem cell policy. Science 298,
1397 (2000)
3. Weissman, I. L. Translating stem and progenitor cell biology
to the clinic: barriers and opportunities. Science 287,
1442-1446 (2000)
4. Gage, F. H. Mammalian neural stem cells. Science 287,
1433-1438 (2000)
5. Potten, C. Stem cells in gastrointestinal epithelium:
numbers, characteristics and death. Phil. Trans R. Soc. Lond. B
353, 821-830 (1998)
Nature 2002 418:41
Web Links: pluripotent stem cells
Related Background Brief:
EMBRYONIC STEM CELL LINES DERIVED FROM HUMAN BLASTOCYSTS. Human
blastocyst-derived, pluripotent cell lines are described that
have normal karyotypes, express high levels of telomerase
activity, and express cell surface markers that characterize
primate embryonic stem cells but do not characterize other early
lineages. After undifferentiated proliferation in vitro for 4 to
5 months, these cells still maintained the developmental
potential to form trophoblast and derivatives of all three
embryonic germ layers, including gut epithelium (endoderm);
cartilage, bone, smooth muscle, and striated muscle (mesoderm);
and neural epithelium, embryonic ganglia, and stratified
squamous epithelium (ectoderm). The authors suggest these cell
lines should be useful in human developmental biology, drug
discovery, and transplantation medicine. Science 1998 Nov
6;282(5391):1145.
Related Background Brief:
TRANSLATING STEM AND PROGENITOR CELL BIOLOGY TO THE CLINIC:
BARRIERS AND OPPORTUNITIES. Stem cells are the natural units of
embryonic generation, and also adult regeneration, of a variety
of tissues. Recently, the list of tissues that use the model of
differentiation from stem to progenitor to mature cell has
increased from blood to include a variety of tissues, including
both central and peripheral nervous systems and skeletal muscle;
it is also possible that all organs and tissues are derived
from, and still contain, stem cells. Because the number and
activities of stem cells and their progeny are homeostatically
regulated, clinical stem cell transplantation could greatly add
to the physician's armamentarium against degenerative diseases.
I.L. Weissman: Science 2000 287:1442.
Related Background Brief:
MAMMALIAN NEURAL STEM CELLS. Neural stem cells exist not only in
the developing mammalian nervous system but also in the adult
nervous system of all mammalian organisms, including humans.
Neural stem cells can also be derived from more primitive
embryonic stem cells. The location of the adult stem cells and
the brain regions to which their progeny migrate in order to
differentiate remain unresolved, although the number of viable
locations is limited in the adult. The mechanisms that regulate
endogenous stem cells are poorly understood. Potential uses of
stem cells in repair include transplantation to repair missing
cells and the activation of endogenous cells to provide
"self-repair. " Before the full potential of neural stem cells
can be realized, we need to learn what controls their
proliferation, as well as the various pathways of
differentiation available to their daughter cells. F.H. Gage:
Science 2000 287:1433.
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2. On Radiation Resistance in D. radiodurans
Jan Mrazek (Stanford University, US) discusses radiation
resistance, the author making the following points:
1) The bacterium Deinococcus radiodurans is exceptional in its
capacity to withstand high doses of ionizing and UV radiation
that are lethal to virtually all other living organisms. It is a
nonpathogenic, red-pigmented bacterium. Although technically
Gram-positive, D. radiodurans features plasma and outer
membranes and a multilayer cell envelope reminiscent of
Gram-negative bacteria (5). Its radioresistance makes it one of
the leading candidates for bioremediation of radioactive waste
sites that contain hazardous mixtures of radionuclides, heavy
metals, and other toxic chemicals. Engineered strains of D.
radiodurans are capable of transforming these mixtures to less
hazardous ones by degrading some of the toxic components.
Understanding molecular mechanisms that allow cells to survive
damaging effects of UV radiation is also of interest in medical
research, especially in conjunction with ongoing environmental
changes that allow more UV radiation to reach the Earth's
surface.
2) Advances in DNA sequencing technology in the past decade have
resulted in rapid production of DNA data including more than 70
complete prokaryotic genomes and several eukaryotic genomes
currently available. This accumulation of sequence data has
provided opportunities for development of proteomics. Proteomic
analyses focus on composition of the protein mixture extracted
from a cell culture and its changes in response to environmental
disturbances or during the cell cycle. A standard scenario is as
follows: First, extract the complex protein mixture from cell
cultures growing under controlled conditions. Then run a
two-dimensional PAGE to separate different proteins into a large
number of often partly overlapping spots. Finally, identify the
spots and assign them to known proteins or genes (e.g., ref. 1).
This last step is facilitated by use of MS (e.g., ref. 2).
Routine use of MS technology in proteomics was made possible by
complete genome sequencing. A complete genomic sequence can be
used to identify all putative proteins encoded in the genome.
This limits the number of possible peptide fragments expected to
be found in the proteins extracted from the cells (3) and, given
sufficient accuracy of the MS measurements, the mass of a
fragment can often be unambiguously associated with a specific
protein.
3) Lipton et al. (4) use an improved MS technology based on
peptide accurate mass tags for proteomic analyses of the
radiation-resistant bacterium Deinococcus radiodurans. The
method uses Fourier transform ion cyclotron resonance (FTICR)
experimentation instead of standard tandem MS, which provides
greater sensitivity and accuracy, yielding a more comprehensive
coverage of the proteome. Thus, the accurate FTICR measurements
applied to D. radiodurans identified accurate mass tags for 61%
of all putative D. radiodurans proteins the most complete
proteome coverage to date.
References (abridged):
1. VanBogelen, R. A. , Hutton, M. E. & Neidhardt, F. C. (1990)
Electrophoresis 11, 1131-1166
2. Figeys, D. , Gygi, S. P. , Zhang, Y. , Watts, J. , Gu, M. &
Aebersold, R. (1998) Electrophoresis 19, 1811-1818
3. Smith, R. D. , Anderson, G. A. , Lipton, M. S. , Pasa-Tolic,
L. , Shen, Y. F. , Conrads, T. P. , Veenstra, T. D. & Udseth, H.
R. (2002) Proteomics 2, 513-523
4. Lipton, M. S. , Paa-Toli, L. , Anderson, G. A. , Anderson, D.
J. , Auberry, D. L. , Battista, J. R. , Daly, M. J. ,
Fredrickson, J. , Hixson, K. K. , Kostandarithes, H. , et al.
(2002) Proc. Natl. Acad. Sci. USA 99, 11049-11054
5. Makarova, K. S. , Aravind, L. , Wolf, Y. I. , Tatusov, R. L.
, Minton, K. W. , Koonin, E. V. & Daly, M. J. (2001) Microbiol.
Mol. Biol. Rev. 65, 44-79
Proc. Nat. Acad. Sci. 2002 99:10943
Web Links: Deinococcus radiodurans
Related Background Brief:
GLOBAL ANALYSIS OF THE DEINOCOCCUS RADIODURANS PROTEOME BY USING
ACCURATE MASS TAGS. Understanding biological systems and the
roles of their constituents is facilitated by the ability to
make quantitative, sensitive, and comprehensive measurements of
how their proteome changes, e.g., in response to environmental
perturbations. To this end, the authors have developed a
high-throughput methodology to characterize an organism's
dynamic proteome based on the combination of global enzymatic
digestion, high-resolution liquid chromatographic separations,
and analysis by Fourier transform ion cyclotron resonance mass
spectrometry. The peptides produced serve as accurate mass tags
for the proteins and have been used to identify with high
confidence >61% of the predicted proteome for the ionizing
radiation-resistant bacterium Deinococcus radiodurans. This
fraction represents the broadest proteome coverage for any
organism to date and includes 715 proteins previously annotated
as either hypothetical or conserved hypothetical. Proc. Nat.
Acad. Sci. 99:11049.
Related Background Brief:
GENOME OF THE EXTREMELY RADIATION-RESISTANT BACTERIUM
DEINOCOCCUS RADIODURANS VIEWED FROM THE PERSPECTIVE OF
COMPARATIVE GENOMICS. The bacterium Deinococcus radiodurans
shows remarkable resistance to a range of damage caused by
ionizing radiation, desiccation, UV radiation, oxidizing agents,
and electrophilic mutagens. D. radiodurans is best known for its
extreme resistance to ionizing radiation; not only can it grow
continuously in the presence of chronic radiation (6
kilorads/h), but also it can survive acute exposures to gamma
radiation exceeding 1,500 kilorads without dying or undergoing
induced mutation. These characteristics were the impetus for
sequencing the genome of D. radiodurans and the ongoing
development of its use for bioremediation of radioactive wastes.
Although it is known that these multiple resistance phenotypes
stem from efficient DNA repair processes, the mechanisms
underlying these extraordinary repair capabilities remain poorly
understood. In this work we present an extensive comparative
sequence analysis of the Deinococcus genome. Deinococcus is the
first representative with a completely sequenced genome from a
distinct bacterial lineage of extremophiles, the
Thermus-Deinococcus group. Phylogenetic tree analysis, combined
with the identification of several synapomorphies between
Thermus and Deinococcus, supports the hypothesis that it is an
ancient group with no clear affinities to any of the other known
bacterial lineages. Distinctive features of the Deinococcus
genome as well as features shared with other free-living
bacteria were revealed by comparison of its proteome to the
collection of clusters of orthologous groups of proteins.
Analysis of paralogs in Deinococcus has revealed several unique
protein families. In addition, specific expansions of several
other families including phosphatases, proteases,
acyltransferases, and Nudix family pyrophosphohydrolases were
detected. Genes that potentially affect DNA repair and
recombination and stress responses were investigated in detail.
Some proteins appear to have been horizontally transferred from
eukaryotes and are not present in other bacteria. For example,
three proteins homologous to plant desiccation resistance
proteins were identified, and these are particularly interesting
because of the correlation between desiccation and radiation
resistance. Compared to other bacteria, the D. radiodurans
genome is enriched in repetitive sequences, namely, IS-like
transposons and small intergenic repeats. In combination, these
observations suggest that several different biological
mechanisms contribute to the multiple DNA repair-dependent
phenotypes of this organism. K.S. Makarova et al: Microbiol.
