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ScienceWeek
SCIENCEWEEK
ScienceWeek - August 16, 2002 Vol. 6 Number 33
An Online Research Digest Published Weekly Since 1997
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Research is the process of going up alleys to see
if they are blind.
-- Marston Bates
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Section 1
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1. On Mineralization in Biological Systems
2. Complete Genome Sequence of the Yeast S. Pombe
3. On the History of Protein Structure Studies
4. Geophysics: On Mid-Mantle Deformation
5. On Asteroid Escape Rates
6. On the Interstellar Medium
7. Bone Density, Bone Strength, and Osteoporotic Fractures
8. On Toxic Proteins in Neurodegenerative Disease
9. An Update on AIDS in the US
10. On Mixed-Phase Structures
11. On Applications of Solid-Phase Polymer Spheres
12. On Structure Sensitivity of Catalytic Reactions
13. In Focus: History: On Drug Receptors
14. ScienceWeek Notices and Subscription Information
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Section 2
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1. ON MINERALIZATION IN BIOLOGICAL SYSTEMS
W.L. Murphy and D.J. Mooney (University of Michigan, US) discuss
mineralization, the authors making the following points:
1) Mineralization in biological systems is an elegant and
structurally complex process involving ionic, stereochemical,
and structural interactions at the biomacromolecule-mineral
interface.(1,2) A wide variety of organisms utilize diverse
schemes to grow biominerals with functions ranging from magnetic
sensing(3) (magnetite in magnetotactic bacteria) to structural
support(4) (dahllite in vertebrate skeletons). The paradigm
linking each biomineralization strategy is a supreme level of
control over the physical chemistry of mineral growth.
2) Mineralization during vertebrate bone growth is a classic
example in which hydrophobic collagen fibrils are organized into
parallel sheets with periodically staggered "hole zones". These
spaces are rich in phospho- and glycoproteins, creating a local
charge accumulation.(5) The anionic nature of the hole zone,
along with structural and stereochemical interactions, are
thought to lead to attraction of calcium-rich mineral nuclei and
initiation of mineral growth. A similar mechanism drives mollusk
shell development, with hydrophobic beta-chitin providing a
substrate for deposition of acidic, anionic proteins that drive
aragonite nucleation. In each case, an organic, hydrophobic
material acts as a framework for deposition of an anionic,
hydrophilic mineral nucleator that, in turn, drives mineral
nucleation. Although the understanding of complex biological
mineralization systems is incomplete and continues to grow, the
fundamental mechanisms outlined above can be mimicked in
synthetic systems to direct ex vivo biomineralization.
3) The highly controlled morphology, physical properties, and
nanostructure of biological minerals have led to the development
of biomimetic systems for controlled mineral formation ex vivo.
The development of ex vivo systems is motivated both by the
desire to more completely understand biomineralization processes
and by the potential utility of biominerals in industrial and
biomedical applications. Prevalent strategies involve pragmatic
presentation of polar functional groups that both increase local
ion accumulation via electrostatic effects(1) and decrease the
energy at the organic substrate-mineral nucleus interface.(1) In
each case, the basic, biomimetic premise is that functional
groups present in large quantities at the mineralization front
in biological systems are capable of inducing mineral nucleation
if presented in the appropriate fashion. Select model systems
have been extended to biomedical applications, such as
hydroxyapatite mineral growth on functionalized titanium and
bioactive, ion-exchange glasses. Carbonated hydroxyapatite is
the major mineral component in human bone extracellular matrix,
and bonelike mineral coatings appear to have pronounced effects
on proper bone tissue development. More specifically, a bonelike
mineral has been shown to be a prerequisite to bonding of
orthopedic implant materials to native bone tissue
(osteoconductivity), and may drive osteogenic differentiation of
adult human stem cells (osteoinductivity). Despite the potential
benefits of biominerals in regenerative medicine, few studies to
date have been aimed at mineral formation on degradable
biomaterials for use in orthopedic tissue regeneration.
References (abridged):
1. Mann, S.; Archibald, D. D.; Didymus, J. M.; et al. Science
1993, 261, 1286
2. Sarikaya, M. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 14183
3. Chasteen, N. D.; Harrison, P. M. J. Struct. Biol. 1999, 126,
182
4. Weiner, S.; Traub, W.; Wagner, H. D. J. Struct. Biol. 1999,
126, 241
5. Lee, S.; Veis, A. J. Peptide Protein Res. 1980, 16, 231
J. Am. Chem. Soc. 2002 124:1910
Web Links: bone formation mineralization in biological
systems
Also: See report #7 this issue.
Related Background:
IMPACT OF GENETICS ON BONE BIOLOGY
In general, the term "connective tissue" refers to tissue which
protects and supports the body and its organs, binds organs
together, stores energy reserves as fat, and provides immunity.
Connective tissue is the most abundant and widely distributed
tissue in the mammalian body, with forms ranging from the fluid
of blood to the solid substance of bone (osseous tissue). Like
other connective tissue, bone contains an abundant matrix
surrounding widely separated cells, the matrix approximately 25
percent water, 25 percent protein, and 50 percent mineral salts.
There are 4 types of cells in mammalian bone tissue:
a) Osteoprogenitor cells (stem cells): undifferentiated cells
capable of developing into other cell types.
b) Osteoblasts: the cells that form bone, secreting collagen and
other organic components needed in bone construction.
c) Osteocytes: mature bone cells derived from osteoblasts, and
which are the principal cells of bone tissue. Osteocytes
maintain the ongoing cellular activities of bone tissue, such as
the exchange of nutrients and wastes with the blood.
d) Osteoclasts: cells on the surface of bone that function in
bone resorption (destruction of matrix), which is important in
the development, growth, maintenance and repair of bone.
Gerard Karsenty (Baylor College of Medicine, US) presents a
review of the recent influences of the field of genetics on bone
biology, the author making the following points:
1) The author states that the entire field of bone biology is
dominated by the impact of bone degenerative diseases such as
*osteoporosis. Similar to research in most other organogenesis
processes, human and mouse genetic studies have been major
driving forces in redefining bone biology. Genetic studies have
opened new areas of research, elucidated at the molecular level
various known phenomena, and sometimes challenged untested
textbook assumptions. In general, genetic studies have
profoundly transformed the field of bone biology.
2) One peculiar characteristic of bone resides in its
physiology. Bone is the only organ that contains a cell type,
the osteoclast, whose only apparent function is to constantly
destroy the organ hosting it. This destruction, or "resorption"
of bone, occurring throughout life and in healthy individuals,
is counterbalanced by new bone formation in a process called
"bone remodeling". It is through bone remodeling that bone mass
is maintained at a constant level between the end of puberty and
gonadal failure, and bone remodeling is the process affected
during osteoporosis, a disease characterized at the cellular
level by a relative increase of bone resorption over bone
formation. In recent years, we have begun to understand at the
molecular level how bone resorption is controlled, but it is
striking how little we know about the molecular mechanisms
governing bone formation.
3) The aspect of bone biology that has made the most progress in
the last few years is the genetic control of osteoclast
differentiation and function. The osteoclast, the cell type
resorbing *mineralized bone matrix, is the last specific cell
type of the skeleton to appear during development, and the
systematic study of mouse mutants has led to the establishment
of a fairly detailed understanding of the *genetic cascade
controlling osteoclast differentiation and function. Some of
this progress has important implications not only for bone
resorption, but also for new hypotheses concerning the molecular
control of bone formation.
4) Bones and teeth are the only tissues that mineralize under
physiological conditions; mineralization or calcification in any
other tissue is pathologic. Thus, a question could be asked as
follows: Is bone mineralization an active function requiring
active expression of one or multiple genes, or rather is the
absence of calcification in every other tissue an active
function genetically controlled? It has long been proposed that
certain proteins in the bone matrix could serve a
crystal-nucleation function at the beginning of the
mineralization process. However, many of the genes encoding
these proteins have been experimentally deleted in mice without
any overt effects on bone mineralization, which indicates that
these proteins do not alone control bone mineralization in vivo.
Although the current lack of success in identifying activators
of bone mineralization does not mean they do not exist, it is
possible that bone mineralization is a passive phenomenon
involving the absence of inhibitors of mineralization in the
bone matrix, and there is some evidence to support this idea.
5) Bone is not made only of cells, it also contains an
extracellular matrix. This bone extracellular matrix contains
mostly *type I collagen, which accounts for 90 percent of the
protein content of the matrix, plus a variety of noncollagenous
proteins and *proteolytic enzymes. Mouse and human genetics have
shown that most of these proteins and proteolytic enzymes are
required for the integrity of bone tissue, although it is not
yet understood how this requirement is manifested at the
molecular level.
6) The author concludes: "In terms of the approaches used, the
history of bone biology can be divided into two parts.
