bluuebunny/crossref_metadata_2025 huggingface dataset:
Dorsal-Ventral Signaling in the
Drosophila
Eye
Authors: Papayannopoulos Venizelos , Tomlinson Andrew , Panin Vladislav M. , Rauskolb Cordelia , Irvine Kenneth D.
Published: July 2002

The development of the
Drosophila
eye has served as a model system for investigations of tissue patterning and cell-cell communication; however, early eye development has not been well understood. The results presented here indicate that specialized cells are established along the dorsal-ventral midline of the developing eye by Notch-mediated signaling between dorsal and ventral cells, and that Notch activation at the midline plays an essential role both in promoting the growth of the eye primordia and in regulating eye patterning. These observations imply that the developmental homology between
Drosophila
wings and vertebrate limbs extends to
Drosophila
eyes.
Induction of Antigen-Specific Cytotoxic T Lymphocytes in Humans by a Malaria DNA Vaccine
Authors: Wang Ruobing , Doolan Denise L. , Le Thong P. , Hedstrom Richard C. , Coonan Kevin M. , Charoenvit Yupin , Jones Trevor R. , Hobart Peter , Margalith Michal , Ng Jennifer , Weiss Walter R. , Sedegah Martha , de Taisne Charles , A. Norman Jon , Hoffman Stephen L.
Published: July 2002

CD8
+
cytotoxic T lymphocytes (CTLs) are critical for protection against intracellular pathogens but often have been difficult to induce by subunit vaccines in animals. DNA vaccines elicit protective CD8
+
T cell responses. Malaria-naı̈ve volunteers who were vaccinated with plasmid DNA encoding a malaria protein developed antigen-specific, genetically restricted, CD8
+
T cell–dependent CTLs. Responses were directed against all 10 peptides tested and were restricted by six human lymphocyte antigen (HLA) class I alleles. This first demonstration in healthy naı̈ve humans of the induction of CD8
+
CTLs by DNA vaccines, including CTLs that were restricted by multiple HLA alleles in the same individual, provides a foundation for further human testing of this potentially revolutionary vaccine technology.
Differentiation of Monocytes into Dendritic Cells in a Model of Transendothelial Trafficking
Authors: Randolph Gwendalyn J. , Beaulieu Sylvie , Lebecque Serge , Steinman Ralph M. , Muller William A.
Published: July 2002

Essential to the dendritic cell system of antigen-presenting cells are the veiled dendritic cells that traverse afferent lymph to enter lymph nodes, where they initiate immune responses. The origin of veiled cells, which were discovered 20 years ago, is unclear. Monocytes cultured with endothelium differentiated into dendritic cells within 2 days, particularly after phagocytosing particles in subendothelial collagen. These nascent dendritic cells migrated across the endothelium in the ablumenal-to-lumenal direction, as would occur during entry into lymphatics. Monocytes that remained in the subendothelial matrix became macrophages. Therefore, monocytes have two potential fates associated with distinct patterns of migration.
Two Modes of Survival of Fission Yeast Without Telomerase
Authors: Nakamura Toru M. , Cooper Julia Promisel , Cech Thomas R.
Published: July 2002

Deletion of the telomerase catalytic subunit gene
trt1
+
in
Schizosaccharomyces pombe
results in death for the majority of cells, but a subpopulation survives. Here it is shown that most survivors have circularized all of their chromosomes, whereas a smaller number maintain their telomeres presumably through recombination. When the telomeric DNA-binding gene
taz1
+
is also deleted,
trt1
−
taz1
−
survivors use the recombinational mode more frequently. Moreover, the massive elongation of telomeres in
taz1
−
cells is absent in the double mutant. Thus, Taz1p appears to regulate telomeric recombination as well as telomerase activity in fission yeast.
Carbon Structures with Three-Dimensional Periodicity at Optical Wavelengths
Authors: Zakhidov Anvar A. , Baughman Ray H. , Iqbal Zafar , Cui Changxing , Khayrullin Ilyas , Dantas Socrates O. , Marti Jordi , Ralchenko Victor G.
Published: July 2002

Porous carbons that are three-dimensionally periodic on the scale of optical wavelengths were made by a synthesis route resembling the geological formation of natural opal. Porous silica opal crystals were sintered to form an intersphere interface through which the silica was removed after infiltration with carbon or a carbon precursor. The resulting porous carbons had different structures depending on synthesis conditions. Both diamond and glassy carbon inverse opals resulted from volume filling. Graphite inverse opals, comprising 40-angstrom-thick layers of graphite sheets tiled on spherical surfaces, were produced by surface templating. The carbon inverse opals provide examples of both dielectric and metallic optical photonic crystals. They strongly diffract light and may provide a route toward photonic band-gap materials.
Force and Velocity Measured for Single Molecules of RNA Polymerase
Authors: Wang Michelle D. , Schnitzer Mark J. , Yin Hong , Landick Robert , Gelles Jeff , Block Steven M.
Published: July 2002

RNA polymerase (RNAP) moves along DNA while carrying out transcription, acting as a molecular motor. Transcriptional velocities for single molecules of
Escherichia coli
RNAP were measured as progressively larger forces were applied by a feedback-controlled optical trap. The shapes of RNAP force-velocity curves are distinct from those of the motor enzymes myosin or kinesin, and indicate that biochemical steps limiting transcription rates at low loads do not generate movement. Modeling the data suggests that high loads may halt RNAP by promoting a structural change which moves all or part of the enzyme backwards through a comparatively large distance, corresponding to 5 to 10 base pairs. This contrasts with previous models that assumed force acts directly upon a single-base translocation step.
Statistics, Fast and Easy
Authors: Wass John
Published: July 2002

