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ScienceWeek
SCIENCE-WEEK - Part 1/3
A Free Weekly Digest of the News of Science
March 13, 1998
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"There is no doubt that great revolutions of human scientific
thought will occur in the next century, and the century after
that, and in thousands of centuries afterward. So which of our
current pet scientific dogmas will be among the first washed away
by new facts and sudden clarities?"
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Contents of This Issue:
Part 1:
1. New Evidence for a Cosmic Antigravity Force
2. Cosmic X-Ray Background: Contribution of Faint Galaxies
3. An Oxygen-Rich Stellar Dust Disk in the Red Rectangle
4. Dephasing in Electron Interference by a Which-Path Detector
5. Electrophoresis in Lyotropic Polymer Liquid Crystals
6. Molten Globules as a Third Phase of Proteins
7. Pressure Dependence of Hydrophobic Interactions of Proteins
8. A Gene for Adhesion and Filamentous Growth in C. Albicans
Part 2:
9. Evidence of De Novo Insertion of an Intron into a Gene
10. New Drosophila Introns Originate by Duplication
11. A Protein that Prohibits Retroviral DNA Autointegration
12. New Antitumor Agent Arrests Mitosis and Induces Apoptosis
13. Molecular Characterization of a Neuronal Calcium Channel
14. Spatial Working Memory Localized in Human Frontal Cortex
15. Target-Specific Presynaptic Plasticity in Neurons
Part 3:
16. A New Type of Synaptic Plasticity of Neocortical Neurons
17. Herpes Virus Molecular Mimicry and Autoimmune Disease
18. An Insulin Receptor Substrate Implicated in Type 2 Diabetes
19. Evidence of Human Genetic Susceptibility to Tuberculosis
20. HIV Trials Controversy and Transmission in Pregnant Women
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1. NEW EVIDENCE FOR A COSMIC ANTIGRAVITY FORCE
Type 1a supernovas are believed to be white dwarf stars that have
accreted enough matter from another star to be pushed over a mass
threshold (the Chandresekhar threshold) and into a thermonuclear
explosion. Since most supernovas of this type have similar
spectral emission curves and absolute magnitudes at maximum, they
can be used as "standard candles" for distance determinations,
i.e., their apparent luminosity becomes a measure of their
distance. At a recent astrophysics meeting (3rd International
Symposium on Sources and Detection of Dark Matter in the
Universe, 18-20 February 1998, Marina del Rey, Calif., US),
Alexei Filippenko (University of California Berkeley, US)
presented a report that 14 distant type Ia supernovas are on the
average 10% to 15% further away than expected, and these results,
coupled with previous independent observations by others on other
type 1a supernovas, are pushing astrophysicists to a consensus
that cosmic expansion is accelerating, rather than decelerating
due to gravitational forces, and that a repulsive antigravity
force may be counteracting gravity on large scales. One
theoretical result has been a renewed interest in Einstein's
"cosmological constant", an intrinsic space-time background
energy that would produce such a force, and which for many years
has been disregarded as an ad hoc theoretical improvisation.
Apparently, astrophysicists are all accepting the new supernova
data, and the question is what to make of it -- and whether some
serious theoretical reformulations are necessary.
QY: James Glanz (Science 27 Feb 98)
2. COSMIC X-RAY BACKGROUND: CONTRIBUTION OF FAINT GALAXIES
X-rays consist of radiation in the frequency range between gamma
rays and the ultraviolet, the energies ranging from about 100
electronvolts to 100K electronvolts (100 keV). The term "active
galactic nucleus" refers to the nucleus of a galaxy that is
emitting unusually large amounts of energy from an apparently
compact source, and it is believed the energy output is derived
from the gravitational potential of a supermassive black hole
(see background notes below). The x-ray background radiation is a
diffuse sky radiation observed by x-ray satellite and believed to
be identified with active galactic nuclei at high redshift.
Redshift (symbol: z) is a lengthening of the wavelengths of
electromagnetic radiation from a source caused either by the
movement of the source (Doppler effect) or by the expansion of
the universe (cosmological redshift). Redshift is defined as the
change in wavelength of a particular spectral line divided by the
unshifted wavelength of that line. Large redshifts imply large
radial velocities (which imply large distances, according to
current cosmological theory), but at redshifts greater than about
0.2 there is a relativistic divergence from a linear relation. A
redshift of 4.0 corresponds to an object receding with a radial
velocity 92% that of the velocity of light. The largest astro-
physical redshifts so far observed are of the order of z=4.9. The
furthest galaxy on record is at a redshift z=4.92), which implies
a distance of approximately 13 billion light years. The term
"hard x-ray" refers to x-rays of relatively high energy.... ...
Ueda et al (11 authors at 6 installations, JP US) report a survey
of the cosmic x-ray background radiation 100 times more sensitive
than previous studies in the 2 to 10 keV photon energy band, and
the existence of many faint resolved sources whose integrated
flux accounts for 30% of the x-ray background in this energy
range, with the average spectrum of the resolved sources harder
than those of nearby bright active galactic nuclei and close to
the spectrum of the x-ray background radiation. The authors
suggest their results indicate that a new class of sources with
hard x-ray spectra dominate the sky at photon energies above 2
keV, and that future missions in the hard x-ray band will be
important for reaching a final solution of the cosmic x-ray
background radiation puzzle.
QY: Y. Ueda, Institute of Space and Astronautical Science,
Yoshinodai, Sagamihara, Kanagawa 299, JP.
