bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement of properties of dynamic random access memories capacitors by PH3 plasma doping process after the formation of hemispherical-grained silicon
Authors: Moon H. S. , Choi H. S. , Jang H. G. , Hwang C. J. , Woo S. H. , Han I. K. , Yang H. S.
Published: July 2002

A novel technology “PH3 plasma doping process” is used to improve the reduction of Cmin/Cmax ratio due to the depletion layer generation on the surface of storage electrode. The storage electrode with hemispherical-grained silicon (HSG–Si) made from amorphous silicon (a-Si) with low concentration of phosphorus has no bald defect but low Cmin/Cmax ratio. In PH3 plasma doping process, phosphorus diffuses in Si by interacting with vacancies. Using the storage electrode with HSG–Si doped in PH3 plasma, the capacitor has 96% of Cmin/Cmax ratio and no degradation of capacitor properties caused by excess phosphorus incorporation into dielectrics.
In situ preparation of the semiconductor–superconductor interface: Nb contacts on InAs quantum wells
Authors: Bellomi G. , Mitchell W. J. , Hu E. L.
Published: July 2002

In this article we describe an in situ, low damage, process sequence designed to provide a more reliable, higher quality metal (superconductor)–semiconductor interface. We produce discrete Nb contacts on an InAs quantum well (125 Å) that is embedded within thick (∼3000 Å) Al0.5Ga0.5Sb barrier layers by utilizing a multichamber ultrahigh vacuum system, in which two Varian GenII, Molecular Beam Epitaxy chambers are directly connected to a high vacuum etch station. The principal process steps include (1) a short, “selective” thermal Cl2 etch of the top barrier layer to expose and define the InAs contact region, (2) a post-etch anneal (under As2 flux) to desorb residual etch products (i.e., InCl3) and restore a clean and well-ordered InAs (2×4) surface, (3) a Sb capping/passivation layer on the treated surface, (4) atmospheric transfer of the capped sample to a remote Nb deposition chamber, and (5) a post-anneal (in vacuum) to desorb the Sb cap immediately followed by Nb deposition. The priority throughout is minimizing damage and impurity exposure to the InAs surface. Morphology and roughness of the etched surface are explicitly considered in terms of the (1) initial native oxide removal: short Ar+ sputter at room temperature versus thermal desorption at 530 °C under Sb2 flux, (2) thermal Cl2 etch temperature (180–260 °C), and (3) annealing temperature for Sb desorption (430–530 °C).
Surface superstructure of Ar+-bombarded highly oriented pyrolytic graphite during recrystallization
Authors: An B. , Fukuyama S. , Yokogawa K. , Yoshimura M.
Published: July 2002

The recrystallization process of highly oriented pyrolytic graphite (HOPG) surface bombarded by argon ions with an ion energy of 2.0–2.5 keV at doses of 2–5×1016 ions/cm2 was examined by scanning tunneling microscopy. The hillocks formed by the ion bombardment of HOPG coalesced to form larger grains with increasing annealing temperature. Three types of ringlike superstructures of (3×3)R30° of graphite were found on the curved surface of the grains after annealing in the temperature range of 1823–2673 K. The specimen surface became flat above 2773 K, where the ringlike superstructure disappeared and the triangular structure of graphite appeared in its place. The effect of the curved surface of the grains on the formation of the ringlike superstructure during graphitization is discussed.
Comparative study of Ni nanowires patterned by electron-beam lithography and fabricated by lift-off and dry etching techniques
Authors: Park Y. D. , Jung K. B. , Overberg M. , Temple D. , Pearton S. J. , Holloway P. H.
Published: July 2002

Using e-beam lithography techniques we have patterned Ni wire widths down to less than 100 nm. The patterning techniques were utilized either to fabricate nanodeposition masks for further direct deposition of Ni and subsequent liftoff or to deposit Nb wire structures used for Ar ion-mill etch masks on top of Ni thin films. The resulting Ni nanowire structures showed strong differences in transport as well as differing morphologies measured by atomic force microscopy (AFM) and scanning electron microscopy. In the case of fabricating nanodeposition masks, direct deposition of Ni was performed by magnetron sputtering, thermal evaporation, and e-beam evaporation. In the resulting nanowires, e-beam evaporated wires show the best residual resistance and magnetoresistance (MR) characteristics. AFM results showed the nanowires produced by evaporation to have granular structure. The nanowires fabricated by dry etching surpassed all nanowires fabricated by direct deposition and liftoff in both residual resistances and MR characteristics. In terms of longitudinal MR response, all nanowires displayed changes from saturation values, which indicated the formation of domain walls during magnetic reversal.
Atomic force microscopy of solid-state reaction of alcohol: Substitution and dehydration
Authors: Zeng Qingdao , Wang Chen , Bai Chunli , Li Yan , Yan Xinjian
Published: July 2002

