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ScienceWeek
SCIENCEWEEK
ScienceWeek November 1, 2002 Vol. 6 Number 44
An Online Research Digest Published Weekly Since 1997
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Nowadays our sciences, quick and fickle, wear out dogmas in 10
years, and axioms take only a little longer.
-- Erwin Chargaff (1905-2002)
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Section 1
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1. A COPPER BIOMINERAL IN WORM JAWS. Biominerals are widely
exploited to harden or stiffen tissues in living organisms, with
calcium-, silicon-, and iron-based minerals being most common.
In contrast, the jaws of the marine bloodworm Glycera
dibranchiata contain the copper-based biomineral atacamite.
2. CELL BIOLOGY: ON MEMBRANE FUSION. The widely accepted model
for membrane fusion suggests that there is an intermediate state
in which the two contacting monolayers become continuous via an
hourglass-shaped structure called a stalk. Observation of the
stalk structure supports the stalk hypothesis for membrane
fusion.
3. ON ORGANIC CHEMISTRY IN WATER. In recent decades, chemists
have begun investigating the possibility of using water as a
solvent for organic reactions, with sometimes surprising and
unforeseen results. Rates, yields, and selectivities observed
for many reactions in water have begun to match, or even
surpass, those observed in organic solvents.
4. ON ANTIMATTER AND CP VIOLATION. CP violation arises only when
particle masses are generated, and the origin of mass in
particle physics is still a mysterious issue. New data suggest
that CP violation in particle decays may be the cause of
matter-antimatter asymmetry.
5. ON THE EVOLUTION OF MEDICAL SCHOOL ADMISSIONS TESTING. The
origins of the Medical College Admission Test (MCAT) coincide
with the rise of scientific psychology and quantitative
approaches to mental measurement in the late 19th and early 20th
centuries. Through its 74-year history, the various renditions
of the MCAT demonstrate that the definition of aptitude for
medical education reflects the professional and social mores and
values of the time.
6. BREAST CANCER: ON RADICAL MASTECTOMY VS. CONSERVATIVE
SURGERY. The long-term survival rate among women who undergo
breast-conserving surgery is the same as that among women who
undergo radical mastectomy. Breast-conserving surgery is
therefore the treatment of choice for women with relatively
small breast cancers.
7. ECOLOGICAL EFFECTS OF CLIMATE FLUCTUATIONS. Climate
influences a variety of ecological processes, and these effects
operate through local weather parameters such as temperature,
wind, rain, snow, and ocean currents, as well as interactions
among these. In the temperate zone, local variations in weather
are often coupled over large geographic areas.
8. ON SMALL-MOLECULE SYNTHESIS PROGRAMMED BY DNA TEMPLATES. New
observations provide experimental support for previously
proposed models invoking multistep nucleic acid-templated
synthesis as mediating the prebiotic translation of replicable
information into the earliest functional molecules.
9. SCIENCEWEEK NOTICES AND SUBSCRIPTION INFORMATION
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Section 2
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1. A COPPER BIOMINERAL IN WORM JAWS
H.C. Lichtenegger et al (University of California Santa Barbara,
US) discuss biomineralization, the authors making the following
points:
1) Most living organisms rely on hard tissues for support,
protection, nutrition, and defense. Biomineralization is a major
strategy for tissue hardening and manifests an astonishing
diversity of bioceramic structures with exquisite
microarchitectures that have specially adapted physical
properties (1-5). Although the variety of architectures seems to
be almost infinite, Ca-, Si-, and Fe-based minerals are most
common. As a basic principle, the hardness of these is largely
governed by the type of mineral and the degree of mineralization.
2) In 1980, Gibbs and Bryan first reported copper levels up to
13% w/w in the jaws of the marine polychaete worm Glycera sp.
Although it was initially suspected that these levels reflected
heavy metal pollution at the collection site, jaw composition
was found to be remarkably consistent and independent of copper
concentration in the seawater. Copper was the most abundant
inorganic component; protein, however, was the most predominant
constituent (measured as percent of dry weight). The authors
concluded that the copper might play a role in mechanically
hardening the proteinaceous material. However, no attempt to
determine the actual hardness was made nor was the form of the
copper further explored.
3) In summary: Biominerals are widely exploited to harden or
stiffen tissues in living organisms, with calcium-, silicon-,
and iron-based minerals being most common. In notable contrast,
the jaws of the marine bloodworm Glycera dibranchiata contain
the copper-based biomineral atacamite [Cu2(OH)3Cl].
Polycrystalline fibers are oriented with the outer contour of
the jaw. Using nanoindentation, the authors demonstrate that the
mineral has a structural role and enhances hardness and
stiffness. Despite the low degree of mineralization, bloodworm
jaws exhibit an extraordinary resistance to abrasion,
significantly exceeding that of vertebrate dentin and
approaching that of tooth enamel.
References (abridged):
1. J. Aizenberg, A. Tkachenko, S. Weiner, L. Addadi, G. Hendler,
Nature 412, 819 (2001)
2. L. Addadi and S. Weiner, Nature 411, 753 (2001)
3. S. Kamat, X. Su, R. Ballarini, A. H. Heuer, Nature 405, 1036
(2000)
4. S. Mann, Nature 365, 499 (1993)
5. J. N. Cha, et al., Proc. Natl. Acad. Sci. U.S.. 96, 361 (1999)
Science 2002 298:389
Web Links: biomineralization
Related Background Brief:
CALCITIC MICROLENSES AS PART OF THE PHOTORECEPTOR SYSTEM IN
BRITTLESTARS. Photosensitivity in most echinoderms has been
attributed to "diffuse" dermal receptors. The authors report
that certain single calcite crystals used by brittlestars for
skeletal construction are also a component of specialized
photosensory organs, conceivably with the function of a compound
eye. The analysis of arm ossicles in Ophiocoma showed that in
light-sensitive species, the periphery of the labyrinthic
calcitic skeleton extends into a regular array of spherical
microstructures that have a characteristic double-lens design.
These structures are absent in light-indifferent species.
Photolithographic experiments in which a photoresist film was
illuminated through the lens array showed selective exposure of
the photoresist under the lens centres. These results provide
experimental evidence that the microlenses are optical elements
that guide and focus the light inside the tissue. The estimated
focal distance (4-7 micrometer below the lenses) coincides with
the location of nerve bundles -- the presumed primary
photoreceptors. The lens array is designed to minimize spherical
aberration and birefringence and to detect light from a
particular direction. The optical performance is further
optimized by phototropic chromatophores that regulate the dose
of illumination reaching the receptors. These structures
represent an example of a multifunctional biomaterial that
fulfills both mechanical and optical functions. J. Aizenberg et
al: Nature. 2001 412:783.
Related Background Brief:
BIOMINERALIZATION: AT THE CUTTING EDGE. In 1962, Heinz Lowenstam
discovered that the outer layer of the teeth of a common
intertidal mollusk, the chiton, is composed of magnetite. This
magnetic iron oxide mineral was then thought to form only at
elevated temperatures and pressures. The discovery focused
attention on the ability of living systems to produce unexpected
minerals, and proved to be a turning point for the field then
known as calcification. Forty years later, Lichtenegger et al.
(2002) now report more dental surprises, demonstrating that a
copper chloride mineral, atacamite, is formed in the teeth of
the carnivorous marine worm Glycera. It is the first copper
mineral to be identified that is formed under controlled
conditions in an organism, prompting the question of how they
can scavenge enough copper from their surroundings to produce
this mineral. The mineral atacamite is the latest addition to
the growing list of known biological minerals. This list,
compiled and monitored periodically by Lowenstam for more than
30 years, has expanded from just over 10 in the early 1960s to
almost 70 today. Many of the minerals do not contain calcium,
prompting a change in the name of the field to
"biomineralization". S. Weiner and L. Addadi: Science 2002
298:375.
Related Background:
ON MINERALIZATION IN BIOLOGICAL SYSTEMS
W.L. Murphy and D.J. Mooney (University of Michigan, US) discuss
mineralization, the authors making the following points:
1) Mineralization in biological systems is an elegant and
structurally complex process involving ionic, stereochemical,
and structural interactions at the biomacromolecule-mineral
interface.(1,2) A wide variety of organisms utilize diverse
schemes to grow biominerals with functions ranging from magnetic
sensing(3) (magnetite in magnetotactic bacteria) to structural
support(4) (dahllite in vertebrate skeletons). The paradigm
linking each biomineralization strategy is a supreme level of
control over the physical chemistry of mineral growth.
2) Mineralization during vertebrate bone growth is a classic
example in which hydrophobic collagen fibrils are organized into
parallel sheets with periodically staggered "hole zones". These
spaces are rich in phospho- and glycoproteins, creating a local
charge accumulation.(5) The anionic nature of the hole zone,
along with structural and stereochemical interactions, are
thought to lead to attraction of calcium-rich mineral nuclei and
initiation of mineral growth. A similar mechanism drives mollusk
shell development, with hydrophobic beta-chitin providing a
substrate for deposition of acidic, anionic proteins that drive
aragonite nucleation. In each case, an organic, hydrophobic
material acts as a framework for deposition of an anionic,
hydrophilic mineral nucleator that, in turn, drives mineral
nucleation. Although the understanding of complex biological
mineralization systems is incomplete and continues to grow, the
fundamental mechanisms outlined above can be mimicked in
synthetic systems to direct ex vivo biomineralization.