InStat 3.0
. GraphPad Software, Inc. San Diego, CA. $119, $149 (bundle), $179 (bundle with book). (619) 457-3909.
www.graphpad.com

In this review, Wass describes InStat 3.0, easy to use software that teaches the basics of statistics to an undergraduate or serves as a workhorse for straightforward statistical analysis in research laboratories.
In Situ Measurements of Organics, Meteoritic Material, Mercury, and Other Elements in Aerosols at 5 to 19 Kilometers
Authors: Murphy D. M. , Thomson D. S. , Mahoney M. J.
Published: July 2002

In situ measurements of the chemical composition of individual aerosol particles at altitudes between 5 and 19 kilometers reveal that upper tropospheric aerosols often contained more organic material than sulfate. Although stratospheric aerosols primarily consisted of sulfuric acid and water, many also contained meteoritic material. Just above the tropopause, small amounts of mercury were found in over half of the aerosol particles that were analyzed. Overall, there was tremendous variety in aerosol composition. One measure of this diversity is that at least 45 elements were detected in aerosol particles. These results have wide implications for the complexity of aerosol sources and chemistry. They also offer possibilities for understanding the transport of atmospheric aerosols.
Regulation of Cocaine Reward by CREB
Authors: Carlezon William A. , Thome Johannes , Olson Valerie G. , Lane-Ladd Sarah B. , Brodkin Edward S. , Hiroi Noboru , Duman Ronald S. , Neve Rachael L. , Nestler Eric J.
Published: July 2002

Cocaine regulates the transcription factor CREB (adenosine 3′,5′-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of κ opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade—culminating in gene expression—through which exposure to cocaine modifies subsequent responsiveness to the drug.
CD1d-Restricted Immunoglobulin G Formation to GPI-Anchored Antigens Mediated by NKT Cells
Authors: Schofield Louis , McConville Malcolm J. , Hansen Diana , Campbell A. Stewart , Fraser-Reid Bert , Grusby Michael J. , Tachado Souvenir D.
Published: July 2002

Immunoglobulin G (IgG) responses require major histocompatibility complex (MHC)–restricted recognition of peptide fragments by conventional CD4
+
helper T cells. Immunoglobulin G responses to glycosylphosphatidylinositol (GPI)- anchored protein antigens, however, were found to be regulated in part through CD1d-restricted recognition of the GPI moiety by thymus-dependent, interleukin-4–producing CD4
+
, natural killer cell antigen 1.1 [(NK1.1)
+
] helper T cells. The CD1-NKT cell pathway regulated immunogobulin G responses to the GPI-anchored surface antigens of
Plasmodium
and
Trypanosoma
and may be a general mechanism for rapid, MHC-unrestricted antibody responses to diverse pathogens.
Turning Brain into Blood: A Hematopoietic Fate Adopted by Adult Neural Stem Cells in Vivo
Authors: Bjornson Christopher R. R. , Rietze Rodney L. , Reynolds Brent A. , Magli M. Cristina , Vescovi Angelo L.
Published: July 2002

Stem cells are found in various organs where they participate in tissue homeostasis by replacing differentiated cells lost to physiological turnover or injury. An investigation was performed to determine whether stem cells are restricted to produce specific cell types, namely, those from the tissue in which they reside. After transplantation into irradiated hosts, genetically labeled neural stem cells were found to produce a variety of blood cell types including myeloid and lymphoid cells as well as early hematopoietic cells. Thus, neural stem cells appear to have a wider differentiation potential than previously thought.
Chlamydia
Infections and Heart Disease Linked Through Antigenic Mimicry
Authors: Bachmaier Kurt , Neu Nikolaus , de la Maza Luis M. , Pal Sukumar , Hessel Andrew , Penninger Josef M.
Published: July 2002

Chlamydia
infections are epidemiologically linked to human heart disease. A peptide from the murine heart muscle–specific α myosin heavy chain that has sequence homology to the 60-kilodalton cysteine-rich outer membrane proteins of
Chlamydia pneumoniae
,
C. psittaci
, and
C. trachomatis
was shown to induce autoimmune inflammatory heart disease in mice. Injection of the homologous
Chlamydia
peptides into mice also induced perivascular inflammation, fibrotic changes, and blood vessel occlusion in the heart, as well as triggering T and B cell reactivity to the homologous endogenous heart muscle–specific peptide.
Chlamydia
DNA functioned as an adjuvant in the triggering of peptide-induced inflammatory heart disease. Infection with
C. trachomatis
led to the production of autoantibodies to heart muscle–specific epitopes. Thus,
Chlamydia
-mediated heart disease is induced by antigenic mimicry of a heart muscle–specific protein.
Prion Domain Initiation of Amyloid Formation in Vitro from Native Ure2p
Authors: Taylor Kimberly L. , Cheng Naiqian , Williams Robert W. , Steven Alasdair C. , Wickner Reed B.
Published: July 2002

The [URE3] non-Mendelian genetic element of
Saccharomyces cerevisiae
is an infectious protein (prion) form of Ure2p, a regulator of nitrogen catabolism. Here, synthetic Ure2p
1−65
were shown to polymerize to form filaments 40 to 45 angstroms in diameter with more than 60 percent β sheet. Ure2p
1−65
specifically induced full-length native Ure2p to copolymerize under conditions where native Ure2p alone did not polymerize. Like Ure2p in extracts of [URE3] strains, these 180- to 220-angstrom-diameter filaments were protease resistant. The Ure2p
1−65
-Ure2p cofilaments could seed polymerization of native Ure2p to form thicker, less regular filaments. All filaments stained with Congo Red to produce the green birefringence typical of amyloid. This self-propagating amyloid formation can explain the properties of [URE3].
Mantle Values of Thermal Conductivity and the Geotherm from Phonon Lifetimes
Authors: Hofmeister A. M.
Published: July 2002

