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ScienceWeek - July 5, 2002 Vol. 6 Number 27

An Online Research Digest Published Weekly Since 1997

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What would have happened if Darwin and Einstein as young men had
needed to apply for government support? Their probability of
getting past the grant reviewers would be similar to a snowball
surviving in Hell. -- Craig Loehle

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Section 1

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1. Gap Junction Channels and Voltage Gating

2. The Cellular Secretory Membrane System and the Endoplasmic
Reticulum

3. On Collagens

4. On the Quantum States of Lasers

5. Salt Bridges and the Stability of Proteins

6. Green Fluorescent Protein and Bioluminescence

7. On Atrial Fibrillation

8. Allergic Diseases and the Hygiene Hypothesis

9. On the Human Embryonic Stem Cell Debate

10. Controlled Binding in Dendrimers and Drug Delivery

11. On Protected Quantum Bits

12. On Porous Silicon

13. In Focus: On the Origin of the Earth

14. Selected Abstracts

15. New Books

16. ScienceWeek Notices and Subscription Information

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Section 2

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1. GAP JUNCTION CHANNELS AND VOLTAGE GATING

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.

Y. Qu and G. Dahl (University of Miami, US) discuss gap junction
channels, the authors making the following points:

1) Gap junction channels are formed by a family of proteins, the
connexins, which are expressed in most tissues of an organism.
Gap junction channels between contacting cells allow the passage
of ions and other small molecules between the cells and thereby
synchronize cells both electrically and metabolically. Molecules
up to 1000 Daltons, including all known second messengers and
some endogenous metabolites, can pass through at least some
connexin channels (1).

2) Most vertebrate gap junction channels are regulated by
voltage (2), the channel closing when a potential difference
develops between the cells. However, closure is only partial.
For most connexins, even a large potential difference reduces
the junctional conductance over time to approximately 30-50% of
the maximal conductance. This incomplete closure of the channels
would not break the electrical continuity of the cells, thus the
function of this voltage regulation is unclear.

3) Like other membrane channels, gap junction channels exhibit
subconductance states. In some connexin channels, the
probability that the channels reside in the subconductance
states is increased by a voltage gradient (3, 4). It seems
possible that the subconductance states have a different
selective permeability than the full conductance state, such
that the flux of larger molecules like second messengers is
reduced. On the basis of the conductance ratios of connexin-43
gap junction channels for different salts such as KCl, Cs
aspartate, or tetraethylammonium aspartate, it has been
suggested that the subconductance state could represent a
slightly higher permeation barrier than the full conductance
state (5). However, by using a statistical approach on the same
channels, Christ and Brink (1999) concluded that subconductance
states do not effectively change selectivity in a
physiologically meaningful manner because of their brevity of
duration in relation to the full open state.

4) The authors report that in Xenopus oocytes expressing
connexin-43 or connexin-46 the activated voltage gate
preferentially restricts the passage of larger ions, such as
fluorescent tracer molecules and cAMP, while having little
effect on the electrical coupling arising from the passage of
small electrolytes. Thus, a conceivable physiological role of
the voltage gate in these channels is to selectively restrict
the passage of large molecules between cells while allowing
electrical coupling.

References (abridged):

1. Bruzzone, R. , White, T. W. & Paul, D. L. (1996) Eur. J.
Biochem. 238, 1-27

2. Spray, D. C. (1996) Clin. Exp. Pharmacol. Physiol. 23,
1038-1040

3. Trexler, E. B. , Bennett, M. V. , Bargiello, T. A. &
Verselis, V. K. (1996) Proc. Natl. Acad. Sci. USA 93, 5836-5841

4. Pfahnl, A. & Dahl, G. (1998) Biophys. J. 75, 2323-2331

5. Valiunas, V. , Bukauskas, F. F. & Weingart, R. (1997) Circ.
Res. 80, 708-719

Proc. Nat. Acad. Sci. 2002 99: 697

Web Links: gap junctions

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2. THE CELLULAR SECRETORY MEMBRANE SYSTEM AND THE ENDOPLASMIC
RETICULUM

The historical differences between physics and biology in the
first half of this century are instructive. In 1950, physicists
could not see the various constituents of matter, but they had
physical theories that produced very good predictions of the
behavior of these constituents. In contrast, in 1950, biologists
could see many constituents of the biological cell, but the cell
in its ensemble of parts appeared so complex that how these
constituents behaved was a mystery. At that time, one
controversial constituent of the biological cell was the so-
called "Golgi apparatus", first discovered in 1898 by Camillo
Golgi (1843-1926). Golgi was the first to introduce the use of
silver salts in staining cells (he received the Nobel Prize for
Physiology and Medicine in 1906), and with this silver stain
method cellular components were revealed that were previously
invisible when cells were treated with organic dyes (the
standard classical method of staining cells). For half a
century, however, many biologists considered the Golgi apparatus
a staining artifact, and it was not until the 1950s and the use
of the electron microscope in biology that the Golgi apparatus
was finally confirmed as a real structure in cells. Still, at
that time there was no clear detailed idea concerning how the
Golgi apparatus contributed to the functioning of the cell,
although it did seem to be involved in secretion, since it
appeared more pronounced in secreting cells than in other cells.
It took the remaining decades of this century for the story of
the Golgi apparatus to be unfolded.

The Golgi apparatus (Golgi complex) is a collection of
organelles (Golgi bodies) in eukaryotic cells (i.e., cells with
internal membrane-bound organelles) that essentially function as
a collecting and packaging center for substances that the cell
manufactures for export. Golgi bodies are thus particularly
abundant in secretory cells. They consist of stacks of
membranous sacs that are pinched off as Golgi vesicles for
delivery to the exterior of the cell.

In this context, a "vesicle" is a small intracellular
membrane-bound volume in which substances are stored or
transported. Another cellular structure of importance in
understanding the operation of the Golgi apparatus is the so-
called "endoplasmic reticulum" (ER), which was first identified
with the use of the electron microscope in the 1950s. In
general, the endoplasmic reticulum is an extensive system of
flattened membranous sacs traversing the cytoplasm of all
eukaryotic cells and continuous with the envelope that surrounds
the nucleus. "Rough" endoplasmic reticulum (called rough because
of its electron-microscopic appearance) is covered with
ribosomes. A ribosome is a small particle, a complex of various
ribonucleic acid component subunits and proteins that functions
as the site of protein synthesis in the cell. The rough
endoplasmic reticulum essentially provides a transportation
system for the delivery of newly synthesized proteins to other
parts of the cell, or for secretion to the exterior (exocytosis)
via the Golgi apparatus. The other type of endoplasmic reticulum
is "smooth" endoplasmic reticulum, which lacks ribosomes, and
which is involved in lipid synthesis.

The essentials of the operation of the endoplasmic
reticulum-Golgi apparatus system are as follows:

The endoplasmic reticulum in effect divides the cytoplasm into
two compartments: the cytosol (the non-membranous part of the
cytoplasm outside the ER) and the cisternal space (the connected
lumens of the ER sacs). The cytosol contains enzymes involved in
metabolic pathways, whereas the ER cisternal space provides a
route for the movement of materials through various
intracellular compartments and, in some cases, to the cell
exterior.

The rough endoplasmic reticulum plays a central role in the
synthesis of secretory proteins, integral membrane proteins, and
proteins destined to reside in the lumen of the endoplasmic
reticulum. Proteins synthesized in the rough endoplasmic
reticulum are routed to the Golgi apparatus by membrane vesicles
that shuttle back and forth between the two structures. Proteins
passing through the Golgi complex contain specific chemical
markers that target them to various locations, including the
endoplasmic reticulum, the Golgi apparatus itself, and secretory
vesicles.

Cells exhibit two types of secretory processes: a) in
"constitutive secretion", protein products are moved to the cell
surface in a continuous fashion by nonselective bulk flow; b) in
contrast, "regulated secretion" occurs only in response to
external stimuli. In both types of secretion, membrane vesicles
fuse with the plasma membrane, discharging their contents into
the extracellular space (exocytosis), and after this process has
occurred, the membrane components are recycled back to the Golgi
apparatus by vesicles that bud from the plasma membrane.

Formulating the above account of the operations of the
endoplasmic reticulum and Golgi apparatus, broad and brief as it
is, has required 50 years and the labor of thousands of
biologists. The outlined dynamics are literally a major part of
the workings of the eukaryotic biological cell.

The term "glycoproteins" refers in general to proteins to which
oligosaccharides are attached. The glycoprotein carbohydrate
chains are often branched rather than linear, and they may or
may not be negatively charged. In general, depending on type,
glycoproteins contain highly variable amounts of carbohydrate.
Membrane-bound glycoproteins participate in a broad range of
cellular phenomena, including cell-surface recognition (by other
cells, by hormones, and by viruses), cell-surface antigenicity
(e.g., blood group antigens), as components of the
*extracellular matrix, and as components of various biological
"lubricants" (mucins) of the gastrointestinal and urogenital
tracts. In addition, almost all the globular proteins present in
human plasma (with the notable exception of albumin), and the
secreted enzymes and proteins, are glycoproteins.

The term "lysosome" refers to a cytoplasmic membrane-bound
vesicle 5 to 8 nanometers in diameter and containing a variety
of glycoprotein hydrolytic enzymes used to digest foreign
material or defective organelles.

