bluuebunny/crossref_metadata_2025 huggingface dataset:
Barrier heights of real Schottky contacts explained by metal-induced gap states and lateral inhomogeneities
Authors: Mönch Winfried
Published: July 2002

Most metal–semiconductor contacts are rectifying. For moderately doped semiconductors, the current transport across such Schottky contacts occurs by thermionic emission over the Schottky barrier. The current–voltage characteristics of real Schottky contacts are described by two fitting parameters that are the effective barrier heights ΦBeff and the ideality factors n. Due to lateral inhomogeneities of the barrier height, both parameters differ from one diode to another. However, their variations are correlated in that ΦBeff becomes smaller with increasing n. Extrapolations of such ΦBeff-versus-n plots to the corresponding image-force-controlled ideality factors nif give the barrier heights of laterally homogeneous contacts. They are then compared with the theoretical predictions for ideal Schottky contacts. Data of Si, GaN, GaAs, and CdTe Schottky contacts reveal that the continuum of metal-induced gap states is the fundamental mechanism that determines the barrier heights. However, there are additional but then secondary mechanisms. As an example, contacts with (7×7)i-reconstructed interfaces have smaller barrier heights than diodes with (1×1)i-unreconstructed interfaces. This lowering of the Schottky barrier is caused by the electric dipole associated with the stacking fault in one of the triangular halves of the (7×7) unit mesh.
Near-field distribution in light-coupling masks for contact lithography
Authors: Paulus Michael , Michel Bruno , Martin Olivier J. F.
Published: July 2002

We discuss the potential and limitations of light-coupling masks for high-resolution subwavelength optical lithography. Using a three-dimensional fully vectorial numerical approach based on Green’s tensor technique, the near-field distribution of the electric field in the photoresist is calculated. We study the dependence of the illuminating light and the angle of incidence on polarization. Furthermore, we investigate the replication of structures of various sizes and separations. It is predicted that the formation of features in the 60 nm range is possible using light with a 248 nm wavelength. However, with decreasing separation among the features, crosstalk limits the ultimate resolution.
In situelectrochemical atomic force microscopy study on Au(100)/Cd interface in sulfuric acid solution
Authors: Vidu Ruxandra , Hara Shigeta
Published: July 2002

The Cd electrodeposition on Au(100) in sulfuric acid solution was investigated by means of in situ electrochemical atomic force microscopy (EC-AFM) and long time polarization experiments. Initially, the Cd adlayer was formed at underpotentials (E=0.05 V/NHE) in a (√×√)R45°-Cd structure, which changed to a (1×1)-Cd structure at E=−0.45 V/NHE. Within the potential range from −0.3 to −0.45 V/NHE, a quick-alloying process was observed at the interface. The dynamic of the surface alloying was found to depend on polarization conditions. EC-AFM observation of the stripping process showed that the removing of the Cd bulk phase and the surface alloyed phase roughened the electrode surface. The mechanism that was proposed for surface alloying took into consideration the turnover process between Au and Cd atoms and the interdiffusion process of either Au or Cd atoms through the vacancy-rich surface alloy within the top layers. During bulk deposition at E=−0.49 V, Cd film was formed by a Stranski–Krastanov mechanism, with the Cd(0001) plane parallel to Au(100).
Dating Caral, a Preceramic Site in the Supe Valley on the Central Coast of Peru
Authors: Solis Ruth Shady , Haas Jonathan , Creamer Winifred
Published: July 2002

Radiocarbon dates from the site of Caral in the Supe Valley of Peru indicate that monumental corporate architecture, urban settlement, and irrigation agriculture began in the Americas by 4090 years before the present (2627 calibrated years B.C.) to 3640 years before the present (1977 calibrated years B.C.). Caral is located 23 kilometers inland from the Pacific coast and contains a central zone of monumental, residential, and nonresidential architecture covering an area of 65 hectares. Caral is one of 18 large preceramic sites in the Supe Valley.
Melt Production Beneath Mt. Shasta from Boron Data in Primitive Melt Inclusions
Authors: Rose Estelle F. , Shimizu Nobumichi , Layne Graham D. , Grove Timothy L.
Published: July 2002

Most arc magmas are thought to be generated by partial melting of the mantle wedge induced by infiltration of slab-derived fluids. However, partial melting of subducting oceanic crust has also been proposed to contribute to the melt generation process, especially when young and hot lithosphere is being subducted. The isotopic composition of boron measured in situ in olivine-hosted primitive melt inclusions in a basaltic andesite from Mt. Shasta, California, is characterized by large negative values that are also highly variable (δ
11
B = –21.3 to –0.9 per mil). The boron concentrations, from 0.7 to 1.6 parts per million, are lower than in most other arc lavas. The relation between concentration and isotopic composition of boron observed here supports a hypothesis that materials left after dehydration of the subducting slab may have contributed to the generation of basaltic andesite lavas at Mt. Shasta.
Allele-Specific Receptor-Ligand Interactions in
Brassica
Self-Incompatibility
Authors: Kachroo Aardra , Schopfer Christel R. , Nasrallah Mikhail E. , Nasrallah June B.
Published: July 2002

Genetic self-incompatibility in
Brassica
is determined by alleles of the transmembrane serine-threonine kinase SRK, which functions in the stigma epidermis, and of the cysteine-rich peptide SCR, which functions in pollen. Using tagged versions of SRK and SCR as well as endogenous stigma and pollen proteins, we show that SCR binds the SRK ectodomain and that this binding is allele specific. Thus, SRK and SCR function as a receptor-ligand pair in the recognition of self pollen. Specificity in the self-incompatibility response derives from allele-specific formation of SRK-SCR complexes at the pollen-stigma interface.
Consequences of Community Drift
Authors: de Mazancourt Claire
Published: July 2002

The Unified Neutral Theory of Biodiversity and Biogeography
. Stephen P. Hubbell. Princeton University Press, Princeton, NJ, 2001. 389 pp. $75, £52. ISBN 0-691-02129-5. Paper, $29.95, £19.95. ISBN 0-691-02128-7.