A model for thermal conductivity κ, based on phonon lifetimes obtained from infrared reflectivity, replicates experimental data at ambient conditions. The pressure and absolute temperature dependences of transport properties are accurately obtained from the Grüneisen parameter γ
Th
, bulk modulus
K
T
, and thermal expansivity α: The lattice contribution κ
lat
equals κ
298
(298/
T
)

a

exp[−(4γ
Th
+ 1/3) ∫
298

T

α(θ)
d
θ] with
a
= 0.33 for silicates (or 0.9 for MgO), and ∂[ln(κ
lat
)]/∂
P
= (1/3 + 4γ
Th
)/
K
T
. The smaller, pressure-independent radiative contribution κ
rad
equals 0.0175 – 0.0001037
T
+ (2.245
T
2
/10
7
) – (3.407
T
3
/10
11
), in units of watts per meter-kelvin, if Fe
2+
is present. The resulting lithospheric geotherm is steep. Consequently, the mantle geotherm is hot if the low-velocity zone is anhydrous, but cold if hydrated.
Motor Cortical Encoding of Serial Order in a Context-Recall Task
Authors: Carpenter Adam F. , Georgopoulos Apostolos P. , Pellizzer Giuseppe
Published: July 2002

The neural encoding of serial order was studied in the motor cortex of monkeys performing a context-recall memory scanning task. Up to five visual stimuli were presented successively on a circle (list presentation phase), and then one of them (test stimulus) changed color; the monkeys had to make a single motor response toward the stimulus that immediately followed the test stimulus in the list. Correct performance in this task depends on memorization of the serial order of the stimuli during their presentation. It was found that changes in neural activity during the list presentation phase reflected the serial order of the stimuli; the effect on cell activity of the serial order of stimuli during their presentation was at least as strong as the effect of motor direction on cell activity during the execution of the motor response. This establishes the serial order of stimuli in a motor task as an important determinant of motor cortical activity during stimulus presentation and in the absence of changes in peripheral motor events, in contrast to the commonly held view of the motor cortex as just an “upper motor neuron.”
Vancomycin Derivatives That Inhibit Peptidoglycan Biosynthesis Without Binding
d
-Ala-
d
-Ala
Authors: Ge Min , Chen Zhong , Russell H. , Onishi  , Kohler Joyce , Silver Lynn L. , Kerns Robert , Fukuzawa Seketsu , Thompson Christopher , Kahne Daniel
Published: July 2002

Vancomycin is an important drug for the treatment of Gram-positive bacterial infections. Resistance to vancomycin has begun to appear, posing a serious public health threat. Vancomycin analogs containing modified carbohydrates are very active against resistant microorganisms. Results presented here show that these carbohydrate derivatives operate by a different mechanism than vancomycin; moreover, peptide binding is not required for activity. It is proposed that carbohydrate-modified vancomycin compounds are effective against resistant bacteria because they interact directly with bacterial proteins involved in the transglycosylation step of cell wall biosynthesis. These results suggest new strategies for designing glycopeptide antibiotics that overcome bacterial resistance.
Quantum Annealing of a Disordered Magnet
Authors: Brooke J. , Bitko D. , F. T. , Rosenbaum  , Aeppli G.
Published: July 2002

Traditional simulated annealing uses thermal fluctuations for convergence in optimization problems. Quantum tunneling provides a different mechanism for moving between states, with the potential for reduced time scales. Thermal and quantum annealing are compared in a model disordered magnet, where the effects of quantum mechanics can be tuned by varying an applied magnetic field. The results indicate that quantum annealing hastens convergence to the optimum state.
Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice
Authors: Bergers Gabriele , Javaherian Kashi , Lo Kin-Ming , Folkman Judah , Hanahan Douglas
Published: July 2002

Solid tumors depend on angiogenesis for their growth. In a transgenic mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), an angiogenic switch occurs in premalignant lesions, and angiogenesis persists during progression to expansive solid tumors and invasive carcinomas. RIP1-Tag2 mice were treated so as to compare the effects of four angiogenesis inhibitors at three distinct stages of disease progression. AGM-1470, angiostatin, BB-94, and endostatin each produced distinct efficacy profiles in trials aimed at preventing the angiogenic switch in premalignant lesions, intervening in the rapid expansion of small tumors, or inducing the regression of large end-stage cancers. Thus, anti-angiogenic drugs may prove most efficacious when they are targeted to specific stages of cancer.
A Post-Stishovite SiO
2
Polymorph in the Meteorite Shergotty: Implications for Impact Events
Authors: Sharp T. G. , Goresy A. El , Wopenka B. , Chen M.
Published: July 2002

Transmission electron microscopy and electron diffraction show that the martian meteorite Shergotty, a shocked achondrite, contains a dense orthorhombic SiO
2
phase similar to post-stishovite SiO
2
with the α-PbO
2
structure. If an SiO
2
mineral exists in Earth's lower mantle, it would probably occur in a post-stishovite SiO
2
structure. The presence of such a high-density polymorph in a shocked sample indicates that post-stishovite SiO
2
structures may be used as indicators of extreme shock pressures.
Selfish Sentinels in Cooperative Mammals
Authors: Clutton-Brock T. H. , O'Riain M. J. , Brotherton P. N. M. , Gaynor D. , Kansky R. , Griffin A. S. , Manser M.
Published: July 2002