Juergen Roth (University of Zurich, CH) discusses the cellular
secretory membrane system, the author making the following
points:

1) Eukaryotic cells contain various highly specialized,
membrane-bounded compartments fulfilling specific functions.
Among them, the endomembrane system that constitutes the
secretory pathway is most prominent and consists of the
endoplasmic reticulum, pre-Golgi intermediates, the Golgi
apparatus, and different types of post-Golgi apparatus carriers
and vesicles. The secretory membrane system accomplishes a
multitude of interrelated functions encompassing the
translocation and transport of de novo synthesized membrane,
secretory, and lysosomal proteins; posttranslational
modifications of proteins; the quality control of glycoprotein
folding and assembly; and the sorting of glycoproteins to their
final cellular destinations, such as the plasma membrane, to
name some of the most important ones. Inherent to these
functions are highly dynamic processes of membrane and cargo
transport between the endoplasmic reticulum, pre-Golgi
intermediates, the Golgi apparatus, and the plasma membrane.(1-3)

2) The endoplasmic reticulum represents not only the entry point
into the secretory pathway but also constitutes its largest part
and represents a highly dynamic organelle.(4,5) Classically, it
is subdivided into three morphologically distinguishable
domains: the ribosome-studded rough endoplasmic reticulum, the
ribosome-free smooth endoplasmic reticulum, and the nuclear
envelope. Regarding the latter, only the ribosome-covered outer
nuclear membrane is considered to be part of the rough
endoplasmic reticulum. The three endoplasmic reticulum domains
are continuous with each other and extend through most of the
cytoplasm to form an intricate network composed of fenestrated
cisternae and anastomosing tubules. Quantitative variation in
the content of the endoplasmic reticulum may be observed,
depending on the cell type and as a consequence of variations of
the functional state of a given cell type.

3) Despite membrane continuities between the endoplasmic
reticulum domains, some specific marker proteins have been
discovered for each of them. In addition to the classical
domains, subdomains of the endoplasmic reticulum either defined
by characteristic morphology or by the presence or absence of
specific proteins have been identified. Over the past decade,
intense research has focused on a particular subdomain of the
endoplasmic reticulum, the so-called transitional elements of
the rough endoplasmic reticulum These elements are
characteristically partly devoid of ribosomes, exhibit buds, are
continuous with the rough endoplasmic reticulum, and appear to
be rather static structures.

References (abridged):

1. von Figura, K.; Hasilik, A. Annu. Rev. Biochem. 1986, 55,
167-193

2. Griffiths, G.; Hoflak, B.; Simons, K.; Mellman, I.; Kornfeld,
S. Cell 1988, 52, 329-341

3. Kornfeld, S.; Mellman, I. Annu. Rev. Cell Biol. 1989, 5,
483-525

4. Powell, K. S.; Latterich, M. Traffic 2000, 1, 689-694

5. Gething, M. J.; Sambrook, J. Semin. Cell Biol. 1990, 1, 65-72

Chem. Rev. 2002 102:285

Web Links: golgi apparatus

Related Background:

CELL BIOLOGY: PROTEIN SORTING AND GOLGI COMPARTMENTS

B.B. Allen and W.E. Balch (Scripps Research Institute, US)
present a review of current research concerning the operation of
the Golgi apparatus, the authors making the following points:

1) Movement of cargo between cell compartments requires
transiently *coated vesicle carriers. Biosynthetic cargo exiting
the endoplasmic reticulum includes the newly synthesized
proteins and lipids that are moved to distinct cellular and
extracellular destinations. Other cargo incorporated into
vesicles includes proteins that are continuously recycled
between compartments. These components encompass the transport
machinery involved in cargo selection, vesicle formation, and
targeting and fusion of vesicles.

2) A fundamental principle of membrane traffic is that vesicle
formation is initiated by the selection and concentration of
cargo. This occurs through interactions between sorting
determinants (markers) on the cargo and cytosolic coat
components that direct cargo to the forming vesicle. Soluble
cargo (cargo found in the lumen of the ER compartment) will
necessarily require sorting receptors to couple the protein to
the cytosolic coat machinery. A variety of coat complexes
participate in vesicle formation.

3) The authors pose the question: How does the Golgi stack of
cisternae mediate transport of cargo from the endoplasmic
reticulum to the cell surface? The authors suggest a possibility
is that cargo-containing vesicles derived from the endoplasmic
reticulum form early Golgi compartments that then mature by
retrieval of processing enzymes from later Golgi compartments.
Maturation continues at terminal Golgi compartments by retrieval
of transport components from the endocytic pathway to promote
sorting of cargo to multiple destinations. Thus, the authors
suggest, retrograde movement may integrate exocytic (secretory)
and endocytic (material uptake) pathways in eukaryotic cells and
coordinate membrane flow and cargo transport through the Golgi
stack.

Science 1999 285:63

Text Notes:

... ... *coated vesicle carriers: Coated vesicles are observed
in the cytoplasm of many eukaryotic cells. They measure 50 to
250 nanometers in diameter, and are characterized by a coat made
up of a polyhedral lattice of clathrin subunits together with
smaller amounts of other proteins. Coated vesicles are concerned
with the rapid and continuous transport of molecules between
specific membranous organelles of the cell and to and from the
cell membrane.

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3. ON COLLAGENS

The term "collagen" refers to a group of fibrous proteins of
very high tensile strength that form the main component of
connective tissue in animals. Collagen of bones and skin is
metabolically stable, in contrast with collagen of organs such
as the liver. The collagens are products of a superfamily of
closely related genes found in multicellular animals, the
products classified into types I to XIII in the order in which
they were purified and characterized. All contain a typical
triple helical domain formed from 3 independent chains. Type 1
collagen is the most abundant collagen, forming well-organized
fibrils.

A.V. Persikov and B. Brodsky (University of Medicine and
Dentistry of New Jersey, US) discuss collagens, the authors
making the following points:

1) Collagens are major structural proteins in the extracellular
matrix, making up about one-third of protein mass in higher
animals. In addition to their sheer bulk, this protein family is
of interest because of their diversity of structural and
morphogenetic roles and the attribution of an increasing number
of hereditary diseases to mutations in collagens (1-4). All
collagens have a distinctive molecular conformation: a
triple-helix composed of three supercoiled polyproline II-like
helical chains (5). This triple-helical conformation places
strict constraints on amino acid sequence, requiring glycine as
every third residue and a high content of proline and
hydroxyproline residues.

2) There are more than 20 distinct genetic types of collagens,
and the most abundant are types I, II, and III, found in fibrils
with a characteristic 67-nanometer axial period (1). Type I
collagen, a heterotrimer composed of two 1(I) chains and one
2(I) chain, forms the prominent fibrils in tendon, bone, and
cornea, whereas type III collagen, a disulfide-linked
homotrimer, is found together with type I in fibrils of blood
vessels and skin. These fibril-forming collagens are synthesized
in a procollagen form, with globular propeptides on each end of
a central triple-helix. Self-association and disulfide
cross-linking of three C-propeptides are responsible for the
initial events of chain selection and trimer formation, whereas
subsequent events include nucleation and zipper-like folding of
the triple-helix domain. After cleavage of the propeptides, the
rod-like triple-helical molecules in the matrix self-associate
in a staggered array, forming fibrils and interacting with other
matrix molecules to provide the strength, flexibility, or
compression required for each tissue.

3) Collagen fibers are inherently stable structures, having
lifetimes of at least 6 months, and often much longer. Turnover
is accomplished through a specialized family of tightly
regulated matrix metalloproteinases, because triple-helices are
resistant to digestion by most proteases. But even though
collagen fibers are long-lived structures, the stability of
their constituent collagen molecules is marginal with respect to
physiological temperature. When heated in physiological buffers,
collagen molecules spontaneously self-associate, but if fibril
formation is prevented, through use of glycerol or low pH,
collagen molecules undergo a thermal transition, from
triple-helical trimers to unfolded monomers. For mammals and
birds, this denaturation temperature appears to be a few degrees
higher than body temperature, whereas the this temperature
correlates with the upper environmental temperature for
poikilotherms.

References (abridged):

1. Kielty, C. M. , Hopkinson, I. & Grant, M. E. (1993) in
Connective Tissue and Its Hereditable Disorders, eds. Royce, P.
M. & Steinmann, B. (Wiley-Liss, New York), pp. 103-147

2. Byers, P. H. (1993) in Connective Tissue and Its Hereditable
Disorders, eds. Royce, P. M. & Steinmann, B. (Wiley-Liss, New
York), pp. 351-407

3. Prockop, D. J. & Kivirikko, K. I. (1995) Annu. Rev. Biochem.
64, 403-434

4. Myllyharju, J. & Kivirikko, K. I. (2001) Ann. Med. 33, 7-21

5. Rich, A. & Crick, F. H. C. (1961) J. Mol. Biol. 3, 483-506

Proc. Nat. Acad. Sci. 2002 99:1101

Web Links: collagen

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4. ON THE QUANTUM STATES OF LASERS

In general, a "laser" (Light Amplification by Stimulated
Emission of Radiation) is a light amplifier commonly used to
produce monochromatic phase-locked (coherent) radiation in
specific regions of the electromagnetic spectrum.

In an ordinary laser, light is bounced back and forth between
two mirrors that form a cavity, and after several passes through
an appropriate amplifying material in the cavity, the
amplification gain can be large enough to produce laser light.
In an ordinary laser, the emitted beam is uniquely parallel
because waves that do not bounce back and forth between the
mirrors ultimately escape through the sides without
amplification.

In a so-called "random laser", the cavity is absent, but
multiple scattering of light between particles in an appropriate
disordered material keeps the light trapped long enough for the
gain in amplification to become efficient and for laser light to
emerge in random directions.

Since their invention in 1960, lasers have found many important
applications in both the physical sciences and biological
sciences, and they continue to be a significant focus of
research in pure and applied physics.

S.J. van Enck and C.A. Fuchs (Bell Laboratories, US) discuss
lasers, the authors making the following points:

1) A laser produces a stable, unidirectional, more or less
monochromatic, possibly very intense light beam with
well-defined coherence and polarization characteristics. These
properties make a laser a wonderful tool for optics experiments,
but they are all classical properties in the sense that they can
be understood perfectly well using Maxwell's equations. When is
the quantum state of a laser field important? As one might
guess, quantum information protocols provide examples. For
instance, a recent paper by Rudolph and Sanders [1] discusses an
instructive case where -- depending upon what the quantum state
of a laser field is taken to be -- a laser apparently may or may
not be used to demonstrate quantum teleportation, and even may
or may not be used to generate entangled quantum states. Their
conclusion, however, is based on an application of the standard
description of a laser field inside the laser cavity.