Hubbell presents a formal mathematical theory that attempts to combine two approaches to population biology, the study of species richness and relative abundance, and the study of the geographic distribution of species.
A New Global Mode of Earth Deformation: Seasonal Cycle Detected
Authors: Blewitt Geoffrey , Lavallée David , Clarke Peter , Nurutdinov Konstantin
Published: July 2002

We have detected a global mode of Earth deformation that is predicted by theory. Precise positioning of Global Positioning System sites distributed worldwide reveals that during February to March, the Northern Hemisphere compresses (and the Southern Hemisphere expands), such that sites near the North Pole move downward by 3.0 millimeters, and sites near the equator are pulled northward by 1.5 millimeters. The opposite pattern of deformation occurs during August to September. We identify this pattern as the degree-one spherical harmonic response of an elastic Earth to increased winter loading of soil moisture, snow cover, and atmosphere. Data inversion shows the load moment's trajectory as a great circle traversing the continents, peaking at 6.9 × 10
22
kilogram meters near the North Pole in winter, indicating interhemispheric mass exchange of 1.0 × 10
16
± 0.2 × 10
16
kilograms.
Iron-Silicon Alloy in Earth's Core?
Authors: Lin Jung-Fu , Heinz Dion L. , Campbell Andrew J. , Devine James M. , Shen Guoyin
Published: July 2002

We have investigated the phase relations in the iron-rich portion of the iron-silicon (Fe-Si) alloys at high pressures and temperatures. Our study indicates that Si alloyed with Fe can stabilize the body-centered cubic (bcc) phase up to at least 84 gigapascals (compared to ∼10 gigapascals for pure Fe) and 2400 kelvin. Earth's inner core may be composed of hexagonal close-packed (hcp) Fe with up to 4 weight percent Si, but it is also conceivable that the inner core could be a mixture of a Si-rich bcc phase and a Si-poor hcp phase.
The Potential Size and Duration of an Epidemic of Bovine Spongiform Encephalopathy in British Sheep
Authors: Kao R. R. , Gravenor M. B. , Baylis M. , Bostock C. J. , Chihota C. M. , Evans J. C. , Goldmann W. , Smith A. J. A. , McLean A. R.
Published: July 2002

Because there is a theoretical possibility that the British national sheep flock is infected with bovine spongiform encephalopathy (BSE), we examined the extent of a putative epidemic. An age cohort analysis based on numbers of infected cattle, dose responses of cattle and sheep to BSE, levels of exposure to infected feed, and number of BSE-susceptible sheep in the United Kingdom showed that at the putative epidemic peak in 1990, the number of cases of BSE-infected sheep would have ranged from fewer than 10 to about 1500. The model predicts that fewer than 20 clinical cases of BSE in sheep would be expected in 2001 if maternal transmission occurred at a rate of 10%. Although there are large uncertainties in the parameter estimates, all indications are that current prevalence is low; however, a simple model of flock-to-flock BSE transmission shows that horizontal transmission, if it has occurred, could eventually cause a large epidemic.
African Pastoralism: Genetic Imprints of Origins and Migrations
Authors: Hanotte Olivier , Bradley Daniel G. , Ochieng Joel W. , Verjee Yasmin , Hill Emmeline W. , Rege J. Edward O.
Published: July 2002

The genetic history of African cattle pastoralism is controversial and poorly understood. We reveal the genetic signatures of its origins, secondary movements, and differentiation through the study of 15 microsatellite loci in 50 indigenous cattle breeds spanning the present cattle distribution in Africa. The earliest cattle originated within the African continent, but Near East and European genetic influences are also identified. The initial expansion of African
Bos taurus
was likely from a single region of origin. It reached the southern part of the continent by following an eastern route rather than a western one. The
B. indicus
genetic influence shows a major entry point through the Horn and the East Coast of Africa and two modes of introgression into the continent.
Trophic Conversion of an Obligate Photoautotrophic Organism Through Metabolic Engineering
Authors: Zaslavskaia L. A. , Lippmeier J. C. , Shih C. , Ehrhardt D. , Grossman A. R. , Apt K. E.
Published: July 2002

Most microalgae are obligate photoautotrophs and their growth is strictly dependent on the generation of photosynthetically derived energy. We show that the microalga
Phaeodactylum tricornutum
can be genetically engineered to thrive on exogenous glucose in the absence of light through the introduction of a gene encoding a glucose transporter (
glut1
or
hup1
). This demonstrates that a fundamental change in the metabolism of an organism can be accomplished through the introduction of a single gene. This also represents progress toward the use of fermentation technology for large-scale commercial exploitation of algae by reducing limitations associated with light-dependent growth.
Cdc13p: A Single-Strand Telomeric DNA-Binding Protein with a Dual Role in Yeast Telomere Maintenance
Authors: Nugent Constance I. , Hughes Timothy R. , Lue Neal F. , Lundblad Victoria
Published: July 2002

The
CDC13
gene has previously been implicated in the maintenance of telomere integrity in
Saccharomyces cerevisiae
. With the use of two classes of mutations, here it is shown that
CDC13
has two discrete roles at the telomere. The

cdc13-2
est

mutation perturbs a function required in vivo for telomerase regulation but not in vitro for enzyme activity, whereas

cdc13-1
ts

defines a separate essential role at the telomere. In vitro, purified Cdc13p binds to single-strand yeast telomeric DNA. Therefore, Cdc13p is a telomere-binding protein required to protect the telomere and mediate access of telomerase to the chromosomal terminus.
Regulation of Replicon Size in
Xenopus
Egg Extracts
Authors: Walter Johannes , Newport John W.
Published: July 2002

