bluuebunny/crossref_metadata_2025 huggingface dataset:
Noise reduction in opticalin situmeasurements for molecular beam epitaxy by substrate wobble normalization
Authors: Bertness K. A. , Hickernell R. K. , Hays S. P. , Christensen D. H.
Published: July 2002

We demonstrate a normalization method for removing noise introduced into optical in situ measurements by sample rotation wobble during molecular beam epitaxy. The technique consists of measuring the angle of rotation of the sample through optical triggers attached to the sample manipulator rotation drive, acquiring a normalization curve at the various trigger points, then applying the normalization appropriate to each trigger to subsequent data. This cyclic normalization is demonstrated on normal-incidence optical reflection data and atomic absorption measurements in which the flux-monitor light beam is reflected from the sample to allow determination of layer thickness in addition to atomic flux. Noise reductions by factors of 3 to 30 were observed in both systems, with the larger improvements for samples with larger wobble angles, while preserving the original time resolution of the data. We achieve normalized optical reflectance data with a noise standard deviation of 1% over a period of one to two hours and similar results for atomic absorption data on shorter time scales. The technique is limited by the long-term mechanical stability of the manipulator and collection optics.
Surface diffusion model accounting for the temperature dependence of tungsten etching characteristics in a SF6 magnetoplasma
Authors: Bounasri F. , Pelletier J. , Moisan M. , Chaker M.
Published: July 2002

To explain the influence of the substrate temperature Ts on the etching characteristics of tungsten in a SF6 magnetoplasma, we have extended the surface diffusion model originally developed for the etching of the W–F system at constant (ambient) temperature. It allows us to understand our experimental observations which include the influence of Ts on the anisotropy and the fact that the lateral (spontaneous) etch rate of W as a function of 1/Ts does not follow an Arrhenius law. The model is valid as long as the pressure is sufficiently low (⩽0.5 mTorr) to neglect the influence of coadsorption and passivation effects, likely related to oxygen contamination of the gas phase coming from the fused silica discharge tube interacting with fluorine atoms. Consistency of the model is well demonstrated by observing that the lateral to vertical etch rate ratio as a function of 1/Ts, under different plasma conditions, leads to a unique value of the activation energy (R=0.65 eV) for the associative desorption of WF6, the volatile reaction product of tungsten with fluorine adatoms.
Advanced techniques for glancing angle deposition
Authors: Robbie K. , Sit J. C. , Brett M. J.
Published: July 2002

When a thin film is deposited by physical vapor deposition, with the vapor flux arriving at an oblique angle from the substrate normal, and under conditions of sufficiently limited adatom mobility to create a columnar microstructure, the resulting structure is somewhat porous and grows at an angle inclined toward the vapor source. For a given material and set of deposition conditions, there is a fixed relationship between the angle of vapor flux incident on the substrate and the inclination angle at which the columnar thin film grows. As the porosity of the film is also dependent on the incident flux angle, column growth angle and porosity cannot be chosen independently. If a large columnar angle (more parallel to the substrate) is desired, the flux must be deposited at a large oblique angle resulting in a very porous film. Conversely, if a near vertical columnar film is desired, the flux must arrive more perpendicular to the substrate and the resulting film has a tightly packed, dense microstructure. We present a technique, based on glancing angle deposition, employing substrate motion during deposition, which allows the columnar growth inclination angle and film density to be controlled independently. With this method, microstructurally controlled materials can be fabricated with three dimensional control on a 10 nm scale for use in optical, chemical, biological, mechanical, magnetic, and electrical applications.
Reflectance difference spectroscopy spectra of clean (3×2), (2×1), and c(2×2) 3C-SiC(001) surfaces: New evidence for surface state contributions to optical anisotropy spectra
Authors: Rossow U. , Lindner K. , Lübbe M. , Aspnes D. E. , Zahn D. R. T.
Published: July 2002

In this study we applied the surface sensitive optical method reflectance difference spectroscopy to investigate the optical response of clean cubic 3C-SiC(001) surfaces. The main reconstructions, the Si-rich (3×2) and (2×1) as well as the C-rich c(2×2) were prepared by annealing in Si flux. For (3×2) we find a strong spectral feature at 4.2 eV that is not observed for the other two reconstructions. Since the direct gap of 3C-SiC is at higher photon energies the 4.2 eV feature must be related to the surface. Angle resolved ultraviolet photoelectron spectroscopy measurements indicate surface states around the X̄ point of the unreconstructed surface Brillouin zone. We conclude that the 4.2 eV feature is associated with this surface state and suggest that it is linked to the E2 gap of bulk Si at 4.2 eV.
Dynamic Monte Carlo simulation for depth profiling by ion-sputter etching: Application to the AlAs/GaAs multilayered system
Authors: Lee Hyung-Ik , Shimizu Ryuichi
Published: July 2002

We present a dynamical simulation approach by Monte Carlo calculation to describe atomic mixing phenomena in depth profiling of multilayered systems. This approach is based on the binary encounter model, taking into account (1) generation of both the interstitial atoms and vacancies and (2) annihilation of the vacancies. The results indicate that the simulation describes very well the depth profiles of AlAs/GaAs multilayered systems obtained by Auger electron spectroscopy. It predicts the existence of preferential sputtering of Al in the AlAs layer, where the Auger intensity of the As (MVV—32 eV) in the AlAs layer is about 1.2 times larger than that of the GaAs layer for 0.5 keV Ar+ sputtering.
Micromachined ultrasharp silicon and diamond-coated silicon tip as a stable field-emission electron source and a scanning probe microscopy sensor with atomic sharpness
Authors: Rangelow I. W. , Shi F. , Hudek P. , Grabiec P. , Volland B. , Givargizov E. I. , Stepanova A. N. , Obolenskaya L. N. , Mashkova E. S. , Molchanov V. A.
Published: July 2002