2) The authors report a demonstration that this is insufficient
to properly interpret various quantum information protocols
involving lasers. As such, this provides an opportunity to
deepen our understanding of what gives quantum information
processing its power.

3) According to textbook laser theory (see, for example, Ref.
[2], Chap. 17, and Ref. [3], Chap. 12) the quantum state of the
field inside a laser cavity in a steady state is well
approximated by a mixed state diagonal in the photon-number
basis. The expectation value of the electric field in such a
state vanishes. On the other hand, many, if not all, standard
optics experiments seem to be consistent with the assumption
that the laser field is in a coherent state. The expectation
value of the electric field in a coherent state is nonzero and
has a well-defined phase and amplitude. It corresponds to a
classical monochromatic light field, a solution of the classical
Maxwell equations. Molmer addressed the apparent contradiction
between the two different descriptions of a laser field in [4].
There, he conjectured that no standard optics experiment has yet
proven the existence of a nonzero expectation value of the
electric field, and the authors agree with that. For instance,
Molmer demonstrates that a standard measurement of the phase
between two independent light beams emanating from cavities
initially in number states leads to measurement records
indistinguishable from those expected of coherent states.

In summary: The authors provide a quantum information-theoretic
description of an ideal propagating continuous-wave laser field
and reinterpret typical quantum-optical experiments in light of
this. In particular, the authors demonstrate that contrary to
recent claims [T. Rudolph and B.C. Sanders, Phys. Rev. Lett. 87,
077903 (2001)], a conventional laser can be used for quantum
teleportation with continuous variables and for generating 
continuous-variable entanglement. Optical coherence is not
required, but phase coherence is. The authors also demonstrate
that coherent states play a privileged role in the description
of laser light.

References (abridged):

1. T. Rudolph and B. C. Sanders, Phys. Rev. Lett. 87, 077903
(2001).

2. M. Sargent, M. 0. Scully, and W. E. Lamb, Laser Physics  
(Addison-Wesley, Reading, MA, 1974).

3. D. F. Walls and G. J. Milburn, Quantum Optics
(Springer-Verlag, Berlin, 1994).

4. K. M0lmer, Phys. Rev. A 55, 3195 (1997); J. Mod. Opt. 44,
1937 (1997).

5. S. J. van Enk and C. A. Fuchs, quant-ph/0111157.

Phys. Rev. Lett. 2002 88:027902

Web Links: lasers

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5. ON SALT BRIDGES AND THE STABILITY OF PROTEINS

In this context, the term "salt bridge" refers to any
electrostatic bond between positively and negatively charged
groups on amino-acid residues of a protein, with an inference
that the salt bridge, when it exists, contributes to the
stability of the protein structure.

The "hydrophobic interaction" (hydrophobic effect), the tendency
for nonpolar molecules to aggregate in solution, is a major
driving force in biology, a force that stabilizes biological
structures ranging from native conformations of proteins to
cellular membranes, and the origin of this effect has been the
topic of much investigation, both experimental and theoretical.

S.E. Thompson and D.B. Smithrud (University of Cincinnati, US)
discuss salt bridges, the authors making the following points:

1) Charged amino acids are found throughout proteins, with a
greater percentage existing in solvent-exposed regions. At first
glance, it may seem natural for these functional groups to form
salt bridges with complementary charged amino acids to provide
protein stability and ligand binding. However, unlike the
hydrophobic effect that provides the driving force for protein
folding(1) and a large portion of the binding energy for protein
complexes, the energy contributed to these processes by salt
bridges is deemed either favorable,(2) approximately none,(3) or
unfavorable,(4) depending on the experiment, calculation, or
computational analysis. The contradictory nature of salt bridges
arises from the opposing energy terms in water, the pairwise
Coulombic interaction energy being favorable, whereas ion
desolvation is an unfavorable process. The magnitude of these
energy terms depends on many factors, including the size of the
charge and the dielectric constant of the media that surround
the isolated ions and the complex.(2-4) Although a large
desolvation penalty generally leads to unfavorable salt bridge
formation, the extreme case of burying a salt bridge within the
hydrophobic core of a protein with almost complete desolvation
of the ion pair may still be energetically favorable.(5)

2) Even though early calculations showed that approximately
10-16 kcal/mol of energy is lost upon transfer of a salt bridge
from water to a protein interior, salt bridges seem to be an
important bond for protein folding and structure. Protein
folding results from an accumulation of small favorable energy
terms, and thus, even weak ionic bonds may contribute to protein
structure and function. One classic example is the allosteric
transition of hemoglobin. Salt bridges are postulated to
stabilize the T state of the protein, and once broken, the
protein reverts to its R state. Recent studies on the
constituents of hyperthermal proteins have shown that they
contain a greater number of salt bridges compared to mesophilic
ones. Deletion of salt bridges can lead to destabilized
proteins, and the addition of salt bridges at the i and i + 4
positions in short peptides or on protein surfaces can promote
the formation of alpha-helices.

3) Consistent with the confusing nature of salt bridges, for all
the cases of favorable salt bridges there seems to be an equal
number of unfavorable ones. Replacing salt bridges within
certain proteins with hydrophobic residues increases protein
stability, and energy estimates of some buried salt bridges
using continuum electrostatic calculations(5) are unfavorable.
Incorporating salt bridges within proteins definitely does not
guarantee a favorable energy term. The addition of a salt bridge
into an alpha-helix dimer destabilizes it, and a salt bridge
incorporated into a surface helix of T4 lysozyme appeared to
have little effect on protein stability.

References (abridged):

1. Dill K. A. Biochemistry 1990, 29, 7133-7155

2. (a) Lounnas, V.; Wade, R. C. Biochemistry 1997, 36,
5402-5417. (b) Xu, D.; Lin, S. L.; Nussinov, R. J. Mol. Biol.
1997, 265, 68-84. (c) Pervushin, K.; Billeter, M.; Siegal, G.;
Wuthrich, K. J. Mol. Biol. 1996, 264, 1002-1012. (d) Marqusee,
S.; Sauer, R. T. Protein Sci. 1994, 3, 2217-2225. (e) Horovitz,
A.; Fersht, A. R. J. Mol. Biol. 1992, 224, 733-740

3. (a) Barril, X.; Aleman, C.; Orozco, M.; Luque, F. J.
Proteins: Struct., Funct. Genet. 1998, 32, 67-79. (b) Serrano,
L.; Horovitz, A.; Avron, B.; Bycroft, M.; Fersht, A. R.
Biochemistry 1990, 29, 9343-9352. (c) Singh, U. C. Proc. Natl
Acad. Sci. U.S.A. 1988, 85, 4280-4284

4. (a) Waldburger, C. D.; Jonsson, T.; Sauer, R. T. Proc. Natl
Acad. Sci. U.S.A. 1996, 93, 2629-2634. (b) Hendsch, Z. S.;
Tidor, B. Protein Sci. 1994, 3, 211-226. (c) Sun, D. P.; Sauer,
U.; Nicholson, H.; Matthews, B. W. Biochemistry 1991, 30,
7142-7153

5. Kumar, S.; Nussinov, R. J. Mol. Biol. 1999, 293, 1241-1255

J. Am. Chem. Soc. 2002 124:442

Web Links: protein stability

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6. GREEN FLUORESCENT PROTEIN AND BIOLUMINESCENCE

Marc Zimmer (Connecticut College, US) discusses green
fluorescent protein, the author making the following points:

1) In the last 10 years, green fluorescent protein (GFP) has
changed from a nearly unknown protein to a commonly used tool in
molecular biology, medicine, and cell biology. GFP is used as a
biological marker. It is particularly useful due to its
stability and the fact that its chromophore is formed in an
autocatalytic cyclization that does not require a cofactor. This
has enabled researchers to use GFP in living systems, and it has
led to GFP's widespread use in cell dynamics and development
studies. Furthermore, it appears that fusion of GFP to a protein
does not alter the function or location of the protein.

2) Pliny the elder (23-79 AD) described bioluminescence as early
as the first century. Bioluminescence is the process by which
visible light is emitted by an organism as a result of a
chemical reaction. The reaction involves the oxidation of a
substrate (called the luciferin) by an enzyme (the luciferase).
Oxygen is usually the oxidant. Bioluminescent organisms are
found in a variety of environments. Common examples are insects,
fish, squid, sea cacti, sea pansies, clam, shrimp, and
jellyfish. The bioluminescent systems in these organisms are not
all evolutionarily conserved, and the genes coding for the
proteins involved in bioluminescence are not homologous. The
emitted light commonly has one of three functions: defense,
offense, or communication.

3) Green fluorescent proteins are found in numerous organisms,
but Aequorea aequorea (A. victoria; A. forskalea; a hydrozoan
jellyfish) GFP was the first GFP for which the gene was cloned
and expressed, and it is the GFP used in most tracer studies. It
was first reported in 1955 that Aequorea fluoresced green when
irradiated with ultraviolet light. Two proteins in Aequorea are
involved in its bioluminescence, aequorin and green fluorescent
protein. Aequorin (the luciferase) contains coelenterazine (the
luciferin). Upon binding three calcium ions the aequorin
oxidizes the coelenterazine with a protein-bound oxygen
resulting in a Ca(sub3)-apo-aequorin-coelenteramide complex
which in vitro emits blue light. However, Aequorea does not emit
blue bioluminescence; instead, the aequorin complex undergoes
radiationless energy transfer to GFP which gives off green
fluorescence.(5) No binding between aequorin and GFP is observed
in solution. In vitro energy transfer can be obtained by
coadsorption of aequorin and GFP on DEAE cellulose membranes.
The crystal structure of aequorin was recently solved.

