bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Requirements for Survival and Proliferation of CD8 Naïve or Memory T Cells
Authors: Tanchot Corinne , Lemonnier François A. , Pérarnau Beatrice , Freitas Antonio A. , Rocha Benedita
Published: July 2002

The requisite molecular interactions for CD8 T cell memory were determined by comparison of monoclonal naı̈ve and memory CD8
+
T cells bearing the T cell receptor (TCR) for the HY antigen. Naı̈ve T cells required only the right major histocompatibility complex (MHC) class I–restricting molecule to survive; to expand, they also needed antigen. In contrast, for survival, memory cells did not require the restricting MHC allele, but needed only a nonspecific class I; for expansion the correct class I, but not antigen, was required. Thus, maintenance of CD8 T cell memory still required TCR–MHC class I interactions, but memory T cells may have a lower functional activation threshold that facilitates secondary responses.
Specification of the Zebrafish Nervous System by Nonaxial Signals
Authors: Woo Katherine , Fraser Scott E.
Published: July 2002

The organizer of the amphibian gastrula provides the neurectoderm with both neuralizing and posteriorizing (transforming) signals. In zebrafish, transplantations show that a spatially distinct transformer signal emanates from tissues other than the organizer. Cells of the germring (nonaxial mesendoderm) posteriorized forebrain progenitors when grafted nearby, resulting in an ectopic hindbrain-like structure; in contrast, cells of the organizer (axial mesendoderm) caused no posterior transformation. Local application of basic fibroblast growth factor, a candidate transformer in
Xenopus
, caused malformation but not hindbrain transformation in the forebrain. Thus, the zebrafish gastrula may integrate spatially distinct signals from the organizer and the germring to pattern the neural axis.
Experimental Simulations of Sulfide Formation in the Solar Nebula
Authors: Lauretta Dante S. , Lodders Katharina , Fegley Bruce
Published: July 2002

Sulfurization of meteoritic metal in H
2
S-H
2
gas produced three different sulfides: monosulfide solid solution [(Fe,Ni)
1−

x

S], pentlandite [(Fe,Ni)
9−

x

S
8
], and a phosphorus-rich sulfide. The composition of the remnant metal was unchanged. These results are contrary to theoretical predictions that sulfide formation in the solar nebula produced troilite (FeS) and enriched the remaining metal in nickel. The experimental sulfides are chemically and morphologically similar to sulfide grains in the matrix of the Alais (class CI) carbonaceous chondrite, suggesting that these meteoritic sulfides may be condensates from the solar nebula.
In Vitro Propagation of the Prion-Like State of Yeast Sup35 Protein
Authors: Paushkin Sergey V. , Kushnirov Vitaly V. , Smirnov Vladimir N. , Ter-Avanesyan Michael D.
Published: July 2002

The yeast cytoplasmically inherited genetic determinant [
PSI
+
] is presumed to be a manifestation of the prion-like properties of the Sup35 protein (Sup35p). Here, cell-free conversion of Sup35p from [
psi
−
] cells (Sup35p

psi

−

) to the prion-like [
PSI
+
]-specific form (Sup35p

PSI

+
) was observed. The conversion reaction could be repeated for several consecutive cycles, thus modeling in vitro continuous [
PSI
+
] propagation. Size fractionation of lysates of [
PSI
+
] cells demonstrated that the converting activity was associated solely with Sup35p

PSI

+
aggregates, which agrees with the nucleation model for [
PSI
+
] propagation. Sup35p

PSI

+
was purified and showed high conversion activity, thus confirming the prion hypothesis for Sup35p.
Cross-Language Analysis of Phonetic Units in Language Addressed to Infants
Authors: Kuhl Patricia K. , Andruski Jean E. , Chistovich Inna A. , Chistovich Ludmilla A. , Kozhevnikova Elena V. , Ryskina Viktoria L. , Stolyarova Elvira I. , Sundberg Ulla , Lacerda Francisco
Published: July 2002

In the early months of life, infants acquire information about the phonetic properties of their native language simply by listening to adults speak. The acoustic properties of phonetic units in language input to young infants in the United States, Russia, and Sweden were examined. In all three countries, mothers addressing their infants produced acoustically more extreme vowels than they did when addressing adults, resulting in a “stretching” of vowel space. The findings show that language input to infants provides exceptionally well-specified information about the linguistic units that form the building blocks for words.
Bipolar Changes in Atmospheric Circulation During the Little Ice Age
Authors: Kreutz K. J. , Mayewski P. A. , Meeker L. D. , Twickler M. S. , Whitlow S. I. , Pittalwala I. I.
Published: July 2002

