bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Flowering Time byArabidopsisPhotoreceptors
Authors: Guo Hongwei , Yang Hongyun , Mockler Todd C. , Lin Chentao
Published: July 2002

The shift in plants from vegetative growth to floral development is regulated by red–far-red light receptors (phytochromes) and blue–ultraviolet A light receptors (cryptochromes). A mutation in theArabidopsis thaliana CRY2gene encoding a blue-light receptor apoprotein (CRY2) is allelic to the late-flowering mutant,fha. Flowering incry2/fhamutant plants is only incompletely responsive to photoperiod. Cryptochrome 2 (cry2) is a positive regulator of the flowering-time geneCO, the expression of which is regulated by photoperiod. Analysis of flowering incry2andphyBmutants in response to different wavelengths of light indicated that flowering is regulated by the antagonistic actions of phyB and cry2.
Large-Scale Molecular Dynamics Simulations of Dislocation Intersection in Copper
Authors: Zhou S. J. , Preston D. L. , Lomdahl P. S. , Beazley D. M.
Published: July 2002

The results of massively parallel three-dimensional molecular dynamics simulations of the perpendicular intersection of extended dislocations in copper are reported. The intersection process, which involves three of the four possible {111} glide planes in the face-centered cubic lattice, begins with junction formation, followed by unzipping, partial dislocation bowing, cutting, and, finally, unit jog formation. The investigation provides insights into this complex atomistic process, which is currently not accessible to experimental investigation.
Structural Basis for a Ca
2+
-Sensing Function of the Metabotropic Glutamate Receptors
Authors: Kubo Yoshihiro , Miyashita Tomoyuki , Murata Yoshimichi
Published: July 2002

The metabotropic glutamate receptors (mGluRs) are widely distributed in the brain and play important roles in synaptic plasticity. Here it is shown that some types of mGluRs are activated not only by glutamate but also by extracellular Ca
2+
(Ca
2+
o
). A single amino acid residue was found to determine the sensitivity of mGluRs to Ca
2+
o
. One of the receptors, mGluR1α, but not its point mutant with reduced sensitivity to Ca
2+
o
, caused morphological changes when transfected into mammalian cells. Thus, the sensing of Ca
2+
o
by mGluRs may be important in cells under physiological condition.
Ultrasound-Stimulated Vibro-Acoustic Spectrography
Authors: Fatemi Mostafa , Greenleaf James F.
Published: July 2002

An ultrasound method based on radiation force is presented for imaging the acoustic response of a material to mechanical excitation. Acoustic energy was emitted from solids and tissues in response to an oscillatory radiation force produced by interfering focused beams of ultrasound. Frequency spectra of ultrasound-stimulated acoustic emission exhibited object resonances. Raster-scanning the radiation force over the object and recording the amplitude and phase of the emitted sound resulted in data from which images related to the elastic compositions of the acoustically emitting objects could be computed. Acoustic emission signals distinguished tuning-fork resonances, submillimeter glass spheres, and calcification in excised arteries and detected object motions on the order of nanometers.
Complete Genome Sequence ofTreponema pallidum, the Syphilis Spirochete
Authors: Fraser Claire M. , Norris Steven J. , Weinstock George M. , White Owen , Sutton Granger G. , Dodson Robert , Gwinn Michelle , Hickey Erin K. , Clayton Rebecca , Ketchum Karen A. , Sodergren Erica , Hardham John M. , McLeod Michael P. , Salzberg Steven , Peterson Jeremy , Khalak Hanif , Richardson Delwood , Howell Jerrilyn K. , Chidambaram Monjula , Utterback Teresa , McDonald Lisa , Artiach Patricia , Bowman Cheryl , Cotton Matthew D. , Fujii Claire , Garland Stacey , Hatch Bonnie , Horst Kurt , Roberts Kevin , Sandusky Mina , Weidman Janice , Smith Hamilton O. , Venter J. Craig
Published: July 2002

The complete genome sequence ofTreponema pallidumwas determined and shown to be 1,138,006 base pairs containing 1041 predicted coding sequences (open reading frames). Systems for DNA replication, transcription, translation, and repair are intact, but catabolic and biosynthetic activities are minimized. The number of identifiable transporters is small, and no phosphoenolpyruvate:phosphotransferase carbohydrate transporters were found. Potential virulence factors include a family of 12 potential membrane proteins and several putative hemolysins. Comparison of theT. pallidumgenome sequence with that of another pathogenic spirochete,Borrelia burgdorferi, the agent of Lyme disease, identified unique and common genes and substantiates the considerable diversity observed among pathogenic spirochetes.
Moho Offset Across the Northern Margin of the Tibetan Plateau
Authors: Zhu Lupei , Helmberger Donald V.
Published: July 2002

Anomalous double-pulse teleseismic
P
-wave arrivals were observed at one station near the northern margin of the Tibetan Plateau. The azimuthal dependence of the waveform distortion and its absence at nearby stations indicated that the distortion was produced by receiver-side crustal heterogeneity. Modeling of the three-component data revealed a 15- to 20-kilometer Moho offset that occurs over a narrow lateral range of less than 5 kilometers. This east-west–striking offset separates the thick Tibetan Plateau crust from the Qaidam Basin crust. Such a sharp crustal thickness change implies a weak Tibetan Plateau crust that thickens vertically in response to penetration by India from the south and to blockage caused by a strong Qaidam Basin crust to the north.
Lunar Fe and Ti Abundances: Comparison of Lunar Prospector and Clementine Data
Authors: Elphic R. C. , Lawrence D. J. , Feldman W. C. , Barraclough B. L. , Maurice S. , Binder A. B. , Lucey P. G.
Published: July 2002