Mol. Biol. Revs 2001 65:44.
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3. On Protein Folding and Misfolding
J. King et al (Massachusetts Institute of Technology, US)
discuss protein folding, the authors making the following points:
1) Proteins begin to fold, creating the intricate
three-dimensional shapes crucial to their function, even before
they are completely pieced together. Living cells need thousands
of different kinds of protein molecules, each consisting of a
different sequence of amino acids. Within cells, these proteins
are formed by ribosomes stringing together amino acids at a
furious pace, about 20 per second in bacteria; closer to 5 to 10
amino acids per second in human cells.
2) The diversity and complexity of these hard-working molecules
are remarkable even within the simplest species. The intestinal
bacterium Escherichia coli, a favorite model organism in
molecular biology, contains some 2,400 types of protein chains,
with an average length of 320 amino adds. One simple animal, the
nematode worm Caenorhabditis elegans, has some 14,261 genes,
each encoding a different protein chain; the shortest among
these chains are 40 to 50 amino acids long, whereas the longest
have close to 2,000 amino acids. Human genes are estimated to
code for more than 30,000 protein species. One of the longest of
these, the muscle protein titin, is 10,000 amino acids long.
Made at a rate of 5 amino acids per second, a cell would need a
half hour to string titin together, but other proteins can be
made in seconds to a few minutes.
3) A gene is commonly described as a stretch of DNA that "codes
for a protein." Indeed, the essential information encoded in
genes is the linear order of amino acids needed to form protein
chains. Access to this information is the main reason for the
great excitement over the elucidation of the complete DNA
sequence of the human genome and other genomes. But to
understand and replicate the process of making a functional
protein requires information that we cannot yet read from a DNA
sequence: the way the protein chain folds. Folding is the key to
the myriad properties and functions of proteins -- from oxygen
binding in hemoglobin to insulation and mechanical strength in
the keratins that form hair and wool, to the countless catalytic
activities of enzymes (1-5).
References (abridged):
1. Betts, S. D., and J. King. Cold rescue of the thermolabile
tailspike intermediate at the junction between productive
folding and off-pathway aggregation. Protein Science 1998
7:1516-1523.
2. Bradley, P., L. Cowen, M. Menke, J. King and B. Berger.
BETAWRAP: successful prediction of parallel beta-helices from
primary sequence reveals an association with many microbial
pathogens. Proc Nat Acad Sci 2001 98:14819-14824.
3. Clark, P. L., and J. King. 2001. A newly synthesized,
ribosome-bound polypeptide chain adopts conformations dissimilar
from early in vitro refolding intermediates. J Biol Chem 2001
276:25411-25420.
4. Emsley, P., I. G. Charles, N. F. Fairweather and N. W.
Isaacs. Structure of Bordetella pertussis virulence factor P69
pertactin. Nature 1996 381:90-92.
5. Haase-Pettingell, C. A., and J. King. Formation of aggregates
from a thermolabile in vivo folding intermediate in P22
tailspike maturation. A model for inclusion body formation. J
Biol Chem 1988 263:4977-4983.
American Scientist 2002 90:445
Web Links: protein folding
Related Background:
PROTEIN FOLDING: ENERGY LANDSCAPE THEORY
Jeffery G. Saven (University of Pennsylvania, US) discusses
protein folding. A predictive understanding of protein folding
is obscured by the complexity of proteins. The hallmark of
protein folding is the ability of an amino acid sequence to
reversibly acquire a well-defined and unique structure in a
moderate amount of time even though an extremely large number of
structures are possible. In the energy landscape approach to
understanding protein folding, the process is viewed as a
collective and cooperative phenomenon, with the focus of theory
on the global nature of the protein's free energy surface. Such
a picture emphasizes those general characteristics shared by
proteins in a structural class as well as those properties
specific to particular proteins. In such an approach,
information about the energetics of the unfolded as well as
folded states must be accounted for. This is an obvious
consideration, since the protein must effectively recognize and
acquire one conformation when a huge number of conformations are
possible. Although much has been learned about the energetics
and features of unfolded states from detailed atom-based
simulations, such calculations are computationally
time-consuming. Given the apparent complexity of the
conformational free energy surface of a protein, the energy
landscape approach focuses on developing concepts that simplify
the description of the process. A prime goal of energy landscape
theory is to identify a handful of thermodynamic and other
simplifying parameters and variables that characterize protein
folding in both the folded state and in the ensemble of
partially folded conformational states.
J. Am. Chem. Soc. 2001 123:3113
Related Background:
ON HYDROPHOBIC CLUSTERS AND PROTEIN FOLDING
Robert L. Baldwin (Stanford University, US) discusses protein
folding, the author making the following points:
1) There is currently a debate about whether a hydrophobic
collapse precedes or occurs concomitantly with the formation of
secondary structures at the beginning of protein folding. The
role of secondary structures in guiding the folding pathway is
readily understood because such structures provide the framework
for the final native structure. It has also long been recognized
that burial of nonpolar (hydrophobic) side chains out of contact
with water provides the major source of the free energy change
that drives folding. But compelling models have been lacking for
how this burial might produce a "hydrophobic collapse" that
initiates folding.
2) The most plausible model has been the "hydrophobic zipper",
in which clusters of nonpolar side chains stabilize secondary
structures such as alpha helices or beta hairpins, and examples
are known in which such hydrophobic clusters guide the folding
process. The clusters persist until folding is complete and can
be visualized in the native structure of proteins. Hydrophobic
patches have also been observed in native protein structures at
sites where two alpha helices interact, and there is good
evidence that hydrophobic clusters of this kind can also guide
the folding process.
3) In these examples, hydrophobic clusters and secondary
structures are formed concomitantly and produce native-like
structures. But hydrophobic clusters have also been found in
denatured proteins, under conditions where secondary structures
are unstable. Some of these clusters must reflect non-native
interactions, since they cannot be found in the structures of
the native proteins. At present, it remains unclear how these
hydrophobic clusters affect the folding process.
References (abridged):
1. S. Akiyama et al., Proc. Natl. Acad. Sci. U.S.A. 99, 1329
(2002)
2. W. Kauzmann, Adv. Protein Chem. 14, 1 (1959)
3. K. A. Dill, K. M. Fiebig, H. S. Chan, Proc. Natl. Acad. Sci.
90, 1942 (1993)
4. K. Zdanowski, M. Dadlez, J. Mol. Biol. 287, 433 (1999)
5. M. E. Hodsdon, C. Frieden, Biochemistry 40, 732 (2001)
Science 2002 295:1657
Web Links: hydrophobicity
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4. On Repulsive Casimir Forces
O. Kenneth et al (Technion, IL) discuss Casimir forces, the
authors making the following points:
1) It is well known that the fluctuations of electromagnetic
fields in vacuum or in material media depend on the boundary
conditions imposed on the fields. This dependence gives rise to
forces which are known as Casimir forces, acting on the
boundaries. The best known example for such forces is the
attractive force experienced by parallel conducting plates in
vacuum [1]. Casimir forces between similar, disjoint objects
such as two conducting or dielectric bodies are known in most
cases to be attractive [2] and are sometimes viewed as the
macroscopic consequence of van der Waals and Casimir-Polder
attraction between molecules. In view of the dominance of the
Casimir forces at the nanometer scale, where the attractive
force could lead to restrictive limits on nanodevices [3,4], the
study of repulsive Casimir forces is of increasing interest.
2) Repulsive van der Waals forces are known to be possible if
the properties of the intermediate medium are intermediate
between the properties of two polarizable molecules [5]. In such
cases the Hamaker constant becomes negative, a property which
was successfully employed to explain the wetting properties of
liquid helium. How can one get a repulsive behavior when the
intermediate substance is vacuum? A partial answer can be
obtained from the observation that a purely magnetically
polarizable particle repels a purely electrically polarizable
particle. Motivated by this result, Boyer, following Casimir's
suggestion, studied interplane Casimir force with one plate a
perfect conductor while the other is infinitely permeable. He
showed that in this case the plates repel.
3) In summary: The authors discuss repulsive Casimir forces
between dielectric materials with nontrivial magnetic
susceptibility. The authors demonstrate that considerations
based on the naive pairwise summation of van der Waals and
Casimir-Polder forces may not only give an incorrect estimate of
the magnitude of the total Casimir force but even the wrong sign
of the force when materials with high dielectric and magnetic
responses are involved. Indeed repulsive Casimir forces may be
found in a large range of parameters, and the authors suggest
that the effect may be realized in known materials. The authors
suggest the phenomenon of repulsive Casimir forces may be of
importance both for experimental study and for nanomachinery
applications.
References (abridged):
1. H.B.G. Casimir, Proc. Koninkl. Ned. Akad. Wet. 51, 793 (1948)
2. 0. Kenneth and S. Nussinov, Phys. Rev. D 65, 085014 (2002)
3. J M. Bordag, U. Mohideen, and V. M. Mostepanenko, Phys. Rep.
353, 1 (2001)
4. E. Buks and M.L. Roukes, Phys. Rev. B 63, 033402 (2001)
5. Jacob N. Israelachvili, Intermolecular and Surface Forces
(Academic Press, London, 1992)
Phys. Rev. Lett. 2002 89:033001
Web Links: Casimir forces
Related Background:
EXPERIMENTAL PHYSICS: ON THE CASIMIR FORCE IN
MICROELECTROMECHANICAL SYSTEMS
In general, in physics, the term "zero-point energy" refers to
the energy associated with a particle or system (in addition to
its mass energy) at the absolute zero of temperature. The
zero-point energy cannot be precisely zero because of quantum
uncertainty. Similarly, the lowest energy state of a field (its
"ground state") also cannot be precisely zero.
The "Casimir effect", first predicted by Hendrik B.G. Casimir
[1909- ] in the late 1940s, is in general a quantum force that
pulls two parallel electrically conducting plates, placed a
short distance apart in a vacuum, towards one another. The basis
of the force is that the zero-point energy between the plates is
reduced compared to the zero-point energy outside the plates.