Annually dated ice cores from Siple Dome, West Antarctica, and central Greenland indicate that meridional atmospheric circulation intensity increased in the polar South Pacific and North Atlantic at the beginning (∼1400 A.D.) of the most recent Holocene rapid climate change event, the Little Ice Age (LIA). As deduced from chemical concentrations at these core sites, the LIA was characterized by substantial meridional circulation strength variability, and this variability persists today despite strong evidence for an end to LIA cooling. Thus, increased late 20th century storm variability may be in part a result of the continuation of these climatic fluctuations.
Differential Ligand Activation of Estrogen Receptors ERα and ERβ at AP1 Sites
Authors: Paech Kolja , Webb Paul , Kuiper George G. J. M. , Nilsson Stefan , Gustafsson Jan-Åke , Kushner Peter J. , Scanlan Thomas S.
Published: July 2002

The transactivation properties of the two estrogen receptors, ERα and ERβ, were examined with different ligands in the context of an estrogen response element and an AP1 element. ERα and ERβ were shown to signal in opposite ways when complexed with the natural hormone estradiol from an AP1 site: with ERα, 17β-estradiol activated transcription, whereas with ERβ, 17β-estradiol inhibited transcription. Moreover, the antiestrogens tamoxifen, raloxifene, and Imperial Chemical Industries 164384 were potent transcriptional activators with ERβ at an AP1 site. Thus, the two ERs signal in different ways depending on ligand and response element. This suggests that ERα and ERβ may play different roles in gene regulation.
Evidence for a Role of CRM1 in Signal-Mediated Nuclear Protein Export
Authors: Ossareh-Nazari Batool , Bachelerie Françoise , Dargemont Catherine
Published: July 2002

Chromosome maintenance region 1 (CRM1), a protein that shares sequence similarities with the karyopherin β family of proteins involved in nuclear import pathway, was shown to form a complex with the leucine-rich nuclear export signal (NES). This interaction was inhibited by leptomycin B, a drug that prevents the function of the CRM1 protein in yeast. To analyze the role of the CRM1-NES interaction in nuclear export, a transport assay based on semipermeabilized cells was developed. In this system, which reconstituted NES-, cytosol-, and energy-dependent nuclear export, leptomycin B specifically blocked export of NES-containing proteins. Thus, the CRM1 protein could act as a NES receptor involved in nuclear protein export.
V(D)J Recombinase Activity in a Subset of Germinal Center B Lymphocytes
Authors: Han Shuhua , Dillon Stacey R. , Zheng Biao , Shimoda Michiko , Schlissel Mark S. , Kelsoe Garnett
Published: July 2002

Reexpression of the V(D)J recombinase-activating genes
RAG1
and
RAG2
in germinal center B cells creates the potential for immunoglobulin gene rearrangement and the generation of new antigen receptor specificities. Intermediate products of V(D)J recombination are abundant in a subset of germinal center B cells, demonstrating that the κ immunoglobulin light-chain locus becomes a substrate for renewed V(D)J recombinase activity. This recombinationally active cell compartment contains many heavy-chain VDJ rearrangements that encode low-affinity or nonfunctional antibody. In germinal centers, secondary V(D)J recombination may be induced by diminished binding to antigen ligands, thereby limiting abrupt changes in receptor specificity to B cells that are usually eliminated from the germinal center reaction. This restriction preserves efficient antigen-driven selection in germinal centers while allowing for saltations in the somatic evolution of B cells.
The Orthorhombic Structure of Iron: An in Situ Study at High-Temperature and High-Pressure
Authors: Andrault D. , Fiquet G. , Kunz M. , Visocekas F. , Häusermann D.
Published: July 2002

An in situ angle-dispersive x-ray diffraction study was undertaken of iron in a laser-heated, diamond-anvil cell up to 2375 kelvin and between 30 and 100 gigapascals in Al
2
O
3
- and SiO
2
-pressure media. The resolution and reliability of diffraction peak intensities allow quantitative assessment of a structural model. The results confirm that iron undergoes a phase transformation at high pressures and temperatures. The space group is
Pbcm
for an orthorhombic lattice, and the atomic topology is close to that of ɛ hexagonal close-packed iron.
Mantle Fluids in the San Andreas Fault System, California
Authors: Kennedy B. M. , Kharaka Y. K. , Evans W. C. , Ellwood A. , DePaolo D. J. , Thordsen J. , Ambats G. , Mariner R. H.
Published: July 2002

Fluids associated with the San Andreas and companion faults in central and south-central California have high
3
He/
4
He ratios. The lack of correlation between helium isotopes and fluid chemistry or local geology requires that fluids enter the fault system from the mantle. Mantle fluids passing through the ductile lower crust must enter the brittle fault zone at or near lithostatic pressures; estimates of fluid flux based on helium isotopes suggest that they may thus contribute directly to fault-weakening high-fluid pressures at seismogenic depths.
Design of a Surface Alloy Catalyst for Steam Reforming
Authors: Besenbacher F. , Chorkendorff I. , Clausen B. S. , Hammer B. , Molenbroek A. M. , Nørskov J. K. , Stensgaard I.
Published: July 2002