The Lunar Prospector neutron spectrometer data correlate well with iron and titanium abundances obtained through analysis of Clementine spectral reflectance data. With the iron and titanium dependence removed, the neutron spectrometer data also reveal regions with enhanced amounts of gadolinium and samarium, incompatible rare earth elements that are enriched in the final phases of magma crystallization. These regions are found mainly around the ramparts of the Imbrium impact basin but not around the other basins, including the much larger and deeper South Pole–Aitken basin. This result confirms the compositional uniqueness of the surface and interior of the Imbrium region.
Smart Engineering in the Mid-Carboniferous: How Well Could Palaeozoic Dragonflies Fly?
Authors: Wootton R. J. , Kukalová-Peck J. , Newman D. J. S. , Muzón J.
Published: July 2002

The wings of archaic Odonatoidea from the mid-Carboniferous of Argentina show features analogous to “smart” mechanisms in modern dragonflies that are associated with the agile, versatile flight necessary to catch prey in flight. These mechanisms act automatically in flight to depress the trailing edge and to facilitate wing twisting, in response to aerodynamic loading. The presence of similar features suggests that the earliest known odonatoids were already becoming adapted for high-performance flight in association with a predatory habit.
Experimental Therapeutics of Neurodegenerative Disorders: Unmet Needs
Authors: Shoulson Ira
Published: July 2002

The experimental therapeutics of neurodegenerative disorders is in its infancy, but neuroprotective strategies are already being applied in healthy persons at high risk of developing disease as well as in patients with manifest illness. Knowledge of etiology and pathogenesis, improved design of clinical trials, the development of biological markers, the advent of genetic animal models, the enhanced identification of susceptibility factors, and more effective drug delivery—such advances have improved the prospects for forestalling onset of illness and clinical decline in the growing numbers of people affected by neurodegenerative disorders.
Detection of Centimeter-Sized Meteoroid Impact Events in Saturn's F Ring
Authors: Showalter Mark R.
Published: July 2002

Voyager images reveal that three prominent clumps in Saturn's F ring were short-lived, appearing rapidly and then spreading and decaying in brightness over periods of ∼2 weeks. These features arise from hypervelocity impacts by ∼10-centimeter meteoroids into F ring bodies. Future ring observations of these impact events could constrain the centimeter-sized component of the meteoroid population, which is otherwise unmeasurable but plays an important role in the evolution of rings and surfaces in the outer solar system. The F ring's numerous other clumps are much longer lived and appear to be unrelated to impacts.
Comparison of the Complete Protein Sets of Worm and Yeast: Orthology and Divergence
Authors: Chervitz Stephen A. , Aravind L. , Sherlock Gavin , Ball Catherine A. , Koonin Eugene V. , Dwight Selina S. , Harris Midori A. , Dolinski Kara , Mohr Scott , Smith Temple , Weng Shuai , Cherry J. Michael , Botstein David
Published: July 2002

Comparative analysis of predicted protein sequences encoded by the genomes ofCaenorhabditis elegansandSaccharomyces cerevisiaesuggests that most of the core biological functions are carried out by orthologous proteins (proteins of different species that can be traced back to a common ancestor) that occur in comparable numbers. The specialized processes of signal transduction and regulatory control that are unique to the multicellular worm appear to use novel proteins, many of which re-use conserved domains. Major expansion of the number of some of these domains seen in the worm may have contributed to the advent of multicellularity. The proteins conserved in yeast and worm are likely to have orthologs throughout eukaryotes; in contrast, the proteins unique to the worm may well define metazoans.
Compensation of Horizontal Temperature and Salinity Gradients in the Ocean Mixed Layer
Authors: Rudnick Daniel L. , Ferrari Raffaele
Published: July 2002

Establishment of the temperature-salinity relationship in the ocean has concerned oceanographers for decades because of its importance for understanding ocean circulation. High-resolution measurements in the ocean mixed layer are used to show that temperature and salinity gradients on horizontal scales of 20 meters to 10 kilometers tend to compensate in their effect on density. These observations support the notion of a horizontal mixing in the mixed layer that depends on density gradient.
Continental Drainage in North America During the Phanerozoic from Nd Isotopes
Authors: Patchett P. Jonathan , Ross Gerald M. , Gleason James D.
Published: July 2002

Neodymium (Nd) isotopic data show consistent patterns in the sources of sedimentary rocks in North America at a continental scale. Between 600 and 450 million years ago (Ma), ancient continental shield sources dominated. Around 450 Ma, detritus from the Caledonian-Appalachian mountains overwhelmed sediment from all older sources, and is documented over large areas of the southern, western, and northern margins of North America. This material continued to dominate the sediment supply until about 150 Ma, probably due to cannibalistic recycling of sedimentary rocks formed earlier. Around 150 Ma, the rising western Cordillera delivered new and different detritus to the sedimentary system.
Condensation of Carbon in Radioactive Supernova Gas
Authors: Clayton Donald D. , Liu Weihong , Dalgarno Alexander
Published: July 2002

Chemistry resulting in the formation of large carbon-bearing molecules and dust in the interior of an expanding supernova was explored, and the equations governing their abundances were solved numerically. Carbon dust condenses from initially gaseous carbon and oxygen atoms because energetic electrons produced by radioactivity in the supernova cause dissociation of the carbon monoxide molecules, which would otherwise form and limit the supply of carbon atoms. The resulting free carbon atoms enable carbon dust to grow faster by carbon association than the rate at which the dust can be destroyed by oxidation. The origin of presolar micrometer-sized carbon solids that are found in meteorites is thereby altered.
The Fermionic Hanbury Brown and Twiss Experiment
Authors: Henny M. , Oberholzer S. , Strunk C. , Heinzel T. , Ensslin K. , Holland M. , Schönenberger C.
Published: July 2002