3) The highly controlled morphology, physical properties, and
nanostructure of biological minerals have led to the development
of biomimetic systems for controlled mineral formation ex vivo.
The development of ex vivo systems is motivated both by the
desire to more completely understand biomineralization processes
and by the potential utility of biominerals in industrial and
biomedical applications. Prevalent strategies involve pragmatic
presentation of polar functional groups that both increase local
ion accumulation via electrostatic effects(1) and decrease the
energy at the organic substrate-mineral nucleus interface.(1) In
each case, the basic, biomimetic premise is that functional
groups present in large quantities at the mineralization front
in biological systems are capable of inducing mineral nucleation
if presented in the appropriate fashion. Select model systems
have been extended to biomedical applications, such as
hydroxyapatite mineral growth on functionalized titanium and
bioactive, ion-exchange glasses. Carbonated hydroxyapatite is
the major mineral component in human bone extracellular matrix,
and bonelike mineral coatings appear to have pronounced effects
on proper bone tissue development. More specifically, a bonelike
mineral has been shown to be a prerequisite to bonding of
orthopedic implant materials to native bone tissue
(osteoconductivity), and may drive osteogenic differentiation of
adult human stem cells (osteoinductivity). Despite the potential
benefits of biominerals in regenerative medicine, few studies to
date have been aimed at mineral formation on degradable
biomaterials for use in orthopedic tissue regeneration.
References (abridged):
1. Mann, S.; Archibald, D. D.; Didymus, J. M.; et al. Science
1993, 261, 1286
2. Sarikaya, M. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 14183
3. Chasteen, N. D.; Harrison, P. M. J. Struct. Biol. 1999, 126,
182
4. Weiner, S.; Traub, W.; Wagner, H. D. J. Struct. Biol. 1999,
126, 241
5. Lee, S.; Veis, A. J. Peptide Protein Res. 1980, 16, 231
J. Am. Chem. Soc. 2002 124:1910
Web Links: bone formation mineralization in biological
systems
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2. CELL BIOLOGY: ON MEMBRANE FUSION
L. Yang and H.W. Huang (Brookhaven National Laboratory, US)
discuss membrane fusion, the authors making the following points:
1) Membrane fusion takes place during many cellular processes,
including membrane traffic, fertilization, and infection by
enveloped viruses. Fusion allows the exchange of contents
between different membrane compartments. In order to maintain
the individuality of each of the intracellular compartments and
of the cell itself, membranes do not fuse easily under normal
circumstances. Thus, the process requires special proteins and
is subject to selective control. Understanding the fusion
mechanism is important not only for fundamental biology but also
for medical applications such as drug delivery and gene therapy.
2) Substantial progress has been made in the elucidation of the
structures of membrane fusion proteins (1,2) and in the
estimations of the free energies for the rearrangement of lipid
bilayers during fusion (3-5). Theoretical studies have
identified the free energy barriers that suggest a requirement
for mechanical work by fusion proteins, providing guidance for
identifying the functions of protein structures. However, how
proteins induce membrane fusion remains speculative, even in the
best-studied case of viral fusion proteins (1), because key
intermediate structures have not been observed.
3) Membrane fusion between phospholipid bilayers can be induced
by a variety of chemicals, perhaps most simply by multivalent
ions. The apparent role of multivalent ions is to bring two
apposing lipid bilayers into contact. The authors report the
observation of a phase of phospholipid that contains a structure
similar to the commonly postulated interbilayer state that is
crucial to membrane fusion. The widely accepted model for
membrane fusion suggests that there is an intermediate state in
which the two contacting monolayers become continuous via an
hourglass-shaped structure called a "stalk". Many efforts have
been made to estimate the free energy for such a state in order
to understand the functionality of membrane fusion proteins and
to define key parameters in energy estimates. This observation
of the stalk structure supports the stalk hypothesis for
membrane fusion and enables the measurement of these parameters
experimentally.
References (abridged):
1. J. M. White, Science 258, 917 (1992)
2. A. T. Brünger, Curr. Opin. Struct. Biol. 11, 163 (2001)
3. D. P. Siegel, Biophys. J. 65, 2124 (1993)
4. Y. A. Chizmadzhev, F. S. Cohen, A. Shcherbakov, J.
Zimmerberg, Biophys. J. 69, 2489 (1995)
5. P. I. Kuzmin, J. Zimmerberg, Y. A. Chizmadzhev, F. S. Cohen,
Proc. Natl. Acad. Sci. U.S.A. 98, 7235 (2001)
Science 2002 297:1877
Web Links: membrane fusion
Related Background Brief:
MEMBRANE FUSION. Common themes are emerging from the study of
viral, cell-cell, intracellular, and liposome fusion. Viral and
cellular membrane fusion events are mediated by fusion proteins
or "fusion machines". Viral fusion proteins share important
characteristics, notably a fusion peptide within a
transmembrane-anchored polypeptide chain. At least one protein
involved in a cell-cell fusion reaction resembles viral fusion
proteins. Components of intracellular fusion machines are
utilized in multiple membrane trafficking events and are
conserved through evolution. Fusion pores develop during and
intracellular fusion events suggesting similar mechanisms for
many, if not all, fusion events. J.M. White: Science 1992
258:917.
Related Background Brief:
ENERGETICS OF INTERMEDIATES IN MEMBRANE FUSION: COMPARISON OF
STALK AND INVERTED MICELLAR INTERMEDIATE MECHANISMS. To
understand the mechanism of membrane fusion, we have to infer
the sequence of structural transformations that occurs during
the process. The author demonstrates how one can estimate the
lipid composition-dependent free energies of intermediate
structures of different geometries. One can then infer which
fusion mechanism is the best explanation of observed behavior in
different systems by selecting the mechanism that requires the
least energy. The treatment involves no adjustable parameters.
It includes contributions to the intermediate energy resulting
from the presence of hydrophobic interstices within structures
formed between apposed bilayers. Results of these calculations
show that a modified form of the stalk mechanism proposed by
others is a likely fusion mechanism in a wide range of lipid
compositions, but a mechanism based on inverted micellar
intermediates (IMIs) is not. This should be true even in the
vicinity of the lamellar/inverted hexagonal phase transition,
where IMI formation would be most facile. Another prediction of
the calculations is that traces of apolar lipids (e.g.,
long-chain alkanes) in membranes should have a substantial
influence on fusion rates in general. The same theoretical
methods can be used to generate and refine mechanisms for
protein-mediated fusion. D.P. Siegel: Biophys J 1993 65:2124.
Related Background Brief:
MEMBRANE MECHANICS CAN ACCOUNT FOR FUSION PORE DILATION IN
STAGES. Once formed, fusion pores rapidly enlarge to semi-stable
conductance values. The membranes lining the fusion pore are
continuous bilayer structures, so variations of conductance in
time reflect bending and stretching of membranes. The authors
report they therefore modeled the evolution of fusion pores
using the theory of the mechanics of deforming homogeneous
membranes. The authors calculated the changes in length and
width of theoretical fusion pores according to standard
dynamical equations of motion. Theoretical fusion pores quickly
achieve semi-stable dimensions, which correspond to energy
minima located in a canyon between energy barriers. The height
of the barrier preventing pore expansion diminishes along the
dimensions of length and width. The bottom of the canyon slopes
gently downward along increasing length. As a consequence,
theoretical fusion pores slowly lengthen and widen as the
dimensions migrate along the bottom of the canyon, until the
barrier vanishes and the pore rapidly enlarges. The dynamics of
growth is sensitive to tension, spontaneous curvature, bending
elasticity, and mobilities. This sensitivity can account for the
quantitative differences in pore evolution observed in two
experimental systems: HA-expressing cells fusing to planar
bilayer membranes and beige mouse mast cell degranulation. The
authors conclude that the mechanics of membranes could cause the
phenomenon of stagewise growth of fusion pores. Y.A. Chizmadzhev
et al: Biophys J 1995 69:2489.
Related Background Brief:
A QUANTITATIVE MODEL FOR MEMBRANE FUSION BASED ON LOW-ENERGY
INTERMEDIATES. The energetics of a fusion pathway is considered,
starting from the contact site where two apposed membranes each
locally protrude (as "nipples") toward each other. The
equilibrium distance between the tips of the two nipples is
determined by a balance of physical forces: repulsion caused by
hydration and attraction generated by fusion proteins. The
energy to create the initial stalk, caused by bending of cis
monolayer leaflets, is much less when the stalk forms between
nipples rather than parallel flat membranes. The stalk cannot,
however, expand by bending deformations alone, because this
would necessitate the creation of a hydrophobic void of
prohibitively high energy. But small movements of the lipids out
of the plane of their monolayers allow transformation of the
stalk into a modified stalk. This intermediate, not previously
considered, is a low-energy structure that can reconfigure into
a fusion pore via an additional intermediate, the prepore. The
lipids of this latter structure are oriented as in a fusion
pore, but the bilayer is locally compressed. All membrane
rearrangements occur in a discrete local region without creation
of an extended hemifusion diaphragm. Importantly, all steps of
the proposed pathway are energetically feasible. P.I. Kuzmin et
al: Proc. Nat. Acad. Sci. 2001 98:7235.