A novel combination of silicon micromachining and deposition on silicon whiskers on (111) oriented silicon substrates shows promise for stable field emission electron emitters and sensors for scanning probe microscopy. As a field emission electron emitters show promise for high-density and high-resolution electron beam applications owing to a small (within 3°) divergence half angle of emitted electrons. Due to the sharpening of the diamond coated Si tips the threshold voltage, which is necessary to create a stable emission current (nanoampers) is decreased from the initial 1300 V to about 150 V. The diamond coating stabilizes the field-emission current as large as about 100 μA from a single tip. Training of the emitter at a current of about 10−7 A for several hours results in an additional improvement of the current stability with an additional slight current increase. Second application of vapor–liquid–solid grown silicon whiskers described here is the recent progress toward high aspect ratio (>100) probes and relates a technique for preparation of cantilevers for atomic force microscopy with atomic resolution on the very end of the tip. The radii are less than 2 nm for silicon tips and the angles at the ends are less than 20°. In the case of diamond, the tip radius is 10 nm.
Patterned negative electron affinity photocathodes for maskless electron beam lithography
Authors: Schneider J. E. , Sen P. , Pickard D. S. , Winograd G. I. , McCord M. A. , Pease R. F. W. , Spicer W. E. , Baum A. W. , Costello K. A. , Davis G. A.
Published: July 2002

This work focuses on two issues crucial to achieving high throughput with a negative electron affinity semiconductor photocathode source. Monte Carlo simulations indicate that for a 50 kV system, as much as 8 μA of current may be delivered to the wafer to achieve a raw throughput of 20 8 in. wafers per hour with 0.1 μm minimum feature size (assuming a resist sensitivity of 10 μC/cm2). In order to achieve the throughput potential of this approach, suboptical emission areas are required; this suggests the use of cathode patterning. Two patterning alternatives have been investigated experimentally, and both approaches have been used to generate arrays of more than 100 electron beams with source sizes as small as 150 nm. However, each type of patterned cathode presents unique challenges to fabrication and performance in a practical multibeam system. Different source configurations (number of beams, beam current, beam spacing, etc.) create a system-level tradeoff between resolution and throughput. Results from patterned cathode experiments and system modeling are presented.
Process dependence of roughness in a positive-tone chemically amplified resist
Authors: He D. , Cerrina F.
Published: July 2002

Line edge roughness becomes an important factor in linewidth control as lithographic dimensions approach the 0.1 μm region. In order to understand different contributions to roughness, we explored the relationship between roughness and deprotection in the case of a positive chemically amplified resist. Experiments show that the roughness of the remaining resist depends on process history and it is not a simple function of the degree of deprotection. Scaling analysis of atomic force microscopy images shows that an equal degree of deprotection yields a self-affine rough surface with constant fractal dimensions which imply a similar surface morphology, but with a different standard deviation. The correlation between sidewall and top surface roughness is also discussed.
Multilayer technique for fabricating Nb junction circuits exhibiting charging effects
Authors: Pavolotsky A. B. , Weimann Th. , Scherer H. , Krupenin V. A. , Niemeyer J. , Zorin A. B.
Published: July 2002

A reliable process has been developed for the fabrication of all Nb single-electron circuits, based on spin-on glass planarization. The process steps are the in situ growth of Nb/AlOx/Nb sandwich, definition of the patterns of junctions, base electrodes, and wiring by use of reactive ion etching and the planarization of a spin-on glass insulation between base electrode and wiring. A single-electron transistor made of 0.3×0.3 μm2 area junctions clearly shows the e-periodic Coulomb blockade modulation by a voltage applied to a gate.
Thermal stability of a Ti-Si-N diffusion barrier in contact with a Ti adhesion layer for Au metallization
Authors: Shalish I. , Shapira Yoram
Published: July 2002

Depth profiling by backscattering spectrometry, x-ray photoelectron spectroscopy and diffractometry, scanning electron microscopy, and sheet resistance measurements were used to study the thermal stability of ternary Ti27Si20N53 films as diffusion barriers between a gold overlayer and substrates of aluminum nitride, silicon oxide, and β-silicon carbide when thin titanium films are added on either side of the barrier to enhance adhesion. It is shown that titanium and gold interdiffuse upon 30 min annealing in vacuum at 400 °C and above, which raises the sheet resistance of the gold layer by factors that increase with the amount of titanium present. For the same annealing ambient and duration, nitrogen begins to diffuse at 600 °C from the Ti27Si20N53 layer into the titanium layer, releasing silicon. This silicon reacts eutectoidally with the gold, leading to breakup of the barrier.
Optical properties of diamond-like carbon synthesized by plasma immersion ion processing
Authors: He Xiao-Ming , Bardeau J.-F. , Lee D. H. , Walter K. C. , Tuszewski M. , Nastasi M.
Published: July 2002

Hard and transparent diamond-like carbon (DLC) films have been prepared on low temperature substrates by using the C2H2-Ar plasma immersion ion processing (PIIP) method. The optical properties of the DLC films deposited on poly(methylmethacrylate) (PMMA), silicon wafers, and glass plates were systematically examined. It was found that careful control of substrate bias was needed for favorable growth of DLC films with low atomic hydrogen contents, high hardness and mass densities, and excellent optical properties. The resultant DLC films exhibited a high hardness of above 22 GPa, an optical gap energy larger than 1.9 eV, a low refractive index of 1.87, and very high optical transmittance in the visible light range. The study confirmed that C2H2-Ar PIIP with low negative bias voltages and suitable C2H2/Ar gas ratios can process optically transparent and hard protective DLC films on PMMA plastics.
Novel process for SiO2/Si selective etching using a novel gas source for preventing global warming
Authors: Fujita Kazushi , Ito Masafumi , Hori Masaru , Goto Toshio
Published: July 2002