A Hanbury Brown and Twiss experiment for a beam of electrons has been realized in a two-dimensional electron gas in the quantum Hall regime. A metallic split gate serves as a tunable beam splitter to partition the incident beam into transmitted and reflected partial beams. In the nonequilibrium case the fluctuations in the partial beams are shown to be fully anticorrelated, demonstrating that fermions exclude each other. In equilibrium, the cross-correlation of current fluctuations at two different contacts is also found to be negative and nonzero, provided that a direct transmission exists between the contacts.
Genetic Control of Branching Morphogenesis
Authors: Metzger Ross J. , Krasnow Mark A.
Published: July 2002

The genetic programs that direct formation of the treelike branching structures of two animal organs have begun to be elucidated. In both the developing
Drosophila
tracheal (respiratory) system and mammalian lung, a fibroblast growth factor (FGF) signaling pathway is reiteratively used to pattern successive rounds of branching. The initial pattern of signaling appears to be established by early, more global embryonic patterning systems. The FGF pathway is then modified at each stage of branching by genetic feedback controls and other signals to give distinct branching outcomes. The reiterative use of a signaling pathway by both insects and mammals suggests a general scheme for patterning branching morphogenesis.
Regulation of Transcription by a Protein Methyltransferase
Authors: Chen Dagang , Ma Han , Hong Heng , Koh Stephen S. , Huang Shih-Ming , Schurter Brandon T. , Aswad Dana W. , Stallcup Michael R.
Published: July 2002

The p160 family of coactivators, SRC-1, GRIP1/TIF2, and p/CIP, mediate transcriptional activation by nuclear hormone receptors. Coactivator-associated arginine methyltransferase 1 (CARM1), a previously unidentified protein that binds to the carboxyl-terminal region of p160 coactivators, enhanced transcriptional activation by nuclear receptors, but only when GRIP1 or SRC-1a was coexpressed. Thus, CARM1 functions as a secondary coactivator through its association with p160 coactivators. CARM1 can methylate histone H3 in vitro, and a mutation in the putativeS-adenosylmethionine binding domain of CARM1 substantially reduced both methyltransferase and coactivator activities. Thus, coactivator-mediated methylation of proteins in the transcription machinery may contribute to transcriptional regulation.
The Vomeronasal Organ
Authors: Keverne Eric B.
Published: July 2002

The vomeronasal organ (VNO) is a chemoreceptor organ enclosed in a cartilaginous capsule and separated from the main olfactory epithelium. The vomeronasal neurons have two distinct types of receptor that differ from each other and from the large family of odorant receptors. The VNO receptors are seven-transmembrane receptors coupled to GTP-binding protein, but appear to activate inositol 1,4,5-trisphosphate signaling as opposed to cyclic adenosine monophosphate. The nature of stimulus access suggests that the VNO responds to nonvolatile cues, leading to activation of the hypothalamus by way of the accessory olfactory bulb and amygdala. The areas of hypothalamus innervated regulate reproductive, defensive, and ingestive behavior as well as neuroendocrine secretion.
The Galactic Center: An Interacting System of Unusual Sources
Authors: Yusef-Zadeh F. , Melia F. , Wardle M.
Published: July 2002

The region bounded by the inner tens of light-years at the center of the Milky Way Galaxy contains five principal components that coexist within the central deep well of gravitational potential. These constituents are a black hole candidate (Sgr A*) with a mass equivalent to 2.6 ± 0.2 × 106solar masses, a surrounding cluster of evolved stars, a complex of young stars, molecular and ionized gas clouds, and a powerful supernova-like remnant. The interaction of these components is responsible for many of the phenomena occurring in this complex and unique portion of the Galaxy. Developing a consistent picture of the primary interactions between the components at the Galactic center will improve our understanding of the nature of galactic nuclei in general, and will provide us with a better-defined set of characteristics of black holes. For example, the accretion of stellar winds by Sgr A* appears to produce far less radiation than indicated by estimates based on models of galactic nuclei.
The Glucocorticoid Receptor: Rapid Exchange with Regulatory Sites in Living Cells
Authors: McNally James G. , Müller Waltraud G. , Walker Dawn , Wolford Ronald , Hager Gordon L.
Published: July 2002

Steroid receptors bind to site-specific response elements in chromatin and modulate gene expression in a hormone-dependent fashion. With the use of a tandem array of mouse mammary tumor virus reporter elements and a form of glucocorticoid receptor labeled with green fluorescent protein, targeting of the receptor to response elements in live mouse cells was observed. Photobleaching experiments provide direct evidence that the hormone-occupied receptor undergoes rapid exchange between chromatin and the nucleoplasmic compartment. Thus, the interaction of regulatory proteins with target sites in chromatin is a more dynamic process than previously believed.
A Time for Restraint
Authors: Young Frank E.
Published: July 2002

The debate on the use of human embryos for research will be one of the more important issues of the 21st century. Unlike recombinant DNA technology, embryonic stem cell research most probably will result in the destruction of living embryos. Many people consider this research immoral, illegal, and unnecessary. Therefore, it is imperative to proceed cautiously. Federal funding of research using human embryos or pluripotent cells derived from them would be inappropriate until further resolution of the ethical issues has been achieved.
Structure of the Hydrated α-Al2O3(0001) Surface
Authors: Eng Peter J. , Trainor Thomas P. , Brown Jr. Gordon E. , Waychunas Glenn A. , Newville Matthew , Sutton Stephen R. , Rivers Mark L.
Published: July 2002

