bluuebunny/crossref_metadata_2025 huggingface dataset:
RNA Folding at Millisecond Intervals by Synchrotron Hydroxyl Radical Footprinting
Authors: Sclavi Bianca , Sullivan Michael , Chance Mark R. , Brenowitz Michael , Woodson Sarah A.
Published: July 2002

Radiolysis of water with a synchrotron x-ray beam permits the hydroxyl radical–accessible surface of an RNA to be mapped with nucleotide resolution in 10 milliseconds. Application of this method to folding of the
Tetrahymena
ribozyme revealed that the most stable domain of the tertiary structure, P4-P6, formed cooperatively within 3 seconds. Exterior helices became protected from hydroxyl radicals in 10 seconds, whereas the catalytic center required minutes to be completely folded. The results show that rapid collapse to a partially disordered state is followed by a slow search for the active structure.
Clouds of High Contrast on Uranus
Authors: Karkoschka Erich
Published: July 2002

Near-infrared images of Uranus taken with the Hubble Space Telescope in July and October 1997 revealed discrete clouds with contrasts exceeding 10 times the highest contrast observed before with other techniques. At visible wavelengths, these 10 clouds had lower contrasts than clouds seen by Voyager 2 in 1986. Uranus' rotational rates for southern latitudes were identical in 1986 and 1997. Clouds in northern latitudes rotate slightly more slowly than clouds in opposite southern latitudes.
Catalytic Activation of the Phosphatase MKP-3 by ERK2 Mitogen-Activated Protein Kinase
Authors: Camps Montserrat , Nichols Anthony , Gillieron Corine , Antonsson Bruno , Muda Marco , Chabert Christian , Boschert Ursula , Arkinstall Steve
Published: July 2002

MAP kinase phosphatase–3 (MKP-3) dephosphorylates phosphotyrosine and phosphothreonine and inactivates selectively ERK family mitogen-activated protein (MAP) kinases. MKP-3 was activated by direct binding to purified ERK2. Activation was independent of protein kinase activity and required binding of ERK2 to the noncatalytic amino-terminus of MKP-3. Neither the gain-of-function Sevenmaker ERK2 mutant D319N nor c-Jun amino-terminal kinase–stress-activated protein kinase (JNK/SAPK) or p38 MAP kinases bound MKP-3 or caused its catalytic activation. These kinases were also resistant to enzymatic inactivation by MKP-3. Another homologous but nonselective phosphatase, MKP-4, bound and was activated by ERK2, JNK/SAPK, and p38 MAP kinases. Catalytic activation of MAP kinase phosphatases through substrate binding may regulate MAP kinase activation by a large number of receptor systems.
In Situ Discovery of Graphite with Interstellar Isotopic Signatures in a Chondrule-Free Clast in an L3 Chondrite
Authors: Mostefaoui S. , Hoppe P. , El Goresy A.
Published: July 2002

Optical and scanning electron microscopy of a chondrule-free clast in the unequilibrated L3 chondrite Khohar revealed a spherical object consisting of an aggregate of small (∼2- micrometer diameter), Ni-poor (0.5 to 2.89 weight percent) metal particles and fine-grained graphite (<1-micrometer diameter). The graphite has large D and15N excesses (δD ∼ 1500 per mil and δ15N ∼ 1300 per mil) with two isotopically distinct signatures: N rich with a high D/H ratio and N poor with a high15N/14N ratio. These excesses are the largest D and15N excesses observed in situ in a well-characterized phase in a meteorite. The isotopic characteristics are suggestive of an interstellar origin, probably by ion-molecule reactions at low temperature in the interstellar molecular cloud from which the solar system formed. The structure and nonchondritic composition of the metal particles suggest they did not form under equilibrium conditions in the solar nebula.
Extrapolating Species Abundance Across Spatial Scales
Authors: Kunin William E.
Published: July 2002

The analysis, measurement, and management of species abundance is central to ecology and conservation biology, but it has proved difficult to find a single index that adequately reflects the commonness or rarity of species across a range of spatial scales. Here, a scale-independent measure of species abundance is developed, using presence-absence maps at varying spatial resolutions. By extrapolating such “scale-area” curves, species abundance can be estimated accurately even at scales finer than those used to parameterize the model, a task that had previously been deemed impossible in principle.
A Mammalian Scaffold Complex That Selectively Mediates MAP Kinase Activation
Authors: Whitmarsh Alan J. , Cavanagh Julie , Tournier Cathy , Yasuda Jun , Davis Roger J.
Published: July 2002

The c-Jun NH
2
-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by the exposure of cells to multiple forms of stress. A putative scaffold protein was identified that interacts with multiple components of the JNK signaling pathway, including the mixed-lineage group of MAP kinase kinase kinases (MLK), the MAP kinase kinase MKK7, and the MAP kinase JNK. This scaffold protein selectively enhanced JNK activation by the MLK signaling pathway. These data establish that a mammalian scaffold protein can mediate activation of a MAP kinase signaling pathway.
Hepatitis C Viral Dynamics in Vivo and the Antiviral Efficacy of Interferon-α Therapy
Authors: Neumann Avidan U. , Lam Nancy P. , Dahari Harel , Gretch David R. , Wiley Thelma E. , Layden Thomas J. , Perelson Alan S.
Published: July 2002