Detailed studies of elementary chemical processes on well-characterized single crystal surfaces have contributed substantially to the understanding of heterogeneous catalysis. Insight into the structure of surface alloys combined with an understanding of the relation between the surface composition and reactivity is shown to lead directly to new ideas for catalyst design. The feasibility of such an approach is illustrated by the synthesis, characterization, and tests of a high–surface area gold-nickel catalyst for steam reforming.
FADD: Essential for Embryo Development and Signaling from Some, But Not All, Inducers of Apoptosis
Authors: Yeh Wen-Chen , Pompa José Luis de la , McCurrach Mila E. , Shu Hong-Bing , Elia Andrew J. , Shahinian Arda , Ng Michelle , Wakeham Andrew , Khoo Wilson , Mitchell Kyran , El-Deiry Wafik S. , Lowe Scott W. , Goeddel David V. , Mak Tak W.
Published: July 2002

FADD (also known as Mort-1) is a signal transducer downstream of cell death receptor CD95 (also called Fas). CD95, tumor necrosis factor receptor type 1 (TNFR-1), and death receptor 3 (DR3) did not induce apoptosis in FADD-deficient embryonic fibroblasts, whereas DR4, oncogenes
E1A
and c-
myc
, and chemotherapeutic agent adriamycin did. Mice with a deletion in the FADD gene did not survive beyond day 11.5 of embryogenesis; these mice showed signs of cardiac failure and abdominal hemorrhage. Chimeric embryos showing a high contribution of
FADD
null mutant cells to the heart reproduce the phenotype of FADD-deficient mutants. Thus, not only death receptors, but also receptors that couple to developmental programs, may use FADD for signaling.
Solidus of Earth's Deep Mantle
Authors: Zerr A. , Diegeler A. , Boehler R.
Published: July 2002

The solidus of a pyrolite-like composition, approximating that of the lower mantle, was measured up to 59 gigapascals by using CO
2
laser heating in a diamond anvil cell. The solidus temperatures are at least 700 kelvin below the melting temperatures of magnesiowüstite, which in the deep mantle has the lowest melting temperatures of the three major components—magnesiowüstite, Mg-Si-perovskite, and Ca-Si-perovskite. The solidus in the deep mantle is more than 1500 kelvin above the average present-day geotherm, but at the core-mantle boundary it is near the core temperature. Thus, partial melting of the mantle is possible at the core-mantle boundary.
Local GABA Circuit Control of Experience-Dependent Plasticity in Developing Visual Cortex
Authors: Hensch Takao K. , Fagiolini Michela , Mataga Nobuko , Stryker Michael P. , Baekkeskov Steinunn , Kash Shera F.
Published: July 2002

Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development.
Structure of the MscL Homolog from
Mycobacterium tuberculosis
: A Gated Mechanosensitive Ion Channel
Authors: Chang Geoffrey , Spencer Robert H. , Lee Allen T. , Barclay Margaret T. , Rees Douglas C.
Published: July 2002

Mechanosensitive ion channels play a critical role in transducing physical stresses at the cell membrane into an electrochemical response. The MscL family of large-conductance mechanosensitive channels is widely distributed among prokaryotes and may participate in the regulation of osmotic pressure changes within the cell. In an effort to better understand the structural basis for the function of these channels, the structure of the MscL homolog from
Mycobacterium tuberculosis
was determined by x-ray crystallography to 3.5 angstroms resolution. This channel is organized as a homopentamer, with each subunit containing two transmembrane α helices and a third cytoplasmic α helix. From the extracellular side, a water-filled opening approximately 18 angstroms in diameter leads into a pore lined with hydrophilic residues which narrows at the cytoplasmic side to an occluded hydrophobic apex that may act as the channel gate. This structure may serve as a model for other mechanosensitive channels, as well as the broader class of pentameric ligand-gated ion channels exemplified by the nicotinic acetylcholine receptor.
Quantum Phase Interference and Parity Effects in Magnetic Molecular Clusters
Authors: Wernsdorfer W. , Sessoli R.
Published: July 2002

An experimental method based on the Landau-Zener model was developed to measure very small tunnel splittings in molecular clusters of eight iron atoms, which at low temperature behave like a nanomagnet with a spin ground state of
S
= 10. The observed oscillations of the tunnel splittings as a function of the magnetic field applied along the hard anisotropy axis are due to topological quantum interference of two tunnel paths of opposite windings. Transitions between quantum numbers
M
= −
S
and (
S
−
n
), with
n
even or odd, revealed a parity effect that is analogous to the suppression of tunneling predicted for half-integer spins. This observation is direct evidence of the topological part of the quantum spin phase (Berry phase) in a magnetic system.
Importance of AMPA Receptors for Hippocampal Synaptic Plasticity But Not for Spatial Learning
Authors: Zamanillo Daniel , Sprengel Rolf , Hvalby Øivind , Jensen Vidar , Burnashev Nail , Rozov Andrei , Kaiser Katharina M. M. , Köster Helmut J. , Borchardt Thilo , Worley Paul , Lübke Joachim , Frotscher Michael , Kelly Peter H. , Sommer Bernd , Andersen Per , Seeburg Peter H. , Sakmann Bert
Published: July 2002