(Nature 26 Feb 98)
-------------------
Related Background:
... If the terminal stages of star death leave a remnant star
mass greater than 3 solar masses, the ultimate gravitational
collapse will produce a black hole, a relativistic singularity. A
black hole is a localized region of space from which neither
matter nor radiation can escape. The "trapping" occurs because
the requisite escape velocity, which can be calculated from the
relevant equations, exceeds the velocity of light and is
therefore unattainable. Another view of a black hole is that it
is a mass that has collapsed to such a small volume that its
gravity prevents the escape of all radiation. Space and time
essentially have no meaning in a black hole. The boundary of the
black hole is called the "event horizon", because any event
within the boundary is invisible outside, the invisibility
resulting from the fact that no radiation can escape to be
detected. The radius of the black hole depends upon how much
matter has fallen into the region; it is called the "Schwarzchild
radius", and it is usually a few kilometers. However, massive
black holes are possible and are thought to be the source of
quasars (quasi-stellar objects), which are extremely luminous
sources radiating energy over the entire spectrum from x-rays to
radio waves, and which are apparently the oldest and most distant
objects in the universe. If quasars indeed involve black holes,
the radiation is from material just outside the black hole, and
not from anything within it. Nothing inside a black hole can get
out of it. (Science-Report, 8 Aug 97)
3. AN OXYGEN-RICH STELLAR DUST DISK IN THE RED RECTANGLE
The "Red Rectangle" nebula, discovered in 1975, is an X-shaped
cloud of gas and dust with an optically thick disk in the center,
and this nebula is considered a prototype of a class of carbon-
rich nebulae surrounding low-mass stars in the final stages of
stellar evolution. The central star of this nebula has apparently
ejected most of its layers during the "red giant" phase, the
layers now forming the surrounding cloud, and the star is rapidly
evolving to a white dwarf. This star is also a member of a binary
system that is surrounded by a thick dusty disk of material (a
"circumbinary" disk) In the context of this report, the term
"grain processing" refers to agglomerations and crystallizations
of interstellar dust grains. ... ... Waters et al (12 authors at
4 installations, NL BE) report infrared observations of the Red
Rectangle that reveal the presence of oxygen-rich material,
including crystalline silicates and carbon dioxide, the material
located in the circumbinary disk, and similar to the material of
dusty disks surrounding young stars. The authors suggest that
grain processing, and perhaps even planet formation may be
occurring in the circumbinary disk of the Red Rectangle evolved
star. QY: L.B.F.M. Waters (Nature 26 Feb 98)
4. DEPHASING IN ELECTRON INTERFERENCE BY A WHICH-PATH DETECTOR
One of the most famous experiments in physics is the "two-slit"
experiment in which a beam of radiation simultaneously penetrates
two adjacent slits in a barrier with the formation of interfer-
ence patterns on the far side of the barrier, the interference
patterns produced by the wave character of the radiation entit-
ies. In physics, the complementarity principle is the principle
that in nature any entity has two complementary aspects, particle
and wave, the two aspects related by momentum, energy, wave-freq-
uency, wavelength, and Planck's constant. In quantum theory, the
complementarity principle is manifested by wave-like behavior
(e.g., interference) occurring only when the different possible
paths that a particle can take are indistinguishable. A "which-
path" detector is any detector that determines the actual path
taken by a particle, the determination inevitably resulting in a
coupling of the particle to the measuring environment, which in
turn results in suppression of interference ("dephasing").
Fermions (electrons, protons, neutrons) are particles that obey
the Pauli exclusion principle: i.e., no two fermions of the same
kind can occupy the same quantum state. In general, an interfer-
ometer is any instrument that detects the interference patterns
of light (radiation) split into two or more beams that are
subsequently combined again. The interferometer in this report
was a microscale device with dimensions of a few microns and
involving a 2-dimensional electron gas. ... ... Buks et al (5
authors at Weizmann Institute of Science, IL) report the
dephasing effects of a which-path detector on electrons
traversing a double-path interferometer, and that varying the
sensitivity of the detector can affect the visibility of the
oscillatory interference signal, thereby verifying the
complementarity principle for fermions. This is apparently the
first study involving controllable dephasing via a which-path
detector. The authors suggest the technique may have other
applications to fundamental problems in quantum mechanics.
QY: M. Heiblum (Nature 26 Feb 98)
5. ELECTROPHORESIS IN LYOTROPIC POLYMER LIQUID CRYSTALS
Electrophoresis is an electrochemical process in which colloidal
particles or macromolecules with a net electric charge migrate in
a solution under the influence of an electric field, and the term
"capillary electrophoresis" is a technique for the electrophor-
etic sequestering of small particles in the lumen of water-filled
glass capillaries for chemical and physical analysis. A liquid
crystal is a liquid whose molecular components form ordered
arrays such that the liquid is not isotropic (i.e., does not have
the same properties in all directions), and a lyotropic liquid
crystal is a liquid crystal prepared by mixing two or more comp-
onents, one of which is polar in character (e.g., water). In
chemistry, a "copolymer" is a mixed polymer, a compound formed by
the combination of two or more substances, or monomers, and a
"block copolymer" is a copolymer in which the monomer units occur
in relatively long alternate sequences in a chain.
... ... Rill et al (4 authors at Florida State University, US)
report a new electrophoresis method involving a distinctly
different class of media consisting of aqueous, lyotropic liquid-
crystalline solutions of uncrosslinked block copolymers, and that
conventional electrophoresis and capillary electrophoresis of DNA
fragments with the new media provides significant advantages over
traditional methods. The authors suggest the ordered structures
of these polymeric phases provide new challenges to those
interested in mechanisms of macromolecular transport in dense
media. QY: Randolph L. Rill
(Proc. Natl. Acad. Sci. US 17 Feb 98)
6. MOLTEN GLOBULES AS A THIRD PHASE OF PROTEINS
The term "heteropolymers" refers to polymers composed of a
variety of monomers, for example, proteins. The term "Monte Carlo
simulation" refers to a simulation method that obtains a probab-
ilistic approximation to the solution of a problem by using
statistical sampling techniques. ... ... Pande and Rokhsar (2
installations, US) report a study of the equilibrium properties
of proteins by Monte Carlo simulation of two simplified models of
protein-like heteropolymers, the models emphasizing the polymeric
entropy of the fluctuating configuration of the polypeptide
chain. The calculations produce a generic phase diagram that
contains a thermodynamically distinct "molten globule" state in
addition to a rigid native state and a nontrivial unfolded state.