The essential reason for the zero-point energy reduction between
the plates is quantum mechanical: in quantum theory,
electromagnetic fields fluctuate and therefore can never be
exactly zero, and the plates act as boundary conditions on the
vibration mode frequencies of the vacuum electromagnetic field
between the plates. The plates as boundaries, in effect, force
certain vibration modes to drop out, producing a net reduction
of vacuum energy in the volume between the plates compared to
the vacuum electromagnetic field elsewhere. This results in an
effective pressure pushing the plates together. From a classical
perspective the effect seems bizarre, since it involves the
difference between two apparently nonexistent electromagnetic
fields producing an attractive force. All of this is related to
the so-called "active vacuum" of quantum physics, which refers
to the idea that the vacuum state in quantum mechanics has a
zero-point energy (minimum energy) which gives rise to vacuum
fluctuations, so the vacuum state does not mean a state of
nothing, but is instead an active state. This idea is now of
considerable importance in certain cosmological theories.
The Casimir force was first detected experimentally by M.J.
Sparnaay in 1958. Both the sign and magnitude of the effect
depend critically on the geometry of the surfaces. For two
ideally smooth parallel plates, the net attractive force per
unit area between the plates is given by F = k/d^(4), where (k)
is a constant involving only Planck's constant and the speed of
light, and (d) is the distance between the plates. If one
surface is spherical and the other surface a plane, the force
becomes F = k'R/d^(3), where (k') is a different constant
involving only Planck's constant and the speed of light, (R) is
the radius of the spherical surface, and (d) is the shortest
distance between the spherical surface and the plane surface.
H.B. Chan et al (5 authors at Bell Laboratories, US) report a
study of actuation of microelectromechanical systems by the
Casimir force, the authors making the following points:
1) The authors point out that microelectromechanical systems are
movable structures fabricated on a semiconductor wafer through
the use of integrated circuit technology, and these systems have
become a key technology in the production of sensors and
actuators. So far, the smallest separations between surfaces of
micromachined components are typically on the order of microns,
and the operation of microelectromechanical systems has been
well described by classical mechanics. But as further
miniaturization occurs, quantum effects may become significant
in device design and operation.
2) The authors report a demonstration of the Casimir effect in
microelectromechanical systems using a micromachined torsional
device. Attraction between a polysilicon plate and a spherical
metallic surface results in a torque that rotates the plate
about two thin torsional rods. The dependence of the rotation
angle on the separation between the surfaces is in agreement
with calculations of the Casimir force. The authors suggest
their results demonstrate that quantum electrodynamical effects
play a significant role in such microelectromechanical systems
when the separation between the components is in the nanometer
range. The authors conclude: "This could open up new
possibilities for novel actuation schemes in
microelectromechanical systems based on the Casimir force and
may be important in the design of nanoelectromechanical systems."
Science 2001 291:1941
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5. On Terrestrial Planet Formation
Q. Yin et al (Harvard University, US) discuss terrestrial planet
formation, the authors making the following points:
1) Determining the chronology for the assembly of planetary
bodies in the early Solar System is essential for a complete
understanding of star- and planet-formation processes. It has
been argued that the rate of terrestrial core formation was
limited by accretion, that it started very early, and that it
was largely completed within the first 10–20 Myr or less of
Earth history. Various radionuclide chronometers (applied to
meteorites) have been used to determine that basaltic lava flows
on the surface of the asteroid Vesta formed within 3 million
years (3 Myr) of the origin of the Solar System(1-3). Such rapid
formation is broadly consistent with astronomical observations
of young stellar objects, which suggest that formation of
planetary systems occurs within a few million years after star
formation(4,5). Some hafnium–tungsten isotope data, however,
require that Vesta formed later (16 Myr after the formation of
the Solar System) and that the formation of the terrestrial
planets took a much longer time (62-14+4504 Myr).
2) Astronomical observations place a severe constraint on the
formation time of a gas-giant planet (possibly with a solid core
of ten Earth masses) to within a few million years after central
star formation and before complete dissipation of nebula
gas(4,5). It is now well accepted from dynamical models that
Mars-sized bodies will form within 0.1 Myr of the origin of the
Solar System. Dynamic accretion models favor the main growth
stage (60%) of the terrestrial planets (from Mars-sized to
Earth-sized bodies) taking about 10–20 Myr, but the "tail" of
accretion may arguably continue for another 80–90 Myr.
3) The authors report measurements of tungsten isotope
compositions and hafnium–tungsten ratios of several meteorites.
The authors suggest their measurements indicate that, contrary
to previous results, the bulk of metal–silicate separation in
the Solar System was completed within <30 Myr. These results are
completely consistent with other evidence for rapid planetary
formation(1-5), and are also in agreement with dynamic accretion
models that predict a relatively short time (10 Myr) for the
main growth stage of terrestrial planet formation.
References (abridged):
1. Lugmair, G. & Shukolyukov, A. Early solar system timescales
according to 53Mn-53Cr systematics. Geochim. Cosmochim. Acta 62,
2863-2886 (1998)
2. Srinivasan, G., Papanastassiou, D. A., Wasserburg, G. J.,
Bhandari, N. & Goswami, J. N. Re-examination of 26Al-26Mg
systematics in the Piplia Kalan eucrite. Lunar Planet. Sci.
XXXI, A1795 (2000)
3. Nyquist, L. E., Reese, Y., Wiesmann, H., Shih, C.-Y. &
Takeda, H. Live 53Mn and 26Al in an unique cumulate eucrite with
very calcic feldspar (An 98). Meteor. Planet. Sci. Suppl. 36,
A151-A152 (2001)
4. Briceño, C. et al. The CIDA-QUEST large-scale survey of Orion
OB1: Evidence for rapid disk dissipation in a dispersed stellar
population. Science 291, 93-96 (2001)
5. Bodenheimer, P. & Lin, D. N. C. Implications of extrasolar
planets for understanding planet formation. Annu. Rev. Earth
Planet. Sci. 30, 113-148 (2002)
Nature 2002 418:951
Web Links: solar system formation
Related Background Brief:
EARLY SOLAR SYSTEM TIMESCALES ACCORDING TO MN-53-CR-53
SYSTEMATICS. The authors present results of a study of the
Mn-53-Cr-53 systematics in various solar system objects:
angrites, eucrites, chondrites, diogenites, pallasites, the
Earth and the Moon, and SNC meteorites. The primary goal of this
study was to explore the capabilities of the Mn-53-Cr-53 isotope
system as a chronometer and as a tracer for events in the early
solar system, to obtain chronological information on different
classes of meteorites, and to investigate the indigenous
distribution of Mn-53 in the late nebula. These studies have
shown that all meteorite groups investigated so far have excess
Cr-53 relative to the terrestrial value. A lunar sample exhibits
Cr-53/Cr-52. ratios which are the same as the terrestrial
normal. The angrites, several eucrites, and the pallasites show
clear evidence for the existence of 53Mn during their formation
while other meteorites were isotopically equilibrated after
essentially all 53Mn had decayed. A well defined whole-rock
Mn-53-Cr-53 isochron for the HED (Howardite-Eucrite-Diogenite)
parent body was obtained. The isochron indicates that this
planetesimal was essentially totally molten and differentiated
similar to 7 Ma before the angrites crystallized. Using the
absolute age of the angrites as a time marker, this event
occurred 4565 Ma, within present uncertainties, at the same time
when high temperature meteorite inclusions (CAI) were formed in
the nebula. The first basalts were deposited onto its surface
within less than 3 Ma. The bulk Mn/Cr ratios of the HED parent
body (presumably Vesta), the angrites, and the pallasites are
consistent with a chondritic Mn/Cr ratio. The results from the
SCN meteorites show that their Cr-53. excesses are less than
half of those found in the other meteorites. Thus, the
characteristic Cr-53/Cr-52 ratio of Mars (assuming SNCs
originate from this planet) are intermediate between that of the
Earth-Moon system and those of the other meteorites. When these
53Cr excesses are plotted as a function of the heliocentric
distance of the place of origin of the samples then a linear
relationship is indicated. Provided that this variation is due
to the decay of Mn-53 then a radial heterogeneous distribution
of Mn-53 must have existed in at least the inner early solar
system. It is argued that radial fractionation within the
nebula, based on the slightly higher volatility of Mn as
compared to that of Cr, is an unlikely cause for this
distribution. Thus, it must be an intrinsic feature of the late
solar nebula. Stochastic mixing processes at the planetary
embryo stage did obviously not eradicate this heterogeneity.
Based on the Mn-53-Cr-53 systematics in HED meteorites and in
chondrites rather narrow limits are inferred for the age of the
solar system or, more accurately, for the start of the decay of
53Mn within the solar nebula; the range of possible values is
4568-4571 Ma. The lower limit is consistent with the Pb-Pb ages
of CAI's. G.W Lugmair and A. Shukolyukov: Geochimica Et
Cosmochimica Acta 1998 62:2863.
Related Background Brief:
IMPLICATIONS OF EXTRA SOLAR PLANETS FOR UNDERSTANDING PLANET
FORMATION. The authors review the observed properties of
extrasolar planets and planetary systems, including discussion
of the mass, period, and eccentricity distributions; the
presence of multiple systems; and the properties of the host
stars. In all cases, the data refer to systems with ages in the
Ga range. Some of the properties primarily reflect the formation
mechanism, while others are determined by postformation
dynamical evolutionary processes. The problem addressed here is
the extraction of information relevant to the identification of
the formation mechanism. The presumed formation sites, namely
disks around young stars, therefore, must provide clues at times
much closer to the actual formation time. The properties of such
disks are briefly reviewed. The amount of material and its
distribution in the disks provide a framework for the
development of a model for planet formation. The strengths of,
as well as the problems with, the two major planet formation
mechanisms -- gravitational instability and core accretion-gas
capture -- are then described. It is concluded that most of the
known planetary systems are best explained by the accretion
process. The timescales for the persistence of disks and for the
formation time by this process are similar, and the mass range
of the observed planets, up to approximately 10 Jupiter masses,
is naturally explained. The mass range of 5-15 Jupiter masses
probably represents an overlapping transition region, with
planetary formation processes dominating below that range and
star formation processes dominating above it. P. Bodenheimer and
D.N. Lin: Annual Review Of Earth And Planetary Sciences 2002
30:113.