To better understand the dynamics of hepatitis C virus and the antiviral effect of interferon-α-2b (IFN), viral decline in 23 patients during therapy was analyzed with a mathematical model. The analysis indicates that the major initial effect of IFN is to block virion production or release, with blocking efficacies of 81, 95, and 96% for daily doses of 5, 10, and 15 million international units, respectively. The estimated virion half-life (t1/2) was, on average, 2.7 hours, with pretreatment production and clearance of 1012virions per day. The estimated infected cell death rate exhibited large interpatient variation (correspondingt1/2= 1.7 to 70 days), was inversely correlated with baseline viral load, and was positively correlated with alanine aminotransferase levels. Fast death rates were predictive of virus being undetectable by polymerase chain reaction at 3 months. These findings show that infection with hepatitis C virus is highly dynamic and that early monitoring of viral load can help guide therapy.
Role of Farnesyltransferase in ABA Regulation of Guard Cell Anion Channels and Plant Water Loss
Authors: Pei Zhen-Ming , Ghassemian Majid , Kwak Christine M. , McCourt Peter , Schroeder Julian I.
Published: July 2002

Desiccation of plants during drought can be detrimental to agricultural production. The phytohormone abscisic acid (ABA) reduces water loss by triggering stomatal pore closure in leaves, a process requiring ion-channel modulation by cytoplasmic proteins. Deletion of the
Arabidopsis
farnesyltransferase gene
ERA1
or application of farnesyltransferase inhibitors resulted in ABA hypersensitivity of guard cell anion-channel activation and of stomatal closing.
ERA1
was expressed in guard cells. Double-mutant analyses of
era1
with the ABA-insensitive mutants
abi1
and
abi2
showed that
era1
suppresses the ABA-insensitive phenotypes. Moreover,
era1
plants exhibited a reduction in transpirational water loss during drought treatment.
Coherent Optical Control of the Quantum State of a Single Quantum Dot
Authors: Bonadeo N. H. , Erland J. , Gammon D. , Park D. , Katzer D. S. , Steel D. G.
Published: July 2002

Picosecond optical excitation was used to coherently control the excitation in a single quantum dot on a time scale that is short compared with the time scale for loss of quantum coherence. The excitonic wave function was manipulated by controlling the optical phase of the two-pulse sequence through timing and polarization. Wave function engineering techniques, developed in atomic and molecular systems, were used to monitor and control a nonstationary quantum mechanical state composed of a superposition of eigenstates. The results extend the concept of coherent control in semiconductors to the limit of a single quantum system in a zero-dimensional quantum dot.
Regulated Delivery of Therapeutic Proteins After in Vivo Somatic Cell Gene Transfer
Authors: Ye Xuehai , Rivera Victor M. , Zoltick Philip , Cerasoli Franklin , Schnell Michael A. , Gao Guang-ping , Hughes Joseph V. , Gilman Michael , Wilson James M.
Published: July 2002

Stable delivery of a therapeutic protein under pharmacologic control was achieved through in vivo somatic gene transfer. This system was based on the expression of two chimeric, human-derived proteins that were reconstituted by rapamycin into a transcription factor complex. A mixture of two adeno-associated virus vectors, one expressing the transcription factor chimeras and one containing erythropoietin (Epo) under the control of a promoter responsive to the transcription factor, was injected into skeletal muscle of immune-competent mice. Administration of rapamycin resulted in 200-fold induction of plasma Epo. Stable engraftment of this humanized system in immune-competent mice was achieved for 6 months with similar results for at least 3 months in a rhesus monkey.
Episodic Fluctuations in Larval Supply
Authors: Dixon Paul A. , Milicich Maria J. , Sugihara George
Published: July 2002

The lack of a clear relationship between spawning output and recruitment success continues to confound attempts to understand and manage temporally variable fish populations. This relationship for a common reef fish is shown to be obscured by nonlinear processes in operation during the larval phase. Nonlinear responses of larval fish to their noisy physical environment may offer a general explanation for the erratic, often episodic, replenishment of open marine populations.
Regulation of Maternal Behavior and Offspring Growth by Paternally Expressed
Peg3
Authors: Li L.-L. , Keverne E. B. , Aparicio S. A. , Ishino F. , Barton S. C. , Surani M. A.
Published: July 2002

Imprinted genes display parent-of-origin–dependent monoallelic expression that apparently regulates complex mammalian traits, including growth and behavior. The
Peg3
gene is expressed in embryos and the adult brain from the paternal allele only. A mutation in the
Peg3
gene resulted in growth retardation, as well as a striking impairment of maternal behavior that frequently resulted in death of the offspring. This result may be partly due to defective neuronal connectivity, as well as reduced oxytocin neurons in the hypothalamus, because mutant mothers were deficient in milk ejection. This study provides further insights on the evolution of epigenetic regulation of imprinted gene dosage in modulating mammalian growth and behavior.
Reexamining Fire Suppression Impacts on Brushland Fire Regimes
Authors: Keeley Jon E. , Fotheringham C. J. , Morais Marco
Published: July 2002

California shrubland wildfires are increasingly destructive, and it is widely held that the problem has been intensified by fire suppression, leading to larger, more intense wildfires. However, analysis of the California Statewide Fire History Database shows that, since 1910, fire frequency and area burned have not declined, and fire size has not increased. Fire rotation intervals have declined, and fire season has not changed, implying that fire intensity has not increased. Fire frequency and population density were correlated, and it is suggested that fire suppression plays a critical role in offsetting potential impacts of increased ignitions. Large fires were not dependent on old age classes of fuels, and it is thus unlikely that age class manipulation of fuels can prevent large fires. Expansion of the urban-wildland interface is a key factor in wildland fire destruction.
Differences in Left-Right Axis Pathways in Mouse and Chick: Functions of FGF8 and SHH
Authors: Meyers Erik N. , Martin Gail R.
Published: July 2002

A molecular pathway leading to left-right asymmetry in the chick embryo has been described, in which FGF8 is a right determinant and Sonic Hedgehog a left determinant. Here evidence is presented that the
Fgf8
and Sonic Hedgehog genes are required for left-right axis determination in the mouse embryo, but that they have different functions from those previously reported in the chick. In the mouse FGF8 is a left determinant and Sonic Hedgehog is required to prevent left determinants from being expressed on the right.
Oxygen and Iron Isotope Studies of Magnetite Produced by Magnetotactic Bacteria
Authors: Mandernack Kevin W. , Bazylinski Dennis A. , Shanks Wayne C. , Bullen Thomas D.
Published: July 2002