The authors suggest the protein molten globule state is analogous
to the liquid state of a bulk system, and that it remains to be
seen whether such a simplified model can provide useful
information regarding the kinetics of protein folding. QY: Daniel
S. Rokhsar, Physical Biosciences, Lawrence Berkeley National
Laboratory, Berkeley, CA 94720 US.
(Proc. Natl. Acad. Sci. US 17 Feb 98)
7. PRESSURE DEPENDENCE OF HYDROPHOBIC INTERACTIONS OF PROTEINS
The term "denaturation of proteins" refers to an alteration of
protein folding structure by heat, acid, alkali, mechanical
shaking, etc., the result a change in physical properties such as
solubility. "Hydrophobic aggregates" are aggregates of nonpolar
moieties, the aggregation often resulting from Van der Waals
interactions (i.e., dispersion interactions), and in the case of
many proteins, such aggregates of hydrophobic protein side chains
play an important role in producing particular folding conform-
ations. Clathrates are molecular compounds formed by the
inclusion of molecules of one type in holes in the lattice of
another type, and clathrate hydrates are clathrates involving
significant hydration as a component of the inclusion compound.
... ... Hummer et al (5 authors at 3 installations, US) report a
model explaining pressure denaturation of proteins by the
pressure destabilization of hydrophobic aggregates, the model
using information theory of hydrophobic interactions, with
clathrate hydrates predicted to form by virtually the same
mechanism that drives pressure denaturation of proteins. The
authors suggest that studies of changes in protein conformation
with pressure will not only elucidate the fundamentals of
conformation thermodynamics, but will also clarify adaptation
processes of barophilic organisms such as those living under
extreme pressures in the deep sea.
QY: Gerhard Hummer
(Proc. Natl. Acad. Sci. US 17 Feb 98)
8. A GENE FOR ADHESION AND FILAMENTOUS GROWTH IN C. ALBICANS
There are many species of microscopic fungi that are pathogenic,
although in most cases the actual disease process is not clear.
Candida albicans is a pathogenic yeast species, and like many
such species it is capable of existing in more than one form. In
the yeast-like form, the cells are isolated from each other and
have an ellipsoidal shape (blastospores). This is the form one
sees when the environment is rich for the organism. In poor
environments, however, C. albicans assumes a filamentous form,
cells remaining attached to each other after dividing, the cells
sometimes assuming a cylindrical shape, and with the growth of
long filaments of attached cells. There is actually more than one
type of filamentous form, and so C. albicans is called polymorph-
ous. "Hyphae" are the branching tubular cells characteristic of
the filamentous fungi. The integrins are a class of proteins that
link the outside of cells to the interior of cells, and mediate
the adhesion of cells to other cells, including the adhesion of
cells of one type to cells of another type. In animals, epithel-
ial cells compose the cell layers that form the interface between
a tissue and the external environment, for example, the cells of
the skin, the lining of the intestinal tract, and the lung airway
passages. ... ... Gale et al (7 authors at 2 installations, US)
report that expression of the gene Int1p, which has limited
similarity to vertebrate integrin genes, is sufficient to direct
the adhesion of normally nonadherent yeast (S. cerevisiae), and
that disruption of this gene in C. albicans suppresses hyphal
growth, adhesion to epithelial cells, and virulence in mice. The
authors suggest that Int1p links adhesion, filamentous growth,
and pathogenicity in C. albicans, and that Int1p may be an
attractive target for antifungal therapies. QY: Judith Berman
(Science 27 Feb 98)
(continued in Part 2)
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SCIENCE-WEEK - Part 2/3
A Free Weekly Digest of the News of Science
March 13, 1998
Contents of Part 2:
9. Evidence of De Novo Insertion of an Intron into a Gene
10. New Drosophila Introns Originate by Duplication
11. A Protein that Prohibits Retroviral DNA Autointegration
12. New Antitumor Agent Arrests Mitosis and Induces Apoptosis
13. Molecular Characterization of a Neuronal Calcium Channel
14. Spatial Working Memory Localized in Human Frontal Cortex
15. Target-Specific Presynaptic Plasticity in Neurons
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9. EVIDENCE OF DE NOVO INSERTION OF AN INTRON INTO A GENE
Complementary DNA, denoted as cDNA, is DNA that is synthesized in
vitro from an RNA template using the enzyme reverse transcript-
ase, and it can be used in cloning to investigate the presence of
various genes, or as a probe for homologous sequences in various
tissues or species. An "exon" is a segment of DNA transcribed to
RNA and subsequently translated into protein, and an "intron" is
a DNA segment intervening between two adjacent exons, the intron
not transcribed into RNA, and therefore not expressed. Marsupials
are an order of mammals having a pouch covering the mammary
glands on the abdomen, and in the pouch the female nurses and
carries her incompletely developed young (e.g. the kangaroo,
opossum, wombat). Dasyurid marsupials are marsupials having 5
toes on each hindfoot. Transposable genetic elements (also called
"jumping genes") are mobile segments of DNA that may appear at
apparently random locations in the genome. ... ... O'Neill et al
(5 authors at La Trobe University, AU) report comparisons of
genomic and cDNA sequences that provide evidence of a de novo
insertion of an intron into the gene of dasyurid
marsupials, with evidence that the recently (approximately 45
million years ago) inserted sequence in not homologous with known
transposable elements. The authors suggest their data indicates
that introns may be inserted as spliced units within a develop-
mentally crucial gene without disrupting its function.