References (abridged):

1. Chalfie, M. Photochem. Photobiol. 1995, 62, 651-656

2. Cubitt, A. B.; Heim, R.; Adams, S. R.; Boyd, A. E.; Gross, L.
A.; Tsien, R. Y. TIBS 1995, 20, 448-455

3. Gerdes, H.-H.; Kaether, C. FEBS Lett. 1996, 389, 4-47

4. Tsien, R. Annu. Rev. Biochem. 1998, 67, 510-544

5. Kendall, J. M.; Badminton, M. N. TIBTECH 1998, 16, 216-224

Chem. Rev. 2002 102:759

Web Links: green fluorescent protein

Related Background:

ON BIOLUMINESCENCE IN COELENTERATES

S.H. Haddock et al (Monterey Bay Aquarium Research Institute,
US) discuss bioluminescence in coelenterates, the authors making
the following points:

1) Bioluminescence of the hydromedusa Aequorea victoria has been
studied more thoroughly than that of any other marine
invertebrate. These jellyfish, readily collected from the waters
of Puget Sound, Washington, have been the source of the first
purified and cloned green-fluorescent protein, and the first
calcium-regulated photoprotein. This photoprotein, aequorin, has
been extensively studied since its discovery nearly 40 years
ago. It is a complex of an apoprotein joined with oxygen and a
light- emitting luciferin called "coelenterazine". Because they
are triggered by calcium ions to produce light, photoproteins
have been widely used as calcium "reporters", and the high level
of interest in these molecules has led to detailed studies of
their chemistry and molecular biology. Photoprotein genes have
been cloned from several species of hydromedusae, and recently
the tertiary structures of two photoproteins have been resolved.
If, however, the gene for apo-aequorin is introduced into an
organism, no light will be emitted unless luciferin is provided
exogenously. As a result, there is great interest in finding the
pathways and genes responsible for the production of luciferin.

2) Photoproteins similar to aequorin have been found in sea
gooseberries (ctenophores), marine pelagic protozoa
(radiolarians) , and other hydromedusae. In addition,
coelenterazine, the imidazolopyrazine luciferin of these
photoprotein systems, is also used by fish, squid, some
crustaceans, arrow worms (chaetognath), and is found in many
non- luminous organisms as well. But despite its occurrence in a
variety of phyla, and recent interest in its anti-oxidative
properties, there has been little experimental evidence to
indicate the origins of this light-emitting molecule in nature.
There are two examples from crustacea: a) a dietary requirement
for coelenterazine has been demonstrated for the lophogastrid
shrimp Gnathophausia ingens, whereas b) the decapod shrimp
Systellaspis debilis appears to have the ability to synthesize
the molecule.

3) The authors report that the hydromedusae A. victoria is
unable to produce its own coelenterazine and is dependent on a
dietary supply of this luciferin for bioluminescence. The
authors suggest this evidence regarding the origins of luciferin
in coelenterates (Cnidaria) has implications for the evolution
of bioluminescence and for understanding the extensive use of
coelenterazine among marine organisms. In addition, the authors
suggest that if jellyfish are unable to synthesize their own
luciferin, then the name "coelenterazine" may be a misnomer,
since the only evidence for production of this molecule in the
ocean comes from crustaceans.

Proc. Nat. Acad. Sci. 2001 98:11148

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7. ON ATRIAL FIBRILLATION

Stanley Nattel (University of Montreal, CA) discusses atrial
fibrillation, the author making the following points:

1) Atrial fibrillation is characterized by rapid and irregular
activation of the atrium, for example, 400–600 pulses of the
atrium muscular wall per minute in humans. The occurrence of
atrial fibrillation increases with age, with a prevalence rising
from 0.5% of people in their 50s to nearly 10% of the
octogenarian population(1, 2). Several cardiac disorders
predispose to atrial fibrillation, including coronary artery
disease, pericarditis, mitral valve disease, congenital heart
disease, congestive heart failure, thyrotoxic heart disease and
hypertension. Many of these are thought to promote atrial
fibrillation by increasing atrial pressure and/or by causing
atrial dilation; however, the precise mechanistic links are
incompletely defined. Atrial fibrillation also occurs in
individuals without any other evidence of heart or systemic
disease -- a condition known as "lone atrial fibrillation".

2) Normally, heart rate is finely attuned to the body's
metabolic needs through physiological control of the cardiac
pacemaker function of the sinoatrial node, which maintains a
rate of about 60 beats per minute at rest and can fire as
rapidly as 180–200 times per minute at peak exercise. During
atrial fibrillation, atrial cells fire at rates of 400–600 times
per minute. If each atrial impulse were conducted to the
ventricles, the extremely rapid ventricular rate would lead to
ineffective cardiac contraction and rapid death. This is
prevented by the filtering function of the atrioventricular
node, which has a limited impulse-carrying capacity and through
which atrial impulses must pass before activating the ventricles.

3) The ventricular rate during atrial fibrillation (the
effective "heart rate") is thus no longer under physiological
control of the sinus node, but instead is determined by
interaction between the atrial rate and the filtering function
of the atrioventricular node. The ventricular rate during atrial
fibrillation is typically in the region of 150 pulses per minute
in the absence of drug therapy. In normal individuals, a brief
period of AF may cause palpitations, chest discomfort and
light-headedness. Sustained atrial fibrillation with an
uncontrolled ventricular response rate can, by itself, cause
severe congestive heart failure after several weeks to months,
but this is reversible with proper rate and/or rhythm control(3).

4) In summary: Atrial fibrillation is a condition in which
control of heart rhythm is taken away from the normal sinus node
pacemaker by rapid activity in different areas within the upper
chambers (atria) of the heart. This results in rapid and
irregular atrial activity and, instead of contracting, the atria
only quiver. It is the most common cardiac rhythm disturbance
and contributes substantially to cardiac morbidity and
mortality. For over 50 years, the prevailing model of atrial
fibrillation involved multiple simultaneous re-entrant waves,
but in light of new discoveries this hypothesis is now
undergoing re-evaluation.(4,5)

References (abridged):

1. Benjamin, E. J. et al. Impact of atrial fibrillation on the
risk of death. The Framingham heart study. Circulation 98,
946-952 (1998)

2. Ho, K. K., Pinsky, J. L., Kannel, W. B. & Levy, D. The
epidemiology of heart failure: the Framingham study. J. Am.
Coll. Cardiol. 22, 6A-13A (1993)

3. Fenelon, G., Wijns, W., Andries, E. & Brugada, P.
Tachycardiomyopathy: mechanisms and clinical implications.
Pacing Clin. Electrophysiol. 19, 95-106 (1996)

4. Hart, R. G. & Halperin, J. L. Atrial fibrillation and stroke:
concepts and controversies. Stroke 32, 803-808 (2001)

5. Nattel, S. Experimental evidence for proarrhythmic mechanisms
of antiarrhythmic drugs. Cardiovasc. Res. 37, 567-577 (1998)

Nature 2002 415:219

Web Links: atrial fibrillation

Related Background:

ON CARDIAC PHYSIOLOGY AND ARRHYTHMIAS

Eduardo Marban (Johns Hopkins University, US) discuss cardiac
physiology and arrhythmias, the author making the following
points:

1) The heart pumps blood throughout the body and never rests,
undergoing roughly three billion cycles in a typical lifetime.
To achieve this, the heart must first relax so that its chambers
(the atria and ventricles) can fill with blood, and then
contract to propel the blood throughout the body. This cycle of
relaxation and contraction occurs in a single heartbeat.

2) Each heartbeat is initiated by a pulse of electrical
excitation that begins in a group of specialized pacemaker cells
and subsequently spreads throughout the heart. This electrical
impulse is made possible by the electrochemical gradient that
exists across the surface membrane of each heart cell, or
"myocyte". At rest, the membrane is selectively permeable to K+
ions, and the electrochemical potential inside the myocyte is
negative with respect to the outside. During electrical
excitation, the membrane becomes permeable to Na+ ions and the
electrochemical potential reverses or "depolarizes". Ca2+ ions
move into the cell and activate the contractile machinery -- a
process that, when it happens en masse, causes the atria and
ventricles to contract and expel blood. The wave of
depolarization is self-limiting; as a negative membrane
potential is restored, the heart relaxes and fills with blood
for the next cycle.

3) Because the heartbeat is so dependent on the proper movement
of ions across the surface membrane, disorders of ion channels
-- or "channelopathies" -- make up a key group of heart
diseases. Channelopathies predispose individuals to disturbances
of normal cardiac rhythm. If the heart beats too slowly
(bradyarrhythmias) or so rapidly that it cannot fill adequately
(tachyarrhythmias), then this leads to circulatory collapse and,
in the extreme case, death. The incidence of arrhythmias is
poorly defined, but conservative estimates are in the range of
several million per year in the United States. Arrhythmias lead
to more than 250,000 sudden deaths per year, countless lost work
days, and financial costs related to treatment, including the
implantation of more than 250,000 electronic pacemakers and more
than 60,000 defibrillators per year. The numbers worldwide are
certainly much greater. Several different genetic and acquired
channelopathies can cause such arrhythmias.(1-5)

4) In summary: Genetic alterations of various ion channels
produce heritable cardiac arrhythmias that predispose affected
individuals to sudden death. The investigation of such
"channelopathies" continues to yield remarkable insights into
the molecular basis of cardiac excitability. The concept of
channelopathies is not restricted to genetic disorders; notably,
changes in the expression or post-translational modification of
ion channels underlie the fatal arrhythmias associated with
heart failure. Recognizing the fundamental defects in
channelopathies provides the basis for new strategies of
treatment, including tailored pharmacotherapy and gene therapy.

References (abridged):

1. Catterall, W. A. Molecular properties of sodium and calcium
channels. J. Bioenerg. Biomembr. 28, 219-230 (1996).

2. Jan, L. Y. & Jan, Y. N. Voltage-gated and inwardly rectifying
potassium channels. J. Physiol. 505, 267-282 (1997).

3. Philipson, K. D. & Nicoll, D. A. Sodium-calcium exchange: a
molecular perspective. Annu. Rev. Physiol. 62, 111-133 (2000).