Like humans engaged in risky activities, group members of some animal societies take turns acting as sentinels. Explanations of the evolution of sentinel behavior have frequently relied on kin selection or reciprocal altruism, but recent models suggest that guarding may be an individual's optimal activity once its stomach is full if no other animal is on guard. This paper provides support for this last explanation by showing that, in groups of meerkats (
Suricata suricatta
), animals guard from safe sites, and solitary individuals as well as group members spend part of their time on guard. Though individuals seldom take successive guarding bouts, there is no regular rota, and the provision of food increases contributions to guarding and reduces the latency between bouts by the same individual.
Math1
: An Essential Gene for the Generation of Inner Ear Hair Cells
Authors: Bermingham Nessan A. , Hassan Bassem A. , Price Steven D. , Vollrath Melissa A. , Ben-Arie Nissim , Eatock Ruth Anne , Bellen Hugo J. , Lysakowski Anna , Zoghbi Huda Y.
Published: July 2002

The mammalian inner ear contains the cochlea and vestibular organs, which are responsible for hearing and balance, respectively. The epithelia of these sensory organs contain hair cells that function as mechanoreceptors to transduce sound and head motion. The molecular mechanisms underlying hair cell development and differentiation are poorly understood.
Math1
, a mouse homolog of the
Drosophila
proneural gene
atonal
, is expressed in inner ear sensory epithelia. Embryonic
Math1
-null mice failed to generate cochlear and vestibular hair cells. This gene is thus required for the genesis of hair cells.
Crystal Structure of the Zα Domain of the Human Editing Enzyme ADAR1 Bound to Left-Handed Z-DNA
Authors: Schwartz Thomas , Rould Mark A. , Lowenhaupt Ky , Herbert Alan , Rich Alexander
Published: July 2002

The editing enzyme double-stranded RNA adenosine deaminase includes a DNA binding domain, Zα, which is specific for left-handed Z-DNA. The 2.1 angstrom crystal structure of Zα complexed to DNA reveals that the substrate is in the left-handed Z conformation. The contacts between Zα and Z-DNA are made primarily with the “zigzag” sugar-phosphate backbone, which provides a basis for the specificity for the Z conformation. A single base contact is observed to guanine in the syn conformation, characteristic of Z-DNA. Intriguingly, the helix-turn-helix motif, frequently used to recognize B-DNA, is used by Zα to contact Z-DNA.
Contribution of Disturbance to Increasing Seasonal Amplitude of Atmospheric CO
2
Authors: Zimov S. A. , Davidov S. P. , Zimova G. M. , Davidova A. I. , Chapin F. S. , Chapin M. C. , Reynolds J. F.
Published: July 2002

Recent increases in the seasonal amplitude of atmospheric carbon dioxide (CO
2
) at high latitudes suggest a widespread biospheric response to high-latitude warming. The seasonal amplitude of net ecosystem carbon exchange by northern Siberian ecosystems is shown to be greater in disturbed than undisturbed sites, due to increased summer influx and increased winter efflux. Increased disturbance could therefore contribute significantly to the amplified seasonal cycle of atmospheric carbon dioxide at high latitudes. Warm temperatures reduced summer carbon influx, suggesting that high-latitude warming, if it occurred, would be unlikely to increase seasonal amplitude of carbon exchange.
Role of Fluids in Faulting Inferred from Stress Field Signatures
Authors: Hardebeck Jeanne L. , Hauksson Egill
Published: July 2002

The stress orientation signature of weak faults containing high-pressure fluids has been observed for segments of the San Andreas fault system in southern California. The inferred lithostatic fluid pressures extend into the surrounding relatively intact rock in a zone scaling with the width of the interseismic strain accumulation. Repeated strain-related fracturing and crack sealing may have created low-permeability barriers that seal fluids into the network of currently active fractures.
Gene Discovery and Product Development for Grain Quality Traits
Authors: Mazur Barbara , Krebbers Enno , Tingey Scott
Published: July 2002

The composition of oils, proteins, and carbohydrates in seeds of corn, soybean, and other crops has been modified to produce grains with enhanced value. Both plant breeding and molecular technologies have been used to produce plants carrying the desired traits. Genomics-based strategies for gene discovery, coupled with high-throughput transformation processes and miniaturized, automated analytical and functionality assays, have accelerated the identification of product candidates. Molecular marker–based breeding strategies have been used to accelerate the process of moving trait genes into high-yielding germplasm for commercialization. These products are being tested for applications in food, feed, and industrial markets.
Quaternary Structure of the Insulin-Insulin Receptor Complex
Authors: Luo Robert Z.-T. , Beniac Daniel R. , Fernandes Allan , Yip Cecil C. , Ottensmeyer F. P.
Published: July 2002

The three-dimensional (3D) structure of the intrinsically dimeric insulin receptor bound to its ligand, insulin, was determined by electron cryomicroscopy. Gold-labeled insulin served to locate the insulin-binding domain. The 3D structure was then fitted with available known high-resolution domain substructures to obtain a detailed contiguous model for this heterotetrameric transmembrane receptor. The 3D reconstruction indicates that the two α subunits jointly participate in insulin binding and that the kinase domains in the two β subunits are in a juxtaposition that permits autophosphorylation of tyrosine residues in the first step of insulin receptor activation.
Acute Activation of Maxi-K Channels (
hSlo
) by Estradiol Binding to the β Subunit
Authors: Valverde Miguel A. , Rojas Patricio , Amigo Julio , Cosmelli Diego , Orio Patricio , Bahamonde Maria I. , Mann Giovanni E. , Vergara Cecilia , Latorre Ramon
Published: July 2002

