bluuebunny/crossref_metadata_2025 huggingface dataset:
Transform-Limited, Narrow-Linewidth Lasing Action in Organic Semiconductor Microcavities
Authors: Bulović V. , Kozlov V. G. , Khalfin V. B. , Forrest S. R.
Published: July 2002

Lasing action in organic vertical-cavity surface-emitting laser (OVCSEL) structures is demonstrated. Optically pumped OVCSELs with an active layer composed of a thin-film organic semiconductor tris-(8-hydroxyquinoline) aluminum (Alq
3
) doped with DCM laser dye produced very narrow linewidth (0.2 ± 0.1 angstrom), high-power (3 watts) emission that could be varied in different devices from orange to red. The efficient energy transfer from Alq
3
to DCM results in a threshold input energy of 300 microjoules per square centimeter. An operational lifetime >10
6
laser pulses was achieved for a device operated well above threshold in atmosphere. The linewidths above threshold are Fourier transform–limited and could potentially be narrowed further.
The Formation of HCS and HCSH Molecules and Their Role in the Collision of Comet Shoemaker-Levy 9 with Jupiter
Authors: Kaiser R. I. , Ochsenfeld C. , Head-Gordon M. , Lee Y. T.
Published: July 2002

The reaction of hydrogen sulfide with ground-state atomic carbon was examined with crossed molecular beams experiments and ab initio calculations. The thiohydroxycarbene molecule, HCSH, was the reactive intermediate, which fragmented into atomic hydrogen and the thioformyl radical HCS. This finding may account for the unassigned HCS source and an unidentified HCSH radical needed to match observed CS abundances from the collision of comet Shoemaker-Levy 9 into Jupiter. In the shocked jovian atmosphere, HCS could further decompose to H and CS, and CS could react with SH and OH to yield the observed CS
2
and COS.
Capacity for Plasticity in the Adult Owl Auditory System Expanded by Juvenile Experience
Authors: Knudsen Eric I.
Published: July 2002

In the process of creating a multimodal map of space, auditory-visual neurons in the optic tectum establish associations between particular values of auditory spatial cues and locations in the visual field. In the barn owl, tectal neurons reveal these associations in the match between their tuning for interaural time differences (ITDs) and the locations of their visual receptive fields (VRFs). In young owls ITD-VRF associations can be adjusted by experience over a wide range, but the range of adjustment normally becomes quite restricted in adults. This normal range of adjustment in adults was greatly expanded in owls that had previously learned abnormal ITD-VRF associations as juveniles. Thus, the act of learning abnormal associations early in life leaves an enduring trace in this pathway that enables unusual functional connections to be reestablished, as needed, in adulthood, even when the associations represented by these connections have not been used for an extended period of time.
The Structure of the Upper Atmosphere of Mars: In Situ Accelerometer Measurements from Mars Global Surveyor
Authors: Keating G. M. , Bougher S. W. , Zurek R. W. , Tolson R. H. , Cancro G. J. , Noll S. N. , Parker J. S. , Schellenberg T. J. , Shane R. W. , Wilkerson B. L. , Murphy J. R. , Hollingsworth J. L. , Haberle R. M. , Joshi M. , Pearl J. C. , Conrath B. J. , Smith M. D. , Clancy R. T. , Blanchard R. C. , Wilmoth R. G. , Rault D. F. , Martin T. Z. , Lyons D. T. , Esposito P. B. , Johnston M. D. , Whetzel C. W. , Justus C. G. , Babicke J. M.
Published: July 2002

The Mars Global Surveyor (MGS)
z
-axis accelerometer has obtained over 200 vertical structures of thermospheric density, temperature, and pressure, ranging from 110 to 170 kilometers, compared to only three previous such vertical structures. In November 1997, a regional dust storm in the Southern Hemisphere triggered an unexpectedly large thermospheric response at mid-northern latitudes, increasing the altitude of thermospheric pressure surfaces there by as much as 8 kilometers and indicating a strong global thermospheric response to a regional dust storm. Throughout the MGS mission, thermospheric density bulges have been detected on opposite sides of the planet near 90°E and 90°W, in the vicinity of maximum terrain heights. This wave 2 pattern may be caused by topographically-forced planetary waves propagating up from the lower atmosphere.
Topography of the Northern Hemisphere of Mars from the Mars Orbiter Laser Altimeter
Authors: Smith D. E. , Zuber M. T. , Frey H. V. , Garvin J. B. , Head J. W. , Muhleman D. O. , Pettengill G. H. , Phillips R. J. , Solomon S. C. , Zwally H. J. , Banerdt W. B. , Duxbury T. C.
Published: July 2002

The first 18 tracks of laser altimeter data across the northern hemisphere of Mars from the Mars Global Surveyor spacecraft show that the planet at latitudes north of 50° is exceptionally flat; slopes and surface roughness increase toward the equator. The polar layered terrain appears to be a thick ice-rich formation with a non-equilibrium planform indicative of ablation near the periphery. Slope relations suggest that the northern Tharsis province was uplifted in the past. A profile across Ares Vallis channel suggests that the discharge through the channel was much greater than previously estimated. The martian atmosphere shows significant 1-micrometer atmospheric opacities, particularly in low-lying areas such as Valles Marineris.
A Signaling Complex of Ca
2+
-Calmodulin-Dependent Protein Kinase IV and Protein Phosphatase 2A
Authors: Westphal Ryan S. , Anderson Kristin A. , Means Anthony R. , Wadzinski Brian E.
Published: July 2002

