ScienceWeek

SCIENCE-WEEK - April 19, 2002 - Vol. 6 Number 16

An Online Research Digest Published Weekly Since 1997


This is our Universe, our museum of wonder and beauty,
our cathedral. -- John Archibald Wheeler


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Section 1

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

[(*) = includes background reports from ScienceWeek] [Subheads
under each report (e.g., 2a) provide supplementary material from
other archives (links available only in the Web Edition of SW).]

Basic Sciences:

1. On Rolling Circle Nucleic Acid Amplification

2. Dynamic Mechanisms of the Biological Membrane Water Channel 
2a. On the Aquaporin Family

3. Radiation Risks, Alpha Particle Effects, and Gap Junctions (*)
3a. On Gap Junctions

4. On Genes and Complex Social Behavior
4a. On Sociobiology

5. Influence of the Sun on Climate Variability
5a. Solar Variability and Climate Change: A Historical Overview

6. A Reassessment of Gamma Ray Bursts (*) 

7. On Synthetic Helical Polymers 

8. Dynamical X-Ray Imaging of Single DNA Molecules 

9. On Chiral Amplification of Oligopeptides 

10. On Water and the Structure of Biomolecules 

11. On Migraine 

12.Differentiation of Human Peripheral-Blood Stem Cells into
Liver Cells and Epithelial Cells 

Praxis:

13. On Smallpox  13a. Smallpox: Clinical and Epidemiological
Features

14. Bovine Spongiform Encephalopathy: Analysis of a Potential
Epidemic in British Sheep 

15. On Data Withholding in Academic Genetics 

16. Questions Concerning the Utility of Neuroblastoma Screening 
16a. On Neuroblastoma

17. On Multi-Drug Resistant Tuberculosis (*)

18. Generation of Protein Nanoarrays by Dip-Pen LIthography 

19. Ultraslow Dynamics, Aging Systems, and Glasses 

20. Magnetoresistance of Carbon Nanotubes 

21. Quantum Decoherence and Quantum Information Processing  
21a. Quantum Measurement and Decoherence

22. On the Confocal Microscope 

23. On the Internet as a Complex System 

24. On Coupling Nanocrystals to Biomolecules 

Miscellany:

25. In Focus: On the History of Paleontology 

26. ScienceWeek Notices and Subscription Information

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Section 2

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1. ON ROLLING CIRCLE NUCLEIC ACID AMPLIFICATION

A.T. Christian et al (Lawrence Livermore National Laboratory,
US) discuss nucleic acid amplification, the authors making the
following points:

1) "Rolling circle amplification" (RCA) is a molecular
cytogenetic technique used with a "padlock" oligonucleotide
probe to detect single base changes in isolated nucleic acids.
Padlock probes are composed of approximately 100 nucleotides
that hybridize to targets of approximately 30 bases. The 30-base
target-binding region is split into two 15-base segments placed
in opposite orientation at each end of the linear probe so that
a circle must be formed for hybridization to occur. At 10 bases
per helical turn, the hybridized probe wraps around its target
three times, and the remaining 70 bases form an unhybridized
single- stranded loop. Posthybridization DNA ligation connects
the two ends of the probe in the middle of the 30-base binding
region. The unbound 70-base loop facilitates probe
circularization and permits approximately 20 bases to serve as a
primer recognition site for DNA polymerase to replicate the
circle. RCA is an isothermal process in which the polymerase
progresses continuously around the loop until the 100 bases have
been replicated hundreds of thousands of times. Incorporating a
labeled nucleotide during the RCA reaction produces sufficient
signal for easy visualization of the target.

2) Application of RCA to in situ targets in fixed or
permeabilized cells has not been uniformly successful to date.
Although recent work has demonstrated that the concept is
viable, DNA detection efficiencies of only 20 to 30 percent
lessen the utility of RCA as an assay.

3) The authors report that by pretreating cells with a
combination of restriction enzymes and exonucleases, RCA in situ
can detect gene copy number and single base mutations in fixed
cells with efficiencies up to 90 percent. The technique can also
detect transcribed RNA in individual cells, making it a
versatile tool for cell-based assays.

Proc. Nat. Acad. Sci. 2001 98:14238

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2. DYNAMIC MECHANISMS OF THE BIOLOGICAL MEMBRANE WATER CHANNEL

Y. Kong and J. Ma (Baylor College of Medicine, US) discuss cell
membrane water channels, the authors making the following points:

1) Water channels belong to a recently discovered family of
membrane channel proteins that allow living cells to adjust to
osmotic and hydrostatic pressure changes in their environment,
and these channels are involved in numerous physiological
processes. The first water channel to be functionally and
structurally characterized was aquaporin-1 from human red blood
cells. This channel allows a high flux of water to pass through
by lowering the activation barrier of a membrane for water
permeation from 10 to 20 kilocalories per mole to less than 5
kilocalories per mole. The rate of water permeation of the
channel is in the range of 10^(9) to 10^(10) molecules per
second per channel. However, while allowing such a high rate of
water permeation, aquaporin-1 excludes small chemical species
such as H+ and NH(sub3). This exquisite selectivity has remained
a puzzle in physiology, since small ions such as protons are
known to be able to translocate through a hydrogen-bonded single
file of water molecules.

2) The authors report molecular dynamics simulations on the
structures of aquaporin-1, their results providing an atomistic
description of the interactions involved in membrane water
permeation. The authors identify two major curvilinear pathways.
The simulations confirm that water selectivity is due primarily
to the size-exclusion effect: only one water molecule is allowed
to pass through the narrow constriction in the aqueous pathway.
Most importantly, in contrast to previous proposals, the
hydrogen bonding interactions of water molecules with various
identified polar side chains were found to be essential for
maintaining the connectivity of water flow in the narrow
constriction region. When such side chains were replaced with
isosteric hydrophobic residues in the simulation, the aqueous
pathways were broken completely. In addition, the size of the
narrow constriction fluctuates significantly during the
simulation, which frequently breaks the flow of water, and thus
breaks the single-file water network necessary for proton
translocation. The simulations suggest specific experimental
gene mutations for further investigation of the water permeation
mechanism of aquaporin-1.

Proc. Nat. Acad. Sci. 2001 98:14345

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3. RADIATION RISKS, ALPHA PARTICLE EFFECTS, AND GAP JUNCTIONS

In addition to extracellular signaling pathways, some biological
cells in tissues use an alternative communications system that
involves direct movement of molecules from one cell to another.
This type of communication is made possible by what are called
"gap junctions", which permit small molecules to move directly
from cell to cell without passage through the extracellular
space. In thin-section electron micrographs, gap junctions
appear as regions in which the plasma membranes of two adjacent
cells are aligned in parallel and separated by a small gap of
approximately 3 nanometers. The membrane surfaces in this region
are covered by hundreds of resolved cylindrical structures
called "connexons", and each connexon is apparently constructed
from a single type of *transmembrane protein called "connexin".
Gap junctions occur in almost every type of cell found in
invertebrates and vertebrates, and they are especially abundant
in tissues where extremely rapid communication between cells is
required for optimal function. In heart tissue, for example, gap
junctions facilitate the flow of electric current that causes
the heart to beat. Several human diseases have been related to
connexin mutations, including developmental anomalies of the
cardiovascular system.

... ... H. Zhou et al (Columbia University, US) discuss alpha
particle radiation risks, the authors making the following
points:

1) Based principally on the cancer incidence found in survivors
of the atomic bombs dropped on Hiroshima and Nagasaki, the
International Commission on Radiation Protection and the US
National Council on Radiation Protection and Measurements have
recommended that estimates of cancer risk for low dose exposure
be extrapolated from higher doses by using a linear no-threshold
model. This recommendation is based on the dogma that the DNA of
the nucleus is the main target for radiation-induced
genotoxicity and, as fewer cells are directly damaged, the
deleterious effects of radiation proportionally decline.

2) The authors used a precision microbeam to target an exact
fraction (either 100 percent or <= 20 percent) of the cells in a
confluent population, and irradiated their nuclei with exactly
one alpha particle each. The authors report that the frequencies
of induced mutations and chromosomal changes in populations
where some known fraction of nuclei were hit are consistent with
non- hit cells contributing significantly to the response. In
fact, irradiation of 10 percent of a confluent mammalian cell
population with a single alpha particle per cell results in a
mutant yield similar to that observed when all of the cells in
the population are irradiated. This effect was significantly
eliminated in cells pretreated with a 1 millimolar dose of
octanol, which inhibits gap junction-mediated intercellular
communication, or in cells carrying a dominant negative connexin
43 vector. The authors suggest the data imply that the relevant
target for radiation mutagenesis is larger than an individual
cell and indicates a need to reconsider the validity of the
linear extrapolation in making risk estimates for low dose high
linear-energy transfer radiation exposure. In summary: The
results "provide clear evidence that a single alpha particle can
induce mutations and chromosome aberrations in cells that
received no direct radiation exposure to their DNA."

Proc. Nat. Acad. Sci. 2001 98:14410

Related Background Material:

MEASURING ONCOGENIC EFFECTS OF SINGLE ALPHA PARTICLES

Domestic exposure to radon gas in homes is generally considered
to be the single largest naturally occurring environmental
hazard. The basic mechanism involves DNA damage to
*bronchioepithelial cells by alpha particles emitted by radon
decay progeny. Recent estimates (1998) are that 10 to 14 percent
of all lung cancer deaths in the US, or 15,400 to 21,800 deaths
per year, are linked to radon gas exposure from the environment.
At domestic exposure levels, the relevant bronchial cells are
very rarely traversed by more than one alpha particle, whereas
at higher radon levels these bronchial cells are frequently
exposed to multiple alpha-particle traversals. It is at the
higher radon exposure levels that epidemiological studies in
uranium miners have allowed lung-cancer risks to be quantified
with reasonable precision. Measuring the oncogenic transforming
effects of exactly one alpha particle without the confounding
effects of multiple traversals has hitherto been unfeasible,
resulting in uncertainty in extrapolations of risk from high
radon levels to domestic radon levels.

... ... R.C. Miller et al (Columbia University, US) now report a
technique to assess the effects of single alpha particles on
*cultured cells, the technique using a charged-particle
microbeam which irradiates individual cells or cell nuclei with
predefined exact numbers of particles. The authors report that
although the technique was previously too slow in data
acquisition to assess the relevant small oncogenic risks, recent
improvements in the technique now permit microbeam irradiation
of large numbers of cells, allowing the first oncogenic risk
measurements for the traversal of exactly one alpha particle
through a cell nucleus. The authors report that in mouse
*fibroblast cells the measured oncogenicity from exactly one
alpha particle was significantly lower than that expected from
statistical extrapolation, implying that cells traversed by
multiple alpha particles contribute most of the risk. The
authors suggest that if this result applies generally,
extrapolation from high-level radon risks (involving cellular
traversal by multiple alpha particles) may overestimate
low-level radon risks (involving only single alpha particles).

Proc. Nat. Acad. Sci. 1999 96:19

Notes:

... ... *bronchioepithelial cells: In animals, epithelial cells
compose the cell layers that form the interface between a tissue
and the external environment, for example, the cells of the
skin, the lining of the intestinal tract, and the lung airway
passages. The term "bronchioepithelial cells" refers to
epithelial cells of the lung bronchi (lung airway passages).