A novel gas source replacing fluorocarbon feed gases has been developed for preventing global warming. The novel gas source was designed to generate fluorocarbon species from polytetrafluoroethylene by CO2 laser ablation. The species generated from the gas source were introduced into an electron cyclotron resonance (ECR) plasma employing Ar gases. To characterize the gas source, CFx (x=1–3) radical densities with and without plasmas were measured by infrared diode laser absorption spectroscopy. In the ECR plasma employing the novel gas source, CFx (x=1–3) radical densities were estimated to be of the order of 1012–1013 cm−3. The gas source has been applied to the selective etching of SiO2 to Si using the ECR plasma. As a result, the etching characteristics by ECR plasma employing the novel gas source were equivalent to those by a conventional ECR plasma employing C4F8 gas. Therefore, this novel gas source is applicable to etching processes for preventing global warming.
Applications of molecular modeling in nanolithography
Authors: Pawloski A. R. , Torres J. A. , Nealey P. F. , de Pablo J. J.
Published: July 2002

The design of resist materials capable of resolution below 100 nm requires a fundamental understanding of the chemical and physical processes that occur at length scales comparable to the dimensions of individual molecules. At these length scales, the thermophysical properties of photoresist films are different from those of the bulk; molecular simulations provide a useful tool to study the behavior of these materials at the molecular level, thereby providing much needed insights into phenomena that are difficult to characterize experimentally. In our group we have developed and implemented molecular based simulations to study materials for nanolithography at various levels of detail. At the chemically detailed, atomistic level, molecular dynamics techniques are used to determine specific effects arising from the molecular architecture of the resist components. In these systems, we explore the intra- and intermolecular structure of the resist resin polymer. The chemical architecture of the resin influences the extent of hydrogen bonding throughout the resist, leading to differences between the diffusivity of water within each of the resins. At a more coarse-grained level, discontinuous molecular dynamics methods are employed to simulate entire resist films modeled as collections of atoms lumped into single interaction sites. While these models lose atomic resolution, the system sizes that can be investigated are two orders of magnitude larger than those studied at the atomistic level. This allows for the modeling of properties of entire photoresist films. We apply these calculations to investigate how the glass transition temperature changes at small film thickness (e.g., below 100 nm), and to investigate how the Young’s modulus of a developed photoresist feature is influenced by its dimensions. Our findings have important implications for the problem of feature collapse.
Development of a projection imaging electron microscope with electrostatic lenses
Authors: Miyoshi M. , Yamazaki Y. , Nagai T. , Nagahama I. , Okumura K.
Published: July 2002

In the semiconductor industry, the inspection technique using an electron beam is expected to play an important role because of its high spatial resolution. In comparison with conventional scanning techniques, direct imaging produced by projection optics offers both faster mapping rates due to parallel detection and higher resolution. An electron microscope based on the projection imaging optics has been designed and constructed. Secondary electrons emitted by the area exposure are projected through the projection optics consisting of fully electrostatic lenses, and then imaged onto the image detection system. A computational analysis indicates resolution of 0.27 μm which can satisfy both adequate resolution and image grab time. An image of a 0.2 μm design rule device is demonstrated.
Patterning of 0.175 μm platinum features using Ar/O2 chemically assisted ion-beam etching
Authors: Gutsche Martin U. , Athavale Satish D. , Williams Kurt , Hines Danielle
Published: July 2002

Argon/oxygen based chemically assisted ion-beam etching has been investigated for the patterning of stacked capacitor platinum electrodes at ground rules of 200 nm and below. Titanium nitride and bilayers of titanium on top of titanium nitride were used as hard mask layers in the patterning of the platinum. The ion-beam platinum etch process relies on physical sputtering by Ar ions with oxygen being added to the chamber during the etch to provide passivation of the Ti or TiN hard mask material. Pt:Ti etch selectivities of up to 20 have been achieved on blanket wafer samples. Sidewall profile angles greater than 80° (measured from the horizontal) were obtained for tightly spaced platinum features with a pitch of 350 nm using a multiple-angle ion-beam etch process. The uniformity of the etch process across 200 mm diam blanket oxide wafers was measured to be 3.5% (3σ value).
Field emitting inks for consumer-priced broad-area flat-panel displays
Authors: Burden A. P. , Bishop H. E. , Brierley M. , Friday J. M. , Hood C. , Jones P. G. A. , Khazov A. Y. , Lee W. , Riggs R. J. , Shaw V. L. , Tuck R. A.
Published: July 2002

Field emitting inks, consisting of conducting and semiconducting particles in an insulating matrix have been formulated and characterized as potential cold cathodes. Samples have been tested in a parallel electrode configuration to characterize their broad-area emission and to demonstrate patterning of the material. This has led to a portable sealed-off unit proving the capabilities of this ink-based technology. In addition, a probe system has been used to measure the emission current uniformity and threshold field distribution over a range of samples at a variety of probe resolutions. A series of tests at different electrode separations has shown that the emission is also a genuine field effect rather than being dependent primarily on the voltage. This has important benefits for producing an energy efficient and inexpensive gated structure with a narrow electrode separation in a working flat-panel display.
Beam steering by integrated electrodes for brighter field-emitter displays
Authors: Py Christophe
Published: July 2002