QY: Rachel J. Waugh O'Neill
(Proc. Natl. Acad. Sci. US 17 Feb 98)
10. NEW DROSOPHILA INTRONS ORIGINATE BY DUPLICATION
The term "phylogenetic distribution" refers to a distribution
across different species, rather than within the same species
(ontogenetic), the phylogenetic distribution a result of
evolutionary factors. The "introns-late" theory of the origin of
genes (also called the "insertional theory of introns") proposes
that ancient genes existed as uninterrupted exons, and that
introns have been introduced during the course of evolution.
... ... Tarrio et al (3 authors at University of California
Irvine, US) report an analysis of the phylogenetic distribution
of introns in the gene coding for the enzyme xanthine dehydrogen-
ase in 37 species, and that the phylogenetic distribution of
these introns favors the "introns-late" theory of the origin of
genes. The study included relevant segment gene sequencing by the
authors of the medfly (Ceratitis capitata), and two fruit flies
(Drosophila willistoni and Drosophila saltans), the data indicat-
ing all 3 introns have arisen by duplication of a preexisting
intron pervasive in Drosophila and other dipterans (an order of
winged insects) and homologous in position to introns found in
humans and other organisms.
QY: Francisco J. Ayala
(Proc. Natl. Acad. Sci. US 17 Feb 98)
11. A PROTEIN THAT PROHIBITS RETROVIRAL DNA AUTOINTEGRATION
Retroviruses are single-stranded RNA viruses that have an enzyme
called reverse transcriptase, and with this enzyme the viral RNA
is used as a template to produce viral DNA from cellular mater-
ial. This DNA is then incorporated into the host cell's genome,
where it codes for proteins that produce the synthesis of viral
components. Successful retroviral replication requires that the
transcribed viral DNA avoid integration into itself, a process
termed "autointegration", and it has been shown that a host-
derived autointegration barrier does indeed exist.
... ... Lee and Craigie (National Institutes of Health, US)
report the host factor involved in the viral autointegration
barrier is a single polypeptide with 89 amino acids (denoted as
BAF: barrier-to-autointegration factor) that does not match any
previously identified protein. The authors suggest an understand-
ing of the molecular mechanisms of the viral defense against
autointegration may indicate new strategies to block retroviral
replication. QY: Robert Craigie
(Proc. Natl. Acad. Sci. US 17 Feb 98)
12. NEW ANTITUMOR AGENT ARRESTS MITOSIS AND INDUCES APOPTOSIS
Noscapine is an isoquinoline alkaloid, occurring in opium, and it
is used medicinally to suppress the cough reflex (i.e., it is an
antitussive). It appears to have no significant side effects, and
it is without addiction liability. The term "stoichiometric bind-
ing" refers to binding in fixed quantitative proportions. Micro-
tubules are part of the cytoskeleton of biological cells, the
quasi-rigid matrix that among other things determines cell shape.
The microtubules are 25 nanometers in diameter, and composed of
the protein tubulin. They occur in regular arrays in cilia,
flagella, the mitotic spindle, and in the cytoplasm in general,
and they contribute not only to cell shape, but also to cell
motility. Mitosis is cell division. The term "apoptosis" refers
to programmed cell death, particularly of defective or wild
cells. Lymphoid tumors are tumors of lymphatic tissue, the tissue
of the lymphatic system that collects and circulates the extra-
cellular fluid called "lymph". Nude mice are laboratory mice that
lack a thymus gland, and are thus unable to produce mature immune
system T-cells or coordinate immunological function.... ... Ye et
al (8 authors at Emory University, US) now report that noscapine
binds stoichiometrically to tubulin, alters conformation of the
protein, affects microtubule assembly, and arrests mammalian
cells in mitosis. Furthermore, noscapine causes apoptosis in many
cell types and has potent antitumor activity against solid mouse
lymphoid tumors, and against human breast and bladder tumors
implanted in nude mice. Because noscapine is water soluble and
absorbed after oral administration, the authors suggest its
chemotherapeutic potential in human cancer merits thorough
evaluation. QY: Harish C. Joshi, Emory University School of
Medicine 404-727-5660 (Proc. Natl. Acad. Sci. US 17 Feb 98)
13. MOLECULAR CHARACTERIZATION OF A NEURONAL CALCIUM CHANNEL
Ion channels are protein channels in cell membranes that allow
ions to pass from extracellular solution to intracellular
solution and vice versa. Most ion channels are selective,
allowing only certain ions to pass, and an individual cell has
ion channels with various ion selectivities. The selectivity of
an ion channel can be "gated", the channel effectively opened or
closed, and ion channels are said to voltage-gated or ligand-
gated, depending on how the change in selectivity is provoked.
The term "T-type channels" refers to channels whose ion currents
are both transient (due to rapid inactivation) and small (due to
small conductance), and such ion channels are believed to be
involved in pacemaker activity, low-threshold calcium ion spikes,
neuronal oscillations, etc. Frog oocytes are frog egg cells, and
they are a common laboratory vehicle for expressing the proteins
of genetically engineered material from other species and
coupling this expression with electrophysiological measurements
of frog oocyte membrane behavior. ... ... Perez-Reyes et al (9
authors at 4 installations, US UK) report the identification via
cloning methods of a neuronal T-type calcium ion channel, with
expression of the protein constituting the channel in frog
oocytes, and electrophysiological characterization of the channel
in these cells. The authors suggest they have cloned the first
member of the low-voltage-activated T-type Ca(sup2+) family, and
one with identified human and mouse genetic homologues.