A series of carefully controlled laboratory studies was carried out to investigate oxygen and iron isotope fractionation during the intracellular production of magnetite (Fe
3
O
4
) by two different species of magnetotactic bacteria at temperatures between 4° and 35°C under microaerobic and anaerobic conditions. No detectable fractionation of iron isotopes in the bacterial magnetites was observed. However, oxygen isotope measurements indicated a temperature-dependent fractionation for Fe
3
O
4
and water that is consistent with that observed for Fe
3
O
4
produced extracellularly by thermophilic Fe
3+
-reducing bacteria. These results contrast with established fractionation curves estimated from either high-temperature experiments or theoretical calculations. With the fractionation curve established in this report, oxygen-18 isotope values of bacterial Fe
3
O
4
may be useful in paleoenvironmental studies for determining the oxygen-18 isotope values of formation waters and for inferring paleotemperatures.
Extrusion Polymerization: Catalyzed Synthesis of Crystalline Linear Polyethylene Nanofibers Within a Mesoporous Silica
Authors: Kageyama Keisuke , Tamazawa Jun-ichi , Aida Takuzo
Published: July 2002

Crystalline nanofibers of linear polyethylene with an ultrahigh molecular weight (6,200,000) and a diameter of 30 to 50 nanometers were formed by the polymerization of ethylene with mesoporous silica fiber–supported titanocene, with methylalumoxane as a cocatalyst. Small-angle x-ray scattering analysis indicated that the polyethylene fibers consist predominantly of extended-chain crystals. This observation indicates a potential utility of the honeycomb-like porous framework as an extruder for nanofabrication of polymeric materials.
Ultrasensitive Isotope Trace Analyses with a Magneto-Optical Trap
Authors: Chen C. Y. , Li Y. M. , Bailey K. , O'Connor T. P. , Young L. , Lu Z.-T.
Published: July 2002

Laser manipulation of neutral atoms has been used to count individual krypton-85 and krypton-81 atoms present in a natural krypton gas sample with isotopic abundances in the range of 10−11and 10−13, respectively. This method of isotope trace analysis is free of contamination from other isotopes and elements and can be applied to several different isotope tracers for a wide range of applications. The demonstrated detection efficiency is 1 × 10−7. System improvements could increase the efficiency by many orders of magnitude.
Is AIDS Man-Made?
Authors: Weiss Robin A.
Published: July 2002

The River
A Journey to the Source of HIVand AIDS. Edward Hooper. Little, Brown, New York, 1999. 1104 pp. $35. ISBN 0-316-37261-7. Penguin, London, 1999. 1104 pp. £25. ISBN 0-7139-9335-9.

Although our reviewer is not persuaded by Hooper's case for the claim that AIDS arose via contaminated oral poliovirus vaccines, he finds there are important lessons--including how lucky we have been to escape other viral zoonoses--to be learned from the author's arguments.
Frontiers in Ultrashort Pulse Generation: Pushing the Limits in Linear and Nonlinear Optics
Authors: Steinmeyer G. , Sutter D. H. , Gallmann L. , Matuschek N. , Keller U.
Published: July 2002

Optical pulses in the 5-femtosecond range are produced by a variety of methods. Although different in technical detail, each method relies on the same three key components: spectral broadening due to the nonlinear optical Kerr effect, dispersion control, and ultrabroadband amplification. The state of the art of ultrashort pulse generation is reviewed with a focus on direct laser oscillator schemes.
Geomicrobiology of Subglacial Ice Above Lake Vostok, Antarctica
Authors: Priscu John C. , Adams Edward E. , Lyons W. Berry , Voytek Mary A. , Mogk David W. , Brown Robert L. , McKay Christopher P. , Takacs Cristina D. , Welch Kathy A. , Wolf Craig F. , Kirshtein Julie D. , Avci Recep
Published: July 2002

Data from ice 3590 meters below Vostok Station indicate that the ice was accreted from liquid water associated with Lake Vostok. Microbes were observed at concentrations ranging from 2.8 × 10
3
to 3.6 × 10
4
cells per milliliter; no biological incorporation of selected organic substrates or bicarbonate was detected. Bacterial 16
S
ribosomal DNA genes revealed low diversity in the gene population. The phylotypes were closely related to extant members of the
alpha
- and
beta
-
Proteobacteria
and the Actinomycetes. Extrapolation of the data from accretion ice to Lake Vostok implies that Lake Vostok may support a microbial population, despite more than 10
6
years of isolation from the atmosphere.
A Nucleation Site and Mechanism Leading to Epitaxial Growth of Diamond Films
Authors: Lee S. T. , Peng H. Y. , Zhou X. T. , Wang N. , Lee C. S. , Bello I. , Lifshitz Y.
Published: July 2002

A diamond nucleation site responsible for epitaxial growth of diamond on silicon by chemical vapor deposition (CVD) is identified in high-resolution transmission electron microscopic images. Other sites in the same sample leading to polycrystalline growth, but deleterious to epitaxial CVD growth, are also described. A mechanism for the heteroepitaxial growth of diamond is suggested, in which etching of the nondiamond carbon binder exposes and removes nonadherent nanodiamond nuclei, leaving intact only those directly nucleated on the silicon substrate. This work enhances our understanding of diamond nucleation and heteroepitaxial growth and its potential applications.
Tectonic Implications of U-Pb Zircon Ages of the Himalayan Orogenic Belt in Nepal
Authors: DeCelles P. G. , Gehrels G. E. , Quade J. , LaReau B. , Spurlin M.
Published: July 2002