... ... *cultured cells: In general, the term "cultured cells"
refers to a population of cells maintained in vitro, the cells
proliferating in a medium of controlled composition. In many
experiments, the cultured cells are subpopulations of "immortal"
cell lines widely used in numerous laboratories.

... ... *fibroblast cells: A type of connective tissue cell,
secreting structural proteins (e.g., collagen) that form certain
tissue components.

Copyright (c) 1997-2002 ScienceWeek http://www.scienceweek.com

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4. ON GENES AND COMPLEX SOCIAL BEHAVIOR

M.J. Krieger and K.G. Ross (University of Georgia, US) discuss
genes and social behavior, the authors making the following
points:

1) The evolution of complex social behavior is among the most
important events in the history of life. Interest in the genes
underlying the expression of key social traits is strong because
knowledge of the genetic architecture will lead to increasingly
realistic models of social evolution, while identification of
the products of major genes can elucidate the molecular bases of
social behavior. Few studies have succeeded in showing that
complex social behaviors have a heritable basis, and fewer still
have suggested that variation in these behaviors is attributable
to the action of one or few genes of major effect. No candidate
genes with major effects on key social polymorphisms have been
identified previously.

2) The fire ant Solenopsis invicta displays a fundamental social
polymorphism that appears to be under simple genetic control. A
basic feature of fire ant colony social organization, the number
of egg-laying queens, is associated with variation at the gene
Gp-9. In the US, where this species has been introduced,
colonies composed of workers bearing only the (B) allele at Gp-9
invariably have a single queen (monogyne social form), whereas
colonies with workers bearing the alternate (b) allele have
multiple queens (polygyne social form). The two social forms
differ in many key reproductive and life history characteristics.

3) The authors report they sequenced the gene Gp-9 and found
that it encodes a pheromone-binding protein, a crucial molecular
component in same-species (conspecific) chemical recognition.
The authors suggest this indicates that differences in worker
Gp-9 genotypes between social forms may cause differences in the
abilities of workers to recognize queens and regulate their
numbers. The authors conclude: "This study demonstrates that
single genes of major effect can underlie the expression of
complex behaviors important in social evolution."

Science 2002 295:328

Related Background:

ON THE CONTROL OF SEX RATIOS IN ANT COLONIES

L. Passera et al (Paul-Sabatier University Toulouse, FR) discuss
the control of sex ratios in fire ant colonies. Social insects
provide some of the most striking examples of elaborate
cooperative behavior, yet life within colonies also entails
conflicts. In ants, the most strident conflict concerns sex
ratio, with workers favoring a more female-biased sex investment
ratio than queens. This conflict arises because of the
hymenopteran haplodiploid system of sex determination, whereby
unfertilized eggs develop into males and fertilized eggs develop
into females. As a result, workers in colonies headed by a
single once-mated queen are three times more related to sisters
than to brothers. Because of this asymmetry in relatedness, the
population-wide sex allocation ratio should equilibrate at 3:1
(female:male) if workers control the colony's investment in
reproductive offspring. In contrast, because queens are equally
related to their daughters and sons, an equal investment in male
and female reproductives is expected if the colony's allocation
of resources is under the control of the queen. Because they
control brood rearing and food flow in the colony, workers can
bias sex allocation, for example, by selectively eliminating
males and/or preferentially feeding females, and workers have
indeed been demonstrated to manipulate colony sex ratios in this
way. The authors report a study in which they exchanged queens
between male- and female-specialist colonies of the fire ant
Solenopsis invicta. These exchanges quickly reversed the sex-
ratio biases of adopting colonies. The sex ratio of queen-laid
eggs differed strongly between male- and female-specialist
colonies. The authors suggest that these findings indicate that
queens can force workers to raise male sexuals by limiting the
number of female brood, and that the findings help to explain
why sex investment ratios lie between the queen and worker
equilibria in this and many other ant species.

Science 2001 293:1308

Related Background:

GENETIC CONTROL OF SOCIAL ORGANIZATION IN ANTS

Biological evolution is marked by a number of major transitions,
one of which is the evolution of complex social behavior. Animal
social life can take a variety of forms, each distinguished by
features such as group size and the reproductive roles of group
members. One focus in evolutionary biology is to identify the
causes of social behavior and its conspicuous variation, and to
determine the extent to which social organization is under
genetic control. Such information is useful for reconstructing
pathways of animal social evolution. Current views on insect
social evolution stress the importance of ecological and
behavioral environments in molding what are largely plastic
social behaviors.

... ... K.G. Ross and L. Keller (2 installations, US CH) report
evidence that major variation in the social organization of fire
ant colonies is under simple genetic control, providing a
demonstration of an apparent strong genetic component to complex
social behavior. The authors report that a single genomic
element (the gene [Gp-9]) is responsible for the existence of
two distinct forms of social organization in the fire ant
*Solenopsis invicta. This genetic factor apparently influences
the reproductive *phenotypes and behavioral strategies of ant
queens and determines whether workers tolerate a single fertile
queen or multiple queens per colony. The authors suggest "these
findings reveal how a single genetic factor can have major
effects on complex social behavior and influence the nature of
social organization."

Proc. Nat. Acad. Sci. 1998 95:14232

Notes:

*Solenopsis invicta: The fire ant S. invicta is an introduced
pest species in the southern US, the species existing in two
distinct social forms. The "monogyne" form features colonies
with a single fertile (egg-laying) queen, whereas the "polygyne"
form features colonies with multiple fertile queens. The two
social forms differ in other major aspects of their reproductive
biology.

*phenotypes: The term "phenotype" refers to the total appearance
of an organism as determined by the interaction during
development between its genetic constitution (genotype) and the
environment.

Related Background:

ON HONEYBEE SOCIAL BEHAVIOR, GENES, AND THE ENVIRONMENT

The so-called social insects live in societies that rival human
societies in complexity and internal cohesion. Honey bees, for
example, apparently always follow 3 rules: a) they live in
colonies with overlapping generations; b) they care
cooperatively for offspring other than their own; and, c) they
maintain a reproductive division of labor. ... ... In a review
of research (much of it from the author's own laboratory)
concerning the genetic and environmental factors responsible for
honey bee behavior, Gene E. Robinson (University of Illinois
Urbana- Champaign, US) makes the following points: 1) Genes do
not play an exclusive role in regulating behavior: biologists
have long realized that behavior is influenced by genes, the
environment, and interactions between the two. 2) Genes never
act alone. They must operate in an environment where they code
for proteins that participate in many systems in an organism,
with these systems in turn influencing the expression of genes.
Consequently, biologists must take a broad approach in assessing
the impact of any gene. 3) The research group of the author uses
the Western honey bee, Apis mellifera. Honey bees pass through
different life stages as they age, and their behavioral
responses to environmental and social stimuli change in
predictable ways. Although worker bees go through a consistent
path of behavioral development, this path is not rigidly
determined. Bees can accelerate, retard, or even reverse their
behavioral development in response to changing environmental and
colony conditions. 4) Experimental evidence indicates that
juvenile hormone, one of the most important hormones influencing
insect development, helps time the pace of behavioral maturation
in honey bees. The rate of endocrine-mediated behavioral
development is influenced by inhibitory social interactions.
Older bees inhibit the behavioral development of younger bees:
the rate of behavioral development is negatively correlated with
the proportion of older bees in a colony. Inhibitory social
interactions that influence the rate of behavioral development
involve chemical communication between colony members. 5)
Evidence from the laboratory of the author in 1993 indicated the
so-called mushroom bodies in the bee brain are involved in the
behavioral changes occurring during maturation, the volume of
the bodies increasing, and the volume increase associated with
an increase in synapses with neurons from brain regions devoted
to sensory input. The author suggests this was the first report
of brain plasticity in an invertebrate. 6) The author suggests
that, in general, two-way interactions between the nervous
system and the genome contribute fundamentally to the control of
social behavior. Information about social conditions that is
acquired by the nervous system is likely to induce changes in
genomic function that in turn produce adaptive modifications of
the structure and function of the nervous system. 7) The author
proposes a new research initiative called "sociogenomics",
defined as a "wide-ranging approach to identify genes that
influence social behavior, determining the influence of these
genes on underlying neural and endocrine mechanisms, and
exploring the effects of the environment -- particularly the
social environment -- on gene action."

American Scientist 1998 86:456

Related Background:

ANIMAL BEHAVIOR: NONGENOMIC TRANSMISSION OF MATERNAL BEHAVIOR

The question of genetic vs. non-genetic determinants of behavior
is an area of controversy in several branches of science, and as
can be seen from the background material attached to this
report, discussion of the question is on occasion contentious.
In humans, individual differences in personality traits often
appear to be transmitted from parents to offspring, and a
critical question concerns the mode of transmission of such
traits. Studies of identical (monozygotic) and non-identical
(dizygotic) twins have provided some evidence for a genetic
mechanism of transmission of even complex personality traits. In
contrast to genomic transmission, parental behavior influences
the development of offspring and could therefore serve as a
mechanism for a non- genomic behavioral mode of transmission of
traits. In rats, for example, it has been known for 50 years
that variations in maternal care are associated with the
development of individual differences in behavioral and
endocrine responses to stress in the offspring, and this species
has served as an animal model in many studies of the effects of
variations in maternal care on the behavior of offspring.

... ... D. Francis et al (4 authors at McGill University, CA)
now present cross-fostering studies examining the possibility
that variations in rat maternal care might be the mechanism for
a behavioral transmission of individual differences across
multiple generations. In the experimental and control protocols,
no more than 2 of 12 rat pups were fostered into or from any one
litter. The authors report their results provide evidence for 1)
a causal relationship between maternal behavior and stress
reactivity in the offspring; and 2) the transmission of such
individual differences in maternal behavior from one generation
of females to the next. In addition, the authors report that an
environmental manipulation imposed during early development that
alters maternal behavior can affect the pattern of transmission
in subsequent generations. The authors suggest that taken
together, these results indicate that variations in maternal
care can serve as the basis for a non-genomic behavioral
transmission of individual differences in stress reactivity
across generations. The authors conclude: "In humans, social,
emotional, and economic contexts influence the quality of the
relationship between parent and child and can show continuity
across generations. Our findings in rats may thus be relevant in
understanding the importance of early intervention programs in
humans."

Science 1999 286:1155

Related Background:

IN FOCUS: ON SOCIOBIOLOGY

"Evolutionary theory itself has an appropriately zoocentric
core... But the zoocentric view can be extended too far into a
caricature often called the "nothing but" fallacy (humans are
"nothing but" animals). The simplistic accounts of human
sociobiology now flooding popular literature embody this
overextended version of zoocentrism. Sociobiology is not just
any statement that biology, genetics, and evolutionary theory
have something to do with human behavior. Sociobiology is a
specific theory about the nature of genetic and evolutionary
input into human behavior. It rests upon the view that natural
selection is a virtually omnipotent architect, constructing
organisms part by part as best solutions to problems of life in
local environments. It fragments organisms into "traits",
explains their existence as a set of best solutions, and argues
that each trait is a product of natural selection operating
"for" the form or behavior in question. Applied to humans, it
must view _specific_ behaviors (not just general potentials) as
adaptations built by natural selection and rooted in genetic
determinants, for natural selection is a theory of genetic
change. Thus, we are presented with unproved and unprovable
speculations about the adaptive and genetic basis of specific
human behaviors: why some (or all) people are aggressive,
xenophobic, religious, acquisitive, or homosexual. Zoocentrism
is the primary fallacy of human sociobiology, for this view of
human behavior rests on the argument that if the actions of
"lower" animals with simple nervous systems arise as genetic
products of natural selection, then human behavior should have a
similar basis."