Once a specific number of cells have been produced in the early
Xenopus laevis
embryo, replicon size during the S phase of the cell cycle increases. Here, it is reported that similar increase in replicon size occurred when the concentration of nuclei in replication-competent
Xenopus
egg extracts exceeded a critical threshold. In this system, the origin recognition complex (ORC) did not become stoichiometrically limiting for initiation, and similar amounts of this complex bound to chromatin regardless of replicon size. These data suggest that in early development, an unidentified factor controls how many preformed ORC-DNA complexes initiate DNA replication.
Novel Colloidal Interactions in Anisotropic Fluids
Authors: Poulin Philippe , Stark Holger , Lubensky T. C. , Weitz D. A.
Published: July 2002

Small water droplets dispersed in a nematic liquid crystal exhibit a novel class of colloidal interactions, arising from the orientational elastic energy of the anisotropic host fluid. These interactions include a short-range repulsion and a long-range dipolar attraction, and they lead to the formation of anisotropic chainlike structures by the colloidal particles. The repulsive interaction can lead to novel mechanisms for colloid stabilization.
The Spectrum and Spatial Distribution of Cyanogen in Comet Hale-Bopp (C/1995 O1) at Large Heliocentric Distance
Authors: Wagner R. Mark , Schleicher David G.
Published: July 2002

Optical spectra of comet Hale-Bopp (C/1995 O1) at a heliocentric distance of 6.45 astronomical units showed emission from cyanogen gas. The spatial distribution of cyanogen was considerably more diffuse and extended compared to the spatial profile of the dust or grains which were sharply peaked near the center. This behavior is consistent with comets at smaller heliocentric distances suggesting the same or a similar formation mechanism. A cyanogen gas production rate of (1.2 ± 0.3) ×10
26
molecules per second was derived. A model band profile derived from fluorescence equilibrium calculations for the comet's heliocentric velocity and distance agrees with the observed band profile.
Requirement of
Drosophila
NF1 for Activation of Adenylyl Cyclase by PACAP38-Like Neuropeptides
Authors: Guo Hui-Fu , The Inge , Hannan Frances , Bernards André , Zhong Yi
Published: July 2002

The human neurofibromatosis type 1 (NF1) tumor suppressor protein functions as a Ras-specific guanosine triphosphatase–activating protein, but the identity of Ras- mediated pathways modulated by NF1 remains unknown. A study of
Drosophila NF1
mutants revealed that NF1 is essential for the cellular response to the neuropeptide PACAP38 (pituitary adenylyl cyclase–activating polypeptide) at the neuromuscular junction. The peptide induced a 100-fold enhancement of potassium currents by activating the Ras-Raf and adenylyl cyclase–adenosine 3’,5’-monophosphate (cAMP) pathways. This response was eliminated in
NF1
mutants. NF1 appears to regulate the
rutabaga
-encoded adenylyl cyclase rather than the Ras-Raf pathway. Moreover, the
NF1
defect was rescued by the exposure of cells to pharmacological treatment that increased concentrations of cAMP.
Design of Surfaces for Patterned Alignment of Liquid Crystals on Planar and Curved Substrates
Authors: Gupta Vinay K. , Abbott Nicholas L.
Published: July 2002

Molecularly designed surfaces formed by chemisorption of alkanethiols on ultrathin films of gold permit control of both the azimuthal and polar orientations of supported nematic liquid crystals (LCs). These surfaces, when patterned, form simple and versatile templates for the fabrication of complex optical structures from LCs. Surfaces patterned with odd or even alkanethiols, or mixtures of long and short alkanethiols, were used to fabricate tunable, micrometer-scale LC diffraction gratings that differed in their polarization sensitivity. Patterned alignment of LCs on curved surfaces is also demonstrated, thereby providing principles for fabrication of optical elements that combine diffractive and refractive optics.
Transmission of Hepatitis C by Intrahepatic Inoculation with Transcribed RNA
Authors: Kolykhalov Alexander A. , Agapov Eugene V. , Blight Keril J. , Mihalik Kathleen , Feinstone Stephen M. , Rice Charles M.
Published: July 2002

More than 1% of the world's population is chronically infected with hepatitis C virus (HCV). HCV infection can result in acute hepatitis, chronic hepatitis, and cirrhosis, which is strongly associated with development of hepatocellular carcinoma. Genetic studies of HCV replication have been hampered by lack of a bona fide infectious molecular clone. Full-length functional clones of HCV complementary DNA were constructed. RNA transcripts from the clones were found to be infectious and to cause disease in chimpanzees after direct intrahepatic inoculation. This work defines the structure of a functional HCV genome RNA and proves that HCV alone is sufficient to cause disease.
Natural Behavior Polymorphism Due to a cGMP-Dependent Protein Kinase of
Drosophila
Authors: Osborne K. A. , Robichon A. , Burgess E. , Butland S. , Shaw R. A. , Coulthard A. , Pereira H. S. , Greenspan R. J. , Sokolowski M. B.
Published: July 2002

Naturally occuring polymorphisms in behavior are difficult to map genetically and thus are refractory to molecular characterization. An exception is the
foraging
gene (
for
), a gene that has two naturally occurring variants in
Drosophila melanogaster
food-search behavior: rover and sitter. Molecular mapping placed
for
mutations in the
dg2
gene, which encodes a cyclic guanosine monophosphate (cGMP)–dependent protein kinase (PKG). Rovers had higher PKG activity than sitters, and transgenic sitters expressing a
dg2
complementary DNA from rover showed transformation of behavior to rover. Thus, PKG levels affected food-search behavior, and natural variation in PKG activity accounted for a behavioral polymorphism.
Microscopic Molecular Diffusion Enhanced by Adsorbate Interactions
Authors: Briner B. G. , Doering M. , Rust H.-P. , Bradshaw A. M.
Published: July 2002