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3. ON ORGANIC CHEMISTRY IN WATER
Ulf M. Lindstroem (Lund University, SE) discusses organic
reactions in water, the author making the following points:
1) In recent decades, chemists have begun investigating the
possibility of using water as a solvent for organic reactions,
with sometimes surprising and unforeseen results. Without
overlooking some earlier contributions, the discoveries made in
the laboratories of Breslow(1-3) and Grieco(4,5) in the early
1980s on the positive effect of water on rates and selectivities
of Diels-Alder reactions are often recognized as the "Big Bang"
in aqueous synthesis that triggered a more widespread interest
in the field. Since then, significant progress has been made in
the field of organic chemistry in water/aqueous media, and new
additions are continuously being made to the list of organic
transformations that can be performed efficiently in aqueous
solvent. Besides the Diels-Alder reaction, other examples
include Claisen-rearrangements, aldol reactions, allylation
reactions, and oxidations and hydrogenations of alkenes, to
mention a few. These types of reactions have been among the most
useful to the synthetic chemist for many decades and, indeed,
still are. Their usefulness is reflected by the effort that has
been devoted to the discovery of methods with which they can be
executed catalytically and stereoselectively. With a few notable
exceptions, however, the development of chiral ligands and
catalysts for asymmetric synthesis has been carried out almost
exclusively in organic media.
2) Is water, then, a viable alternative solvent? Over the last
5-10 years, the concept of efficient and stereoselective
synthesis in water has been solidified as the rates, yields, and
selectivities observed for many reactions in water have begun to
match, or even surpass, those observed in organic solvents. In
view of recent achievements, the answer to the above question is
"yes". From a less synthetic standpoint, increased appreciation
of organic reactions in water may also contribute to our
understanding of the basic mechanisms of life.
3) Since until recently, the use of water as solvent for organic
reactions was mainly restricted to simple hydrolysis reactions,
most reagents and catalysts in organic synthesis have been
imperiously developed for use in anhydrous, organic reaction
media. Why should we now spend time "rediscovering" reactions
for use in water that already work well in familiar organic
solvents such as tetrahydrofuran (THF), toluene, or methylene
chloride? Because there are many potential advantages in
replacing these and other unnatural solvents with water. The
most obvious are the following. (a) Cost. It does not get any
cheaper than water! (b) Safety. Most of the organic solvents
used in the lab today are associated with risks: Flammables,
explosives, carcinogenics, etc. (c) Environmental concerns. The
chemical industry is a major contributor to environmental
pollution. With increasing regulatory pressure focusing on
organic solvents, the development of nonhazardous alternatives
is of great importance.
References (abridged):
1. Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816
2. Breslow, R.; Maitra, U.; Rideout, D. C. Tetrahedron Lett.
1983, 24, 1901
3. Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239
4. Grieco, P. A.; Garner, P.; He, Z. Tetrahedron Lett. 1983, 25,
1897
5. Grieco, P. A.; Yoshida, K.; Garner, P. J. Org. Chem. 1983,
48, 3137
Chem. Rev. 2002 102:2751
Web Links: organic reactions in water
Related Background Brief:
HYDROPHOBIC ACCELERATION OF DIELS-ALDER REACTIONS. The kinetics
of the Diels-Alder reactions of cyclopentadiene with buten-3-one
and acrylonitrile were examined in 2,2,4-trimethylpentane, in
MeOH, and in H2O. Large accelerations by H2O compared with the
nonpolar medium are ascribed to hydrophobic stabilization of the
transition state. In the Diels-Alder addition of
N-ethylmaleimide to anthracene-9-carbinol increasing polarity of
the solvent slows the reaction, but H2O actually speeds it up
since the hydrophobic effect more than compensates for the high
polarity of H2O. The Diels-Alder reactions of cyclopentadiene
with butenone and acrylonitrile are further accelerated by
b-cyclodextrin (cycloheptaamylose), but inhibited by
a-cyclodextrin (cyclohexaamylose). This is ascribed to the
hydrophobic binding of both the diene and dienophile into the
same b-cyclodextrin cavity, but not into the smaller
a-cyclodextrin cavity. In the bulkier reaction of
anthracene-9-carbinol and N-ethylmaleimide even the
b-cyclodextrin cavity is too small, and b-cyclodextrin is an
inhibitor. D.C. Rideout and R. Breslow: J. Am. Chem. Soc. 1980
102:7816.
Related Background Brief:
POWERFUL SOLVENT EFFECT OF WATER IN RADICAL REACTION:
TRIETHYLBORANE-INDUCED ATOM-TRANSFER RADICAL CYCLIZATION IN
WATER. Triethylborane-induced atom-transfer radical cyclization
of iodo acetals and iodoacetates in water is described. Radical
cyclization of iodo acetal proceeded smoothly both in aqueous
methanol and in water. Atom-transfer radical cyclization of
allyl iodoacetate (3a) is much more efficient in water than in
benzene or hexane. For instance, treatment of 3a with
triethylborane in benzene or hexane at room temperature did not
yield the desired lactone. In contrast, 3a cyclized much more
smoothly in water and yielded the corresponding lactone in high
yield. The remarkable solvent effect of water was observed in
this reaction, although the medium effect is believed to be
small in radical reactions. Powerful solvent effects also
operate in the preparation of medium- and large-ring lactones.
Water as a reaction solvent strikingly promoted the cyclization
reaction of large-membered rings. Stirring a solution of
3,6-dioxa-8-nonenyl iodoacetate in water in the presence of
triethylborane at 25 C for 10 h provided a 12-membered ring
product, 4-iodo-6,9-dioxa-11-undecanolide, in 84% yield. On the
other hand, reaction in benzene afforded the lactone in only 22%
yield. Ab initio calculations were conducted to reveal the
origin of the solvent effect of water in the cyclization of
allyl iodoacetate. Calculations with the SCRF/CPCM option
indicate that the large dielectric constant of water lowers the
barrier not only to rotation from the Z-rotamer to the E-rotamer
that can cyclize but also to cyclization constructing the
lactone framework. Moreover, the high cohesive energy density of
water also effects acceleration of the cyclization because water
forces a decrease in the volume of the reactant. J. Am. Chem.
Soc. 2000 122:11041.
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4. ON ANTIMATTER AND CP VIOLATION
Michael Peskin (Stanford University, US) discusses antimatter,
the author making the following points:
1) Every elementary particle has an antiparticle, a counterpart
with precisely the same mass and the opposite electric charge.
It would seem natural that all of the interactions of
antiparticles are just the opposite of those of particles. But
in 1964, in a Nobel-prize-winning experiment, Cronin and Fitch
showed that this is not so(1). Their measurement showed up a
tiny difference, one part in a million of the strength of the
weak interaction. New measurements from the BaBar experiment(2)
at Stanford University (US) and from the Belle experiment(3) at
Tsukuba, Japan, seem finally to have established a definite
origin for this small difference in the behavior of particles
and antiparticles. The new data are a triumph for a theory
proposed 30 years ago. But they are also a disappointment. The
results so far do not help us understand the most obvious
matter–antimatter asymmetry in nature -- the fact that we see
matter, but no antimatter, in the Universe at large.
2) The asymmetry in question is a basic one. It is well
established that the laws of physics are the same irrespective
of the position, time or orientation of the observer. From this
statement, it would seem obvious that the laws of physics would
also be the same when reflected in a mirror. But in 1956,
following the suggestion of Lee and Yang, it was found that the
weak interactions that mediate radioactive decay are completely
mirror-asymmetric: nuclear beta-decay preferentially produces
particles that spin in the left-handed sense and antiparticles
that spin in the right-handed sense. The interaction, however,
seemed to respect the combined operation of mirror reflection
(which turns a left-handed spin into a right-handed one) and
interchange of particle and antiparticle. Physicists refer to
these two operations as P ("parity") and C ("charge
conjugation"), so the combined operation is called "CP".