Field-emitter displays need to become more luminous. It is shown in this article by means of simulations and experiments that adding a second gate on top of the first one permits focusing and deflecting the beams emitted by microtips. A setup combining integrated focusing and deflection to increase the current density received by a pixel without increasing the current density emitted by the cathode is then described. While the row addressing power is increased, the luminous efficiency is not significantly affected and can even be enhanced.
Genomic and Genetic Definition of a Functional Human Centromere
Authors: Schueler Mary G. , Higgins Anne W. , Rudd M. Katharine , Gustashaw Karen , Willard Huntington F.
Published: July 2002

The definition of centromeres of human chromosomes requires a complete genomic understanding of these regions. Toward this end, we report integration of physical mapping, genetic, and functional approaches, together with sequencing of selected regions, to define the centromere of the human X chromosome and to explore the evolution of sequences responsible for chromosome segregation. The transitional region between expressed sequences on the short arm of the X and the chromosome-specific alpha satellite array DXZ1 spans about 450 kilobases and is satellite-rich. At the junction between this satellite region and canonical DXZ1 repeats, diverged repeat units provide direct evidence of unequal crossover as the homogenizing force of these arrays. Results from deletion analysis of mitotically stable chromosome rearrangements and from a human artificial chromosome assay demonstrate that DXZ1 DNA is sufficient for centromere function. Evolutionary studies indicate that, while alpha satellite DNA present throughout the pericentromeric region of the X chromosome appears to be a descendant of an ancestral primate centromere, the current functional centromere based on DXZ1 sequences is the product of the much more recent concerted evolution of this satellite DNA.
Role of Nucleoporin Induction in Releasing an mRNA Nuclear Export Block
Authors: Enninga Jost , Levy David E. , Blobel Günter , Fontoura Beatriz M. A.
Published: July 2002

Signal-mediated nuclear import and export proceed through the nuclear pore complex (NPC). Some NPC components, such as the nucleoporins (Nups) Nup98 and Nup96, are also associated with the nuclear interior. Nup98 is a target of the vesicular stomatitis virus (VSV) matrix (M) protein–mediated inhibition of messenger RNA (mRNA) nuclear export. Here, Nup98 and Nup96 were found to be up-regulated by interferon (IFN). M protein–mediated inhibition of mRNA nuclear export was reversed when cells were treated with IFN-γ or transfected with a complementary DNA (cDNA) encoding Nup98 and Nup96. Thus, increased Nup98 and Nup96 expression constitutes an IFN-mediated mechanism that reverses M protein–mediated inhibition of gene expression.
The Peopling of the Americas
Authors: Gibbons Ann
Published: July 2002

Last week the U.S. government put up $12.7 million to begin large-scale sequencing of Arabidopsis thaliana, a small, flowering member of the mustard family. The awards will fund the U.S. portion of an international collaboration that will attempt to decipher the plant's entire genome by 2004. Arabidopsis has several features that make sequencing its genome a worthwhile challenge. Sequencing Arabidopsis should also have a significant impact on plant science, because all 250,000 species of flowering plants, from corn to tulips to cherry trees, are genetically very similar.
A Conformational Switch in
Escherichia coli
16
S
Ribosomal RNA During Decoding of Messenger RNA
Authors: Lodmell J. Stephen , Dahlberg Albert E.
Published: July 2002

Direct evidence is presented for a conformational switch in 16
S
ribosomal RNA (rRNA) that affects tRNA binding to the ribosome and decoding of messenger RNA (mRNA). These data support the hypothesis that dynamic changes in rRNA structure occur during translation. The switch involves two alternating base-paired arrangements apparently facilitated by ribosomal proteins S5 and S12, and produces significant changes in the rRNA structure. Chemical probing shows reciprocal enhancements or protections at sites in 16
S
rRNA that are at or very near sites that were previously crosslinked to mRNA. These data indicate that the switch affects codon-anticodon arrangement and proper selection of tRNA at the ribosomal A site, and that the switch is a fundamental mechanism in all ribosomes.
In Situ Visualization of DNA Double-Strand Break Repair in Human Fibroblasts
Authors: Nelms Benjamin E. , Maser Richard S. , MacKay James F. , Lagally Max G. , Petrini John H. J.
Published: July 2002

A method was developed to examine DNA repair within the intact cell. Ultrasoft x-rays were used to induce DNA double-strand breaks (DSBs) in defined subnuclear volumes of human fibroblasts and DNA repair was visualized at those sites. The DSBs remained in a fixed position during the initial stages of DNA repair, and the DSB repair protein hMre11 migrated to the sites of damage within 30 minutes. In contrast, hRad51, a human RecA homolog, did not localize at sites of DNA damage, a finding consistent with the distinct roles of these proteins in DNA repair.
Landscape Structure and Biological Control in Agroecosystems
Authors: Thies Carsten , Tscharntke Teja
Published: July 2002

Biological pest control has primarily relied on local improvements in populations of natural enemies, but landscape structure may also be important. This is shown here with experiments at different spatial scales using the rape pollen beetle (
Meligethes aeneus
), an important pest on oilseed rape (
Brassica napus
). The presence of old field margin strips along rape fields was associated with increased mortality of pollen beetles resulting from parasitism and adjacent, large, old fallow habitats had an even greater effect. In structurally complex landscapes, parasitism was higher and crop damage was lower than in simple landscapes with a high percentage of agricultural use.
Dynamically Controlled Protein Tunneling Paths in Photosynthetic Reaction Centers
Authors: Balabin Ilya A. , Onuchic José N.
Published: July 2002