Gene-targeted mice lacking the
l
-α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR-A exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. In hippocampal CA1 pyramidal neurons, GluR-A
−/−
mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced, but glutamatergic synaptic currents were unaltered; and evoked dendritic and spinous Ca
2+
transients, Ca
2+
-dependent gene activation, and hippocampal field potentials were as in the wild type. In adult GluR-A
−/−
mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggest that CA1 hippocampal LTP is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between LTP in CA1 and acquisition of spatial memory.
Prehistoric Polymers: Rubber Processing in Ancient Mesoamerica
Authors: Hosler Dorothy , Burkett Sandra L. , Tarkanian Michael J.
Published: July 2002

Ancient Mesoamerican peoples harvested latex from
Castilla elastica
, processed it using liquid extracted from
Ipomoea alba
(a species of morning glory vine), and fashioned rubber balls, hollow rubber figurines, and other rubber artifacts from the resulting material. Chemical and mechanical analyses of the latex and of the processed rubber indicate that the enhanced elastic behavior of the rubber relative to the unprocessed latex is due to purification of the polymer component and to an increase in the strength and number of interchain interactions that are induced by organic compounds present in
I. alba
. These ancient peoples' control over the properties of latex and processed rubber gave rise to the Mesoamerican ball game, a central ritual element in all ancient Mesoamerican societies.
Radar and Optical Observations of Asteroid 1998 KY26
Authors: Ostro Steven J. , Pravec Petr , Benner Lance A. M. , Hudson R. Scott , S̆arounová Lenka , Hicks Michael D. , Rabinowitz David L. , Scotti James V. , Tholen David J. , Wolf Marek , Jurgens Raymond F. , Thomas Michael L. , Giorgini Jon D. , Chodas Paul W. , Yeomans Donald K. , Rose Randy , Frye Robert , Rosema Keith D. , Winkler Ron , Slade Martin A.
Published: July 2002

Observations of near-Earth asteroid 1998 KY26 shortly after its discovery reveal a slightly elongated spheroid with a diameter of about 30 meters, a composition analogous to carbonaceous chondritic meteorites, and a rotation period of 10.7 minutes, which is an order of magnitude shorter than that measured for any other solar system object. The rotation is too rapid for 1998 KY26 to consist of multiple components bound together just by their mutual gravitational attraction. This monolithic object probably is a fragment derived from cratering or collisional destruction of a much larger asteroid.
Correlational Structure of Spontaneous Neuronal Activity in the Developing Lateral Geniculate Nucleus in Vivo
Authors: Weliky Michael , Katz Lawrence C.
Published: July 2002

The properties of spontaneous activity in the developing visual pathway beyond the retina are unknown. Multielectrode recordings in the lateral geniculate nucleus (LGN) of awake behaving ferrets, before eye opening, revealed patterns of spontaneous activity that reflect a reshaping of retinal drive within higher visual stages. Significant binocular correlations were present only when cortico-thalamic feedback was intact. In the absence of retinal drive, cortico-thalamic feedback was required to sustain correlated LGN bursting. Activity originating from the contralateral eye drove thalamic activity far more strongly than that originating from the ipsilateral eye. Thus, in vivo patterns of LGN spontaneous activity emerge from interactions between retina, thalamus, and cortex.
KDR Receptor: A Key Marker Defining Hematopoietic Stem Cells
Authors: Ziegler B. L. , Valtieri M. , Porada G. Almeida , Maria R. De , Müller R. , Masella B. , Gabbianelli M. , Casella I. , Pelosi E. , Bock T. , Zanjani E. D. , Peschle C.
Published: July 2002

Studies on pluripotent hematopoietic stem cells (HSCs) have been hindered by lack of a positive marker, comparable to the CD34 marker of hematopoietic progenitor cells (HPCs). In human postnatal hematopoietic tissues, 0.1 to 0.5% of CD34
+
cells expressed vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR). Pluripotent HSCs were restricted to the CD34
+
KDR
+
cell fraction. Conversely, lineage-committed HPCs were in the CD34
+
KDR
−
subset. On the basis of limiting dilution analysis, the HSC frequency in the CD34
+
KDR
+
fraction was 20 percent in bone marrow (BM) by mouse xenograft assay and 25 to 42 percent in BM, peripheral blood, and cord blood by 12-week long-term culture (LTC) assay. The latter values rose to 53 to 63 percent in LTC supplemented with VEGF and to greater than 95 percent for the cell subfraction resistant to growth factor starvation. Thus, KDR is a positive functional marker defining stem cells and distinguishing them from progenitors.
Whole-Genome Shotgun Optical Mapping of
Deinococcus radiodurans
Authors: Lin Jieyi , Qi Rong , Aston Christopher , Jing Junping , Anantharaman Thomas S. , Mishra Bud , White Owen , Daly Michael J. , Minton Kenneth W. , Venter J. Craig , Schwartz David C.
Published: July 2002