The diffusion of carbon monoxide molecules on the (110) surface of copper was investigated in the temperature range between 42 and 53 kelvin. The activation energy for thermal motion was determined directly by imaging individual molecular displacements with a scanning tunneling microscope. An attractive interaction between carbon monoxide molecules gave rise to the formation of dimers and longer chains. Carbon monoxide chains diffused substantially faster than isolated molecules although the chains moved by a sequence of single-molecule jumps. A higher preexponential factor in the Arrhenius law was found to be responsible for the observed efficiency of chain hopping.
The Homeotic Gene
lin-39
and the Evolution of Nematode Epidermal Cell Fates
Authors: Eizinger Andreas , Sommer Ralf J.
Published: July 2002

The fate of ventral epidermal cells differs among nematode species. Nonvulval cells fuse with the epidermis in
Caenorhabditis elegans
, whereas the homologous cells undergo apoptosis in
Pristionchus pacificus
. The homeotic gene
lin-39
is involved in the regulation of these epidermal cell fates. In
Caenorhabditis
,
lin-39
prevents cell fusion of potential vulval cells and specifies the vulva equivalence group.
Pristionchus
vulvaless mutants that displayed apoptosis of the vulval precursor cells were isolated, and point mutations in
lin-39
were identified. Thus, the evolution of these epidermal cell fates is driven by different intrinsic properties of homologous cells.
Inhibition of the Hammerhead Ribozyme Cleavage Reaction by Site-Specific Binding of Tb(III)
Authors: Feig Andrew L. , Scott William G. , Uhlenbeck Olke C.
Published: July 2002

Terbium(III) [Tb(III)] was shown to inhibit the hammerhead ribozyme by competing with a single magnesium(II) ion. X-ray crystallography revealed that the Tb(III) ion binds to a site adjacent to an essential guanosine in the catalytic core of the ribozyme, approximately 10 angstroms from the cleavage site. Synthetic modifications near this binding site yielded an RNA substrate that was resistant to Tb(III) binding and capable of being cleaved, even in the presence of up to 20 micromolar Tb(III). It is suggested that the magnesium(II) ion thought to bind at this site may act as a switch, affecting the conformational changes required to achieve the transition state.
Elevation Change of the Southern Greenland Ice Sheet
Authors: Davis Curt H. , Kluever Craig A. , Haines Bruce J.
Published: July 2002

Seasat and Geosat satellite altimeter measurements for the Greenland ice sheet (south of 72°N latitude) show that surface elevations above 2000 meters increased at an average rate of only 1.5 ± 0.5 centimeters per year from 1978 to 1988. In contrast, elevation changes varied regionally from –15 to +18 centimeters per year, seasonally by ±15 centimeters, and interannually by ±8 centimeters. The average growth rate is too small to determine if the Greenland ice sheet is undergoing a long-term change due to a warmer polar climate.
Quantitation of HIV-1-Specific Cytotoxic T Lymphocytes and Plasma Load of Viral RNA
Authors: Ogg Graham S. , Jin Xia , Bonhoeffer Sebastian , Dunbar P. Rod , Nowak Martin A. , Monard Simon , Segal Jeremy P. , Cao Yunzhen , Rowland-Jones Sarah L. , Cerundolo Vincenzo , Hurley Arlene , Markowitz Martin , Ho David D. , Nixon Douglas F. , McMichael Andrew J.
Published: July 2002

Although cytotoxic T lymphocytes (CTLs) are thought to be involved in the control of human immunodeficiency virus–type 1 (HIV-1) infection, it has not been possible to demonstrate a direct relation between CTL activity and plasma RNA viral load. Human leukocyte antigen–peptide tetrameric complexes offer a specific means to directly quantitate circulating CTLs ex vivo. With the use of the tetrameric complexes, a significant inverse correlation was observed between HIV-specific CTL frequency and plasma RNA viral load. In contrast, no significant association was detected between the clearance rate of productively infected cells and frequency of HIV-specific CTLs. These data are consistent with a significant role for HIV-specific CTLs in the control of HIV infection and suggest a considerable cytopathic effect of the virus in vivo.
Interleukin-13: Central Mediator of Allergic Asthma
Authors: Wills-Karp Marsha , Luyimbazi Jackie , Xu Xueying , Schofield Brian , Neben Tamlyn Y. , Karp Christopher L. , Donaldson Debra D.
Published: July 2002

The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4
+
T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.
Conversion of Supramolecular Clusters to Macromolecular Objects
Authors: Zubarev Eugene R. , Pralle Martin U. , Li Leiming , Stupp Samuel I.
Published: July 2002

In a reaction proceeding within a nanoscopic volume, supramolecular clusters were transformed to polymer objects while retaining their shape and size. Spatial isolation of the cross-linkable blocks of oligobutadiene that were involved in this stitching reaction was achieved by self-assembly of the molecules that made up the clusters. Thermal activation of cross-linking yielded macromolecules (molecular weight of 70,000) with a narrow size distribution that was similar to that of the supramolecular clusters. The macromolecules obtained have an anisotropic shape (2 nanometers by 8 nanometers), as determined by electron microscopy and small-angle x-ray scattering, and form materials that exhibit a liquid crystalline state.
Semimajor Axis Mobility of Asteroidal Fragments
Authors: Farinella Paolo , Vokrouhlický David
Published: July 2002