Marcus theory has explained how thermal nuclear motions modulate the energy gap between donor and acceptor sites in protein electron transfer reactions. Thermal motions, however, may also modulate electron tunneling between these reactions. Here we identify a new mechanism of nuclear dynamics amplification that plays a central role when interference among the dominant tunneling pathway tubes is destructive. In these cases, tunneling takes place in protein conformations far from equilibrium that minimize destructive interference. As an example, we demonstrate how this dynamical amplification mechanism affects certain reaction rates in the photosynthetic reaction center and therefore may be critical for biological function.
A Novel Action of the Proton Pump Inhibitor Rabeprazole and Its Thioether Derivative against the Motility of
Helicobacter pylori
Authors: Tsutsui Nanako , Taneike Ikue , Ohara Tatsuki , Goshi Satoshi , Kojio Seiichi , Iwakura Nobuhiro , Matsumaru Hiroyuki , Wakisaka-Saito Noriko , Zhang Hui-Min , Yamamoto Tatsuo
Published: July 2002

The motility of
Helicobacter pylori
was maximum at 37°C and at pH 6. A newly developed proton pump inhibitor, rabeprazole (RPZ), and its thioether derivative (RPZ-TH) markedly inhibited the motility of
H. pylori
. The concentrations of the drug necessary to inhibit 50% of the motility were 0.25, 16, 16, and >64 μg/ml for RPZ-TH, RPZ, lansoprazole, and omeprazole, respectively. No such inhibitory effects were observed with H
2
blockers or anti-
H. pylori
agents. The motilities of
Campylobacter jejuni
and
C. coli
—but not those of
Vibrio cholerae
O1 and O139,
Vibrio parahaemolyticus
,
Salmonella enterica
serovar Typhimurium, and
Proteus mirabilis
—were also inhibited. Prolonged incubation with RPZ or RPZ-TH inhibited bacterial growth of only
H. pylori
, except for a turbid colony mutant. The results indicate that RPZ and RPZ-TH have a characteristic inhibitory effect against the motility of
H. pylori
(spiral-shaped bacteria), which is distinguished from that against bacterial growth.
Combinations of Artemisinin and Quinine for Uncomplicated Falciparum Malaria: Efficacy and Pharmacodynamics
Authors: de Vries Peter J. , Bich Nguyen Ngoc , Van Thien Huynh , Hung Le Ngoc , Anh Trinh Kim , Kager Piet A. , Heisterkamp Siem H.
Published: July 2002

Combinations of artemisinin and quinine for uncomplicated falciparum malaria were studied. A total of 268 patients were randomized to 7 days of quinine at 10 mg/kg of body weight three times a day (Q) or to artemisinin at 20 mg/kg of body weight followed by 3 (AQ3) or 5 (AQ5) days of quinine. Recrudescence rates were 16, 38, and 15% for the Q, AQ3, and AQ5 groups, respectively (
P
< 0.001). Recrudescence was associated with shorter parasite clearance time (PCT) and longer treatment after the blood smear had become negative (eradication time). However, classification of patients to outcome—recrudescence or radical cure—was correct in only 77% of patients. The population kinetics of the parasitemia was estimated with nonlinear mixed-effect models. Several models were tested, but the best model was a monoexponential decline of the parasitemia in which the mean parasite elimination half-life was shorter after artemisinin (5.1 h; 95% confidence interval [CI], 4.9 to 5.2 h) than after quinine (8.0 h [95% CI, 7.5 to 8.3 h]). Attempts to simulate the initial increase of the parasitemia did not result in better models with a biologically plausible interpretation. Recrudescence was associated with slower parasite clearance and a higher simulated terminal parasitemia (
P
term
). The classification of patients to outcome groups based on
P
term
was correct in 78% of patients. The data suggest that parasite strains with reduced sensitivity to quinine are prevalent in Vietnam, with slower parasite clearance and consequent recrudescence. A single dose of artemisinin induces rapid parasite reduction and lowers the value of
P
term
, but to prevent recrudescence, this should be followed by quinine for at least 3 days after parasite clearance, or 5 days in total.
Pharmacokinetics and Pharmacodynamics of Levofloxacin againstStreptococcus pneumoniaeandStaphylococcus aureusin Human Skin Blister Fluid
Authors: Trampuz Andrej , Wenk Markus , Rajacic Zarko , Zimmerli Werner
Published: July 2002

The pharmacokinetics of levofloxacin in serum and in skin blister fluid (SBF) was determined for 20 volunteers after a single 500-mg oral dose of levofloxacin. In addition, ex vivo bactericidal activity of SBF againstStreptococcus pneumoniaeandStaphylococcus aureuswas studied. SBF containing levofloxacin and granulocytes killed 5.2 log ofStreptococcus pneumoniaebacteria and 2.0 log ofStaphylococcus aureusbacteria during a 6-h incubation.
Nitrofurantoin Is Active against Vancomycin-Resistant Enterococci
Authors: Zhanel George G. , Hoban Daryl J. , Karlowsky James A.
Published: July 2002

The activity of nitrofurantoin was tested against 300 isolates of
Enterococcus faecium
,
Enterococcus faecalis
, and
Enterococcus gallinarum
. No isolates tested were resistant to nitrofurantoin (MIC, ≥128 μg/ml), including vancomycin-resistant
E. faecium
isolates with
vanA
- and
vanB
-positive genotypes and vancomycin-resistant
E. gallinarum
isolates. We conclude that nitrofurantoin may provide effective treatment of urinary tract infections caused by vancomycin-resistant enterococci.
Xenograft Model for Identifying Chemotherapeutic Agents against Papillomaviruses
Authors: Pawellek A. , Hewlett G. , Kreuter J. , Rübsamen-Waigmann H. , Weber O.
Published: July 2002