A whole-genome restriction map of
Deinococcus radiodurans
, a radiation-resistant bacterium able to survive up to 15,000 grays of ionizing radiation, was constructed without using DNA libraries, the polymerase chain reaction, or electrophoresis. Very large, randomly sheared, genomic DNA fragments were used to construct maps from individual DNA molecules that were assembled into two circular overlapping maps (2.6 and 0.415 megabases), without gaps. A third smaller chromosome (176 kilobases) was identified and characterized. Aberrant nonlinear DNA structures that may define chromosome structure and organization, as well as intermediates in DNA repair, were directly visualized by optical mapping techniques after γ irradiation.
Parametric Generation of Tunable Light from Continuous-Wave to Femtosecond Pulses
Authors: Dunn Malcolm H. , Ebrahimzadeh Majid
Published: July 2002

By exploiting nonlinear optical effects, a technology of unprecedented flexibility for the production of tunable coherent light has been developed. Referred to as optical parametric generation, it provides sources with spectral coverage extending all the way from the ultraviolet to the mid-infrared, and with temporal coverage extending over all time domains from the femtosecond pulse to the continuous wave. Such sources generate coherent light of outstanding optical quality and are now finding wide-ranging applications.
Role of the Enteric Nervous System in the Fluid and Electrolyte Secretion of Rotavirus Diarrhea
Authors: Lundgren Ove , Peregrin Attila Timar , Persson Kjell , Kordasti Shirin , Uhnoo Ingrid , Svensson Lennart
Published: July 2002

The mechanism underlying the intestinal fluid loss in rotavirus diarrhea, which often afflicts children in developing countries, is not known. One hypothesis is that the rotavirus evokes intestinal fluid and electrolyte secretion by activation of the nervous system in the intestinal wall, the enteric nervous system (ENS). Four different drugs that inhibit ENS functions were used to obtain experimental evidence for this hypothesis in mice in vitro and in vivo. The involvement of the ENS in rotavirus diarrhea indicates potential sites of action for drugs in the treatment of the disease.
Quantum Criticality: Competing Ground States in Low Dimensions
Authors: Sachdev Subir
Published: July 2002

Small changes in an external parameter can often lead to dramatic qualitative changes in the lowest energy quantum mechanical ground state of a correlated electron system. In anisotropic crystals, such as the high-temperature superconductors where electron motion occurs primarily on a two-dimensional square lattice, the quantum critical point between two such lowest energy states has nontrivial emergent excitations that control the physics over a significant portion of the phase diagram. Nonzero temperature dynamic properties near quantum critical points are described, using simple theoretical models. Possible quantum phases and transitions in the two-dimensional electron gas on a square lattice are discussed.
Stellar Production Rates of Carbon and Its Abundance in the Universe
Authors: Oberhummer H. , Csótó A. , Schlattl H.
Published: July 2002

The bulk of the carbon in our universe is produced in the triple-alpha process in helium-burning red giant stars. We calculated the change of the triple-alpha reaction rate in a microscopic 12-nucleon model of the
12
C nucleus and looked for the effects of minimal variations of the strengths of the underlying interactions. Stellar model calculations were performed with the alternative reaction rates. Here, we show that outside a narrow window of 0.5 and 4% of the values of the strong and Coulomb forces, respectively, the stellar production of carbon or oxygen is reduced by factors of 30 to 1000.
Negative Regulation of the
SHATTERPROOF
Genes by FRUITFULL During
Arabidopsis
Fruit Development
Authors: Ferrándiz Cristina , Liljegren Sarah J. , Yanofsky Martin F.
Published: July 2002

The terminal step of fruit development in
Arabidopsis
involves valve separation from the replum, allowing seed dispersal. This process requires the activities of the
SHATTERPROOF
MADS-box genes, which promote dehiscence zone differentiation at the valve/replum boundary. Here we show that the
FRUITFULL
MADS-box gene, which is necessary for fruit valve differentiation, is a negative regulator of
SHATTERPROOF
expression and that constitutive expression of
FRUITFULL
is sufficient to prevent formation of the dehiscence zone. Our studies suggest that ectopic expression of
FRUITFULL
may directly allow the control of pod shatter in oilseed crops such as canola.
Pleistocene Milestones on the Out-of-Africa Corridor at Gesher Benot Ya'aqov, Israel
Authors: Goren-Inbar Naama , Feibel Craig S. , Verosub Kenneth L. , Melamed Yoel , Kislev Mordechai E. , Tchernov Eitan , Saragusti Idit
Published: July 2002

The Acheulean site of Gesher Benot Ya'aqov in the Dead Sea Rift of Israel documents hominin movements and technological development on a corridor between Africa and Eurasia. New age data place the site at 780,000 years ago (oxygen isotope stage 19), considerably older than previous estimates. The archaeological data from the site portray strong affinities with African stone tool traditions. The findings also reflect adroit technical skills and in-depth planning abilities, more advanced and complex than those of earlier archaeological occurrences in the Levant.
Long-Term Survival But Impaired Homeostatic Proliferation of Naïve T Cells in the Absence of p56
lck
Authors: Seddon Benedict , Legname Giuseppe , Tomlinson Peter , Zamoyska Rose
Published: July 2002