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6. Nucleotide Dangling Ends and Duplex Stability
T. Ohmichi et al (Konan University, JP) discuss nucleotide
dangling ends, the authors making the following points:
1) Non-Watson-Crick base pairs in RNA and DNA play important
roles as catalytic and tertiary contact domains.(1) Their
structures and thermodynamic properties have been investigated
in an effort to understand the biological function associated
with these unpaired regions.(2-5) Terminal unpaired nucleotides,
also known as "dangling ends", may play interesting roles in
biological systems. Dangling nucleotides on RNA and DNA duplexes
can stabilize a helical structure through stacking of adjacent
base pairs. For example, the dangling nucleotides represented by
5'ACCA3' at the 3' terminus of tRNA stabilize the cloverleaf
structure of tRNA, and the interaction between mRNA and tRNA is
stabilized by the dangling ends adjacent to the codon-anticodon
pair. It has also been reported that a dangling nucleotide at
the 3' end of a pseudoknot RNA stabilizes the stem structure.
Moreover, recent studies of RNAi (RNA interference) have shown
that 2-3 nucleotides dangling ends are important for RNAi
functionality.
2) In the case of RNAi, short double-stranded RNAs (dsRNA) are
formed with the 2-3 nt RNA dangling ends after cleavage with
RNase III.14 Although the 2-3 nucleotides RNA dangling end
results after treatment with RNase III, a short dsRNA not
possessing a 2-3 nucleotides RNA dangling end displays no gene
silencing activity. These observations clearly show that long
dangling residues have the requisite energy contributions needed
to stabilize the helix, thus resulting in the observed
biological activities. However, previous studies only dealt with
the energy contributions of single dangling bases. The
systematic energy contributions of long dangling ends, which
consist of many dangling bases, have hitherto not been reported.
The authors report a quantitative increase in the stability of
an RNA-RNA duplex containing a long RNA dangling end. The
authors found that the stabilizing effect of dangling ends on
RNA duplexes is much larger than that on DNA duplexes.
3) In summary: Long terminal unpaired nucleotides known as
"dangling ends" play interesting roles in biological systems.
Previous studies, however, only dealt with the energy
contributions of single dangling bases. The energy contributions
of long dangling ends on the stability of duplexes have not been
systematically studied. The authors now report a quantitative
increase in stability of RNA-RNA and DNA-DNA duplexes containing
a long dangling end. The authors report they found a larger
enhancement of the stability by the long RNA dangling end of the
RNA-RNA duplex than has been observed for the DNA duplexes. It
is also found that structural stabilizations by long dangling
ends seem to originate from the single-stranded stacking
interactions of nucleotides. These results indicate that RNA
stability can be achieved by increasing the length of the
dangling end. The thermodynamic parameters of the long dangling
ends are useful for designing ribozymes and antisense
oligonucleotides, and for the prediction of the RNA secondary
structure like the pseudoknot.
References (abridged):
1. (a) Hertel, K. J.; Stage-Zimmermann, T. K.; Ammons, G.;
Uhlenbeck, O. C. Biochemistry 1998, 37, 16983-16988.(b) Wu, M.;
Tinoco, I., Jr. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
11555-11560. (c) Testa, S. M.; Gryaznov, S. M.; Turner, D. H.
Biochemistry 1998, 37, 9379-9385. (d) Ohmichi, T.; Kool, E. T.
Nucleic Acids Res. 2000, 28, 776-783
2. Xia, T.; SantaLucia, J., Jr.; Burkard, M. E.; Kierzek, R.;
Schroeder, S. J.; Jiao, X.; Cox, C.; Turner, D. H. Biochemistry
1998, 37, 14719-14735
3. SantaLucia, J., Jr.; Allawi, H. T.; Seneviratne, P. A.
Biochemistry 1996, 35, 3555-3562
4. Sugimoto, N.; Nakano, S.; Yoneyama, M.; Honda, K. Nucleic
Acids Res. 1996, 24, 4501-4505
5. Sugimoto, N.; Nakano, S.; Katoh, M.; Matsumura, A.; Nakamuta,
H.; Ohmichi, T.; Yoneyama, M.; Sasaki, M. Biochemistry 1995, 34,
11211-11216
J. Am. Chem. Soc. 2002 124:10367
Web Links: RNA duplex stability
Related Background Brief:
THE VIRTUES OF SELF-BINDING: HIGH SEQUENCE SPECIFICITY FOR RNA
CLEAVAGE BY SELF-PROCESSED HAMMERHEAD RIBOZYMES. Naturally
occurring hammerhead ribozymes are produced by rolling circle
replication followed by self-cleavage. This results in
monomer-length catalytic RNAs which have self-complementary
sequences that can occupy their trans-binding domains and
potentially block their ability to cleave other RNA strands.
Using small self-processed ribozymes, the authors demonstrate
that this self-binding does not necessarily inhibit
trans-cleavage and can result in greatly elevated discrimination
against mismatches. The authors utilized a designed 63
nucleotide circular DNA to encode the synthesis of a
self-processed ribozyme, MDR63. Rolling circle transcription
followed by self-processing produced the desired 63 nucleotide
ribozyme, which potentially can bind mdr-1 RNA with 9+9
nucleotides of complementarity or bind itself with 4+5
nucleotides of self-complementarity by folding back its ends to
form hairpins. Kinetics of trans-cleavage of short complementary
and mismatched RNAs were measured under multiple turnover
conditions, in comparison to a standard 40 nucleotide ribozyme
(MDR40) that lacks the self-complementary ends. The results show
that MDR63 cleaves an mdr-1 RNA target with a k (cat)/ K(m)
almost the same as MDR40, but with discrimination against
mismatches up to 20 times greater. Based on folding predictions,
a second self-processed ribozyme (UG63) having a single point
mutation was synthesized; this displays even higher specificity
(up to 100-fold) against mismatches. The authors suggest the
results indicate that self-binding ends may be generally useful
for increasing sequence specificity of ribozymes. T. Ohmichi and
E.T. Kool: Nucleic Acids Res 2000 28:776.
Related Background Brief:
THERMODYNAMIC PARAMETERS FOR AN EXPANDED NEAREST-NEIGHBOR MODEL
FOR FORMATION OF RNA DUPLEXES WITH WATSON-CRICK BASE PAIRS.
Improved thermodynamic parameters for prediction of RNA duplex
formation are derived from optical melting studies of 90
oligoribonucleotide duplexes containing only Watson-Crick base
pairs. To test end or base composition effects, new sets of
duplexes are included that have identical nearest neighbors, but
different base compositions and therefore different ends.
Duplexes with terminal GC pairs are more stable than duplexes
with the same nearest neighbors but terminal AU pairs.
Penalizing terminal AU base pairs by 0.45 kcal/mol relative to
terminal GC base pairs significantly improves predictions of
DeltaG degrees-37 from a nearest-neighbor model. A physical
model is suggested in which the differential treatment of AU and
GC ends accounts for the dependence of the total number of
Watson-Crick hydrogen bonds on the base composition of a duplex.
On average, the new parameters predict DeltaG degrees-37, DeltaH
degrees, DeltaS degrees, and TM within 3.2%, 6.0%, 6.8%, and 1.3
degrees C, respectively. These predictions are within the limit
of the model, based on experimental results for duplexes
predicted to have identical thermodynamic parameters. T. Xia et
al: Biochemistry 1998 37:14719.
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7. On the Prion Hypothesis
Susan W. Liebman (University of Illinois, US) discusses the
prion hypothesis, the author making the following points:
1) Early indications that the infectious agent responsible for
scrapie did not contain nucleic acid (1) led to several
insightful hypotheses to explain this conundrum (2). Eventually
considerable data came to support one of these ideas, dubbed the
prion hypothesis, also shown to be applicable to related fatal
transmissible spongiform encephalopathies including
Creutzfeldt-Jakob and mad cow disease (3). According to the
prion hypothesis, the prion protein (PrP) can exist in the
normal cellular form (PrPC), or in an "infectious" prion form
(PrPSc) that causes disease by converting the cellular form into
the prion form. Whereas PrPC is soluble and easily digested by
protease K, PrPSc is rich in beta-sheets, aggregates into
fibrils, and has a protease K-resistant core that forms amyloid.
2) The prion hypothesis has now been extended to explain
phenomena involving other proteins (4). Using genetic criteria,
Wickner (4) identified the non-Mendelian yeast elements [URE3]
(5) and [PSI+] (6), as prions of the Ure2 and Sup35 proteins,
respectively. A great deal of additional genetic and biochemical
evidence now supports this hypothesis. Evidence for other yeast
prions, as well as for [Het-s] of Podospora anserina, is now
emerging. Although the evidence for the prion hypothesis is
compelling, a direct demonstration that infectious activity is
caused by pure protein when in the prion form has been lacking.
Using the [Het-s] prion, Maddelein et al. (Proc. Nat. Acad. Sci.
Sci. 2002 99:7402) have come tantalizingly close to achieving
that aim.
3) The work of Maddelein et al demonstrates for the first time
that distinct in vitro-made fibers (the complete HET-s and the
protease K-resistant core) can cause in vivo prion appearance.
The ability to introduce different in vitro-made fibers into
cells and the intriguing phenomenon of prion "strains" together
may provide the ingredients to prove unambiguously that in
vitro-made aggregates are truly infectious. Clinically distinct
heritable versions of prion diseases (called strains) can occur
within the same inbred mammalian line even though the PrP gene
is identical in these inbred animals. Curiously, the different
disease strains appear to be caused by distinct conformations of
the PrP, and these conformation differences seem to be
maintained during in vitro propagation.