The report describes the establishment and characterization of a mouse xenograft transplantation model for the study of papillomavirus infection of bovine skin. Calf scrotal skin was inoculated with bovine papillomavirus type 2 before grafting it to the dorsum of severe combined immunodeficient mice. The grafted skin contained epidermis, dermis, and a thin layer of fat. After 5 months the induced warts not only showed histological features of papillomavirus infections but also tested positive for viral DNA and papillomavirus capsid antigen. The formation of infectious virions was demonstrated by inoculation of new transplants with crude extract from the induced warts as well as in a cell culture focus assay. Topical application of bromovinyl-2′-deoxyuridine led to a reduction in viral DNA content in the developing wart. This small-animal xenograft model should be useful for characterizing antiviral compounds and providing an understanding of the regulation of papillomavirus infections.
In Vitro Activity of a Novel Antimycobacterial Compound,
N
-Octanesulfonylacetamide, and Its Effects on Lipid and Mycolic Acid Synthesis
Authors: Parrish Nikki M. , Houston Todd , Jones Paul B. , Townsend Craig , Dick James D.
Published: July 2002

β-Sulfonyl carboxamides have been proposed to serve as transition-state analogues of the β-ketoacyl synthase reaction involved in fatty acid elongation. We tested the efficacy of
N
-octanesulfonylacetamide (OSA) as an inhibitor of fatty acid and mycolic acid biosynthesis in mycobacteria. Using the BACTEC radiometric growth system, we observed that OSA inhibits the growth of several species of slow-growing mycobacteria, including
Mycobacterium tuberculosis
(H37Rv and clinical isolates), the
Mycobacterium avium
complex (MAC),
Mycobacterium bovis
BCG,
Mycobacterium kansasii
, and others. Nearly all species and strains tested, including isoniazid and multidrug resistant isolates of
M. tuberculosis
, were susceptible to OSA, with MICs ranging from 6.25 to 12.5 μg/ml. Only three clinical isolates of
M. tuberculosis
(CSU93, OT2724, and 401296), MAC, and
Mycobacterium paratuberculosis
required an OSA MIC higher than 25.0 μg/ml. Rapid-growing mycobacterial species, such as
Mycobacterium smegmatis, Mycobacterium fortuitum
, and others, were not susceptible at concentrations of up to 100 μg/ml. A 2-dimensional thin-layer chromatography system showed that OSA treatment resulted in a significant decrease in all species of mycolic acids present in BCG. In contrast, mycolic acids in
M. smegmatis
were relatively unaffected following exposure to OSA. Other lipids, including polar and nonpolar extractable classes, were unchanged following exposure to OSA in both BCG and
M. smegmatis
. Transmission electron microscopy of OSA-treated BCG cells revealed a disruption in cell wall synthesis and incomplete septum formation. Our results indicate that OSA inhibits the growth of several species of mycobacteria, including both isoniazid-resistant and multidrug resistant strains of
M. tuberculosis
. This inhibition may be the result of OSA-mediated effects on mycolic acid synthesis in slow-growing mycobacteria or inhibition via an undescribed mechanism. Our results indicate that OSA may serve as a promising lead compound for future antituberculous drug development.
Pharmacodynamic Evaluation of RWJ-270201, a Novel Neuraminidase Inhibitor, in a Lethal Murine Model of Influenza Predicts Efficacy for Once-Daily Dosing
Authors: Drusano G. L. , Preston S. L. , Smee D. , Bush K. , Bailey K. , Sidwell R. W.
Published: July 2002

We examined RWJ-270201 in a lethal model of influenza in BALB/c mice. The aim was to delineate the pharmacodynamically linked variable for the drug. Challenge was performed with influenza virus A/Shongdong/09/93 (H3N2). Treatment was administered by gavage. Five doses (1 to 10 mg/kg of body weight) and three schedules (every 24, 12, and 8 h) were evaluated with 10 mice per group. There were 39 placebo-treated mice. Drug exposure was evaluated for infected mice. Exposures were calculated after population modeling of all the plasma concentration-time data simulataneously using the NPEM3 program. Evaluation of dose and schedule with Kaplan-Meier analysis and Cox proportional hazards modeling demonstrated that schedule offered no explanatory power relative to dose alone. Evaluation of peak concentration, trough concentration, and area under the concentration-time curve (AUC) by the same methods revealed that AUC was the dynamically linked variable. Again, schedule offered no further explanatory power when included in the model with AUC. This indicates that AUC is the linked variable and that the anti-influenza effect of RWJ-270201 is independent of schedule. We conclude that once-daily dosing of RWJ-270201 should be evaluated in clinical trials of influenza therapy.
In Vitro and In Vivo Activities of CS-758 (R-120758), a New Triazole Antifungal Agent
Authors: Kamai Yasuki , Harasaki Tamako , Fukuoka Takashi , Ohya Satoshi , Uchida Katsuhisa , Yamaguchi Hideyo , Kuwahara Shogo
Published: July 2002