Interactions between the T cell receptor (TCR) and major histocompatibility complex antigens are essential for the survival and homeostasis of peripheral T lymphocytes. However, little is known about the TCR signaling events that result from these interactions. The peripheral T cell pool of p56
lck
(lck)–deficient mice was reconstituted by the expression of an inducible lck transgene. Continued survival of peripheral naı̈ve T cells was observed for long periods after switching off the transgene. Adoptive transfer of T cells from these mice into T lymphopoienic hosts confirmed that T cell survival was independent of lck but revealed its essential role in TCR-driven homeostatic proliferation of naı̈ve T cells in response to the T cell–deficient host environment. These data suggest that survival and homeostatic expansion depend on different signals.
A Stable Bicyclic Compound with Two Si=Si Double Bonds
Authors: Iwamoto Takeaki , Tamura Makoto , Kabuto Chizuko , Kira Mitsuo
Published: July 2002

In contrast to carbon, silicon does not readily form double bonds, and compounds containing silicon-silicon double bonds can usually be stabilized only by protection with bulky substituents. We have isolated a silicon analog of spiropentadiene
1
, a carbon double-ring compound that has not been isolated to date. In the crystal structure of tetrakis[tri(
t
-butyldimethylsilyl)silyl]spiropentasiladiene
2
, a substantial deviation from the perpendicular arrangement of the two rings is observed, and the silicon-silicon double bonds are shown to be distorted. Spectroscopic data indicate pronounced interaction between two remote silicon-silicon double bonds in the molecule. Silicon-silicon bonds may be more accessible to synthesis than previously assumed.
Intracellular Parasitism by
Histoplasma capsulatum
: Fungal Virulence and Calcium Dependence
Authors: Sebghati Tricia Schurtz , Engle Jacquelyn T. , Goldman William E.
Published: July 2002

Histoplasma capsulatum
is an effective intracellular parasite of macrophages and causes the most prevalent fungal respiratory disease in the United States. A “dimorphic” fungus,
H. capsulatum
exists as a saprophytic mold in soil and converts to the parasitic yeast form after inhalation. Only the yeasts secrete a calcium-binding protein (CBP) and can grow in calcium-limiting conditions. To probe the relation between calcium limitation and intracellular parasitism, we designed a strategy to disrupt
CBP1
in
H. capsulatum
using a telomeric linear plasmid and a two-step genetic selection. The resulting
cbp1
yeasts no longer grew when deprived of calcium, and they were also unable to destroy macrophages in vitro or proliferate in a mouse model of pulmonary infection.
Timing of Millennial-Scale Climate Change in Antarctica and Greenland During the Last Glacial Period
Authors: Blunier Thomas , Brook Edward J.
Published: July 2002

A precise relative chronology for Greenland and West Antarctic paleotemperature is extended to 90,000 years ago, based on correlation of atmospheric methane records from the Greenland Ice Sheet Project 2 and Byrd ice cores. Over this period, the onset of seven major millennial-scale warmings in Antarctica preceded the onset of Greenland warmings by 1500 to 3000 years. In general, Antarctic temperatures increased gradually while Greenland temperatures were decreasing or constant, and the termination of Antarctic warming was apparently coincident with the onset of rapid warming in Greenland. This pattern provides further evidence for the operation of a “bipolar see-saw” in air temperatures and an oceanic teleconnection between the hemispheres on millennial time scales.
Views of Earth's Magnetosphere with the IMAGE Satellite
Authors: Burch J. L. , Mende S. B. , Mitchell D. G. , Moore T. E. , Pollock C. J. , Reinisch B. W. , Sandel B. R. , Fuselier S. A. , Gallagher D. L. , Green J. L. , Perez J. D. , Reiff P. H.
Published: July 2002

The IMAGE spacecraft uses photon and neutral atom imaging and radio sounding techniques to provide global images of Earth's inner magnetosphere and upper atmosphere. Auroral imaging at ultraviolet wavelengths shows that the proton aurora is displaced equatorward with respect to the electron aurora and that discrete auroral forms at higher latitudes are caused almost completely by electrons. Energetic neutral atom imaging of ions injected into the inner magnetosphere during magnetospheric disturbances shows a strong energy-dependent drift that leads to the formation of the ring current by ions in the several tens of kiloelectron volts energy range. Ultraviolet imaging of the plasmasphere has revealed two unexpected features—a premidnight trough region and a dayside shoulder region—and has confirmed the 30-year-old theory of the formation of a plasma tail extending from the duskside plasmasphere toward the magnetopause.
Cherenkov Radiation at Speeds Below the Light Threshold: Phonon-Assisted Phase Matching
Authors: Stevens T. E. , Wahlstrand J. K. , Kuhl J. , Merlin R.
Published: July 2002