3) The Cronin–Fitch experiment, however, showed that the CP
symmetry could be violated in specific particle decays. But it
was not clear how to develop new equations to include this
effect. CP violation arises only when particle masses are
generated, and the origin of mass in particle physics is even
now a mysterious issue, one that the elusive Higgs boson might
solve. The new BaBar and Belle data suggest that CP violation
in particle decays may be the cause of matter-antimatter
asymmetry.(4,5)
References (abridged):
1. Christenson, J. H., Cronin, J. W., Fitch, V. L. & Turlay, R.
Phys. Rev. Lett. 13, 138-140 (1964)
2. Aubert, B. et al. (BaBar collaboration) Preprint
hep-ex/0207042 (2002); http://arXiv.org
3. Abe, K. et al. (Belle collaboration) Preprint hep-ex/0207098
(2002); http://arXiv.org
4. Sakharov, A. D. JETP Lett. 5, 24-27 (1967)
5. Kobayashi, M. & Maskawa, T. Prog. Theor. Phys. 49, 652-657
(1973)
Nature 2002 419:24
Web Links: antimatter CP violation
Related Background:
SPOTLIGHT: NEUTRINO OSCILLATIONS
The history of particle physics during the first 30 years of the
20th century is an excellent example of the intimate interplay
between theory and experiment. One of the central problems in
the physics of matter during this period was to understand the
emissions of radioactive substances first discovered in 1896 by
Henri Becquerel (1852-1908). Spontaneous radioactive decay is
essentially a spontaneous transmutation of an unstable atomic
nucleus (nuclide) A into nuclide B, with nuclide A initially in
a higher energy state and losing energy to transmute into the
"daughter" nuclide B. During the early years of particle
physics, the energy loss was considered to be accomplished by
emission of one of three types, depending on the nature of
nuclide A: positively charged alpha particles (helium nuclei),
negatively charged beta particles (electrons), or neutral gamma
rays (high energy electromagnetic radiation). Since the energies
of decaying nuclides and daughter nuclides are fixed according
to nuclide identity, one would expect the observed energies of
the 3 types of particles to also be fixed for each species of
decaying nuclide. During the period before 1927, this was known
to be true for alpha particles and gamma rays, but there was
intense controversy about whether it was true for beta
particles. Indeed, some early experiments indicated that it was
not true for beta particles, and this posed a problem, since
conservation laws require an accounting for all the energy and
the numbers for beta decay did not add up. The controversy
continued for nearly 30 years, particularly among
experimentalists who disagreed concerning experimental methods
and interpretations of experimental results, until finally in
the late 1920s it was conclusively demonstrated by experiment
that during the beta-decay process high-speed electrons of
various energies are emitted with a continuous beta-emission
energy distribution spectrum (i.e., a plot of the number of
electrons vs. energy of these electrons) over the range of
energies.
Given the experimental evidence of a continuous beta-decay
spectrum, theoreticians tackled the problem of accounting for
beta decay without violating conservation laws. In 1930,
Wolfgang Pauli (1900-1958) proposed that when a beta particle
was emitted, another particle, without charge, and perhaps
without mass, was also emitted, and that this second particle
carried off the missing energy. Enrico Fermi (1901-1954)
suggested the particle carrying the missing energy be called
"neutrino", which is Italian for "little neutral one", and in
1934 Fermi incorporated the neutrino into his theory of beta
decay.
Most theoretical and experimental physicists immediately
accepted the proposed existence of the neutrino as the best
solution to an important puzzle, but it was not until 1956 that
Frederick Reines (1918-1998) and Clyde Cowan (1919-1974) managed
to finally obtain experimental evidence for the existence of the
elusive neutrino by means of experiments involving emission
beams from a fission reactor. Enrico Fermi received the Nobel
Prize in Physics in 1938; Wolfgang Pauli received the Nobel
Prize in Physics in 1945; and Frederick Reines received the
Nobel Prize in Physics in 1995. (Clyde Cowan was not eligible
for the Nobel Prize at the time it was awarded to Reines, since
the Nobel Prize is not awarded posthumously.)
In general, beta-decay is a type of interaction in which an
unstable atomic nucleus changes into a nucleus of the same mass
number but different proton number. The change involves the
conversion of a neutron into a proton with the emission of an
electron and an electron *antineutrino, or of a proton into a
neutron with the emission of a positron and an electron
neutrino. The electrons or positrons emitted are called "beta
particles". (Positrons are electron antiparticles. See
*antineutrino.)
An "antiparticle" (antimatter) is a subatomic particle that has
the same mass as another particle and equal but opposite values
of some other property or properties. For example, the
antiparticle of the electron is the positron. An antineutrino,
the antiparticle to the neutrino, has zero mass, *spin 1/2, and
positive helicity. There are 2 antineutrinos, one associated
with the electron and one associated with the *muon.
"Leptons" are a class of elementary particles. Although they are
affected by electromagnetic and gravitational forces, apart from
that they are involved only with weak interactions, acted upon
by weak forces but not by strong forces, as opposed to quarks,
which are acted upon by strong forces but not by weak forces.
One further difference between leptons and quarks is that
leptons can be isolated as single particles, whereas quarks
apparently cannot. The leptons include the electron, the muon,
the tau, and their associated neutrinos. The mass of the tau is
approximately 3484 times the mass of the electron; the mass of
the muon is intermediate.
In quantum mechanics, "spin" is the intrinsic angular momentum
of a subatomic particle. Spin states are quantized, multiples of
h/2(pi), where h = Planck's constant, and each particle is
characterized by a quantum spin number which is the multiple
factor. All subatomic particles can be classified as one of two
types: "fermions" are particles with half-integer values of
spin, and "bosons" are particles with integer values of spin.
Leptons are fermions.
The "Z boson" is an electrically neutral elementary particle,
discovered in 1983, which is believed to mediate weak
interactions. The "W boson", also discovered in 1983, is of two
types, positively charged or negatively charged, and like the Z
boson it mediates weak interactions. The particle now called the
"muon" was discovered in 1936 by Carl Anderson (1905-1991), who
discovered the particle while studying cosmic rays. The muon is
a negatively-charged lepton similar to the electron except that
its mass is approximately 207 times the electron mass. The muon
has a average lifetime of 2.2 microseconds, and decays into an
electron, a neutrino, and an antineutrino. "Mesons" are a class
of elementary particles involved in strong interactions in the
atomic nucleus. Muons were originally called "mu-mesons" because
they were thought to be mesons, but that idea was eventually
abandoned, and muons are now recognized as leptons. Similar to
the electron, which has an associated positive particle called
the "positron", there exists a positively charged muon.
A "quark" is a hypothetical fundamental particle, having charges
whose magnitudes are one-third or two-thirds of the electron
charge, and from which the elementary particles may in theory be
constructed.
In particle physics, the "Standard Model" is a theoretical
framework whose basic idea is that all the visible matter in the
universe can be described in terms of the elementary particles
leptons and quarks and the forces acting between them. The
fundamental forces comprise the gravitational force, the
electromagnetic force, the nuclear strong force, and the nuclear
weak force. The "electroweak interactions" are a unification of
the electromagnetic and nuclear weak interactions, and are
described by the Weinberg-Salam theory (sometimes called
"quantum flavordynamics"; also called the Glashow-Weinberg-Salam
theory).
The 3 leptons (electron, muon, tau) differ from each other only
in mass. The muon is 200 times more massive than the electron.
In this context, the term "flavor" is a label used to
distinguish different types of leptons.
"Cosmic rays" are highly energetic particles moving at close to
the speed of light and continuously bombarding the Earth's
atmosphere from all directions. The energies of the particles
are enormous and range from 10^(8) to over 10^(19) electronvolts.
Discovered in 1934 by Cerenkov (1904-1990), Cerenkov (Cherenkov)
radiation is electromagnetic radiation, usually bluish light,
emitted by a beam of high-energy charged particles passing
through a transparent medium at a speed greater than the speed
of light in that medium. The radiation is essentially a shock
wave, the effect analogous to that of a sonic boom.
C. Bemporad et al (University of Pisa, IT) discuss neutrino
oscillations, the authors making the following points:
1) Neutrinos have the distinction of being the first elementary
particle whose existence was predicted by a theorist in order to
explain seemingly unrelated phenomena (1). Wolfgang Pauli
(1900-1958) made this prediction in 1930 in his famous letter
attempting to explain the continuous electron energy
distribution in nuclear beta decay. It became immediately clear
that neutrinos would be difficult to observe, because the
corresponding cross sections are so tiny. But in a series of
experiments from 1953 to 1959, Reines and Cowan (2) were able to
prove convincingly that electron antineutrinos are emitted by
nuclear reactors and hence that they are real particles. Shortly
afterwards, in 1962, the separate identity of muon neutrinos was
demonstrated (3). Another decade later, in 1975, the tau lepton
was discovered (4) and the observation of its decay properties
implied the existence of a third neutrino that was directly
observed only very recently (5). Precise measurements of the
decay width of the Z boson have shown that just three neutrino
flavors participate in weak interactions, at least for neutrinos
with masses less than M(subZ)/2.
2) Phenomenologically, it is obvious that neutrinos of each
flavor are either massless or at least many orders of magnitude
lighter than the corresponding charged leptons with which they
form weak-interaction doublets. Based on these empirical facts,
the standard model of electroweak interactions postulates that
all neutrinos are massless and consequently have conserved
helicity (which is the same as chirality in this case), and that
the separate lepton numbers for electron, muon, and tau flavors
are conserved. Challenging this postulate of the vanishing
neutrino mass has recently become a central issue in many
disciplines of fundamental science, including particle and
nuclear physics, cosmology, and astrophysics.