Metasedimentary rocks of the Greater Himalaya are traditionally viewed as Indian shield basement that has been thrust southward onto Lesser Himalayan sedimentary rocks during the Cenozoic collision of India and Eurasia. Ages determined from radioactive decay of uranium to lead in zircon grains from Nepal suggest that Greater Himalayan protoliths were shed from the northern end of the East African orogen during the late Proterozoic pan-African orogenic event. These rocks were accreted onto northern Gondwana and intruded by crustal melts during Cambrian-Ordovician time. Our data suggest that the Main Central thrust may have a large amount of pre-Tertiary displacement, that structural restorations placing Greater Himalayan rocks below Lesser Himalayan rocks at the onset of Cenozoic orogenesis are flawed, and that some metamorphism of Greater Himalayan rocks may have occurred during early Paleozoic time.
Location of a Major Susceptibility Locus for Familial Schizophrenia on Chromosome 1q21-q22
Authors: Brzustowicz Linda M. , Hodgkinson Kathleen A. , Chow Eva W. C. , Honer William G. , Bassett Anne S.
Published: July 2002

Schizophrenia is a complex disorder, and there is substantial evidence supporting a genetic etiology. Despite this, prior attempts to localize susceptibility loci have produced predominantly suggestive findings. A genome-wide scan for schizophrenia susceptibility loci in 22 extended families with high rates of schizophrenia provided highly significant evidence of linkage to chromosome 1 (1q21-q22), with a maximum heterogeneity logarithm of the likelihood of linkage (lod) score of 6.50. This linkage result should provide sufficient power to allow the positional cloning of the underlying susceptibility gene.
Satellite Measurements of Sea Surface Temperature Through Clouds
Authors: Wentz Frank J. , Gentemann Chelle , Smith Deborah , Chelton Dudley
Published: July 2002

Measurements of sea surface temperature (SST) can be made by satellite microwave radiometry in all weather conditions except rain. Microwaves penetrate clouds with little attenuation, giving an uninterrupted view of the ocean surface. This is a distinct advantage over infrared measurements of SST, which are obstructed by clouds. Comparisons with ocean buoys show a root mean square difference of about 0.6°C, which is partly due to the satellite-buoy spatial-temporal sampling mismatch and the difference between the ocean skin temperature and bulk temperature. Microwave SST retrievals provide insights in a number of areas, including tropical instability waves, marine boundary layer dynamics, and the prediction of hurricane intensity.
El Niño-Like Climate Teleconnections in New England During the Late Pleistocene
Authors: Rittenour Tammy M. , Brigham-Grette Julie , Mann Michael E.
Published: July 2002

A glacial varve chronology from New England spanning the 4000-year period from 17,500 to 13,500 calendar years before the present was analyzed for evidence of climate variability during the late Pleistocene. The chronology shows a distinct interannual (3 to 5 years) band of enhanced variability suggestive of El Niño–Southern Oscillation (ENSO) teleconnections into North America during the late Pleistocene, when the Laurentide ice sheet was near its maximum extent and climatic boundary conditions were different than those of today. This interannual variability largely disappears by the young end of the 4000-year chronology, with only the highest frequency components (roughly 3-year period) persisting. This record provides evidence of ENSO-like climate variability during near-peak glacial conditions.
Status and Improvements of Coupled General Circulation Models
Authors: Grassl Hartmut
Published: July 2002

Coupled general circulation models (CGCMs) integrate our knowledge about atmospheric and oceanic circulation. Different versions of CGCMs are used to provide a better understanding of natural climate variability on interannual and decadal time scales, for extended weather forecasting, and for making seasonal climate scenario projections. They also help to reconstruct past climates, especially abrupt climate change processes. Model intercomparisons, new test data (mainly from satellites), more powerful computers, and parameterizations of atmospheric and oceanic processes have improved CGCM performance to such a degree that the model results are now used by many decision-makers, including governments. They are also fundamental for the detection and attribution of climate change.
Cholinergic Synaptic Inhibition of Inner Hair Cells in the Neonatal Mammalian Cochlea
Authors: Glowatzki Elisabeth , Fuchs Paul A.
Published: July 2002

Efferent feedback onto sensory organs provides a means to modulate input to the central nervous system. In the developing mammalian cochlea, inner hair cells are transiently innervated by efferent fibers, even before sensory function begins. Here, we show that neonatal inner hair cells are inhibited by cholinergic synaptic input before the onset of hearing. The synaptic currents, as well as the inner hair cell's response to acetylcholine, are mediated by a nicotinic (α9-containing) receptor and result in the activation of small-conductance calcium-dependent potassium channels.
Generation of G-to-A and C-to-U Changes in HIV-1 Transcripts by RNA Editing
Authors: Bourara K. , Litvak S. , Araya A.
Published: July 2002

RNA editing involves posttranscriptional alterations of messenger RNA (mRNA) sequences modifying the information content encoded by the genetic message. Here, it is shown that, in chronically infected H9 cells, human immunodeficiency virus–type 1 (HIV-1) mRNAs undergo guanine-to-adenine (G-to-A) and cytosine-to-uracil (C-to-U) changes. G-to-A modification in the untranslated region of exon 1 was present only in spliced HIV-1 mRNAs. The creation of stop codons in HIV-1 mRNAs may function to control the translation of viral proteins, such as viral protein R, that are involved in the regulation of HIV-1 expression and the survival of chronically infected cells.
Fuzzing the Boundary of Animal Life
Authors: LaBarbera Michael
Published: July 2002

The Extended Organism
The Physiology of Animal-Built Structures. J. Scott Turner. Harvard University Press, Cambridge, MA, 2000. 247 pp. $47.50. ISBN 0-674-00151-6.