References (abridged):
1. Alper, T. , Cramp, W. A. , Haig, D. A. & Clarke, M. C.
(1967) Nature (London) 214, 764-766
2. Griffith, J. S. (1967) Nature (London) 215, 1043-1044
3. Prusiner, S. B. (1998) Proc. Natl. Acad. Sci. USA 95,
13363-13383
4. Wickner, R. B. (1994) Science 264, 566-569
5. Aigle, M. & Lacroute, F. (1975) Mol. Gen. Genet. 136, 327-335
Proc. Nat. Acad. Sci. 2002 99:9098
Web Links: prions
Related Background Brief:
PRIONS. Prions are unprecedented infectious pathogens that cause
a group of invariably fatal neurodegenerative diseases by an
entirely novel mechanism. Prion diseases may present as genetic,
infectious, or sporadic disorders, all of which involve
modification of the prion protein (PrP). Bovine spongiform
encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob
disease (CJD) of humans are among the most notable prion
diseases. Prions are transmissible particles that are devoid of
nucleic acid and seem to be composed exclusively of a modified
protein (PrPSc). The normal, cellular PrP (PrPC) is converted
into PrPSc through a posttranslational process during which it
acquires a high beta-sheet content. The species of a particular
prion is encoded by the sequence of the chromosomal PrP gene of
the mammals in which it last replicated. In contrast to
pathogens carrying a nucleic acid genome, prions appear to
encipher strain-specific properties in the tertiary structure of
PrPSc. Transgenetic studies argue that PrPSc acts as a template
upon which PrPC is refolded into a nascent PrPSc molecule
through a process facilitated by another protein. Miniprions
generated in transgenic mice expressing PrP, in which nearly
half of the residues were deleted, exhibit unique biological
properties and should facilitate structural studies of PrPSc.
While knowledge about prions has profound implications for
studies of the structural plasticity of proteins, investigations
of prion diseases suggest that new strategies for the prevention
and treatment of these disorders may also find application in
the more common degenerative diseases. Stanley B. Prusiner:
Proc. Nat. Acad. Sci. 95:13363.
Related Background Brief:
[URE3] AS AN ALTERED URE2 PROTEIN: EVIDENCE FOR A PRION ANALOG
IN SACCHAROMYCES CEREVISIAE. A cytoplasmically inherited
element, [URE3], allows yeast to use ureidosuccinate in the
presence of ammonium ion. Chromosomal mutations in the URE2 gene
produce the same phenotype. [URE3] depends for its propagation
on the URE2 product (Ure2p), a negative regulator of enzymes of
nitrogen metabolism. Saccharomyces cerevisiae strains cured of
[URE3] with guanidium chloride were shown to return to the
[URE3]-carrying state without its introduction from other cells.
Overproduction of Ure2p increased the frequency with which a
strain became [URE3] by 100-fold. In analogy to mammalian
prions, [URE3] may be an altered form of Ure2p that is inactive
for its normal function but can convert normal Ure2p to the
altered form. The author suggests the genetic evidence presented
indicates that protein-based inheritance, involving a protein
unrelated to the mammalian prion protein, can occur in a
microorganism. R.B. Wickner: Science 1994 264:528.
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8. On House Pets and Risk of Allergic Sensitization
D.R. Ownby et al (Medical College of Georgia, US) discuss
allergic sensitization, the authors making the following points:
1) The increasing prevalence of asthma in the United States and
other developed countries over the last few decades has been a
cause for concern.(1,2) While many factors appear to be involved
in the development of childhood asthma, allergic sensitization
to common allergens has consistently been shown to be related to
the risk of developing asthma and to the risk of asthma
persisting from childhood into adulthood.(3-5) Many studies have
attempted to elucidate relationships between environmental
exposures, especially during infancy, and the risk of allergic
sensitization in later life. These studies are based on the
theory that an individual's genetic predisposition to allergic
disease is activated or enhanced by early allergen exposure. The
outcome of interactions between genetic influences and allergen
exposures may be influenced by other environmental exposures,
such as passive exposure to environmental tobacco smoke. If
these relationships were better understood it might become
possible to reduce the prevalence of allergic sensitization and
perhaps asthma in children.
2) Exposure to dogs and cats during infancy has been thought to
increase the risk of subsequent allergy to these animals. This
assumption is primarily based on a few retrospective studies
reporting an increased likelihood of allergic sensitization
following exposure during infancy. Some studies, however, have
suggested that exposure to dogs or cats during infancy is
associated with reduced risk of allergic disease. Others have
shown that children growing up on farms, especially farms with
animals, were less likely to be allergic than were children
growing up in urban environments.
3) The authors report a study to evaluate the relationship
between dog and cat exposure in the first year of life and
allergic sensitization at 6 to 7 years of age. The subjects
consisted of a prospective birth cohort study of healthy,
full-term infants enrolled in a health maintenance organization
in suburban Detroit, Michigan, who were born between April 15,
1987, and August 31, 1989, and followed up yearly to a mean age
of 6.7 years. Of 835 children initially in the study at birth,
474 (57%) completed follow-up evaluations at age 6 to 7 years.
Main outcome measures: Atopy, defined as any skin prick test
positivity to 6 common aeroallergens (dust mites
[Dermatophagoides farinae, D pteronyssinus], dog, cat, short
ragweed [Ambrosia artemisiifolia], and blue grass [Poa
pratensis]); seroatopy, defined as any positive
allergen-specific IgE test result for the same 6 allergens or
for Alternaria species. From the results, the authors conclude
that exposure to 2 or more dogs or cats in the first year of
life may reduce subsequent risk of allergic sensitization to
multiple allergens during childhood.
References (abridged):
1. Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd
SC. Surveillance for asthma United States, 1980-1999. Mor Mortal
Wkly Rep CDC Surveill Summ. 2002;51:1-13
2. Yunginger JW, Reed CE, O'Connell EJ, Melton LJ III, O'Fallon
WM, Silverstein MD. A community-based study of the epidemiology
of asthma: incidence rates, 1964-1983. Am Rev Respir Dis.
1992;146:888-894
3. Sears MR, Burrows B, Flannery EM, Herbison GP, Holdaway MD.
Atopy in childhood, I: gender and allergen related risks for
development of hay fever and asthma. Clin Exp Allergy.
1993;23:941-948
4. Platts-Mills TA, Vervloet D, Thomas WR, Aalberse RC, Chapman
MD. Indoor allergens and asthma: report of the third
international workshop. J Allergy Clin Immunol. 1997;100:S2-S24
5. Litonjua AA, Sparrow D, Weiss ST, O'Connor GT, Long AA, Ohman
JL Jr. Sensitization to cat allergen is associated with asthma
in older men and predicts new-onset airway hyperresponsiveness.
Am J Respir Crit Care Med. 1997;156:23-27
J. Am. Med. Assoc. 2002 288:963
Web Links: allergic sensitization
Related Background Brief:
A COMMUNITY-BASED STUDY OF THE EPIDEMIOLOGY OF ASTHMA. INCIDENCE
RATES, 1964-1983. To determine whether the incidence of asthma
had increased in Rochester, Minnesota, from January 1, 1964
through December 31, 1983, the authors used a population-based
computer-linked medical diagnosis system to identify individual
medical records with diagnosis of asthma or other conditions
mimicking asthma. All records were reviewed using explicit
predetermined diagnostic criteria; the authors identified 3,622
incident cases of asthma, including definite asthma (n = 1,547),
probable asthma (n = 952), and single wheezing episodes (n =
1,123). The annual age- and sex-adjusted incidence of definite +
probable asthma rose from 183 per 100,000 in 1964 to 284 per
100,000 in 1983. This rise was entirely accounted for by
increased incidence rates in children and adolescents (age
range, 1 to 14 yr); incidence rates for infants younger than 1
yr of age and for adults remained constant. For definite +
probable asthma cases, the incidence rates for males were higher
than for females from infancy through 9 yr of age and for
persons older than 50; incidence rates for females were higher
than for males from 15 through 49 yr of age. The median age at
onset was 3 yr for males and 8 yr for females. The authors
conclude that asthma begins in early childhood, with a higher
incidence and earlier onset in males, and that the increase in
incidence rates seen from 1964 to 1983 occurred only in children
and in adolescents. J.W. Yunginger et al: Am Rev Respir Dis 1992
146:888.
Related Background Brief:
ATOPY IN CHILDHOOD. I. GENDER AND ALLERGEN RELATED RISKS FOR
DEVELOPMENT OF HAY FEVER AND ASTHMA. Reasons for the gender
differences in prevalence rates for asthma remain unclear. The
authors report they have examined the relationships between
allergen skin-test reactions and diagnoses of hay fever and
asthma in New Zealand boys and girls examined at the age of 13
years. Information on current and past wheezing, diagnosed
asthma, and hay fever was obtained for 662 subjects (341 boys)
of a birth cohort followed longitudinally to the age of 13
years, using a physician-administered questionnaire. Atopic
status was determined by skin-prick tests to 11 common
allergens. The proportion of 13-year-old boys with current
asthma was 1.6 times higher and of ever-diagnosed asthma 1.4
times higher than in girls, but the prevalence of recurrent
wheeze (> or = three episodes per year) not diagnosed as asthma,
or of hay fever, was not significantly different between the
sexes. The prevalence of diagnosed asthma increased with
increasing numbers of positive skin tests, but hay fever without
asthma was little affected above one positive skin-test. Boys
had a greater prevalence of any positive skin-test (50.1% vs
37.1%), two or more positive tests (29.3% vs 21.8%), and
responses to house dust mite (34.0% vs 23.1%) and cat (14.7% vs
11.2%). Gender differences for asthma became insignificant when
adjusted for skin-test responsiveness to house dust mite and/or
cat. The proportion of children with diagnosed asthma increased
with increasing size of weals to house dust mite and cat dander.
Gender differences in allergen sensitivities partly explain the
gender differences in diagnosed asthma in children. In both
sexes, risk of asthma was primarily associated with
sensitization to indoor allergens (house dust mite and cat), and
was related to the magnitude of the skin-test response, while
the risk of hay fever was primarily associated with grass pollen
sensitivity. M.R. Sears et al: Clin Exp Allergy. 1993 23:883.