Maxi-K channels consist of a pore-forming α subunit and a regulatory β subunit, which confers the channel with a higher Ca
2+
sensitivity. Estradiol bound to the β subunit and activated the Maxi-K channel (
hSlo
) only when both α and β subunits were present. This activation was independent of the generation of intracellular signals and could be triggered by estradiol conjugated to a membrane-impenetrable carrier protein. This study documents the direct interaction of a hormone with a voltage-gated channel subunit and provides the molecular mechanism for the modulation of vascular smooth muscle Maxi-K channels by estrogens.
Drosophila
S6 Kinase: A Regulator of Cell Size
Authors: Montagne Jacques , Stewart Mary J. , Stocker Hugo , Hafen Ernst , Kozma Sara C. , Thomas George
Published: July 2002

Cell proliferation requires cell growth; that is, cells only divide after they reach a critical size. However, the mechanisms by which cells grow and maintain their appropriate size have remained elusive.
Drosophila
deficient in the
S6 kinase
gene (
dS6K
) exhibited an extreme delay in development and a severe reduction in body size. These flies had smaller cells rather than fewer cells. The effect was cell-autonomous, displayed throughout larval development, and distinct from that of ribosomal protein mutants (
Minutes
). Thus, the
dS6K
gene product regulates cell size in a cell-autonomous manner without impinging on cell number.
Evidence of Nonlinear Elasticity of the Crust from the Mw7.6 Manyi (Tibet) Earthquake
Authors: Peltzer Gilles , Crampé Frédéric , King Geoffrey
Published: July 2002

Satellite synthetic aperture radar (SAR) interferometry shows that the magnitude 7.6 Manyi earthquake of 8 November 1997 produced a 170-kilometer-long surface break with up to 7 meters of left-lateral slip, reactivating a N76°E quaternary fault in western Tibet. The radar interferometric map reveals asymmetric, along-strike displacement profiles between the two sides of the surface rupture, a pattern that cannot be explained with linear elastic theory. This observation suggests that the elastic moduli of the crust in tension and in compression are different because of the presence of cracks in the crust at shallow depth. A model indicates that a ratio of 2 between compressive and tensile elastic moduli can account for the observed asymmetry, a ratio that is consistent with laboratory and borehole measurements.
The Presenilins in Alzheimer's Disease--Proteolysis Holds the Key
Authors: Haass Christian , Strooper Bart De
Published: July 2002

Alzheimer's disease (AD) research has shown that patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-β (the primary component of the amyloid deposits found in AD brains). However, it is not clear how the presenilins contribute to this increase. New findings now show that the presenilins affect APP processing through their effects on γ-secretase, an enzyme that cleaves APP. Also, it is known that the presenilins are involved in the cleavage of the Notch receptor, hinting that they either directly regulate γ-secretase activity or themselves are protease enzymes. These findings suggest that the presenilins may prove to be valuable molecular targets for the development of drugs to combat AD.
Abrupt Climate Change at the End of the Last Glacial Period Inferred from Trapped Air in Polar Ice
Authors: Severinghaus Jeffrey P. , Brook Edward J.
Published: July 2002

The last glacial period was terminated by an abrupt warming event in the North Atlantic ∼15,000 years before the present, and warming events of similar age have been reported from low latitudes. Understanding the mechanism of this termination requires that the precise relative timing of abrupt climate warming in the tropics versus the North Atlantic be known. Nitrogen and argon isotopes in trapped air in Greenland ice show that the Greenland Summit warmed 9 ± 3°C over a period of several decades, beginning 14,672 years ago. Atmospheric methane concentrations rose abruptly over a ∼50-year period and began their increase 20 to 30 years after the onset of the abrupt Greenland warming. These data suggest that tropical climate became warmer or wetter (or both) ∼20 to 80 years after the onset of Greenland warming, supporting a North Atlantic rather than a tropical trigger for the climate event.
Calmodulin Dependence of Presynaptic Metabotropic Glutamate Receptor Signaling
Authors: O'Connor Vincent , Far Oussama El , Bofill-Cardona Elisa , Nanoff Christian , Freissmuth Michael , Karschin Andreas , Airas José M. , Betz Heinrich , Boehm Stefan
Published: July 2002

Glutamatergic neurotransmission is controlled by presynaptic metabotropic glutamate receptors (mGluRs). A subdomain in the intracellular carboxyl-terminal tail of group III mGluRs binds calmodulin and heterotrimeric guanosine triphosphate–binding protein (G protein) βγ subunits in a mutually exclusive manner. Mutations interfering with calmodulin binding and calmodulin antagonists inhibit G protein–mediated modulation of ionic currents by mGluR 7. Calmodulin antagonists also prevent inhibition of excitatory neurotransmission via presynaptic mGluRs. These results reveal a novel mechanism of presynaptic modulation in which Ca
2+
-calmodulin is required to release G protein βγ subunits from the C-tail of group III mGluRs in order to mediate glutamatergic autoinhibition.
Enhancement of Interdecadal Climate Variability in the Sahel by Vegetation Interaction
Authors: Zeng Ning , Neelin J. David , Lau K.-M. , Tucker Compton J.
Published: July 2002

The role of naturally varying vegetation in influencing the climate variability in the West African Sahel is explored in a coupled atmosphere–land-vegetation model. The Sahel rainfall variability is influenced by sea-surface temperature variations in the oceans. Land-surface feedback is found to increase this variability both on interannual and interdecadal time scales. Interactive vegetation enhances the interdecadal variation substantially but can reduce year-to-year variability because of a phase lag introduced by the relatively slow vegetation adjustment time. Variations in vegetation accompany the changes in rainfall, in particular the multidecadal drying trend from the 1950s to the 1980s.
Pressure Effect on Hydrogen Isotope Fractionation Between Brucite and Water at Elevated Temperatures
Authors: Horita Juske , Driesner Thomas , Cole David R.
Published: July 2002