The activity of CS-758 (R-120758), a new triazole antifungal agent, was evaluated and compared with those of fluconazole, itraconazole, and amphotericin B in vitro and with those of fluconazole and itraconazole in vivo. CS-758 exhibited potent in vitro activity against clinically important fungi. The activity of CS-758 against
Candida
spp. was superior to that of fluconazole and comparable or superior to those of itraconazole and amphotericin B. CS-758 retained potent activity against
Candida albicans
strains with low levels of susceptibility to fluconazole (fluconazole MIC, 4 to 32 μg/ml). Against
Aspergillus
spp. and
Cryptococcus neoformans
, the activity of CS-758 was at least fourfold superior to those of the other drugs tested. CS-758 also exhibited potent in vivo activity against murine systemic infections caused by
C. albicans
,
C. neoformans
,
Aspergillus fumigatus
, and
Aspergillus flavus
. The 50% effective doses against these infections were 0.41 to 5.0 mg/kg of body weight. These results suggest that CS-758 may be useful in the treatment of candidiasis, cryptococcosis, and aspergillosis.
NB2001, a Novel Antibacterial Agent with Broad-Spectrum Activity and Enhanced Potency against β-Lactamase-Producing Strains
Authors: Li Qing , Lee Jean Y. , Castillo Rosario , Hixon Mark S. , Pujol Catherine , Doppalapudi Venkata Ramana , Shepard H. Michael , Wahl Geoffrey M. , Lobl Thomas J. , Chan Ming Fai
Published: July 2002

Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. β-Lactamase overexpression is a common mechanism of bacterial resistance to β-lactam antibiotics. We present here the results for one of the β-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional β-lactam antibiotics, where hydrolysis of the β-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by β-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 β-lactamase, forming triclosan with a second-order rate constant (
k
cat
/

K
m

) of greater than 77,000 M
−1
s
−1
. (ii) Triclosan is detected in NB2001-treated, β-lactamase-producing
Escherichia coli
but not in
E. coli
that does not express β-lactamase. (iii) NB2001 activity against β-lactamase-producing
E. coli
is decreased in the presence of the β-lactamase inhibitor clavulanic acid. NB2001 was similar to or more potent than reference antibiotics against clinical isolates of
Staphylococcus aureus
(including MRSA),
Staphylococcus epidermidis
,
Streptococcus pneumoniae
, vancomycin-resistant
Enterococcus faecalis
,
Moraxella catarrhalis
and
Haemophilus influenza
e. NB2001 is also active against
Klebsiella pneumoniae
,
Enterobacter aerogenes
, and
Enterobacter cloacae
. The results indicate that NB2001 is a potent, broad-spectrum antibacterial agent and demonstrate the potential of ECTA in overcoming β-lactamase-mediated resistance.
Characterization of a Laboratory-Derived, High-Level Ampicillin-ResistantSalmonella entericaSerovar Typhimurium Strain That Caused Meningitis in an Infant
Authors: Chiu Cheng-Hsun , Chu Chishih , Su Lin-Hui , Wu Wan-Yu , Wu Tsu-Lan
Published: July 2002

ASalmonella entericaserovar Typhimurium strain that harbored a plasmid carrying a TEM-1-type β-lactamase gene was isolated from the blood and cerebrospinal fluid of an infant with meningitis. This 3.2-kb plasmid was further characterized to be a nonconjugative pGEM series cloning vector containing a foreign insert. The strain was likely laboratory derived and contaminated the environment before it caused the infection.
Identification of Collagen-Binding Proteins in
Lactobacillus
spp. with Surface-Enhanced Laser Desorption/Ionization–Time of Flight ProteinChip Technology
Authors: Howard Jeffrey C. , Heinemann Christine , Thatcher Bradley J. , Martin Brian , Gan Bing Siang , Reid Gregor
Published: July 2002

Biosurfactants produced by
Lactobacillus fermentum
RC-14,
L. rhamnosus
GR-1 and 36, and
L. casei
Shirota were found to contain proteins that bind to both collagen types III and VI, as determined by surface-enhanced laser desorption/ionization (SELDI)–time of flight mass spectrometry. Both collagen types III and VI immobilized on SELDI preactivated ProteinChip arrays detected several different sizes (2 to 48 kDa) of collagen-binding proteins. Overall, the RC-14-produced biosurfactant contained the greatest number of collagen-binding proteins (RC-14 > GR-1 > 36 > Shirota), including the mature form of a previously cloned 29-kDa collagen-binding protein (referred to in its mature 26-kDa form). Although biosurfactants isolated from
L. casei
Shirota and
L. rhamnosus
36 and GR-1 also contain several collagen-binding proteins, they do not contain the 26-kDa collagen-binding protein. Together, these results demonstrate the utility of the SELDI system as a means of rapidly characterizing clinically important but complex biosurfactant solutions.
Whole-Cell versus Total RNA Extraction for Analysis of Microbial Community Structure with 16S rRNA-Targeted Oligonucleotide Probes in Salt Marsh Sediments
Authors: Frischer Marc E. , Danforth Jean M. , Healy Michele A. Newton , Saunders F. Michael
Published: July 2002

rRNA-targeted oligonucleotide probes have become powerful tools for describing microbial communities, but their use in sediments remains difficult. Here we describe a simple technique involving homogenization, detergents, and dispersants that allows the quantitative extraction of cells from formalin-preserved salt marsh sediments. Resulting cell extracts are amenable to membrane blotting and hybridization protocols. Using this procedure, the efficiency of cell extraction was high (95.7% ± 3.7% [mean ± standard deviation]) relative to direct DAPI (4′,6′-diamidino-2-phenylindole) epifluorescence cell counts for a variety of salt marsh sediments. To test the hypothesis that cells were extracted without phylogenetic bias, the relative abundance (depth distribution) of five major divisions of the gram-negative mesophilic sulfate-reducing delta proteobacteria were determined in sediments maintained in a tidal mesocosm system. A suite of six 16S rRNA-targeted oligonucleotide probes were utilized. The apparent structure of sulfate-reducing bacteria communities determined from whole-cell and RNA extracts were consistent with each other (
r
2
= 0.60), indicating that the whole-cell extraction and RNA extraction hybridization approaches for describing sediment microbial communities are equally robust. However, the variability associated with both methods was high and appeared to be a result of the natural heterogeneity of sediment microbial communities and methodological artifacts. The relative distribution of sulfate-reducing bacteria was similar to that observed in natural marsh systems, providing preliminary evidence that the mesocosm systems accurately simulate native marsh systems.
Anaerobic Xylose Fermentation by Recombinant
Saccharomyces cerevisiae
Carrying
XYL1
,
XYL2
, and
XKS1
in Mineral Medium Chemostat Cultures
Authors: Eliasson Anna , Christensson Camilla , Wahlbom C. Fredrik , Hahn-Hägerdal Bärbel
Published: July 2002