4. Marban, E., Yamagishi, T. & Tomaselli, G. F. Structure and
function of voltage-gated sodium channels. J. Physiol. 508,
647-657 (1998).

5. Zeng, J. & Rudy, Y. Early afterdepolarizations in cardiac
myocytes: mechanism and rate dependence. Biophys. J. 68, 949-964
(1995).

Nature 2002 415:213

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8. ALLERGIC DISEASES AND THE HYGIENE HYPOTHESIS

M. Yazdanbakhsh et al (Leiden University, NL) discuss allergic
diseases, the authors making the following points:

1) There has been a significant increase in the prevalence of
allergic diseases over the past 2 to 3 decades. Currently, more
than 130 million people suffer from asthma, and the numbers are
increasing (1); nevertheless, there is a considerably lower
prevalence of allergic diseases in developing countries (2).
There are also clear differences in the prevalence of allergies
between rural and urban areas within one country. For example,
in Ethiopia, asthma is more prevalent in urban areas than in
rural villages (3), and asthma is more common in residents of
urban Germany than in farmers living in rural Bavaria (4). To
explain these observations, environmental factors associated
with more industrialized and urban living have been studied
intensively, but there is little consistent evidence to suggest
that obvious risk factors, such as increased exposure to indoor
allergens, pollution, or changes in diet and breastfeeding,
could account for the rise in atopic diseases. However, another
category of environmental factors, childhood infections, shows
an overwhelming and consistent negative association with atopy
and allergic diseases. Allergic sensitization is overrepresented
among first-born but is less frequent in children from large
families (5) and those attending day care, suggesting that a
frequent exchange of infections may have a protective effect (5).

2) Atopy, characterized by raised immunoglobulin (Ig)E levels,
underlies allergic diseases such as asthma, rhinoconjunctivitis,
and eczema. The interaction of an environmental allergen with
the innate immune system, its uptake by antigen-presenting
cells, and the subsequent T cell priming leads to the
stimulation of cytokines such as interleukin (IL)-4, IL-5, and
IL-13. These cytokines interact with their receptors to
stimulate IgE production and increased numbers of eosinophils
and mast cells; all of these components are capable of
precipitating inflammation in the respiratory tract.

3) Exposure to food and orofecal pathogens, such as hepatitis A,
Toxoplasma gondii, and Helicobacter pylori, reduces the risk of
atopy by >60%. Studies of gut commensals indicate differences in
the rate of microbial colonization, as well as the bacterial
type involved (clostridia versus lactobacilli) in children with
and without a predisposition to allergy. On the basis of these
data, it has been proposed that the lack of intense infections
in industrialized countries owing to improved hygiene,
vaccination, and use of antibiotics may alter the human immune
system such that it responds inappropriately to innocuous
substances. This so-called "hygiene hypothesis" (5) has been
given an immunological framework in which the balance between
type 1 immune responses (TH1, associated with bacterial and
viral infections and autoimmune diseases) and type 2 immune
responses (TH2, associated with helminth infections and allergic
diseases) is pivotal. It has been postulated that limited
exposure to bacterial and viral pathogens during early childhood
results in an insufficient stimulation of TH1 cells, which in
turn cannot counterbalance the expansion of TH2 cells and
results in a predisposition to allergy.

4) In summary: The increase of allergic diseases in the
industrialized world has often been explained by a decline in
infections during childhood. The immunological explanation has
been put into the context of the functional T cell subsets known
as T helper 1 (TH1) and T helper 2 (TH2) that display polarized
cytokine profiles. It has been argued that bacterial and viral
infections during early life direct the maturing immune system
toward TH1, which counterbalance proallergic responses of TH2
cells. Thus, a reduction in the overall microbial burden will
result in weak TH1 imprinting and unrestrained TH2 responses
that allow an increase in allergy.The authors suggest this
notion is contradicted by observations that the prevalence of
TH1-autoimmune diseases is also increasing and that TH2-skewed
parasitic worm (helminth) infections are not associated with
allergy. More recently, elevations of anti-inflammatory
cytokines, such as interleukin-10, that occur during long-term
helminth infections have been shown to be inversely correlated
with allergy. The authors suggest thst the induction of a robust
anti-inflammatory regulatory network by persistent immune
challenge offers a unifying explanation for the observed inverse
association of many infections with allergic disorders.

References (abridged):

1. M. R. Sears, Lancet 350, 1015 (1997)

2. The International Study of Asthma and Allergies in Childhood
Steering Committee, Lancet 351, 1225 (1998)

3. H. Yemaneberhan, et al., Lancet 350, 85 (1997)

4. O. S. von Ehrenstein, et al., Clin. Exp. Allergy 30, 187
(2000)

5. D. P. Strachan, Br. Med. J. 299, 1259 (1989)

Science 2002 296:490

Web Links: allergic diseases hygiene hypothesis

Related Background:

MEDICAL BIOLOGY: ON THE BIOLOGY OF ALLERGY AND ALLERGIC DISEASES

The term "allergy" refers to a hypersensitive reaction by the
body to foreign substances (antigens) that in similar amounts
and circumstances are harmless within the bodies of people who
do not manifest such a reaction. Antigens that provoke an
allergic reaction are called "allergens", and these include
various pollens, drugs, lints, bacteria, foods, dyes and other
chemicals.

The term "antibodies" refers to proteins produced by the immune
system, these proteins binding to and destroying or neutralizing
antigens. Lymphocytes (lymph cells, lympho-leukocytes) are a
type of leukocyte (white blood cell) involved in the immune
response. There are two classes of such lymphocytes: 1) the
"B-cells", which after a cascade of immune system events
involving a specific antigen change into proliferating specific
antibody producing blood-plasma cells; 2) the "T-cells", one
subclass of which (cytotoxic T-cells) interacts directly with
foreign invaders such as bacteria and viruses, while the other
subclass of T-cells (helper T-cells) is involved in the
proliferation of antibody-specific B-cells.

There are several types of allergic reactions. So-called "type 1
reactions" include hay fever, insect venom allergy, and asthma,
and they involve a class of antibodies known as immunoglobulin E
(IgE). IgE molecules are bound to *mast cells, which are located
in loose connective tissue. When enough antigen has bound with
the IgE antibodies, the mast cells release granules of
*histamine and *heparin, and produce other substances such as
*leukotrienes. These chemicals dilate blood vessels and
constrict bronchial air passages. Histamine is apparently
responsible for the visible symptoms of an allergic attack:
e.g., running nose, wheezing, and tissue swelling. The
predisposition of a person to type 1 allergic reactions is
apparently genetically determined.

A.B. Kay (Imperial College School of Medicine London, UK)
presents a review of allergy and allergic diseases, the author
making the following points concerning the biology of allergy:

1) The author points out that the term "allergy" was introduced
in 1906 by Clemens P. Pirquet [von Cesenatico] (1874- 1929), who
used the term to describe both protective immunity and
hypersensitivity reactions, but over time, the term has come to
be used exclusively for hypersensitivity reactions. The term
"atopy" (from the Greek _atopos_, meaning out of place) is often
used to describe IgE-mediated diseases. Persons with atopy have
a hereditary predisposition to produce IgE antibodies against
common environmental allergens and have one or more "atopic
diseases": allergic rhinitis, asthma, or atopic eczema. Some
allergic diseases, such as *contact dermatitis and
*hypersensitivity pneumonitis, develop via IgE-independent
mechanisms and can be considered non-atopic allergic conditions.

2) The author points out that everyone inhales aero- allergens
derived from pollen, house-dust mites, and cat dander. In
general, adults and children without atopy mount a low-grade
immune response to these aero-allergens, producing several types
of immunoglobulin antibodies, but not IgE antibodies. Persons
with atopy, by contrast, have an exaggerated immune response to
these aero-allergens, the response characterized by the
production of allergen-specific IgE antibodies, and such persons
have elevated serum levels of IgE antibodies and positive
reactions to extracts of common aero-allergens in skin-prick
tests. In general, the immunopathological hallmark of allergic
disease is the infiltration of affected tissue by a specific
type (type 2) of T-helper cells. The types of T-helper cells are
distinguished on the basis of the types of *cytokines they
produce when activated.

3) In utero, T cells of the fetus are primed by common
environmental allergens that cross the placenta, with the immune
response of virtually all newborn infants dominated by type 2
T-helper cells. It has been proposed that during subsequent
development the normal (i.e., non-atopic) infant's immune system
shifts in favor of a type 1 T-helper cell-mediated response to
inhaled allergens, whereas in the potentially atopic infant
there is a further increase in type 2 T-helper cells that were
primed in utero. Microbes are probably the chief stimuli of
protective type 1 T-helper cell immunity.

4) The author suggests the marked increase in the prevalence of
atopic disease in western Europe, the US, and Australasia during
recent years indicates the importance of environmental
influences. An informative example is the change in the
incidence of seasonal allergic rhinitis and asthma after the
reunification of Germany. These disorders were less common in
East Germany than in West Germany before reunification, whereas
since reunification, the prevalence of atopy and hay fever, but
not asthma, has increased among children who spent their early
childhood in East Germany. The author suggests this phenomenon
raises the possibility that a Western lifestyle accounts for the
increase in prevalence. Perhaps in Western countries the
developing immune system is deprived of the microbial antigens
that stimulate type 1 T-helper cells, because the environment is
relatively clean and the use of antibiotics for minor illnesses
in early life is widespread. The author suggests the results of
epidemiological studies seaport this theory.

New Engl. J. Med. 2001 344:30

Text Notes:

... ... *mast cells: Mast cells are white blood cells
(leukocytes) containing dense granules of various substances,
with mast cells often associated with connective tissue.

... ... *histamine: A local hormone that acts as a powerful
stimulant of gastric secretion, constriction of bronchial smooth
muscle, and dilation of blood vessels.