Initially, bone biology, like most fields, was dominated by cell
biology; however, in the past 10 years it has been ruled by
mouse genetics. Mouse and human genetics are here to stay and
rightly so. However, no single approach, whether it is cell
biology, genetics, or biochemistry, will have all answers for
any field of biology. Thus, the main challenge in the short term
will be to understand at the biochemical level how many of the
new gene products that have been identified fulfill their
functions."
Genes & Development 1999 13:3037
Text Notes:
... ... *osteoporosis: Osteoporosis is a generalized progressive
diminution of bone density (bone mass per unit volume) that
causes skeletal weakness. The ratio of mineral to organic
elements is unchanged. The major clinical manifestations of
osteoporosis are bone fractures resulting from a reduction below
the fracture threshold of the amount of bone available for
mechanical support.
... ... *mineralized bone matrix: The inorganic part of bone
consists largely of calcium phosphate organized into small
crystals of hydroxyapatite 0.8 to 1.5 nanometers thick, 2.4
nanometers wide, 20 to 40 nanometers long. Other anions present
are carbonate, fluoride, hydroxide, and citrate. Most of the
body's magnesium, approximately 25 percent of its sodium, and a
smaller proportion of its potassium is found in bone.
... ... *genetic cascade: The "cascade" of sequential gene
expressions occurring during development.
... ... *type I collagen: The term "collagen" refers to a group
of fibrous proteins of very high tensile strength that form the
main component of connective tissue in animals. Collagen of
bones and skin is metabolically stable, in contrast with
collagen of organs such as the liver. The collagens are products
of a superfamily of closely related genes found in multicellular
animals, the products classified into types I to XIII in the
order in which they were purified and characterized. All contain
a typical triple helical domain formed from 3 independent
chains. Type 1 collagen is the most abundant collagen, forming
well-organized fibrils.
... ... *proteolytic enzymes: In general, "proteolysis" is the
enzyme-catalyzed degradation of protein by hydrolysis of one or
more peptide bonds.
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2. COMPLETE GENOME SEQUENCE OF THE YEAST S. POMBE.
In general, the term "yeast" refers to a group of single-celled
fungi, most of which are in the class Ascomycetes, and others in
the class Basidiomycetes. Yeasts are ubiquitous in soils and on
plant surfaces and are especially abundant in sugary mediums
such as flower nectar and fruits. There are hundreds of
varieties of ascomycetan yeasts. The types of yeast commonly
used in the production of bread, beer, and wine are selected
strains of Saccharomyces cerevisiae. The small cakes and packets
of yeast used in food- and beverage-processing contain billions
of individual yeast cells, each approximately 75 microns in
diameter. Most yeasts reproduce asexually by budding: a small
bump protrudes from a parent cell, enlarges, matures, and
detaches. A few types of yeasts reproduce by fission, the parent
cell dividing into two equal cells. Some yeasts are mild to
dangerous pathogens of humans and other animals (e.g., Candida
albicans, Histoplasma, Blastomyces).
In cells with chromosomes, the chromosomes are the physical
structures into which DNA is organized and on which genes are
carried. The "centromere" is a region of the chromosome to which
traction fibers are attached during replication, and
"centromeric DNA" is the DNA of that region.
V. Weod et al (Wellcome Trust Sanger Institute, UK) report
completion of a yeast genome sequence, the authors making the
following points:
1) The authors report the completion of the fully annotated
genome sequence of the simple eukaryote Schizosaccharomyces
pombe, a fission yeast. It becomes the sixth eukaryotic genome
to be sequenced, following Saccharomyces cerevisiae(1),
Caenorhabditis elegans(2), Drosophila melanogaster(3),
Arabidopsis thaliana(4) and Homo sapiens(5). The entire sequence
of the unique regions of the three yeast chromosomes is
complete, with gaps in the centromeric regions of about 40 kb,
and about 260 kb in the telomeric regions. The completion of
this sequence, the availability of sophisticated research
methodologies, and the expanding community working on S. pombe,
will accelerate the use of S. pombe for functional and
comparative studies of eukaryotic cell processes.
2) Schizosaccharomyces pombe is a single-celled free living
archiascomycete fungus sharing many features with cells of more
complicated eukaryotes. From gene sequence comparisons and
phylogenetic analyses, it has been suggested that fission yeast
diverged from budding yeast around 330–420 million years (Myr)
ago, and from Metazoa and plants around 1,000–1,200 Myr ago,
although a more recent estimate has put these times at 1,144 and
1,600 Myr, respectively. Some gene sequences are as equally
diverged between the two yeasts as they are from their human
homologues, probably reflecting a more rapid evolution within
fungal lineages than in the Metazoa. S. pombe was first
described in the 1890s and has been extensively studied since
the 1950s, resulting in the characterization of approximately
1,200 genes (http://www.genedb.org/pombe). The ease with which
it can be genetically manipulated is second only to S.
cerevisiae among eukaryotes and it has served as an excellent
model organism for the study of cell-cycle control, mitosis and
meiosis, DNA repair and recombination, and the checkpoint
controls important for genome stability.
3) In summary: The authors have sequenced and annotated the
genome of fission yeast (Schizosaccharomyces pombe), which
contains the smallest number of protein-coding genes yet
recorded for a eukaryote: 4,824. The centromeres are between 35
and 110 kilobases (kb) and contain related repeats including a
highly conserved 1.8-kb element. Regions upstream of genes are
longer than in budding yeast (Saccharomyces cerevisiae),
possibly reflecting more-extended control regions. Some 43% of
the genes contain introns, of which there are 4,730. Fifty genes
have significant similarity with human disease genes; half of
these are cancer related. The authors identify highly conserved
genes important for eukaryotic cell organization including those
required for the cytoskeleton, compartmentation, cell-cycle
control, proteolysis, protein phosphorylation and RNA splicing.
These genes may have originated with the appearance of
eukaryotic life. Few similarly conserved genes that are
important for multicellular organization were identified,
suggesting that the transition from prokaryotes to eukaryotes
required more new genes than did the transition from unicellular
to multicellular organization.
References (abridged):
1. Goffeau, A. et al. The yeast genome directory. Nature 387
(suppl.), 1-105 (1997)
2. The C. elegans Sequencing Consortium. Genome sequence of the
nematode C. elegans: a platform for investigating biology.
Science 282, 2012-2018 (1998)
3. Adams, M. D. et al. The genome sequence of Drosophila
melanogaster. Science 287, 2185-2195 (2000)
4. The Arabidopsis Genome Initiative. Analysis of the genome
sequence of the flowering plant Arabidopsis thaliana. Nature
408, 796-815 (2000)
5. Lander, E. S. et al. Initial sequencing and analysis of the
human genome. Nature 409, 860-921 (2001)
Nature 2002 415:871
Web Links: yeast genome
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3. ON THE HISTORY OF PROTEIN STRUCTURE STUDIES
H.M. Berman et al (Rutgers University, US) discuss the history
of protein structure studies, the authors making the following
points:
1) The pioneers of structural biology toiled for years to
determine the first protein structures. In 1957, after 22 years
of work, John Kendrew announced the determination of the
three-dimensional structure of myoglobin. For the first time,
the atomic structure of a protein was revealed, providing a
close look at how this protein selectively stores oxygen. As
with all of science, this landmark result built on earlier
discoveries.
2) In 1913, Max von Laue and the father-son team of William
Henry Bragg and William Lawrence Bragg discovered that crystals
diffract x rays and that the orderly pattern of this diffraction
could be used to deduce the location of every atom in a crystal.
Early experiments in x-ray diffraction explored the structure of
inorganic salts and small organic molecules. As the size of the
molecules whose structures were deciphered grew, it became
apparent that even the large molecules in cells could be
studied. Pioneers such as Dorothy Hodgkin (1910-1994), John D.
Bernal (1901-1971), Max Perutz (1914-2002) and John Kendrew
(1917-1997) set to work jumping many experimental hurdles. Their
work opened the atomic world of large molecules to study, and
Kendrew, the Braggs, von Laue, Hodgkin and Perutz were all
recognized for their contributions with Nobel Prizes.
3) In the decade after 1957, a dozen or so structures were
determined. Each new structure provided a wealth of information
about a previously invisible world, and an enthusiastic
scientific community greeted each publication with excitement.
In 1967, when ribonuclease, the first structure solved by an
American group, was announced at a packed meeting of the
American Crystallographic Association, crystallographers skipped
their dinner rather than miss the groundbreaking presentations
by Gopinath Kartha and Hal Wyckoff. These first structures
revealed many of the basic principles of protein structure and
function. Protein architecture was shown to involve a complex
combination of highly ordered local structures -- alpha helices
and beta sheets glued together by hydrogen bonds, with a
geometry perfect enough to satisfy any engineer -- bent and
folded into an intricate globular structure. The basic
mechanisms of enzyme catalysis were revealed, showing the
perfect placement of key chemical groups and the use of forcible
distortion to stimulate reactions.