Experimental evidence for a pressure effect on isotopic partitioning at elevated temperatures demonstrates that equilibrium deuterium-protium fractionation between the mineral brucite [Mg(OH)
2
] and pure water systematically increases by 12.4 per mil as pressure increases from 15 to 800 megapascals at 380°C. A linear relation is observed between the measured fractionation factor and the density of water (0.070 to 1.035 grams per cubic centimeter). The trend of the isotope pressure effect is the same as that of recent theoretical studies, but the magnitude is smaller. The pressure effect must be accounted for in the interpretation of isotopic data of geologic systems involving water (paleotemperature, source of fluids).
Increased Cortical Oxidative Metabolism Due to Sensory Stimulation: Implications for Functional Brain Imaging
Authors: Vanzetta Ivo , Grinvald Amiram
Published: July 2002

Modern functional brain mapping relies on interactions of neuronal electrical activity with the cortical microcirculation. The existence of a highly localized, stimulus-evoked initial deoxygenation has remained a controversy. Here, the activity-dependent oxygen tension changes in the microcirculation were measured directly, using oxygen-dependent phosphorescence quenching of an exogenous indicator. The first event after sensory stimulation was an increase in oxygen consumption, followed by an increase in blood flow. Because oxygen consumption and neuronal activity are colocalized but the delayed blood flow is not, functional magnetic resonance imaging focused on this initial phase will yield much higher spatial resolution, ultimately enabling the noninvasive visualization of fundamental processing modules in the human brain.
Quality Control Mechanisms During Translation
Authors: Ibba Michael , Söll and Dieter
Published: July 2002

Translation uses the genetic information in messenger RNA (mRNA) to synthesize proteins. Transfer RNAs (tRNAs) are charged with an amino acid and brought to the ribosome, where they are paired with the corresponding trinucleotide codon in mRNA. The amino acid is attached to the nascent polypeptide and the ribosome moves on to the next codon. The cycle is then repeated to produce a full-length protein. Proofreading and editing processes are used throughout protein synthesis to ensure the faithful translation of genetic information. The maturation of tRNAs and mRNAs is monitored, as is the identity of amino acids attached to tRNAs. Accuracy is further enhanced during the selection of aminoacyl-tRNAs on the ribosome and their base pairing with mRNA. Recent studies have begun to reveal the molecular mechanisms underpinning quality control and go some way to explaining the phenomenal accuracy of translation first observed over three decades ago.
The Crystal Structure of a T Cell Receptor in Complex with Peptide and MHC Class II
Authors: Reinherz Ellis L. , Tan Kemin , Tang Lei , Kern Petra , Liu Jin-huan , Xiong Yi , Hussey Rebecca E. , Smolyar Alex , Hare Brian , Zhang Rongguang , Joachimiak Andrzej , Chang Hsiu-Ching , Wagner Gerhard , Wang Jia-huai
Published: July 2002

The crystal structure of a complex involving the D10 T cell receptor (TCR), 16-residue foreign peptide antigen, and the I-A
k
self major histocompatibility complex (MHC) class II molecule is reported at 3.2 angstrom resolution. The D10 TCR is oriented in an orthogonal mode relative to its peptide-MHC (pMHC) ligand, necessitated by the amino-terminal extension of peptide residues projecting from the MHC class II antigen–binding groove as part of a mini β sheet. Consequently, the disposition of D10 complementarity-determining region loops is altered relative to that of most pMHCI-specific TCRs; the latter TCRs assume a diagonal orientation, although with substantial variability. Peptide recognition, which involves P–1 to P8 residues, is dominated by the Vα domain, which also binds to the class II MHC β
1
helix. That docking is limited to one segment of MHC-bound peptide offers an explanation for epitope recognition and altered peptide ligand effects, suggests a structural basis for alloreactivity, and illustrates how bacterial superantigens can span the TCR-pMHCII surface.
Structural Basis of Smad2 Recognition by the Smad Anchor for Receptor Activation
Authors: Wu Geng , Chen Ye-Guang , Ozdamar Barish , Gyuricza Cassie A. , Chong P. Andrew , Wrana Jeffrey L. , Massagué Joan , Shi Yigong
Published: July 2002

The Smad proteins mediate transforming growth factor–β (TGFβ) signaling from the transmembrane serine-threonine receptor kinases to the nucleus. The Smad anchor for receptor activation (SARA) recruits Smad2 to the TGFβ receptors for phosphorylation. The crystal structure of a Smad2 MH2 domain in complex with the Smad-binding domain (SBD) of SARA has been determined at 2.2 angstrom resolution. SARA SBD, in an extended conformation comprising a rigid coil, an α helix, and a β strand, interacts with the β sheet and the three-helix bundle of Smad2. Recognition between the SARA rigid coil and the Smad2 β sheet is essential for specificity, whereas interactions between the SARA β strand and the Smad2 three-helix bundle contribute significantly to binding affinity. Comparison of the structures between Smad2 and a comediator Smad suggests a model for how receptor-regulated Smads are recognized by the type I receptors.
A Role for Nuclear Inositol 1,4,5-Trisphosphate Kinase in Transcriptional Control
Authors: Odom Audrey R. , Stahlberg Alke , Wente Susan R. , York John D.
Published: July 2002