Stephen Jay Gould: _Hen's Teeth and Horse's Toes_ (W.W. Norton,
New York 1983, p.243)

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5. INFLUENCE OF THE SUN ON CLIMATE VARIABILITY

Joanna D. Haigh (Imperial College London, UK) discusses climate
variability, the author making the following points:

1) The search for the signs of solar variability in climate
records has historically been dogged by overstated claims and
dubious statistics. In addition, ground-based measurements were
insufficiently sensitive to detect variations in the Sun's
radiative output. As a result, the subject has tended to be
marginalized by the meteorological establishment. However,
recent evidence from satellite data has demonstrated that the
term "solar constant" is a misnomer. Furthermore, climate change
attribution requires the ability to separate natural climate
forcing mechanisms from human-induced factors. It is thus more
important than ever that the influence of solar variability on
climate is assessed and understood.

2) To detect a solar influence on climate, two key challenges
must be met. First, reliable and consistent long-term indices of
meteorological and solar parameters must be constructed. Second,
any solar influence must be separated from other influences in
what is an inherently highly variable and noisy nonlinear
system. Even when a statistically robust solar signal emerges
from the data, the mechanisms by which the solar influence acts
remain to be explained, particularly because the irradiance
variations are small and their direct effect must be amplified
in the climate system. Hence, dynamical and physical feedbacks
need to be considered. Among these effects may be coupling of
processes in the lower atmosphere to ocean circulation or to the
middle atmosphere.

3) Recent observations demonstrate that each of the expansions
of cooler water that occur approximately every 1500 years was
associated with a strong minimum of solar activity, and this
remarkable result provides strong evidence that solar activity
does indeed modulate climate on centennial to millennial time
scales.

Science 2001 294:2109,2130

Copyright (c) 1997-2002 ScienceWeek http://www.scienceweek.com

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6. A REASSESSMENT OF GAMMA RAY BURSTS

Gamma ray bursts are intense flashes of gamma rays detected at
energies up to 10^(6) *electronvolts. They were discovered by US
Air Force satellites in 1967 but not declassified until 1973.
The detection of these bursts averages about 1 per day, and
measurements indicate the distribution of bursts is isotropic,
i.e., they are uniformly distributed across the sky. Recent
views are that gamma ray bursts are produced by the merger of
two neutron stars, or a neutron star with a black hole, or a
massive star with a black hole. Up to this point, the bursts
that have been noted apparently originate outside our own galaxy.

Gamma rays are radiation of high energy, from about 10^(5)
*electronvolts to more than 10^(14) electronvolts -- radiation
with the shortest wavelengths and highest frequencies, the gamma
ray region of the electromagnetic spectrum merging into the
adjacent lower energy x-ray region.

Stan Woosley (University of California Santa Cruz, US) discusses
gamma ray bursts, the author making the following points:

1) Though sometimes touted as the largest explosions since the
Big Bang, gamma ray bursts are now seeming less energetic than
they did just two years ago, and recent observations suggest
that the energy required to produce these bursts may not be much
more than that of an ordinary supernova in which emitted energy
is somehow focused into a narrow jet moving very close to the
speed of light and pointing directly towards Earth. New
evidence, based on measurements of the size of the jets,
suggests that all gamma ray bursts release approximately the
same amount of energy.

2) The energies inferred from gamma ray burst observations are
enormous, amounting in some cases to the mass of the Sun being
converted directly into gamma rays within a few seconds. In the
late 1990s, model builders struggled to reproduce these sorts of
burst energies in computer simulations, and wondered whether the
energies were really that large. In particular, would a gamma
ray burst be just as bright if it were seen from some other
angle?

3) In the past decade, theoretical astrophysicists began
suggesting that much less energy would be needed to produce the
same brightness if gamma ray bursts broadcast their energy in a
narrow cone or jet. Most models of gamma ray burst formation
involve either the cataclysmic collapse of a massive rotating
star into a black hole, or a neutron star merging with a black
hole. Because the material accreting into the black hole forms a
rotating disk, it blocks the outflow of mass, so any material
that does escape [before being swallowed up by the black hole]
is forced into two narrow and oppositely directed jets. Other
astronomical phenomena thought to be powered by accreting black
holes, such as quasars, are also known to produce jets, so why
not gamma ray bursts? Recent experimental estimates of the
angular size of gamma ray bursts, based on observations of their
afterglows, suggests that even if we assume that the original
emission is spherical, matter released by a gamma ray burst is
accelerated close to the speed of light and so emits radiation
in a narrow beam along its path.

Nature 2001 414:853

GAMMA RAY BURSTS: THE LARGEST EXPLOSIONS IN THE UNIVERSE Gamma
rays are extremely high energy electromagnetic radiation with
wavelengths of less than approximately 0.01 nanometers. X-rays
are radiation of wavelengths approximately 0.01 to 10
nanometers, shorter than ultraviolet radiation but longer than
gamma rays. Gamma ray bursts are intense flashes of gamma rays
and x-rays detected at energies up to 10^(6) *electron volts.
They were discovered by US Air Force satellites in 1967 but not
declassified until 1973. The detection of these bursts averages
approximately 1 per day, and measurements indicate the
distribution of bursts is isotropic, i.e., they are uniformly
distributed across the sky. The nature of gamma ray bursts
remains mysterious. Astronomers have obtained rigorous distance
estimates only recently, placing gamma ray bursts definitely in
the realm of cosmology. *Redshift measurements suggest extremely
large distances, making gamma ray bursts the most powerful
catastrophic energy releases known to mankind. ... ... Dieter H.
Hartmann (Clemson University, US) presents a review of current
research concerning gamma ray bursts, the author making the
following points: 1) Gamma ray bursts are short flashes of
almost pure high- energy emission (x-rays and gamma rays) that
occur randomly on the sky, and from loci which apparently do not
emit more than once. Typical durations are of the order of
seconds, but can range from a few milliseconds to over 1000
seconds. The bursts are extremely bright, outshining all other
objects on the gamma ray sky, but their spectra are featureless
and reveal little about the underlying physical processes.
Integrating burst spectra over energy and time yields large
fluences (received energy per unit area), but does not determine
the total burst energy until the distance is known. 2) Although
the statistical properties of gamma ray bursts long supported
the idea that bursts occur at cosmological distances, this
distance scale was finally established by a burst on 8 May 1997,
for which a faint extended object was optically identified as
the host, the object showing clear evidence of absorption lines
that indicated a lower redshift limit of z = 0.835. On 14
December 1997, another burst showed absorption lines at z =
3.42, and then a third burst on 3 July 1998 had associated
absorption lines at z = 0.966 -- all of this indicating that
gamma ray bursts, along with *quasars, are the most distant
objects in the Universe. Such large distances imply large
energies, and in fact the assumption of isotropic emission
implies burst energies in excess of 10^(53) ergs, comparable to
*supernova energies but released predominantly in the gamma ray
band. The optical afterglows of gamma ray bursts are much
brighter than supernova, hence the name "hypernova" has been
proposed. 3) Studies of gamma ray burst host galaxies suggest
they are normal star-forming galaxies, and not galaxies with
*active nuclei. The estimated star formation rates in these
hosts, together with other evidence from x-ray spectra and
photometry of the gamma ray burst afterglows suggests that gamma
ray bursts may be directly associated with star-forming regions.
If that turns out to be correct, astronomers would have a
powerful new tool for the study of structure formation in the
Universe, a tool that could reach further back in time than
quasars. 4) Despite recent breakthroughs in gamma ray burst
observations, many questions remain about the nature of the
underlying processes and the evolutionary sequences leading up
to the creation of the central engine driving these outbursts.
The ultimate goal of understanding this engine may be
accomplished through simultaneous optical observations, and such
is the objective of dedicated experiments under development
throughout the world. ----------- Proc. Nat. Acad. Sci. US 27
Apr 99 96:4752 ----------- Notes: ... ... *electron volts: An
electronvolt is defined as the energy acquired by an electron
falling freely through a potential difference of one volt, and
is equal to 1.6022 x 10^(-19) joule. ... ... *Redshift: Redshift
(symbol: z) is a lengthening of the wavelengths of
electromagnetic radiation from a source caused either by the
movement of the source (Doppler effect) or by the expansion of
the universe (cosmological redshift). Redshift is defined as the
change in wavelength of a particular spectral line divided by
the unshifted wavelength of that line. Large redshifts imply
large radial velocities (which imply large distances, according
to current cosmological theory), but at redshifts greater than
about 0.2 there is a relativistic divergence from a linear
relation. A redshift of 4.0 corresponds to an object receding
with a radial velocity 92% that of the velocity of light. The
largest astrophysical redshifts so far observed are of the order
of z = 5. ... ... *quasars: (quasi-stellar objects) Extremely
luminous sources radiating energy over the entire spectrum from
x-rays to radio waves, and which are apparently among oldest and
most distant objects in the universe. ... ... *supernova: A
violent explosion in which certain stars end their lives. The
star may become more than 10^(9) times as bright as the Sun and
may outshine its host galaxy for weeks. ... ... *active nuclei:
(active galactic nuclei) Central regions of galaxies in which
considerable energy is generated by processes other than those
operating in ordinary stars. The energy may result from the
accretion of material into a massive black hole situated at the
core of the galaxy.