4) Protein crystallography became an established part of
research in molecular biology in the summer of 1971 at a Cold
Spring Harbor symposium entitled "Structure and Function of
Proteins at the Three-Dimensional Level." The topics covered
diverse aspects of biology, including structure-function studies
of proteases, glycolytic enzymes, dehydrogenases, muscle
proteins, hemoglobins, immunoglobulins and even viruses. The
discussions within the meeting room, on the lawn and on the
beach were exciting, intense and forward-looking. There was a
sense that a new era in biology had arrived; Sir David Phillips,
one of the pioneers in protein crystallography, described
structural biology as "coming of age."(1-5)
References (abridged):
1. Berman, H. M., T. N. Bhat, P. E. Bourne, Z. Feng, G.
Gilliland, H. Weissig and J. Westbrook. 2000. The Protein Data
Bank and the challenge of structural genomics. Nature Structural
Biology 7:957-959.
2. Berman, H. M., J. Westbrook, Z. Feng, G. Gilliland, T. N.
Bhat, H. Weissig, I. N. Shindyalov and P. E. Bourne. 2000. The
Protein Data Bank. Nucleic Acids Research 28:235-242.
3. Goodsell, D. S. 1996. Our Molecular Nature: The Body's
Motors, Machines and Messages. Springer-Verlag, New York.
4. Richardson, J. S. 1981. The anatomy and taxonomy of protein
structure. Advances in Protein Chemistry 34:167-339.
5. Steven, R. C., S. Yokoyama and I. A. Wilson. 2001. Global
efforts in structural genomics. Science 294:89-92.
American Scientist 2002 90:350
Web Links: protein structure
Related Background:
ON RECOGNITION OF NATIVE-LIKE PROTEIN STRUCTURES
P. Koehl and M. Levitt (Stanford University, US) discuss protein
structures, the authors making the following points:
1) Knowing the structure of a protein is most useful for
predicting, analyzing, and modifying its function. As it is not
feasible to determine experimentally the structure of every
protein, structure prediction has become central to the field of
structural biology and more specifically to structural genomics.
On the basis of their study of ribonuclease A (1), Anfinsen and
coworkers provided the first clues that all of the information
required for folding a protein is to be found in its sequence.
Not long after this discovery, people took on the challenge of
discovering the rules that allow the protein to fold. This
problem is far from simple and has not yet been solved (2).
Three major routes are usually considered paths to the solution:
homology modeling, threading, and ab initio prediction. To study
a protein with unknown conformation C, the first two methods
follow the same scheme: a similar protein whose
three-dimensional structure is known is identified, and this
protein is used as a scaffold to generate a model for C. When
the sequences of the two proteins are homologous (i.e., when
they have an obvious common ancestry), sequence similarity is
assumed to infer structural similarity (3, 4), and the method is
then referred to as "homology modeling." When the two sequences
show no obvious evolutionary relationship, the method is
referred to as "fold recognition," which works by assessing the
compatibility of the target sequence with each member of a
library of known structures (5).
2) Ab initio structure prediction methods try to build a model
for the target protein structure without using a specific
template protein. Most of these methods proceed by first
generating a large collection of possible conformations
(decoys), which are then searched with a scoring function to
identify native or, more realistically, near-native
conformations. This second step resembles the fold recognition
problem, with the major difference that the library of folds
considered includes computer-generated models instead of
naturally occurring protein folds.
3) In summary: The goal of the inverse protein folding problem
is to identify amino acid sequences that stabilize a given
target protein conformation. Methods that attempt to solve this
problem have proven useful for protein sequence design. The
authors report a demonstration that the same methods can provide
valuable information for protein fold recognition and for ab
initio protein structure prediction. The authors present a
measure of the compatibility of a test sequence with a target
model structure, based on computational protein design. The
model structure is used as input to design a family of low free
energy sequences, and these sequences are compared with the test
sequence by using a metric in sequence space based on
nearest-neighbor connectivity. The authors report that this
measure is able to recognize the native fold of a myoglobin
sequence among different globin folds. It is also powerful
enough to recognize near-native protein structures among
nonnative models.
References (abridged):
1. Anfinsen, C. (1973) Science 181, 223-230
2. Murzin, A. (2001) Nat. Struct. Biol. 8, 110-112
3. Chothia, C. & Lesk, A. (1986) EMBO J. 5, 823-826
4. Sander, C. & Schneider, R. (1991) Proteins Struct. Funct.
Genet. 9, 6-68
5. Jones, D. T. , Taylor, W. R. & Thornton, J. M. (1992) Nature
(London) 358, 86-89
Proc. Nat. Acad. Sci. 2002 99:691
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4. GEOPHYSICS: ON MID-MANTLE DEFORMATION
J. Wookey et al (University of Leeds, UK) discuss mantle
deformation and make the following points:
1) With time, convective processes in the Earth's mantle will
tend to align crystals, grains and inclusions. This mantle
fabric is detectable seismologically, as it produces an
anisotropy in material properties — in particular, a directional
dependence in seismic-wave velocity. This alignment is enhanced
at the boundaries of the mantle where there are rapid changes in
the direction and magnitude of mantle flow(1), and therefore
most observations of anisotropy are confined to the uppermost
mantle or lithosphere(2,3) and the lowermost-mantle analogue of
the lithosphere, the D" region(4).
2) Seismic anisotropy in the upper 200 km of the Earth's mantle
is primarily attributed to the preferred alignment of olivine
crystals which have deformed by dislocation creep(5). The origin
of anisotropy at greater depths is more speculative, but there
is evidence for anisotropy in the transition zone in some
regions, but not in others. In an effort to reconcile
discrepancies in global velocity models derived from body-wave
travel times and normal-mode observations, Montagner and Kennett
(1996) allowed both anisotropy and attenuation in a joint
inversion of these data sets. Their final model shows
significant levels of anisotropy in the uppermost and lowermost
mantle, but also in the vicinity of the 660-km discontinuity.
This motivated an investigation of mid-mantle anisotropy on a
regional scale.
3) The authors present evidence from shear-wave splitting
measurements for mid-mantle anisotropy in the vicinity of the
660-km discontinuity, the boundary between the upper and lower
mantle. Deep-focus earthquakes in the Tonga–Kermadec and New
Hebrides subduction zones recorded at Australian seismograph
stations record some of the largest values of shear-wave
splitting hitherto reported. The results suggest that, at least
locally, there may exist a mid-mantle boundary layer, which
could indicate the impediment of flow between the upper and
lower mantle in this region.
References (abridged):
1. Montagner, J.-P. Where can seismic anisotropy be detected in
the Earth's mantle? In boundary layers .... Pure Appl. Geophys.
151, 223-256 (1998)
2. Silver, P. G. Seismic anisotropy beneath the continents:
Probing the depths of geology. Annu. Rev. Earth Planet Sci. 24,
385-432 (1996)
3. Savage, M. K. Seismic anisotropy and mantle deformation: What
have we learned from shear wave splitting? Rev. Geophys. 37,
65-106 (1999)
4. Kendall, J.-M. & Silver, P. G. in The Core-Mantle Boundary
Region (eds Gurnis, M., Wysession, M., Knittle, E. & Buffett,
B.) 97-118 (Geodynamics series 28, American Geophysical Union,
Washington DC, 1998)
5. Karato, S. & Wu, P. Rheology of the upper mantle: A
synthesis. Science 260, 771-778 (1993)
Nature 2002 415:777
Web Links: structure of the Earth Earth mantle deformation
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5. ON ASTEROID ESCAPE RATES
C. Jaffe et al (California Institute of Technology, US) discuss
asteroid escape rates, the authors making the following points:
1) While large-scale chaos exists in the Solar System, it is
sufficiently weak that the motions of most of the planets appear
quite regular, at least on relatively short time scales [1]. In
contrast, smaller bodies such as asteroids and comets, through
their interactions with the planets and the Sun, can exhibit
strongly chaotic motion. Nevertheless, the ability to predict
the behavior of populations of these small but numerous objects
is essential for understanding such problems as the evolution of
both short- and long-range comets originating in the Kuiper Belt
and the Oort Cloud, respectively [2], the dynamics of near-Earth
asteroids [4,5], zodiacal and circumplanetary dust dynamics [3],
and the gravitationally assisted transport of spacecraft. The
discovery of possible traces of a living organism in a Martian
meteorite found in Antarctica [Science 1996 243:924] has
stimulated investigations into the feasibility of viable
microbes transporting through space and illustrates the
fundamental importance of understanding mass transport in the
Solar System to theories of the origin of life.
2) The authors report a study of the problem of computing
average rates of asteroid escape from Mars, the study undertaken
because of its bearing on understanding the feasibility of
transport of viable microorganisms between the two planets.