The physical and chemical properties of the hydrated α-Al2O3(0001) surface are important for understanding the reactivity of natural and synthetic aluminum-containing oxides. The structure of this surface was determined in the presence of water vapor at 300 kelvin by crystal truncation rod diffraction at a third-generation synchrotron x-ray source. The fully hydrated surface is oxygen terminated, with a 53% contracted double Al layer directly below. The structure is an intermediate between α-Al2O3and γ-Al(OH)3, a fully hydroxylated form of alumina. A semiordered oxygen layer about 2.3 angstroms above the terminal oxygen layer is interpreted as adsorbed water. The clean α-Al2O3(0001) surface, in contrast, is Al terminated and significantly relaxed relative to the bulk structure. These differences explain the different reactivities of the clean and hydroxylated surfaces.
Kinesin Superfamily Motor Protein KIF17 and mLin-10 in NMDA Receptor-Containing Vesicle Transport
Authors: Setou Mitsutoshi , Nakagawa Terunaga , Seog Dae-Hyun , Hirokawa Nobutaka
Published: July 2002

Experiments with vesicles containing
N
-methyl-
d
-aspartate (NMDA) receptor 2B (NR2B subunit) show that they are transported along microtubules by KIF17, a neuron-specific molecular motor in neuronal dendrites. Selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of mLin-10 (Mint1/X11), which is a constituent of a large protein complex including mLin-2 (CASK), mLin-7 (MALS/Velis), and the NR2B subunit. This interaction, specific for a neurotransmitter receptor critically important for plasticity in the postsynaptic terminal, may be a regulatory point for synaptic plasticity and neuronal morphogenesis.
Cross Talk Between Interferon-γ and -α/β Signaling Components in Caveolar Membrane Domains
Authors: Takaoka Akinori , Mitani Yukiko , Suemori Hirofumi , Sato Mitsuharu , Yokochi Taeko , Noguchi Shigeru , Tanaka Nobuyuki , Taniguchi Tadatsugu
Published: July 2002

Definition of cellular responses to cytokines often involves cross-communication through their respective receptors. Here, signaling by interferon-γ (IFN-γ) is shown to depend on the IFN-α/β receptor components. Although these IFNs transmit signals through distinct receptor complexes, the IFN-α/β receptor component, IFNAR1, facilitates efficient assembly of IFN-γ–activated transcription factors. This cross talk is contingent on a constitutive subthreshold IFN-α/β signaling and the association between the two nonligand-binding receptor components, IFNAR1 and IFNGR2, in the caveolar membrane domains. This aspect of signaling cross talk by IFNs may apply to other cytokines.
Synaptic Integration Mediated by Striatal Cholinergic Interneurons in Basal Ganglia Function
Authors: Kaneko Satoshi , Hikida Takatoshi , Watanabe Dai , Ichinose Hiroshi , Nagatsu Toshiharu , Kreitman Robert J. , Pastan Ira , Nakanishi Shigetada
Published: July 2002

The physiological role of striatal cholinergic interneurons was investigated with immunotoxin-mediated cell targeting (IMCT). Unilateral cholinergic cell ablation caused an acute abnormal turning behavior. These mice showed gradual recovery but displayed abnormal turning by both excess stimulation and inhibition of dopamine actions. In the acute phase, basal ganglia function was shifted to a hyperactive state by stimulation and suppression of striatonigral and striatopallidal neurons, respectively. D1 and D2 dopamine receptors were then down-regulated, relieving dopamine-predominant synaptic perturbation but leaving a defect in controlling dopamine responses. The acetylcholine-dopamine interaction is concertedly and adaptively regulated for basal ganglia synaptic integration.
Osmium Isotopic Evidence for Mesozoic Removal of Lithospheric Mantle Beneath the Sierra Nevada, California
Authors: Lee Cin-Ty , Yin Qingzhu , Rudnick Roberta L. , Chesley John T. , Jacobsen Stein B.
Published: July 2002

Thermobarometric and Os isotopic data for peridotite xenoliths from late Miocene and younger lavas in the Sierra Nevada reveal that the lithospheric mantle is vertically stratified: the shallowest portions (<45 to 60 kilometers) are cold (670° to 740°C) and show evidence for heating and yield Proterozoic Os model ages, whereas the deeper portions (45 to 100 kilometers) yield Phanerozoic Os model ages and show evidence for extensive cooling from temperatures >1100°C to 750°C. Because a variety of isotopic evidence suggests that the Sierran batholith formed on preexisting Proterozoic lithosphere, most of the original lithospheric mantle appears to have been removed before the late Miocene, leaving only a sliver of ancient mantle beneath the crust.
Phase Evolution in a Kondo-Correlated System
Authors: Ji Yang , Heiblum M. , Sprinzak D. , Mahalu D. , Shtrikman Hadas
Published: July 2002

We measured the phase evolution of electrons as they traverse a quantum dot (QD) formed in a two-dimensional electron gas that serves as a localized spin. The traversal phase, determined by embedding the QD in a double path electron interferometer and measuring the quantum interference of the electron wave functions manifested by conductance oscillation as a function of a weak magnetic field, evolved by π radians, a range twice as large as theoretically predicted. As the correlation weakened, a gradual transition to the familiar phase evolution of a QD was observed. The specific phase evolution observed is highly sensitive to the onset of Kondo correlation, possibly serving as an alternative fingerprint of the Kondo effect.
Early Permian Bipedal Reptile
Authors: Berman David S. , Reisz Robert R. , Scott Diane , Henrici Amy C. , Sumida Stuart S. , Martens Thomas
Published: July 2002

A 290-million-year-old reptilian skeleton from the Lower Permian (Asselian) of Germany provides evidence of abilities for cursorial bipedal locomotion, employing a parasagittal digitigrade posture. The skeleton is of a small bolosaurid,
Eudibamus cursoris
, gen. et sp. nov
.
, and confirms the widespread distribution of Bolosauridae across Laurasia during this early stage of amniote evolution.
E. cursoris
is the oldest known representative of Parareptilia, a major clade of reptiles.
Geodynamic Evidence for a Chemically Depleted Continental Tectosphere
Authors: Forte Alessandro M. , Claire Perry H. K.
Published: July 2002