---------- Related Background: ASTROPHYSICS: SUPERNOVAE AND
GAMMA RAY BURSTS Supernovae are violent explosions marking the
terminal stage of certain stars. They are classified into two
broad types, Type I and Type II. A Type II supernova shows
hydrogen in its spectrum, while a Type I supernova shows no
hydrogen in its spectrum. Type I supernovae are further
classified as Type 1a, Type 1b, and Type Ic. A Type 1a supernova
is believed to be due to the explosion of a *white dwarf star in
a binary star system, the result of matter falling onto it from
the companion star. When the mass of the white dwarf exceeds the
*Chandrasekhar limit, the white dwarf undergoes runaway carbon
burning and explodes. Type Ib and Ic supernovae are thought to
result from the collapse of the cores of massive stars which
have lost their hydrogen envelopes. Type II supernovae arise
from the explosion of stars of more than 8 solar masses. In this
case, the explosion involves a violent blow-off of outer-layer
material after the massive star has collapsed into a *neutron
star or a black hole. Despite the existing classification
scheme, Type Ib and Type Ic supernovae are more closely related
to Type II supernovae than to Type Ia supernovae. Gamma ray
bursts are intense flashes of *gamma rays detected at energies
up to 10^(6) *electronvolts. They were discovered by US Air
Force satellites in 1967 but not declassified until 1973. The
detection of these bursts averages about 1 per day, and
measurements indicate the distribution of bursts is isotropic,
i.e., they are uniformly distributed across the sky. The current
consensus is that gamma ray bursts are produced by the merger of
two neutron stars, and up to this point, the bursts that have
been noted apparently originate outside our own galaxy. ... ...
In 3 contiguous reports in the same journal, 3 research teams
now report an association of the gamma ray burst of 25 April
1998 (GRB980425) with the supernova SN1998bw, which exploded at
approximately the same time as the gamma ray burst. Although in
general the properties of supernovae are very different from
those of gamma ray bursts, the apparent new consensus is that
supernova SN1998bw establishes a second class of gamma ray burst
which is distinctly different from the cosmological kind. It is
suggested that in some supernovae the outer layer of the
exploding star is given sufficient energy to cause it to expand
at speeds approaching the speed of light, and that this
initially produces a burst of gamma rays and a subsequent radio
emission. If this suggestion is correct, gamma ray bursts may be
produced by two substantially different mechanisms. -----------
Nature 15 Oct 98 395:663,670,672 ----------- Notes: ... ...
*white dwarf star: White dwarf stars are extremely dense and
compact stars that have undergone gravitational collapse. They
are the final stage in the evolution of low-mass stars after
they have lost their outer layers. White dwarf stars are about
the size of Earth, but with a mass about that of the Sun. ...
... *Chandrasekhar limit: The remnant mass after the blow-off
during the terminal stage of the life of a star determines the
ultimate fate of the star. If the remnant mass is less than 1.44
solar masses (the Chandrasekhar limit for a star with no
hydrogen content), the star collapses into a white dwarf. If the
remnant mass is greater than 1.44 solar masses, depending on the
remnant mass, the star collapses into either a neutron star or a
black hole. Named after Subrahmanyan Chandrasekhar (1910-1995),
who first proposed the modern theory of stellar gravitational
collapse, and who received the Nobel Prize in Physics 1983. ...
... *neutron star: If, following its terminal stages, the
remnant mass of a star is between 1.4 and 2 to 3 solar masses,
the star will collapse into a neutron star, a body with a radius
of 10 to 15 kilometers, with a core so dense that its component
protons and electrons have merged into neutrons. The average
density of a neutron star is 10^(15) grams per cubic centimeter,
and the weight of an object on the surface of a neutron star
would be 10^(11) its weight on the surface of the Earth. Neutron
stars apparently have an outer shell of iron, but it is iron
like no Earth iron, an iron of 4 orders of magnitude greater
density. ... ... *gamma rays: Gamma rays are radiation of high
energy, from about 10^(5) electronvolts to more than 10^(14)
electronvolts -- radiation with the shortest wavelengths and
highest frequencies, the gamma ray region of the electromagnetic
spectrum merging into the adjacent lower energy x-ray region.
... ... *electronvolts: (eV) A unit of energy defined as the
energy acquired by an electron in falling through a potential
difference of 1 volt. 1 electronvolt = 1.602 x 10^(-19) joule.

------------------- Related Background: ANALYSIS OF A GAMMA RAY
BURST FROM A HIGH REDSHIFT GALAXY Gamma rays are radiation of
high energy, from about 10^(5) electronvolts to more than
10^(14) electronvolts -- radiation with the shortest wavelengths
and highest frequencies, the gamma ray region of the
electromagnetic spectrum merging into the adjacent lower energy
x-ray region. Gamma ray bursts are intense flashes of gamma rays
detected at energies up to 10^(6) electron volts. Knowledge of
the properties of gamma-ray bursts has increased substantially
following recent detections of counterparts at x-ray, optical,
and radio wavelengths. But the nature of the underlying physical
mechanism that powers these sources remains unclear. An
important question is the total energy in the burst, for which
an satisfactory estimate of the distance is required, and until
now the best estimate is that the bursts lie at cosmological
distances. ... ... Kulkarni et al (16 authors at 9
installations, US IN IT) now report identification of the host
galaxy of a previously optically detected burst (GRB971214),
with a determination of the galaxy redshift at z = 3.42. When
combined with the measured flux of gamma-rays from the burst,
this large redshift implies an energy of 3 x 10^(53) ergs in the
gamma-rays alone, assuming the emission is isotropic. This is
much larger than the energies previously considered, and the
authors suggest it poses a challenge for theoretical models of
the bursts. Nature 1998 393:35

------------------- Related Background: GAMMA RAY BURST FIREBALL
MODEL MAY NEED REVISION ... The current consensus is that gamma
ray bursts are produced by the merger of two neutron stars, and
up to this point, the bursts that have been noted apparently
originate outside our own galaxy. ... ... Castro-Tirado et al
(27 authors at 15 installations, ES DE SE DK IT UK US) report an
optical transient from a gamma ray burst (GRB 970508) imaged 4
hours after the event, displaying a strong ultraviolet excess
and reaching maximum brightness 2 days later. The optical
spectra did not show any emission lines, and no variations on
time scales of minutes were observed for 1 hour during the
decline phase. The authors suggest the observations are
incompatible with the fireball and afterglow models of gamma ray
bursts, and that another physical mechanism may be responsible
for the constant phase seen the first few hours after the burst
occurs. Science 13 Feb 98

------------------- Related Background: OPTICAL STUDIES OF A
GAMMA-RAY BURST SUGGEST FIREBALL MODEL Studies of the mysterious
gamma-ray bursts seen in every part of the sky daily continue to
be reported. This week we have the results of observations of
gamma ray burst (GRB) GRB970508, which occurred on May 8, 1997
(hence the name). Optical studies of the source of the burst by
M. R. Metzger et al (California Institute of Technology, US;
National Radio Astronomy Observatory, US; Institute of Space
Astrophysics, Frascati IT; University of Ferrara, IT) using data
from the recently orbited Italian-Dutch satellite BeppoSAX
indicate the source of the GRB is extra- galactic at a distance
of 5 billion parsecs (1 parsec = about 20 trillion miles).
Taking into account the recorded energy and its loss by
intervening absorption across that distance, we are considering
an initial energy burst with a magnitude equal to the total
radiation from our Sun during the entire age of the universe.
The computed energy figure is 10^(51) ergs of gamma-rays. A
consensus among astrophysicists is forming that these GRBs
involve "relativistic fireballs" produced by colliding neutron
stars, either two neutron stars colliding with each other, or
single neutron stars colliding with black holes. The various
radiant energy data are coming in so rapidly now, there is a
feeling the physical nature of GRBs will soon be completely
understood. Nature 26 Jun 97

---------- Related Background: GAMMA RAY BURSTS AND POSSIBLE
TERRESTRIAL DISASTER ... Neutron stars are one of the possible
end-products of stellar evolution. If, following its terminal
stages, the remnant mass of a star is between 1.4 and 2 to 3
solar masses, the star will collapse into a neutron star, a body
with a radius of 10 to 15 kilometers, with a core so dense that
its component protons and electrons have merged into neutrons.
The average density of a neutron star is 10^(15) grams per cubic
centimeter, and the weight of an object on the surface of a
neutron star would be 10^(11) its weight on the surface of the
Earth. Neutron stars apparently have an outer shell of iron, but
it is iron like no Earth iron, an iron of 4 orders of magnitude
greater density. Theory predicts that a neutron star should
rotate very rapidly, be extremely hot, and have an intense
magnetic field. ... ... Leonard and Bonnell (US National
Aeronautics and Space Administration, US), in a review of gamma
ray bursts and the important data on these phenomena collected
during 1997, point out the following: 1) The current consensus
is that gamma ray bursts are produced by the merger of two
neutron stars; 2) up to this point, the bursts that have been
noted apparently originate outside our own galaxy; 3)
considering the known neutron stars inside our own galaxy, a
case can be made that evolutionary disjunctions in Earth's past
may have been caused not only by asteroid impacts, but also by
gamma- ray bursts from merging neutron stars a few thousand
light years distant in our galaxy. Sky & Telescope February 1998

------------------- Related Background: EVIDENCE FOR DISTANT
SOURCE OF GAMMA RAY BURSTS Gamma Ray Bursts have been much in
the news recently. They were first accidentally discovered some
30 years ago by military satellites, and then interest was
rekindled when the Compton Gamma Ray Observatory was launched by
NASA in 1991. The Compton orbiting device has been detecting
Gamma Ray Bursts in all parts of the sky on a daily basis. One
controversy among astronomers is whether the source is within
our galaxy or extra-galactic. Now Mark R. Metzger, leader of a
team at the California Institute of Technology (Pasadena CA US),
reports that the bursts detected here are coming to us through a
stellar gas cloud about 7 billion light-years away, which means
the source of the bursts must be at least that far, certainly
extra-galactic, and travelling to us for about half the age of
the universe. At least one part of a 30 year old puzzle has
apparently been solved -- the source of the bursts. UPI 15 May 97

---------- Related Background: DETECTION OF X-RAY AFTERGLOW
ASSOCIATED WITH GAMMA-RAY SOURCE Gamma ray bursts (GRBs)
continue to tantalize astrophysicists. The distribution of these
bursts is isotropic across the sky, but inhomogeneous in space,
and with a deficit of faint bursts. The problem is that present
gamma ray telescopes have poor imaging capabilities, and the
phenomenology is unusual in that the bursts last only from a
fraction of a second to hundreds of seconds. At present, it is
not clear whether the bursts are produced in our own galaxy or
at cosmological distances. This week Costa et al (a team of 26
researchers in IT and NL) report an analysis of a GRB of 28
February 1997 (GRB970228). The major discovery is that of an
associated x-ray afterglow which fades within a few days
according to a power-law decay function (empirical). The authors
suggest that for the first time since the discovery of GRBs, it
will now be possible to correlate gamma-ray, x-ray, optical, and
radioastronomy observations. Nature 19 Jun 97

---------- Related Background: AN HISTORIC MEETING DEVOTED TO
GAMMA RAY BURSTS Gamma ray bursts (GRBs) have been much in the
news the past 10 months, principally because of correlative data
from x-ray, optical, and radio instruments. Last month saw the
Fourth Huntsville Symposium on Gamma Ray Bursts (15-20 Sep 1997,
Huntsville AL US), and the meeting is being called "historic".
There is apparently now a consensus that GRBs are cosmological
rather than galactic in origin, in other words from outside our
Milky Way galaxy. So that part of the 30-year puzzle concerning
GRBs is evidently solved. The other part of the puzzle concerns
the physical events producing the bursts, and for that part of
the puzzle there is apparently no consensus yet. It has recently
been proposed that GRBs are associated with the cataclysmic end
of massive stars, and if this is true, it is believed the
appearance of GRBs should provide data concerning the rate of
formation of such stars, a critical parameter that has evidently
been established by observation. In any case, the gamma ray
burst field has apparently now shifted to data analysis at new
wavelengths of the electromagnetic spectrum, with the emphasis
now on x-ray, optical, and radio observations from several
instrument sources, including the valuable BeppoSAX satellite,
the Hubble Space Telescope, and the Burst and Transient Source
Experiment (BATSE) aboard the Compton Gamma Ray Observatory. QY:
Bohdan Paczynski  (Nature 9 Oct 97)

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7. ON SYNTHETIC HELICAL POLYMERS

T. Nakano and Y. Okamoto (Nara Institute of Science and
Technology, JP) discuss helical polymers, the authors making the
following points:

1) The history of helical macromolecules can be traced back to
the discovery of this conformation for some natural polymers.
The helical structure of alpha-amylose was first proposed in
1937 by Hanes and extended by Freudenberg. Pauling proposed an
alpha- helical structure for natural polypeptides, and then
Watson and Crick found the double-helical structure for DNA in
the early 1950s. These two findings were major breakthroughs in
the field of molecular biology.