3) On its face it might seem that once individual orbits are
known the problem is solved. However, deeper insights can be
obtained by computing rates because these allow models of the
evolution of populations of particles to be constructed. In
principle, the computation of rates of mass transport can be
accomplished by large numerical simulations in which the orbits
of vast numbers of test particles are propagated in time
including as many interactions as desirable [2]. However, such
calculations are computationally demanding and it may be
difficult to extract from them information about key dynamical
mechanisms. They do have the considerable advantage, however,
that a variety of nongravitational effects can easily be
included, even if these destroy the Hamiltonian nature of the
problem.
In summary: Transition states in phase space are identified and
shown to regulate the rate of escape of asteroids temporarily
captured in circumplanetary orbits. The transition states,
similar to those occurring in chemical reaction dynamics, are
then used to develop a statistical semianalytical theory for the
rate of escape of asteroids temporarily captured by Mars. Theory
and numerical simulations are found to agree to better than 1%.
These calculations suggest that further development of
transition state theory in celestial mechanics, as an
alternative to large-scale numerical simulations, will be a
fruitful approach to mass transport calculations.
References (abridged):
1. J. Laskar, Nature (London) 338, 237 (1989).
2. P. Weigert and S. Tremaine, Icarus 137, 84 (1998).
3. P. Michel, F. Migliorini, A. Morbidelli, and V. Zappala,
Icarus 145, 332 (2000).
4. P. Farinella et al., Nature (London) 371, 314 (1994).
5. M. Horanyi, Annu. Rev. Astron. Astrophys. 34, 383 (1996)
Phys. Rev. Lett. 2002 89:011101
Web Links: asteroids asteroid escape
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6. ON THE INTERSTELLAR MEDIUM
Ralf I. Kaiser (University of York, UK) discusses the
interstellar medium, the author making the following points:
1) The physical and chemical processes leading to the formation
of molecules in the interstellar medium (ISM) -- the vast voids
between the stars -- fascinated scientists since the first
detection of CH, CH+, and CN radicals in extraterrestrial
environments 60 years ago. Although more than 50 years have
passed and 121 species from molecular hydrogen to polyatomics
such as the sugar glycolaldehyde, benzene, cyanopentaacetylene,
and possibly the amino acid glycine have been identified so far,
the enigma of how these molecules are actually formed under the
harsh conditions in the interstellar medium is still under
debate.(1)
2) The ISM contains approximately 10% of the mass of our Galaxy
and consists of gas (99%) and submicrometer-sized grain
particles (1%) with averaged number densities of 1 H atom
cm^(-3) and 10^(-11) grains cm^(-3), respectively.(2-5) These
data translate to pressures of approximately 10^(-18) mbar at 10
K, which is beyond any ultrahigh vacuum achieved in terrestrial
laboratories so far. The chemical composition of the
interstellar medium is dominated by neutral hydrogen (93.38%)
and helium (6.49%), whereas biogenic elements oxygen, carbon,
and nitrogen contribute 0.11% (O:C:N 7:3:1). The third-row
elements neon, silicon, magnesium, and sulfur are less copious
(0.002%) and have relative abundances of 8:3:3:2; all remaining
elements furnish only 0.02%.
3) This elementary classification is well-reflected in the
molecular composition of the interstellar medium. Molecules,
radicals, and ions are ubiquitous in extraterrestrial
environments and have been detected in extraordinary diversity
ranging from small molecules such as hydrogen to
astrobiologically important species such as the simplest sugar
glycolaldehyde and possibly the amino acid glycine. Many of the
species are thermally unstable and extremely reactive in
terrestrial laboratories. The majority of these molecules were
detected by radio telescopes observing their rotational
transitions in emission; to a minor extent, infrared, visible,
and ultraviolet astronomy fostered their identification.
Diatomic molecules with second- and third-row elements are
particularly prevalent; in particular, carbon and silicon
bearing species. CP and PN are the only phosphorus-containing
molecules identified so far; NO, NS, and SO represent the sole
extraterrestrial radicals carrying atoms of the fifth and sixth
period.
References (abridged):
1. Chemistry and Physics of Molecules and Grains in Space.
Faraday Discuss.1998, 109.
2. Hollenbach; D. J.; Thronson, H. A. Interstellar Processes;
Reidel: Dordrecht, 1987.
3. Tielens, A. G. G. M.; Allamandolla, L. J. In Interstellar
Processes; Hollenbach, D. J., Thronson, H. A., Eds.; Reidel:
Dordrecht, 1987; pp 397-469.
4. Carbon in the Galaxy: Studies from Earth and Space;
NASA-SP-3061, NASA: Washington, D.C.,1990.
5. Interstellar Dust; NASA-SP-3036, NASA: Washington, D.C., 1989.
Chem. Rev. 2002 102:1309
Web Links: interstellar medium
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7. BONE DENSITY, BONE STRENGTH, AND OSTEOPOROTIC FRACTURES
The term "osteocyte" (bone cell) refers to a cell of osseous
tissue that occupies a lacuna and has cytoplasmic processes that
extend into canaliculi and make contact by means of gap
junctions with the processes of other osteocytes.
The term "osteoblast" refers to a bone-forming cell that forms
an osseous matrix in which it becomes enclosed as an osteocyte.
The term "osteoclast" refers to a large multinucleated cell,
possibly of monocytic origin, with abundant acidophilic
cytoplasm, functioning in the absorption and removal of osseous
tissue. "Monocytes" are relatively large mononuclear leukocytes
(16–22 microns in diameter), that normally constitutes 3–7% of
the leukocytes of the circulating blood, and are normally found
in lymph nodes, spleen, bone marrow, and loose connective tissue.
The term "osteoporosis" refers to a generalized, progressive
diminution of bone density (bone mass per unit volume), causing
skeletal weakness, although the ratio of mineral to organic
elements is unchanged. In normal bone, bone formation and bone
resorption are closely coupled. In osteoporosis, the net rate of
bone resorption exceeds the rate of bone formation, resulting in
a decrease in bone mass without a defect in bone mineralization.
In women, osteoclast activity is increased because of decreased
estrogen; as men and women age > 60 yr, osteoblast activity
drops off. Men with prematurely decreased testosterone may have
increased osteoclast activity. These changes result in further
net loss of bone. The amount of bone available for mechanical
support of the skeleton eventually falls below the fracture
threshold, and the patient may sustain a fracture with little or
no trauma.
G.H. Gunaratne et al (University of Houston, US) discuss bone
strength, the authors making the following points:
1) Osteoporosis is a multifaceted metabolic disease that reduces
bone strength and leads to a significant number of fractures
occurring in older adults [1,2]. Unfortunately, therapeutic
agents available for the prevention and treatment of
osteoporosis often induce adverse effects in patients [3]. Thus,
noninvasive diagnostic tools to determine the need for
therapeutic intervention are essential for ef fective management
of osteoporosis. Simple models can form a useful complement to
traditional studies of osteoporosis. Large bones such as thigh
bones and vertebrae consist of an outer cylindrical shaft
(cortex) and an inner porous region (trabecular architecture)
[2]. The cortex is made of compact bone and has a thickness of
several millimeters. The structure of the trabecular
architecture (TA) is that of a disordered cubic network of
"trabeculae" whose axial and cross sectional dimensions are of
the order of 1 mm and 0.1 mm, respectively [2].
2) Routine activities (e.g., climbing stairs) inflict
micro-damage on bone. Material in the neighborhood of these
fractures is resorbed by a class of cells known as
"osteoclasts." Their presence attracts a second group of cells,
"osteoblasts," which help regenerate lost bone [2]. This
sequence of events, referred to as "bone remodeling", reduces
the accumulation of microdamage shallower than about 0.1 mm
[3,4]. The full restoration of bone strength typically takes a
period of 2-3 months. In the cortex, deeper fractures, created
during occasional trauma, are not repaired through remodeling.
The resulting microfracture accumulation leads to lower bone
quality and fracture toughness [4,5], reducing the load bearing
capacity of the cortex with aging. Since the thickness of
trabecalae is approximately 0.1 mm, fractures that do not sever
them can be remodeled. Clinical studies also indicate that
perforated trabeculae are seldom regenerated and that cross
sections of those surviving change little. Thus, even though the
connectivity of the TA reduces with aging, the surviving
trabeculae can (mostly) be expected to retain their quality.
3) In summary: Inner porous regions play a critical role in the
load bearing capability of large bones. The authors demonstrate
that an extension of disordered elastic networks exhibits
analogs of several known mechanical features of bone. The
"stress backbones" and histograms of stress distributions for
healthy and weak networks are shown to be qualitatively
different. A model relating bone density and bone strength is
presented.
References (abridged):
1. D. Marshall, 0. Johnell, and H. Wedel, Br. Med. J. 312,1254
(1996); L.J. Melton et al., J. Bone Miner. Res. 7, 1005 (1992).
2. Y. C. Fung, Biomechanics: Mechanical Properties of Living
Tissue (Springer-Veriag, New York, 1993).