3) Ironically, while our knowledge of intrinsic neutrino
properties remains quite poor, these particles have been used as
tools to understand other phenomena. The tradition of
underground neutrino detectors began 30 years ago, when Davis
and his collaborators were first able to detect neutrinos from
the Sun. (For a description of the history of solar neutrino
research, see Bahcall (6)) Together with all the other
experimental observations of solar neutrinos, this was, and
still is, the only clear proof that the basic energy generation
in stars is understood.
4) In summary: The technique of neutrino searches using nuclear
reactors as sources, a direct continuation of the experiments
that proved the existence of neutrinos, is today an essential
tool in investigating the indications of oscillations found in
studying neutrinos produced in the Sun and in the Earth's
atmosphere.
References (abridged):
1) Winter, K., 1991, Ed., Neutrino Physics (Cambridge
University, Cambridge, England).
2) Reines, F, and C. L. Cowan, Jr., 1953, Phys. Rev 92, 830;
1959, Phys. Rev. 113, 273.
3) Danby, G., J.-M. Gaillard, K. Goulianos, L. M. Lederman, N.
Mistry, M. Schwatz, and J. Steinberger, 1962, Phys. Rev Lett.
9,36.
4) Peri, M. L., et al., 1975, Phys. Rev. Lett. 35, 1489.
5) Kodama, K., et al., 2001, Phys. Lett. B 504, 218.
6) Bahcall, J. N., 1989, Neutrino Astrophysics (Cambridge
University, Cambridge, England).
Rev. Mod. Phys. 2002 74:297
Web Links: neutrino neutrino oscillations Wolfgang Pauli
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5. ON THE EVOLUTION OF MEDICAL SCHOOL ADMISSIONS TESTING
William C. McGaghie (Northwestern University, US) discusses
medical school admissions, the author making the following
points:
1) The origins of the Medical College Admission Test (MCAT)
coincide with the rise of scientific psychology and quantitative
approaches to mental measurement in the late 19th and early 20th
centuries. The intellectual foundation of this work has been
traced to ideas of Charles Darwin (1809-1882) expressed in his
_On the Origin of Species_ (first published in 1859) concerning
individual variation and natural selection. Sir Francis Galton
(1822-1911), Darwin's cousin, subsequently attempted to measure
human variation in intellectual abilities using a variety of
laboratory tests. At the turn of the 20th century Alfred Binet
(1857-1911) and Theodore Simon created early versions of
intelligence tests, while E. L. Thorndike (1874-1949) developed
several achievement tests and interpreted their results, in
part, using the Karl Pearson (1857-1936) newly developed
correlation coefficient. Early individual tests of intelligence
and school achievement were quickly adapted for group
administration in service of efficiency and extensive use.(1)
2) The technology of intelligence and achievement testing of
school children was soon applied to other educational and social
measurement problems. Psychological historian Murray Levine(1)
observes:
"It is likely that the experience in group testing in the
schools before World War I prepared the way for the group
intelligence tests developed by Army psychologists for the
selection of officers and for screening out those who were
intellectually inadequate for service. It was after the war that
group tests came into wide use and became firmly entrenched in
the schools and in our culture."
3) Scholastic aptitude has been defined as a fixed trait.
Furthermore, there are individual differences in knowledge or
skills that contribute to educational achievement. Scholastic
aptitude emphasizes verbal, quantitative, and frequently
subject-centered (eg, biology, chemistry, physics) knowledge and
skill that enhance educational success. Operationally, academic
aptitude is similar, if not identical, to common conceptions of
intelligence. From their inception, intelligence, achievement,
and aptitude tests have been judged by the extent to which, when
given to a group, they yield a normal distribution of scores
that clearly separates high, medium, and low performers.
Reliable score differences allow for objective (scientific)
norm-referenced selection, classification, or placement
decisions about individuals.
4) In summary: The attrition rate of 5% to 50% from US medical
schools in the 1920s propelled the development of a test that
would measure aptitude for medical studies. Since its
development in 1928, the Medical College Admission Test (MCAT)
has undergone 5 revisions. The first version was divided into 6
to 8 subtests that focused on memory, knowledge of scientific
terminology, reading and comprehension, and logic. The second,
which appeared in 1946, was reduced to 4 categories: verbal and
quantitative skills, science knowledge, and added a category
called understanding modern society. The major difference in the
third version, launched in 1962, expanded the test's
understanding modern society section to a broader test of
general information. In 1977, the MCAT underwent its fourth
change: its science section, reading and quantitative skill
assessment sections were expanded; its general liberal arts
knowledge section was eliminated; its scoring report structure
and scoring range were altered; and its cultural and social bias
was minimized. The current version, beginning in 1991, has
undergone another significant change. Although it does not
contain independent measures of either liberal arts or numeracy
as separate categories, quantitative skills are needed to solve
some of the problems in biological and physical sciences.
However, its principal innovation is the writing sample section.
Through its 74-year history, the various renditions of the MCAT
demonstrate that the definition of aptitude for medical
education reflects the professional and social mores and values
of the time.
References (abridged):
1. Monroe WS. An Introduction to the Theory of Educational
Measurements. Boston, Mass: Houghton Mifflin; 1923. Cited by:
Levine M. The academic achievement test. Am Psychol.
1976;31:228-238.
2. Barzansky B, Etzel SI. Educational programs in US medical
schools. JAMA. 2001;286:1049-1055.
3. Flexner A. Medical Education in the United States and Canada.
New York, NY: Carnegie Foundation for the Advancement of
Teaching; 1910. Bulletin No. 4.
4. Ludmerer KM. Learning to Heal. Baltimore, Md: Johns Hopkins
University Press; 1985.
5. Scholastic Aptitude Test for Medical Schools, Form 15, First
Edition. 1941; Hollinger Box No. 1; IM Box No. 501982734.
Located at: Association of American Medical Colleges.
J. Am. Med. Assoc. 2002 288:1085
Web Links: MCAT medical education
Related Background Brief:
EDUCATIONAL PROGRAMS IN US MEDICAL SCHOOLS, 2000-2001. The
authors report they used data from the 2000-2001 Liaison
Committee on Medical Education Annual Medical School
Questionnaire, which had a 100% response rate, and other sources
to describe the status of medical education programs in the
United States. In 2000-2001, the number of full-time medical
school faculty members was 103,553, a 1.1% increase from
1999-2000. The 37,092 applicants for the class entering in 2000
represented a 3.7% decrease from the number of applicants in
1999. The majority of medical schools (58%) were in the process
of major curriculum review and change during 2000-2001. In 72
schools (58%), students were required to pass both Steps 1 and 2
of the United States Medical Licensing Examinations to advance
or graduate. The availability of patients to participate in
clinical teaching during 2000-2001 decreased in almost half of
schools compared with 1999-2000. Many schools reported
difficulty in recruiting or retaining volunteer faculty members
to provide clinical education in the community. Forty medical
schools provided monetary payment to some or all community
volunteer faculty members. B. Barzansky and S.I. Etzel: JAMA
2001 286:1075.
Related Background Brief:
OUR COMPACT WITH TOMORROW'S DOCTORS. In recent years, the image
of medicine as a caring profession has been badly tarnished by a
rash of critical reports in the media. In the face of this
negative publicity, do young people still want to be doctors?
The author reviews conventional reasons given for the declining
applicant pool (e.g., issues of declining income, loss of
autonomy, etc.) and posits that an additional reason may be
perceptions that doctors no longer command respect and that they
are being oppressed by, rather than being guardians of, the
health care system. Such views challenge academic medicine to
broadcast to the world a realistic picture of the fabulous
opportunities and gratifications that lie ahead for the next
generation of physicians. However, academic medicine must also
address some current realities within medical education, such as
the admission process (where at present there is a tendency to
overemphasize indices of academic achievement and underemphasize
the personal characteristics sought in applicants) and the
acculturation process in medical school (which can often
dehumanize students and convert idealistic ones into cynics).
The author acknowledges that these are tough challenges. He
suggests as a first step that leaders of academic medicine
prepare and disseminate an explicit statement of their
commitments, a kind of compact between teachers and learners of
medicine. He outlines these commitments, and states his hope
that by fulfilling them, the academic medicine community can
make clear that medicine -- which at its core is still about the
doctor-patient relationship -- is a true calling, not just a
beleaguered occupation. J.J. Cohen: Acad Med 2002 77:475.