Stimulation of T lymphocytes results in a rapid increase in intracellular calcium concentration ([Ca
2+
]
i
) that parallels the activation of Ca
2+
-calmodulin–dependent protein kinase IV (CaMKIV), a nuclear enzyme that can phosphorylate and activate the cyclic adenosine monophosphate (cAMP) response element–binding protein (CREB). However, inactivation of CaMKIV occurs despite the sustained increase in [Ca
2+
]
i
that is required for T cell activation. A stable and stoichiometric complex of CaMKIV with protein serine-threonine phosphatase 2A (PP2A) was identified in which PP2A dephosphorylates CaMKIV and functions as a negative regulator of CaMKIV signaling. In Jurkat T cells, inhibition of PP2A activity by small t antigen enhanced activation of CREB-mediated transcription by CaMKIV. These findings reveal an intracellular signaling mechanism whereby a protein serine-threonine kinase (CaMKIV) is regulated by a tightly associated protein serine-threonine phosphatase (PP2A).
Near Extinction of a Large, Widely Distributed Fish
Authors: Casey Jill M. , Myers Ransom A.
Published: July 2002

Are extinctions of marine vertebrates as rare and unlikely as current data indicate? Long-term research surveys on the continental shelf between the Grand Banks of Newfoundland and southern New England reveal that one of the largest skates in the northwest Atlantic, the barndoor skate (
Raja laevis
), is close to extinction. Forty-five years ago, research surveys on St. Pierre Bank (off southern Newfoundland) recorded barndoor skates in 10% of their tows; in the last 20 years, none has been caught, and this pattern of decline is similar throughout the range of the species.
Host-Race Formation in the Common Cuckoo
Authors: Marchetti Karen , Nakamura Hiroshi , Gibbs H. Lisle
Published: July 2002

The exploitation of a new host by a parasite may result in host-race formation or speciation. A brood parasitic bird, the common cuckoo, is divided into host races, each characterized by egg mimicry of different host species. Microsatellite DNA markers were used to examine cuckoo mating patterns and host usage in an area where a new host has been recently colonized. Female cuckoos show strong host preferences, but individual males mate with females that lay in the nests of different hosts. Female host specialization may lead to the evolution of sex-linked traits such as egg mimicry, even though gene flow through the male line prevents completion of the speciation process.
An MTP Inhibitor That Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits
Authors: Wetterau John R. , Gregg Richard E. , Harrity Thomas W. , Arbeeny Cynthia , Cap Michael , Connolly Fergal , Chu Ching-Hsuen , George Rocco J. , Gordon David A. , Jamil Haris , Jolibois Kern G. , Kunselman Lori K. , Lan Shih-Jung , Maccagnan Thomas J. , Ricci Beverly , Yan Mujing , Young Douglas , Chen Ying , Fryszman Olga M. , Logan Janette V. H. , Musial Christa L. , Poss Michael A. , Robl Jeffrey A. , Simpkins Ligaya M. , Slusarchyk William A. , Sulsky Richard , Taunk Prakash , Magnin David R. , Tino Joseph A. , Lawrence R. Michael , Dickson John K. , Biller Scott A.
Published: July 2002

Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B–containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound
9
) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound
9
, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.
Role of α-Dystroglycan as a Schwann Cell Receptor for
Mycobacterium leprae
Authors: Rambukkana Anura , Yamada Hiroki , Zanazzi George , Mathus Todd , Salzer James L. , Yurchenco Peter D. , Campbell Kevin P. , Fischetti Vincent A.
Published: July 2002

α-Dystroglycan (α-DG) is a component of the dystroglycan complex, which is involved in early development and morphogenesis and in the pathogenesis of muscular dystrophies. Here, α-DG was shown to serve as a Schwann cell receptor for
Mycobacterium leprae
, the causative organism of leprosy.
Mycobacterium leprae
specifically bound to α-DG only in the presence of the G domain of the α2 chain of laminin-2. Native α-DG competitively inhibited the laminin-2–mediated
M. leprae
binding to primary Schwann cells. Thus,
M. leprae
may use linkage between the extracellular matrix and cytoskeleton through laminin-2 and α-DG for its interaction with Schwann cells.
Abrupt Climate Oscillations During the Last Deglaciation in Central North America
Authors: Yu Zicheng , Eicher Ulrich
Published: July 2002

Evidence from stable isotopes and a variety of proxies from two Ontario lakes demonstrate that many of the late glacial–to–early Holocene events that are well known from the North Atlantic seaboard, such as the Gerzensee-Killarney Oscillation (also known as the Intra-Allerød Cold Period), Younger Dryas, and Preboreal Oscillation, also occurred in central North America. These results thus imply that climatic forcing acted in the same manner in both regions and that atmospheric circulation played an important role in the propagation of these events.
Imaging Protein Kinase Cα Activation in Cells
Authors: Ng Tony , Squire Anthony , Hansra Gurdip , Bornancin Frederic , Prevostel Corinne , Hanby Andrew , Harris William , Barnes Diana , Schmidt Sandra , Mellor Harry , Bastiaens Philippe I. H. , Parker Peter J.
Published: July 2002

Spatially resolved fluorescence resonance energy transfer (FRET) measured by fluorescence lifetime imaging microscopy (FLIM), provides a method for tracing the catalytic activity of fluorescently tagged proteins inside live cell cultures and enables determination of the functional state of proteins in fixed cells and tissues. Here, a dynamic marker of protein kinase Cα (PKCα) activation is identified and exploited. Activation of PKCα is detected through the binding of fluorescently tagged phosphorylation site–specific antibodies; the consequent FRET is measured through the donor fluorophore on PKCα by FLIM. This approach enabled the imaging of PKCα activation in live and fixed cultured cells and was also applied to pathological samples.
Limb and Skin Abnormalities in Mice Lacking IKKα
Authors: Takeda Kiyoshi , Takeuchi Osamu , Tsujimura Tohru , Itami Satoshi , Adachi Osamu , Kawai Taro , Sanjo Hideki , Yoshikawa Kunihiko , Terada Nobuyuki , Akira Shizuo
Published: July 2002