3. R.S. Weinstein, J. Bone Miner. Res. 15, 621 (2000); S.J.
Wimalawansa, J. Clin. Dens. 3, 1 (2000).
4. T. L. Norman, Y. N. Yeni, C. U. Brown, and Z. Wang, Bone
(N.Y.) 24, 303 (1998).
5. J. Finberg and M. Marder, Phys. Rep. 313, 1 (1999).
Phys. Rev. Lett. 2002 88:068101
Web Links: osteoporosis
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8. ON TOXIC PROTEINS IN NEURODEGENERATIVE DISEASE
J.P. Taylor et al (National Institutes of Health, US) discuss
toxic proteins, the authors making the following points:
1) Neurodegenerative disorders as diverse as Alzheimer's
disease, Parkinson's disease, prion diseases, Huntington's
disease, frontotemporal dementia, and motor neuron disease all
share a conspicuous common feature: aggregation and deposition
of abnormal protein. Expression of mutant proteins in transgenic
animal models recapitulates features of these diseases (1).
Neurons are particularly vulnerable to the toxic effects of
mutant or misfolded protein. The common characteristics of these
neurodegenerative disorders suggest parallel approaches to
treatment based on an understanding of the normal cellular
mechanisms for disposing of unwanted and potentially noxious
proteins.
2) Correct folding requires proteins to assume one particular
structure from a constellation of possible but incorrect
conformations. The failure of polypeptides to adopt their proper
structure is a major threat to cell function and viability.
Consequently, elaborate systems have evolved to protect cells
from the deleterious effects of misfolded proteins. The first
line of defense against misfolded protein are the molecular
chaperones, which associate with nascent polypeptides as they
emerge from the ribosome, promoting correct folding and
preventing harmful interactions. A large fraction of newly
translated proteins nonetheless fail to fold correctly,
generating a substantial burden of defective polypeptide (2).
These proteins are degraded primarily by the
ubiquitin-proteasome system, a multicomponent system that
identifies and degrades unwanted proteins (3). In addition to
its role in clearing defective proteins, this system carries out
selective degradation of many short-lived normal proteins,
thereby contributing to the regulation of numerous cellular
processes. Failure to detect and eliminate misfolded proteins
may contribute to the pathogenesis of neurodegenerative disease.
Conversely, it has been suggested that the ubiquitin=proteasome
system itself may be a target for toxic proteins (4).
3) Under some circumstances, misfolded proteins may evade the
quality control systems designed to promote correct folding and
eliminate faulty proteins. When they accumulate in sufficient
quantity, misfolded proteins are prone to aggregation. Insoluble
aggregates of disease-related proteins may be deposited in
microscopically visible inclusions or plaques, the
characteristics of which are often disease specific. It has been
widely assumed that the formation of intracellular inclusions is
a passive process driven by mass-action chemistry, with
self-assembly of misfolded monomers into a single growing
aggregate. However, this assumption has been challenged by
evidence that some intracellular inclusions are formed as part
of a physiological response to excess misfolded protein.
References (abridged):
1. A. Aguzzi and A. J. Raeber, Brain Pathol. 8, 695 (1998)
2. U. Schubert, et al., Nature 404, 770 (2000)
3. A. Hershko and A. Ciechanover, Cell 79, 13 (1997)
4. N. F. Bence, R. M. Sampat, R. R. Kopito, Science 292, 1552
(2001)
5. R. R. Kopito, Trends Cell Biol. 10, 524 (2000)
Science 2002 296:1991
Web Links: neurodegenerative diseases
Related Background:
ON PROTEIN MISFOLDING DISEASES
M. Bucciantini et al (University of Firenze, IT) discuss protein
misfolding diseases and make the following points:
1) An increasing body of evidence suggests that amyloid
formation is the fundamental cause of protein deposition
diseases(1, 2). The nature of the pathogenic species and the
mechanism by which the aggregation process results in cell
damage are, however, the subject of intense debate(3-5). In
systemic non-neurological diseases the accumulation of large
quantities (sometimes kilograms) of aggregated species within a
variety of organs and tissues may itself be the major cause of
clinical symptoms. In other cases, particularly the degenerative
neurological diseases, it appears likely that impairment of
cellular function is directly linked to the interaction of
protein aggregates with cellular components.
2) One specific indicator of the significance of aggregate
formation in pathological conditions is the evidence for a high
variability in the age of disease onset, an observation that has
recently been linked to the evidence that aggregates form by
nucleation. Further clues to the molecular basis of amyloid
diseases and the biological significance of protein aggregation
have been provided by recent observations that a range of
proteins not associated with amyloid diseases are able to
aggregate in vitro into fibrils indistinguishable from those
found in pathologic conditions. This finding has led to the
proposal that aggregation can be viewed as a general property of
polypeptide chains rather than one restricted to a small number
of sequences.(2)
3) The authors report they have examined the effects on cell
viability of aggregated species produced in vitro from two
proteins not associated with amyloid diseases. The authors
demonstrate that species formed early in the aggregation of
these non-disease-associated proteins can be inherently highly
cytotoxic. The authors suggest this finding provides added
evidence that avoidance of protein aggregation is crucial for
the preservation of biological function and suggests common
features in the origins of this family of protein deposition
diseases.
4) The authors suggest that the present findings, that early
aggregates formed by a wider range of proteins than those known
to be associated with neurological diseases can be cytotoxic,
provide new opportunities to define the nature of amyloid
diseases and the mechanism of amyloid toxicity at the molecular
level. They also raise the possibility that trace amounts of
aggregates of a variety of proteins might occur spontaneously,
particularly during ageing, and that such aggregates could
account for subtle impairments of cellular function in the
absence of an evident amyloid phenotype.
References (abridged):
1. Kelly, J. W. The alternative conformations of amyloidogenic
proteins and their multi-step assembly pathways. Curr. Opin.
Struct. Biol. 8, 101-106 (1998).
2. Dobson, C. M. The structural basis of protein folding and its
links with human disease. Phil. Trans. R. Soc. Lond. B 356,
133-145 (2001).
3. Lambert, M. P. et al. Diffusible, nonfibrillar ligands
derived from A-42 are potent central nervous system neurotoxins.
Proc. Natl Acad. Sci. USA 95, 6448-6453 (1998).
4. Hartley, D. M. et al. Protofibrillar intermediates of amyloid
beta-protein induce acute electrophysiological changes and
progressive neurotoxicity in cortical neurons. J. Neurosci. 19,
8876-8884 (1999).
5. Pillot, T. et al. The nonfibrillar amyloid -peptide induces
apoptotic neuronal cell death: involvement of its C-terminal
fusogenic domain. J. Neurochem. 73, 1626-1634 (1999).
Nature 2002 416:507
Web Links: protein misfolding
Related Background:
POLYGLUTAMINE SEQUENCES AND NEURODEGENERATIVE DISEASES
Gillian P. Bates (King's College, UK) discusses repeat sequences
and neurodegenerative diseases, the author making the following
points:
1) A potentially deadly repetitive sequence of nucleotides,
CAGCAGCAG... (cytosine-adenine-guanine...), lies at the start of
the huntingtin gene associated with Huntington's disease. The
triplet CAG codes for the amino acid glutamine, and the
repetitive sequence therefore codes for a stretch of
polyglutamine at one end of the huntingtin protein. People with
more than 40 glutamines in the sequence will develop
Huntington's disease, while those with fewer than 38 glutamines
in the sequence will be unaffected.
2) The elongated polyglutamine tract is associated with the
progressive degeneration and death of neurons characteristic of
Huntington's disease, and new work by Steffan et al (2001)
demonstrates that the expanded tract interferes with the
apparatus for switching on and regulating genes.
3) There are currently 9 neurodegenerative diseases apparently
caused by the expansion of a polyglutamine tract in one protein
or another, and all of these disorders are associated with the
formation in nerve cells of insoluble aggregates containing the
affected protein. However, stretches of polyglutamine are not
always harmful: such polyglutamine sequences are also occur
normally in many of the proteins that constitute transcription
factor complexes that regulate gene expression. For example, an
acetyltransferase enzyme known as CBP contains a tract of 18
glutamines. Acetyltransferases activate transcription by adding
acetyl groups to histones, the proteins that help to package DNA
into a compact form.
Nature 2001 413:691,739
Related Background:
MEDICAL BIOLOGY: ON NEURODEGENERATIVE DISEASES AND PRIONS
Prions are a class of poorly understood proteins implicated in a
number of exotic human neurological diseases and in some common
animal diseases such as sheep scrapie and bovine spongiform
encephalopathy in cattle ("mad cow disease"). Spongiform
encephalopathies are a type of brain disease found in humans and
animals and are characterized by macroscopic vacancies produced
by the disease process (the brain has a sponge-like appearance).
