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ScienceWeek
SCIENCEWEEK
ScienceWeek
December 6, 2002
Vol. 6 Number 49
An Online Research Digest Published Weekly Since 1997
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The full area of ignorance is not mapped:
we are at present only exploring its fringes.
-- J.D. Bernal (1901-1971)
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Section 1
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Thematic Reports:
1. Innate Immunity: Humans, Flies, and Worms.
2. Multiple Sclerosis, Statins, and Autoimmune Disease.
3. Nonlinear Optics, Solitons, and Matter Waves.
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Section 2
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1. INNATE IMMUNITY: HUMANS, FLIES, AND WORMS.
All biological organisms are subject to invasive attack by
microbial pathogens, and the survivability of biological
organisms depends on the activation of various protective
mechanisms (immune responses) when a microbial invasion occurs.
In biology, the "immunity" of organisms to infection by various
pathogens is functionally characterized into 2 types: The term
"innate immunity" refers to non-specific antimicrobial systems of
response (e.g., phagocytosis: engulfment and digestion of
microbes by "killer" cells) that are innate and not intrinsically
affected by prior contact with the infectious agent; the term
"adaptive immunity" refers to immune responses which involve an
enhanced ability to respond to specific molecular *antigens
presented by the invading pathogenic entity, the enhancement
dependent on prior contact with the same pathogen. In addition,
the concept of innate immunity generally refers to the first-line
host defense that serves to limit infection in the early hours
after exposure to microorganisms. Recent data have highlighted
similarities between pathogen recognition, signaling pathways,
and *effector mechanisms of innate immunity in both the fruit fly
Drosophila and in mammals, pointing to a common ancestry of these
defenses. In addition to its role in the early phase of defense,
innate immunity in mammals appears to play a key role in
stimulating the subsequent *clonal response of adaptive immunity.
H.R. Nicholas and J. Hodgkin (University of Oxford, UK) discuss
innate immunity, the authors making the following points:
1) The nematode Caenorhabditis elegans is susceptible to
infection by a variety of fungal and bacterial pathogens [1]. In
other animals and plants, such infections are known to be
challenged by innate immune defenses. These detect conserved
pathogen-specific cellular components such as lipopolysaccharide
(LPS) and peptidoglycan. They then counter the invasion with
various responses which limit the infection or kill the invading
microorganism. In Drosophila, for example, the Toll receptor is
activated on infection by fungi and Gram-positive bacteria,
initiating an intracellular signaling cascade that culminates in
the activation of Rel/NFkB transcription factors. These factors
then promote expression of antimicrobial peptides [2]. Signaling
from Toll-like receptors also constitutes a major arm of the
mammalian innate immune response [3], suggesting common
evolutionary roots for these defense mechanisms.
2) Surprisingly, however, Toll-dependent defense appears absent
from C. elegans [4]. Not only are genes encoding a number of
components of the cascade missing from the worm genome --
including, critically, a Rel/NFkB homolog -- but also deletion of
the components that are present was found not to alter nematode
resistance to a number of pathogens [4]. Apparently then, C.
elegans does not use this otherwise conserved pathway for immune
defense. Indeed, until recently, there was no clear evidence for
a defense system in the worm, despite the fact that it normally
inhabits an environment teeming with potential pathogens. Recent
data [5,6], however, demonstrate both the existence of a
conserved innate immune signaling pathway in C. elegans and the
induction of various genes in response to infection.
3) In summary: Recent studies provide the first evidence of a
conserved innate immune defense system in C. elegans and
demonstrate the inducibility of defense genes in response to
infection. With the ever-growing number of known C. elegans
pathogens, and the tractability of this organism for genetic
studies, the worm is likely to provide new insights into
mechanisms of innate immune defense.
References (abridged):
1. Ewbank J.J. (2002) Tackling both sides of the host-pathogen
equation with Caenorhabditis elegans Microbes Infect., 4:247-256.
2. Tzou P., De Gregorio E. and Lemaitre B. (2002) How Drosophila
combats microbial infection: a model to study innate immunity and
host-pathogen interactions. Curr. Opin. Microbiol., 5:102-110.
3. Medzhitov R. (2001) Toll-like receptors and innate immunity.
Nat. Rev. Immunol., 1:135-145.
4. Pujol N., Link E.M., Liu L.X., Kurz L.C., Alloing G., Tan
M.W., Ray K.P., Solari R., Johnson C.D. and Ewbank J.J. (2001) A
reverse genetic analysis of components of the Toll signalling
pathway in Caenorhabditis elegans Curr. Biol., 11:809-821.
5. Kim D.H., Feinbaum R., Alloing G., Emerson F.E., Garsin D.A.,
Inoue H., Tanaka-Hino M., Hisamoto N., Matsumoto K. and Tan M.W.
et al. (2002) A conserved p38 MAP kinase pathway in
Caenorhabditis elegans innate immunity. Science, 297:623-626.
6. Mallo G.V., Kurz C.L., Couillault C., Pujol N., Granjeaud S.,
Kohara Y. and Ewbank J.J. (2002) Inducible antibacterial defense
system in C. elegans Curr. Biol., 12:1209-1214.
Current Biology 2002 12:R731
Related Background:
A REVERSE GENETIC ANALYSIS OF COMPONENTS OF THE TOLL SIGNALING
PATHWAY IN CAENORHABDITIS ELEGANS.
N. Pujol et al (University of the Mediterranean Marseilles, FR)
discuss innate immunity in C. elegans, the authors making the
following points:
1) Both animals and plants respond rapidly to pathogens by
inducing the expression of defense-related genes. Whether such an
inducible system of innate immunity is present in the model
nematode Caenorhabditis elegans is currently an open question.
Among conserved signaling pathways important for innate immunity,
the Toll pathway is the best characterized. In Drosophila, this
pathway also has an essential developmental role. C. elegans
possesses structural homologs of components of this pathway, and
this observation raises the possibility that a Toll pathway might
also function in nematodes to trigger defense mechanisms or to
control development.
2) The authors report they have generated and characterized
deletion mutants for four genes supposed to function in a
nematode Toll signaling pathway. These genes are tol-1, trf-1,
pik-1, and ikb-1, and are homologous to the Drosophila
melanogaster Toll, dTraf, pelle, and cactus genes, respectively.
Of these four genes, only tol-1 is required for nematode
development. None of them are important for the resistance of C.
elegans to a number of pathogens. On the other hand, C. elegans
is capable of distinguishing different bacterial species and has
a tendency to avoid certain pathogens, including Serratia
marcescens. The tol-1 mutants are defective in their avoidance of
pathogenic S. marcescens, although other chemosensory behaviors
are wild type.
3) The authors conclude: In C. elegans, tol-1 is important for
development and pathogen recognition, as is Toll in Drosophila,
but remarkably for the latter r“le, it functions in the context
of a behavioral mechanism that keeps worms away from potential
danger.(1-5)
References (abridged):
1. Boman H.G., Nilsson I. and Rasmuson B. (1972) Inducible
antibacterial defence system in Drosophila Nature, 237:232-235.
2. Meister M., Lemaitre B. and Hoffmann J.A. (1997) Antimicrobial
peptide defense in Drosophila Bioessays, 19:1019-1026.
3. Lemaitre B., Reichhart J.M. and Hoffmann J.A. (1997)
Drosophila host defense: differential induction of antimicrobial
peptide genes after infection by various classes of
microorganisms. Proc Natl Acad Sci USA, 94:14614-14619.