For ethanol production from lignocellulose, the fermentation of xylose is an economic necessity.
Saccharomyces cerevisiae
has been metabolically engineered with a xylose-utilizing pathway. However, the high ethanol yield and productivity seen with glucose have not yet been achieved. To quantitatively analyze metabolic fluxes in recombinant
S. cerevisiae
during metabolism of xylose-glucose mixtures, we constructed a stable xylose-utilizing recombinant strain, TMB 3001. The
XYL1
and
XYL2
genes from
Pichia stipitis
, encoding xylose reductase (XR) and xylitol dehydrogenase (XDH), respectively, and the endogenous
XKS1
gene, encoding xylulokinase (XK), under control of the
PGK1
promoter were integrated into the chromosomal
HIS3
locus of
S. cerevisiae
CEN.PK 113-7A. The strain expressed XR, XDH, and XK activities of 0.4 to 0.5, 2.7 to 3.4, and 1.5 to 1.7 U/mg, respectively, and was stable for more than 40 generations in continuous fermentations. Anaerobic ethanol formation from xylose by recombinant
S. cerevisiae
was demonstrated for the first time. However, the strain grew on xylose only in the presence of oxygen. Ethanol yields of 0.45 to 0.50 mmol of C/mmol of C (0.35 to 0.38 g/g) and productivities of 9.7 to 13.2 mmol of C h
−1
g (dry weight) of cells
−1
(0.24 to 0.30 g h
−1
g [dry weight] of cells
−1
) were obtained from xylose-glucose mixtures in anaerobic chemostat cultures, with a dilution rate of 0.06 h
−1
. The anaerobic ethanol yield on xylose was estimated at 0.27 mol of C/(mol of C of xylose) (0.21 g/g), assuming a constant ethanol yield on glucose. The xylose uptake rate increased with increasing xylose concentration in the feed, from 3.3 mmol of C h
−1
g (dry weight) of cells
−1
when the xylose-to-glucose ratio in the feed was 1:3 to 6.8 mmol of C h
−1
g (dry weight) of cells
−1
when the feed ratio was 3:1. With a feed content of 15 g of xylose/liter and 5 g of glucose/liter, the xylose flux was 2.2 times lower than the glucose flux, indicating that transport limits the xylose flux.
Regulation of Polyglutamic Acid Synthesis by Glutamate in
Bacillus licheniformis
and
Bacillus subtilis
Authors: Kambourova Margarita , Tangney Martin , Priest Fergus G.
Published: July 2002

The synthesis of polyglutamic acid (PGA) was repressed by exogenous glutamate in strains of
Bacillus licheniformis
but not in strains of
Bacillus subtilis
, indicating a clear difference in the regulation of synthesis of capsular slime in these two species. Although extracellular γ-glutamyltranspeptidase (GGT) activity was always present in PGA-producing cultures of
B. licheniformis
under various growth conditions, there was no correlation between the quantity of PGA and enzyme activity. Moreover, the synthesis of PGA in the absence of detectable GGT activity in
B. subtilis
S317 indicated that this enzyme was not involved in PGA biosynthesis in this bacterium. Glutamate repression of PGA biosynthesis may offer a simple means of preventing unwanted slime production in industrial fermentations using
B. licheniformis.
Development of a
Saccharomyces cerevisiae
Strain with Enhanced Resistance to Phenolic Fermentation Inhibitors in Lignocellulose Hydrolysates by Heterologous Expression of Laccase
Authors: Larsson Simona , Cassland Pierre , Jönsson Leif J.
Published: July 2002

To improve production of fuel ethanol from renewable raw materials, laccase from the white rot fungus
Trametes versicolor
was expressed under control of the
PGK1
promoter in
Saccharomyces cerevisiae
to increase its resistance to phenolic inhibitors in lignocellulose hydrolysates. It was found that the laccase activity could be enhanced twofold by simultaneous overexpression of the homologous
t
-SNARE Sso2p. The factors affecting the level of active laccase obtained, besides the cultivation temperature, included pH and aeration. Laccase-expressing and Sso2p-overexpressing
S. cerevisiae
was cultivated in the presence of coniferyl aldehyde to examine resistance to lignocellulose-derived phenolic fermentation inhibitors. The laccase-producing transformant had the ability to convert coniferyl aldehyde at a faster rate than a control transformant not expressing laccase, which enabled faster growth and ethanol formation. The laccase-producing transformant was also able to ferment a dilute acid spruce hydrolysate at a faster rate than the control transformant. A decrease in the content of low-molecular-mass aromatic compounds, accompanied by an increase in the content of high-molecular-mass compounds, was observed during fermentation with the laccase-expressing strain, illustrating that laccase was active even at the very low levels of oxygen supplied. Our results demonstrate the importance of phenolic compounds as fermentation inhibitors and the advantage of using laccase-expressing yeast strains for producing ethanol from lignocellulose.