Turner applies the idea of an extended phenotype to discuss structures animals use to capture and channel physical and chemistry energy from their environments.
Optically Defined Multifunctional Patterning of Photosensitive Thin-Film Silica Mesophases
Authors: Doshi Dhaval A. , Huesing Nicola K. , Lu Mengcheng , Fan Hongyou , Lu Yunfeng , Simmons-Potter Kelly , Potter B. G. , Hurd Alan J. , Brinker C. Jeffrey
Published: July 2002

Photosensitive films incorporating molecular photoacid generators compartmentalized within a silica-surfactant mesophase were prepared by an evaporation-induced self-assembly process. Ultraviolet exposure promoted localized acid-catalyzed siloxane condensation, which can be used for selective etching of unexposed regions; for “gray-scale” patterning of refractive index, pore size, surface area, and wetting behavior; and for optically defining a mesophase transformation (from hexagonal to tetragonal) within the film. The ability to optically define and continuously control both structure and function on the macro- and mesoscales is of interest for sensor arrays, nanoreactors, photonic and fluidic devices, and low-dielectric-constant films.
Regional Changes in Carbon Dioxide Fluxes of Land and Oceans Since 1980
Authors: Bousquet Philippe , Peylin Philippe , Ciais Philippe , Le Quéré Corinne , Friedlingstein Pierre , Tans Pieter P.
Published: July 2002

We have applied an inverse model to 20 years of atmospheric carbon dioxide measurements to infer yearly changes in the regional carbon balance of oceans and continents. The model indicates that global terrestrial carbon fluxes were approximately twice as variable as ocean fluxes between 1980 and 1998. Tropical land ecosystems contributed most of the interannual changes in Earth's carbon balance over the 1980s, whereas northern mid- and high-latitude land ecosystems dominated from 1990 to 1995. Strongly enhanced uptake of carbon was found over North America during the 1992–1993 period compared to 1989–1990.
Nanoelectromechanical Systems
Authors: Craighead H. G.
Published: July 2002

Nanoelectromechanical systems are evolving, with new scientific studies and technical applications emerging. Mechanical devices are shrinking in thickness and width to reduce mass, increase resonant frequency, and lower the force constants of these systems. Advances in the field include improvements in fabrication processes and new methods for actuating and detecting motion at the nanoscale. Lithographic approaches are capable of creating freestanding objects in silicon and other materials, with thickness and lateral dimensions down to about 20 nanometers. Similar processes can make channels or pores of comparable dimensions, approaching the molecular scale. This allows access to a new experimental regime and suggests new applications in sensing and molecular interactions.
High Shear Strain of Olivine Aggregates: Rheological and Seismic Consequences
Authors: Bystricky M. , Kunze K. , Burlini L. , Burg J. -P.
Published: July 2002

High-pressure and high-temperature torsion experiments on olivine aggregates in dislocation creep show about 15 to 20% strain weakening before steady-state behavior, characterized by subgrain-rotation recrystallization and a strong lattice preferred orientation. Such weakening may provide a way to focus flow in the upper mantle without a change in deformation mechanism. Flow laws derived from low strain data may not be appropriate for use in modeling high strain regions. In such areas, seismic wave propagation will be anisotropic with an axis of approximate rotational symmetry about the shear direction. In contrast to current thinking, the anisotropy will not indicate the orientation of the shear plane in highly strained, recrystallized olivine-rich rocks.
Glucose-Dependent Insulin Release from Genetically Engineered K Cells
Authors: Cheung Anthony T. , Dayanandan Bama , Lewis Jamie T. , Korbutt Gregory S. , Rajotte Ray V. , Bryer-Ash Michael , Boylan Michael O. , Wolfe M. Michael , Kieffer Timothy J.
Published: July 2002

Genetic engineering of non-β cells to release insulin upon feeding could be a therapeutic modality for patients with diabetes. A tumor-derived K-cell line was induced to produce human insulin by providing the cells with the human insulin gene linked to the 5'-regulatory region of the gene encoding glucose-dependent insulinotropic polypeptide (GIP). Mice expressing this transgene produced human insulin specifically in gut K cells. This insulin protected the mice from developing diabetes and maintained glucose tolerance after destruction of the native insulin-producing β cells.
Comparison of a New Triazole, Posaconazole, with Itraconazole and Amphotericin B for Treatment of Histoplasmosis following Pulmonary Challenge in Immunocompromised Mice
Authors: Connolly Patricia , Wheat L. Joseph , Schnizlein-Bick Carol , Durkin Michelle , Kohler Steve , Smedema Melinda , Goldberg Janet , Brizendine Edward , Loebenberg David
Published: July 2002

A murine model of intratracheally induced histoplasmosis in immunocompromised B6C3F1mice was used to evaluate a new triazole antifungal agent, posaconazole. This compound was previously shown to be comparable to amphotericin B and superior to itraconazole for the treatment of histoplasmosis in immunocompetent mice. The current study used mice that were depleted of T lymphocytes by intraperitoneal injection of anti-CD4 and anti-CD8 monoclonal antibodies beginning 2 days before infection and continuing at 5-day intervals until completion of the study. Groups of B6C3F1mice that were depleted of CD4 and CD8 T cells were infected with an inoculum of 104Histoplasma capsulatumyeasts. All mice receiving posaconazole at 1 or 0.1 mg/kg of body weight/day, amphotericin B at 2 mg/kg every other day (qod), or itraconazole at 75 mg/kg/day survived to day 29. Only 60% of mice receiving itraconazole at 10 mg/kg/day and none receiving amphotericin B at 0.2 mg/kg qod survived to that date. Fungal burdens were determined at day 14 of infection, 1 day after discontinuation of therapy. Quantitative colony counts andHistoplasmaantigen levels in lung and spleen tissues declined following treatment with amphotericin B at 2 mg/kg qod, posaconazole at 5 and 1 mg/kg/day, and itraconazole at 75 mg/kg/day but not in mice treated with amphotericin B at 0.2 mg/kg qod or itraconazole at 10 mg/kg/day. Posaconazole at 0.1 mg/kg/day reduced fungal colony counts and antigen levels in spleens but not in lungs. This study shows posaconazole activity for the treatment of histoplasmosis in immunosuppressed animals.
Detection of Florfenicol Resistance Genes inEscherichia coliIsolated from Sick Chickens
Authors: Keyes Kathleen , Hudson Charlene , Maurer John J. , Thayer Stephan , White David G. , Lee Margie D.
Published: July 2002