QY: Edward Perez-Reyes (Nature 26 Feb 98)
14. SPATIAL WORKING MEMORY LOCALIZED IN HUMAN FRONTAL CORTEX
Magnetic resonance imaging is a technique involving images
produced by mobile protons of a tissue excited by the application
of a magnetic field, and when used in functional cerebral
imaging, the basis of the technique is that it images very small
metabolic, blood-flow, and perfusion-diffusion changes in vivo,
in real time, and with no risk to the subject, with the essential
idea of mapping activity in the brain in response to external
stimuli or during sensory, perceptual, or cognitive events. The
brain-anatomical term "superior frontal sulcus" refers to a
fissure on the superior frontal surface of each frontal lobe. In
this report, "working memory" is the process of maintaining an
active representation of information so that it is available for
use, and "spatial working memory" refers to working memory
involved with spatial memory tasks (remembering locations of
briefly displayed objects or images). ... ... Courtney et al (5
authors at National Institutes of Health, US), using functional
magnetic resonance imaging in humans, report an area in the
superior frontal sulcus specialized for spatial working memory.
The authors suggest that localization of the area in a more
superior and posterior region in the human brain than in the
monkey brain may explain why it has not been recognized
previously. QY: Susan M. Courtney
(Science 27 Feb 98)
15. TARGET-SPECIFIC PRESYNAPTIC PLASTICITY IN NEURONS
The term "mossy fibers" refers to a type of nerve fiber in the
brain with large axon terminal endings, and their synapses
(connections to other nerve cells) are among the largest in the
mammalian central nervous system. The term "synaptic transmiss-
ion" refers to the transmission of electrical activity from one
nerve cell to another via the synapse -- the connection between
them. The hippocampus is a deep region of the brain involved with
many fundamental activities, including memory storage. The term
"interneurons" refers to nerve cells localized in a succinct
region (population of nerve cells), with the primary function of
these nerve cells an involvement with information processing in
the region, rather than with input to the region or output from
the region: interneurons are therefore involved in "local
circuitry". "Rat brain slices" are exactly that, the rat brain
removed from the animal and a thin slice of a particular region
prepared in an appropriate solution for electrophysiological
recording of nerve cell activity. The term "tetanic stimulation"
refers to repetitive stimulation. "Long-term potentiation" is an
apparent facilitation of synaptic transmission following repetit-
ive stimulation under certain conditions. In this context, the
term "depression" refers to a long-term reduction in efficacy of
synaptic transmission. Cyclic adenosine monophosphate (cAMP) is
an important postsynaptic intracellular substance activated by
incoming synaptic activity, a "messenger" involved in various
aspects of cell regulation and protein synthesis. In general, the
term "afferent pathway" refers to any input pathway, as opposed
to an output pathway (efferent). ... ... Maccaferri et al (3
authors at National Institutes of Health, US) report a comparison
of mossy fiber synaptic transmission at hippocampal pyramidal
cells and interneurons in rat brain slices, finding that tetanic
stimulation of mossy fibers induces long-term potentiation in
pyramidal neurons, but is either without effect or induces
depression at synapses with interneurons. Furthermore, unlike
transmission onto pyramidal neurons, transmission onto
interneurons was not potentiated after cAMP activation. The
authors suggest their results indicate that synaptic terminals
arising from a common afferent pathway do not behave as a single
computational unit, but are functionally specialized with effects
depending on the postsynaptic target.
QY: Chris J. McBain (Science 27 Feb 98)
(continued in Part 3)
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
SCIENCE-WEEK - Part 3/3
A Free Weekly Digest of the News of Science
March 13, 1998
Contents of Part 3:
16. A New Type of Synaptic Plasticity of Neocortical Neurons
17. Herpes Virus Molecular Mimicry and Autoimmune Disease
18. An Insulin Receptor Substrate Implicated in Type 2 Diabetes
19. Evidence of Human Genetic Susceptibility to Tuberculosis
20. HIV Trials Controversy and Transmission in Pregnant Women
----------------------------------------------------------------
16. A NEW TYPE OF SYNAPTIC PLASTICITY OF NEOCORTICAL NEURONS
The term "synaptic plasticity" refers to a changeability of
synaptic connections and/or the efficacy of particular connect-
ions. "Cultured neurons" are embryological neurons separated from
the animal and growing and making connections in a suitable
experimental chamber. Glutamate is a major excitatory amino acid
neurotransmitter (transmitter substance at synapses) in the
brain, involved in about 40% of all brain activity. The term
"Hebbian modification" (named after the neuropsychologist Donald
Hebb) refers to the Hebbian "rule" that essentially states that
when one nerve cell repeatedly activates another nerve cell,
changes involving growth or metabolism occur in one or both nerve
cells that increase the efficiency of the activation.
... ... Turrigiano et al (5 authors at Brandeis University, US)
report a new form of synaptic plasticity in cultured neurons that
increases or decreases the strength of all of a neuron's
synaptic
inputs as a function of activity, the changes partly due to
postsynaptic alterations in the response to glutamate. The
authors suggest that such "synaptic scaling" may help prevent
saturation of firing rates during developmental changes in the
number and strength of synaptic inputs, may stabilize synaptic
strengths during Hebbian modification, and may facilitate
competition between synapses and associated elimination of
synapses during development.
QY: Gina G. Turrigiano
(Nature 26 Feb 98)
17. HERPES VIRUS MOLECULAR MIMICRY AND AUTOIMMUNE DISEASE
An autoimmune disease is one of a large group of diseases
characterized by cells of the immune system attacking other cells
of the body, in effect failing to recognize these other cells as
"friendly". Antigens are chemical moieties, often proteins, that
provoke immune responses, and the "epitope" is the small region
of the antigen apparently involved in binding or recognition of
the antigen. T-cells, of which there are various types, are
aggressive immune system cells, first formed in bone marrow, then
maturing in the thymus gland [hence: T(hymus)-cell]. A keratitis
is an inflammation of the cornea, and stromal keratitis is an
inflammation of the connective tissue framework of the cornea.