The gene encoding inhibitor of kappa B (IκB) kinase α (IKKα; also called IKK1) was disrupted by gene targeting. IKKα-deficient mice died perinatally. In IKKα-deficient fetuses, limb outgrowth was severely impaired despite unaffected skeletal development. The epidermal cells in IKKα-deficient fetuses were highly proliferative with dysregulated epidermal differentiation. In the basal layer, degradation of IκB and nuclear localization of nuclear factor kappa B (NF-κB) were not observed. Thus, IKKα is essential for NF-κB activation in the limb and skin during embryogenesis. In contrast, there was no impairment of NF-κB activation induced by either interleukin-1 or tumor necrosis factor–α in IKKα-deficient embryonic fibroblasts and thymocytes, indicating that IKKα is not essential for cytokine-induced activation of NF-κB.
Modulation of Polyketide Synthase Activity by Accessory Proteins During Lovastatin Biosynthesis
Authors: Kennedy Jonathan , Auclair Karine , Kendrew Steven G. , Park Cheonseok , Vederas John C. , Richard Hutchinson C.
Published: July 2002

Polyketides, the ubiquitous products of secondary metabolism in microorganisms, are made by a process resembling fatty acid biosynthesis that allows the suppression of reduction or dehydration reactions at specific biosynthetic steps, giving rise to a wide range of often medically useful products. The lovastatin biosynthesis cluster contains two type I polyketide synthase genes. Synthesis of the main nonaketide-derived skeleton was found to require the previously known iterative lovastatin nonaketide synthase (LNKS), plus at least one additional protein (LovC) that interacts with LNKS and is necessary for the correct processing of the growing polyketide chain and production of dihydromonacolin L. The noniterative lovastatin diketide synthase (LDKS) enzyme specifies formation of 2-methylbutyrate and interacts closely with an additional transesterase (LovD) responsible for assembling lovastatin from this polyketide and monacolin J.
Molecular Identification of a Eukaryotic, Stretch-Activated Nonselective Cation Channel
Authors: Kanzaki Makoto , Nagasawa Masahiro , Kojima Itaru , Sato Chikara , Naruse Keiji , Sokabe Masahiro , Iida Hidetoshi
Published: July 2002

Calcium-permeable, stretch-activated nonselective cation (SA Cat) channels mediate cellular responses to mechanical stimuli. However, genes encoding such channels have not been identified in eukaryotes. The yeast
MID1
gene product (Mid1) is required for calcium influx in the yeast
Saccharomyces cerevisiae
. Functional expression of Mid1 in Chinese hamster ovary cells conferred sensitivity to mechanical stress that resulted in increases in both calcium conductance and the concentration of cytosolic free calcium. These increases were dependent on the presence of extracellular calcium and were reduced by gadolinium, a blocker of SA Cat channels. Single-channel analyses with cell-attached patches revealed that Mid1 acts as a calcium-permeable, cation-selective stretch-activated channel with a conductance of 32 picosiemens at 150 millimolar cesium chloride in the pipette. Thus, Mid1 appears to be a eukaryotic, SA Cat channel.
Room Temperature Lasing at Blue Wavelengths in Gallium Nitride Microcavities
Authors: Someya Takao , Werner Ralph , Forchel Alfred , Catalano Massimo , Cingolani Roberto , Arakawa Yasuhiko
Published: July 2002

Lasing action has been demonstrated at blue wavelengths in vertical cavity surface-emitting lasers at room temperature. The microcavity was formed by sandwiching indium gallium nitride multiple quantum wells between nitride-based and oxide-based quarter-wave reflectors. Lasing action was observed at a wavelength of 399 nanometers under optical excitation and confirmed by a narrowing of the linewidth in the emission spectra from 0.8 nanometer below threshold to less than 0.1 nanometer (resolution limit) above threshold. The result suggests that practical blue vertical cavity surface-emitting lasers can be realized in gallium-nitride–based material systems.
Arabidopsis
NPH3: A NPH1 Photoreceptor-Interacting Protein Essential for Phototropism
Authors: Motchoulski Andrei , Liscum Emmanuel
Published: July 2002

Phototropism of
Arabidopsis thaliana
seedlings in response to a blue light source is initiated by nonphototropic hypocotyl 1 (NPH1), a light-activated serine-threonine protein kinase. Mutations in three loci [
NPH2
, root phototropism 2 (
RPT2
), and
NPH3
] disrupt early signaling occurring downstream of the NPH1 photoreceptor. The
NPH3
gene, now cloned, encodes a NPH1-interacting protein. NPH3 is a member of a large protein family, apparently specific to higher plants, and may function as an adapter or scaffold protein to bring together the enzymatic components of a NPH1-activated phosphorelay.
Sex Determination in Malaria Parasites
Authors: Paul Richard E. L. , Coulson Timothy N. , Raibaud Anna , Brey Paul T.
Published: July 2002