What is remarkable about prions is that they behave as
infectious agents, but they are 100 times smaller than viruses
and their mechanism of replication is unclear. One human disease
in which prions have been strongly implicated is
*Creutzfeldt-Jakob disease (CJD), which appears to have a
genetic basis in about 15% of the cases. All the prion diseases
are apparently associated with the accumulation in the brain of
an abnormal *protease-resistant isoform of the prion protein. In
other words, an abnormal variant of the normal prion protein is
somehow copied or produced by the disease process, which can be
initiated by introducing infectious prion into the system.
The term "amyloid" ("starch-like") refers to a variety of
polypeptide molecules defined by their properties, particularly
by their tendency to arrange in a twisted *beta-pleated
fibrillar structure. Amyloid is in general a proteinaceous
material, deposits of which have been classically noted to occur
in the brains of *Alzheimer's disease and older *Down syndrome
patients, and to a much lesser degree, in association with
normal aging. Amyloid material consists primarily of a highly
aggregated 42-amino acid polypeptide called "beta-amyloid".
In general, a "somatic mutation" is a mutation occurring in
non-germ cells, which means the mutation is not transmitted to
the next generation. In contrast, a "germ-line mutation" is a
mutation occurring in germ cells, and is thus transmitted to the
next generation.
In this context, the term "sporadic" means non-familial.
In 1997 Stanley B. Prusiner was awarded the Nobel Prize in
Physiology or Medicine for his discovery of prions, an entirely
new genre of disease-causing agents.
Stanley B. Prusiner (University of California San Francisco, US)
presents a review of current research on the role of prions in
neurodegenerative diseases, the author making the following
points:
1) The author points out that Alzheimer's disease is the most
common neurodegenerative disorder, with approximately 4 million
people in the US having this disease. In the US at present,
approximately 1 million people have *Parkinson's disease. Much
less common are *frontotemporal dementia (40,000 people),
*Huntington's disease (30,000 people), *amyotrophic lateral
sclerosis (20,000 people), and *spinocerebellar ataxia (12,000
people), and prion diseases (400 people). Among persons who are
60 years of age, the prevalence of Alzheimer's disease is
approximately 1 in 10,000, but among those who are 85 years of
age, the prevalence is greater than 1 in 3. These data suggest
that by 2025, there will be more than 10 million cases of
Alzheimer's disease in the US, and by 2050, the number will
approach 20 million. The current annual cost associated with
Alzheimer's disease in the US is estimated at $200 billion. Age
is also the most important risk factor for Parkinson's disease,
with at least 50 percent of persons who are 85 years of age
having at least one symptom or sign of parkinsonism.
2) The author points out that nearly all neurodegenerative
disorders involve abnormal processing of neuronal proteins. The
aberrant mechanism can involve a misfolding of proteins, altered
*post-translational modification of newly synthesized proteins,
abnormal *proteolytic cleavage, anomalous *gene splicing,
improper gene expression, or diminished clearance of degraded
protein. Misprocessed proteins often accumulate because the
cellular mechanisms for removing them are ineffective, and the
particular protein that is improperly processed determines the
malfunction of distinct sets of neurons and thus the clinical
manifestation of the disease.
3) The author points out that prions are infectious proteins. In
mammals, prions replicate by recruiting normal cellular prion
protein and stimulating its conversion to the disease-causing
prion isoform ("scrapie prion"; Prp[supSC]). A major feature
that distinguishes prions from viruses is that scrapie prion can
be encoded by a chromosomal gene resulting from a mutation of
the normal prion gene. Limited proteolysis of scrapie prion
produces a smaller and protease-resistant molecule of
approximately 142 amino acids which polymerizes into amyloid.
4) The author points out that the polypeptide chains of normal
prion and scrapie prion are identical in composition but differ
in their 3-dimensional folded structures. Normal prion is rich
in spiral-like formations of amino acids (alpha-helices) and has
little flattened strands (beta-sheets) of amino acids, whereas
scrapie prion is less rich in alpha-helices and has much more
beta-sheet domains. There is evidence that normal prion has 3
alpha-helices and 2 short beta-strands; in contrast, a plausible
model suggests that scrapie prion may have only 2 alpha-helices
and more beta-strands. This structural transition from
alpha-helices to beta-sheet in prion protein is apparently the
fundamental event underlying prion disease.
5) The author points out that four new concepts have emerged
from studies of prions:
... ... a) Prions are the only known example of infectious
pathogens that are devoid of nucleic acid. All other infectious
agents have genomes composed of either RNA or DNA that direct
the synthesis of their progeny.
... ... b) Prion diseases may be manifested as infectious,
genetic, or sporadic disorders. No other group of illnesses with
a single cause has such a wide spectrum of clinical
manifestations.
... ... c) Prion diseases result from the accumulation of
scrapie prion, which has a substantially different molecular
conformation from that of its precursor, normal prion.
... ... d) Scrapie prion can have a variety of conformations,
each of which seems to be associated with a specific disease.
How a particular conformation of scrapie prion is imparted to
normal prion during replication in order to produce a nascent
scrapie prion with that conformation is unknown. The factors
that determine the site in the central nervous system where a
particular scrapie prion is deposited are also not known.
6) The author tabulates the known pathogenic features of known
prion diseases as follows:
... ... a) *Kuru: Human hosts, "Fore" people in New Guinea.
Infection occurs via ritualistic cannibalism.
... ... b) Creutzfeldt-Jakob disease:
... ... ... Via medical procedures (iatrogenic): Human hosts.
Infection from prion-contaminated human *growth hormone, *dura
mater grafts, etc.
... ... ... *New variant: Human hosts. Possible infection from
bovine prions.
... ... ... Familial: Human hosts. Results from germ-line
mutations in the prion gene.
... ... ... Sporadic: Human hosts. Results from somatic mutation
or spontaneous conversion of normal prion into scrapie prion.
.... ... c) *Gerstmann-Straeussler-Scheinker disease: Human
hosts. Results from germ-line mutations in the prion gene.
... ... d) *Fatal familial insomnia: Human hosts. Results from
germ-line mutations in the prion gene.
... ... e) *Scrapie: Sheep hosts. Results from infection in
genetically susceptible sheep.
... ... f) Bovine spongiform encephalopathy: Cattle hosts.
Results from infection with prion-contaminated meat and bone
meal.
... ... g) Transmissible mink encephalopathy: Mink hosts.
Results from infection with prion from sheep or cattle.
... ... h) Chronic wasting disease: Mule, deer, elk hosts.
Mechanism of pathogenesis unknown.
... ... i) Feline spongiform encephalopathy: Cat hosts. Results
from infection with prion-contaminated beef.
... ... j) Exotic *ungulate encephalopathy: Greater kudu, nyala,
oryx hosts. Results from infection with prion-contaminated meat
and bone meal.
7) Concerning the general paradigm that virtually all
neurodegenerative disorders involve abnormal processing of
neuronal proteins, the author states: "It is tempting to
speculate that abnormal processing of neuronal proteins also
occurs in other diseases of the central nervous system, such as
schizophrenia, bipolar disorders, autism, and narcolepsy. Most
cases of these diseases are sporadic, but a substantial minority
appear to be familial."
8) The author concludes: "Over the past two decades, remarkable
progress has been made in elucidating the causes of
neurodegenerative diseases, and the time has come to intensify
the search for drug targets and for compounds that interrupt the
disease processes. Drugs that block the mishandling of a
particular protein may be most effective for certain disorders;
for others, drugs that enhance the clearance of an aberrant
protein or fragment may prove most useful. Regardless of the
therapeutic approach, accurate, early detection of
neurodegeneration will be extremely important so that drugs can
be given before substantial damage to the central nervous system
has occurred. However, the enormity of these tasks -- developing
useful diagnostic tests and discovering effective therapies
--should not be underestimated."
New Engl. J. Med. 2001 344:1516
Text Notes:
... ... *Creutzfeldt-Jakob disease (CJD): Until 30 years ago,
Creutzfeldt-Jakob disease was an obscure form of dementia
unknown to most physicians. The name is now familiar to the
medical community as the major prion disease in humans.
... ... *protease: In general, any enzyme that cleaves proteins,
usually by hydrolysis.
... ... *beta-pleated: In general, protein chains fold into
alpha-helices or beta-sheet structures. The beta-sheet is a
protein structure where the peptide is extended and stabilized
by hydrogen bonding between NH and CO groups of different
polypeptide chains or of separate regions of the same chain.
... ... *Alzheimer's disease: There are various forms of
dementia produced by various causes. Alzheimer-type dementia
(Alzheimer's disease) is apparently related to what appear to be
specific cellular and histological degenerative processes, with
loss of cells from several specific brain areas, the brain
showing moderate to marked atrophy. Memory loss is the most
prominent early symptom.
... ... *Down syndrome: A birth defect marked by mental
retardation and many physical defects, the syndrome arising from
an extra chromosome 21 (trisomy 21).