4. Ip Y.T., Reach M., Engstrom Y., Kadalayil L., Cai H. and
Gonzalez-Crespo S. et al. (1993) Dif, a dorsal-related gene that
mediates an immune response in Drosophila Cell, 75:753-763.
5. Lemaitre B., Nicolas E., Michaut L., Reichhart J.M. and
Hoffmann J.A. (1996) The dorsoventral regulatory gene cassette
spatzle/Toll/cactus controls the potent antifungal response in
Drosophila adults. Cell, 86:973-983.
Current Biology 2001 11:809
Related Background Brief:
INDUCIBLE ANTIBACTERIAL DEFENSE SYSTEM IN C. ELEGANS. The term
innate immunity refers to a number of evolutionary ancient
mechanisms that serve to defend animals and plants against
infection. Genetically tractable model organisms, especially
Drosophila, have contributed greatly to advances in our
understanding of mammalian innate immunity. Essentially, nothing
is known about immune responses in the nematode Caenorhabditis
elegans. Using high-density cDNA microarrays, the authors
demonstrate that infection of C. elegans by the Gram-negative
bacterium Serratia marcescens provokes a marked upregulation of
the expression of many genes. Among the most robustly induced are
genes encoding lectins and lysozymes, known to be involved in
immune responses in other organisms. Certain infection-inducible
genes are under the control of the DBL-1/TGF pathway. The authors
report that dbl-1 mutants exhibit increased susceptibility to
infection. Conversely, overexpression of the lysozyme gene lys-1
augments the resistance of C. elegans to S. marcescens. The
authors suggest that these results constitute the first
demonstration of inducible antibacterial defenses in C. elegans
and open new avenues for the investigation of evolutionary
conserved mechanisms of innate immunity. G.V. Mallo et al:
Current Biology 2002 12:1209.
Related Background:
ON INNATE VERSUS ADAPTIVE IMMUNITY
N. Silverman and T. Maniatis (Harvard University, US) discuss
immunity:
Innate immunity is the first line of defense against infectious
microorganisms. The innate immune system relies on germ line-
encoded pattern recognition receptors to recognize pathogen-
derived substances. Activation of the innate immune system
through these receptors leads to the expression of a vast array
of antimicrobial effector molecules that attack microorganisms at
many different levels. The innate immune system appears early in
evolution, and the basic mechanisms of pathogen recognition and
activation of the response are conserved throughout much of the
animal kingdom. Insects, for example, have a very potent innate
immune response that effectively combats a broad spectrum of
pathogens. The fruit fly Drosophila can withstand and clear
bacterial burdens that relative to the size of the host would be
lethal to mammals. In contrast to innate immunity, the adaptive
immune system generates antigen-specific receptors, antibodies,
and T-cell receptors by somatic cell DNA rearrangement. These
receptors, found only in higher eukaryotes, recognize specific
pathogen-encoded proteins. Mammals have a complex immune
response, which relies on communication between the innate and
adaptive arms of the immune system. The innate immune response
generates a "co-stimulatory signal", which is required in
combination with antigen-specific recognition to activate T-cells
and the adaptive immune system. Antigen-specific recognition in
the absence of co-stimulation can lead to absence of response
(anergy) rather than to activation. Thus, the activation of an
antigen-specific response is coupled to infection through the
innate immune system.
Genes and Development 2001 15:2321
Related Background:
MEDICAL BIOLOGY: ON THE IMMUNE SYSTEM
Our environment is filled with a variety of infectious agents,
including bacteria, viruses, parasites, and fungi, and the
essential line of defense against these pathogenic invaders is
the "immune system". This system, an evolutionary development in
vertebrates, involves a complex set of dynamic interactions
between various specialized cells, the interactions mediated by
chemistry. An important component is an evolved genomic apparatus
that essentially provides for an "immune memory", which in
general is a capability of the immune system to modify and
enhance its responses based on its previous experience with
particular pathogens. Nowhere is the idea of the human body as a
colony of cells more clear than in consideration of the
cooperative interactions of the various cells of the immune
system functioning to protect the entire organism.
P.J. Delves and I.M. Roitt (University College London, UK)
present an extensive 2-part review of current knowledge
concerning the human immune system, the authors making the
following points:
1) In humans, there are two fundamentally different types of
responses to invading microbes: a) innate (natural) responses
that occur to the same extent however many times the infectious
agent is encountered; b) acquired (adaptive) responses that
improve after repeated exposure to a given infection.
2) The innate immune response involves a) various specialized
"phagocytes" (neutrophils, monocytes, macrophages), cells that
"eat" pathogens; b) various cells (basophils, mast cells,
eosinophils) that release *inflammatory mediator substances; c)
*natural "killer" cells. The molecular components of innate
responses include a variety of identified proteins (e.g.,
*complement, *cytokines).
3) The acquired immune response involves the proliferation of
*antigen-specific *B and T cells, which occurs when the surface
receptors of these cells bind to antigen. Specialized cells,
called "antigen-presenting cells", display the antigen to
*lymphocytes and collaborate with them in the response to the
antigen. B cells secrete *immunoglobulins, the antigen-specific
*antibodies responsible for eliminating extracellular
microorganisms. T cells help B cells to make antibody and can
also eradicate intracellular pathogens by activating macrophages
and by killing virally infected host cells. In general, innate
and acquired responses usually work together to eliminate
pathogens.
4) The various cells of the immune system develop from
*pluripotent stem cells in the fetal liver and in bone marrow and
then circulate throughout the extracellular fluid. B cells reach
maturity within the bone marrow, but T cells must travel to the
thymus gland to complete their development.
5) Adaptive immune responses are generated in the *lymph nodes,
spleen, and *mucosa-associated lymphoid tissue, all of which are
called "secondary lymphoid tissues": a) In the spleen and lymph
nodes, the activation of lymphocytes by circulating antigen
occurs in distinctive B cell and T cell compartments of lymphoid
tissue. b) The mucosa-associated lymphoid tissues, including the
tonsils, adenoids, and *Peyer's patches, defend mucosal surfaces.
c) Diffuse collections of lymphoid cells are present throughout
the lung and *lamina propria of the intestinal wall.
6) To establish an infection, a pathogen must first overcome
numerous surface barriers, such as enzymes and mucus, that are
either directly antimicrobial or that inhibit attachment of the
microbe. Because neither the *keratinized surface of the skin nor
the mucus-lined body cavities are ideal habitats for most
organisms, microbes must breach the *ectoderm. Any organism that
breaks through this first barrier encounters the two further
levels of defense, the innate and acquired immune responses.
New Engl. J. Med. 2000 343:37,108
Notes:
... ... *inflammatory mediator substances: In general, an
"inflammatory change" is a response of tissues to irritation or
injury. The response involves a dynamic complex of cellular and
chemical reactions that occur in the affected blood vessels and
adjacent tissues.
... ... *natural "killer" cells: Cells of the innate immune
response that recognize and then kill abnormal cells such as
certain infected cells and tumor cells.
... ... *complement: A group of 9 interacting serum proteins,
mostly enzymes, which are activated during the immune response,
and which participate in bacterial lysis (destruction of bacteria
by disruption of cell membrane) and macrophage chemotaxis
(chemical attraction of macrophages, immune system amoeba-like
cells active in phagocytosis of bacteria and other particulates.)
... ... *cytokines: A cytokine is any substance that promotes
cell growth and cell division. Cytokines mediate many functions
of the immune system.