Invasion of the corneal stroma by herpes simplex virus is one of
the possible consequences of herpes simplex infection. Viral
infection is sometimes associated with the initiation or exacer-
bation of autoimmune disease, although the underlying mechanisms
have been unclear. One proposed mechanism is that viral chemical
moieties that mimic host antigens trigger certain T-cells to
destroy host tissue. ... ... Zhao et al (5 authors at 2 install-
ations, US) report that an epitope of a coat protein of herpes
simplex virus type 1 (KOS strain) is recognized by autoreactive
T-cells that target corneal antigens in a mouse model of auto-
immune herpes stromal keratitis. Mutant viruses that lacked this
epitope did not induce autoimmune disease. The authors suggest
that expression of molecular mimics can influence the development
of autoimmune disease after viral infection. QY: Zi-Shan Zhao,
Dept. of Pathology, Harvard Univ. Medical School 617-432-1550
(Science 27 Feb 98)
18. AN INSULIN RECEPTOR SUBSTRATE IMPLICATED IN TYPE 2 DIABETES
Insulin is a polypeptide hormone secreted by so-called beta cells
in the pancreas, the hormone promoting glucose utilization,
protein synthesis, and the formation and storage of neutral (in
the acid/base sense) lipids. The term "homeostasis" refers to a
physiological equilibrium necessary in general for the viability
of an organism, and in particular for the operation of many
cellular functions. Homeostatic mechanisms in biological systems
usually involve an element of negative feedback signaling. In
vertebrates, for example, when blood temperature is too high,
temperature receptors provoke a sequence of events involving many
pathways that ultimately results in a lowering of body temper-
ature. Similar homeostatic mechanisms operate at cellular levels.
Type 2 diabetes (formerly called adult-onset diabetes) is the
less severe non-insulin dependent form of the disease.
... ... Withers et al (12 authors at 2 installations, US) report
that disruption of insulin receptor substrate protein type 2
(IRS-2) impairs both peripheral insulin signaling and pancreatic
beta-cell function, with IRS-2 deficient mice showing progressive
deterioration of glucose homeostasis because of insulin
resistance in the liver and skeletal muscle and a lack of beta-
cell compensation for this insulin resistance. The authors
suggest that dysfunction of IRS-2 may contribute to the
pathophysiology of type 2 diabetes.
QY: Morris F. White
(Nature 26 Feb 98)
19. EVIDENCE OF HUMAN GENETIC SUSCEPTIBILITY TO TUBERCULOSIS
A genetic polymorphism is a naturally occurring variation in the
normal nucleotide sequence of the genome within individuals in a
population. Variations are denoted as polymorphisms only if they
cannot be accounted for by recurrent mutation and occur with a
frequency of at least about 1%. Macrophages, of which there are
many varieties, are large, mononuclear cells of the immune system
that usually engage in phagocytosis (physical incorporation and
digestion) of foreign material such as bacteria, particularly in
the lung, but may also be involved with immune system signaling.
Tuberculosis kills more people in the world than any other
disease caused by an infectious pathogen. ... ... Bellamy et al
(6 authors at 2 installations, UK GM) report the use of molecular
genetic techniques in a study of human polymorphisms in the
macrophage protein gene in 410 adults with pulmonary
tuberculosis (and 417 ethnically matched healthy controls) in the
Gambia, West Africa, and that 4 polymorphisms were each
significantly associated with tuberculosis. The authors suggest
that genetic variation in affects susceptibility to
tuberculosis in West Africans, and that the results support the
strategy of mapping and identifying genes for resistance to
infectious disease in mice and then testing their human homo-
logues as candidate genes for susceptibility to related infect-
ions in humans. QY: Adrian V.S. Hill, Wellcome Trust Center for
Human Genetics, Windmill Rd., Oxford OX3 7BN UK.
(New England J. Med. 5 Mar 98)
-------------------
Related Background:
MECHANISM OF MACROPHAGE INVASION BY TUBERCULOSIS PATHOGEN
The mycobacteria include bacterial species in the genus
Mycobacterium. They are a group of rod-shaped bacteria with large
amounts of mycolic acid in their cell walls. Many mycobacteria
are free-living, but two notorious pathogens are in this group:
M. tuberculosis, the cause of tuberculosis in humans and cattle;
and M. leprae, the cause of leprosy in humans. Tuberculosis was
recently under control in the U.S. (25,000 cases in 1990), but
the combination of immunodeficiency disease and drug-resistant
mutant variants of M. tuberculosis has alarmed epidemiologists,
and the incidence of tuberculosis among certain sub-populations
appears to be rising markedly. The fact is tuberculosis worldwide
is the leading cause of death due to an infectious organism, with
an estimated 3 million deaths annually. Pathogenic mycobacteria
evidently require entry into host macrophages (large ameboid
leukocytes that are part of the vertebrate immunological defense
system) in order to begin the disease process. Now Jeffrey S.
Schorey et al (Washington University School of Medicine, US;
Harvard Medical School, US) have presented evidence that
pathogenic mycobacteria, as opposed to non-pathogenic myco-
bacteria, are able to utilize cleavage products (C2a) of
complement proteins (plasma proteins specifically involved with
immune responses) to achieve invasion of macrophages. The authors
suggest this invasion mechanism is crucial in mycobacterial
pathogenesis, and that the mycobacterial cell wall component
required for this invasion process may provide a new target for
therapeutic intervention. QY: Eric J. Brown, Washington Univ.