The semimajor axes of asteroids up to about 20 kilometers in diameter drift as a result of the Yarkovsky effect, a subtle nongravitational mechanism related to radiation pressure recoil on spinning objects that orbit the sun. Over the collisional lifetimes of these objects (typically, 10 to 1000 million years), orbital semimajor axes can be moved by a few hundredths of an astronomical unit for bodies between 1 and 10 kilometers in mean radius. This has implications for the delivery of multikilometer near-Earth asteroids, because the Yarkovsky drift drives many small main-belt asteroids into the resonances that transport them to the Mars-crossing state and eventually to near-Earth space. Recent work has shown that, without such a drift, the Mars-crossing population would be depleted over about 100 million years, a time scale much smaller than the age of the solar system. Moreover, the Yarkovsky semimajor axis mobility may spread in an observable way the tight semimajor axis clustering of small asteroids produced as a consequence of disruptive collisions.
Efficient Persistence of Extrachromosomal KSHV DNA Mediated by Latency-Associated Nuclear Antigen
Authors: Ballestas Mary E. , Chatis Pamela A. , Kaye Kenneth M.
Published: July 2002

Primary effusion lymphoma (PEL) cells harbor Kaposi's sarcoma–associated herpesvirus (KSHV) episomes and express a KSHV-encoded latency-associated nuclear antigen (LANA). In PEL cells, LANA and KSHV DNA colocalized in dots in interphase nuclei and along mitotic chromosomes. In the absence of KSHV DNA, LANA was diffusely distributed in the nucleus or on mitotic chromosomes. In lymphoblasts, LANA was necessary and sufficient for the persistence of episomes containing a specific KSHV DNA fragment. Furthermore, LANA colocalized with the artificial KSHV DNA episomes in nuclei and along mitotic chromosomes. These results support a model in which LANA tethers KSHV DNA to chromosomes during mitosis to enable the efficient segregation of KSHV episomes to progeny cells.
Inactivation of Misselected CD8 T Cells by CD8 Gene Methylation and Cell Death
Authors: Pestano Gary A. , Zhou Yaling , Trimble Linda A. , Daley John , Weber Georg F. , Cantor Harvey
Published: July 2002

Misselected CD8 cells that express T cell receptors (TCRs) that do not recognize class I major histocompatibility complex (MHC) protein can emerge from thymic selection. A postthymic quality control mechanism that purges these cells from the repertoire is defined here. The failure of mature CD8 cells to simultaneously engage their TCR and CD8 coreceptor triggers an activation process that begins with inhibition of CD8 gene expression through remethylation and concludes with up-regulation of surface Fas and Fas ligand and cellular apoptosis. Thus, inhibition of a death signal through continued TCR-CD8 coengagement of MHC molecules is a key checkpoint for the continued survival of correctly selected T cells. Molecular defects that prevent delivery of the death signal to mistakenly selected T cells underlie the expansion of double-negative T cells, which is the cellular signature of a subset of systemic autoimmune diseases.
Genetics of Mouse Behavior: Interactions with Laboratory Environment
Authors: Crabbe John C. , Wahlsten Douglas , Dudek Bruce C.
Published: July 2002

Strains of mice that show characteristic patterns of behavior are critical for research in neurobehavioral genetics. Possible confounding influences of the laboratory environment were studied in several inbred strains and one null mutant by simultaneous testing in three laboratories on a battery of six behaviors. Apparatus, test protocols, and many environmental variables were rigorously equated. Strains differed markedly in all behaviors, and despite standardization, there were systematic differences in behavior across labs. For some tests, the magnitude of genetic differences depended upon the specific testing lab. Thus, experiments characterizing mutants may yield results that are idiosyncratic to a particular laboratory.
Receptor for Motilin Identified in the Human Gastrointestinal System
Authors: Feighner Scott D. , Tan Carina P. , McKee Karen Kulju , Palyha Oksana C. , Hreniuk Donna L. , Pong Sheng-Shung , Austin Christopher P. , Figueroa David , MacNeil Douglas , Cascieri Margaret A. , Nargund Ravi , Bakshi Raman , Abramovitz Mark , Stocco Rino , Kargman Stacia , O'Neill Gary , Van Der Lex H. T. , Ploeg  , Evans Jilly , Patchett Arthur A. , Smith Roy G. , Howard Andrew D.
Published: July 2002

Motilin is a 22–amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum and duodenal contractions. A heterotrimeric guanosine triphosphate–binding protein (G protein)–coupled receptor for motilin was isolated from human stomach, and its amino acid sequence was found to be 52 percent identical to the human receptor for growth hormone secretagogues. The macrolide antibiotic erythromycin also interacted with the cloned motilin receptor, providing a molecular basis for its effects on the human GI tract. The motilin receptor is expressed in enteric neurons of the human duodenum and colon. Development of motilin receptor agonists and antagonists may be useful in the treatment of multiple disorders of GI motility.
Gene Expression Profile of Aging and Its Retardation by Caloric Restriction
Authors: Lee Cheol-Koo , Klopp Roger G. , Weindruch Richard , Prolla Tomas A.
Published: July 2002

The gene expression profile of the aging process was analyzed in skeletal muscle of mice. Use of high-density oligonucleotide arrays representing 6347 genes revealed that aging resulted in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes. Most alterations were either completely or partially prevented by caloric restriction, the only intervention known to retard aging in mammals. Transcriptional patterns of calorie-restricted animals suggest that caloric restriction retards the aging process by causing a metabolic shift toward increased protein turnover and decreased macromolecular damage.
The Changing Morphology and Increasing Deceleration of Supernova 1993J in M81
Authors: Bartel N. , Bietenholz M. F. , Rupen M. P. , Beasley A. J. , Graham D. A. , Altunin V. I. , Venturi T. , Umana G. , Cannon W. H. , Conway J. E.
Published: July 2002