Related Background Brief:
INFLUENCE OF MEDICAL SCHOOL APPLICANTS' DEMOGRAPHIC AND
COGNITIVE CHARACTERISTICS ON INTERVIEWERS' RATINGS OF
NONCOGNITIVE TRAITS. Interviews are commonly used to measure
noncognitive traits of medical school applicants. The present
study investigated the influence of knowledge of applicants'
cognitive abilities on interviewers' ratings of noncognitive
traits. Academic and demographic predictors of interview ratings
of applicants' noncognitive traits were examined at the Medical
University of South Carolina College of Medicine during two
years: 1992, when applicants' Medical College Admission Test
(MCAT) total scores and undergraduate grade-point averages
(GPAs) were available to interviewers; and 1993, when MCAT and
GPA data were not available. In 1992, 226 applicants met study
criteria (i.e., they received ratings from three interviewers in
addition to having MCAT and GPA data on file); in 1993, 245
applicants met the criteria. Step-wise regression analyses were
conducted to measure the influences of seven independent
variables on applicants' interview ratings. Two-way analyses of
variances and t-tests were used to determine the effects of
gender of applicants and interviewers. Cronbach's alpha
coefficients were used as measures of interviewers' reliability.
Results: GPA was the best predictor for both years but accounted
for double the amount of variance in interview ratings in 1992
(15.7%) compared with 1993 (7.4%). The reliability coefficients
for the interviewers were 0.496 for 1992 and 0.473 for 1993. The
authors conclude: If the goal of the medical school admission
interview is to assess noncognitive traits independently from
academic skills, the authors recommend that MCAT and GPA data
not be available to interviewers during interviews. The authors
also found that gender and race influenced interview ratings in
accordance with affirmative-action goals. Finally, the authors
found that interview scores were only moderately reliable across
different interviewers. They discuss ways to increase their
reliability. D.L. Shaw et al: Acad Med 1995 70:532.
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6. BREAST CANCER: ON RADICAL MASTECTOMY VS. CONSERVATIVE SURGERY
U. Veronesi et al (European Institute of Oncology Milan, IT)
discuss breast cancer surgery, the authors making the following
points:
1) The radical mastectomy introduced by Halsted(1) was the
treatment of choice for breast cancer of any size or type,
regardless of the patient's age, for 80 years. Apart from a few
modifications, such as enlarging the extent of the dissection to
include the internal mammary nodes or reducing it to spare the
pectoralis muscles, the Halsted mastectomy was performed as
originally described throughout this period. The possibility of
attempting a surgical procedure that would conserve the breast
was not widely considered during those years.(2,3)
2) In 1969, a randomized study to compare radical mastectomy
with breast-conserving surgery, which was termed
"quadrantectomy", was approved by the World Health Organization
Committee of Investigators for Evaluation of Methods of
Diagnosis and Treatment of Breast Cancer.(4) The recruitment of
patients began at the Milan Cancer Institute in 1973, after the
new procedure was standardized, and preliminary data showing
that survival rates were equal after radical and
breast-conserving surgery were published in 1977(5) and 1981.
3) The main criticism of the data was that they were too
preliminary; patients with small breast cancers must be followed
for a very long time, even decades, to ensure that the
evaluation of the efficacy of any new treatment is accurate. The
authors carefully monitored the 701 women in the trial for up to
29 years, and they now report the results.
4) Thirty women in the group that underwent breast-conserving
therapy had a recurrence of tumor in the same breast, whereas
eight women in the radical-mastectomy group had local
recurrences (P<0.001). The crude cumulative incidence of these
events was 8.8 percent and 2.3 percent, respectively, after 20
years. In contrast, there was no significant difference between
the two groups in the rates of contralateral-breast carcinomas,
distant metastases, or second primary cancers. After a median
follow-up of 20 years, the rate of death from all causes was
41.7 percent in the group that underwent breast-conserving
surgery and 41.2 percent in the radical-mastectomy group
(P=1.0). The respective rates of death from breast cancer were
26.1 percent and 24.3 percent (P=0.8).
5) The authors conclude: The long-term survival rate among women
who undergo breast-conserving surgery is the same as that among
women who undergo radical mastectomy. Breast-conserving surgery
is therefore the treatment of choice for women with relatively
small breast cancers.
References (abridged):
1. Halsted WS. A clinical and histological study of certain
adenocarcinomata of the breast: and a brief consideration of the
supraclavicular operation and of the results of operations for
cancer of the breast from 1889 to 1898 at the Johns Hopkins
Hospital. Ann Surg 1898;28:557-576.
2. Hirsch J. Radiumchirurgie des Brustkrebses. Dtsch Med
Wochenschr 1927;53:1419-1421.
3. Keynes G. Conservative treatment of cancer of the breast. BMJ
1937;2:643-647.
4. Meeting of investigators for evaluation of methods of
diagnosis and treatment of breast cancer: final report. Geneva:
World Health Organization, December 1969.
5. Veronesi U, Banfi A, Saccozzi R, et al. Conservative
treatment of breast cancer: a trial in progress at the Cancer
Institute in Milan. Cancer 1977;39:Suppl:2822-2826.
New Engl. J. Med. 2002 347:1227
Web Links: radical mastectomy breast cancer surgery
Related Background Brief:
CONSERVATIVE TREATMENT OF BREAST CANCER. A TRIAL IN PROGRESS AT
THE CANCER INSTITUTE OF MILAN. The authors report a clinical
trial on conservative surgery in progress at the National Cancer
Institute of Milan, Italy. The randomized clinical trial
compares radical mastectomy with a more conservative procedure
consisting of mammary resection plus axillary dissection plus
radiotherapy. The resection comprises an entire quadrant of the
breast together with the overlying skin and the corresponding
portion of the fascial sheet of the pectoralis major. The
axillary dissection is performed in continuity with the resected
breast quadrant except in cases with tumors of lower inner
quadrants, who need two separate incisions. After surgery the
patients receive 6000 rads to the residual breast tissue over
five to six weeks, starting 15 days after operation. The
cosmetic results are satisfactory in approximately 70% of cases.
The trial is limited to cases with tumors less than 2 cm and no
palpable axillary nodes (T1N0M0). Patients with histologically
positive lymph nodes (N+) are submitted to adjuvant chemotherapy
with CMF for one year. From September 1973, to October 1976, 331
cases entered the trial. One hundred sixty were treated with
radical mastectomy and 164 with the conservative procedure.
Axillary metastases were found in 23% of the radical and in 29%
of the conservative surgery group. Four local-regional
recurrences have occurred till now, two in each group. Five
cases in the radical mastectomy group and one in the
conservative group had distant metastases. The clinical trial
will collect some 500 cases by the end of 1977 and significant
preliminary results are expected to be available from 1978. U.
Veronesi et al: Cancer 1977 39(6 Suppl):2822.
Related Background Brief:
COMPARING RADICAL MASTECTOMY WITH QUADRANTECTOMY, AXILLARY
DISSECTION, AND RADIOTHERAPY IN PATIENTS WITH SMALL CANCERS OF
THE BREAST. The authors report that from 1973 to 1980 they
carried out a controlled study at the National Cancer Institute
in Milan to consider the value of a conservative procedure in
patients with breast cancer of small size. The authors
randomized 701 patients with breast cancer measuring less than 2
cm in diameter and with no palpable axillary lymph nodes to
Halsted radical mastectomy or to "quadrantectomy" with axillary
dissection and radiotherapy to the ipsilateral residual breast
tissue. The authors treated 349 patients with Halsted mastectomy
and 352 with quadrantectomy. The two groups were comparable in
age distribution, size and site of primary tumor, menopausal
status, and frequency of axillary metastases. There were three
local recurrences in the Halsted group and one in the
quadrantectomy group. Actuarial curves showed no difference
between the two groups in disease-free or overall survival. From
these results, mastectomy appears to involve unnecessary
mutilation in patients with breast cancer of less than 2 cm and
no palpable axillary nodes. U Veronesi, et al: New Engl. J. Med.
1981 305:6.
Related Background Brief:
CUMULATIVE CAUSE-SPECIFIC MORTALITY FOR CANCER PATIENTS IN THE
PRESENCE OF OTHER CAUSES: A CRUDE ANALOGUE OF RELATIVE SURVIVAL.
A common population-based cancer progress measure for net
survival (survival in the absence of other causes) of cancer
patients is relative survival. Relative survival is defined as
the ratio of a population of observed survivors in a cohort of
cancer patients to the proportion of expected survivors in a
comparable set of cancer-free individuals in the general public,
thus giving a measure of excess mortality due to cancer.
Relative survival was originally designed to address the
question of whether or not there is evidence that patients have
been cured. It has proven to be a useful survival measure in
several areas, including the evaluation of cancer control
efforts and the application of cure models. However, it is not
representative of the actual survival patterns observed in a
cohort of cancer patients. This paper suggests a measure for
cumulative crude (in the presence of other causes)
cause-specific probability of death for a population diagnosed
with cancer. The measure does not use cause of death information
which can be unreliable for population cancer registries. Point
estimates and variances are derived for crude cause-specific
probability of death using relative survival instead of cause of
death information. Examples are given for men diagnosed with
localized prostate cancer over the age of 70 and women diagnosed
with regional breast cancer using Surveillance, Epidemiology and
End Results (SEER) Program data. The examples emphasize the
differences in crude and net mortality measures and suggest
areas where a crude measure is more informative. Estimates of
this type are especially important for older patients as new
screening modalities detect cancers earlier and choice of
treatment or even "watchful waiting" become viable options. K.A.