The gas-solid chemical reactions of pure crystalline alcohol, such as triphenyl carbinol (1) and 1,1-diphenylethanol-1 (3), with HCl gas and their mechanism are studied using atomic force microscopy (AFM) and known crystal packing data. AFM reveals that the main crystal face (001) of 1 exhibits volcanoes, whereas the long side face (100) gives volcanoes and craters in turn. Both (010) and (100) of 3 exhibit islands. All of those are guided by the crystal structure. Molecular interpretations of the AFM features are given.
On-wafer spectrofluorometric evaluation of the response of photoacid generator compounds in chemically amplified photoresists
Authors: Feke G. D. , Hessman D. , Grober R. D. , Lu B. , Taylor J. W.
Published: July 2002

The enhanced photospeed of chemically amplified photoresists is crucial for high throughput lithography required by the semiconductor industry. The photospeed depends directly on the efficiency of the generation of photoacid during exposure, which is a function of the properties of the photoacid generator compound used in the resist. We report a novel technique for photoacid generator evaluation which is convenient, fast, and robust. This technique involves “whole wafer” imaging of resist doped with pH-sensitive fluorophores and patterned with an array of fields of varying doses. A spatially encoded map of the response of the compound under study is thus obtained in a single camera image. We measure the amount of photoacid produced as a function of dose for three photoacid generator compounds with reference to the commercial resist Shipley SAL 605. The results demonstrate a one-to-one correspondence with lithographic performance as determined by the normalized remaining thickness technique.
Effect of post-nitride-passivation processing on the long-term stability of polysilicon integrated circuit resistors
Authors: Rydberg Matts , Smith Ulf , Sjödin Håkan
Published: July 2002

Results from 24 h experiments show that heat treatments of nitride-passivated polysilicon resistors at temperatures below that of the contact anneal, 450 °C, have a decisive influence on the stability of the resistors. In stress tests at 150 °C, it is shown that for heat treatments at 230 °C, the amount of loosely bound hydrogen in the grain boundaries and, consequently, the resistance drift is reduced by more than a factor of 2. For heat treatments above 270 °C, the drift is larger due to a reoccupation of released dangling-bond sites in the temperature range 230–270 °C during cool down. This is also the temperature range in which the largest reduction in the resistance drift is found. The heat treatments did not affect the mechanisms involved in the drift. There are no indications that hydrogen is released from the nitride at the highest temperatures, the reoccupation being independent of temperature. Possible mechanisms are discussed and the results are evaluated in terms of a previously introduced model for the time-dependent loss of loosely bound hydrogen.
Active corner engineering in the process integration for shallow trench isolation
Authors: Balasubramanian N. , Johnson E. , Peidous I. V. , Ming-Jr Shiu , Sundaresan R.
Published: July 2002

The electrical characteristics of metal–oxide–semiconductor field effect transistor devices with shallow trench isolation (STI) have been studied to evaluate the active corner shaping and the trench-fill dielectric densification techniques. The suppression of corner parasitic transistor effects was observed in the two different corner shaping schemes used. In the first approach, an undercut of pad oxide below the nitride mask defining the active region facilitated corner oxidation during liner oxide growth. In the second approach, a high temperature post-chemical mechanical polishing (CMP) oxidation created a rounded corner, forming a minibird’s beak under the nitride mask edge. Cross-sectional transmission electron microscopy shows that, while the post-CMP oxidation “rounds” the corner, the pad oxide undercut produces a concave corner profile. Though both approaches improved the subthreshold characteristics of the transistor, the leakage current of field-edge-intensive diodes became very high for post-CMP oxidation. The leakage was also strongly influenced by the annealing ambient during densification of STI gap-fill dielectric. An oxidizing ambient resulted in high leakage current whereas a nonoxidizing ambient resulted in low levels of leakage current. The excessive leakage is attributed to the silicon defects generated along the STI edge as a result of stress exerted by the gap-fill oxide. Densification in nonoxidizing ambient also helped improve the subthreshold characteristics of the transistors with STI fabricated using the pad oxide undercut scheme.
Simulations of tapered Goubau line for coupling microwave signals generated by resonant laser-assisted field emission
Authors: Alonso Kevin , Hagmann Mark J.
Published: July 2002

Simulations of photomixing in resonant laser-assisted field emission show oscillations of the tunneling current at frequencies from dc to over 100 THz. Thus far prototype devices using this effect have been limited to operation from dc to 1 MHz because of inefficient coupling of the load to the apex of the emitting tip where the signals are generated. Goubau line, which is a broadband surface-wave transmission line, could be formed by coating the emitting tip with a dielectric. We have used the finite-difference time-domain method to model coupling with tapered Goubau line. We conclude that a power of 1 nW could be coupled to a 50 Ω load from an oscillating tunneling current of 1 μA at 10 GHz. The output power is proportional to the square of the current, and we consider methods for obtaining current oscillations of 1 mA or greater.
Influence of getter activation and aging in a frit-sealed field emission display panel
Authors: Kwon Sang Jik , Hong Kun Jo , Lee Jong Duk , Oh Chang Woo , Yoo Jae Soo , Kwon Yong Bum
Published: July 2002