... ... *antigen: In general, an antigen is any entity that
provokes an immune response, and this includes, in certain
disease states, entities that are not "foreign" to the body.
... ... *B and T cells: (B and T lymphocytes) Lymphocytes (lymph
cells, lympho-leukocytes) are a type of leukocyte (white blood
cell) responsible for the immune response. In general, there are
two classes of lymphocytes: 1) the B-cells, when presented with a
foreign chemical entity (antigen), change into antibody producing
plasma cells; 2) the T-cells, which interact directly with
foreign invaders such as bacteria and viruses, and some types of
which assist B-cells in the B-cell response. The general
terminological differentiation between B-cells and T-cells is
based on where the cells mature: B-cells mature in (b)one marrow,
and T-cells mature in the (t)hymus gland.
... ... *lymphocytes: See above note.
... ... *immunoglobulins: (antibody): The immunoglobulins are a
large glycoprotein category that includes antibodies as a subset.
In general, an "antibody" is a protein molecule produced by the
immune system of vertebrate organisms, the molecule designed to
specifically interact with a particular antigen.
... ... *antibodies: See above note.
... ... *pluripotent stem cells: In general, the term "stem"
cells refers to undifferentiated cells that upon differentiation
can give rise to various specialized cell lines such as blood
cells, skin cells, nerve cells, etc. Adult bone marrow, for
example, contains stem cells that are the precursors of the
various specialized types of blood cells. "Pluripotent stem
cells" are stem cells that have the capacity to differentiate
into various cell types.
... ... *lymph nodes: The lymphatic system is a complex network
for the distribution of lymph fluid (which is similar to blood
plasma -- blood without red cells). Lymph is collected by
drainage from the tissues throughout the body, flows in the
lymphatic vessels through the lymph nodes, and is eventually
added to the venous blood circulation. Lymph consists of a clear
liquid portion, varying numbers of white blood cells (chiefly
lymphocytes), and a few red blood cells. The lymph nodes are
small bodies located throughout the lymph system and varying in
diameter from 0.1 to 2.5 centimeters.
... ... *mucosa: In general, a multilayer tissue lining various
tubular structures in the body.
... ... *Peyer's patches: Aggregated lymphoid nodules of the
small intestine.
... ... *lamina propria: The layer of connective tissue
underlying the *epithelial layer of a mucosa.
... ... *epithelial layer: In animals and humans, epithelial
cells compose the cell layers that form the interface between a
tissue and the external environment, for example, the cells of
the skin, the lining of the intestinal tract, and the lung airway
passages.
... ... *keratinized: Keratin is a protein which helps waterproof
and protect the skin and underlying tissues.
... ... *ectoderm: In the embryos of higher animals, there occurs
the transformation of a single-layer "blastula" into a 3-layered
"gastrula" consisting of ectoderm (outermost layer), mesoderm
(middle layer), and endoderm (innermost layer) surrounding a
cavity with one opening. The 3 layers are called the "germ
layer", and these layers, via further cell differentiation and
proliferation, determine the development of all the major body
systems and organs.
Related Background:
ON EPITHELIA AND INNATE IMMUNITY
Tomas Ganz (University of California Los Angeles, US) discuss
epithelia, the author making the following points:
1) Epithelia are tissues consisting of sheets of similar cells
bound closely together, which include the epidermis, the surfaces
of the eyes, the surfaces of the hollow tubes and sacs that make
up the digestive, respiratory, reproductive, and urinary tracts,
and the secretory cells and ducts of various glands. Depending on
their predominant function, epithelia can be described further as
barrier, secretory, or absorptive, but often all three functions
coexist. These are the tissues most exposed to environmental
bacteria. The importance of epithelia in host defense is best
illustrated by the common experience that disruption of the
epithelial layers, such as occurs in a minor skin scrape or a
burn, greatly increases the likelihood of penetrating infection.
Mechanical barrier properties of epithelia, the physical
cleansing effects of their secretions, and the shedding of
colonized cells normally contribute to protection from microbes
(1). Moreover, injured or infected epithelial cells help initiate
the inflammatory response by emitting chemotactic signals that
attract blood-borne host defense cells.
2) Although the ability of various glands to produce
antimicrobial substances has been appreciated since Alexander
Fleming's (2) pioneering studies of lysozyme in tears,
respiratory secretions, and saliva, more recently it has become
clear that barrier and absorptive epithelia also produce numerous
antimicrobial substances (3-5). There are impressive similarities
between the polypeptide arsenal of various epithelial cells and
the prototypical professional host defense cells, the
polymorphonuclear leukocytes. In some cases (e.g., lysozyme and
lactoferrin), the same genes are highly expressed in both cell
types; in other cases (e.g., defensins, peroxidase), the two cell
types express different members of the same gene family. These
similarities reinforce the notion that epithelial cells, like
polymorphonuclear leukocytes, are important effectors of innate
immunity.
3) Canny et al (Proc. Nat. Acad. Sci. 2002 99:3902) have now
demonstrated that appropriately stimulated human epithelial cell
lines, as well as several specimens of human epithelial tissues,
express on their cell membranes bactericidal permeability-
increasing protein (BPI), heretofore known as an abundant
antimicrobial constituent of polymorphonuclear leukocytes. BPI is
bactericidal to many Gram-negative bacteria, a specificity that
is determined by its avid binding to lipopolysaccharide, the
major component of the external layer of the outer membrane of
these bacteria.
References (abridged):
1. Metchnikoff, E. (1905) Immunity in Infective Diseases
(Cambridge Univ. Press, Cambridge, U.K.), pp. 403-432.
2. Fleming, A. (1922) Proc. R. Soc. London B Biol. Sci. 93, 306-
317.
3. Diamond, G. , Zasloff, M. , Eck, H. , Brasseur, M. , Maloy, W.
L. & Bevins, C. L. (1991) Proc. Natl. Acad. Sci. USA 88, 3952-
3956.
4. Valore, E. V. , Park, C. H. , Quayle, A. J. , Wiles, K. R. ,
McCray, P. B. & Ganz, T. (1998) J. Clin. Invest. 101, 1633-1642.
5. Harder, J. , Bartels, J. , Christophers, E. & Schroeder, J.-M.
(1997) Nature (London) 387, 861-862.
Proc. Nat. Acad. Sci. 2002 99:3357
Related Background:
ON THE PHYLOGENY OF INNATE IMMUNITY
J.A. Hoffmann et al (4 authors at 4 installations, FR DE US)
present an extensive review of innate immunity in Drosophila, the
essential characteristics of mammalian innate immunity, and the
links between innate and adaptive immunity. The authors make the
following points:
1) The fruit fly Drosophila is particularly resistant to
microbial infections, and 3 mechanisms contribute to this
resistance: a) phagocytosis of invading microorganisms by blood
cells; b) *proteolytic cascades leading to localized blood
clotting, *melanin formation, and *opsonization; c) transient
synthesis of potent antimicrobial peptides. These reactions all
take place within a short period after pathogenic injury.
2) Drosophila is capable of discriminating between classes of
invading microorganisms, for instance, between bacteria and
fungi, and of responding by preferentially producing peptides
that target destruction of the recognized pathogen.
3) A key feature of innate immunity in mammals is the ability to
rapidly limit the infectious challenge. This is based on the
capacity to discriminate species self from infectious nonself.