Florfenicol is an antibiotic approved for veterinary use in cattle in the United States in 1996. Although this drug is not used in poultry, we have detected resistance to florfenicol in clinical isolates of avianEscherichia coli. Molecular typing demonstrated that the florfenicol resistance gene,flo, was independently acquired and is plasmid encoded.
Efficacy of FK463, a New Lipopeptide Antifungal Agent, in Mouse Models of Disseminated Candidiasis and Aspergillosis
Authors: Ikeda Fumiaki , Wakai Yoshimi , Matsumoto Satoru , Maki Katsuyuki , Watabe Etsuko , Tawara Shuichi , Goto Toshio , Watanabe Yuji , Matsumoto Fumio , Kuwahara Shogo
Published: July 2002

The efficacy of intravenous injection of FK463, a novel water-soluble lipopeptide, was evaluated in mouse models of disseminated candidiasis and aspergillosis and was compared with those of fluconazole (FLCZ) and amphotericin B (AMPH-B). In the candidiasis model, FK463 significantly prolonged the survival of intravenously infected mice at doses of 0.125 mg/kg of body weight or higher. In disseminated candidiasis caused by
Candida
species, including FLCZ-resistant
Candida albicans
, FK463 exhibited an efficacy 1.4 to 18 times inferior to that of AMPH-B, with 50% effective doses (ED
50
s) ranging from 0.21 to 1.00 mg/kg and 0.06 to 0.26 mg/kg, respectively, and was much more active than FLCZ. The protective effect of FK463 was not obviously influenced by the fungal inoculum size, the starting time of the treatment, or the immunosuppressed status of the host. The reduction in efficacy was less than that observed with FLCZ or AMPH-B. The efficacy of FK463 was also evaluated in the disseminated candidiasis target organ assay and was compared with those of FLCZ and AMPH-B. Efficacies were evaluated on the basis of a comparison between the mean log
10
CFU in kidneys in the groups treated with antifungal agents and that in control group. A single dose of FK463 at 0.5 mg/kg or higher significantly reduced the viable counts in kidneys compared with the numbers of yeast cells before treatment, and its efficacy was comparable to that of AMPH-B, while FLCZ at 4 mg/kg showed only a suppressive effect on the growth of
C. albicans
in the kidneys. In the disseminated aspergillosis model, FK463 given at doses of 0.5 mg/kg or higher significantly prolonged the survival of mice infected intravenously with
Aspergillus fumigatus
conidia. The efficacy of FK463 was about 2 times inferior to that of AMPH-B, with ED
50
s ranging from 0.25 to 0.50 mg/kg and 0.11 to 0.29 mg/kg, respectively. These results indicate that FK463 may be a potent parenterally administered therapeutic agent for disseminated candidiasis and aspergillosis.
In Vitro Activities of Nontraditional Antimicrobials against Multiresistant
Acinetobacter baumannii
Strains Isolated in an Intensive Care Unit Outbreak
Authors: Appleman Maria D. , Belzberg Howard , Citron Diane M. , Heseltine Peter N. R. , Yellin Albert E. , Murray James , Berne Thomas V.
Published: July 2002

Fifteen multiresistant
Acinetobacter baumannii
isolates from patients in intensive care units and 14 nonoutbreak strains were tested to determine in vitro activities of nontraditional antimicrobials, including cefepime, meropenem, netilmicin, azithromycin, doxycycline, rifampin, sulbactam, and trovafloxacin. The latter five drugs were further tested against four of the strains for bactericidal or bacteriostatic activity by performing kill-curve studies at 0.5, 1, 2, and 4 times their MICs. In addition, novel combinations of drugs with sulbactam were examined for synergistic interactions by using a checkerboard configuration. MICs at which 90% of the isolates tested were inhibited for antimicrobials showing activity against the multiresistant
A. baumannii
strains were as follows (in parentheses): doxycycline (1 μg/ml), azithromycin (4 μg/ml), netilmicin (1 μg/ml), rifampin (8 μg/ml), polymyxin (0.8 U/ml), meropenem (4 μg/ml), trovafloxacin (4 μg/ml), and sulbactam (8 μg/ml). In the kill-curve studies, azithromycin and rifampin were rapidly bactericidal while sulbactam was more slowly bactericidal. Trovafloxacin and doxycycline were bacteriostatic. None of the antimicrobials tested were bactericidal against all strains tested. The synergy studies demonstrated that the combinations of sulbactam with azithromycin, rifampin, doxycycline, or trovafloxacin were generally additive or indifferent.
Control of Staphylococcal Adhesion to Polymethylmethacrylate and Enhancement of Susceptibility to Antibiotics by Poloxamer 407
Authors: Veyries Marie-Laure , Faurisson Francois , Joly-Guillou Marie-Laure , Rouveix Bernard
Published: July 2002

We studied the antiadhesive effect of Poloxamer 407 (P407), together with modifications in the antimicrobial susceptibility of residual adherent staphylococci. Bacterial adherence was markedly inhibited (77% to more than 99.9%) whether polymethylmethacrylate was exposed to P407 before or during the adherence assay. Furthermore, residual adherent staphylococci appeared to be more susceptible to antibiotic activity, suggesting that combination of P407 with antibiotics could be a promising approach to the prevention of infection of foreign material.
Contributions of the AmpC β-Lactamase and the AcrAB Multidrug Efflux System in Intrinsic Resistance of
Escherichia coli
K-12 to β-Lactams
Authors: Mazzariol Annarita , Cornaglia Giuseppe , Nikaido Hiroshi
Published: July 2002