The tectosphere, namely the portions of Earth's mantle lying below cratons, has a thermochemical structure that differs from average suboceanic mantle. The tectosphere is thought to be depleted in its basaltic components and to have an intrinsic buoyancy that balances the mass increase associated with its colder temperature relative to suboceanic mantle. Inversions of a large set of geodynamic data related to mantle convection, using tomography-based mantle flow models, indicate that the tectosphere is chemically depleted and relatively cold to 250 kilometers depth below Earth's surface. The approximate equilibrium between thermal and chemical buoyancy contributes to cratonic stability over geological time.
SME-Type Carbapenem-Hydrolyzing Class A β-Lactamases from Geographically Diverse
Serratia marcescens
Strains
Authors: Queenan Anne Marie , Torres-Viera Carlos , Gold Howard S. , Carmeli Yehuda , Eliopoulos George M. , Moellering Robert C. , Quinn John P. , Hindler Janet , Medeiros Antone A. , Bush Karen
Published: July 2002

Three sets of carbapenem-resistant
Serratia marcescens
isolates have been identified in the United States: 1 isolate in Minnesota in 1985 (before approval of carbapenems for clinical use), 5 isolates in Los Angeles (University of California at Los Angeles [UCLA]) in 1992, and 19 isolates in Boston from 1994 to 1999. All isolates tested produced two β-lactamases, an AmpC-type enzyme with pI values of 8.6 to 9.0 and one with a pI value of approximately 9.5. The enzyme with the higher pI in each strain hydrolyzed carbapenems and was not inhibited by EDTA, similar to the chromosomal class A SME-1 β-lactamase isolated from the 1982 London strain
S. marcescens
S6. The genes encoding the carbapenem-hydrolyzing enzymes were cloned in
Escherichia coli
and sequenced. The enzyme from the Minnesota isolate had an amino acid sequence identical to that of SME-1. The isolates from Boston and UCLA produced SME-2, an enzyme with a single amino acid change relative to SME-1, a substitution from valine to glutamine at position 207. Purified SME enzymes from the U.S. isolates had β-lactam hydrolysis profiles similar to that of the London SME-1 enzyme. Pulsed-field gel electrophoresis analysis revealed that the isolates showed some similarity but differed by at least three genetic events. In conclusion, a family of rare class A carbapenem-hydrolyzing β-lactamases first described in London has now been identified in
S. marcescens
isolates across the United States.
Candida albicansMutants Deficient in Respiration Are Resistant to the Small Cationic Salivary Antimicrobial Peptide Histatin 5
Authors: Gyurko Csilla , Lendenmann Urs , Troxler Robert F. , Oppenheim Frank G.
Published: July 2002

Histatins are a group of small cationic peptides in human saliva which are well known for their antibacterial and antifungal activities. In a previous study we demonstrated that histatin 5 kills both blastoconidia and germ tubes ofCandida albicansin a time- and concentration-dependent manner at 37°C, whereas no killing was detected at 4°C. This indicated that killing activity depends on cellular energy. To test histatin 5 killing activity at lower cellular ATP levels at 37°C, respiratory mutants, or so-called petite mutants, ofC. albicanswere prepared. These mutants are deficient in respiration due to mutations in mitochondrial DNA. Mutants were initially identified by their small colony size and were further characterized with respect to colony morphology, growth characteristics, respiratory activity, and cytochrome spectra. The killing activity of histatin 5 at the highest concentration was only 28 to 30% against respiratory mutants, whereas 98% of the wild-type cells were killed. Furthermore, histatin 5 killing activity was also tested on wild-type cells in the presence of the respiratory inhibitor sodium azide or, alternatively, the uncoupler carbonyl cyanidem-chlorophenylhydrazone. In both cases histatin 5 killing activity was significantly reduced. Additionally, supernatants and pellets of cells incubated with histatin 5 in the presence or absence of inhibitors of mitochondrial ATP synthesis were analyzed by sodium dodecyl sulfate gel electrophoresis. It was observed that wild-type cells accumulated large amounts of histatin 5, while wild-type cells treated with inhibitors or petite mutants did not accumulate significant amounts of the peptide. These data showed first that cellular accumulation of histatin 5 is necessary for killing activity and second that accumulation of histatin 5 depends on the availability of cellular energy. Therefore, mitochondrial ATP synthesis is required for effective killing activity of histatin 5.
In Vivo Characterization of the Pharmacodynamics of Flucytosine in a Neutropenic Murine Disseminated Candidiasis Model
Authors: Andes D. , van Ogtrop M.
Published: July 2002

In vivo pharmacodynamic parameters have been characterized for a variety of antibacterial agents. These parameters have been studied in correlation with in vivo outcomes in order to determine (i) which dosing parameter is predictive of outcome and (ii) the magnitude of that parameter associated with efficacy. Very little is known of the pharmacodynamics of antifungal agents. We used a neutropenic murine model of disseminated candidiasis to correlate the pharmacodynamic parameters (percentage of time above the MIC, area under the concentration-time curve [AUC]/MIC and peak level/MIC) for flucytosine (5-FC) in vivo with efficacy as measured by organism number in homogenized kidney cultures after 24 h of therapy. The pharmacokinetics of 5-FC in infected mice were linear. Serum half-lives ranged from 0.36 to 0.43 h. Infection was achieved by intravenous inoculation of 10
6
CFU of yeast cells per ml via the lateral tail vein of neutropenic mice. Groups of mice were treated with fourfold escalating total doses of 5-FC ranging from 1.56 to 400 mg/kg of body weight/day divided into one, two, four, or eight doses over 24 h. Increasing doses produced minimal concentration-dependent killing ranging from 0 to 0.9 log
10
CFU/kidneys. 5-FC did, however, produce a dose-dependent suppression of growth after levels in serum had fallen below the MIC. The fungistatic dose increased from 6 to 8 mg/kg with dosing every 3 and 6 h to 70 mg/kg at with dosing every 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Time above the MIC was the parameter best predictive of outcome, while AUC/MIC was only slightly less predictive (time above MIC,
R
2
= 85%; AUC/MIC,
R
2
= 77%; peak level/MIC,
R
2
= 53%). Maximal efficacy was observed when levels exceeded the MIC for only 20 to 25% of the dosing interval. If one considers drug kinetics in humans, these results suggest reevaluation of current dosing regimens.
Aminoglycoside-Streptothricin Resistance Gene Cluster
aadE–sat4–aphA-3
Disseminated among Multiresistant Isolates of
Enterococcus faecium
Authors: Werner Guido , Hildebrandt Bianca , Witte Wolfgang
Published: July 2002