Microbes display molecular arrays or patterns that are apparently
recognized by pattern recognition molecules or receptors, and
these patterns are evidently shared among groups of pathogens,
e.g.: lipopolysaccharides of *gram-negative bacteria; lipotechoic
acids of *gram-positive bacteria; mannans of *yeast; double-
stranded RNA of viruses. To limit infection, the mammalian host
uses a wide variety of pattern recognition molecules, including
*complement, *collectins, and a battery of antimicrobial peptides
that act together with effector cells to combat the infectious
challenge.
4) The adaptive immune system apparently appeared approximately
450 million years ago when a *transposon that carried the
forerunners of certain *recombinase-activating genes was inserted
into the germ-line of early jawed vertebrates. The ability to
mount an adaptive immune response allowed organisms to "remember"
the pathogens they had already encountered, and natural selection
made the adaptive immune response a virtually universal
characteristic of vertebrates. But the innate immune system was
not discarded, and indeed the innate immune system has been co-
opted in vertebrates to serve a second function, that of
stimulating and orienting the primary adaptive immune response by
controlling the expression of "*costimulatory molecules".
5) Concerning innate immunity, it is a provocative thought that
innate immunity in both plants and animals may have evolved from
common ancestral modules that have been used to protect against
infection for more than 1 billion years of evolution.
Science 1999 284: 1313
Notes:
... ... *antigens: In general, any chemical entity that activates
an immune response, especially an entity originating outside the
body. Antibodies are specific proteins synthesized by the immune
system which interact with specific antigens.
... ... *effector mechanisms: In this context, an "effector
mechanism" is any process which is part of the response of the
biological system to microbial invasion.
... ... *clonal response: In this context, the term "clonal
response" refers to an immune system effector mechanism involving
proliferation of a single line of cells producing a single
antibody to a single specific antigen.
... ... *proteolytic cascades: In general, "proteolysis" is the
enzyme-catalyzed degradation of protein by hydrolysis of one or
more peptide bonds. A "proteolytic cascade" is a sequence of
proteolytic reactions involving a series of enzymes, with each
reaction serving to activate the next reaction in the sequence.
... ... *melanin: A dark brown pigment product of tyrosine
metabolism, usually bound to proteins.
... ... *opsonization: (opsonification) Opsonin is a blood
protein that when combined with microorganisms or other
particulate matter renders them more susceptible to phagocytosis.
The term "opsonization" refers to the coating of microorganisms
or other particulate matter with opsonin.
... ... *gram-negative/gram positive bacteria: Most bacteria can
be classified into two types, depending on the chemistry of their
outer coat, which chemistry determines whether a bacterium will
admit certain dyes into the interior. The classification,
according to the differential staining technique, is gram-
negative vs. gram-positive, named after the bacteriologist H.C.
Gram (1853-1938). Gram-positive bacteria take up a crystal violet
stain and turn purple, while gram-negative bacteria exclude the
crystal violet and counterstain instead with stains such as
safranin, eosin red, or brilliant green. As might be expected,
since the technique differentiates the outer coats of bacteria,
some antibiotics are effective against one type and not
the other type, and vice versa.
... ... *complement: A group of 9 interacting serum proteins,
mostly enzymes, which are activated during the immune response,
and which participate in bacterial lysis (destruction of bacteria
by disruption of cell membrane) and macrophage chemotaxis
(chemical attraction of macrophages, immune system amoeba-like
cells active in phagocytosis of bacteria and other particulates.)
... ... *collectins: A family of plasma lectins (a group of
antibody-like proteins which agglutinate cells and particulates).
... ... *transposon: A transposon is a limited DNA sequence that
under the proper dynamic conditions can effectively translocate
from one DNA system to another, either in the same cell, or
between cells, or between cells of different organisms of the
same or different species, and remain functional.
... ... *recombinase: In general, an enzyme that plays a specific
role in recombining DNA sequences into genes that encode for
antibodies.
... ... *costimulatory molecules: An alternative name for the
interleukins, a heterogeneous group of *cytokines that act as
signaling molecules between different populations of immune
system white blood cells (leukocytes).
... ... *cytokines: A cytokine is any substance that promotes
cell growth and cell division. As a promoter of cell growth and
division, a cytokine acts as a messenger to cells, and the
transmission of the message requires a binding of the cytokine
molecule to a cytokine-specific receptor on the cell surface.
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2. MULTIPLE SCLEROSIS, STATINS, AND AUTOIMMUNE DISEASE.
Hartmut Wekerle (Max-Planck Institute of Neurobiology, DE)
discusses multiple sclerosis, the author making the following
points:
1) Multiple sclerosis owes its enormous socioeconomic importance
to several factors. Worldwide, as many as one million people are
affected by the disease. It tends to afflict sufferers for most
of their lives, often taking a severe, disabling course. And
there are no effective treatments that stop multiple sclerosis in
its tracks (although there are some that slow its progression).
New therapies are desperately needed, and one attractive
candidate is atorvastatin, a drug that is already used to reduce
blood cholesterol levels in people with atherosclerosis or heart
disease(2).
2) Multiple sclerosis is generally believed to develop when the
body's immune cells -- led by so-called helper T cells -- attack
myelin, the insulating, fatty sheath around nerve cells. This
damages the myelin and the underlying neurons in both the brain
and the spinal cord, leading to impaired transmission of nerve
impulses and progressive physical disability. Treatments
available today include one that involves engineered interferon-
beta proteins, which reduce the inflammation associated with
nerve damage. Another is based on copaxone, a random composite of
basic peptides, which probably activates brain-protein-detecting
T cells that inhibit rather than support the autoimmune attack.
Both drugs reduce the number of clinical relapses and the damage
to the central nervous system. But both also come at a price --
quite literally in one sense, as they are very expensive.
Moreover, they must be administered frequently by injection,
which is a severe bother and carries a risk of side-effects. New
treatments are needed that can be given orally and that,
hopefully, also have a greater effect on the disease.(1,3-5)
References (abridged):
1. Youssef, S. et al. Nature 420, 78-84 (2002).
2. Maron, D. J., Fazio, S. & Linton, M. F. Circulation 101, 207-
213 (2000).
3. Stanislaus, R. Neurosci. Lett. 269, 71-74 (1999).
4. Ludewig, B. et al. J. Immunol. 166, 3369-3376 (2001).
5. Kwak, B., Mulhaupt, F., Myit, S. & Mach, F. Nature Med. 6,
1399-1402 (2000).
Nature 2002 420:39
Related Background:
THE HMG-COA REDUCTASE INHIBITOR, ATORVASTATIN, PROMOTES A TH2
BIAS AND REVERSES PARALYSIS IN CENTRAL NERVOUS SYSTEM AUTOIMMUNE
DISEASE.
S. Youssef et al (Stanford University, US) discuss statins and
autoimmune disease, the authors making the following points:
1) Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors, which are approved for cholesterol
reduction, may also be beneficial in the treatment of
inflammatory diseases(1-3). The authors report they tested
atorvastatin (Lipitor) in chronic and relapsing experimental
autoimmune encephalomyelitis (EAE), a CD4+ Th1-mediated central
nervous system (CNS) demyelinating disease model of multiple
sclerosis(4,5).
2) In 1995, it was reported that pravastatin treatment of cardiac
transplant recipients was associated with a reduction in
hemodynamically significant rejection episodes and increased
survival, independent of its cholesterol-lowering effects(1).
Subsequent studies demonstrated that certain statins could
inhibit production of specific pro-inflammatory molecules(2,3).