2) Regarding the helix of polypeptides, in 1956 Doty
demonstrated helix formation for poly(gamma-benzyl-L-glutamate)
arising from the polymerization of the N-carboxyanhydride of the
corresponding amino acid, where a random coil conformation
changes into an alpha-helix as the chain grows. Investigations
of the conformation of poly(beta-amino acid)s began in the
1970s. Although beta-structures were proposed for several of
these polymers, experimental results suggesting a helical
conformation were first obtained by Subirana in 1984. Later, in
1996, Seebach and Gellman independently proved that beta-peptide
oligomers take a helical conformation that is different from the
alpha-helical structure of the alpha-peptide polymers.

3) But already in 1955, Natta found that stereoregular isotactic
polypropylene has a helical structure in the solid state, and
this was the actual beginning of the field of synthetic helical
macromolecules, leading to the wide variety of helical polymers
available today.

Chem Revs. 2001 101:4013

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8. DYNAMICAL X-RAY IMAGING OF SINGLE DNA MOLECULES

Y.C. Sasaki et al (Japan Synchrotron Radiation Research
Institute, JP) discuss imaging of DNA molecules, the authors
making the following points:

1) Imaging methodologies in cell biology ultimately involve both
ultrafast time resolution and in-vivo atomic-scale precision
observations of structural changes in single biomolecules. For
ultrafast time resolution, ultrashort pulsed sources need to be
generated. With x-ray techniques, free-electron laser-type hard
x-ray sources are used to estimate the potential for imaging
single protein molecules and small assemblies. At the wavelength
of visible light, in-vivo observations have greatly advanced due
to the development of fluorescence single-molecule detection
techniques, which have been providing positional information at
an accuracy of approximately 0.01 of the wavelength of visible
light, far below the optical diffraction limit of approximately
half that wavelength. The authors have previously provided data
concerning slow Brownian motions of individual DNA molecules in
various aqueous solutions.

2) The authors report they have now for the first time
demonstrated time-resolved dynamical x-ray imaging of individual
DNA molecules with picometer-scale precision. Diffracted x-ray
tracking, a single-molecule technique using x-rays, monitors the
rotating motions, rather than the translational motions, of a
labeled nanocrystal. The authors suggest the method of
diffracted x-ray tracking can provide information concerning the
dynamics of single molecules via a quantitative analysis, since
the signals in this method are independent of chemical
conditions.

Phys. Rev. Lett. 2001 87:248102

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9. ON CHIRAL AMPLIFICATION OF OLIGOPEPTIDES

H. Zepik et al (Weizmann Institute of Science, IL) discuss
chirality of biopolymers, the authors making the following
points:

1) Theories on the emergence of the homochiral biopolymers of
life at prebiotic times suggest the involvement of
enantioselective reactions that started from heterochiral
mixtures of alpha-amino acid and nucleic acid precursors.
Polymerization reactions of racemates in isotropic media would
lead, however, to formation of polymers comprising a random
sequence of left- and right-handed repeat units in a binomial
distribution. Thus, the probability of obtaining oligomers with
homochiral sequence will become negligible with increasing
length. A possible way to obtain oligopeptides of homochiral
sequence from racemic mixtures would be through the
self-assembly of the precursor molecules into ordered
architectures followed by lattice-controlled reactions.

2) The authors report that differences in the 2-dimensional
packing arrangements of racemic and enantiomeric crystalline
self-assemblies on the water surface of amphiphilic activated
analogs of lysine and glutamic acid have been used to prepare
oligopeptides of homochiral sequence and oligopeptides of single
handedness from chiral nonracemic mixtures. The crystalline
structures on the water surface were determined by grazing
incidence x-ray diffraction and the diasteriomeric composition
of the oligopeptides by matrix-assisted laser desorption
time-of- flight mass spectrometry with enantio-labeling.

The authors suggest their results indicate that reactivity of
ordered clusters at interfaces might have played a role in the
generation of early homochiral biopolymers.

Science 2002 295:1266

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10. ON WATER AND THE STRUCTURE OF BIOMOLECULES

M.S. Pometun et al (University of Louisville, US) discuss water
and biomolecules, the authors making the following points:

1) Water is a critical entity in the structure and function of
biomolecules. For example, when a protein folds into its native
structure, hydrophobic amino acid residues are buried within the
hydrophobic interior. Based on thermodynamic studies in which
hydrophobic amino acids are transferred from aqueous to nonpolar
media, this process is found to lead to a decrease in solvent
ordering, and the resultant entropy gain of the solvent is a
substantial driving force in protein folding. Consequently, the
degree to which water associated with a protein is "ordered" is
an important physical property.

2) X-ray crystallographic study of protein structure has
advanced substantially in its treatment of solvate structure.
Early x-ray studies of proteins assumed a structureless
background. More recent studies, however, identify water
positions for a substantial fraction of the total hydrate in the
crystalline protein lattice. Complementary solid-state deuterium
NMR measurements indicate that the lattice water molecules in
crystalline globular proteins are highly mobile and rapidly
diffuse in the lattice. The possibility of lattice water
molecules occupying discrete sites and rapidly jumping among
these sites has been confirmed for hydrates of cyclodextrins, in
which case the water coordinates were determined by neutron
crystallography. Moreover, solution NMR methods demonstrate that
the number of water molecules strongly bound to globular
proteins is small compared to the number of surface water
molecules identified in the x-ray structure. However, in the
case of fibrous proteins, water likely plays a more important
structural role.

J. Am. Chem. Soc. 2002 124:2345

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11. ON MIGRAINE

P.J. Goadsby et al (Institute of Neurology London, UK) discuss
migraine, the authors making the following points:

1) Migraine is a common, chronic, incapacitating neurovascular
disorder, characterized by attacks of severe headache, autonomic
nervous system dysfunction, and in some patients an aura
involving neurological symptoms. Recent advances in basic and
applied clinical neuroscience have led to the development of a
new class of selective serotonin receptor agonists that activate
specific serotonin receptors, these drugs known as "triptans".
These agents have changed the lives of countless patients with
migraine. But despite such progress, migraine remains
underdiagnosed and the available therapies underused.

2) In terms of diagnostic criteria, migraine is defined as
episodic attacks of headache lasting 4 to 72 hours; with 2 of
the following symptoms: unilateral pain, throbbing, aggravation
on movement, pain of moderate or severe intensity; and one of
the following symptoms: nausea or vomiting, photophobia or
phonophobia.

3) The above symptoms distinguish migraine from tension-type
headache, the most common form of primary headache, which is
characterized by the lack of associated features. Any severe and
recurrent headache is most likely to be a form of migraine and
to be responsive to anti-migraine therapy. In 15 percent of
patients, migraine attacks are usually preceded or accompanied
by transient focal neurological symptoms, which are usually
visual; such patients have migraine with aura (previously known
as "classic migraine"). In a recent large population-based
study, 64 percent of patients with migraine had only migraine
without auras, 18 percent had only migraine with aura, 13
percent had both types of migraine, 3 percent had aura without
headache. Thus, up to 31 percent of patients with migraine have
aura on some occasions, but clinicians who rely on the presence
of aura for the diagnosis of migraine will miss some cases.

4) Migraine is best understood as a primary disorder of the
brain. It is a form of neurovascular headache: a disorder in
which neural events result in the dilation of blood vessels,
which in turn results in pain and further nerve activation.
Migraine is not caused by a primary vascular event, and migraine
attacks are episodic and vary within and among patients. The
basic biological problem in migraine is apparently the
dysfunction of an ion channel in the aminergic brain stem nuclei
that normally modulate sensory input and exert neural influences
on cranial blood vessels.

New Engl. J. Med. 2002 346:257

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12. DIFFERENTIATION OF HUMAN PERIPHERAL-BLOOD STEM CELLS INTO
LIVER CELLS AND EPITHELIAL CELLS

M. Korbling et al (University of Texas, US) discuss
differentiation of blood stem cells, the authors making the
following points:

1) Circulating blood is known to contain stem cells that can
completely restore the production of blood cells (hematopoiesis)
after ablation of the bone marrow. Recently, mesenchymal stem
cells with a capacity for self-renewal and the potential to
differentiate into bone, cartilage, fat, tendon, muscle, or
marrow stroma have been identified in human bone marrow. Whether
such stem cells circulate in the blood is unsettled. A stem cell
in rat bone marrow has been found to differentiate into the
epithelial lineage that generates hepatic oval cells, and in
mice with a metabolic defect that impairs liver function, the
infusion of purified hematopoietic stem cells can restore both
hematopoiesis and liver function. Progenitor cells in mouse bone
marrow have also been shown to differentiate into muscle cells
and can induce muscle regeneration.

2) The existence of stem cells with multiple differentiating
capabilities was conclusively demonstrated by Krause et al
(2001), who showed that a single bone marrow stem cell not only
can restore hematopoiesis in mice that have received otherwise
lethal doses of radiation, but also can differentiate into
mature epithelial cells of the skin, lungs, and gastrointestinal
tract. Moreover, human progenitor cells transplanted into fetal
sheep have been reported to differentiate into hematopoietic
cells and hepatocytes. There is also evidence that human kidney,
liver, and muscle cells can transform into blood-forming cells.
Moreover, two groups have reported the presence of donor-derived
hepatocytes and cholangiocytes in recipients of sex-mismatched
bone marrow transplants.

3) The authors report their investigations indicate that human
blood contains stem cells that can differentiate into cells of
the liver, gastrointestinal tract, and skin. The origin of these
stem cells and the ways in which they generate hepatocytes and
epithelial cells are unknown.

New Engl. J. Med. 2002 346:738

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13. ON SMALLPOX

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

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

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

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

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

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14. BOVINE SPONGIFORM ENCEPHALOPATHY: ANALYSIS OF A POTENTIAL
EPIDEMIC IN BRITISH SHEEP

R.R. Kao et al (University of Oxford, UK) discuss bovine
spongiform encephalopathy, the authors making the following
points:

1) Bovine spongiform encephalopathy (BSE) in the UK was spread
through feed containing meat and bone meal contaminated with
BSE- infected animal material. Sheep in the UK were also fed the
same materials, and it is known that sheep can be infected with
BSE by the oral route. No field cases of sheep BSE have been
observed, but it has been a concern for a number of years,
partly because sheep are the natural hosts of scrapie, a
transmissible spongiform encephalopathy that has clinical signs
indistinguishable from BSE.