... ... *heparin: The heparins are polymers of O- and N-linked
sulfated glucosamines and hexuronic acids (iduronic and
glucouronic) joined by glycoside linkages, and they are the most
acidic organic acids in the human body. When administered as
pharmacological agents, the heparins have anticoagulant
activity, but they are not ordinarily present in blood, and
their normal function has been a mystery. Mast cells are one of
the two types of cells (the other type being basophils) that
synthesize heparin.

... ... *leukotrienes: In general, a "leukotriene" is a member
of a family of pharmacologically active substances derived from
polyunsaturated fatty acids (especially from arachidonic acid),
some of which contain a peptide moiety based on cysteine. The
leukotrienes are classified as "local hormones", i.e., hormones
that are not stored, but which are synthesized in response to
specific stimuli. They are formally derived from eicosanoic acid
and contain a set of 3 conjugated double bonds (thus the suffix
"triene").

... ... *contact dermatitis: In general, a skin rash resulting
from exposure to either an irritating (e.g., an acid) or
allergic substance.

... ... *hypersensitivity pneumonitis: A chronic progressive
form of pneumonia resulting from exposure to any of a variety of
antigens.

... ... *cytokines: In general, a cytokine is any substance that
promotes cell growth and cell division.

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9. ON THE HUMAN EMBRYONIC STEM CELL DEBATE

Human embryonic stem cells come from preimplantation embryos,
most of which are generated at in vitro fertilization clinics.
Within days after fertilization, the embryo consists of a hollow
sphere, the blastocyst, which contains a cluster of a few
hundred identical cells called the "inner cell mass" that can
eventually develop into a fetus. When removed from the
blastocyst, these cells can be propagated indefinitely in
specialized media. When the media are changed to allow
differentiation, cells continue to divide and aggregate, forming
"embroid" bodies. Although these cell clusters lack the
organization of an embryo, they contain all tissue types,
including skin, muscle, bone, and neurons. Because embryonic
stem cells can become any cell in the body, there is hope that
they will lead to treatment for diseases like diabetes,
Parkinson's disease, Alzheimer's disease, and heart failure. The
problem is controlling cell growth and differentiation. If large
numbers of embryonic stem cells are transplanted into an organ
like the brain, they grow into every cell type and form
tumor-like masses called teratomas. eventually killing their
host. The problem is thus to restrict embryonic stem cells to
produce useful cells without overgrowing. (Curt R. Freed: Proc.
Nat. Acad. Sci. 2002 99:1755,2344)

Irving L. Weissman (Stanford University, US) discusses the stem
cell debate, the author making the following points:

1) What if nuclear transplantation for the production of stem
cells is banned in the United States but allowed in other
countries (for example, China, Sweden, and the United Kingdom)?
Biomedical researchers in the United States will have to learn
of new advances by reading about them, rather than participating
in them, or they will have to leave the United States in order
to participate in research. New biomedical companies that
translate these discoveries into therapies will be created in
other countries, not here. And what if these companies succeed?
Their products could not be imported to treat our patients
(according to provisions of the Weldon bill [H.R.2505] and the
Brownback bill [S.790, the "Human Cloning Prohibition Act of
2001"]), and only the wealthy would gain access to such
treatments abroad. Even if these therapies could be imported, it
is possible that physicians might withhold them from their
patients for religious reasons.

2) Unfortunately, there are few in Congress or the President's
council who can evaluate the scientific and medical issues in
order to make an appropriately informed decision. Too often in
recent Senate hearings, the views expressed by senators have
been based on articles in newspapers and popular magazines
rather than reports of the National Academies or articles in
peer-reviewed journals. Some journalists are failing the public
trust by publicizing findings that have not been published in
the scientific literature or independently replicated.

3) In summary: Experiments in animals have shown that nuclear
transplantation for the production of embryonic stem-cell lines
can be accomplished with mature cell nuclei, including nuclei
containing medically important genetic defects and mutations.
There is already evidence that these embryonic stem-cell lines
can help unlock secrets of developmental and pathogenic events
that might not be revealed otherwise. The technology is ready
for the production of human embryonic stem-cell lines from
diverse members of our society, from somatic cells of patients
with heritable diseases, and from diseased cells (for example,
all cancers) whose nuclei are a repository of the history of
inherited and somatic mutations that caused these diseases. The
method has the potential for producing cells for the treatment
of a variety of diseases. The author suggests that Congress, the
President, and the medical community now face a difficult
decision: to prevent the production of blastocysts by nuclear
transplantation, or to pursue paths of medical research and
therapies that will affect hundreds of thousands of lives.(1-5)

References (abridged):

1. Becker AJ, McCulloch EA, Till JE. Cytological demonstration
of the clonal nature of spleen colonies derived from
transplanted mouse marrow cells. Nature 1963;197:452-454.

2. Siminovitch L, McCulloch EA, Till JE. The distribution of
colony-forming cells among spleen colonies. J Cell Comp Physiol
1963;62:327-36.

3. Weissman IL. Translating stem and progenitor cell biology to
the clinic: barriers and opportunities. Science
2000;287:1442-1446.

4. Evans MJ, Kaufman MH. Establishment in culture of pluripotent
cells from mouse embryos. Nature 1981;292:154-156.

5. Martin GR. Isolation of a pluripotent cell line from early
mouse embryos cultured in medium conditioned by teratocarcinoma
stem cells. Proc Natl Acad Sci U S A 1981;78:7634-7638.

New Engl. J. Med. 2002 346:1576

Web Links: human embryonic stem cells

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10. CONTROLLED BINDING IN DENDRIMERS AND DRUG DELIVERY

K. Yamamoto et al (Keio University, JP) discuss binding in
dendrimers, the authors making the following points:

1) Dendrimers(1-5) are highly branched organic macromolecules
with successive layers or "generations" of branch units
surrounding a central core. Organic–inorganic hybrid versions
have also been produced by trapping metal ions or metal clusters
within the voids of the dendrimers. The unusual, tree-like
topology endows these nanometre-sized macromolecules with a
gradient in branch density from the interior to the exterior,
which can give rise to an energy gradient that directs the
transfer of charge and energy from the dendrimer periphery to
its core(4,5).

2) The authors report a demonstration that tin ions, Sn2+,
complex to the imine groups of a spherical polyphenylazomethine
dendrimer in a stepwise fashion. This behaviour reflects a
gradient in the electron density associated with the imine
groups, with complexation in a more peripheral generation
proceeding only after complexation in generations closer to the
core has been completed. By attaching an electron-withdrawing
group to the dendrimer core, the authors were able to change the
complexation pattern, so that the core imines were complexed
last. The authors suggest that by further extending this
strategy, it should be possible to control the number and
location of metal ions incorporated into dendrimer structures,
which might find uses as tailored catalysts or building blocks
for advanced materials.

3) In a commentary on this report, Christopher Gorman (North
Carolina State University, US) states: "One especially active
area is the investigation of dendrimers for use in molecular
recognition. This uses large molecules as hosts to recognize and
manipulate smaller, guest molecules to catalyse a reaction, for
example, or to transport the guest molecules into new
environments. In drug delivery and medical imaging, the type of
complexation studied by Yamamoto et al. could open up new
opportunities. Dendrimers that bind to antibodies in their outer
regions and to therapeutics in their inner regions, for
instance, might offer an improved way to target cancerous cells
with poisonous antitumour drugs."

References (abridged):

1. Tomalia, D. A., Dewald, J., Hall, M., Martin, S. & Smith, P.
B. in Preprints 1st SPSJ Int. Polym. Conf. (ed. Uematsu, I.) 65
(Society of Polymer Science, Japan, Tokyo, 1984).

2. Tomalia, D. A. et al. A new class of polymers:
starburst-dendritic macromolecules. Polym. J. 17, 117-132 (1985).

3. Newkome, G. R., Yao, Z. Q., Baker, G. R. & Gupta, V. K.
Cascade molecules: a new approach to micelles. A [27]-arborol.
J. Org. Chem. 50, 2003-2004 (1985).

4. Devadoss, C., Bharathi, P. & Moore, J. S. Energy transfer in
dendritic macromolecules: molecular size effects and the role of
an energy gradient. J. Am. Chem. Soc. 118, 9635-9644 (1996).

5. Jiang, D. L. & Aida, T. Photoisomerization in dendrimers by
harvesting of low-energy photons. Nature 388, 454-456 (1997).

Nature 2002 415:487,509

Web Links: dendrimer drug delivery

Related Background:

ON THE HISTORY OF DENDRIMER POLYMERS

S.M. Grayson and J.M. Frechet (University of California
Berkeley, US) discuss dendrimer polymers, the authors making the
following points:

1) Dendrimers represent a key stage in the ongoing evolution of
macromolecular chemistry. From the origins of polymer chemistry
until 20 years ago, a major focus was the synthesis and
characterization of linear polymers. Although the molecular
interactions and the many conformations of linear polymers
involve three dimensions, their covalent assembly is strictly a
1-dimensional process. Half a century ago, in theoretical
studies, P.J. Flory (1910-1985) was among the first to examine
the potential role of branched units in macromolecular
architectures, but it was not until the mid-1980s that methods
for the orderly preparation of these polymers became
sufficiently developed to enable the practical study of these
entities.

2) In 1978, Vogtle developed an iterative cascade method for the
synthesis of low molecular weight branched amines. Using
chemistry and conditions less prone to cyclization
side-reactions and therefore more suitable for repetitive
growth, Tomalia et disclosed the synthesis and characterization
of the first family of dendrimers in 1984-1985. The synthesis
was initiated by an addition reaction (Michael addition) of a
"core" molecule of ammonia to three molecules of methyl
acrylate, followed by exhaustive amidation of the triester
adduct, using a large excess of ethylenediamine, a process that
generates a molecule with 6 terminal amine groups. Iterative
growth is then continued, using alternate Michael addition and
amidation steps with appropriate excess of reagents, and
optimization of this procedure enables the synthesis of globular
poly(amidoamine) dendrimers on a commercial scale with molecular
weights well above 25,000.