Lovastatin inhibited production of TNF-alpha and inducible nitric
oxide synthetase (iNOS) by microglia and astrocytes(2). MHC class
II expression is central to immune regulation in T-cell-mediated
autoimmune disease(5). Statins prevented IFN-gamma-inducible MHC
class II expression on non-professional APC9, suggesting that
statins might inhibit antigen presentation to pro-inflammatory
Th1 cells.
3) The authors demonstrate that oral atorvastatin prevented or
reversed chronic and relapsing paralysis. Atorvastatin induced
STAT6 phosphorylation and secretion of Th2 cytokines (interleukin
(IL)-4, IL-5 and IL-10) and transforming growth factor (TGF)-
beta. Conversely, STAT4 phosphorylation was inhibited and
secretion of Th1 cytokines was suppressed. Atorvastatin promoted
differentiation of Th0 cells into Th2 cells. In adoptive
transfer, these Th2 cells protected recipient mice from EAE
induction. Atorvastatin reduced CNS infiltration and major
histocompatibility complex (MHC) class II expression. Treatment
of microglia inhibited IFN-gamma-inducible transcription at
multiple MHC class II transactivator (CIITA) promoters and
suppressed class II upregulation. Atorvastatin suppressed IFN-
gamma-inducible expression of CD40, CD80 and CD86 co-stimulatory
molecules. L-Mevalonate, the product of HMG-CoA reductase,
reversed atorvastatin's effects on antigen-presenting cells (APC)
and T cells. Atorvastatin treatment of either APC or T cells
suppressed antigen-specific T-cell activation. Thus, atorvastatin
has pleiotropic immunomodulatory effects involving both APC and
T-cell compartments. The authors suggest that statins may be
beneficial for multiple sclerosis and other Th1-mediated
autoimmune diseases.
References (abridged):
1. Kobashigawa, J. A. et al. Effect of pravastatin on outcomes
after cardiac transplantation. N. Engl. J. Med. 333, 621-627
(1995).
2. Pahan, K., Sheikh, F. G., Namboodiri, A. M. & Singh, I.
Lovastatin and phenylacetate inhibit the induction of nitric
oxide synthase and cytokines in rat primary astrocytes,
microglia, and macrophages. J. Clin. Invest. 100, 2671-2679
(1997).
3. Wong, B. et al. Statins suppress THP-1 cell migration and
secretion of matrix metalloproteinase 9 by inhibiting
geranylgeranylation. J. Leukoc. Biol. 69, 959-962 (2001).
4. Zamvil, S. S. & Steinman, L. The T lymphocyte in experimental
allergic encephalomyelitis. Annu. Rev. Immunol. 8, 579-621
(1990).
5. Slavin, A. J. et al. Requirement for endocytic antigen
processing and influence of invariant chain and H-2M deficiencies
in CNS autoimmunity. J. Clin. Invest. 108, 1133-1139 (2001).
Nature 2002 420:78
Related Background:
EPSTEIN-BARR VIRUS AND MULTIPLE SCLEROSIS
A. Ascherio et al (Harvard University, US) discuss Epstein-Barr
virus and multiple sclerosis, the authors making the following
points:
1) The etiology of multiple sclerosis is largely unknown, but
evidence supports the idea of an autoimmune process triggered by
infection or other environmental factors. Epstein-Barr virus, a
herpesvirus, infects more than 90 percent of the human
population, establishing a persistent and highly immunogenic
infection of B lymphocytes. The population of antigen-specific
cytotoxic T cells is massively expanded in response to primary
infection and persists at high levels for several years.
Autoimmunity could result if some of these cells carry T-cell
receptors that recognize self-peptides. Epstein-Barr virus has
been related to nasopharyngeal carcinoma, Burkitt lymphoma, and
Hodgkin disease, and a relation to autoimmune diseases has been
proposed by remains unproven.
2) Infection with Epstein-Barr virus is usually asymptomatic in
childhood but frequently causes infectious mononucleosis in
adolescents and adults. The similarity in the epidemiology of
multiple sclerosis and infectious mononucleosis led to the
proposition that multiple sclerosis could be caused by infection
with Epstein-Barr virus during or after adolescence in
genetically susceptible individuals. This hypothesis is supported
by observations suggesting an increased risk of multiple
sclerosis following infectious mononucleosis, the rarity of
multiple sclerosis among individuals without serum anti-Epstein-
Barr virus antibodies, and the higher serum titers of anti-
Epstein-Barr virus antibodies in multiple sclerosis patients than
in controls.
3) The authors report a prospective study of the role of Epstein-
Barr virus in the etiology of multiple sclerosis, the study
involving examination of the association between serum anti-
Epstein-Barr virus antibody titers and risk of developing
multiple sclerosis in 2 large cohorts of US women. The total
number of women in the study was 62,439. The authors report that
their results support a role of Epstein-Barr virus in the
etiology of multiple sclerosis. A 4-fold difference in titers of
antibodies to Epstein-Barr virus antigens was associated with a
4-fold increase in risk of multiple sclerosis.
J. Am. Med. Assoc. 2001 286:3083
Related Background:
MEDICAL BIOLOGY: A POSSIBLE CAUSE OF MULTIPLE SCLEROSIS
In the vertebrate central nervous system, the axons of nerve
cells involved in physiological functions that require rapid
signaling (for example, the neural control of voluntary muscle)
are wrapped in a special sheath called myelin. The myelin sheath
consists of concentric layers of electrically insulating lipid-
protein material, but the sheath is periodically interrupted
along the length of the axon, and at the points where the sheath
is interrupted so is the electrical insulation interrupted. The
result, predictable from the classical physics of electrical
transmission lines and the electrical parameters of nerve fibers,
is that the propagation of an electrical pulse along such nerve
fibers occurs at a velocity much higher than that found in
unmyelinated fibers. Multiple sclerosis is a human disease
characterized by the progressive loss of the myelin of the brain
and spinal cord, with the physiological disruptions to be
expected from such loss, considering the significance of myelin
in the functioning of nerve cells. The cause of the disease is
unknown, but an immunological abnormality is suspected. It has
also been postulated that the cause is infection by a latent
virus, with viral activation and expression triggering a
secondary immune response. There is some evidence for genetic
susceptibility, and there is also evidence that environment may
be a factor, since the disease is 5 times more common in
temperate climates than in the tropics.
D.C. Shields et al (4 authors at 2 installations, US JP) present
a study of the mechanism of demyelinization in multiple
sclerosis, the authors reporting the following:
1) In autoimmune demyelinating diseases such as multiple
sclerosis, the degradation of myelin proteins results in the
destabilization of the myelin sheath. Protein-degrading enzymes
(proteases, proteinases) have been implicated in myelin protein
degradation, and recent studies have demonstrated increased
expression and activity of a calcium-activated neutral proteinase
(calpain) in experimental allergic encephalomyelitis, the
corresponding animal model of multiple sclerosis.
2) In the present study, calpain activity and expression were
evaluated in white matter from human patients with multiple
sclerosis and Parkinson's and Alzheimer's diseases and compared
with that of white matter from normal controls. Analysis
indicates that the active form of calpain and calpain-specific
degradation products were increased by 90.1 percent and 52.7
percent, respectively, in multiple sclerosis plaques compared
with normal white matter, and that calpain expression increased
by more than a factor of 4 compared with normal white matter.
Calpain activity and expression were not increased significantly
in white matter from patients with Parkinson's or Alzheimer's
diseases compared with that of normal controls.