A century ago, W. G. MacCallum identified distinct male and female forms in malaria parasites of both birds and humans. Since then, scientists have been puzzled by the high female-to-male ratios of parasites in
Plasmodium
infections and by the mechanism of sex determination. The sex ratio of malaria parasites was shown to become progressively more male as conditions that allow motility and subsequent fertilization by the male parasites become adverse. This resulted from an increased immune response against male gametes, which coincides with intense host erythropoietic activity. Natural and artificial induction of erythropoiesis in vertebrate hosts provoked a shift toward male parasite production. This change in parasite sex ratio led to reduced reproductive success in the parasite, which suggests that sex determination is adaptive and is regulated by the hematologic state of the host.
Observation of Antiferromagnetic Domains in Epitaxial Thin Films
Authors: Scholl A. , Stöhr J. , Lüning J. , Seo J. W. , Fompeyrine J. , Siegwart H. , Locquet J.-P. , Nolting F. , Anders S. , Fullerton E. E. , Scheinfein M. R. , Padmore H. A.
Published: July 2002

Antiferromagnetic domains in an epitaxial thin film, LaFeO
3
on SrTiO
3
(100), were observed using a high-spatial-resolution photoelectron emission microscope with contrast generated by the large x-ray magnetic linear dichroism effect at the multiplet-split
L
edge of Fe. The antiferromagnetic domains are linked to 90° twinned crystallographic regions in the film. The Néel temperature of the thin film is reduced by 70 kelvin relative to the bulk material, and this reduction is attributed to epitaxial strain. These studies open the door for a microscopic understanding of the magnetic coupling across antiferromagnetic-ferromagnetic interfaces.
Effects of Environment on Compensatory Mutations to Ameliorate Costs of Antibiotic Resistance
Authors: Björkman J. , Nagaev I. , Berg O. G. , Hughes D. , Andersson D. I.
Published: July 2002

Most types of antibiotic resistance impose a biological cost on bacterial fitness. These costs can be compensated, usually without loss of resistance, by second-site mutations during the evolution of the resistant bacteria in an experimental host or in a laboratory medium. Different fitness-compensating mutations were selected depending on whether the bacteria evolved through serial passage in mice or in a laboratory medium. This difference in mutation spectra was caused by either a growth condition–specific formation or selection of the compensated mutants. These results suggest that bacterial evolution to reduce the costs of antibiotic resistance can take different trajectories within and outside a host.
Role of the Mouse
ank
Gene in Control of Tissue Calcification and Arthritis
Authors: Ho Andrew M. , Johnson Michelle D. , Kingsley David M.
Published: July 2002

Mutation at the mouse
progressive ankylosis
(
ank
) locus causes a generalized, progressive form of arthritis accompanied by mineral deposition, formation of bony outgrowths, and joint destruction. Here, we show that the
ank
locus encodes a multipass transmembrane protein (ANK) that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. A highly conserved gene is present in humans and other vertebrates. These results identify ANK-mediated control of pyrophosphate levels as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals.
Evidence for Mating of the "Asexual" Yeast
Candida albicans
in a Mammalian Host
Authors: Hull Christina M. , Raisner Ryan M. , Johnson Alexander D.
Published: July 2002

Since its classification nearly 80 years ago, the human pathogen
Candida albicans
has been designated as an asexual yeast. In this report, we describe the construction of
C. albicans
strains that were subtly altered at the mating-type–like (
MTL
) locus, a cluster of genes that resembles the mating-type loci of other fungi. These derivatives were capable of mating after inoculation into a mammalian host.
C. albicans
is a diploid organism, but most of the mating products isolated from a mouse host were tetrasomic for the two chromosomes that could be rigorously monitored and, overall, exhibited substantially higher than 2n DNA content. These observations demonstrated that
C. albicans
can recombine sexually.
Structure of Yeast Poly(A) Polymerase Alone and in Complex with 3'-dATP
Authors: Bard Joel , Zhelkovsky Alexander M. , Helmling Steffen , Earnest Thomas N. , Moore Claire L. , Bohm Andrew
Published: July 2002

Polyadenylate [poly(A)] polymerase (PAP) catalyzes the addition of a polyadenosine tail to almost all eukaryotic messenger RNAs (mRNAs). The crystal structure of the PAP from
Saccharomyces cerevisiae
(Pap1) has been solved to 2.6 angstroms, both alone and in complex with 3′-deoxyadenosine triphosphate (3′-dATP). Like other nucleic acid polymerases, Pap1 is composed of three domains that encircle the active site. The arrangement of these domains, however, is quite different from that seen in polymerases that use a template to select and position their incoming nucleotides. The first two domains are functionally analogous to polymerase palm and fingers domains. The third domain is attached to the fingers domain and is known to interact with the single-stranded RNA primer. In the nucleotide complex, two molecules of 3′-dATP are bound to Pap1. One occupies the position of the incoming base, prior to its addition to the mRNA chain. The other is believed to occupy the position of the 3′ end of the mRNA primer.
The Contribution of Noise to Contrast Invariance of Orientation Tuning in Cat Visual Cortex
Authors: Anderson Jeffrey S. , Lampl Ilan , Gillespie Deda C. , Ferster David
Published: July 2002

Feedforward models of visual cortex appear to be inconsistent with a well-known property of cortical cells: contrast invariance of orientation tuning. The models' fixed threshold broadens orientation tuning as contrast increases, whereas in real cells tuning width is invariant with contrast. We have compared the orientation tuning of spike and membrane potential responses in single cells. Both are contrast invariant, yet a threshold-linear relation applied to the membrane potential accurately predicts the orientation tuning of spike responses. The key to this apparent paradox lies in the noisiness of the membrane potential. Responses that are subthreshold on average are still capable of generating spikes on individual trials. Unlike the iceberg effect, contrast invariance remains intact even as threshold narrows orientation selectivity. Noise may, by extension, smooth the average relation between membrane potential and spike rate throughout the brain.
Differential Shunting of EPSPs by Action Potentials
Authors: Häusser Michael , Major Guy , Stuart Greg J.
Published: July 2002