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9. Nonfinancial Conflicts of Interest in Medical Research
Norman G. Levinsky (Boston University, US) discusses
nonfinancial conflicts of interest in medical research, the
author making the following points:
1) The dual motives, advancement of medical science and personal
benefits from publications and acquisition of grants, have not
changed over the past 40 years as clinical research has
burgeoned. Presumably, they have been and still are universal
motives among academic investigators. They are reinforced by the
interest of institutions in enhancing their reputations as
research centers. This institutional goal influences the
attitude not only of individual investigators but also of
institutional review boards (IRBs), which for the past three
decades have been responsible for weighing the benefits and
risks of research involving human subjects. The personal
interest of an investigator in advancing knowledge coincides
with the altruistic desire of many subjects to participate in
research because it is of potential benefit to humanity. The
interests of subjects and investigators may also be aligned if
the subjects have reason to hope that they may benefit medically
themselves. However, an investigator's interest in career
advancement, although entirely ethical and appropriate in
itself, may conflict, or appear to conflict, with the interest
of subjects in minimizing the risk of psychological harm,
physical injury, or death.
2) During the past decade, increasing attention has been paid to
financial conflicts of interest in research. The dramatic growth
of relations between investigators and industry has raised
justifiable concern about the influence of financial rewards on
the conduct, interpretation, and reporting of research. Academic
organizations have published guidelines for avoiding or managing
financial conflicts of interest, and federal regulations for
this purpose are expected soon. A critical event that
accelerated efforts to address the influence of financial
conflicts of interest on the safety of research subjects was the
death in 1999 of a subject enrolled in a study in which both the
principal investigator and the institutional sponsor had
substantial financial interests.(1)
3) However, the deaths of three other research subjects that
have been reported publicly in the past six years apparently did
not involve financial conflicts of interest.(2,3,4) A broad
spectrum of problems has been identified in these cases,
involving both individual researchers and IRBs. The problems
include the excessive zeal of an investigator in trying to
complete a study, the failure of a researcher to report an
adverse event in a previous subject to the IRB, an inadequate
search of the literature on the toxicity of a drug, use of
poorly trained personnel to measure the dose of a substance
administered to a subject, the potential vulnerability of
employees and students to pressure to serve as research
subjects, and the influence of payments to subjects. These
deaths all occurred at prominent research institutions. Since
all the subjects were healthy volunteers, the author suggests
there is no doubt that the deaths were caused by the research
procedures.(5)
References (abridged):
1. Marshall E. Penn report, agency heads home in on clinical
research. Science 2000;288:1558-1559
2. Steinbrook R. Protecting research subjects -- the crisis at
Johns Hopkins. N Engl J Med 2002;346:716-720
3. Solov D, McEnery R. Healthy woman died in UH Alzheimer's
study. Cleveland Plain Dealer. December 21, 2001:A1
4. Wentzel M. Toxic dose given UR student. Rochester Democrat
and Chronicle. April 4, 1996:1a
5. Cardon PV, Dommel FW Jr, Trumble RR. Injuries to research
subjects: a survey of investigators. N Engl J Med
1976;295:650-654
New Engl. J. Med. 2002 347:759
Web Links: research conflicts of interest
Related Background Brief:
INJURIES TO RESEARCH SUBJECTS: A SURVEY OF INVESTIGATORS. A task
force of the Department of Health, Education, and Welfare
conducted a survey aimed at estimating the incidence of
research-related injuries, with a view to determining the
feasibility of compensating subjects injured during research.
The data were obtained by telephone from 331 investigators
conducting research on nearly 133,000 human subjects over the
previous three years. Eighty-five investigators reported at
least one injury. Of the 4957 reported injuries, 3926 were
classified as trivial, and 974 as temporarily disabling; of 57
injuries resulting in death or permanent disability, one
disabling stroke, not clearly related to the research, occurred
three days after a non-therapeutic procedure; the rest resulted
from treatments expected to benefit the patients directly,
usually cancer chemotherapy. The data suggest that the risks of
participation in nontherapeutic research may be of no greater
than those of everyday life, and in therapeutic research, no
greater than those of treatment in other settings. P.V. Cardon
et al: New Engl. J. Med. 1976 295:650.
Related Background Brief:
PROTECTING RESEARCH SUBJECTS -- THE CRISIS AT JOHNS HOPKINS.
Ellen Roche, a 24-year-old technician at the Johns Hopkins
Asthma and Allergy Center and a healthy volunteer in a study of
asthma funded by the National Institutes of Health, died on June
2, 2001. Prompted by Roche's death, the federal Office for Human
Research Protections reviewed the system at the Johns Hopkins
Medical Institutions for protecting research subjects and found
widespread deficiencies. On July 19, 2001, the office suspended
all federally supported research projects at Johns Hopkins and
several affiliated institutions -- not because of Roche's death
but because of the additional problems that had been identified.
Johns Hopkins quickly took corrective action, and the suspension
was lifted. Nonetheless, the suspension was "a gigantic shock"
to an institution that "has always prided itself on excellence
in care and excellence in research," according to Dr. Edward D.
Miller, dean of the Johns Hopkins University School of Medicine.
Along with the 1999 death of 18-year-old Jesse Gelsinger in a
gene-transfer trial at the University of Pennsylvania and the
suspension of federally supported research at other prominent
institutions, the shutdown at Johns Hopkins has focused
attention on the safety of medical research, particularly when
the subjects are healthy volunteers or are employed at the
institution where the research takes place. The shutdown has
also spurred efforts to improve the effectiveness of the various
groups that have a role in protecting research subjects,
including investigators, institutional review boards (IRBs),
sponsors, and the institutions where the research is conducted.
Robert Steinbrook: New Engl. J. Med. 2002 346:716.
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10. On High-Tesla Superconducting Magnets
S.W. Van Sciver and K.R. Madden (National High Magnetic Field
Laboratory, US) discuss superconducting magnets, the authors
making the following points:
1) The primary motivation for developing high-field
superconducting magnets is to support scientific research in a
variety of disciplines. Because the magnetic field is a
thermodynamic variable, it can be used to manipulate phase
diagrams of magnetic materials in which the spins of the
electrons order ferromagnetically or antiferromagnetically. The
quantized orbital motion of electrons in the presence of
magnetic fields allows researchers to probe Fermi surfaces, and
the quantized electron energy levels associated with fields of
order 20 tesla (T) or greater permit access to the quantum and
fractional quantum Hall regime. Nuclear magnetic resonance (NMR)
techniques, applicable to physical, chemical, and biological
systems, have led to a remarkable technology for nondestructive
imaging of living systems.
2) Many investigations require, or at least can benefit from,
the homogeneous, low-noise, and temporally stable magnetic
fields that can only be achieved with superconducting magnets.
Cost and material properties, though, limit the fields that can
be produced with superconducting coils. A number of
manufacturers now sell 20-T superconducting magnets with bore
sizes in the range of 50 mm: Many of those magnets are
incorporated into research instruments such as NMR spectrometers
or magnetometers. (For comparison, the highest magnetic fields
are generated at facilities such as the National High Magnetic
Field Laboratory. The NHMFL operates a 45-T "hybrid"
superconducting magnet with a resistive insert and also operates
60-T pulsed magnets.) New superconducting materials, including
high-temperature (HT) superconductors are enabling the design
and construction of solenoidal magnets that have fields
approaching 25 T. But achieving 20-T magnets has required many
years of work, and as magnet builders develop magnets that
produce stronger fields, they find the cost and difficulty of
production growing rapidly. Going beyond 20 T in a
superconducting magnet demands long development schedules, large
R&D groups, and the application of complex engineering
principles. Still, superconducting magnets with ever higher
fields are in demand, and efforts to meet that demand continue.
References (abridged):
1. R. de Bruyn Ouboter, IEEE Trans. Magn. 23, 355 (1987)
2. Y. Iwasa, Case Studies in Superconducting Magnets: Design and
Operational Issues, Plenum Press, New York (1994)
3. H. Kolm, B. Lax, F. Bitter, R. Mills, eds., High Magnetic
Fields, (proc. conf.), grant no. AF-AFOSR 61-31, MIT Press,
Cambridge, Mass., and J. Wiley, New York (1962)
4. J. E. Kunzler, IEEE Trans. Magn. 23, 396 (1987)
5. H. Wada, T. Kiyoshi, IEEE Trans. Appl. Supercond. 10 (in
press)
Physics Today 2002 August
Web Links: superconducting magnets
Related Background:
EARLY HISTORY OF HIGH-TEMPERATURE SUPERCONDUCTORS
D. Larbalestier et al (University of Wisconsin, US) discuss
high-temperature superconductors, the authors making the
following points:
1) The potential applications of superconductors -- the name
Kamerlingh Onnes (1853-1926) gave to materials that lose
electric resistance on cooling below a specific transition
temperature --were apparent to Onnes almost immediately. In
1913, just two years after his discovery, Onnes talked in
Chicago about the design of very powerful magnets far exceeding
the fields achievable by iron; these would cost as much as a
battleship if made from copper and cooled with liquid air, but
be affordable if made from superconducting wires. By that time
he had already tested a nickel alloy coated with lead-rich
superconducting solder, but this lost superconductivity at
fields of less than 50 millitesla. He ascribed this unexpected
setback to bad places in the wire, a problem he anticipated
would soon be fixed without difficultly.
2) In fact, applications had to wait 50 more years, particularly
because the physics of superconductivity in magnetic fields was
seriously misunderstood. This need not have been so, because
London and Shubnikov made important breakthroughs in
understanding the magnetic properties of superconductors in the
1930s. By careful alloying experiments, Shubnikov pointed out
the vital distinction between type I superconductors, in which
currents flow only at the surface and superconductivity is
destroyed by weak fields, as in Onnes's 1913 experiment, and a
new type of superconductor, now called a type II superconductor,
capable of carrying bulk supercurrent at high fields. The key
understanding that the behavior of type II superconductors is
due to quantized magnetic vortices was achieved by Abrikosov in
the 1950s.