Phospholipase C and two inositol polyphosphate (IP) kinases constitute a signaling pathway that regulates nuclear messenger RNA export through production of inositol hexakisphosphate (IP
6
). The inositol 1,4,5-trisphosphate kinase of this pathway in
Saccharomyces cerevisiae
, designated Ipk2, was found to be identical to Arg82, a regulator of the transcriptional complex ArgR-Mcm1. Synthesis of inositol 1,4,5,6-tetrakisphosphate, but not IP
6
, was required for gene regulation through ArgR-Mcm1. Thus, the phospholipase C pathway produces multiple IP messengers that modulate distinct nuclear processes. The results reveal a direct mechanism by which activation of IP signaling may control gene expression.
Driving AMPA Receptors into Synapses by LTP and CaMKII: Requirement for GluR1 and PDZ Domain Interaction
Authors: Hayashi Yasunori , Shi Song-Hai , Esteban José A. , Piccini Antonella , Poncer Jean-Christophe , Malinow Roberto
Published: July 2002

To elucidate mechanisms that control and execute activity-dependent synaptic plasticity, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) with an electrophysiological tag were expressed in rat hippocampal neurons. Long-term potentiation (LTP) or increased activity of the calcium/calmodulin-dependent protein kinase II (CaMKII) induced delivery of tagged AMPA-Rs into synapses. This effect was not diminished by mutating the CaMKII phosphorylation site on the GluR1 AMPA-R subunit, but was blocked by mutating a predicted PDZ domain interaction site. These results show that LTP and CaMKII activity drive AMPA-Rs to synapses by a mechanism that requires the association between GluR1 and a PDZ domain protein.
Motility Powered by Supramolecular Springs and Ratchets
Authors: Mahadevan L. , Matsudaira P.
Published: July 2002

Not all biological movements are caused by molecular motors sliding along filaments or tubules. Just as springs and ratchets can store or release energy and rectify motion in physical systems, their analogs can perform similar functions in biological systems. The energy of biological springs is derived from hydrolysis of a nucleotide or the binding of a ligand, whereas biological ratchets are powered by Brownian movements of polymerizing filaments. However, the viscous and fluctuating cellular environment and the mechanochemistry of soft biological systems constrain the modes of motion generated and the mechanisms for energy storage, control, and release.
Extension of Cell Life-Span and Telomere Length in Animals Cloned from Senescent Somatic Cells
Authors: Lanza Robert P. , Cibelli Jose B. , Blackwell Catherine , Cristofalo Vincent J. , Francis Mary Kay , Baerlocher Gabriela M. , Mak Jennifer , Schertzer Michael , Chavez Elizabeth A. , Sawyer Nancy , Lansdorp Peter M. , West Michael D.
Published: July 2002

The potential of cloning depends in part on whether the procedure can reverse cellular aging and restore somatic cells to a phenotypically youthful state. Here, we report the birth of six healthy cloned calves derived from populations of senescent donor somatic cells. Nuclear transfer extended the replicative life-span of senescent cells (zero to four population doublings remaining) to greater than 90 population doublings. Early population doubling level complementary DNA-1 (EPC-1, an age-dependent gene) expression in cells from the cloned animals was 3.5- to 5-fold higher than that in cells from age-matched (5 to 10 months old) controls. Southern blot and flow cytometric analyses indicated that the telomeres were also extended beyond those of newborn (<2 weeks old) and age-matched control animals. The ability to regenerate animals and cells may have important implications for medicine and the study of mammalian aging.
Granuloma-Specific Expression of Mycobacterium Virulence Proteins from the Glycine-Rich PE-PGRS Family
Authors: Ramakrishnan Lalita , Federspiel Nancy A. , Falkow Stanley
Published: July 2002

Pathogenic mycobacteria, including the agent of tuberculosis,
Mycobacterium tuberculosis
, must replicate in macrophages for long-term persistence within their niche during chronic infection: organized collections of macrophages and lymphocytes called granulomas. We identified several genes preferentially expressed when
Mycobacterium marinum
, the cause of fish and amphibian tuberculosis, resides in host granulomas and/or macrophages. Two were homologs of
M. tuberculosis
PE/PE-PGRS genes, a family encoding numerous repetitive glycine-rich proteins of unknown function. Mutation of two PE-PGRS genes produced
M. marinum
strains incapable of replication in macrophages and with decreased persistence in granulomas. Our results establish a direct role in virulence for some PE-PGRS proteins.
A Subset of Viral Transcripts Packaged Within Human Cytomegalovirus Particles
Authors: Bresnahan Wade A. , Shenk Thomas
Published: July 2002

A human cytomegalovirus gene array was used to identify a previously unidentified class of viral transcripts. These transcripts, termed virion RNAs, were packaged within infectious virions and were delivered to the host cell on infection. This mechanism of herpesvirus gene expression allows for viral genes to be expressed within an infected cell immediately after virus entry and in the absence of transcription from the viral genome.
The Role of GTP-Binding Protein Activity in Fast Central Synaptic Transmission
Authors: Takahashi Tomoyuki , Hori Tetsuya , Kajikawa Yoshinao , Tsujimoto Tetsuhiro
Published: July 2002

Guanosine 5′-triphosphate (GTP)–binding proteins (G proteins) are involved in exocytosis, endocytosis, and recycling of vesicles in yeast and mammalian secretory cells. However, little is known about their contribution to fast synaptic transmission. We loaded guanine nucleotide analogs directly into a giant nerve terminal in rat brainstem slices. Inhibition of G-protein activity had no effect on basal synaptic transmission, but augmented synaptic depression and significantly slowed recovery from depression. A nonhydrolyzable GTP analog blocked recovery of transmission from activity-dependent depression. Neither effect was accompanied by a change in presynaptic calcium currents. Thus, G proteins contribute to fast synaptic transmission by refilling synaptic vesicles depleted after massive exocytosis.
PAX8-PPAR
γ
1
Fusion in Oncogene Human Thyroid Carcinoma
Authors: Kroll Todd G. , Sarraf Pasha , Pecciarini Lorenza , Chen Chang-Jie , Mueller Elisabetta , Spiegelman Bruce M. , Fletcher Jonathan A.
Published: July 2002