Neurons encode information and communicate via action potentials, which are generated following the summation of synaptic events. It is commonly assumed that action potentials reset the membrane potential completely, allowing another round of synaptic integration to begin. We show here that the conductances underlying the action potential act instead as a variable reset of synaptic integration. The strength of this reset is cell type–specific and depends on the kinetics, location, and timing of the synaptic input. As a consequence, distal synapses, as well as inputs mediated by
N
-methyl-
d
-aspartate receptor activation, can contribute disproportionately to synaptic integration during action potential firing.
Migration Along Orthodromic Sun Compass Routes by Arctic Birds
Authors: Alerstam Thomas , Gudmundsson Gudmundur A. , Green Martin , Hedenström Anders
Published: July 2002

Flight directions of birds migrating at high geographic and magnetic latitudes can be used to test bird orientation by celestial or geomagnetic compass systems under polar conditions. Migration patterns of arctic shorebirds, revealed by tracking radar studies during an icebreaker expedition along the Northwest Passage in 1999, support predicted sun compass trajectories but cannot be reconciled with orientation along either geographic or magnetic loxodromes (rhumb lines). Sun compass routes are similar to orthodromes (great circle routes) at high latitudes, showing changing geographic courses as the birds traverse longitudes and their internal clock gets out of phase with local time. These routes bring the shorebirds from high arctic Canada to the east coast of North America, from which they make transoceanic flights to South America. The observations are also consistent with a migration link between Siberia and the Beaufort Sea region by way of sun compass routes across the Arctic Ocean.
Cooperation, Control, and Concession in Meerkat Groups
Authors: Clutton-Brock T. H. , Brotherton P. N. M. , Russell A. F. , O'Riain M. J. , Gaynor D. , Kansky R. , Griffin A. , Manser M. , Sharpe L. , McIlrath G. M. , Small T. , Moss A. , Monfort S.
Published: July 2002

“Limited control” models of reproductive skew in cooperative societies suggest that the frequency of breeding by subordinates is determined by the outcome of power struggles with dominants. In contrast, “optimal skew” models suggest that dominants have full control of subordinate reproduction and allow subordinates to breed only when this serves to retain subordinates' assistance with rearing dominants' own litters. The results of our 7-year field study of cooperative meerkats,
Suricata suricatta
, support the predictions of limited control models and provide no indication that dominant females grant reproductive concessions to subordinates to retain their assistance with future breeding attempts.
Reversible Surface Morphology Changes of a Photochromic Diarylethene Single Crystal by Photoirradiation
Authors: Irie Masahiro , Kobatake Seiya , Horichi Masashi
Published: July 2002

The surface morphology of a diarylethene single crystal [1,2-bis(2,4-dimethyl-5-phenyl-3-thienyl)perfluorocyclopentene] determined by atomic force microscopy changed reversibly upon photoirradiation. The crystal underwent a thermally irreversible but photochemically reversible color change (colorless to blue) upon alternate irradiation with ultraviolet (wavelength λ = 366 nm) and visible (λ > 500 nm) light that drove reversible photocyclization reactions. Upon irradiation with 366-nm light, new steps appeared on the (100) single-crystalline surface that disappeared upon irradiation with visible light (λ > 500 nm). The step height, about 1 nm, corresponds to one molecular layer. Irradiation with 366-nm light formed valleys on the (010) surface that also disappeared by bleaching upon irradiation with visible light (λ > 500 nm). The surface morphological changes can be explained by the molecular structural changes of diarylethenes regularly packed in the single crystal. These crystals could potentially be used as photodriven nanometer-scale actuators.
Characterization of Passage-Selected Vancomycin-Resistant
Staphylococcus aureus
Strains of Diverse Parental Backgrounds
Authors: Pfeltz Richard F. , Singh Vineet K. , Schmidt Jennifer L. , Batten Michael A. , Baranyk Christopher S. , Nadakavukaren Matthew J. , Jayaswal Radheshyam K. , Wilkinson Brian J.
Published: July 2002

A series of 12
Staphylococcus aureus
strains of various genetic backgrounds, methicillin resistance levels, and autolytic activities were subjected to selection for the glycopeptide-intermediate
S. aureus
(GISA) susceptibility phenotype on increasing concentrations of vancomycin. Six strains acquired the phenotype rapidly, two did so slowly, and four failed to do so. The vancomycin MICs for the GISA strains ranged from 4 to 16 μg/ml, were stable to 20 nonselective passages, and expressed resistance homogeneously. Neither ease of acquisition of the GISA phenotype nor the MIC attained correlated with methicillin resistance hetero- versus homogeneity or autolytic deficiency or sufficiency. Oxacillin MICs were generally unchanged between parent and GISA strains, although the
mec
members of both isogenic methicillin-susceptible and methicillin-resistant pairs acquired the GISA phenotype more rapidly and to higher MICs than did their susceptible counterparts. Transmission electron microscopy revealed that the GISA strains appeared normal in the absence of vancomycin but had thickened and diffuse cell walls when grown with vancomycin at one-half the MIC. Common features among GISAs were reduced doubling times, decreased lysostaphin susceptibilities, and reduced whole-cell and zymographic autolytic activities in the absence of vancomycin. This, with surface hydrophobicity differences, indicated that even in the absence of vancomycin the GISA cell walls differed from those of the parents. Autolytic activities were further reduced by the inclusion of vancomycin in whole-cell and zymographic studies. The six least vancomycin-susceptible GISA strains exhibited an increased capacity to remove vancomycin from the medium versus their parent lines. This study suggests that while some elements of the GISA phenotype are strain specific, many are common to the phenotype although their expression is influenced by genetic background. GISA strains with similar glycopeptide MICs may express individual components of the phenotype to different extents.
Resistance to Mercury and Antimicrobial Agents in
Streptococcus mutans
Isolates from Human Subjects in Relation to Exposure to Dental Amalgam Fillings
Authors: Leistevuo Jorma , Järvinen Helinä , Österblad Monica , Leistevuo Tiina , Huovinen Pentti , Tenovuo Jorma
Published: July 2002