Twenty consecutive Very Long Baseline Interferometry images of supernova 1993J from the time of explosion to the present show the dynamic evolution of the expanding radio shell of an exploded star. High-precision astrometry reveals that the supernova expands isotropically from its explosion center. Systematic changes in the images may reflect a pattern of anisotropies and inhomogeneities in the material left over from the progenitor star. As the shock front sweeps up the material in the surrounding medium, it is increasingly decelerated and influenced by the material. After 5 years, the supernova has slowed to half of its original expansion velocity and may have entered the early stages of the adiabatic phase common in much older supernova remnants in the Milky Way Galaxy.
Comparative Pharmacokinetics of Ciprofloxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Trovafloxacin, and Moxifloxacin after Single Oral Administration in Healthy Volunteers
Authors: Lubasch Annette , Keller Ivonne , Borner Klaus , Koeppe Peter , Lode Hartmut
Published: July 2002

In an open, randomized, six-period crossover study, the pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin were compared after a single oral dose in 12 healthy volunteers (6 men and 6 women). The volunteers received 250 mg of ciprofloxacin, 400 mg of gatifloxacin, 600 mg of grepafloxacin, 500 mg of levofloxacin, 400 mg of moxifloxacin, and 200 mg of trovafloxacin. The concentrations of the six fluoroquinolones in serum and urine were measured by a validated high-performance liquid chromatography method. Blood and urine samples were collected before and at different time points up to 48 h after medication. Levofloxacin had the highest peak concentration (
C
max
, in micrograms per milliliter) (6.21 ± 1.34), followed by moxifloxacin (4.34 ± 1.61) and gatifloxacin (3.42 ± 0.74). Elimination half-lives ranged from 12.12 ± 3.93 h (grepafloxacin) to 5.37 ± 0.82 h (ciprofloxacin). The total areas under the curve (AUC
tot
, in microgram-hours per milliliter) for levofloxacin (44.8 ± 4.4), moxifloxacin (39.3 ± 5.35), and gatifloxacin (30 ± 3.8) were significantly higher than that for ciprofloxacin (5.75 ± 1.25). Calculated from a normalized dose of 200 mg, the highest
C
max
s (in micrograms per milliliter) were observed for levofloxacin (2.48 ± 0.53), followed by moxifloxacin (2.17 ± 0.81) and trovafloxacin (2.09 ± 0.58). The highest AUC
tot
(in microgram-hours per milliliter) for a 200-mg dose were observed for moxifloxacin (19.7 ± 2.67) and trovafloxacin (19.5 ± 3.1); the lowest was observed for ciprofloxacin (4.6 ± 1.0). No serious adverse event was observed during the study period. The five recently developed fluoroquinolones (gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin) showed greater bioavailability, longer half-lives, and higher
C
max
s than ciprofloxacin.
Anti-
Candida
Activity of a New Platinum Derivative
Authors: Watanabe T. , Takano M. , Ogasawara A. , Mikami T. , Kobayashi T. , Watabe M. , Matsumoto T.
Published: July 2002

A new platinum derivative of the form H[Pt(IV)(Hdigly)Cl
2
(OH)
2
] (Hdiglyglycylglycine) damaged the
Candida albicans
cell membrane and inhibited the growth of the cells. The cytotoxic activity of H[Pt(IV)(Hdigly)Cl
2
(OH)
2
] on mammalian cells was 10-fold lower than that of
cis
-diammine-dichloroplatinum (cisplatin). Substitution of platinum for peptides is effective for enhancement of antifungal activity and reduction of the toxicity to mammalian cells.
Genetic Diversity of the
tet
(M) Gene in Tetracycline-Resistant Clonal Lineages of
Streptococcus pneumoniae
Authors: Doherty Neil , Trzcinski Krzysztof , Pickerill Paul , Zawadzki Piotr , Dowson Christopher G.
Published: July 2002

The aim of the present study was to examine the stability and evolution of
tet
(M)-mediated resistance to tetracyclines among members of different clonal lineages of
Streptococcus pneumoniae
. Thirty-two tetracycline-resistant isolates representing three national (Spanish serotype 14, Spanish serotype 15, and Polish serotype 23F) and one international (Spanish serotype 23F) multidrug-resistant epidemic clones were all found to be
tet
(M) positive and
tet
(O),
tet
(K), and
tet
(L) negative. These isolates all carried the integrase gene,
int
, which is associated with the Tn
1545
-Tn
916
family of conjugative transposons. High-resolution restriction analysis of
tet
(M) products identified six alleles,
tet
(M)1 to
tet
(M)6:
tet
(M)1 to
tet
(M)3 and
tet
(M)5 in isolates of the Spanish serotype 14 clone,
tet
(M)4 in both the Spanish serotype 15 and 23F clones, and
tet
(M)6, the most divergent allele, in the Polish 23F clone. This indicates that
tet
(M) variation can occur at the inter- and intraclone levels in pneumococci. Two alleles of
int
were identified, with
int1
being found in all isolates apart from members of the international Spanish 23F clone, which carried
int2
. Susceptibility to tetracycline, doxycycline, and minocycline was evaluated for all isolates with or without preincubation in the presence of subinhibitory concentrations of tetracyclines. Resistance to tetracyclines was found to be inducible in isolates of all clones; however, the strongest induction was observed in the Spanish serotype 15 and 23F clones carrying
tet
(M)4. Tetracycline was found to be the strongest inducer of resistance, and minocycline was found to be the weakest inducer of resistance.
Genetic Analysis of Azole Resistance in the Darlington Strain of
Candida albicans
Authors: Kakeya Hiroshi , Miyazaki Yoshitsugu , Miyazaki Haruko , Nyswaner Katherine , Grimberg Brian , Bennett John E.
Published: July 2002