Chem. Rev. 2001 101:3819

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11. ON PROTECTED QUANTUM BITS

L.B. Ioffe et al (Rutgers University, US) discuss quantum
computation, the authors making the following points:

1) All physical implementations of quantum bits (or qubits, the
logical elements in a putative quantum computer) must overcome
conflicting requirements: the qubits should be manipulable
through external signals, while remaining isolated from their
environment. Proposals based on quantum optics emphasize optimal
isolation(1-3), while those following the solid-state route
exploit the variability and scalability of nanoscale fabrication
techniques(4,5). Recently, various designs using superconducting
structures have been successfully tested for quantum coherent
operation; however, the ultimate goal of reaching coherent
evolution over thousands of elementary operations remains a
formidable task. Protecting qubits from decoherence by
exploiting topological stability is a qualitatively new proposal
that holds promise for long decoherence times, but its physical
implementation has remained unclear.

2) Any quantum computer has to incorporate some fault tolerance
because we cannot hope to eliminate every source of decoherence.
Quantum error-correction schemes have been developed using
redundant multi-qubit encoding of the quantum data combined with
error-detection and recovery steps. Such error-correction
schemes are generic (and hence are applicable to any hardware
implementation), but require repeated active interference with
the computer during run-time; the delocalization of the data,
often in a hierarchical structure, boosts the system size by a
factor of 10^(2) to 10^(3). Delocalization of the quantum
information is also at the heart of topological quantum
computing; however, the stabilization against decoherence is
deferred to the hardware level (and so it is tied to the
specific implementation) and is achieved passively. In searching
for a physical implementation of topological qubits we strive
for an extended (many body) quantum system where the Hilbert
space of quantum states decomposes into mutually orthogonal
sectors, each sector remaining isolated under the action of
local perturbations. Choosing the two qubit states from ground
states in different sectors protects these states from unwanted
mixing through noise; protection from leakage within the sector
has to be secured through a gapped excitation spectrum. As no
local operator can interfere with these states, global operators
must be found (and implemented) that allow the manipulation of
the qubit state.

3) The authors demonstrate how strongly correlated systems
developing an isolated twofold degenerate quantum dimer liquid
ground state can be used in the construction of topologically
stable qubits. The authors discuss their implementation using
Josephson junction arrays. Although the complexity of their
architecture challenges the technology base available today, the
authors suggest that such topological qubits greatly benefit
from their built-in fault-tolerance.

References (abridged):

1. Cirac, J. I. & Zoller, P. Quantum computations with cold
trapped ions. Phys. Rev. Lett. 74, 4091-4094 (1995).

2. Monroe, C., Meekhof, D., King, B., Itano, W. & Wineland, D.
Demonstration of a fundamental quantum logic gate. Phys. Rev.
Lett. 75, 4714-4717 (1995).

3. Turchette, Q., Hood, C., Lange, W., Mabushi, H. & Kimble, H.
J. Measurement of conditional phase shifts for quantum logics.
Phys. Rev. Lett. 75, 4710-4713 (1995).

4. Loss, D. & DiVincenzo, D. P. Quantum computation with quantum
dots. Phys. Rev. A 57, 120-126 (1998).

5. Shnirman, A., Schön, G. & Hermon, Z. Quantum manipulations of
small Josephson junctions. Phys. Rev. Lett. 79, 2371-2374 (1997).

Nature 2002 415:503

Web Links: quantum computing

Related Background:

ON NOISE AND QUANTUM INFORMATION PROCESSING

L. Viola et al (Los Alamos National Laboratory, US) discuss
noise and quantum information processing. Quantum information is
represented in terms of superposition states of elementary two-
level systems known as "qubits". The coherence properties of
such superpositions are essential to the extraordinary
capabilities that quantum mechanics promises for quantum
simulation, computation, and communication. At the same time,
these coherence properties are also extremely vulnerable to the
decoherence processes that real-world quantum devices undergo
due to unwanted couplings with their surrounding environment.
Thus, achieving noise control is indispensable for practical
quantum information processing. While a variety of strategies
have been devised to meet this challenge, no single method can
compensate for a completely arbitrary noise process. Rather,
constructing a reliable quantum-information-processing scheme
depends crucially on the errors that occur. If the interaction
with the environment is sufficiently weak, then to a good
approximation a restricted set of errors dominates the
information loss, and active quantum error correction can be
successfully implemented. Another instance where the relevant
errors are a subset of all possible errors occurs when the
system-environment interaction, no matter how strong, exhibits a
symmetry. This has provoked the development of passive
noise-control schemes based on encoding quantum information into
"noiseless" subspaces.

Science 2001 293:2059

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12. ON POROUS SILICON

Jillian M. Buriak (Purdue University, US) discusses porous
silicon, the author making the following points:

1) In 1990, Canham made the important discovery that
nanocrystalline porous silicon can emit visible light through
photoluminescence at room temperature.(27) This discovery was
quickly followed up by electro- and chemiluminescence and a
subsequent explosion of interest.(28-30) Porous silicon has been
the subject of over 3500 papers since 1990, which is testament
not only to its technological potential, but to the fundamental
interest in understanding the luminescence phenomena of this
material.(31) Porous silicon has a highly complex nanoscale
architecture made up of 1-dimensional crystalline nanowires and
0-dimensional nanocrystallites.

2) The major barrier preventing commercial applications of
porous silicon is the instability of its native interface, a
metastable Si-H termination, and thus surface chemistry has
proven to be a crucial element for the technological success of
this material. The photoluminescence of porous silicon depends
strongly upon the surface passivation, with certain
functionalities (i.e., halogens, styrenyl and phenethynyl
groups) resulting in complete quenching of light emission. While
highly debated in the literature, it is generally accepted that
due to quantum confinement effects, radiative recombination of
entrapped electron-hole pairs (excitons) within the boundaries
of nanocrystallites/nanowires with diameters of 2 nanometers is
favorable, leading to the observed luminescence. Surface states
associated with various interface species can have dramatic
quenching effects if they provide sites for nonradiative
recombination of the excitons ("smart" quantum confinement
model).

3) The precision of organic chemistry promises to allow for
fine-tuning of these important interfacial effects, leading
ultimately toward an understanding of the role of surface states
on semiconducting nanoparticles in general. The nature of the
surface bond, sterics, conjugation, and electronics of organic
substituents can all be modulated at will and should provide the
following: (i) stable porous silicon surfaces, (ii) modifiable
surface characteristics, and (iii) potential to interface with
organic conductor/semiconductors/LEDs and biologically relevant
molecules for an array of applications, such as sensing,
photonics, and other analytical uses. From a technological
standpoint, light-emitting porous silicon is especially
attractive because it could be readily integrated with existing
silicon-based integrated circuit (IC) manufacturing processes.
Other non-silicon-based light-emitting materials such as GaAs or
organic light-emitting compounds will require extensive
modification of the IC processes for their incorporation into
silicon-based chips.

4) Porous silicon is an especially attractive testing ground for
surface chemistry due to its high surface area, which renders
analysis relatively straightforward through conventional
transmission Fourier transform infrared (FTIR) or diffuse
reflectance infrared (DRIFT) spectroscopy. As a result, routine
characterization of this material is practical and facile for
most chemists.

References (abridged):

27. Canham, L. T. Appl. Phys. Lett. 1990, 57, 1046.

28. Halimaoui, A.; Oules, C.; Bomchil, G.; Bsiesy, A.; Gaspard,
F.; Herino, R.; Ligeon, M.; Muller, F. Appl. Phys. Lett. 1991,
59, 304.

29. McCord, P.; Yau, S. L.; Bard, A. J. Science 1992, 257, 68.

30. Stewart, M. P.; Buriak, J. M. Adv. Mater. 2000, 12, 859.

31. Fauchet, P. M. J. Lumin. 1996, 70, 294.

Chem. Rev. 2002 102:1271

Web Links: porous silicon

Related Background:

ON FABRICATION OF POROUS SILICON ARRAYS

Y. Harada et al (University of Illinois Urbana-Champaign, US)
discuss porous silicon arrays. Porous silicon has been
extensively studied since the discovery in 1990 of its efficient
luminescence properties at room temperature. The current
technological interests in porous silicon focus on the
remarkable high surface area, enhanced chemical reactivity, and
novel physical properties of this material. Biological and
chemical sensors that operate by detecting changes in
Fabry-Perot interference fringes have been fabricated on
chemically modified porous silicon thin films. Porous silicon
has also shown some promise as a substrate material and trap for
analyte molecules in matrix-free desorption/ionization mass
spectrometry. In this latter application, the porous silicon
serves a dual function, acting both as a sample host and as an
energy transduction medium for the high-energy laser radiation
used to vaporize and ionize the analyte. Because many of the
potential applications for porous silicon lie in
microelectronics, microoptics, and related fields that require
miniaturization, development of an efficient method for
micropatterning this material is highly desirable. The formation
of porous silicon is typically accomplished either by anodic
etching in hydrofluoric acid solution or by stain etching in
hydrofluoric acid/nitric acid solution. The structures, and thus
the properties, of the porous silicon films generated by these
methods depend sensitively both on the substrate type and on the
etching conditions used.

J. Am. Chem. Soc. 2001 123:8709

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13. IN FOCUS: ON THE ORIGIN OF THE EARTH

"The Earth was not constructed with a delicate hand. It was
hammered into shape slowly, by the brute force of a meteor
bombardment that lasted hundreds of millions of years. The
soils, the seas, and our primitive microbial ancestors emerged
in the midst of apparent chaos and catastrophe. The process
began billions of years ago as our entire solar system was
congealing from a swirling cloud of hot gases and nuclear ashes
left behind by exploded stars. Some of the objects colliding
with the Earth at this time were planetesimals -- objects as big
as small planets. The kinetic energy released by these impacts
literally shook the Earth to its core and melted much of the
rocky crust and interior. Some chunks of the planetesimals and
meteors became permanently embedded in the Earth, while other
pieces were sent hurtling off into space like giant shrapnel.
The mass of the primordial Earth accumulated slowly, like a
globe that grows as a sculptor slaps on clay, one handful at a
time. With greater size, Earth increased in its gravitational
force, attracting even more of the wandering debris of space.