Resistance to cefuroxime, penicillin, tetracycline, and mercury is reported for 839
Streptococcus mutans
isolates from 209 human study subjects. The MICs of these drugs did not differ for isolates from one dental amalgam group and two nonamalgam subsets: a group with no known exposure to amalgam and a group whose members had their amalgam fillings removed.
Pharmacokinetics of SCH 56592, a New Azole Broad-Spectrum Antifungal Agent, in Mice, Rats, Rabbits, Dogs, and Cynomolgus Monkeys
Authors: Nomeir Amin A. , Kumari Pramila , Hilbert Mary Jane , Gupta Samir , Loebenberg David , Cacciapuoti Anthony , Hare Roberta , Miller George H. , Lin Chin-Chung , Cayen Mitchell N.
Published: July 2002

SCH 56592 is a new broad-spectrum azole antifungal agent that is in phase 3 clinical trials for the treatment of serious systemic fungal infections. The pharmacokinetics of this drug candidate were evaluated following its intravenous (i.v.) or oral (p.o.) administration as a solution in hydroxypropyl-β-cyclodextrin (HPβCD) or oral administration as a suspension in 0.4% methylcellulose (MC) in studies involving mice, rats, rabbits, dogs, and cynomolgus monkeys. SCH 56592 was orally bioavailable in all species. The oral bioavailability was higher with the HPβCD solution (range, 52 to ∼100%) than from the MC suspension (range, 14 to 48%) and was higher in mice (∼100% [HPβCD] and 47% [MC]), rats (∼66% [HPβCD] and 48% [MC]), and dogs (72% [HPβCD] and 37% [MC]) than in monkeys (52% [HPβCD] and 14% [MC]). In rabbits, high concentrations in serum suggested good oral bioavailability with the MC suspension. The i.v. terminal-phase half-lives were 7 h in mice and rats, 15 h in dogs, and 23 h in monkeys. In rabbits, the oral half-life was 9 h. In species given increasing oral doses (mice, rats, and dogs), serum drug concentrations were dose related. Food produced a fourfold increase in serum drug concentrations in dogs. Multiple daily doses of 40 mg of SCH 56592/kg of body weight for eight consecutive days to fed dogs resulted in higher concentrations in serum, indicating accumulation upon multiple dosing, with an accumulation index of approximately 2.6. Concentrations above the MICs and minimum fungicidal concentrations for most organisms were observed at 24 h following a single oral dose in MC suspension in all five species studied (20 mg/kg for mice, rats, and rabbits and 10 mg/kg for dogs and monkeys), suggesting that once-daily administration of SCH 56592 in human subjects would be a therapeutically effective dosage regimen.
Pefloxacin-Induced Achilles Tendon Toxicity in Rodents: Biochemical Changes in Proteoglycan Synthesis and Oxidative Damage to Collagen
Authors: Simonin Marie-Agnes , Gegout-Pottie Pascale , Minn Alain , Gillet Pierre , Netter Patrick , Terlain Bernard
Published: July 2002

Despite a relatively low incidence of serious side effects, fluoroquinolones and the fluoroquinolone pefloxacin have been reported to occasionally promote tendinopathy that might result in the complication of spontaneous rupture of tendons. In the present study, we investigated in rodents the intrinsic deleterious effect of pefloxacin (400 mg/kg of body weight) on Achilles tendon proteoglycans and collagen. Proteoglycan synthesis was determined by measurement of in vivo and ex vivo radiosulfate incorporation in mice. Collagen oxidative modifications were measured by carbonyl derivative detection by Western blotting. An experimental model of tendinous ischemia (2 h) and reperfusion (3 days) was achieved in rats. Biphasic changes in proteoglycan synthesis were observed after a single administration of pefloxacin, consisting of an early inhibition followed by a repair-like phase. The depletion phase was accompanied by a marked decrease in the endogenous serum sulfate level and a concomitant increase in the level of sulfate excretion in urine. Studies of ex vivo proteoglycan synthesis confirmed the in vivo results that were obtained. The decrease in proteoglycan anabolism seemed to be a direct effect of pefloxacin on tissue metabolism rather than a consequence of the low concentration of sulfate. Pefloxacin treatment for several days induced oxidative damage of type I collagen, with the alterations being identical to those observed in the experimental tendinous ischemia and reperfusion model. Oxidative damage was prevented by coadministration of
N
-acetylcysteine (150 mg/kg) to the mice. These results provide the first experimental evidence of a pefloxacin-induced oxidative stress in the Achilles tendon that altered proteoglycan anabolism and oxidized collagen.
Antimalarial Bioavailability and Disposition of Artesunate in Acute Falciparum Malaria
Authors: Newton Paul , Suputtamongkol Yupin , Teja-Isavadharm Paktiya , Pukrittayakamee Sasithon , Navaratnam V , Bates Imelda , White Nicholas
Published: July 2002

The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated
Plasmodium falciparum
malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (
P
≤ 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunate-associated antimalarial activity.
Evernimicin Binds Exclusively to the 50S Ribosomal Subunit and Inhibits Translation in Cell-Free Systems Derived from both Gram-Positive and Gram-Negative Bacteria
Authors: McNicholas Paul M. , Najarian David J. , Mann Paul A. , Hesk David , Hare Roberta S. , Shaw Karen J. , Black Todd A.
Published: July 2002