High-level azole resistance in the Darlington strain of
Candida albicans
was investigated by gene replacement in
C. albicans
and expression in
Saccharomyces cerevisiae
. We sequenced the
ERG11
gene, which encodes the sterol C
14
α-demethylase, from our copy of the Darlington strain. Both alleles contained the histidine for tyrosine substitution at position 132 (Y132H) reported in Darlington by others, but we also found a threonine-for-isoleucine substitution (I471T) not previously reported in the
C. albicans ERG11
. The encoded I471T change in amino acids conferred azole resistance when overexpressed alone and increased azole resistance when added to the Y132H amino acid sequence in an
S. cerevisiae
expression system. Replacement of one copy of
ERG11
in an azole-susceptible strain of
C. albicans
with a single copy of the Darlington
ERG11
resulted in expression of the integrated copy and a modest increase in azole resistance. The profound azole resistance of the Darlington strain is the result of multiple mutations.
Flow Cytometric Detection of
Leishmania
Parasites in Human Monocyte-Derived Macrophages: Application to Antileishmanial-Drug Testing
Authors: Di Giorgio C. , Ridoux O. , Delmas F. , Azas N. , Gasquet M. , Timon-David P.
Published: July 2002

A flow cytometric technique was developed for detection of amastigotes of the protozoan
Leishmania infantum
in human nonadherent monocyte-derived macrophages. The cells were fixed and permeabilized with paraformaldehyde-ethanol, and intracellular amastigotes were labeled with
Leishmania
lipophosphoglycan-specific monoclonal antibody. Results showed that flow cytometry provided accurate quantification of the infection rates in human macrophages compared to the rates obtained by the conventional microscopic technique, with the advantage that a large number of cells could be analyzed rapidly. The results demonstrated, moreover, that labeling of intracellular amastigotes could reliably be used to evaluate the antileishmanial activities of conventional drugs such as meglumine antimoniate, amphotericin B, pentamidine, and allopurinol. They also established that various
Leishmania
species (
L. mexicana
,
L. donovani
) could be detected by this technique in other host-cell models such as mouse peritoneal macrophages and suggested that the flow cytometric method could be a valid alternative to the conventional method.
Use of Cotton Rats to Evaluate the Efficacy of Antivirals in Treatment of Measles Virus Infections
Authors: Wyde Philip R. , Moore-Poveda Donna K. , De Clercq Erik , Neyts Johan , Matsuda Akira , Minakawa Noriaki , Guzman Efrain , Gilbert Brian E.
Published: July 2002

No practical animal models for the testing of chemotherapeutic or biologic agents identified in cell culture assays as being active against measles virus (MV) are currently available. Cotton rats may serve this purpose. To evaluate this possibility, 5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (EICAR) and poly(acrylamidomethyl propanesulfonate) (PAMPS), two compounds that have been reported to inhibit MV in vitro, and ribavirin, an established antiviral drug with MV-inhibitory activity, were evaluated for their antiviral activities against MV and respiratory syncytial virus (RSV) in tissue culture and in hispid cotton rats. A single administration of PAMPS markedly inhibited pulmonary RSV or MV replication (>3 log10reduction in pulmonary titer compared to that for controls), but only if this compound was administered intranasally at about the time of virus inoculation. Both EICAR and ribavirin exhibited therapeutic activity against RSV and MV in cotton rats when they were administered parenterally. However, both of these compounds were less effective against MV. On the basis of the pulmonary virus titers on day 4 after virus inoculation, the minimal efficacious dose of EICAR against MV (120 mg/kg of body weight/day when delivered intraperitoneally twice daily) appeared to be three times lower against this virus than that of ribavirin delivered at a similar dose (i.e., 360 mg/kg/day). These findings correlated with those obtained in vitro. The data obtained suggest that cotton rats may indeed be useful for the initial evaluation of the activities of antiviral agents against MV.
Cerebrospinal Fluid Penetration and Pharmacokinetics of Vancomycin Administered by Continuous Infusion to Mechanically Ventilated Patients in an Intensive Care Unit
Authors: Albanèse Jacques , Léone Marc , Bruguerolle Bernard , Ayem Marie-Laure , Lacarelle Bruno , Martin Claude
Published: July 2002

Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after continuous infusion (50 to 60 mg/kg of body weight/day after a loading dose of 15 mg/kg) in 13 mechanically ventilated patients hospitalized in an intensive care unit. Seven patients were treated for a sensitive bacterial meningitis and the other six patients, who had a severe concomitant neurologic disease with intracranial hypertension, were treated for various infections. Vancomycin CSF penetration was significantly higher (
P
< 0.05) in the meningitis group (serum/CSF ratio, 48%) than in the other group (serum/CSF ratio, 18%). Vancomycin pharmacokinetic parameters did not differ from those obtained with conventional dosing. No adverse effect was observed, in particular with regard to renal function.
Furazolidone- and Nitrofurantoin-Resistant
Helicobacter pylori
: Prevalence and Role of Genes Involved in Metronidazole Resistance
Authors: Kwon Dong H. , Lee Miae , Kim J. J. , Kim J. G. , El-Zaatari F. A. K. , Osato M. S. , Graham D. Y.
Published: July 2002

The prevalence of furazolidone, nitrofurantoin, and metronidazole resistance among
Helicobacter pylori
strains was assessed with 431 clinical isolates. Fifty-two percent were metronidazole resistant, compared to 2% (7 of 431) with resistance to furazolidone and nitrofurantoin. All seven furazolidone- and nitrofurantoin-resistant isolates were also metronidazole resistant.
rdxA
,
frxA
, and
fdxB
knockouts did not result in furazolidone or nitrofurantoin resistance. These data suggest that furazolidone and nitrofurantoin may be good alternatives to metronidazole for treating
H. pylori
infection.
Effective Combination Therapy for Invasive Pneumococcal Pneumonia with Ampicillin and Intravenous Immunoglobulins in a Mouse Model
Authors: De Hennezel Laetitia , Ramisse Françoise , Binder Patrice , Marchal Gilles , Alonso Jean-Michel
Published: July 2002