2) Because there is a theoretical possibility that the British
national sheep flock is already infected with BSE, the authors
examined the extent of a putative epidemic. An age cohort
analysis based on numbers of infected cattle, dose responses of
cattle and sheep to BSE, levels of exposure to infected feed,
and number of BSE-susceptible sheep in the UK showed that at the
putative epidemic peak in 1990, the number of cases of BSE-
infected sheep would have ranged from fewer than 10 to about
1500. The model predicts that fewer than 20 clinical cases of
BSE in sheep would expected in 2001 if maternal transmission
occurred at a rate of 10 percent. Although there are large
uncertainties in the parameter estimates, all indications are
that current prevalence is low. However, a simple model of
flock-to-flock BSE transmission demonstrates that horizontal
transmission, if it has occurred, could eventually cause a large
epidemic.

Science 2002 295:332

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15. ON DATA WITHHOLDING IN ACADEMIC GENETICS

E.G. Campbell et al (Massachusetts General Hospital Boston, US)
discuss data withholding in academic genetics, the authors
making the following points:

1) The free and open sharing of information, data, and materials
regarding published research is vital to the replication of
published results, the efficient advancement of science, and the
education of students. Yet in daily practice, the ideal of free
sharing is often breached. To understand the nature, extent, and
consequences of data withholding in academic genetics, the
authors conducted a mail survey in the year 2000 of geneticists
and other life scientists in the 100 US universities that
received the most funding from the National Institutes of Health
in 1998. Of 2893 potential eligible respondents, 1849 responded.
The authors analyzed a sub-sample of 1240 self-identified
geneticists and made a limited number of comparisons with 600
self-identified non-geneticists.

2) 47 percent of geneticists who asked other faculty for
additional information, data, or materials regarding published
research reported that at least 1 of their requests had been
denied in the preceding 3 years. 10 percent of all post-
publication requests for additional information were denied.
Because they were denied access to data, 28 percent of
geneticists reported they had been unable to confirm published
research. 12 percent said that in the previous 3 years they had
denied another academician's request for data concerning
published results. Among geneticists who said they had
intentionally withheld data regarding their published work, 80
percent reported that it required too much effort to produce the
materials or information; 64 percent that they were protecting
the ability of a graduate student, postdoctoral fellow, or
junior faculty member to publish; and 53 percent that they were
protecting their own ability to publish. 35 percent of
geneticists said that sharing had decreased during the last
decade; 14 percent said that sharing had increased. Geneticists
were as likely as other life scientists to deny requests by
others and to have their own requests denied. However, other
life scientists were less likely to report that withholding had
a negative impact on their own research as well as their field
of research.

3) The authors conclude that data withholding occurs in academic
genetics and that it affects essential scientific activities
such as the ability to confirm published results.

J. Am. Med. Assoc. 2002 287:473

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16. QUESTIONS CONCERNING UTILITY OF NEUROBLASTOMA SCREENING

F.H. Schilling et al (Olgahospital Stuttgart, DE) discuss
neuroblastoma screening, the authors making the following points:

1) Neuroblastoma is the second most common tumor or childhood,
and between 1987 and 1991, the incidence of neuroblastoma in
Germany was 1.1 per 100,000 children under the age of 15. The
prognosis of patients with neuroblastoma depends on their age
and the stage of the disease at the time of diagnosis; infants
have the best prognosis. In unscreened populations, fewer than
50 percent of all neuroblastomas are localized at the time of
diagnosis. In Europe, the overall survival of children with this
disease has improved only slightly over the past two decades,
and there has been particularly little improvement among older
patients with advanced disease. Early detection has thus been
considered a promising approach to improving the outcome in
patients with neuroblastoma.

2) Most neuroblastomas produce catecholamines, and the
catecholamine metabolites vanillylmandelic acid and homovanillic
acid can easily be measured quantitatively in the urine as a
screen for the disease. However, it is known that neuroblastomas
may undergo spontaneous regression, and therefore some cases
diagnosed by screening might never have become clinically
apparent. In particular, it is not known whether screening for
neuroblastoma at one year of age reduces the incidence of
metastatic disease or mortality due to neuroblastoma.

3) The authors offered urine screening for neuroblastoma at
approximately one year of age to 2,581,188 children in 6 of 16
German states from 1995 to 2000. A total of 2,117,000 eligible
children in the remaining states served as controls. The authors
compared the two groups in terms of the incidence of
disseminated disease and mortality from neuroblastoma.

4) The authors report that their findings do not support the
usefulness of general screening for neuroblastoma at one year of
age. In general, such screening did not reduce the incidence of
disseminated disease, nor did it appear to reduce mortality. The
authors conclude that many of the children with neuroblastoma
that is diagnosed by mass screening may undergo unnecessary
treatment of a tumor that would otherwise spontaneously regress.

New Engl. J. Med. 2002 346:1047

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17. ON MULTI-DRUG RESISTANT TUBERCULOSIS

C. Dye et al (World Health Organization) discuss tuberculosis,
the authors making the following points:

1) The Mycobacterium tuberculosis complex, including its drug-
resistant forms, is a group of pathogens with low reproductive
rates and long generation times, causing epidemics that run over
centuries. Tuberculosis ranks among the most important burdens
on human health, not because the total number of cases is
especially large (approximately 9 million per year worldwide),
but because approximately one-quarter of sufferers die, most of
them young adults. Untreated or untreatable disease would kill
more, approximately half of all cases. Globally, the number of
tuberculosis cases is rising at 2 percent per year, and the fear
is that the number of cases resistant to antibiotics may be
increasing much faster.

2) The perceived threat of drug-resistant tuberculosis is
enormous. The biggest menace is multi-drug-resistant
tuberculosis, caused by strains resistant to at least isoniazid
and rifampcin, the two principal first-time drugs used in
combination chemotherapy. Health warnings have been issued in
correspondingly strong language, not just in the popular press,
but also in principal scientific and medical journals. Among
various readings of the evidence, the spread of multi-drug-
resistant tuberculosis has been classified as a global pandemic
more deadly than AIDS, with the potential to destabilize
society. Drug-resistant mycobacteria are said to be on the
rampage, and multi-drug-resistant tuberculosis is thought to
have become the norm. In the year 2000, an estimated 273,000 of
8.7 million new tuberculosis cases were multi-drug resistant,
with the highest proportion of multi-drug resistant new cases in
Estonia (14 percent); Henan Province, China (11 percent); Latvia
(9 percent); and the Ivanovo and Tomsk provinces in Russia (9
percent and 7 percent, respectively). Resistance is very
unevenly distributed around the world: an estimated 70 percent
of new multi-drug- resistant tuberculosis cases occur in just 10
countries.

Science 2002 295:2042

Related Background:

TUBERCULOSIS AS A GLOBAL DISEASE Clinical tuberculosis is a
disease caused by Mycobacterium tuberculosis, Mycobacterium
bovis, or Mycobacterium africanum. Other *mycobacteria cause
diseases similar to tuberculosis, but they generally respond
poorly to drugs effective for tuberculosis. In developed
countries, human tuberculosis occurs almost exclusively from
inhalation of organisms dispersed as droplet nuclei from a
person with pulmonary tuberculosis whose *sputum smear is
positive. The organism may float in the air for several hours,
thus increasing the chance of spread. Case rates vary by
country, age, race, sex, and socioeconomic status. In the US,
21,337 cases were reported in 1996. The incidence of
tuberculosis has increased markedly among persons infected with
human immunodeficiency virus (HIV), particularly among male drug
users 25 to 44 years old. Signs of what is considered a
potentially very dangerous epidemic of tuberculosis have already
appeared, with the advent of HIV infection creating the
circumstances not only for an increased incidence of
tuberculosis, but also for the development of organisms
resistant to all first-line drugs. ... ... C. Dye et al (5
authors at World Health Organization, CH) present the results of
a study to estimate the risk and prevalence of Mycobacterium
tuberculosis infection and tuberculosis incidence, prevalence,
and mortality, including disease attributable to HIV, for 212
countries in 1997. The authors report as follows: 1) In 1997,
new cases of tuberculosis worldwide ("incidence") totaled an
estimated 7.96 million, including 3.52 million of infectious
pulmonary disease (smear positive). 2) In 1997, there were 16.2
million existing cases of tuberculosis ("prevalence"). 3) In
1997, an estimated 1.87 million people died of tuberculosis, and
the global case fatality rate was 23 percent, but exceeded 50
percent in some African countries with high HIV rates. 4) In
1997, global prevalence of Mycobacterium tuberculosis infection
was 32 percent (1.86 billion people). In 1997, 80 percent of all
incident tuberculosis cases were found in 22 countries, with
more than half the cases occurring in 5 Southeast Asian
countries (India, Indonesia, Bangladesh, Thailand, Myanmar). 5)
The authors conclude: "The global burden of tuberculosis remains
enormous, mainly because of poor control in Southeast Asia,
sub-Saharan Africa, and eastern Europe, and because of high
rates of Mycobacterium tuberculosis and HIV co-infection in some
African countries." ----------- J. Amer. Med. Assoc. 1999
282:477 ----------- Notes: ... ... *mycobacteria: The
Mycobacteria are rod-shaped aerobic bacteria that do not form
spores. Although they do not stain readily, once stained, they
resist decoloration by acid or alcohol, and are therefore called
"acid-fast" bacilli. There are more than 50 mycobacteria
species. Mycobacterium leprae causes leprosy. In tissue,
Mycobacterium tuberculosis bacilli are thin straight rods
measuring approximately 0.4 x 3 microns. On artificial media,
both spherical and rod forms occur. True tubercle bacilli are
acid-fast, the characteristic dependent on the integrity of the
waxy envelope of the organism. ... ... *sputum smear: A standard
technique for detection of tuberculosis is examination of sputum
or other material for acid- fast bacilli by Ziehl-Neelsen
acid-fast staining. If acid-fast organisms are found in an
appropriate specimen, this is considered presumptive evidence of
mycobacterial infection.