3) The authors suggest that because calpain degrades all major
myelin proteins, the increased activity and expression of this
proteinase may play a critical role in the degradation of myelin
in autoimmune demyelinating diseases such as multiple sclerosis.
Proc. Nat. Acad. Sci. 1999 96:11486
Related Background Brief:
HERPESVIRUS LINKED TO MULTIPLE SCLEROSIS. The herpesviruses are a
class of viruses producing the complex of herpes diseases, and
HHV-6 is a recently discovered strain of herpesvirus that
apparently causes an infant and early childhood disease called
roseala infantum. Jacobson et al (National Institutes of Health,
US) report that a study of multiple sclerosis patients (36
patients and 66 controls) revealed that 70% of these patients
were infected with the strain of herpesvirus HHV-6. They also
report that magnetic resonance imaging detected numerous myelin
lesions in the brain of a deceased multiple sclerosis patient,
and an autopsy revealed HHV-6 in the lesions but not in the
adjoining normal tissues. Some multiple sclerosis specialists are
expressing reservations about the interpretation of these
results, stating it is possible the viral infection is a
consequence rather than a cause of multiple sclerosis. Nature
Medicine 1997 December.
Related Background Brief:
CURRENT PERSPECTIVES ON STATINS. Statins (HMG-CoA reductase
inhibitors) are used widely for the treatment of
hypercholesterolemia. They inhibit HMG-CoA reductase
competitively, reduce LDL levels more than other cholesterol-
lowering drugs, and lower triglyceride levels in
hypertriglyceridemic patients. Statins are well tolerated and
have an excellent safety record. Clinical trials in patients with
and without coronary heart disease and with and without high
cholesterol have demonstrated consistently that statins reduce
the relative risk of major coronary events by approximately 30%
and produce a greater absolute benefit in patients with higher
baseline risk. Proposed mechanisms include favorable effects on
plasma lipoproteins, endothelial function, plaque architecture
and stability, thrombosis, and inflammation. Mechanisms
independent of LDL lowering may play an important role in the
clinical benefits conferred by these drugs and may ultimately
broaden their indication from lipid-lowering to antiatherogenic
agents. D.J. Maron et al: Circulation 2000 101:207.
Related Background Brief:
AMELIORATION OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS IN LEWIS
RATS BY LOVASTATIN. Proinflammatory cytokines and inducible
nitric oxide synthase (iNOS) are involved in the pathogenesis of
experimental allergic encephalomyelitis (EAE), an animal model of
multiple sclerosis (MS). The authors have previously reported
that lovastatin (J. Clin. Invest. 1997 100:2671), an inhibitor of
the mevalonate pathway, inhibits the expression of iNOS and
proinflammatory cytokines in rat primary glial cells (astroglia
and microglia) and macrophages. The present study underlines the
therapeutic importance of lovastatin in ameliorating the
neuroinflammatory disease process in the central nervous system
of EAE rats. Immunohistochemical results show a higher degree of
expression of iNOS, tumor necrosis factor-alpha (TNF-alpha) and
interferon-gamma (IFN-gamma) in brains of rats with acute
monophasic EAE relative to the control animals. Administration of
lovastatin inhibited the expression of iNOS, TNF-alpha and IFN-
gamma in the CNS of EAE rats and improved the clinical signs of
EAE suggesting that this compound may have therapeutic potential
in the treatment of neuroinflammatory diseases like multiple
sclerosis. R. Stanislaus et al: Neurosci Lett 1999 269:71.
HYPERCHOLESTEROLEMIA EXACERBATES VIRUS-INDUCED IMMUNOPATHOLOGIC
LIVER DISEASE VIA SUPPRESSION OF ANTIVIRAL CYTOTOXIC T CELL
RESPONSES. The immune system has to be optimally balanced to be
highly effective against infections with cytopathic microbial
pathogens and must guarantee efficient destruction of cells
infected with noncytopathic agents while leaving the integrity of
noninfected cells largely unaltered. The authors describe the
effects of genetically induced hypercholesterolemia on cellular
immunity in apolipoprotein E (ApoE(-/-)) and low density
lipoprotein receptor-deficient (LDLR(-/-)) mice during infection
with the hepatotropic lymphocytic choriomeningitis virus WE
strain. In both ApoE(-/-) and LDLR(-/-) mice hypercholesterolemia
aggravated virus-induced immunopathologic liver disease. ApoE(-/-
) mice exhibited a higher susceptibility to virus-induced
immunopathology than LDLR(-/-) mice and usually succumbed to
immunopathologic disease when infected with high doses of virus.
Initial virus spread was not influenced by the
hypercholesterolemia, whereas clearance of the virus from spleen
and nonlymphoid organs, including liver, was delayed. Activation
of antiviral CTL, measured by ex vivo cytotoxicity and IFN-gamma
production, and recruitment of specific CTL into blood and liver
were impaired in hypercholesterolemic mice, indicating that
hypercholesterolemia had a significant suppressive effect on
cellular immunity. The authors suggest that taken together these
data provide evidence that hypercholesterolemia suppresses
antiviral immune responses, thereby changing the host-virus
balance, and can increase susceptibility to acute or chronic and
potentially lethal virus-induced immunopathologic disease. These
findings impinge on our understanding of hypercholesterolemia as
a disease parameter and may explain aspects of the frequent
association of persistent pathogens with hypercholesterolemia-
induced diseases, such as atherosclerosis. B. Ludewig et al: J
Immunol 2001 166:3369.
STATINS AS A NEWLY RECOGNIZED TYPE OF IMMUNOMODULATOR. Inhibitors
of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, or
statins, are effective lipid-lowering agents, extensively used in
medical practice. Statins have never been shown to be involved in
the immune response, although a report has indicated a better
outcome of cardiac transplantation in patients under Pravastatin
therapy. Major histocompatibility complex class II (MHC-II)
molecules are directly involved in the activation of T
lymphocytes and in the control of the immune response. Whereas
only a limited number of specialized cell types express MHC-II
constitutively, numerous other cells become MHC-II positive upon
induction by interferon gamma (IFN-gamma). This complex
regulation is under the control of the transactivator CIITA. The
authors demonstrate that statins act as direct inhibitors of
induction of MHC-II expression by IFN-gamma and thus as
repressors of MHC-II-mediated T-cell activation. This effect of
statins is due to inhibition of the inducible promoter IV of the
transactivator CIITA and is observed in several cell types,
including primary human endothelial cells (ECs) and monocyte-
macrophages (Mstraight phi). It is of note that this inhibition
is specific for inducible MHC-II expression and does not concern
constitutive expression of CIITA and MHC-II. In repressing
induction of MHC-II, and subsequent T-lymphocyte activation,
statins therefore provide a new type of immunomodulation. The
authors suggest this unexpected effect provides a scientific
rationale for using statins as immunosuppressors, not only in
organ transplantation but in numerous other pathologies as well.
B. Kwak et al: Nat Med 2000 6:1399.
ScienceWeek http://www.scienceweek.com
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3. ON NONLINEAR OPTICS, SOLITONS, AND MATTER WAVES.
The term "nonlinear optics" refers to the study of the optical
properties of matter subjected to intense electromagnetic fields.
In order for nonlinearity to be exhibited, the external field
should not be negligible compared to the internal fields of the
atoms and molecules composing the material. Lasers are capable of
generating external fields of sufficient intensity for
nonlinearity to occur, and the field of nonlinear optics has
developed largely as a result of the invention of the laser. In
general, in nonlinear optics, the induced electric polarization
of the medium is not a linear function of the strength of the
external electromagnetic radiation, which leads to phenomena more
complicated than phenomena occurring in linear optics.