Chromosomal translocations that encode fusion oncoproteins have been observed consistently in leukemias/lymphomas and sarcomas but not in carcinomas, the most common human cancers. Here, we report that t(2;3)(q13;p25), a translocation identified in a subset of human thyroid follicular carcinomas, results in fusion of the DNA binding domains of the thyroid transcription factor PAX8 to domains A to F of the peroxisome proliferator–activated receptor (PPAR) γ1. PAX8-PPARγ1 mRNA and protein were detected in 5 of 8 thyroid follicular carcinomas but not in 20 follicular adenomas, 10 papillary carcinomas, or 10 multinodular hyperplasias. PAX8-PPARγ1 inhibited thiazolidinedione-induced transactivation by PPARγ1 in a dominant negative manner. The experiments demonstrate an oncogenic role for PPARγ and suggest that PAX8-PPARγ1 may be useful in the diagnosis and treatment of thyroid carcinoma.
Regulated Cleavage of a Contact-Mediated Axon Repellent
Authors: Hattori Mitsuharu , Osterfield Miriam , Flanagan John G.
Published: July 2002

Contact-mediated axon repulsion by ephrins raises an unresolved question: these cell surface ligands form a high-affinity multivalent complex with their receptors present on axons, yet rather than being bound, axons can be rapidly repelled. We show here that ephrin-A2 forms a stable complex with the metalloprotease Kuzbanian, involving interactions outside the cleavage region and the protease domain. Eph receptor binding triggered ephrin-A2 cleavage in a localized reaction specific to the cognate ligand. A cleavage-inhibiting mutation in ephrin-A2 delayed axon withdrawal. These studies reveal mechanisms for protease recognition and control of cell surface proteins, and, for ephrin-A2, they may provide a means for efficient axon detachment and termination of signaling.
Active Remodeling of Somatic Nuclei in Egg Cytoplasm by the Nucleosomal ATPase ISWI
Authors: Kikyo Nobuaki , Wade Paul A. , Guschin Dmitry , Ge Hui , Wolffe Alan P.
Published: July 2002

Cloning by the transplantation of somatic nuclei into unfertilized eggs requires a dramatic remodeling of chromosomal architecture. Many proteins are specifically lost from nuclei, and others are taken up from the egg cytoplasm. Recreating this exchange in vitro, we identified the chromatin-remodeling nucleosomal adenosine triphosphatase (ATPase) ISWI as a key molecule in this process. ISWI actively erases the TATA binding protein from association with the nuclear matrix. Defining the biochemistry of global nuclear remodeling may facilitate the efficiency of cloning and other dedifferentiation events that establish new stem cell lineages.
The Ins and Outs of Body Surface Immunology
Authors: Hayday Adrian , Viney Joanne L.
Published: July 2002

Rather than being confined to the secondary lymphoid tissue of the spleen and lymph nodes, large numbers of lymphocytes are intrinsically associated with the epithelial surfaces of the body. The best studied is gut-associated lymphoid tissue, but distinct epithelium-associated lymphoid tissue also exists in the reproductive tract, the lung, and the skin. The multiple cell types and functions composing these lymphoid tissues are increasingly seen as the key to how antigens delivered to body surfaces can elicit either immunogenic or tolerogenic responses. In some instances, these responses occur purely within the local body surface tissue, yet in other cases both local and systemic responses are elicited.
Blue-Fluorescent Antibodies
Authors: Simeonov Anton , Matsushita Masayuki , Juban Eric A. , Thompson Elizabeth H. Z. , Hoffman Timothy Z. , Beuscher IV Albert E. , Taylor Matthew J. , Wirsching Peter , Rettig Wolfgang , McCusker James K. , Stevens Raymond C. , Millar David P. , Schultz Peter G. , Lerner Richard A. , Janda Kim D.
Published: July 2002

The forte of catalytic antibodies has resided in the control of the ground-state reaction coordinate. A principle and method are now described in which antibodies can direct the outcome of photophysical and photochemical events that take place on excited-state potential energy surfaces. The key component is a chemically reactive optical sensor that provides a direct report of the dynamic interplay between protein and ligand at the active site. To illustrate the concept, we used a
trans
-stilbene hapten to elicit a panel of monoclonal antibodies that displayed a range of fluorescent spectral behavior when bound to a
trans
-stilbene substrate. Several antibodies yielded a blue fluorescence indicative of an excited-state complex or “exciplex” between
trans
-stilbene and the antibody. The antibodies controlled the isomerization coordinate of
trans
-stilbene and dynamically coupled this manifold with an active-site residue. A step was taken toward the use of antibody-based photochemical sensors for diagnostic and clinical applications.
Deleterious Mutations and the Evolution of Sex
Authors: Keightley Peter D. , Eyre-Walker Adam
Published: July 2002

It has been suggested that sexual reproduction is maintained because it reduces the load imposed by recurrent deleterious mutations. If rates of deleterious mutation per diploid genome per generation (
U
) exceed 1, and mutations interact synergistically, then sexuals can overcome their inherent twofold disadvantage. We have tested this hypothesis by estimating genomic point mutation rates for protein-coding genes in a range of animal taxa. We find a positive linear relationship between
U
and generation time. In species with short generation times,
U
is predicted to be far below 1, suggesting that sex is not maintained by its capacity to purge the genome of deleterious mutations.