Nature 2001 414:368
Related Background:
ON THE DISCOVERY OF HIGH TEMPERATURE SUPERCONDUCTIVITY
One of the operating tenets of 20th century "big science" is
that important breakthroughs in science can be more or less
engineered if appropriate conditions are constructed and
appropriate individual researchers placed in those conditions.
When this approach produces a success, the various bureaucrats
who support the idea feel reaffirmed; when various
counter-examples to the approach occur, it is the turn of the
doubters to feel reaffirmed. A cogent instance of a
counter-example was provided in 1986 by the Bednorz-Mueller
discovery of high-temperature superconductivity -- a discovery
of signal importance in experimental physics made by two
relatively unknown researchers working in what can be
characterized as a backwater and poorly-equipped laboratory. Not
only was the discovery of high-temperature superconductivity
totally unexpected by the international physics community, but
the discovery of the phenomenon by outsiders under "little
science" conditions caused a degree of shock in the science
policy system. Ordinary superconductivity is a property of many
metals, alloys, and chemical compounds at temperatures near
absolute zero, at which temperatures (their "critical
temperatures") their electrical resistivity vanishes and they
become strongly diamagnetic. (Diamagnetic substances such as the
alkalis and alkaline earth metals, the halogens, and the noble
gases are repelled by magnets and tend to position themselves at
right angles to the magnetic lines of force.) High-temperature
superconductors were unknown until 1986, but at present there
are some known high-temperature superconductors with critical
temperatures greater than 100 kelvins. The accepted theory of
ordinary superconductivity is the Bardeen-Cooper-Schrieffer
theory (BCS theory) (1957). At the present time, a successful
theory of high-temperature superconductivity has not been
developed, in spite of a great deal of effort. Johannes Georg
Bednorz (1950- ) and K. Alexander Mueller (1927- ) shared the
Nobel Prize in Physics in 1987 for their discovery of
high-temperature superconductivity in a ceramic oxide
(lanthanum-barium-copper) alloy at 30 kelvins, at that time the
highest superconductivity temperature ever observed, the work
having been carried out at the IBM Zurich Research Laboratories
at Rueschlikon.
Helga Nowotny (Swiss Federal Institute of Technology, CH)
presents an essay on innovation in research and the modern
partnership between basic research and applied science, the
author making the following points:
1) One of the most exciting recent success stories of science
began in September 1986 with the appearance in the _Zeitschrift
fur Physik_ of an article with the cautious title, "Possible
high-T(subc) superconductivity in the Ba-La-Cu-O system." A few
weeks later, the names of the two authors, Alexander Mueller and
Georg Bednorz, and their discovery hit the front pages of _The
New York Times_ and researchers around the world were caught in
an unprecedented frenzy, attempting to replicate and surpass the
findings of the initial breakthrough. The race for
high-temperature superconducting systems was on.
2) The discovery of high-temperature superconductivity was
unexpected in terms of its discoverers, the place of its
discovery, and the scientific ideas involved. It contradicted
conventional wisdom and the expectations of peers and research
administrators. Mueller and Bednorz were outsiders, Mueller a
specialist on perovskites (a type of oxide mineral) and Bednorz
a crystallographer. They benefited from the novice effect, but
they also enjoyed a degree of autonomy that allowed them to
prepare for the unpredictable. Of the 3 superconductivity
laboratories of IBM, the Rueschlikon laboratory where the two
researchers were based was by far the most modestly equipped.
And the discovery contradicted long-held views, not only
overturning certain established empirical rules concerning
superconductivity, but also unveiling previously unknown
phenomena not accounted for by the classic
Bardeen-Cooper-Schrieffer theory.
3) The author points out that even if we knew how to create
conditions under which creativity can flourish, and how to favor
the occurrence of what cannot be planned, the problem remains of
how to turn highly individualistic bursts of scientific
creativity into socially desired techno-scientific outcomes.
"For the most disturbing paradox is this: there has been a
relative decline in the importance of the individual creative
act, while its proliferation is encouraged. Individual
scientific creativity has become a necessary, but no longer
sufficient, precondition in a long, branching sequence of
possibilities."
Nature 1999 401:859
ScienceWeek http://www.scienceweek.com
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11. On Vesicular Nanoparticles
K. Katagiri et al (Nara Institute of Science and Technology, JP)
discuss vesicular nanoparticles, the authors making the
following points:
1) Lipid bilayer vesicles with an inner aqueous compartment have
been extensively employed as biomembrane models in the field of
supramolecular chemistry. Over the years it has become apparent
that the bilayer vesicles can be effectively utilized as
nanocapsules for the drug delivery or gene transfection
systems,(1) artificial cell membranes,(2) and artificial
enzymes.(3) From the point of view of recently growing
nanotechnology, however, the bilayer vesicle with a nanometer
size seems to have another potential as a fascinating
nanomaterial candidate for designing functional supramolecular
devices.(4) For such a purpose it would be important to develop
a new methodology to form hierarchically integrated vesicular
assemblies, since the multicellular bodies in the biological
system can create highly organized architectures and exhibit
many more functions as compared to the unicellular ones.
2) While the lipid bilayer vesicles have a wide variety of
advantages in the control of the aggregate morphology, particle
size, lipid composition, and various physical properties based
on molecular design of the lipid components, the morphological
stability seems to be generally insufficient to create
hierarchical nanoarchitectures. For example, the authors have
previously developed synthetic peptide lipids bearing an amino
acid residue interposed between a polar head moiety and a
hydrophobic double-chain segment through the peptide bond.(5)
Formation of the hydrogen-belt domain in the peptide lipid
membrane stabilized the small unilamellar vesicles without
morphological change for over several months. Even for such
stable bilayer vesicles, however, the aggregate morphology could
not be maintained in the presence of polyelectrolyte with
opposite charges to afford membrane fusion, and the behavior is
now common knowledge in lipid membrane chemistry.
3) In summary: The authors report that a three-dimensional
packed vesicular assembly was successfully prepared by using an
organic-inorganic hybrid, the Cerasome. This assembly was
achieved by using an alternate layer-by-layer adsorption
technique with the anionic and the cationic Cerasome derived
from corresponding organoalkoxysilane amphiphiles. Adsorption
quantities of each Cerasome layer were evaluated by employing a
quartz crystal microbalance. The surface structure of the
Cerasome paving on a substrate obtained in this way was observed
by atomic force microscopy. The Cerasome particles closely
packed like a stone pavement were clearly observed in both
layers. In addition, the difference in the particle size for
each layer indicates the cationic and anionic Cerasomes
undoubtedly formed the layer-by-layer assembly. The layered
paving of the vesicular nanoparticles was seen in every layer at
least up to ten adsorption steps.
References (abridged):
1. (a) Scheule, R. K.; Cheng, S. H. In Artificial
Self-Assembling System for Gene Delivery; Felgner, P. L.,
Heller, M. J., Lehn, P., Behr, J. P., Szoka, F. C., Jr., Eds.;
American Chemical Society: Washington, DC, 1996; pp 177-190. (b)
Allen, T. M. Curr. Opin. Colloid Interface Sci. 1996, 1,
645-651. (c) Lasic, D. D.; Papahadjopoulos, D. Curr. Opin. Solid
State Mater. Sci. 1996, 1, 392-400.
2. (a) Kunitake, T. In Comprehensive Supramolecular Chemistry;
Lehn, L.-M., Atwood, J. L., Davies, J. E. D., MacNicol, D. D.,
Vögtle, F., Eds.; Pergamon: Oxford, UK, 1996; Vol. 9, pp
351-406. (b) Gokel, G. W.; De Wall, S. L. In Advances in
Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press:
Stamford, CT, 1999; Vol. 5, pp 203-235. (c) Davidson, S. K. M.;
Regen, S. L. Chem. Rev. 1997, 97, 1269-1279.
3. (a) Murakami, Y.; Kikuchi, J.; Hisaeda, Y.; Hayashida, O.
Chem. Rev. 1996, 96, 721-758. (b) Murakami, Y.; Kikuchi, J.;
Hisaeda, Y.; Ohno, T. In Comprehensive Supramolecular Chemistry;
Lehn, L.-M., Atwood, J. L., Davies, J. E. D., MacNicol, D. D.,
Vögtle, F., Eds.; Pergamon: Oxford, UK, 1996; Vol. 4, pp
415-472. (c) Feiters, M. C. In Comprehensive Supramolecular
Chemistry; Lehn, L.-M., Atwood, J. L., Davies, J. E. D.,
MacNicol, D. D., Vögtle, F., Eds.; Pergamon: Oxford, UK, 1996;
Vol. 10, pp 267-360.
4. (a) Cornell, B. A.; Braach-Maksvytis, V. L. B.; King, L. G.;
Osman, P. D. J.; Raguse, B.; Wieczorek, L.; Pace, R. J. Nature
1997, 387, 580-583. (b) Steinberg-Yfrach, G.; Gigaud, J.-L.;
Durantini, E. N.; Moore, A. L.; Gust, D.; Moore, T. A. Nature
1998, 392, 479-482. (c) Kikuchi, J.; Ariga, K.; Miyazaki, T.;
Ikeda, K. Chem. Lett. 1999, 253-254. (d) Kikuchi, J. In
Precision Polymers and Nano-Organized Systems; Kunitake, T.,
Nakahama, S., Takahashi, S., Toshima, N., Eds.; Kodansha: Tokyo,
Japan, 2000; pp 177-180.
5. Murakami, Y.; Kikuchi, J. In Bioorganic Chemistry Frontiers;
Dugas, H., Ed.; Springer-Verlag: Berlin, Germany, 1991; Vol. 2,
pp 73-113.