M.C. Downer (University of Texas Austin, US) discusses nonlinear
optics, the author making the following points:
1) In the first nonlinear optics experiment, Franken et al. (1)
focused a 3-joule red ruby laser pulse into a quartz crystal to
generate a few nanojoules of ultraviolet light at exactly twice
the incident frequency. The photographic recording of the signal
was so weak that the editor mistook it for a blemish and erased
it before publication. The memory of nonlinear optics might have
been erased, too, except that since then, a series of
breakthroughs has increased the efficiency of many nonlinear
optical frequency conversion processes by orders of magnitude,
transforming them into useful tools for science and technology.
2) In the 1960s, researchers discovered a class of crystals, now
standard in laser laboratories, that could convert pulses one-
thousandth as strong as Franken's ruby pulse to another color
with as much as 50% efficiency simply by matching the index of
refraction of the input and output frequencies (2). In the 1990s,
a new class of synthetic nonlinear optical multilayer structures
was developed and commercialized that efficiently converted still
weaker, fixed-frequency beams from small solid-state lasers to
tunable visible and infrared radiation for applications in
materials processing, remote sensing of environmentally sensitive
gases, and interferometry (3).
3) Along an independent line, chemists discovered in the 1970s
that another notoriously weak nonlinear optical process,
spontaneous Raman scattering, used to fingerprint molecular
vibrations (4), could be enhanced dramatically by attaching
molecules to rough metal surfaces or metal nanoparticles (5).
With this approach, Raman spectra of single molecules can now be
measured. Benabid et al (6) recently reported a breakthrough in
the nonlinear optics of molecular gases that adds a new milestone
to these historical examples. After pressurizing the hollow core
of a meter-long glass photonic-crystal fiber with hydrogen gas,
they demonstrated that green laser pulses propagating through the
core with microjoule energy -- two orders of magnitude weaker
than previous demonstrations in gases -- convert efficiently
(30%) to red pulses by stimulated Raman scattering from the
hydrogen stretch vibration. Reductions in fiber loss and laser
line width, and an increase in fiber length, should lower the
threshold energy for gas-phase stimulated Raman scattering even
further.
References (abridged):
1. P. Franken, A. E. Hill, C. W. Peters, G. Weinrich, Phys. Rev.
Lett. 7, 118 (1962).
2. V. G. Dmitriev, G. G. Gurzadyan, D. N. Nikogosyan, Handbook of
Nonlinear Optical Crystals (Springer-Verlag, New York, ed. 3,
1999).
3. M. Fejer, IEEE J. Quantum Electron. 28, 2631 (1992).
4. C. V. Raman, K. S. Krishnan, Indian J. Phys. 2, 399 (1928).
5. A. Otto, in Light Scattering in Solids IV, M. Cardona, G.
Guntherodt, Eds. (Springer, Berlin, 1984), p. 289.
6. F. Benabid et al., Science 298, 399 (2002).
Science 2002 298:373
Related Background Brief:
PROBING SINGLE MOLECULES AND SINGLE NANOPARTICLES BY SURFACE-
ENHANCED RAMAN SCATTERING. Optical detection and spectroscopy of
single molecules and single nanoparticles have been achieved at
room temperature with the use of surface-enhanced Raman
scattering. Individual silver colloidal nanoparticles were
screened from a large heterogeneous population for special size-
dependent properties and were then used to amplify the
spectroscopic signatures of adsorbed molecules. For single
rhodamine 6G molecules adsorbed on the selected nanoparticles,
the intrinsic Raman enhancement factors were on the order of 1014
to 1015, much larger than the ensemble-averaged values derived
from conventional measurements. This enormous enhancement leads
to vibrational Raman signals that are more intense and more
stable than single-molecule fluorescence. S. Nie and S.R. Emory:
Science 1997 275:1102.
Related Background Brief:
STIMULATED RAMAN SCATTERING IN HYDROGEN-FILLED HOLLOW-CORE
PHOTONIC CRYSTAL FIBER. The authors report a study of stimulated
Raman scattering in an approximately 1-meter-long hollow-core
photonic crystal fiber filled with hydrogen gas under pressure.
Light was guided and confined in the 15-micrometer-diameter
hollow core by a two-dimensional photonic bandgap. Using a pulsed
laser source (pulse duration, 6 nanoseconds; wavelength, 532
nanometers), the threshold for Stokes (longer wavelength)
generation was observed at pulse energies as low as 800 ñ 200
nanojoules, followed by a coherent anti-Stokes (shorter
wavelength) generation threshold at 3.4 ñ 0.7 microjoules. The
pump-to-Stokes conversion efficiency was 30 ñ 3% at a pulse
energy of only 4.5 microjoules. These energies are almost two
orders of magnitude lower than any other reported energy, moving
gas-based nonlinear optics to previously inaccessible parameter
regimes of high intensity and long interaction length. F. Benabid
et al: Science 2002 298:399.
Related Background:
NONLINEAR AND QUANTUM ATOM OPTICS.
S.L. Rolston and W.D. Phillips (National Institute of Standards
and Technology, US) discuss nonlinear optics, the authors making
the following points:
1) Coherent matter waves in the form of Bose Einstein condensates
have led to the development of nonlinear and quantum atom optics
-- the de Broglie wave analogues of nonlinear and quantum optics
with light. In nonlinear atom optics, four-wave mixing of matter
waves and mixing of combinations of light and matter waves have
been observed; such progress culminated in the demonstration of
phase-coherent matter-wave amplification. Solitons represent
another active area in nonlinear atom optics: these non-
dispersing propagating modes of the equation that governs Bose
Einstein condensates have been created experimentally, and
observed subsequently to break up into vortices. Quantum atom
optics is concerned with the statistical properties and
correlations of matter-wave fields. A first step in this area is
the measurement of reduced number fluctuations in a Bose Einstein
condensate partitioned into a series of optical potential wells.
2) The advent of the laser in 1960 began a new era in optics,
eventually leading to numerous technological innovations, from
laser surgery to CD-ROMs. Laser light has a combination of high
coherence and high intensity that had been previously
unattainable. These properties represent a significant difference
from earlier light sources, and new kinds of phenomena became
possible. Among them were nonlinear optical phenomena and the
production of non-classical (that is, quantum) light. The
production of atomic-gas Bose Einstein condensates (BECs)(1,2)
brought a similar change in the optics of matter waves (atom
optics).
3) One of the first, qualitatively new experiments to follow the
appearance of the laser was second harmonic generation, or
frequency doubling(3). An intense pulse of red laser light
irradiated a transparent crystal and the emerging pulse included
a small amount of blue light, with twice the frequency (half the
wavelength) of the red light. The blue light arose because the
crystal responded nonlinearly to the electric field of the
incident laser (the index of refraction depends on the light
intensity). This and other nonlinear phenomena have made
nonlinear optics an important and exciting field of research for
the past 40 years4, with applications in physics, chemistry and
biology.(4,5)
References (abridged):
1. Anderson, M. H. et al. Observation of Bose-Einstein
condensation in a dilute atomic vapor. Science 269, 198-201
(1995).
2. Inguscio, M., Stringari, S. & Wieman, C. (eds) Bose-Einstein
Condensation in Atomic Gases(Int. School Phys. "Enrico Fermi"
Course 140) (IOS Press, Amsterdam, 1999).