Cronin and E.J. Feuer: Stat Med 2000 19:1729.
Relative Background Brief:
TWENTY-YEAR FOLLOW-UP OF A RANDOMIZED TRIAL COMPARING TOTAL
MASTECTOMY, LUMPECTOMY, AND LUMPECTOMY PLUS IRRADIATION FOR THE
TREATMENT OF INVASIVE BREAST CANCER. In 1976, the authors
initiated a randomized trial to determine whether lumpectomy
with or without radiation therapy was as effective as total
mastectomy for the treatment of invasive breast cancer. A total
of 1851 women for whom follow-up data were available and nodal
status was known underwent randomly assigned treatment
consisting of total mastectomy, lumpectomy alone, or lumpectomy
and breast irradiation. Kaplan–Meier and cumulative-incidence
estimates of the outcome were obtained. Results: The cumulative
incidence of recurrent tumor in the ipsilateral breast was 14.3
percent in the women who underwent lumpectomy and breast
irradiation, as compared with 39.2 percent in the women who
underwent lumpectomy without irradiation (P<0.001). No
significant differences were observed among the three groups of
women with respect to disease-free survival,
distant-disease–free survival, or overall survival. The hazard
ratio for death among the women who underwent lumpectomy alone,
as compared with those who underwent total mastectomy, was 1.05
(95 percent confidence interval, 0.90 to 1.23; P=0.51). The
hazard ratio for death among the women who underwent lumpectomy
followed by breast irradiation, as compared with those who
underwent total mastectomy, was 0.97 (95 percent confidence
interval, 0.83 to 1.14; P=0.74). Among the lumpectomy-treated
women whose surgical specimens had tumor-free margins, the
hazard ratio for death among the women who underwent
postoperative breast irradiation, as compared with those who did
not, was 0.91 (95 percent confidence interval, 0.77 to 1.06;
P=0.23). Radiation therapy was associated with a marginally
significant decrease in deaths due to breast cancer. This
decrease was partially offset by an increase in deaths from
other causes. The authors conclude: Lumpectomy followed by
breast irradiation continues to be appropriate therapy for women
with breast cancer, provided that the margins of resected
specimens are free of tumor and an acceptable cosmetic result
can be obtained. B. Fisher et al: New Engl. J. Med. 2002
347:1233.
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7. ECOLOGICAL EFFECTS OF CLIMATE FLUCTUATIONS
The term "El Nino" refers to an aperiodic intermittent (2 to 10
years) flow of unusually warm surface water along the western
coast of South America, the flow capable of causing abnormally
high rainfall in usually dry areas and severe local ecosystem
dislocations -- what is termed an El Nino "event". El Ninos are
regional phenomena, but they have global consequences. The name
"El Nino" ("The Child") arose because the phenomenon usually
occurs around Christmas. In 1986, M.A. Cane and S.A. Zebiak
proposed a model for making forecasts of El Nino several seasons
ahead by applying Newton's equations of motion and the laws of
thermodynamics to the dynamics of the ocean and atmosphere of
the tropical Pacific.
The term "Southern Oscillation" (SO) refers to a coherent
interannual fluctuation of atmospheric pressure over the
tropical Indo-Pacific region. The El Nino/Southern Oscillation
phenomenon (called ENSO), the interaction between El Nino and
the Southern Oscillation, is the strongest source of natural
variability in Earth's climate system. Although ENSO originates
in the tropical latitudes of the Pacific Ocean, its climate
impact is felt globally. Variations in major rainfall systems
that are attributed to ENSO range from droughts in Indonesia and
Australia to storms and flooding in Ecuador and the US. The
crucial role of the interaction between the ocean and the
atmosphere in the tropical Pacific was first postulated in 1969
by Jacob Bjerknes (1897-1975), and the development of
quantitative models has progressed during the past 3 decades.
The essence of the current Bjerknes hypothesis, as it is called,
is that ENSO arises as a coupled cycle in which anomalies in sea
surface temperature in the Pacific cause the trade winds to
strengthen or slacken and, in turn, drive the changes in ocean
circulation that produce anomalous sea surface temperatures.
Ocean-atmosphere feedback can amplify perturbations in either
the equatorial sea surface temperature or what is called the
Walker Circulation -- the thermodynamic circulation of air
parallel to the equator. Although the oscillatory aspect of ENSO
behavior is now understood reasonably well, the irregularity of
the observed cycle is a subject of active research.
N.C. Stenseth et al (University of Oslo, NO) discuss climate
fluctuations, the authors making the following points:
1) Ecological processes are influenced by prevailing climatic
conditions (1). Early studies typically focused on local weather
parameters such as temperature, precipitation, and snow depth.
By so doing, an important dimension is overlooked: the holistic
nature of the climate system (2). Recently, therefore,
increasing attention has been given to large-scale patterns of
climate variability with marked ecological impacts on
interannual and longer time scales. Of particular interest are
the North Atlantic Oscillation (NAO) (3) and the El
Nino-Southern Oscillation (ENSO) (4,5). These patterns account
for major variations in weather and climate around the world and
have been shown to affect terrestrial vegetation, herbivores and
carnivores, and marine biology and fish stocks (4) through both
direct and indirect pathways.
2) Increasing awareness among and interactions between
biologists and climate scientists are rapidly advancing our
insights into the critical issue of the response of ecosystems
to climate variability and climate change. Moreover, mutual
interest in climate processes is serving as an impetus for new
interdisciplinary research. Climate as a synchronizing agent for
population fluctuations in space, the so-called "Moran effect",
has received much attention. Rainfall changes associated with
ENSO, for instance, produce a highly synchronic pattern of
massive germination of annuals, rodent outbreaks, and vertebrate
predators responses over arid and semiarid regions of South
America. Similarly, across the boreal forest of Canada, lynx and
snowshoe hare population cycles have a closely related dynamic
structure within climatologically based regions defined by the
spatial influences of the NAO. This indicates that climate
affects the hunting behavior (and success) of the lynx,
presumably through snow condition. Also, muskrat (Ondatra
zibethicus) and mink (Mustela vison) populations are more
synchronous over eastern Canada, where the influence of the NAO
is strongest.
3) In summary: Climate influences a variety of ecological
processes. These effects operate through local weather
parameters such as temperature, wind, rain, snow, and ocean
currents, as well as interactions among these. In the temperate
zone, local variations in weather are often coupled over large
geographic areas through the transient behavior of atmospheric
planetary-scale waves. These variations drive temporally and
spatially averaged exchanges of heat, momentum, and water vapor
that ultimately determine growth, recruitment, and migration
patterns. Recently, there have been several studies of the
impact of large-scale climatic forcing on ecological systems.
The authors review how two of the best-known climate phenomena
-- the North Atlantic Oscillation and the El Nino-Southern
Oscillation -- affect ecological patterns and processes in both
marine and terrestrial systems.
References (abridged):
1. B.-E. Sæther, Trends Ecol. Evol. 12, 143 (1997)
2. J. Namias and D. R. Cayan, Science 214, 869 (1981)
3. J. W. Hurrell, Science 269, 676 (1995)
4. S. G. Philander, El Niño, La Niña, and the Southern
Oscillation (Academic Press, New York, 1990)
5. K. E. Trenberth, in Encyclopedia of Ocean Sciences, J.
Steele, S. Thorpe, K. Turekian, Eds. (Academic Press, London,
2001), pp. 4 and 815.
Science 2002 297:1292
Web Links: El Nino La Nina
Related Background Brief:
ENVIRONMENTAL STOCHASTICITY AND POPULATION DYNAMICS OF LARGE
HERBIVORES: A SEARCH FOR MECHANISMS. Recently, the results from
several long-term individual-based population studies of
ungulates have been published. One major conclusion is that the
population dynamics of ungulates in predator-free environments
is strongly influenced by a combination of stochastic variation
in the environment, and population density. Both density
dependence and environmental stochasticity operate through
changes in life history traits, correlated with variation in
body weight. This generates delays in the response of the
population to changes in environment. In the absence of
predation, a stable equilibrium is therefore unlikely to exist
between an ungulate population and its food resources. This
thorough understanding of the mechanisms generating population
fluctuations suggests that studies of ungulates will provide an
important source for examining effects of long-term changes in
the environment, for instance, resulting from a climatic change.
B.E. Saether: Trends in Ecology & Evolution 1997 12:143.
Related Background Brief:
EL NINO EFFECTS ON THE DYNAMICS OF TERRESTRIAL ECOSYSTEMS. New
studies are showing that the El Nino Southern Oscillation (ENSO)
has major implications for the functioning of different
ecosystems, ranging from deserts to tropical rain forests.