Charged particles traveling through matter at speeds larger than the phase velocity of light in the medium emit Cherenkov radiation. Calculations reveal that a given angle of the radiation conical wavefront is associated with two velocities, one above and one below a certain speed threshold. Emission at subluminal but not superluminal speeds is predicted and verified experimentally for relativistic dipoles generated with an optical method based on subpicosecond pulses moving in a nonlinear medium. The dipolar Cherenkov field, in the range of infrared-active phonons, is identical to that of phonon polaritons produced by impulsive laser excitation.
Structural Mechanism of Endosome Docking by the FYVE Domain
Authors: Kutateladze Tatiana , Overduin Michael
Published: July 2002

The recruitment of trafficking and signaling proteins to membranes containing phosphatidylinositol 3-phosphate [PtdIns(3)P] is mediated by FYVE domains. Here, the solution structure of the FYVE domain of the early endosome antigen 1 protein (EEA1) in the free state was compared with the structures of the domain complexed with PtdIns(3)P and mixed micelles. The multistep binding mechanism involved nonspecific insertion of a hydrophobic loop into the lipid bilayer, positioning and activating the binding pocket. Ligation of PtdIns(3)P then induced a global structural change, drawing the protein termini over the bound phosphoinositide by extension of a hinge. Specific recognition of the 3-phosphate was determined indirectly and directly by two clusters of conserved arginines.
ENSO-like Forcing on Oceanic Primary Production During the Late Pleistocene
Authors: Beaufort Luc , de Garidel-Thoron Thibault , Mix Alan C. , Pisias Nicklas G.
Published: July 2002

Late Pleistocene changes in oceanic primary productivity along the equator in the Indian and Pacific oceans are revealed by quantitative changes in nanoplankton communities preserved in nine deep-sea cores. We show that variations in equatorial productivity are primarily caused by glacial-interglacial variability and by precession-controlled changes in the east-west thermocline slope of the Indo-Pacific. The precession-controlled variations in productivity are linked to processes similar to the Southern Oscillation phenomenon, and they precede changes in the oxygen isotopic ratio, which indicates that they are not the result of ice sheet fluctuations. The 30,000-year spectral peak in the tropical Indo-Pacific Ocean productivity records is also present in the Antarctica atmospheric CO
2
record, suggesting an important role for equatorial biological productivity in modifying atmospheric CO
2
.
Determinants of Ceftazidime Clearance by Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodialysis
Authors: Matzke Gary R. , Frye Reginald F. , Joy Melanie S. , Palevsky Paul M.
Published: July 2002

Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m
2
acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m
2
polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m
2
polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CI
diffusion
) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17% ± 7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood flow rates of 75 to 250 ml/min for all three filters. Significant linear relationships (
P
< 0.0001) were observed between CI
diffusion
of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed.
Identification and Characterization of the Penicillin-Binding Protein 2a of
Streptococcus pneumoniae
and Its Possible Role in Resistance to β-Lactam Antibiotics
Authors: Zhao Genshi , Meier Timothy I. , Hoskins Joann , McAllister Kelly A.
Published: July 2002

To further understand the role of penicillin-binding protein 2a (PBP 2a) of
Streptococcus pneumoniae
in penicillin resistance, we confirmed the identity of the protein as PBP 2a. The PBP 2a protein migrated electrophoretically to a position corresponding to that of PBP 2x, PBP 2a, and PBP 2b of
S. pneumoniae
and was absent in a
pbp2a
insertional mutant of
S. pneumoniae
. We found that the affinities of PBP 2a for penicillins were lower than for cephalosporins and a carbapenem. When compared with other
S. pneumoniae
PBPs, PBP 2a exhibited lower affinities for β-lactam antibiotics, especially penicillins. Therefore, PBP 2a is a low-affinity PBP for β-lactam antibiotics in
S. pneumoniae.
Dose-Dependent Pharmacokinetics of Amphotericin B Lipid Complex in Rabbits
Authors: Walsh Thomas J. , Jackson Andre J. , Lee James W. , Amantea Michael , Sein Tin , Bacher John , Zech Loren
Published: July 2002

Amphotericin B lipid complex (ABLC) was recently approved by the Food and Drug Administration for treatment of patients with invasive fungal infections who are intolerant of or refractory to conventional amphotericin B therapy. Little is known, however, about the pharmacokinetics of this new antifungal compound. We therefore investigated the pharmacokinetics of ABLC in comparison with those of conventional desoxycholate amphotericin B (DAmB) in rabbits. The pharmacokinetics of DAmB in a rabbit model were similar to those previously reported in humans. The pharmacokinetics of ABLC differed substantially from those of DAmB. Plasma amphotericin B levels following ABLC administration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DAmB model by (i) a dose- and time-dependent uptake and return between the plasma compartment and apparent cellular components of the blood-sediment compartment and (ii) time-dependent tissue uptake and return to plasma from serially connected compartments. Following infusion of ABLC, there was a nonlinear uptake into the apparent cellular components of the blood-sediment compartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The transfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution back to the plasma. The study describes a detailed model of the pharmacokinetics of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue.
Mutant Prevention Concentration as a Measure of Antibiotic Potency: Studies with Clinical Isolates of
Mycobacterium tuberculosis
Authors: Dong Yuzhi , Zhao Xilin , Kreiswirth Barry N. , Drlica Karl
Published: July 2002