... ... *Parkinson's disease: A neurological disorder first
described by James Parkinson (1817) and associated with
degeneration of a specific small region of the brain and a
resultant loss of projection to several important brain centers.
One must distinguish "parkinsonism" from Parkinson's disease.
Parkinsonism is a syndrome (a complex of symptoms; in this
context, a complex of various movement symptoms) that may be
caused by Parkinson's disease, but which may also be caused by
infectious, vascular, pharmacological, toxic, metabolic,
structural, and various degenerative disorders.
... ... *frontotemporal dementia: Dementia associated with loss
of functions associated with the frontotemporal lobes of the
brain.
... ... *Huntington's disease: (Huntington's chorea) First
described by George Huntington (1850-1916), the disease attacks
specific regions of the brain (e.g., caudate nucleus and
putamen), and leads to insanity and eventual death.
... ... *amyotrophic lateral sclerosis: A progressive disease of
motor neurons (spinal cord nerve cells that control voluntary
muscles). 50 percent of patients die within 3 years of the first
symptoms.
... ... *spinocerebellar ataxia: In general, an ataxia is an
inability to coordinate muscle activity during voluntary
movement. Spinocerebellar ataxia is the most common hereditary
ataxia. The spinocerebellar degenerative disorders are a group
of diseases involving neurons in several nervous system
structures, including the spinal cord and cerebellum.
... ... *post-translational: In this context, translation is
protein synthesis, the process during which polypeptides are
synthesized in accordance with RNA code.
... ... *proteolytic: In general, "proteolysis" is the
enzyme-catalyzed degradation of protein by hydrolysis of one or
more peptide bonds.
... ... *gene splicing: In this context, the production of new
genes by an abnormal replication process that combines fragments
of DNA in new arrangements.
... ... *Kuru: This disease is similar to Creutzfeldt-Jakob
disease, and is a human spongiform encephalopathy. Kuru occurs
only in the easter highlands of New Guinea, occurs more
frequently in women than in men, which apparently coincides with
the customs surrounding cannibalism in a society where the
remains of dead relatives are handled and eaten primarily by
children and women. After cannibalism was outlawed, the
incidence of the disease decreased, and the current consensus is
that cannibalism was the primary mode of transmission of the
pathological agent.
... ... *growth hormone: A vertebrate polypeptide hormone that
regulates growth. In general, hormones are signaling molecules
secreted into the blood stream by endocrine cells and acting on
target cells that possess receptors for the hormone.
... ... *dura mater: In this context, a thick protective
membrane that surrounds the brain. There is also a dura mater
surrounding the spinal cord.
... ... *New variant CJD: In 1996, the new variant of
Creutzfeldt-Jakob disease (new-variant CJD) was recognized in
the UK population, primarily in younger people, the new disease
with distinctive pathological characteristics similar to those
seen in macaque monkeys infected with the agent of bovine
spongiform encephalopathy.
... ... *Gerstmann-Straeussler-Scheinker disease: A slowly
progressive neurodegenerative genetic disease similar to
Creutzfeldt-Jakob disease and transmissible to experimental
animals. The disease is much rarer than Creutzfeldt-Jakob
disease and has an earlier onset.
... ... *Fatal familial insomnia: insomnia: Another familial
form of Creutzfeldt-Jakob disease. This very rare disease is
difficult to transmit to experimental animals. The age of onset
varies widely, the course of the disease averaging 13 months.
(Note: All the human spongiform encephalopathies are invariably
fatal.)
... ... *Scrapie: Susceptibility to scrapie varies among
different breeds of sheep, with goats 100 percent susceptible.
The disease is transmissible to laboratory monkeys, mice, and
hamsters.
... ... *ungulate: In general, a hoofed mammal.
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9. AN UPDATE ON AIDS IN THE US
K.M. De Cock and R.S. Janssen (CDC-Kenya, KE) discuss AIDS, the
authors making the following points:
1) In July 2002, approximately 15,000 clinicians, researchers,
and other interested persons will gather once again, this time
at the XIV International AIDS Conference in Barcelona, to
discuss what is arguably the worst plague the world has ever
known. These international conferences and their venues are
milestones in the history of this tragic epidemic. In 1985,
Atlanta hosted the first meeting; in 1996, the Vancouver meeting
introduced combination therapy and viral load testing to the
world; and in 2000, Durban drew international attention to
Africa's plight. Barcelona offers further opportunity for
dialogue, reflection on epidemiology and response, and
strengthening global resolve.
2) The United States is the most heavily affected country in the
industrialized world with almost 1 million persons living with
HIV (human immunodeficiency virus).(1) Important successes have
included the prevention of HIV/AIDS (acquired immunodeficiency
syndrome) transmitted through blood and blood products; progress
toward elimination of pediatric HIV disease as a result of
prevention of mother-to-child transmission of HIV; and
reductions in AIDS incidence and deaths since 1996 through use
of highly active antiretroviral therapy (HAART); however, the
trend in incidence and death has now stabilized.(2)
3) Despite some advances, HIV incidence in the US has not
declined significantly over the past decade, with approximately
40,000 new infections occurring annually.(1) Unfortunately, HIV
infection continues to affect disproportionately communities of
color, especially African Americans.(1,2) Moreover, with
unchanged incidence and longer survival, a slow increase has
occurred in the total number of persons living with HIV. Because
HAART has delayed the development of AIDS, back calculation, a
technique used to model HIV incidence from AIDS case
surveillance data,(3) is no longer possible. Of note, in part
because of the successes of HAART, there has been a recent
resurgence of unsafe behavior among men who have sex with men,
resulting in well-characterized outbreaks of sexually
transmitted infections such as syphilis, and, perhaps, increased
HIV transmission.(4,5)
References (abridged):
1. Karon JM, Fleming PL, Steketee RW, De Cock KM. HIV in the
United States at the turn of the century: an epidemic in
transition. Am J Public Health. 2001;91:1060-1068.
2. HIV/AIDS Surveillance Report. Atlanta, Ga: Centers for
Disease Control and Prevention; 2001;13(No.1):1-41.
3. Rosenberg PS, Biggar RJ. Trends in HIV incidence among young
adults in the United States. JAMA. 1998;279:1894-1899.
4. Stall RD, Hays RB, Waldo CR, et al. The Gay '90s: a review of
research in the 1990s on sexual behavior and HIV risk among men
who have sex with men. AIDS. 2000;14(suppl 3):S101-S114.
5. Katz MH, Schwarcz SK, Kellogg TA, et al. Impact of highly
active antiretroviral treatment on HIV seroincidence among men
who have sex with men: San Francisco. Am J Public Health.
2002;92:388-394.
J. Am. Med. Assoc. 2002 288:236
Web Links: world AIDS epidemic
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10. ON MIXED-PHASE STRUCTURES
J. Banhart and D. Weaire (Technical University of Berlin, DE)
discuss mixed-phase structures, the authors making the following
points:
1) Solid-state physics has currently extended its horizons to
encompass all of condensed matter and the wide world of
materials science. Physicists share with physical chemists and
industrial engineers an eclectic interest in the exceptional
properties that can emerge from mixed phases. For example, ice
cream -- consisting of crystalline solids, liquid, and gas -- is
much more than the sum of its parts. Offered separately, those
parts might provide the same nutritional value, but the pleasure
of consumption would be lost. Here, structure is as important as
composition, and it owes more to culinary artifice than to the
laws of thermodynamics. In the metastable world of mixed-phase
structures, science meets art.
2) The current interest in mixed phases was heralded in the
1950s by the MIT metallurgist Cyril Stanley Smith, as recounted
in his testament, "A Search for Structure".(1) Smith was
particularly attracted to the elegant liquid-gas system that is
called a foam, a prototype for much of materials science. A foam
is typically disordered, and each sample is a product of its
particular history, yet its internal local arrangements are not
arbitrary. They conform to rules, dictated by surface tension,
that were expounded by Joseph Plateau (1801-1883) in the 19th
century. Those rules require that only three of the thin films
that separate bubbles can meet on a line (called a Plateau
border), and only four of those lines can meet at a point. Films
and lines meet symmetrically, at equal angles. The rules
strictly apply only in the limit of zero liquid fraction, but
most foams have low enough liquid fraction to conform well to
them.(2)
3) The beautiful structure described by Plateau is common to
most liquid foams, and hence also to the solid foams that result
from freezing them. Solid foams encounteredin everyday life
include polyurethane and polystyrene products for cushioning,
packaging, and insulation. Many other materials, such as
ordinary glass, can be foamed. Even metals are produced as
foams. A comparatively new entry in the foam catalog, metal
foams are attracting much attention as promising applications
are identified.(3) A metal foam consists primarily of a network
of thin, frozen Plateau borders meeting at junctions that
usually have the prescribed tetrahedrally symmetric form. The
relative density of a solid metal foam (overall density divided
by that of its solid constituent) is typically less than 15%.