School of Medicine (314) 889-6000 (Science 22 Aug 97)
20. HIV TRIALS CONTROVERSY AND TRANSMISSION IN PREGNANT WOMEN
We have had a number of reports in this publication about a
controversy concerning ethical aspects of anti-HIV drug trials in
undeveloped countries, the controversy, in brief, focusing on the
use of placebos when the placebo groups might benefit consider-
ably from the test drug, and when such research placebo protocols
in drug trials involving a drug known to be efficacious are not
allowed in the industrialized nations. Now a US-funded drug trial
in Thailand, designed to test the drug AZT in pregnant women as
an agent against transmission of HIV from the women to their
newborn children, has been halted early and declared to demonstr-
ate that administration of AZT during the final weeks of preg-
nancy does indeed reduce the transmission of HIV to newborn
children by 50%. The drug was already known to do this in con-
junction with other drugs in an expensive regimen, but this trial
was designed to determine if AZT is useful alone in an inexpens-
ive regimen as opposed to a placebo. Those who support such
placebo trials say the speedy conclusion of the research was
facilitated by the placebo controls, while those who oppose such
research continue to argue that the use of placebos in this
instance was unnecessary and unethical, and that data comparable
to the Thailand trial have been available since 1994.
QY: Eliot Marshall (Science 27 Feb 98)
-------------------
Related Background:
A PROBLEMATIC DOUBLE STANDARD IN BIOETHICS
During the past year, a schism of sorts has developed among
bioethicists and people concerned with bioethics. The particular
focus has been the protocols of AIDS research in so-called
developing countries, but the issue concerns more than AIDS, and
indeed pertains to any clinical research involving human subjects
in such regions. The problem is essentially as follows: Consider
two countries A and B. A is rich and B is poor, and in both
countries, the same serious lethal disease is rampant. A drug
treatment exists, affordable by the government of the rich
country but not affordable by the government of poor country. In
the rich country, research guidelines prohibit protocols that
involve withholding drug treatment from patients diagnosed with
the disease; in the poor country, since the drug is unavailable,
no such guidelines exist. Some clinical researchers in the poor
country wish to focus on assessment of locally available
treatment methods, particularly preventive methods involving
vaccines, but the country is too poor for these research efforts.
The rich country is also interested in vaccine research, but such
research is now difficult to do in the rich country because the
ethical requirements of drug treatment in the rich country have
"contaminated" the patient population so that it is difficult if
not impossible to assess the effectiveness of a vaccine. Research
teams from the rich country therefore collaborate with research
teams in the poor country to carry out the relevant vaccine
research in the poor country, the protocol involving the
withholding of the life-saving drug treatment from the control
patient group with the rationalization that the drug is not
available in the poor country anyway. Such, it appears, is the
ethical problem now facing the international medical research
community. Are clinical researchers to do their research with
human patients with two standards of ethics, one standard for
rich countries and another standard for poor countries? One has
the feeling this is one of those questions whose answer one way
or the other will be a defining moment in the history of bio-
ethics. In a family, if one member is ill, the members of the
family usually pool resources. The same occurs in a group, a
tribe, or a country. But it does not yet occur on an internat-
ional scale, which means patients in poor countries are denied
access to life-saving drugs because they do not have the requis-
ite cash to pay for the pills they need. Pills -- not hospitals
or expensive machines or expensive facilities for state-of-the-
art surgery. This is people dying for lack of a pill that exists
in plenty in one place but not in another place. The editors of
the New England Journal of Medicine not long ago condemned
research protocols based on such disparities, but there are
clinicians in both rich and poor countries who say a double
standard is indeed required if any progress is to be made.... ...
E. Mbidde (Makerere Univ., UG), in an editorial in the journal
Science, calls for a double standard and states that "a
discussion of ethical principles in biomedical research that
ignores the socioeconomic heterogeneity of society is not ethical
and not worth holding", and that the International Ethical
Guidelines for Biomedical Research Involving Human Subjects, in
place since 1993, will in their present form "delay development
of badly needed vaccines and treatment regimens." QY: Edward
Mbidde, Uganda Cancer Institute, Makerere University, UG
(Science 9 Jan 98)
-------------------
AIDS RESEARCH IN POOR COUNTRIES: BIOETHICS REVISITED
B. Bloom (Albert Einstein College of Medicine, US), in a review
of international ethical issues in research in AIDS vaccines, the
review appearing in the same issue of Science as the editorial
mentioned in the previous report, concludes it is necessary to
clarify the existing guidelines to make clear what is attainable
for implementation in developing countries whose health care
resources are severely constrained. The author mentions only in
passing the editorial in the New England Journal of Medicine last
year that began the public discussion.
QY: Barry R. Bloom (Science 9 Jan 98)
-------------------
NADER GROUP CALLS AIDS TRIALS UNETHICAL
Ralph Nader's Public Citizen's Organization has charged that
international AIDS therapy trials in developing countries are
unethical. The basis of the accusation is that patients given
placebos rather than the drug AZT are compromised by not re-
ceiving the most effective treatment for the disease. Health
officials state that on the contrary the studies are ethical
and are vital for international treatment of the AIDS epidemic.
Nader held a press conference on 22 April.
(Science-Week 1 May 97)
-------------------
ETHICAL DILEMMAS IN THIRD WORLD CLINICAL RESEARCH
It is not often that a leading scientific journal publishes an
eight page front article and in the same issue of the journal
also publishes eight pages of editorial matter most of which
calls the front article an example of unethical research. But
that is exactly what happened last week in connection with a
study of drug therapy against tuberculosis in patients already
infected with HIV. The reported study, by Christopher C. Whalen
et al (Case Western Reserve University, US; other installations
in US and UG), took place in Uganda, and included a placebo group
of HIV infected individuals who were not given any anti-
tuberculosis drug therapy at all (the drugs isoniazid, rifampin,
pyrazin-amide) even though these drugs have been shown in other
studies to have preventive action against tuberculosis in people
who carry tuberculosis antibodies. In the editorial matter,
presented in three separate pieces by 5 physicians, Marcia
Angell, the Executive Editor of the journal, calls into question
the ethics of the Whalen study. It appears the justification of
the Whalen study by its authors was the desire to glean
definitive data con-cerning the expected effectiveness of the
known anti-tuberculosis drugs in HIV infected patients in both
the U.S. and Africa. Angell states: "An essential condition for a
randomized clinical trial comparing two treatments for a disease
is that there be no good reason for thinking one is better than
the other." Everyone apparently agrees that the study could not
possibly have been carried out in the U.S. because it would be
prohibited by current U.S. regulations. These prohibitions
evidently do not exist in Uganda. (New England J. Med. 18 Sep 97)
-------------------
HEAD OF NIH COMMENTS ON CLINICAL STUDIES IN THIRD WORLD
There is evidently a flap brewing concerning U.S. management of
clinical studies of diseases in developing countries in which
placebo groups are used as controls, the placebo groups receiving
no medication at all, even if such medication is available and
known to have therapeutic value. Such placebo studies in the U.S.