Seventy-two
Enterococcus faecium
isolates of different origins highly resistant to nourseothricin and streptomycin were studied. Sequencing of a genomic fragment from two isolates identified a gene cluster,
aadE–
sat4
–
aphA-3
, which has been isolated recently in staphylococci and
Campylobacter coli
. Patterns of digested PCR products of
aadE–sat4–aphA-3
were identical for all isolates.
Antifungal Activity and Pharmacokinetics of Posaconazole (SCH 56592) in Treatment and Prevention of Experimental Invasive Pulmonary Aspergillosis: Correlation with Galactomannan Antigenemia
Authors: Petraitiene Ruta , Petraitis Vidmantas , Groll Andreas H. , Sein Tin , Piscitelli Stephen , Candelario Myrna , Field-Ridley Aida , Avila Nilo , Bacher John , Walsh Thomas J.
Published: July 2002

The antifungal efficacy, safety, and pharmacokinetics of posaconazole (SCH 56592) (POC) were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to
Aspergillus fumigatus
in persistently neutropenic rabbits. Antifungal therapy consisted of POC at 2, 6, and 20 mg/kg of body weight per os; itraconazole (ITC) at 2, 6, and 20 mg/kg per os; or amphotericin B (AMB) at 1 mg/kg intravenously. Rabbits treated with POC showed a significant improvement in survival and significant reductions in pulmonary infarct scores, total lung weights, numbers of pulmonary CFU per gram, numbers of computerized-tomography-monitored pulmonary lesions, and levels of galactomannan antigenemia. AMB and POC had comparable therapeutic efficacies by all parameters. By comparison, animals treated with ITC had no significant changes in outcome variables in comparison to those of untreated controls (UC). Rabbits receiving prophylactic POC at all dosages showed a significant reduction in infarct scores, total lung weights, and organism clearance from lung tissue in comparison to results for UC (
P
< 0.01). There was dosage-dependent microbiological clearance of
A. fumigatus
from lung tissue in response to POC. Serum creatinine levels were greater (
P
< 0.01) in AMB-treated animals than in UC and POC- or ITC-treated rabbits. There was no elevation of serum hepatic transaminase levels in POC- or ITC-treated rabbits. The pharmacokinetics of POC and ITC in plasma demonstrated dose dependency after multiple dosing. The 2-, 6-, and 20-mg/kg dosages of POC maintained plasma drug levels above the MICs for the entire 24-h dosing interval. In summary, POC at ≥6 mg/kg/day per os generated sustained concentrations in plasma of ≥1 μg/ml that were as effective in the treatment and prevention of invasive pulmonary aspergillosis as AMB at 1 mg/kg/day and more effective than cyclodextrin ITC at ≥6 mg/kg/day per os in persistently neutropenic rabbits.
Multicenter Survey of the Changing In Vitro Antimicrobial Susceptibilities of Clinical Isolates of
Bacteroides fragilis
Group,
Prevotella, Fusobacterium, Porphyromonas
, and
Peptostreptococcus
Species
Authors: Aldridge Kenneth E. , Ashcraft Deborah , Cambre Karl , Pierson Carl L. , Jenkins Stephen G. , Rosenblatt Jon E.
Published: July 2002

In vitro surveys of antimicrobial resistance among clinically important anaerobes are an important source of information that can be used for clinical decisions in the choice of empiric antimicrobial therapy. This study surveyed the susceptibilities of 556 clinical anaerobic isolates from four large medical centers using a broth microdilution method. Piperacillin-tazobactam was the only antimicrobial agent to which all the isolates were susceptible. Similarly, imipenem, meropenem, and metronidazole were highly active (resistance, <0.5%), whereas the lowest susceptibility rates were noted for penicillin G, ciprofloxacin, and clindamycin. For most antibiotics, blood isolates were less susceptible than isolates from intra-abdominal, obstetric-gynecologic, and other sources. All isolates of the
Bacteroides fragilis
group were susceptible to piperacillin-tazobactam and metronidazole, while resistance to imipenem and meropenem was low (<2%). For these same isolates, resistance rates (intermediate and resistant MICs) to ampicillin-sulbactam, cefoxitin, trovafloxacin, and clindamycin were 11, 8, 7, and 29%, respectively. Among the individual species of the
B. fragilis
group, the highest resistance rates were noted among the following organism-drug combinations: for clindamycin,
Bacteroides distasonis
and
Bacteroides ovatus
; for cefoxitin,
Bacteroides thetaiotaomicron, B. distasonis
, and
Bacteroides uniformis;
for ampicillin-sulbactam,
B. distasonis, B. ovatus
, and
B. uniformis
; and for trovafloxacin,
Bacteroides vulgatus
. For the carbapenens, imipenem resistance was noted among
B. fragilis
and meropenem resistance was seen among
B. fragilis, B. vulgatus
, and
B. uniformis
. With few exceptions all antimicrobial agents were highly active against isolates of
Prevotella, Fusobacterium, Porphyromonas
, and
Peptostreptococcus
. These data further establish and confirm that clinically important anaerobes can vary widely in their antimicrobial susceptibilities. Fortunately most antimicrobial agents were active against the test isolates. However, concern is warranted for what appears to be a significant increases in resistance to ampicillin-sulbactam and clindamycin.
In Vitro and In Vivo Activities of Amikacin, Cefepime, Amikacin plus Cefepime, and Imipenem against an SHV-5 Extended-Spectrum β-Lactamase-ProducingKlebsiella pneumoniaeStrain
Authors: Szabó Dóra , Máthé András , Filetóth Zsolt , Anderlik Piroska , Rókusz László , Rozgonyi Ferenc
Published: July 2002