3. Franken, P. A., Hill, A. E., Peters, C. W. & Weinreich, G.
Generation of optical harmonics. Phys. Rev. Lett. 7, 118-119
(1961).
4. Evans, M. & Kielich, S. Modern Nonlinear Optics Vols 1-3
(Wiley, New York, 1997).
5. Migdall, A. Correlated-photon metrology without absolute
standards. Phys. Today 52, 41-46 (1999).
Nature 2002 416:219
Related Background:
FOUR-WAVE MIXING WITH MATTER WAVES.
L. Deng et al (National Institutes of Standards and Technology,
US) discuss matter waves, the authors making the following
points:
1) The advent of the laser as an intense source of coherent light
gave rise to nonlinear optics, which now plays an important role
in many areas of science and technology. One of the first
applications of nonlinear optics was the multi-wave mixing(1,2)
of several optical fields in a nonlinear medium (one in which the
refractive index depends on the intensity of the field) to
produce coherent light of a new frequency. The recent
experimental realization of the matter-wave "laser"(3,4) -- based
on the extraction of coherent atoms from a Bose Einstein
condensate5 -- opens the way for analogous experiments with
intense sources of matter waves: nonlinear atom optics.
2) The authors report coherent four-wave mixing in which three
sodium matter waves of differing momenta mix to produce, by means
of nonlinear atom atom interactions, a fourth wave with new
momentum. The authors find a clear signature of a four-wave
mixing process in the dependence of the generated matter wave on
the densities of the input waves. The authors suggest their
results may ultimately facilitate the production and
investigation of quantum correlations between matter waves.(5)
References (abridged):
1. Franken, P. A., Hill, A. E., Peters, C. W. & Weinreich, G.
Generation of optical harmonics. Phys. Rev. Lett. 7, 118-119
(1961).
2. Maker, P. D. & Terhune, R. W. Study of optical effects due to
an induced polarization third order in the electric field
strength. Phys. Rev. 137A, A801-A818 (1965).
3. Mewes, M.-O. et al. Output coupler for Bose-Einstein condensed
atoms. Phys. Rev. Lett. 78, 582-585 (1997).
4. Hagley, E. W. et al. A well-collimated quasi-continuous atom
laser. Science 283, 1706-1709 (1999).
5. Anderson, M. H. et al. Observation of Bose-Einstein
condensation in a dilute atomic vapor. Science 269, 198-201
(1995).
Nature 1999 398:218
Related Background:
ON OPTICAL SOLITONS
J.C. Bronski et al (University of Illinois Urbana, US) discuss
optical solitons, the authors making the following points:
1) Research in optical solitons has its roots in two advances of
the 1960s: a) the development of the mathematical theory of
solitons starting in 1965, and b) the development of the laser.
These seemingly unrelated developments came together in 1973 with
the theoretical prediction of temporal optical solitons and their
experimental realization in 1980.
2) It is easiest to describe an optical soliton in the spatial
domain, where it is simply a self-guided wave. Consider an
optical beam as narrow as 10 optical wavelengths (approximately 5
microns for visible light). If such beam propagates in a linear
medium, it diffracts and broadens after even a short distance
(e.g., 1 millimeter). In a nonlinear material, light actually
changes the index of refraction of the medium in which it
propagates, leading to self-focusing. This self-focusing competes
with refractive effects, and at sufficient intensities can lead
to the development of a structure for which diffraction and self-
focusing exactly balance -- a soliton.
3) The field of optical solitons has greatly developed over the
past decade, and optical temporal solitons have become a
promising candidate for optical communication networks. At the
same time, optical spatial solitons have become one of the most
exciting research areas in optics and nonlinear science. Until
1995, all optical soliton experiments used a coherent "pulse",
but in 1996 researchers demonstrated the self-trapping of beams
in which the phase varied randomly. This incoherent wave-packet
self-trapped to form a localized nondiffracting beam, an
incoherent soliton. Further experiments demonstrated that white
light, which is both temporally and spatially incoherent, can
also self-trap.
Proc. Nat. Acad. Sci. 2001 98:12872
Related Background:
ON WAVE PHENOMENA IN PHYSICS
The idea of "wave" phenomena, the characterization of certain
phenomena as waves, must rank as one of the most important
concepts in both classical and modern physics. In general, a
"wave" is a time-varying quantity that is also a function of
position, a disturbance either continuous or transient, traveling
through a medium as a result of certain properties of the medium,
the resulting displacements of the medium returning to zero when
the disturbance has passed. The chief parameters of a wave are
its speed of propagation, its frequency, its wavelength, and its
amplitude.
J.A. Scales and R. Sneider (2 installations, US NL) present an
essay on waves in physics, the authors making the following
points:
1) The authors note that when scientists (including physicists)
are asked to define a wave, the answers are often ambiguous.
Students may state that a wave is a solution to the wave
equation; professionals may make some ambiguous statement about
propagation velocity; mathematicians tend to give a formal
characterization based on the hyperbolic character of certain
differential equations. The authors suggest that the term "wave"
be defined as an "organized propagating imbalance", with the
caveat: "Just don't ask us to define 'organized'."
2) The authors state that at the simplest levels, the ubiquity of
(classical) waves can be attributed to the desire of nature for
stable equilibria. Whatever the forces that connect bits of
matter together (e.g., electromagnetic or gravitational), for
small perturbations about a stable equilibrium point, the forces
are approximately linear. A linear restoring force implies
harmonic oscillations, and coupled systems of oscillators support
both propagating and standing disturbances. Linearity also
implies superposition, so that periodic solutions can be added
together to obtain finite wave "packets". Thus, for small
perturbations about an equilibrium state in coupled or decoupled
(extended) systems, waves are the natural consequence of the
stability of simple harmonic motion.
3) Wave propagation is in many situations described by a linear
differential equation. In reality, nonlinearity is of great
importance, and this nonlinearity may destroy the waves. When
this happens, organized wave motion changes into turbulent
motion, and in this process it is impossible to state exactly at
which point the wave ceases to be a wave.
4) Heat is the manifestation of microscopic motion. Computing the
classical resonant frequencies of atoms or molecules in a lattice
gives numbers of the order of 10^(13) Hz, i.e., in the infrared
part of the electromagnetic spectrum, so that when molecules
vibrate they produce heat. These lattice vibrations are called
"phonons", and they have both wave-like and particle-like
character. Lattice vibrations are responsible for the transport
of heat in a lattice, and we know that heat is a diffusive
phenomenon. However, if the lattice is cooled to near absolute
zero, the mean free scattering path of the phonons becomes
comparable to the macroscopic size of the sample, and when this
happens, lattice vibrations no longer behave diffusively but are
actually wave-like. By controlling the temperature of a sample,
one can control the extent to which heat is ballistic (wave-like)
or diffusive.
5) Waves have a central role in quantum mechanics, according to
which theory everything has a wave character. Einstein (1879-
1955) used the relation E = hf (energy equals Planck's constant
times frequency) to connect the wave frequency of light with the
energy of discrete light quanta (photons). De Broglie (1875-1960)
extended this to electrons and other entities of matter. For
classical waves, dissipation generally damps the wave motion, and
ultimately everything appears to come to rest. Quantum mechanics
demonstrates that matter waves do not exhibit dissipation: even
the ground state of a harmonic oscillator is in harmonic motion.
Matter waves never come to rest.
Nature 1999 401:739
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