---------- Related Background: A CALL FOR ACTION AGAINST
MULTIDRUG-RESISTANT TUBERCULOSIS A group at the Harvard School
of Public Health (US) led by S.J. Heymann has called for global
action against multidrug resistant tuberculosis. The authors
report that global surveillance of tuberculosis indicates that
multidrug-resistant tuberculosis now exists in almost every
country in the world, with a mean prevalence of 4.3 per cent of
all tuberculosis cases, including both new and retreatment
cases. The authors suggest that by inadequately treating
multidrug-resistant tuberculosis, the global community is not
only acceding to the current burden of disease in infected
individuals but to the seeding of successive generations with
infections that will lead to illness, disease transmission, and
premature death. One of the major obstacles to global treatment
of such cases is apparently the high cost: US$800 to US$10,000
per patient. The authors state that the expertise for combating
multidrug-resistant tuberculosis already exists, and that "the
global community can afford to treat all cases of tuberculosis
-- both drug susceptible and multidrug resistant. Clearly, it
cannot afford not to." J. Amer. Med. Assoc. 1999 281:2138

---------- Related Background: ON THE CURRENT STATUS OF
TUBERCULOSIS Roy M. Anderson (University of Oxford, UK) presents
a review of the growing domestic and international problem of
tuberculosis, the author making the following points: 1) In New
York City, from 1985 to 1992, reported cases of tuberculosis
rose by more than 20 percent. This followed a 30-year period of
decline in the incidence of the disease. 2) The reasons for the
reversal include the role of *HIV-1 infection in enhancing
disease progression and transmission, homelessness in the city,
the emergence of multi- drug resistant strains of the
etiological agent (*Mycobacterium tuberculosis), and a failing
public health infrastructure. 3) Globally, the scale of the
tuberculosis problem is enormous, with the World Health
Organization estimating that a third of the population of the
world is infected with the bacterium and predicting 90 million
new cases in the decade up to the year 2000. 4) As the magnitude
of the problem continues to grow, the dream of eradication of
tuberculosis fades into the distant future, despite the fact
that the treatment of the disease by mass chemotherapy is a very
cost-effective public health intervention. 5) Tuberculosis is
likely to remain one of the 10 most important causes of
premature mortality worldwide in the coming 2 decades. ... ...
In an paper in the same issue of the journal (the article the
subject of a commentary by the Anderson review), C.J.L. Murray
and J.A. Salomon (Harvard University, US) present the results of
a mathematical epidemiological modeling study of tuberculosis,
the model applied to 5 regions of the world. The authors report
that 6.7 million new cases of tuberculosis and 2.4 million
deaths from tuberculosis are estimated for 1998. Based on
current trends in international treatment strategy, the authors
report they expect a total of 225 million new cases and 79
million deaths from tuberculosis between 1998 and 2030. The
authors propose that active case-finding could save 23 million
lives over this period. A single contact treatment of
tuberculosis could avert 24 million cases and 11 million deaths,
and combined with active screening could reduce mortality by
nearly 40 percent. A new vaccine with 50 percent efficacy could
lower incidence by 36 million cases and mortality by 9 million
deaths. The authors suggest that support for major extensions to
global tuberculosis control strategies will occur only if the
size of the problem and the potential for action are recognized
more widely. ----------- Proc. Natl. Acad. Sci. 1998
95:13352,13881 ----------- Notes: ... ... *HIV-1: HIV-1 is the
subtype of HIV (human immune- deficiency virus) that causes most
cases of AIDS in the Western Hemisphere, Europe, and Central,
South, and East Africa. ... ... *Mycobacterium tuberculosis: The
mycobacteria (of which there are more than 50 species) are
rod-shaped aerobic bacteria that do not form spores. The two
chief mycobacteria human disease pathogens are M. tuberculosis
(which causes tuberculosis) and M. leprae (which causes
leprosy). The form of the tuberculosis bacterium actually
varies, since on artificial media spherical and filamentous
forms are seen, while in tissue the tubercle bacilli are thin
straight rods measuring approximately 0.4 x 3 microns.

---------- Related Background: ANTI-TUBERCULOSIS DRUG RESISTANCE
1994-1997 In the past 50 years, the proliferation of
anti-microbial agents for use in humans and animals has placed
enormous selective pressure on microorganisms. Drug resistance
in patients with Mycobacterium tuberculosis infection became
apparent soon after the introduction of effective
antituberculosis agents in the 1940s, but it was not until the
early 1990s, when outbreaks of multi-drug-resistant tuberculosis
were reported in patients with human immunodeficiency virus
(HIV) infection in the US and Europe, that the problem received
international attention. ... ... Pablos-Mendez et al (12 authors
at 7 installations, US FR CA NL KR and the World Health
Organization) report a study of the prevalence of resistance to
4 first-line drugs (isoniazid, rifampin, ethambutol,
streptomycin) in 35 countries participating in an international
collaborative study of the problem between 1994 and 1997. Among
patients with no prior treatment, a median of 9.9 percent of M.
tuberculosis strains were resistant to at least one drug. The
prevalence of primary multi-drug resistance (resistance to at
least isoniazid and rifampin) in this group was 1.4 percent.
Among patients with histories of treatment for one month or
less, the prevalence of resistance to any of the four drugs was
36 percent, and the prevalence of multi-drug resistance was 13
percent. Particularly high prevalences of multi-drug resistance
were found in the former Soviet Union, Asia, the Dominican
Republic, and Argentina. The authors conclude that resistance to
antituberculosis drugs exists in all 35 countries and regions
surveyed, and they suggest that it is a global problem. In an
editorial in the same issue of the journal, D.E. Snider and K.G.
Castro (Centers for Disease Control, US) warn that a greater
commitment by the developed countries is needed "if we are to
ward off what could become a global health disaster." ----------
New Engl. J. Med. 4 Jun 1998 338:1641,1689

---------- Related Background: EVIDENCE OF HUMAN GENETIC
SUSCEPTIBILITY TO TUBERCULOSIS A genetic polymorphism is a
naturally occurring variation in the normal nucleotide sequence
of the genome within individuals in a population. Variations are
denoted as polymorphisms only if they cannot be accounted for by
recurrent mutation and occur with a frequency of at least about
1%. Macrophages, of which there are many varieties, are large,
mononuclear cells of the immune system that usually engage in
phagocytosis (physical incorporation and digestion) of foreign
material such as bacteria, particularly in the lung, but may
also be involved with immune system signaling. Tuberculosis
kills more people in the world than any other disease caused by
an infectious pathogen. ... ... Bellamy et al (6 authors at 2
installations, UK GM) report the use of molecular genetic
techniques in a study of human polymorphisms in the macrophage
protein gene [Nramp1] in 410 adults with pulmonary tuberculosis
(and 417 ethnically matched healthy controls) in the Gambia,
West Africa, and that 4 [Nramp1] polymorphisms were each
significantly associated with tuberculosis. The authors suggest
that genetic variation in [Nramp1] affects susceptibility to
tuberculosis in West Africans, and that the results support the
strategy of mapping and identifying genes for resistance to
infectious disease in mice and then testing their human
homologues as candidate genes for susceptibility to related
infections in humans. ---------- New Engl. J. Med. 5 Mar 1998

---------- Related Background: MECHANISM OF MACROPHAGE INVASION
BY TUBERCULOSIS PATHOGEN The mycobacteria include bacterial
species in the genus Mycobacterium. They are a group of
rod-shaped bacteria with large amounts of mycolic acid in their
cell walls. Many mycobacteria are free-living, but two notorious
pathogens are in this group: M. tuberculosis, the cause of
tuberculosis in humans and cattle; and M. leprae, the cause of
leprosy in humans. Tuberculosis was recently under control in
the U.S. (25,000 cases in 1990), but the combination of
immunodeficiency disease and drug-resistant mutant variants of
M. tuberculosis has alarmed epidemiologists, and the incidence
of tuberculosis among certain sub-populations appears to be
rising markedly. The fact is tuberculosis worldwide is the
leading cause of death due to an infectious organism, with an
estimated 3 million deaths annually. Pathogenic mycobacteria
evidently require entry into host macrophages (large ameboid
leukocytes that are part of the vertebrate immunological defense
system) in order to begin the disease process. Now Jeffrey S.
Schorey et al (Washington University School of Medicine, US;
Harvard Medical School, US) have presented evidence that
pathogenic mycobacteria, as opposed to non-pathogenic
mycobacteria, are able to utilize cleavage products (C2a) of
complement proteins (plasma proteins specifically involved with
immune responses) to achieve invasion of macrophages. The
authors suggest this invasion mechanism is crucial in
mycobacterial pathogenesis, and that the mycobacterial cell wall
component required for this invasion process may provide a new
target for therapeutic intervention. ---------- Science 22 Aug
1997

---------- Related Background: DISCOVERY OF
TUBERCULOSIS-ANTAGONIST BODY CHEMICAL Although one-third to
one-half the world's population is infected with tuberculosis,
only a fraction of those who are infected actually get the
life-threatening disease. This has always been a medical
mystery. Now the mystery may be solved, and with it we may have
a new technique for treating tuberculosis that does not involve
antibiotics. Richard A. Young and Gerald J. Nau (Whitehead
Institute for Biomedical Research, Cambridge MA US;
Massachusetts General Hospital, Boston MA US) report the
discovery of a substance called osteopontin that is produced by
the body when the lungs are infected with the tuberculosis
bacillus. Osteopontin, which is produced by macrophages after
they fail to eliminate the infection, acts as a signal for other
defense cells to form a mass of tissue around the invader and
imprison it. These small granulomas are characteristic of
tuberculosis, and are also found in healthy people whose
tuberculosis infection has not become virulent. Young and Nau
believe it may be osteopontin production and the formation of
granulomas that prevent worse infections, and they suggest
osteopontin as a candidate for tuberculosis therapy. Osteopontin
was discovered by comparing thousands of genes operating in
tuberculosis infected tissues with those operating in uninfected
tissues. Apparently, the only noticeable difference is that
infected tissue produces osteopontin. ---------- Proc. Nat.
Acad. Sci. 10 Jun 1997

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18. GENERATION OF PROTEIN NANOARRAYS BY DIP-PEN LITHOGRAPHY

K-B. Lee et al (Northwestern University, US) discuss generation
of protein nanoarrays, the authors making the following points:

1) Arrays of microscopic features comprising different proteins
are important for proteomics and cell research, pharmaceutical
screening processes, and panel immunoassays. Many conventional
patterning techniques, including photolithography, microcontact
printing, and spot arraying, have been used for fabrication such
arrays. Submicrometer spot arrays of proteins have been
generated by finely focused ion beam lithography, and individual
micrometer and submicrometer features have been prepared by
atomic force microscopy techniques with varying degrees of
success.

2) One of the advantages of miniaturization is that when a
feature composed of receptors is miniaturized to the scale of
the biological analytes, new methods for screening reactions
involving such receptors and analytes become available, because
almost every physical property of the receptor feature is
changed upon reaction with the analyte, including the height,
hydrophobicity, roughness, and shape of each feature, which are
all variables easily probed with a conventional atomic force
microscope.

3) The authors report they have used dip-pen lithography to
construct arrays of proteins with 100- to 350-nanometer
features. These nanoarrays exhibit almost no detectable
nonspecific binding of proteins to their passivated portions
even in complex mixtures of proteins, and therefore provide the
opportunity to study a variety of surface-mediated biological
recognition processes. For example, reactions involving the
protein features and antigens in complex solutions can be
screened easily by atomic force microscopy. As further
proof-of-concept, these arrays were used to study cellular
adhesion at the submicrometer scale.

Science 2002 295:1702

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19. ULTRA-SLOW DYNAMICS, AGING SYSTEMS, AND GLASSES

L. Ramos and L. Cipelletti (University of Montpellier, FR)
discuss aging systems, the authors making the following points:

1) The extremely slow dynamics and aging properties of
disordered out-of-equilibrium systems have raised puzzling
questions. A theoretical approach by Sollich et al (1997)
introduced the idea of considering soft glassy materials, and
modeled the glasslike transition and the linear and nonlinear
rheology properties of out-of-equilibrium soft systems with a
theory adapted from the theory of glasses. But despite the large
variety of materials which belong to the soft glassy materials
classification (dense emulsions, pastes, foams, gels, etc.),
experimental investigations of their out-of-equilibrium
properties are scarce, mostly because of experimental
difficulties.

2) The authors studied close-packed multilamellar vesicles.
These systems are typically formed by shearing a surfactant
lamellar phase, otherwise relatively flat, above a critical
shear rate. In the authors's experiments, a compact arrangement
of multilamellar vesicles is obtained by incorporating an
amphiphilic block copolymer into the surfactant lamellar phase.
The authors demonstrate that this system is metastable, as
evidenced by the evolution of its dynamics and mechanical
properties, and they present an experimental investigation of
the aging process of this material using two independent
techniques: dynamic light scattering and linear rheology.