Evernimicin (SCH 27899) is a new antibiotic with activity against a wide spectrum of gram-positive bacteria and activity against some gram-negative bacteria. Previous metabolic labeling studies indicated that evernimicin specifically inhibited protein synthesis in
Staphylococcus aureus
. Using a susceptible
Escherichia coli
strain, we demonstrated that evernimicin also inhibited protein synthesis in
E. coli
. In cell-free translation assays with extracts from either
E. coli
or
S. aureus
, evernimicin had a 50% inhibitory concentration of approximately 125 nM. In contrast, cell-free systems derived from wheat germ and rabbit reticulocytes were inhibited only by very high levels of evernimicin. Evernimicin did not promote transcript misreading. [
14
C]evernimicin specifically bound to the 50S subunit from
E. coli
. Nonlinear regression analysis of binding data generated with 70S ribosomes from
E. coli
and
S. aureus
and 50S subunits from
E. coli
returned dissociation constants of 84, 86, and 160 nM, respectively. In binding experiments, performed in the presence of excess quantities of a selection of antibiotics known to bind to the 50S subunit, only the structurally similar drug avilamycin blocked binding of [
14
C]evernimicin to ribosomes.
Geographic Distribution of a Large Mobile Element That Transfers Ampicillin and Vancomycin Resistance between
Enterococcus faecium
Strains
Authors: Hanrahan Jennifer , Hoyen Claudia , Rice Louis B.
Published: July 2002

In several clonally unrelated VanB-type vancomycin-resistant
Enterococcus faecium
strains, we demonstrated a common physical relationship between
pbp5
and Tn
5382
as well as common mutations within
pbp5
. The majority of these strains transferred vancomycin and ampicillin resistance to
E. faecium
in vitro, suggesting the dissemination of similar transferable
pbp5-vanB
-containing mobile elements throughout the United States.
Pharmacokinetics and Tolerability of Gemifloxacin (SB-265805) after Administration of Single Oral Doses to Healthy Volunteers
Authors: Allen Ann , Bygate Elizabeth , Oliver Stuart , Johnson Martin , Ward Christopher , Cheon Ae-Jin , Choo Youn Sung , Kim In-Chull
Published: July 2002

Gemifloxacin (known as SB-265805 or LB-20304) is a potent, novel fluoroquinolone compound with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were characterized in healthy male volunteers after a single dose of 20, 40, 80, 160, 320, 600, or 800 mg. Multiple serum and urine samples were collected and analyzed for gemifloxacin using high-performance liquid chromatography with fluorescence detection. Safety assessments included vital signs, 12-lead electrocardiogram readings, hematology, clinical chemistry, urinalysis, and adverse-experience monitoring. Gemifloxacin was rapidly absorbed after all doses. Maximum concentrations of gemifloxacin in serum (
C
max
) were achieved approximately 1 h after dosing, after which concentrations in serum declined in a biexponential manner. Values of
C
max
and the area under the concentration-time curve in serum from 0 h to infinity (serum AUC
0–∞
) increased linearly with dose. Serum AUC
0–∞
values (mean ± standard deviation) were 0.65 ± 0.01, 1.28 ± 0.22, 2.54 ± 0.31, 5.48 ± 1.24, 9.82 ± 2.70, 24.4 ± 7.1, and 31.4 ± 7.6 μg · h/ml following 20-, 40-, 80-, 160-, 320-, 600-, and 800-mg doses, respectively. The terminal phase elimination half-life was independent of dose, with an overall mean of 7.4 ± 2.0 h. The profiles indicated that the pharmacokinetic profile is suitable for a once-daily dosing regimen. Approximately 25 to 40% of the administered dose was excreted unchanged in the urine, and renal clearance (ca. 150 ml/min) was independent of dose. There were no significant changes in clinical chemistry, hematology, or urinalysis parameters, vital signs, or 12-lead electrocardiogram readings in subjects, irrespective of dose. The results of these studies support the further investigation of once-daily administration of gemifloxacin.
Characterization of a Variant of
vga
(A) Conferring Resistance to Streptogramin A and Related Compounds
Authors: Haroche Julien , Allignet Jeanine , Buchrieser Carmen , El Solh Névine
Published: July 2002

A variant of the
vga
(A) gene (1,575 bp), encoding an ATP-binding cassette protein conferring resistance to streptogramin A and related antibiotics, was cloned from the chromosome of a
Staphylococcus aureus
clinical isolate and sequenced. The sequence of the variant was similar to that of the
vga
(A) gene (83.2% identity). However, the G+C content of the variant (35.6%) was higher than that of
vga
(A) (29%) and there was no cross hybridization between
vga
(A) and the variant at high stringency (≥60°C), the highest temperature at which a signal was detected being 55°C. Unlike previous reports for
vga
(A) and
vga
(B), the variant of
vga
(A) may be present in multiple copies in the genome. These copies are chromosomal in some isolates and both chromosomal and plasmid-borne in others. Nucleotide sequences hybridizing at 65°C with the
vga
(A) variant were found in all the staphylococcal strains harboring plasmids carrying both
vga
(B) and
vat
(B), which also encode resistance to streptogramin A.
Drug Interaction Studies of a Glucan Synthase Inhibitor (LY 303366) and a Chitin Synthase Inhibitor (Nikkomycin Z) for Inhibition and Killing of Fungal Pathogens
Authors: Stevens David A.
Published: July 2002