are not allowed, but they are allowed in many developing countr-
ies, and in the September 18th issue of the respected New England
Journal of Medicine a paper reporting such a study in Uganda by a
U.S. managed research team of the clinical effectiveness of three
anti-tuberculosis drugs in HIV infected Ugandans was published.
In the same issue of the journal, as many pages as the report
were devoted by the journal to editorial criticism of the ethics
involved. Now Harold Varmus, head of the U.S. National Institutes
of Health, which was involved in the Uganda study, and David
Satcher of the U.S. Centers for Disease Control and Prevention,
which was also involved in the Uganda study, have an article in
that journal defending such studies in developing countries. The
crux of the Varmus-Satcher position is apparently as follows:
"The most compelling reason to use a placebo controlled study is
that it provides definitive answers to questions about the safety
and value of an intervention in the setting in which the study is
performed, and these answers are the point of the research." One
wishes Varmus and Satcher would have in the very next sentence
considered why, despite this "compelling" reason, such placebo
studies are not permitted in the U.S. The evident answer is that
in the U.S., the "compelling" reason has not been found compell-
ing enough. So that is the fundamental question: Why the applic-
ation of one ethical standard in the U.S. and another ethical
standard in Uganda? And this is the question addressed by the
editorial matter in the 18th September issue of the journal. The
New England Journal of Medicine has announced it will later
publish responses to the Varmus-Satcher article by Marcia Angell,
Executive Editor of the journal, who with others previously
criticized the reported Uganda study. (Our first report of the
Uganda study is in the SCIENCE-WEEK/SCIENCE-REPORT issue of 26
Sep 1997) QY: H. Varmus, National Institutes of Health, Bethesda
MD 20892-0148 US (New England J. Med. 2 Oct 97)
-------------------
ESTIMATED 20 MILLION INFECTED WITH AIDS IN SUB-SAHARAN AFRICA
There is perhaps too much of a tendency in many quarters to think
of a plague only as a state of affairs in which people drop dead
in expensive restaurants and get hauled away in trucks containing
piles of bodies. Our current plague, although not as dramatic as
some plagues of the past, is no less an international calamity.
The United Nations AIDS Program recently released a report
containing the following:
-- In 1997, 5.8 million people worldwide were newly infected with
HIV.
-- The number of new HIV infections this year rose 9% over 1996.
-- The total number of infected adults is now a little under 30
million, about 1% of the world's adult population.
-- This year, the total number of people infected with HIV
increased by 13%
-- More than 20 million people in sub-Saharan Africa are infected
with HIV, which is 7% of that adult population.
-- This year, 2.3 million people worldwide will have died of
AIDS, the consequent stage of HIV infection.
-- In South and Southeast Asia, 6 million people are infected
with HIV.
-- In Latin America, 1.3 million people are infected with HIV.
-- In North America, 860,000 people are infected with HIV.
-- In Western Europe, 150,000 people are infected with HIV.
(Nature 27 Nov 97)
---------------------------------------------
BOOK NOTES:
Charles Coulston Gillespie: PIERRE-SIMON LAPLACE (1749-1827)
A Life in Exact Science
Princeton Univ., 1998, 322p, US49.50 UK35
An authoritative biography of Laplace, with explications of
Laplacian mathematics and physics by I. Grattan-Guinness and
Robert Fox. 36-page critical bibliography.
J. M. Lafferty (ed.): FOUNDATIONS OF VACUUM SCIENCE TECHNOLOGY
Wiley, 1998, 728p, US150 CA210.50
A comprehensive survey of the physical and chemical principles
underlying the production, measurement, and use of high vacuums.
An anthology of contributions from leading specialists in vacuum
techniques.
Richard L. Liboff: KINETIC THEORY
Classical, Quantum, and Relativistic Descriptions.
Wiley, 1998, 568p, US79.95 CA118.95
2nd edition. A graduate text. Includes discussion of applications
in aerospace, mechanical and chemical engineering, solid state
and laser physics, astrophysics, controlled thermonuclear fusion.
Problem sets. Appendices with special mathematical functions and
physical constants.
L.E. Reichl: A MODERN COURSE IN STATISTICAL PHYSICS
2nd Edition
Wiley, 1998, 832p, US94.95 CA132.50
An advanced undergraduate and graduate text. A self-contained
treatment of the subject from foundations to modern research
topics. Exercises, experimental data, examples, and a solutions
manual.
V. Szebehely and H. Mark: ADVENTURES IN CELESTIAL MECHANICS
2nd Edition
Wiley, 1998, 320p, US64.95 CA90.95
An introductory text for students of astronomy, physics, and
aerospace engineering. Basic principles involved in the motions
of natural and human bodies in space. Earth's gravity, the Sun,
space probes, galaxies.
L. Wolpert et al: PRINCIPLES OF DEVELOPMENT
Oxford Univ., 1998, 484p, US65 UK25.95
An undergraduate text by specialists. Model organisms, formation
of the basic body plan, developmental genetics, morphogenetics,
cell differentiation, sex determination, neuronal development,
evolution of developmental mechanisms.
---------------------------------------------
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