The in vitro and in vivo effectiveness of amikacin, cefepime, and imipenem was studied using a high inoculum of an extended-spectrum β-lactamase-producingKlebsiella pneumoniaestrain. An in vitro susceptibility test at the standard inoculum predicted the in vivo outcome of amikacin or imipenem while it did not do so for cefepime due to the inoculum effect.
Thalidomide Inhibits Granulocyte Responses in Healthy Humans after Ex Vivo Stimulation with Bacterial Antigens
Authors: Juffermans Nicole P. , Verbon Annelies , Schultz Marc J. , Hack C. Erik , van Deventer Sander J. H. , Speelman Peter , van der Poll Tom
Published: July 2002

Ingestion of thalidomide was associated with a reduction in the upregulation of the granulocyte activation marker CD11b and a reduced capacity to release elastase and lactoferrin after stimulation with lipopolysaccharide or lipoteichoic acid. A single oral dose of thalidomide attenuates neutrophil activation upon ex vivo stimulation with bacterial antigens.
Prospective Study of
Candida
Species in Patients at a Comprehensive Cancer Center
Authors: Safdar Amar , Chaturvedi Vishnu , Cross Emily W. , Park Steven , Bernard Edward M. , Armstrong Donald , Perlin David S.
Published: July 2002

Since most nosocomial systemic yeast infections arise from the endogenous flora of the patient, we prospectively evaluated the species stratification and antifungal susceptibility profile of
Candida
spp. associated with heavy colonization and systemic infection in patients at Memorial Sloan-Kettering Cancer Center in New York. A total of 349
Candida
isolates were obtained from 223 patients during the later half of 1998. Cancer was the most common underlying disease, occurring in 91% of the patients, including 61.8% with organ and 23.7% with hematological malignancies; 4.4% of the patients had AIDS.
Candida albicans
was the predominant species (67.3%); among 114 non-
albicans Candida
spp.,
C. glabrata
(45.6%) was the most frequent, followed by
C. tropicalis
(18.4%),
C. parapsilosis
(16.6%), and
C. krusei
(9.6%). The overall resistance to triazole-based agents among all yeast isolates was 9.4 and 10.8% for fluconazole and itraconazole, respectively. A total of 5% of
C. albicans
strains were resistant to triazole antifungals, whereas 30.8 and 46.2% of
C. glabrata
strains were resistant to fluconazole (MIC ≥ 64 μg/ml) and itraconazole (MIC ≥ 1 μg/ml), respectively. A significant association was observed between prior treatment with triazole and isolation of fluconazole-resistant
C. albicans
(
P
= 0.005, OR 36), although this relationship was not seen in
C. glabrata
isolates (
P
= 0.4). This study reinforces the importance of periodic, prospective surveillance of clinical fungal isolates to determine appropriate prophylactic, empiric, and preemptive antifungal therapy for the highly susceptible patient population.
In Vitro Susceptibilities of Wild-Type or Drug-Resistant Hepatitis B Virus to (−)-β-d-2,6-Diaminopurine Dioxolane and 2′-Fluoro-5-Methyl-β-l-Arabinofuranosyluracil
Authors: Chin Ruth , Shaw Tim , Torresi Joseph , Sozzi Vittina , Trautwein Christian , Bock Thomas , Manns Michael , Isom Harriet , Furman Phil , Locarnini Stephen
Published: July 2002

Prolonged treatment of chronic hepatitis B virus (HBV) infection with lamivudine ([−]-β-l-2′,3′-dideoxy-3′ thiacytidine) or famciclovir may select for viral mutants that are drug resistant due to point mutations in the polymerase gene. Determining whether such HBV mutants are sensitive to new antiviral agents is therefore important. We used a transient transfection system to compare the sensitivities of wild-type HBV and four lamivudine- and/or famciclovir-resistant HBV mutants to adefovir [9-(2-phosphonyl-methoxyethyl)-adenine; PMEA] and the nucleoside analogues (−)-β-d-2, 6-diaminopurine dioxolane (DAPD) and 2′-fluoro-5-methyl-β-l-arabinofuranosyluracil (l-FMAU). The drug-resistant mutants contained amino acid substitutions in the polymerase protein. We found that the M550I and M550V plus L526M substitutions, which confer lamivudine resistance, did not confer cross-resistance to adefovir or DAPD, but conferred cross-resistance tol-FMAU. The M550V substitution in isolation conferred a similar phenotype to M550I, except that it did not confer significant resistance tol-FMAU. The L526M substitution, which is associated with famciclovir resistance, conferred cross-resistance tol-FMAU but not to adefovir or DAPD. Inhibition of HBV secretion by DAPD,l-FMAU, and adefovir did not always correlate with inhibition of the generation of intracellular HBV replicative intermediates, suggesting that these analogs may preferentially inhibit specific stages of the viral replication cycle.
BAL9141, a Novel Extended-Spectrum Cephalosporin Active against Methicillin-Resistant
Staphylococcus aureus
in Treatment of Experimental Endocarditis
Authors: Entenza J. M. , Hohl P. , Heinze-Krauss I. , Glauser M. P. , Moreillon P.
Published: July 2002