Intranasal immunotherapy forStreptococcus pneumoniaeinvasive pneumonia with polyvalent immunoglobulins (IVIG) was effective in mice against pneumonia but failed to prevent bacteremia. The combination of subcurative doses of IVIG and of ampicillin was fully protective. Such an approach, successfully applied in the preantibiotic era, offers new perspectives for modern therapies.
Biochemical Characterization of the FEZ-1 Metallo-β-Lactamase of
Legionella gormanii
ATCC 33297
T
Produced in
Escherichia coli
Authors: Mercuri Paola Sandra , Bouillenne Fabrice , Boschi Letizia , Lamotte-Brasseur Josette , Amicosante Gianfranco , Devreese Bart , van Beeumen Jozef , Frère Jean-Marie , Rossolini Gian Maria , Galleni Moreno
Published: July 2002

The
bla
FEZ-1
gene coding for the metallo-β-lactamase of
Legionella (Fluoribacter) gormanii
ATCC 33297
T
was overexpressed via a T7 expression system in
Escherichia coli
BL21(DE3)(pLysS). The product was purified to homogeneity in two steps with a yield of 53%. The FEZ-1 metallo-β-lactamase exhibited a broad-spectrum activity profile, with a preference for cephalosporins such as cephalothin, cefuroxime, and cefotaxime. Monobactams were not hydrolyzed. The β-lactamase was inhibited by metal chelators. FEZ-1 is a monomeric enzyme with a molecular mass of 29,440 Da which possesses two zinc-binding sites. Its zinc content did not vary in the pH range of 5 to 9, but the presence of zinc ions modified the catalytic efficiency of the enzyme. A model of the FEZ-1 three-dimensional structure was built.
Molecular Basis of Rifampin and Isoniazid Resistance in
Mycobacterium bovis
Strains Isolated in Sardinia, Italy
Authors: Sechi L. A. , Zanetti S. , Sanguinetti M. , Molicotti P. , Romano L. , Leori G. , Delogu G. , Boccia S. , La Sorda M. , Fadda G.
Published: July 2002

Fourteen of 22 (68%)
Mycobacterium bovis
strains isolated from cattle in Sardinia were found to be resistant to rifampin and isoniazid. Analysis of the
rpoB
and the
katG, oxyR-ahpC
, and
inhA
gene regions of these strains was performed in order to investigate the molecular basis of rifampin and isoniazid resistance, respectively. The most frequent mutation, encountered in 6 of 10 strains (60%), was in the
rpoB
gene; it occurred, at codon position 521 and resulted in leucine changed to proline. This suggests that codon 521 may be important for the development of rifampin resistance in
M. bovis
. Resistance to isoniazid is associated in
Mycobacterium tuberculosis
with a variety of mutations affecting one or more genes. Our results confirm the difficulty of interpreting the sequence variations observed in clinical strains of
M. bovis. M. bovis
strains isolated from the same geographic area showed similar mutations within the genes responsible for rifampin and isoniazid resistance. Our results represent the first study to elucidate the molecular genetic basis of drug resistance in
M. bovis
isolated from cattle.
Macrolide Resistance Gene
mreA
of
Streptococcus agalactiae
Encodes a Flavokinase
Authors: Clarebout Gervais , Villers Corinne , Leclercq Roland
Published: July 2002

The
mreA
gene from
Streptococcus agalactiae
COH31 γ/δ, resistant to macrolides and clindamycin by active efflux, has recently been cloned in
Escherichia coli
, where it was reported to confer macrolide resistance (J. Clancy, F. Dib-Hajj, J. W. Petitpas, and W. Yuan, Antimicrob. Agents Chemother. 41:2719–2723, 1997). Cumulative data suggested that the
mreA
gene was located on the chromosome of
S. agalactiae
COH31 γ/δ. Analysis of the deduced amino acid sequence of
mreA
revealed significant homology with several bifunctional flavokinases/(flavin adenine dinucleotide (FAD) synthetases, which convert riboflavin to flavin mononucleotide (FMN) and FMN to FAD, respectively. High-performance liquid chromatography experiments showed that the
mreA
gene product had a monofunctional flavokinase activity, similar to that of RibR from
Bacillus subtilis
. Sequences identical to those of the
mreA
gene and of a 121-bp upstream region containing a putative promoter were detected in strains of
S. agalactiae
UCN4, UCN5, and UCN6 susceptible to macrolides.
mreA
and its allele from
S. agalactiae
UCN4 were cloned on the shuttle vector pAT28. Both constructs were introduced into
E. coli
, where they conferred a similar two- to fourfold increase in the MICs of erythromycin, spiramycin, and clindamycin. The MICs of a variety of other molecules, including crystal violet, acriflavin, sodium dodecyl sulfate, and antibiotics, such as certain cephalosporins, chloramphenicol, doxycycline, nalidixic acid, novobiocin, and rifampin, were also increased. In contrast, resistance to these compounds was not detected when the constructs were introduced into
E. faecalis
JH2–2. In conclusion, the
mreA
gene was probably resident in
S. agalactiae
and may encode a metabolic function. We could not provide any evidence that it was responsible for macrolide resistance in
S. agalactiae
COH31 γ/δ; broad-spectrum resistance conferred by the gene in
E. coli
could involve multidrug efflux pumps by a mechanism that remains to be elucidated.