The roles of the AmpC chromosomal β-lactamase and the AcrAB efflux system in levels of intrinsic resistance and susceptibility of
Escherichia coli
to β-lactams were studied with a set of isogenic strains. MICs of ureidopenicillins, carbenicillin, oxacillin, and cloxacillin were drastically reduced by the inactivation of AcrAB, whereas those of the earlier cephalosporins were affected mostly by the loss of AmpC β-lactamase.
Correlation of Fluconazole MICs with Clinical Outcome in Cryptococcal Infection
Authors: Aller A. I. , Martin-Mazuelos E. , Lozano F. , Gomez-Mateos J. , Steele-Moore L. , Holloway W. J. , Gutiérrez M. J. , Recio F. J. , Espinel-Ingroff A.
Published: July 2002

We have correlated the in vitro results of testing the susceptibility of
Cryptococcus neoformans
to fluconazole with the clinical outcome after fluconazole maintenance therapy in patients with AIDS-associated cryptococcal disease. A total of 28 isolates of
C. neoformans
from 25 patients (24 AIDS patients) were tested. The MICs were determined by the broth microdilution technique by following the modified guidelines described in National Committee for Clinical Standards (NCCLS) document M27-A, e.g., use of yeast nitrogen base medium and a final inoculum of 10
4
CFU/ml. The fluconazole MIC at which 50% of isolates are inhibited (MIC
50
) and MIC
90
, obtained spectrophotometrically after 48 h of incubation, were 4 and 16 μg/ml, respectively. Of the 25 patients studied, 4 died of active cryptococcal disease and 2 died of other causes. Therapeutic failure was observed in five patients who were infected with isolates for which fluconazole MICs were ≥16 μg/ml. Four of these patients had previously had oropharyngeal candidiasis (OPC); three had previously had episodes of cryptococcal infection, and all five treatment failure patients had high cryptococcal antigen titers in either serum or cerebrospinal fluid (titers, >1:4,000). Although 14 of the 18 patients who responded to fluconazole therapy had previously had OPC infections, they each had only a single episode of cryptococcal infection. It appears that the clinical outcome after fluconazole maintenance therapy may be better when the infecting
C. neoformans
strain is inhibited by lower concentrations of fluconazole for eradication (MICs, <16 μg/ml) than when the patients are infected with strains that require higher fluconazole concentrations (MICs, ≥16 μg/ml). These findings also suggest that the MICs determined by the modified NCCLS microdilution method can be potential predictors of the clinical response to fluconazole therapy and may aid in the identification of patients who will not respond to fluconazole therapy.
Evaluation of Voriconazole Pharmacodynamics Using Time-Kill Methodology
Authors: Klepser Michael E. , Malone Dennis , Lewis Russell E. , Ernst Erika J. , Pfaller Michael A.
Published: July 2002

Voriconazole is an investigational azole antifungal agent with activity against a variety of fungal species, including fluconazole-susceptible and -resistant
Candida
species and
Cryptococcus neoformans
. In this study, we employed in vitro time-kill methods to characterize the relationship between concentrations of voriconazole and its fungistatic activity against
Candida albicans
,
Candida glabrata
,
Candida tropicalis
, and
C. neoformans
. Isolates were exposed to voriconazole concentrations ranging from 0.0625 to 16 times the MIC, and the viable colony counts were determined over time. The 50 and 90% effective concentrations (EC
50
and EC
90
, respectively) were determined at 8, 12, and 24 h following the addition of voriconazole. At each time point, near-maximal fungistatic activity, as indicated by the EC
90
, was noted at a drug concentration of approximately three times the MIC. Additionally, EC
50
and EC
90
did not change over time, thus suggesting that the rate of activity was not improved by increasing concentrations. Voriconazole exhibits non-concentration-dependent pharmacodynamic characteristics in vitro.
Efficacy of Oral Cochleate-Amphotericin B in a Mouse Model of Systemic Candidiasis
Authors: Santangelo Rosaria , Paderu Padmaja , Delmas Guillaume , Chen Zi-Wei , Mannino Raphael , Zarif Leila , Perlin David S.
Published: July 2002

Amphotericin B (AMB) remains the principal therapeutic choice for deep mycoses. However, its application is limited by toxicity and a route of administration requiring slow intravenous injection. An oral formulation of this drug is desirable to treat acute infections and provide prophylactic therapy for high-risk patients. Cochleates are a novel lipid-based delivery system that have the potential for oral administration of hydrophobic drugs. They are stable phospholipid-cation crystalline structures consisting of a spiral lipid bilayer sheet with no internal aqueous space. Cochleates containing AMB (CAMB) inhibit the growth of
Candida albicans
, and the in vivo therapeutic efficacy of CAMB administered orally was evaluated in a mouse model of systemic candidiasis. The results indicate that 100% of the mice treated at all CAMB doses, including a low dosage of 0.5 mg/kg of body weight/day, survived the experimental period (16 days). In contrast, 100% mortality was observed with untreated mice by day 12. The fungal tissue burden in kidneys and lungs was assessed in parallel, and a dose-dependent reduction in
C. albicans
from the kidneys was observed, with a maximum 3.5-log reduction in total cell counts at 2.5 mg/kg/day. However, complete clearance of the organism from the lungs, resulting in more than a 4-log reduction, was observed at the same dose. These results were comparable to a deoxycholate AMB formulation administered intraperitoneally at 2 mg/kg/day (
P
< 0.05). Overall, these data demonstrate that cochleates are an effective oral delivery system for AMB in a model of systemic candidiasis.
In Vitro Antiproliferative Effects and Mechanism of Action of the New Triazole Derivative UR-9825 against the Protozoan ParasiteTrypanosoma(Schizotrypanum)cruzi
Authors: Urbina Julio A. , Lira Renee , Visbal Gonzalo , Bartrolí Javier
Published: July 2002