The interaction between inhibitors of components of the fungal cell wall, glucan and chitin, was studied in vitro with the respective synthase enzyme inhibitors LY 303366 and nikkomycin Z. With
Aspergillus fumigatus
synergy was noted for inhibition and killing, and synergistic activity was also noted for some isolates of other species presently regarded as difficult to treat.
Molecular Characterization of FOX-4, a New AmpC-Type Plasmid-Mediated β-Lactamase from an
Escherichia coli
Strain Isolated in Spain
Authors: Bou Germán , Oliver Antonio , Ojeda Mar , Monzón Carmelo , Martínez-Beltrán Jesús
Published: July 2002

A clinical strain of
Escherichia coli
(Ec GCE) displayed resistance to cefoxitin, cefotetan, cefotaxime, and ceftazidime. Susceptibility was not restored by the addition of clavulanic acid. Two β-lactamases with apparent pIs of 5.4 and 6.4 were identified; the β-lactamase with a pI of 6.4 was transferred by conjugation and associated with a 40-kb plasmid. Analysis of the nucleotide sequence showed a new
ampC
β-lactamase gene that is closely related to those encoding the FOX-3, FOX-2, and FOX-1 β-lactamases but whose product has four novel amino acid mutations, at positions 11 (M→T), 43 (A→E), 233 (V→A), and 280 (Y→H). This first cephamycinase from Spain was named FOX-4.
Fluconazole Penetration into the Pancreas
Authors: Shrikhande Shailesh , Friess Helmut , Issenegger Claudia , Martignoni Marcus E. , Yong Huang , Gloor Beat , Yeates Rodney , Kleeff Jörg , Büchler Markus W.
Published: July 2002

Because of antibiotic prophylaxis for necrotizing pancreatitis, the frequency of fungal superinfection in patients with pancreatic necrosis is increasing. In this study we analyzed the penetration of fluconazole into the human pancreas and in experimental acute pancreatitis. In human pancreatic tissues, the mean fluconazole concentration was 8.19 ± 3.38 μg/g (96% of the corresponding concentration in serum). In experimental edematous and necrotizing pancreatitis, 88 and 91% of the serum fluconazole concentration was found in the pancreas. These data show that fluconazole penetration into the pancreas is sufficient to prevent and/or treat fungal contamination in patients with pancreatic necrosis.
Enhancement of Fluoroquinolone Activity by C-8 Halogen and Methoxy Moieties: Action against a Gyrase Resistance Mutant of
Mycobacterium smegmatis
and a Gyrase-Topoisomerase IV Double Mutant of
Staphylococcus aureus
Authors: Lu Tao , Zhao Xilin , Li Xinying , Drlica-Wagner Alex , Wang Jian-Ying , Domagala John , Drlica Karl
Published: July 2002

The increasing prevalence of antibiotic resistance among bacterial pathogens prompted a microbiological study of fluoroquinolone structure-activity relationships with resistant mutants. Bacteriostatic and bactericidal activities for 12 fluoroquinolones were examined with a gyrase mutant of
Mycobacterium smegmatis
and a gyrase-topoisomerase IV double mutant of
Staphylococcus aureus
. For both organisms C-8 halogen and C-8 methoxy groups enhanced activity. The MIC at which 99% of the isolates tested were inhibited (MIC
99
) was reduced three- to fivefold for the
M. smegmatis
mutant and seven- to eightfold for the
S. aureus
mutant by C-8 bromine, chlorine, and methoxy groups. With both organisms a smaller reduction in the MIC
99
(two- to threefold) was associated with a C-8 fluorine moiety. In most comparisons with
M. smegmatis
the response to a C-8 substituent was similar (within twofold) for wild-type and mutant cells. In contrast, mutant
S. aureus
was affected more than the wild type by the addition of a C-8 substituent. C-8 halogen and methoxy groups also improved the ability to kill the two mutants and the respective wild-type cells when measured with various fluoroquinolone concentrations during an incubation period equivalent to four to five doubling times. Collectively these data help define a group of fluoroquinolones that can serve (i) as a base for structure refinement and (ii) as test compounds for slowing the development of fluoroquinolone resistance during infection of vertebrate hosts.
Acyclovir for Treatment of Postherpetic Neuralgia: Efficacy and Pharmacokinetics
Authors: Acosta Edward P. , Balfour Henry H.
Published: July 2002

Postherpetic neuralgia is the most common complication of herpes zoster (shingles) in the immunocompetent host. Its mechanism is incompletely understood, but one postulate is that continuous replication of varicella-zoster virus (VZV) in nerve tissues may be responsible for the pain. If this is so, antiviral treatment could be advantageous. To test this hypothesis, we performed a randomized, double-blind, placebo-controlled trial of intravenous acyclovir (10 mg/kg every 8 h [q8h]) for 14 days, followed by oral acyclovir (800 mg q6h) for 42 days in 10 subjects (median age, 71 years) who had experienced at least 6 months of severe pain (median duration of postherpetic neuralgia before enrollment, 3.2 years). Intensive and sparse pharmacokinetic sampling occurred during both dosing phases of the study. One- and two-compartment models were fitted to the oral and intravenous concentration-time data, respectively. The four men and four women assigned to acyclovir during either or both dosing phases tolerated it well. Pharmacokinetic results were similar to those previously reported in younger individuals. The mean oral clearance and elimination half-life following oral dosing were 1.47 liters/h/kg and 2.78 h, respectively. Total clearance and terminal half-life following intravenous administration were 0.16 liters/h/kg and 3.67 h, respectively. Only 1 of 10 participants reported definite improvement in the severity of postherpetic pain, and treatment had no effect on titers of humoral antibody to VZV. We concluded that 56 days of intravenous and oral acyclovir therapy were well tolerated but had little or no effect on the clinical course of postherpetic neuralgia.