"It is hard to come up with a specific date of birth for our
planet, given its gradual development. Basing their calculations
on the "radioactive clock" -- measurements of the level of
radioactive decay of certain elements found within the Earth's
crust, such as uranium and lead -- most geologists place the
Earth's age at about four and a half billion years. The Earth
went through horrendous growing pains during its first billion
years. Just as the frequency of meteor impacts began to decline,
violent volcanic eruptions began to spring up around the globe
as the planet's hot interior "degassed." When the Earth's
surface temperature finally began to cool, the massive volume of
water vapor in the atmosphere condensed and poured down from the
heavens in fierce rainstorms of truly biblical proportions. The
torrential rains lasted millions of years, creating our oceans
-- the hydrosphere as we know it -- in the process.

"The original igneous and metamorphic rocks on the Earth's
surface, left behind by volcanic eruptions and upliftings from
the mantle layer below, were washed by the relentless rains, and
their minerals flowed into the oceans. This was an essential
first step in the formation of primitive soils that would
eventually support a vibrant plant and animal life. These
primitive soils lacked organic matter but contained sand, silt,
and clay minerals in various proportions.

"Clays are unique among the mineral components of soil. They are
chemically reactive, microscopic, crystal-like structures that
form out of saturated solutions of silicate and metal oxides.
Sand and silt, in contrast, are large, chemically inert
particles formed by the simple weathering and pulverization of
rock. Some clays are crystallized deep within the Earth's mantle
layer, at high temperature and pressure, and then brought to the
surface by the churning motions of the Earth. This process is
driven by radioactive heating deep within Earth's mantle and is
part of the same plate tectonic geological cycle that gradually
moves the continental crusts."

David W. Wolfe: Tales from the Underground: A Natural History of
Subterranean Life

Perseus Publishing, Cambridge (MA) 2001, p.17.

Web Links: origin of the Earth

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14. SELECTED ABSTRACTS

Measurement of Long-Range Repulsive Forces between Charged
Particles at an Oil-Water Interface. R. Aveyard et al
(University of Hull, UK). Using a laser tweezers method, we have
determined the long-range repulsive force as a function of
separation between two charged, spherical polystyrene particles
(2.7 microns diameter) present at a nonpolar oil-water
interface. At large separations (6 to 12 microns between
particle centers) the force is found to decay with distance to
the power -4 and is insensitive to the ionic strength of the
aqueous phase. The results are consistent with a model in which
the repulsion arises primarily from the presence of a very small
residual electric charge at the particle-oil interface. This
charge corresponds to a fractional dissociation of the total
ionizable (sulfate) groups present at the particle-oil surface
of approximately 3 x 10^(-4). Phys. Rev. Lett. 2002 88:246102

Deciphering the Cross-Talk of Implantation: Advances and
Challenges B. C. Paria et al (University of Kansas, US).
Implantation involves a series of steps leading to an effective
reciprocal signaling between the blastocyst and the uterus.
Except for a restricted period when ovarian hormones induce a
uterine receptive phase, the uterus is an unfavorable
environment for blastocyst implantation. Because
species-specific variations in implantation strategies exist,
these differences preclude the formulation of a unifying theme
for the molecular basis of this event. However, an increased
understanding of mammalian implantation has been gained through
the use of the mouse model. This review summarizes recognized
signaling cascades and new research in mammalian implantation,
based primarily on available genetic and molecular evidence from
implantation studies in the mouse. Although the identification
of new molecules associated with implantation in various species
provides valuable insight, important questions remain regarding
the common molecular mechanisms that govern this process.
Understanding the mechanisms of implantation promises to help
alleviate infertility, enhance fetal health, and improve
contraceptive design. Science 2002 296:2185

Phospholipid/Protein Cones. Bijaya K. Mishra and Britt N. Thomas
(Louisiana State University, US). The presence of protein in
tubule-forming solutions of the diacetylenic phospholipid
1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3 -phosphocholine
results in the formation of hollow cones rather than the
expected hollow cylinders. Differential phase-contrast video
microscopy reveals that cones grow from proteinaceous nodules in
a fashion similar to cylindrical tubule growth from spherical
vesicles. Spatially resolved electron-beam energy-dispersive
X-ray fluorescence spectroscopy shows the protein to be
associated with the cone wall. Small-angle X-ray scattering
shows that, like the protein-free cylinders, the cones are
multilamellar with essentially identical interlamellar spacing.
J. Am. Chem. Soc. 2002 124:6866

Tobacco Advertising in the United States: A Proposal for a
Constitutionally Acceptable Form of Regulation. R. Bayer et al
(Columbia University, US). Lorillard Tobacco Co. v Reilly is the
latest in a series of Supreme Court cases striking down public
health regulation of advertising as a violation of the First
Amendment. In its decision, the Supreme Court significantly
reduced the scope of constitutionally acceptable forms of
regulation of tobacco advertising and created an almost
insoluble dilemma for public health authorities. Control over
advertising, along with taxes and restrictions on smoking in
public settings, plays an important role in the public health
response to tobacco. Those committed to reducing the patterns of
cigarette-related morbidity and mortality should broaden their
advertising-related strategies and consider the role that
greater disclosure of the health harms of tobacco can have on
reducing consumption. Toward this end, we propose a
comprehensive system of taxation and regulation designed to
increase public appreciation and comprehension of the health
risks of cigarettes. First, we consider a tax to be levied on
tobacco advertising and promotion or, as an alternative, a new
excise tax, the proceeds of which would be used exclusively to
fund a Centers for Disease Control and Prevention -- directed
national antitobacco campaign. Second, all print advertising
should be required to carry public health warnings equivalent to
50% of the space devoted to the advertisement. Third,
manufacturers should be required to devote one full side of
cigarette packages to graphic pictorials displaying the dangers
of smoking. The tobacco industry would no doubt respond by
declaring such efforts an unwarranted burden, an example of
constitutionally suspect compelled speech. However, this would
be a battle worth engaging, because it might have an impact on
tobacco-related morbidity and mortality in the United States.
J. Am. Med. Assoc. 2002:287:2990

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15. NEW BOOKS:

150 Years of Quantum Many-Body Theory R. K Bishop, K. A.
Gernoth, N. R. Walet, eds. Series on Advances in Quantum
Many-Body Theory 5. Proc. wksp., Manchester, England, July 2000.
World Scientific, River Edge, N.J., 2001. $98.00 (345 pp.). ISBN
9810247303

A Beautiful Mind: The Life of Mathematical Genius and Nobel
Laureate John Nash. S. Nasart Touchstone, New York, 1998. $16.00
paper (461 pp.). ISBN 0743224574

The Book of the Cosmos: Imagining the Universe from Heraclitus
to Hawking. D. R. Danielson, ed. Perseus, Cambridge, Mass.,
2000. $20.Oopaper (556 pp.). ISBN 0743224574

A Century of Physics. D. A. Bromley. Springer-Verlag, New York,
2002. $59.95 (114 pp.) ISBN 0387952470

The Collected Works of Eugene Paul Wigner. Part B: Historical,
Philosophical, and Socio-Political Papers. Vol. 7: Historical
and Biographical Reflections and Syntheses. J. Mehra, ed.
Springer-Verlag, New York, 2001. $129.00 (535 pp.) ISBN
3540572945

Earth-Moon Relationships. C. Barbien, F. Rampazzi, eds. Proc.
conf., Padova, Italy, Nov. 2000. Kluwer Academic, Nor-well,
Mass., 2001. $199.00 (575 pp.). ISBN 0792370899

Einstein and Soviet Ideology. A. Vucinich. Stanford Nuclear Age
Series. Stanford U. Press, Stanford, Calif, 2001. $60.00 (291
pp.). ISBN 080474209X

Einstein from B to Z. J. Stachel. Birkhtiuser, Boston, 2002.
$69.95 (556 pp.). ISBN 0817641432

The Golden Age of Theoretical Physics. Vols. 1 and 2. J. Mehra.
World Scientific, River Edge, N.J., 2001. $90.00 set (1408 pp.
set). ISBN 9810243421

Great Physicists: The Life and Times of Leading Physicists from
Galileo to Hawking. W. H. Cropper. Oxford U. Press, New York,
2001. $35.00 (500 pp.) ISBN 0195137485

The Interpretation of Quantum Mechanics. W. E. Lamb Jr; J.
Mehra, ed. Rinton Press, Princeton, N.J., 2001. $88.00 (486
pp.). ISBN 1589490053

Letters to Father: Suor Maria Celeste to Galileo, 1623971633. D.
Sobel (in English and original languages). Walker, New York,
2001. $40.00 (377 pp.) ISBN 0802713874

Memoirs: A Twentieth-Century Journey in Science and Politics. E.
Teller Perseus, Cambridge, Mass., 2001. $35.00 (628 pp.). ISBN
073820532X

Newton to Einstein: The Trail of Light. R. Baienlein. Cambridge
U. Press, New York, 2001 [1996, reissued]. $29.95 paper (329
pp.). ISBN 0521423236

Newton's Tyranny: The Suppressed Scientific Discoveries of
Stephen Gray and John Flamsteed. D. H. Clark, S. P. H. Clark.
Freeman, New York, 2001. $14.00 paper (188 pp.). ISBN 0716747014

Nothingness: The Science of Empty Space. H. Genz (translated
from German by Karin Heusch). Perseus, Cambridge, Mass., 1999.
$20.00 paper (340 pp.). ISBN 0738206105

Portraits of Great American Scientists. L. M. Ledennan, J.
Scheppler, eds. Prometheus Books, Amherst, N.Y., 2001. $28.00
(305 pp.). ISBN 1573929328

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