We describe the in vitro antiproliferative effects of the new triazole derivative UR-9825 against the protozoan parasiteTrypanosoma(Schizotrypanum)cruzi, the causative agent of Chagas' disease in Latin America. The compound was found to be extremely active against the cultured (epimastigote) form of the parasite, equivalent to that present in the reduviid vector, with a MIC of 30 nM, a concentration 33-fold lower than that required with the reference compound ketoconazole. At that MIC, growth arrest coincided with depletion of the parasite's 4,14-desmethyl endogenous sterols (ergosterol, 24-ethylcholesta-5,7,22-trien-3b-ol, and precursors) and their replacement by methylated sterols (lanosterol, 24-methylenedihydrolanosterol, and obtusifoliol), as revealed by high-resolution gas chromatography coupled with mass spectrometry. This indicated that the primary mechanism of action of UR-9825 was inhibition of the parasite's sterol C14α demethylase, as seen with other azole derivatives. The phospholipid composition of growth-arrested epimastigotes was also altered, when compared to controls, with a significant increase in the content of phosphatidylethanolamine and phosphatidylserine and a concomitant reduction of the content of phosphatidylcholine. The clinically relevant intracellular amastigote form, grown in cultured Vero cells at 37°C, was even more sensitive to UR-9825, with a MIC of 10 nM, comparable to that for ketoconazole. The results showed that UR-9825 is among the most potent azole derivatives tested against this parasite and support in vivo studies with this compound.
Susceptibilities of
Haemophilus influenzae
and
Moraxella catarrhalis
to ABT-773 Compared to Their Susceptibilities to 11 Other Agents
Authors: Credito Kim L. , Lin Gengrong , Pankuch Glenn A. , Bajaksouzian Saralee , Jacobs Michael R. , Appelbaum Peter C.
Published: July 2002

The activity of the ketolide ABT-773 against
Haemophilus
and
Moraxella
was compared to those of 11 other agents. Against 210
Haemophilus influenzae
strains (39.0% β-lactamase positive), microbroth dilution tests showed that azithromycin and ABT-773 had the lowest MICs (0.5 to 4.0 and 1.0 to 8.0 μg/ml, respectively), followed by clarithromycin and roxithromycin (4.0 to >32.0 μg/ml). Of the β-lactams, ceftriaxone had the lowest MICs (≤0.004 to 0.016 μg/ml), followed by cefixime and cefpodoxime (0.008 to 0.125 and ≤0.125 to 0.25 μg/ml, respectively), amoxicillin-clavulanate (0.125 to 4.0 μg/ml), and cefuroxime (0.25 to 8.0 μg/ml). Amoxicillin was only active against β-lactamase-negative strains, and cefprozil had the highest MICs of all oral cephalosporins tested (0.5 to >32.0 μg/ml). Against 50
Moraxella catarrhalis
strains, all of the compounds except amoxicillin and cefprozil were active. Time-kill studies against 10
H. influenzae
strains showed that ABT-773, at two times the MIC, was bactericidal against 9 of 10 strains, with 99% killing of all strains at the MIC after 24 h; at 12 h, ABT-773 gave 90% killing of all strains at two times the MIC. At 3 and 6 h, killing by ABT-773 was slower, with 99.9% killing of four strains at two times the MIC after 6 h. Similar results were found for azithromycin, with slightly slower killing by erythromycin, clarithromycin, and roxithromycin, especially at earlier times. β-Lactams were bactericidal against 8 to 10 strains at two times the MIC after 24 h, with slower killing at earlier time periods. Most compounds gave good killing of five
M. catarrhalis
strains, with β-lactams killing more rapidly than other drugs. ABT-773 and azithromycin gave the longest postantibiotic effects (PAEs) of the ketolide-macrolide-azalide group tested (4.4 to >8.0 h), followed by clarithromycin, erythromycin, and roxithromycin. β-Lactam PAEs were similar and shorter than those of the ketolide-macrolide-azalide group for all strains tested.
RL-37, an Alpha-Helical Antimicrobial Peptide of the Rhesus Monkey
Authors: Zhao Chengquan , Nguyen Tung , Boo Lee Ming , Hong Teresa , Espiritu Cesar , Orlov Dmitri , Wang Wei , Waring Alan , Lehrer Robert I.
Published: July 2002

Rhesus monkey bone marrow expresses a cathelicidin whose C-terminal domain comprises a 37-residue alpha-helical peptide (RL-37) that resembles human LL-37. Like its human counterpart, RL-37 rapidly permeabilized the membranes of
Escherichia coli
ML-35p and lysed liposomes that simulated bacterial membranes. When tested in media whose NaCl concentrations approximated those of extracellular fluids, RL-37 was considerably more active than LL-37 against staphylococci. Whereas human LL-37 contains five acidic residues and has a net charge of +6, rhesus RL-37 has only two acidic residues and a net charge of +8. Speculating that the multiple acidic residues of human LL-37 reduced its efficacy against staphylococci, we made a peptide (LL-37 pentamide) in which each aspartic acid of LL-37 was replaced by an asparagine and each glutamic acid was replaced by a glutamine. LL-37 pentamide's antistaphylococcal activity was substantially greater than that of LL-37. Thus, although the precursor of LL-37 is induced in human skin keratinocytes by injury or inflammation, its insufficiently cationic antimicrobial domain may contribute to the success of staphylococci in colonizing and infecting human skin.