ENSO-induced pulses of enhanced plant productivity can cascade
upward through the food web invoking unforeseen feedbacks, and
can cause open dryland ecosystems to shift to permanent
woodlands. These insights suggest that the predicted change in
extreme climatic events resulting from global warming could
profoundly alter biodiversity and ecosystem functioning in many
regions of the world. Our increasing ability to predict El Nino
effects can be used to enhance management strategies for the
restoration of degraded ecosystems. M. Holmgren et al: Trends
Ecol Evol 2001 Feb 1;16(2):89.
Related Background Brief:
A LONG-TERM STUDY OF VERTEBRATE PREDATOR RESPONSES TO AN EL NINO
(ENSO) DISTURBANCE IN WESTERN SOUTH AMERICA. The authors report
they analyzed the putative effects of the El Nino Southern
Oscillation (ENSO) of 1991-92 in a semi-arid locality of
northern Chile. The authors obtained 30 months of pre ENSO data,
followed by 36 months of peak and post ENSO data (total = 5.5
yr). The rainy winter of 1991 resulted in a three-fold increase
in total seed bank (perennial and ephemerals pooled) and in
ephemeral (but not perennial) herb cover. Seed and herbage
eaters (rodents) irrupted to population levels ca 20 times
higher during the breeding season of 1991 than the preceding
wintering season. Diurnal carnivorous predators (hawks, owls,
and foxes) showed a delayed response to the irruption,
increasing from seven individuals sighted during the wintering
season of 1991 to 13 during the wintering season of 1992. A
seemingly counterclockwise trajectory of predator abundance
versus prey levels suggested a pattern of prey-driven dynamics,
but confidence intervals were likely broad. In this semiarid
locality, it appears that ENSO effects did not cascade down from
higher to lower trophic levels, but rather the opposite. In this
bottom-up scenario, the authors predict that as primary
productivity varies with rainfall, so should secondary (mammal
prey densities), and tertiary productivity (vertebrate
predators). Long-term monitoring of this terrestrial ecosystem
is needed to test this prediction. F.M. Jaksic et al: Oikos 1997
78:341.
ScienceWeek http://www.scienceweek.com
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8. ON SMALL-MOLECULE SYNTHESIS PROGRAMMED BY DNA TEMPLATES.
Z.J. Gartner et al (Harvard University, US) discuss the use of
DNA templates, the authors making the following points:
1) Chemists generate molecules with new function by synthesizing
structures, assaying their properties, formulating
structure-activity relationships, and then synthesizing new
candidates. In contrast, nature generates functional proteins
and nucleic acids through iterated cycles of translation,
selection, amplification, and diversification, collectively
referred to as molecular evolution. Although the power of
nature's approach is well appreciated,(1) we cannot apply
molecular evolution to molecules other than proteins or nucleic
acids because we lack a method of translating an amplifiable
information carrier such as DNA into arbitrary structures. One
approach to this problem uses DNA-templated synthesis to
translate libraries of DNA sequences into corresponding
synthetic molecules.
2) The authors recently found(2) that DNA-templated synthesis
can direct a variety of powerful chemical reactions with high
sequence specificity and without requiring structural mimicry of
the DNA backbone. The application of this approach to synthetic
molecules of potentially useful complexity, however, requires
the development of methods that enable the product of a
DNA-templated reaction to undergo subsequent DNA-templated
transformations. The authors now report the first DNA-templated
multistep small-molecule syntheses. The authors suggest their
results represent a general approach to translating DNA
sequences into corresponding multistep synthetic products in a
form suitable for their in vitro evolution.
3) In summary: The translation of DNA sequences into synthetic
products is a key requirement of the approach of the authors to
evolving synthetic molecules through iterated cycles of
translation, selection, and amplification. The authors now
report general linker and purification strategies for
sequence-specific DNA-templated synthesis that collectively
enable the product of a DNA-templated reaction to be isolated
and to undergo subsequent DNA-templated reactions. Using these
strategies, the authors report they have achieved the first
multistep nucleic acid-templated small-molecule syntheses to
generate two different molecules. In addition to representing a
method for translating DNA templates sequence-specifically into
corresponding multistep synthetic products, the authors suggest
their findings also provide experimental support for previously
proposed models invoking multistep nucleic acid-templated
synthesis as mediating the prebiotic translation of replicable
information into the earliest functional molecules.(3-5)
References (abridged):
1. (a) Arnold, F. H.; Volkov, A. A. Curr. Opin. Chem. Biol.
1999, 3, 54-59. (b) Jaschke, A.; Seelig, B. Curr. Opin. Chem.
Biol. 2000, 4, 257-262.
2. (a) Gartner, Z. J.; Liu, D. R. J. Am. Chem. Soc. 2001, 123,
6961-6963. (b) Gartner, Z. J.; Kanan, M. W.; Liu, D. R. Angew.
Chem., Int. Ed. 2002, 41, 1796-1800.
3. Kramer, M. F.; Coen, D. M. In Current Protocols in Molecular
Biology; Ausubel, F. M., Ed.; Wiley: 1999; Vol. 3, p 15.11-15.13.
4. (a) Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000,
100, 2091-2157.
5. Hughes, I. Tetrahedron Lett. 1996, 37, 7595-7598.
J. Am. Chem. Soc. 2002 124:10304
Web Links: DNA templates
Related Background Brief:
THE GENERALITY OF DNA-TEMPLATED SYNTHESIS AS A BASIS FOR
EVOLVING NON-NATURAL SMALL MOLECULES. Despite their limited
chemical functionality, proteins and nucleic acids dominate the
solutions to many complex chemical problems because they can be
evolved through iterated cycles of diversification, selection,
and amplification. Researchers have demonstrated extensively
that proteins and nucleic acids initially lacking desired
activities can be mutated, amplified, and re-selected to afford
evolved molecules with greatly enhanced properties. The authors
are interested in creating amplifiable and evolvable libraries
of non-natural small molecules by developing methods to
translate DNA into synthetic structures. Achieving this goal
requires using DNA to direct chemical reactions
sequence-specifically in a manner much more general than has
been reported thus far. Researchers have previously demonstrated
the ability of nucleic acid templates to promote the coupling of
adjacently annealed oligonucleotides to form nucleic acids and
nucleic acid analogs. The authors hypothesized that the
proximity effect provided by DNA-templated synthesis can be used
to generate libraries of synthetic small molecules unrelated in
structure to the DNA backbone in one-pot, parallel reactions.
The authors examined the ability of two DNA architectures to
support solution-phase DNA-templated synthesis. Both hairpin (H)
and end-of-helix (E) templates bearing electrophilic maleimide
groups reacted efficiently with one equivalent of thiol reagent
linked to a complementary DNA oligonucleotide to yield the
thioether product in minutes at 25 °C. DNA-templated reaction
rates were similar for H and E architectures despite significant
differences in the relative orientation of their reactive
groups. In contrast, no product was observed when using reagents
containing sequence mismatches, or when using templates
pre-quenched with excess b-mercaptoethanol. Both H and E
templates therefore support the sequence-specific DNA-templated
addition of a thiol to a maleimide even though the structures of
the resulting products differ markedly from the structure of the
natural phosphodiester backbone. Little or no non-templated
intermolecular reaction products are produced under the reaction
conditions (pH 7.5, 25 degrees C, 250 mM NaCl, 60 nM template
and reagent). Surprisingly, sequence-specific DNA-templated
reactions spanning a variety of reaction types (SN2
substitutions, additions to a,b-unsaturated carbonyl systems,
and additions to vinylsulfones), nucleophiles (thiols and
amines), and reactant structures all proceeded in good yields
with excellent sequence selectivity. In each case, matched but
not mismatched reagents afforded product efficiently despite
considerable variations in their transition-state geometry,
steric hindrance, and conformational flexibility. The authors
suggest that collectively these findings indicate that
DNA-templated synthesis is a general phenomenon capable of
supporting a range of reaction types and is not limited to the
creation of structures resembling nucleic acid backbones. Z.J.
Gartner and D.R. Liu: jacs 2001 123:6961.
Related Background Brief:
INFORMATION TRANSFER FROM DNA TO PEPTIDE NUCLEIC ACIDS BY
TEMPLATE-DIRECTED SYNTHESES. Peptide nucleic acids (PNAs) are
analogs of nucleic acids in which the ribose-phosphate backbone
is replaced by a backbone held together by amide bonds. PNAs are
interesting as models of alternative genetic systems because
they form potentially informational base paired helical
structures. Oligocytidylates have been shown to act as templates
for formation of longer oligomers of G from PNA G2 dimers. In
this paper the authors demonstrate that information can be
transferred from DNA to PNA. DNA C4T2C4 is an efficient template
for synthesis of PNA G4A2G4 using G2 and A2 units as substrates.
The corresponding synthesis of PNA G4C2G4 on DNA C4G2C4 is less
efficient. Incorporation of PNA T2 into PNA products on DNA
C4A2C4 is the least efficient of the three reactions. These
results, obtained using PNA dimers as substrates, parallel those
obtained using monomeric activated nucleotides. J.G. Schmidt et
al: Nucleic Acids Research 1997 25:4792.
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