J. Am. Chem. Soc. 2002 124:792
Web Links: lipid bilayer vesicles liposomes
Related Background Brief:
LIGHT-DRIVEN PRODUCTION OF ATP CATALYZED BY F0F1-ATP SYNTHASE IN
AN ARTIFICIAL PHOTOSYNTHETIC MEMBRANE. Energy-transducing
membranes of living organisms couple spontaneous to
non-spontaneous processes through the intermediacy of
protonmotive force (p.m.f.) -- an imbalance in electrochemical
potential of protons across the membrane. In most organisms,
p.m.f. is generated by redox reactions that are either
photochemically driven, such as those in photosynthetic reaction
centers, or intrinsically spontaneous, such as those of
oxidative phosphorylation in mitochondria. Transmembrane
proteins (such as the cytochromes and complexes I, III and IV in
the electron-transport chain in the inner mitochondrial
membrane) couple the redox reactions to proton translocation,
thereby conserving a fraction of the redox chemical potential as
p.m.f. Many transducer proteins couple p.m.f. to the performance
of biochemical work, such as biochemical synthesis and
mechanical and transport processes. Recently, an artificial
photosynthetic membrane was reported in which a photocyclic
process was used to transport protons across a liposomal
membrane, resulting in acidification of the liposome's internal
volume. If significant p.m.f. is generated in this system, then
incorporating an appropriate transducer into the liposomal
bilayer should make it possible to drive a non-spontaneous
chemical process. The authors report the incorporation of
F0F1-ATP synthase into liposomes containing the components of
the proton-pumping photocycle. Irradiation of this artificial
membrane with visible light results in the uncoupler- and
inhibitor-sensitive synthesis of adenosine triphosphate (ATP)
against an ATP chemical potential of approximately 12 kcal/mol,
with a quantum yield of more than 7%. This system mimics the
process by which photosynthetic bacteria convert light energy
into ATP chemical potential. G. Steinberg-Yfrach et al: Nature
1998 392:479.
Related Background Brief:
FUSOGENIC BEHAVIOR OF SINGLE-WALLED VESICLES COMPOSED OF
SYNTHETIC PEPTIDE LIPIDS. The authors report that fusogenic
behavior of the single-walled vesicle formed with mixed or
individual synthetic peptide lipids,
R(CH2)5CONHCHMeCON[(CH2)mMe]2 (I, R = N+Me3 Br- or NaOSO2, m =
14 or 16), was investigated in the presence of various
water-soluble polymers or a nonbilayer-forming lipid by electron
microscopy, differential scanning calorimetry, and turbidity
measurements. The following ionic polymers having opposite
charges to the net surface charges of the vesicles immediately
induced fusion via vesicle aggregation; heparin, chondroitin
sulfate C, chondroitin, and the K salt of poly(vinyl sulfate)
for the cationic vesicles, and polybrene for the anionic ones.
On the other hand, ionic polymers having electrostatic charges
identical with the vesicular surface charges and nonionic ones,
such as amylose, poly(vinyl alc.), polyethylene glycol 20000,
and polyethylene glycol 6000, induced neither fusion nor
aggregation. A nonbilayer-forming lipid [I, R =
(1R)-1a,3a,4a,5b-tetrahydroxycyclohexylcarbonylamino, n = 14]
incorporated into the I (R = N+Me3Br-) vesicles induced fusion
at kinetic rates much slower than those triggered by the ionic
polymers. The authors discuss the observations with attention to
the dehydration effect and the participation of nonbilayer
structures in the fusion process. Y. Murakami et al: Bull. Chem.
Soc. Jpn. 1986 59:3145.
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12. On Polyacrylamides and Acrylamide
M.J. Caulfield et al (University of Melbourne, AU) discuss
acrylamide, the authors making the following points:
1) The polyacrylamide family of polymers and copolymers is a
highly versatile group used in a multitude of applications
including clarification of drinking water, flocculants for
wastewater treatment, oil recovery, soil conditioning,
agriculture, and biomedical applications. However, the
neurotoxicity of the acrylamide monomer has led to some concerns
and even reluctance to accept polyacrylamides as safe materials
particularly in situations where the polymer is in direct
contact with bodily fluids (e.g., renal dialysis, blood
filtration, etc.) or where the polymer is used in making
therapeutic products. There are lingering concerns regarding the
possibility that residual acrylamide is present in the polymeric
materials and whether polyacrylamides can degrade back to the
monomer.
2) Acrylamide is a white odorless crystalline solid with a
melting point of 84.5 C. It is soluble in many polar solvents,
including acetone, acetonitrile, and water, where 215.5 g can be
dissolved in 100 mL of water at 30 C. Acrylamide contains two
principle functional groups, the vinylic carbon-carbon double
bond and an amide group. The German chemist Moureu first
synthesized acrylamide in 1893; however, it was not widely
commercially available until the 1950s, when Hercules Corp.
started making commercial quantities. Acrylamide is generally
formed from the hydration of acrylonitrile with either sulfuric
acid at between 90 and 100 C or more recently by catalytic
hydration using copper catalyst. The total world production
capacity for acrylamide is more than 300,000 metric tons per
year.
3) The electron deficient double bond of acrylamide is
susceptible to a wide range of chemical reactions including
nucleophilic additions, Diels-Alder, and radical reactions.
Thus, ammonia, aliphatic amines, phosphines, chlorine, bromine,
bisulfite, and dithiocarbamates readily react with the vinylic
double bond as do proteins, hence the reasons for concern in
biological systems. Reactions of the amide residue include
hydrolysis, dehydration, alcoholysis, and condensation with
aldehydes. Acrylamide's extreme water solubility contributes to
it being readily absorbed by a variety of microorganisms such as
bacteria from widely diverse habitats, including soil, aquatic,
and sewage. Once absorbed, enzymes are involved in its
transformation to water, carbon dioxide, ammonia, and other
constituent products. It has been demonstrated that acrylamide
can act as the sole carbon and nitrogen sources for microbial
growth. Higher animals are also capable of absorbing compounds
such as acrylamide and metabolizing them via suitable enzymes.
4) Acrylamide is an acute eye, skin, and respiratory tract
irritant and is absorbed by all routes of exposure, including
intravenous, intraperitoneal, subcutaneous, intramuscular, oral,
and dermal. The toxicity of acrylamide has been exhaustively
examined and well documented. In higher animals, once absorbed,
acrylamide causes damage to the central nervous system,
producing an ascending central/peripheral axonopathy. The
severity and length of the axonopathy is depended on the level
of intoxication, and is generally characterized by disruption of
sensory, motor, and autonomic function of the peripheral and
ascending tracts of the spinal chord. Acrylamide has been
classified by the U. S. Environmental Protection Agency (EPA) as
a Group B2 probable carcinogen.(1-5)
References (abridged):
1. MacWilliams, D. C. In Functional Monomers: Their Preparation,
Polymerization, and Application; Yocum, R. H., Nyquist, E. B.,
Eds., M. Dekker, New York, 1973; Vol. 1, p 1.
2. Hunkeler, D.; Barajas, J. H. In Handbook of Thermoplastics;
Olabisi, O., Ed.; Marcel Dekker: New York, 1997; p 227
3. Windholz, M. The Merck Index: An Encyclopaedia of Chemicals,
Drugs and Biologicals; 10th ed.; Merck and Co., Rahway, NJ, 1983
4. Molak, V. Acrylamide: A Review of the Literature in NIOH and
NIOSH Basis for an Occupational Health Standard. US Department
of Health and Human Services 1991
5. Thomas, W.; Wang, D. W. In Encyclopaedia of Polymer Science
and Engineering; Mark, H. F., Bikales, N. M., Overberger, C. G.,
Menges, G., Kroschwitz, J. I., Eds.; John Wiley & Sons: New
York, 1985; Vol. 1, p 169.
Chem. Rev. 2002 102:3067
Web Links: acrylamide polyacrylamides
Related Background Brief:
FAST AXONAL TRANSPORT: A SITE OF ACRYLAMIDE NEUROTOXICITY? The
cellular and molecular site and mode of action of acrylamide
leading to neurotoxicity has been investigated for four decades,
without resolution. Although fast axonal transport compromise
has been the central theme for several hypotheses, the results
of many studies appear contradictory. The authors report that
their analysis of the literature suggests that differing
experimental designs and parameters of measurement are
responsible for these discrepancies. Further investigation has
demonstrated consistent inhibition of the quantity of
bi-directional fast transport following single acrylamide
exposures. Repeated compromise in fast anterograde transport
occurs with each exposure. Modification of neurofilaments,
microtubules, energy-generating metabolic enzymes and motor
proteins are evaluated by the authors as potential sites of
action causing the changes in fast transport. Supportive and
contradictory data to the hypothesis that deficient delivery of
fast-transported proteins to the axon causes, or contributes to,
neurotoxicity are critically summarized. A hypothesis of
acrylamide action is presented as a framework for future
investigations. D.W. Sickles DW et al: Neurotoxicology 2002
23:223.
Related Background Brief:
TOXIC NEUROFILAMENTOUS AXONOPATHIES AND FAST ANTEROGRADE AXONAL
TRANSPORT. I. THE EFFECTS OF SINGLE DOSES OF ACRYLAMIDE ON THE
RATE AND CAPACITY OF TRANSPORT. Acrylamide (ACR) produces a
neuropathy in the central and peripheral nervous systems
characterized by neurofilament-containing swellings in the
distal nerve and eventual dying-back degeneration of axons. The
author reports that the effects of a single exposure to ACR on
the rate and quantity of protein transported in the rat sciatic
nerve has been measured to determine whether fast axonal
transport is compromised by this toxicant. Using the segmental
analysis of radioactive label of proteins following 3H-leucine
injections into the dorsal root ganglion, ACR (50-100 mg/kg)
significantly reduced the rate of fast anterograde transport by
9.3 to 20.8% but, more importantly, reduced the quantity of
transported protein by 42.4 to 51.3%. The non-neurotoxic
analogue methylene bis-acrylamide did not significantly change
either parameter. The reductions in transport were not due to
general effects of the toxicant upon protein synthesis.
Therefore, fast anterograde transport was significantly affected
by a single exposure to ACR in the same magnitude as retrograde
transport. Discovery of these dramatic changes was due to
differences from previous studies in the time frame of study of
transport in relation to toxicant injection and to measurements
of the quantity of protein transported rather than only the
rate. These changes may be significant in terms of the
pathogenesis of distal nerve degeneration. D.W. Sickles:
Neurotoxicology 1989 10:91.
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