The mutant prevention concentration (MPC) of a C-8-methoxy fluoroquinolone exhibited a narrow distribution for 14 genetically diverse clinical isolates of
Mycobacterium tuberculosis
, indicating that results from single-isolate studies are likely to be representative. When one isolate was challenged with a variety of antituberculosis agents, C-8-methoxy fluoroquinolones were exceptional in having MPCs below the maximum concentration attained in serum by use of commonly recommended doses.
Mechanisms of Streptomycin Resistance: Selection of Mutations in the 16S rRNA Gene Conferring Resistance
Authors: Springer Burkhard , Kidan Yishak G. , Prammananan Therdsak , Ellrott Kerstin , Böttger Erik C. , Sander Peter
Published: July 2002

Chromosomally acquired streptomycin resistance is frequently due to mutations in the gene encoding the ribosomal protein S12,
rpsL
. The presence of several rRNA operons (
rrn
) and a single
rpsL
gene in most bacterial genomes prohibits the isolation of streptomycin-resistant mutants in which resistance is mediated by mutations in the 16S rRNA gene (
rrs
). Three strains were constructed in this investigation:
Mycobacterium smegmatis rrnB
,
M. smegmatis rpsL
3+
, and
M. smegmatis rrnB rpsL
3+
.
M. smegmatis rrnB
carries a single functional
rrn
operon, i.e.,
rrnA
(comprised of 16S, 23S, and 5S rRNA genes) and a single
rpsL
+
gene;
M. smegmatis rpsL
3+
is characterized by the presence of two
rrn
operons (
rrnA
and
rrnB
) and three
rpsL
+
genes; and
M. smegmatis rrnB rpsL
3+
carries a single functional
rrn
operon (
rrnA
) and three
rpsL
+
genes. By genetically altering the number of
rpsL
and
rrs
alleles in the bacterial genome, mutations in
rrs
conferring streptomycin resistance could be selected, as revealed by analysis of streptomycin-resistant derivatives of
M. smegmatis rrnB rpsL
3+
. Besides mutations well known to confer streptomycin resistance, novel streptomycin resistance conferring mutations were isolated. Most of the mutations were found to map to a functional pseudoknot structure within the 530 loop region of the 16S rRNA. One of the mutations observed, i.e., 524G→C, severely distorts the interaction between nucleotides 524G and 507C, a Watson-Crick interaction which has been thought to be essential for ribosome function. The use of the single rRNA allelic
M. smegmatis
strain should help to elucidate the principles of ribosome-drug interactions.
DPC 681 and DPC 684: Potent, Selective Inhibitors of Human Immunodeficiency Virus Protease Active against Clinically Relevant Mutant Variants
Authors: Kaltenbach Robert F. , Trainor George , Getman Daniel , Harris Greg , Garber Sena , Cordova Beverly , Bacheler Lee , Jeffrey Susan , Logue Kelly , Cawood Pamela , Klabe Ronald , Diamond Sharon , Davies Marc , Saye Joanne , Jona Janan , Erickson-Viitanen Susan
Published: July 2002

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC90). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC90s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC50values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC50values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).
Association of Genetic Mutations in
Plasmodium vivax dhfr
with Resistance to Sulfadoxine-Pyrimethamine: Geographical and Clinical Correlates
Authors: Imwong Mallika , Pukrittakayamee Sasithon , Looareesuwan Sornchai , Pasvol Geoffrey , Poirreiz Jean , White Nicholas J. , Snounou Georges
Published: July 2002

Mutations in the
Plasmodium falciparum
gene (
dhfr
) encoding dihydrofolate reductase are associated with resistance to antifols.
Plasmodium vivax
, the more prevalent malaria parasite in Asia and the Americas, is considered antifol resistant. Functional polymorphisms in the
dhfr
gene of
P. vivax
(
pvdhfr
) were assessed by PCR-restriction fragment length polymorphism using blood samples taken from 125 patients with acute vivax malaria from three widely separated locations, Thailand (
n
= 100), India (
n
= 16), and Madagascar and the Comoros Islands (
n
= 9). Upon evaluation of the three important codons (encoding residues 57, 58, and 117) of
P. vivax dhfr
(
pvdhfr
), double- or triple-mutation genotypes were found in all but one case from Thailand (99%), in only three cases from India (19%) and in no cases from Madagascar or the Comoros Islands (
P
< 0.0001). The
dhfr
PCR products of
P. vivax
from 32 Thai patients treated with the antifolate sulfadoxine-pyrimethamine (S-P) were investigated. All samples showed either double (53%) or triple (47%) mutations. Following treatment, 34% of the patients had early treatment failures and only 10 (31%) of the patients cleared their parasitemias for 28 days. There were no significant differences in cure rates, but parasite reduction ratios at 48 h were significantly lower for patients whose samples showed triple mutations than for those whose samples showed double mutations (
P
= 0.01). The three mutations at the
pvdhfr
codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in
P. vivax
. These mutations presumably arose from selection pressure.