3) In these experiments, light scattering data indicate
rearrangement of the gel through an unusual ultraslow ballistic
motion. A dramatic slowdown of the dynamics with sample age was
observed with both light-scattering and rheology techniques,
suggesting that these methods probe similar processes in this
system, the relaxation of applied or internal stresses for
rheology or light scattering, respectively. The authors present
a simple phenomenological model to account for the observed
dynamics.

Phys. Rev. Lett. 2001 87:245503

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20. ON MAGNETORESISTANCE OF CARBON NANOTUBES

S. Roche and R. Saito (Atomic Energy Commission Grenoble, FR)
discuss magnetoresistance of carbon nanotubes, the authors
making the following points:

1) Single-walled carbon nanotubes exhibit either a metallic or a
semiconducting character depending on their helicity. Metallic
tubes have micron-long mean free paths and behave as long
ballistic conductors. Conversely, the intrinsic properties of
conducting multi-walled nanotubes are elusive. Indeed, reported
ballistic, diffusive, or insulating experimental behaviors
remain difficult to relate to the number and helicities of
constitutive shells and interlayer coupling. It is usually
assumed that the outermost shell, in contact with metallic
electrodes, determines the metallic or semiconducting character
of multi-walled carbon nanotubes.

2) Two fundamental issues concerning these systems are the role
of magnetic fields in transport mechanisms, and the sign and
oscillations of "magnetofingerprints". In general, measuring
magnetoresistance in mesoscopic systems is a formidable tool to
investigate quantum coherent phenomena beyond classical effects.
An elegant perturbation theory of localization has been
developed for metallic cylinders when the mean free path is
smaller than the cylinder circumference. By applying a magnetic
field, time reversal invariance is broken, and dephasing of the
electronic pathways reduces the enhancement of the probability
of "return to the origin" (weak localization). Accordingly, a
decrease of resistance with magnetic field results (negative
magnetoresistance). If the mean free path becomes much larger
than the circumference, the electronic conduction is called
"quasiballistic", and a larger magnetic field is needed to
suppress weak localization. The conduction is finally called
"ballistic" when the mean free path is larger than the distance
between electrodes.

3) In a study of magnetoresistance in these systems, the author
demonstrate that for small nanotube diameters, the location of
the chemical potential and the orientation of the magnetic field
are parameters that enable tuning from positive to negative
magnetoresistance, a phenomenon not related to weak
localization. For larger diameters (=> 10 nanometers), the
conventional mesoscopic behavior of magnetotransport is
recovered.

Phys. Rev. Lett. 2001 87:246803

Notes:

The term "magnetoresistance" refers to a change in the
electrical resistance of a conductor or semiconductor upon the
application of a magnetic field, a property of certain systems.

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

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21. QUANTUM DECOHERENCE AND QUANTUM INFORMATION PROCESSING

D. Bacon et al (University of California Berkeley, US) discuss
quantum information processing, the authors making the following
points:

1) One of the most severe experimental difficulties in quantum
information processing is the fragile nature of quantum
information. Every real quantum system is an open system which
readily couples to its environment, and this coupling causes
quantum information in the system to become entangled with its
environment, which in turn results in the system information
losing its intrinsic quantum nature. This process is known as
"decoherence". Circumvention of this "decoherence problem" has
been shown to be theoretically possible with the development of
the theory of fault-tolerant quantum error correction. However,
the set of requirements to reach the threshold for such fault-
tolerant quantum computation is extremely daunting.

2) In the absence of coupling between a system and its
environment, the system and environment have separate temporal
evolutions determined by their individual energy spectra. When a
small interaction (relative to these energy scales) is switched
on between the two, the resulting evolution is dominated by
pathways that conserve the energy of the unperturbed
system-plus- environment. Under the assumption of such a
perturbative interaction, energetics play a key role in
determining the rate of decoherence processes. Such
energy-conserving decoherence has three possible forms: a)
energy is supplied from the system to the environment (cooling);
b) energy is supplied from the environment to the system
(heating); c) or no energy is exchanged at all
(non-dissipative). Thus, even when the environment is a heat
bath at zero temperature, cooling, and especially non-
dissipative interactions, can be a major source of decoherence.

3) The authors present a quantum informatics method for
suppressing the detrimental effects of decoherence, while at the
same time allowing for robust manipulation of the quantum
information, the objective to aid in breaching the threshold for
robust quantum computation.

Phys. Rev. Lett. 2001 87:247902

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22. ON THE CONFOCAL MICROSCOPE

Steve Paddock (University of Wisconsin Madison, US) discusses
the confocal microscope, the author making the following points:

1) Since its introduction, the confocal microscope has
contributed to many fields of biomedical research and enhanced
the display of biological information. Confocal microscopy came
of age in the early 1980s with the introduction of laser
scanning confocal microscopes for biology. Before this time,
images of relatively thick fluorescently labeled biological
specimens such as embryos were technically challenging to
capture with the use of a conventional wide-field
epifluorescence light microscope. With this latter type of
microscope, background from labeled structures within the
specimen can mask the signal from the focal plane of interest
because the entire specimen is flooded with light. The power of
the confocal approach lies in its ability to collect images in
optical sections at different excitation wavelengths from intact
fluorescently labeled biological specimens.

2) The images produced by a confocal microscope are called
"optical sections" because the instrument effectively reduces
the background signal by scanning the specimen with discrete
points of light. For example, the laser scanning confocal
microscope produces optical sections by using a focused laser
beam to scan the specimen. A spatial filter, usually an
adjustable iris, blocks the passage of any background
fluorescence from above and below the focal plane. The laser
scanning confocal microscope does not create a real image.
Instead, a light-sensitive photomultiplier tube detects light
that passes through the iris, and the resulting signal is sent
to a digital imaging system that constructs it into an image.
Thus, a confocal microscope can yield images of sections of a
specimen without the need to physically slice the specimen, as
would be necessary for conventional microscopy.

Science 2002 295:1319

Copyright (c) 1997-2002 ScienceWeek http://www.scienceweek.com

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23. ON THE INTERNET AS A COMPLEX SYSTEM

W. Willinger et al (ATT Labs-Research, US) discuss the Internet,
the authors making the following points:

1) Today's Internet is a prime example of a large-scale, highly
engineered, yet highly complex system. It is characterized by an
enormous degree of heterogeneity any way one looks and continues
to undergo significant changes over time. In terms of size, by
mid-2001, the Internet consisted of approximately 120 million
hosts, or endpoints, and more than 100,000 distinct networks,
totaling millions of routers and links connecting the hosts to
the routers and the routers to one another. These links differ
widely in speed (from slow modem connections to high-speed
"backbone links) as well as in technology (e.g., wired,
wireless, satellite communications).

2) At the largest scale, the Internet is divided into autonomous
systems, each of which is a collection of routers and links
under a single administrative domain. The global Internet
currently consists of several thousand separate autonomous
systems interlinked to give users the illusion of a single
seamlessly connected network capable of providing a universal
data-delivery service. The foundation of the ubiquitous
connectivity is a datagram (packet) delivery mechanism termed
the Internet Protocol (IP).

3) Given all of the efforts devoted to understanding today's
Internet, it is surprising how often networking researchers
observe "emergent phenomena" -- measurement-driven discoveries
that come as a complete surprise, cannot be explained or
predicted within the framework of the traditionally considered
mathematical models -- phenomena which depend crucially on the
large-scale nature of the Internet, and which are almost always
absent when considering small-scale IP networks.

Proc. Nat. Acad. Sci. 2002 99:2573

Copyright (c) 1997-2002 ScienceWeek http://www.scienceweek.com

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24. ON COUPLING NANOCRYSTALS TO BIOMOLECULES

Y.A. Wang et al (University of Arkansas, US) discuss
applications of nanocrystals, the authors making the following
points:

1) Highly luminescent semiconductor nanocrystals are being
developed as a new generation of biomedical labeling reagents.
This specific application, along with many others, requires
reliable, general, and practical methods to conjugate
nanocrystals with other chemical or biochemical species, methods
that are difficult to accomplish with the nanocrystal/ligand
complexes available at present. This is mainly because these
nanocrystal/ligand complexes cannot survive the coupling
environment and/or the subsequent purification procedures. The
lack of stability of colloidal semiconductor nanocrystals has
also caused some major problems. For example, the synthesis of
"nanocrystal molecules" of colloidal semiconductor nanocrystals
has been limited to the homodimers, because nanocrystals coated
with conventional ligands cannot withstand the desired coupling
and separation processes.

2) A similar situation exists for other types of colloidal
nanocrystals. For example, colloidal gold nanocrystals modified
with single-strand DNA have been used for developing sensitive
detection schemes for the complementary single-strand DNA and
for assembling such nanocrystals into nanocrystal molecules. In
both cases, single-strand DNA is directly attached onto the
surface of gold nanocrystals, and traditional coupling reactions
are again found to be too vigorous for the nanocrystals.

3) The authors present data concerning a series of hydrophilic
organic dendron ligands designed and synthesized for the
stabilization of high-quality semiconductor and noble metal
nanocrystals. The focal point of the dendron ligand is a thiol
group that acts as a universal coordinating site.

J. Am. Chem. Soc. 2002 124:293

Copyright (c) 1997-2002 ScienceWeek http://www.scienceweek.com

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25. IN FOCUS: ON THE HISTORY OF PALEONTOLOGY "It is a remarkable
fact that the human mind, which has had a presence on Earth for
over 2 million years, only began rational thought on how species
came into existence during the last three centuries. Prior to
this age of enlightenment people were content with mythological
explanations. These were later supplanted by formal religious
beliefs, as in the Genesis account of the Creation. Fossils,
which are central to the issue origins, have been known since
the classical time of the Greeks. But it was not until the
second half of the 18th century that the stony objects, dug from
the ground, were correctly interpreted as the remains of former
inhabitants of the Earth. Even then, the intellectuals who
studied fossils were often unable to identify them correctly,
far less to place them in their proper context. For example, the
bilobed bony fossil that Robert Plot of Oxford ascribed to a
giant human in 1676, and which R. Brooks labeled as Scrotum
humanum in 1763, was actually the lower end of the femur of a
dinosaur. Dinosaurs, and their reptilian kin, therefore passed
unrealized, if not unnoticed, until the early part of the 19th
century. Why did it take so long for paleontology---and even
longer for evolutionary studies---to come of age in this age of
discovery? This question is made all the more perplexing when
account is taken of the progress that had been made in many
other branches of science by the 19th century... The reason for
the differential development of the various branches of science
probably has much to do with the graded response of the
established church, specifically the Anglican Church in England.
English theologians and clerics had no argument with those who
tinkered with chemistry or physics, but intellectuals who
questioned the biblical account of the Creation could expect the
full and considerable weight of the church to bear down upon
them." ------------------------------ Christopher McGowan: The
Dragon Seekers: How an Extraordinary Circle of Fossilists
Discovered the Dinosaurs and Paved the Way for Darwin. Perseus
Publishing, Cambridge MA 2001, p.3 (Source information at
Amazon.Com

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