(4,5)
References (abridged):
1. C. S. Smith, A Search for Structure: Selected Essays on
Science, Art, and History, MIT Press, Cambridge, Mass. (1981).
2. D. Weaire, S. Hutzler, The Physics of Foams, Clarendon Press,
New York (1999).
3. For the latest developments on metal foams, see
http://www.metalfoam.net
4. L. J. Gibson, M. F. Ashby, Cellular Solids: Structure and
Properties, Cambridge U. Press, Cambridge, UK (1997).
5. B. Sosnick, "Process for Making Foamlike Mass of Metal," US
Patent 2,434,775 (20 January 1948).
Physics Today 2002 July
Web Links: mixed phase structures foams
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11. ON APPLICATIONS OF SOLID-PHASE POLYMER SPHERES
R.A. Farrer et al (Boston College, US) discuss polymer spheres,
the authors making the following points:
1) The synthesis of organic molecules on solid-phase synthesis
beads has experienced an explosion of interest since
Merrifield's pioneering work in the peptide area several decades
ago.(1-5) In large part, this renaissance has been driven by the
advent of combinatorial chemistry, which takes advantage of the
ability to synthesize large and diverse libraries of compounds
efficiently on solid supports. Despite the tremendous practical
advantages afforded by solid-phase synthesis, relatively few
reports have appeared in which a direct determination of the
on-resin chemistry has been made. Examples of techniques that
have been used include radiography, nanoprobe nuclear magnetic
resonance, single-bead fluorescence microscopy, IR spectroscopy,
and optical analysis.
2) The in situ screening of libraries of resin-bound compounds
represents a frontier in this area of research. However, the
approach has to date been applied with caution, in part because
of questions concerning the spatial location of molecules on, or
within, a given bead. A related question concerns the
diffusivity of macromolecular targets within the polymer matrix
that comprises the solid-phase bead.
3) The authors report the direct observation of both on-resin
bead functionalization and ligand binding, using a
high-resolution, three-dimensional optical technique. Two-photon
microscopy has been used to carry out in situ cross-sectional
analysis of individual synthesis beads that have been
functionalized with peptides that bind other fluorogenic
molecules. The ability to observe the properties of the
interiors of synthesis beads has further allowed the authors to
develop a verifiable synthetic route to multiple-shelled beads
wherein different shells are functionalized with different
compounds. The authors report they have used this technique to
prepare three-shelled beads in which each shell is
functionalized with a unique tripeptide sequence. On the basis
of the individual molecular recognition properties of each
tripeptide sequence, the authors demonstrate the shell-selective
binding of unique ligands within the interiors of the individual
beads.
References (abridged):
1. Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149-2154
2. Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D.
Tetrahedron 1996, 52, 4527-4554
3. Ellman, J. A. Acc. Chem. Res. 1996, 29, 132-143
4. Fruchtel, J. S.; Jung, G. Angew. Chem., Int. Ed. Eng. 1996,
35, 17-42.
5. Nuss, J. M.; Renhowe, P. A. Curr. Opin. Drug Discovery Dev.
1999, 2, 631-650
J. Am. Chem. Soc. 2002 124:1994
Web Links: solid phase polymer spheres
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12. ON STRUCTURE SENSITIVITY OF CATALYTIC REACTIONS
B. Hammer (University of Aarhus, DK) discusses catalytic
reactions, the author making the following points:
1) Structure sensitivity in heterogeneous catalytic reactions
provides a means of optimizing the reactivity and selectivity of
a catalyst. In general, the structure of a catalyst is subject
to the thermodynamic and chemical conditions during reaction.
For oxide supported metal particle catalysts, the support serves
as a structural promoter that, in combination with the metal
deposition conditions, determines the size and shape of the
catalyst particles and thereby the types of metal crystal faces
exposed [1-3]. Owing to improved particle preparation
techniques, the reaction of very small catalyst particles is
currently receiving much attention. Nano-scaled metal particles
supported on metal oxide surfaces are now routinely synthesized
with a narrow particle size dispersion [2] if not as size
selected, monodispersed particles [4]. Surface-science
characterization of, e.g., CO oxidation at 25-60-angstrom-wide
gold particles on ti-tania [5] and NO reduction at
28-156-angstrom-wide palladium particles on magnesia have
revealed intermediate sized particles to be the most reactive.
Likewise, studies of, e.g., Pd(subn) or Au(subn) (1 =< n =<
20-30) particles on magnesia films have revealed "magic" metal
particle sizes (Pd(sub13), Au(sub8)) of particular high
reactivity for reactions such as acetylene cyclotrimerization
and CO oxidation.
2) The observed structure sensitivity of reactions on oxide
supported metal particles is generally believed to arise from
several different factors including strain, charge transfer,
special reaction sites, and electronic structure changes of the
metal systems due to their nano-sized dimensions. Goodman and
coworkers conclude in their CO oxidation studies [5] that the
metal particle thickness is an important parameter, with 2
monolayer (ML) thick Au clusters showing the highest reactivity.
In their combined experimental and theoretical work on CO
oxidation at atomic sized gold clusters on magnesia, Landman and
co-workers (1999) emphasize the significance of electronic
charging of the metal clusters and the presence of defects in
the oxide support. The suggestions for the atomistic reasons
behind structurally enhanced activity at certain metal clusters
are thus several.
3) In summary: The author reports a calculation of the potential
energy diagram for the NO + CO reaction on 1, 2, and 3 monolayer
(ML) Pd films supported by MgO(l00) using density functional
theory. Thin Pd films are generally found to be more reactive
than thick films, with a notable exception for nitrogen
adsorption on 2 ML Pd/MgO(100). For this system, an attractive
through-the-metal adsorbate-oxide interaction of 0.5 eV is
identified. Nitrogen adsorption is consequently estimated to
provide a thermodynamic driving force for the reconstruction of
MgO(l00) supported 3 ML (or thicker) Pd clusters into thinner Pd
clusters.
References (abridged):
1. C.T. Campbell, Surf. Sci. Rep. 27, 1 (1997).
2. C.R. Henry, Surf. Sci. Rep. 31, 235 (1998).
3. M. Baumer and H.J. Freund, Prog. Surf. Sci. 61, 127 (1999).
4. U. Heiz and W.-D. Schneider, J. Phys. D 33, R85 (2000).
5. M. Valden, X. Lai, and D. W. Goodman, Science 281, 1647
(1998).
Phys. Rev. Lett. 89:016102
Web Links: heterogeneous catalytic reactions
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13. HISTORY: ON DRUG RECEPTORS
Rod Flower (William Harvey Research Institute, UK) discusses
drug receptors, the author making the following points:
1) The notion that drugs act through receptors has its true
origins in the late 19th century, when dogma held that the cell
protoplasm is a single very large molecule. Paul Ehrlich
(1854-1915) introduced the term "receptor" in 1900 to describe
sites on this molecule to which bacterial toxins (and, later,
drugs) bind to bring about changes in cellular metabolism. The
idea of discrete and specific binding sites was also supported
by the experiments of John Newport Langley (1852-1925). His
observations on the antagonistic actions of curare and nicotine
on skeletal muscle eventually led to the key concept that drugs
possess two properties: the ability to bind to the "receptive
substance" (as he called it) or affinity; and the ability of an
agonist to cause an effect, later dubbed its efficacy. The final
impetus came from Alfred Joseph Clark (1885-1941), who realized
that the relationship between drug concentration and response
could be described using a simple mathematical model, and who
thus bequeathed us the rudiments of receptor theory.
2) By the late 1940s, the balance of evidence and opinion had
swung towards the Ehrlich–Langley–Clark model of drug action,
and in the ensuing years it was to become as close to a credo as
science allows. These early pioneers had laid the foundations of
experimental pharmacology and had ensured that even if its
practitioners did not know what receptors actually were, they at
least had the conceptual tools to work with them.
3) Originally, the term "receptor" was applied generically to
all drug targets because there was no clear sense of how binding
gives rise to a biological effect. Some of these targets
subsequently turned out to be enzymes or other molecules, and
today the term "receptor" is generally reserved for a molecule
that acts as a biological signal transducer -- usually for
endogenous hormones or neurotransmitters.(1-3,6)
References (abridged):
1. Clark, A. J. J. Physiol. (Lond.) 61, 530–546; 547–557 (1926).
2. Langley, J. N. J. Physiol. (Lond.) 33, 374–413 (1905).
3. Parascandola, J. in: Discoveries in Pharmacology Vol. 3 (eds
Parnham, M.J. & Bruinvels, J.) 129-156 (Elsevier, Amsterdam,
1986)
6. de Jongh, D. K. in Molecular Pharmacology (ed. Ariens, E. J.)
(Academic, New York, 1964).
Nature 2002 415:587
Web Links: drug receptors
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