The therapeutic efficacy of BAL9141 (formerly Ro 63-9141), a novel cephalosporin with broad in vitro activity that also has activity against methicillin-resistant
Staphylococcus aureus
(MRSA), was investigated in rats with experimental endocarditis. The test organisms were homogeneously methicillin-resistant
S. aureus
strain COL transformed with the penicillinase-encoding plasmid pI524 (COL Bla+) and homogeneously methicillin-resistant, penicillinase-producing isolate P8-Hom, selected by serial exposure of parent strain P8 to methicillin. The MICs of BAL9141 for these organisms (2 mg/liter) were low, and BAL9141was bactericidal in time-kill curve studies after 24 h of exposure to either two, four, or eight times the MIC. Rats with experimental endocarditis were treated in a three-arm study with a continuous infusion of BAL5788 (formerly Ro 65-5788), a carbamate prodrug of BAL9141, or with amoxicillin-clavulanate or vancomycin. The rats were administered BAL9141 to obtain steady-state target levels of 20, 10, and 5 mg of per liter or were administered either 1.2 g of amoxicillin-clavulanate (ratio 5:1) every 6 h or 1 g of vancomycin every 12 h at changing flow rates to simulate the pharmacokinetics produced in humans by intermittent intravenous treatment. Treatment was started 12 h after bacterial challenge and lasted for 3 days. BAL9141 was successful in the treatment of experimental endocarditis due to either MRSA isolate COL Bla+ or MRSA isolate P8-Hom at the three targeted steady-state concentrations and sterilized >90% of cardiac vegetations (
P
< 0.005 versus controls;
P
< 0.05 versus amoxicillin-clavulanate and vancomycin treatment groups). These promising in vivo results with BAL9141 correlated with the high affinity of the drug for PBP 2a and its stability to penicillinase hydrolysis observed in vitro.
In Vitro Potentiation of Antibiotic Activities by a Catecholate Iron Chelator against Chloroquine-ResistantPlasmodium falciparum
Authors: Pradines Bruno , Ramiandrasoa Florence , Rolain Jean Marc , Rogier Christophe , Mosnier Joel , Daries William , Fusai Thierry , Kunesch Gerhard , Le Bras Jacques , Parzy Daniel
Published: July 2002

FR160, a catechol iron chelator, and tetracyclines or norfloxacin exert in vitro additive or synergistic activity against a chloroquine-resistantPlasmodium falciparumclone. FR160 shows antagonistic effects in association with macrolides, ofloxacin, and rifampin.
Involvement of Multidrug Resistance-Associated Protein 2 in Intestinal Secretion of Grepafloxacin in Rats
Authors: Naruhashi Kazumasa , Tamai Ikumi , Inoue Natsuko , Muraoka Hiromi , Sai Yoshimichi , Suzuki Nagao , Tsuji Akira
Published: July 2002

We investigated the contribution of multidrug resistance-associated protein 2 (MRP2) to the secretory transport of grepafloxacin and compared its functional role with that of P-glycoprotein (P-gp) by using Sprague-Dawley rats (SDRs) and Eisai hyperbilirubinemic rats (EHBRs), in which MRP2 is hereditarily defective. In intestinal tissue from SDRs mounted in Ussing chambers, the level of transport in the direction from the serosal layer to the mucosal layer was twofold greater than that in the direction from the mucosal layer to the serosal layer. This secretory transport of grepafloxacin was diminished by both probenecid, an MRP2 inhibitor, and cyclosporine, a P-gp inhibitor. In intestinal tissue from EHBRs, the secretory transport of grepafloxacin was lower than that in intestinal tissue from SDRs and was inhibited by cyclosporine but not by probenecid. The absorption of grepafloxacin from intestinal loops in SDRs was in the order of duodenum > jejunum > ileum and was increased by cyclosporine but not by probenecid. The absorption in EHBRs was not higher than that in SDRs. The intestinal secretory clearance in SDRs after intravenous administration of grepafloxacin was shown to be greater for the ileum than for the duodenum, which is in good agreement with the previously reported regional expression profile of MRP2 mRNA. The intestinal secretory clearance was lower in EHBRs than in SDRs. Accordingly, in addition to P-gp, MRP2 might play a role in the secretory transport of grepafloxacin. The function of MRP2 in facilitating grepafloxacin transport in the secretory direction is more pronounced both in vitro and in vivo, while the restriction of entry from the lumen into the cell by MRP2 seems to be negligible, compared with that by P-gp, in the case of grepafloxacin.
Quantitative PCR Assay To Evaluate Ampicillin, Ofloxacin, and Doxycycline for Treatment of Experimental Leptospirosis
Authors: Truccolo Johann , Charavay Françoise , Merien Fabrice , Perolat Philippe
Published: July 2002

The susceptibility ofLeptospira interrogansserovar icterohaemorrhagiae strain Verdun to selected antibiotics used in medical practice (ampicillin, doxycycline, and ofloxacin) was evaluated in a Syrian hamster model, to determine the efficacy of these antibiotics during the course of the disease. A quantitative PCR assay was used to monitor the density of leptospires in blood and in target organs (liver, kidney, lung, heart, and spleen). Our results demonstrated the ability of ampicillin at a high dose (100 mg/kg of body weight) to clear leptospires from the host, except from kidneys and heart, where 102leptospires/g remained at day 6. Ofloxacin (30 mg/kg) was unable to clear bacteria from blood or kidneys. With doxycycline (10 mg/kg), the clearance of leptospires occurred in 2 days in all the target organs studied, with the exception of liver, which required 3 days. Our data demonstrate the value of monitoring the kinetics of experimental leptospiral infection in order to accurately evaluate the efficacy of antibiotics. We have demonstrated the potential value of doxycycline for the treatment of leptospirosis cases, except in circumstances where it is contraindicated. This experimental model could be used to define better therapeutic strategies for human leptospirosis, by testing associations or new formulations of antibiotics.