A field emission display (FED) panel system was successfully built through integration of a 0.7 in diagonal Si-based Mo-tip field emitter array with 25×25 pixels, a Y2O3:Eu or ZnO:Zn phosphor screen, and vacuum sealing through an exhausting glass tube, including a getter. The panel system was driven by an external driver circuit that has a pulse width modulation driving scheme. We have tried to evaluate quantitatively the activation effect of a getter. The getter activated at a relatively low temperature was shown to act as a good in situ minipump during the life of the FED. Before character imaging, it was stabilized through tip aging by slowly increasing a pulse-mode emission current and phosphor aging by a Coulombic charging process. After aging, luminescent characteristics such as emission uniformity, charging and arcing phenomena were shown to be improved significantly.
Water-assisted repair of plasma-induced damage in the silicon/silicon-dioxide system
Authors: Itsumi Manabu , Maeda Masahiko , Takeuchi Hideaki , Morie Takashi
Published: July 2002

We have investigated the effects of pouring deionized water onto a silicon (Si)/silicon-dioxide (SiO2) system wafer to repair plasma-induced damage. We found that the distribution of repair effectiveness across the wafer was not uniform but depended strongly on both the pouring method and where on the wafer the water was poured. When the water was poured onto a rotating plasma-damaged wafer, the damage was most effectively repaired in the areas onto which the water was poured, and the effect decreased sharply with increasing distance from these areas. We propose a simplified hypothesis: some of the H+ ions produced by the friction between the water and the SiO2 migrate to the Si–SiO2 interface and passivate the dangling bonds (which are related to plasma damage) at the interface.
Schottky barrier formation at Cu/TiB2/TiSi2/Si interface
Authors: Pelleg Joshua
Published: July 2002

The Cu/TiB2/TiSi2/Si system has been examined as a potential Schottky barrier contact suitable for very large scale integration circuits in silicon technology. The current–voltage characteristics of diodes based on the above system were studied and the effect of postsilicidation heat treatment on the barrier height and the ideality factor was evaluated. The Schottky barrier height and the ideality factor at a temperature interval of 300–973 K were in the range of 0.65–0.68 V and 1.03–1.08, respectively.
Kinetic simulation of metal chemical-vapor deposition on high aspect ratio features in modern very-large-scale-integrated processing
Authors: Li Ming , Dew Steven , Brett Michael , Smy Tom
Published: July 2002

Chemical-vapor deposition of tungsten is extensively used for very-large-scalae-integrated metallization because of its ability to adequately coat the bottom of high aspect ratio features. Despite this, a detailed model of the surface kinetics is not yet widely accepted. Such a model is essential for predicting film coverage over deep topography where fluxes and adsorbate coverage can be very different from those on flat surfaces. By considering the dissociative adsorption of H2 and WF6 and the desorption of H2 and HF molecules, a new surface kinetic model for tungsten deposition is presented. The model includes temperature- and coverage-dependent sticking coefficients of adsorbing reactions, the inhibiting effects of F on H2 adsorption, and multiple reaction pathways. Predictions of the model show reasonable agreement with experimental measurements of H2 partial pressure dependence of tungsten deposition rate over a wide pressure range. Particularly, the model explains the recently observed effect of reduced deposition rate when the H2 pressure becomes comparable to the WF6 pressure. This kinetic model is used by a kinetic thin-film simulator, GROFILMS, to study the W film deposition over high aspect ratio topography. The film growth profile, the coverage of F and H, and the impingement fluxes along the film surface are analyzed.
Resonance enhanced multiphoton ionization as a diagnostic tool in glow discharge plasmas
Authors: Senkan Selim , Ly Anna
Published: July 2002

Resonance enhanced multiphoton ionization (REMPI) has been used to quantitatively detect benzene in an Ar dc plasma. The plasma reactor was fabricated from a 5 cm diam Pyrex tube that was about 30 cm long. The reactor also possessed two plasma electrodes that were separated by 3 cm. The plasma was generated at 160 mTorr pressure under continuous flow of Ar that was seeded with 100–1000 ppm of benzene. Ions generated by REMPI were detected using a separate electrode placed at the edge of the plasma zone. We were able to obtain well-resolved and unambiguous benzene REMPI spectra in the 250–265 nm laser wavelength under a broad range of plasma conditions. The spectra obtained were well resolved, exhibited sharp spectral features and were in complete agreement with the results reported in the literature under nonplasma conditions. Measured REMPI signal intensities also were linearly proportional to the benzene concentration, suggesting that REMPI can be a useful quantitative plasma diagnostic.
Requirement for the SLP-76 Adaptor GADS in T Cell Development
Authors: Yoder Jeff , Pham Christine , Iizuka Yoshie-Matsubayashi , Kanagawa Osami , Liu Stanley K. , McGlade Jane , Cheng Alec M.
Published: July 2002

GADS is an adaptor protein implicated in CD3 signaling because of its ability to link SLP-76 to LAT. A GADS-deficient mouse was generated by gene targeting, and the function of GADS in T cell development and activation was examined. GADS
–
CD4
–
CD8
–
thymocytes exhibited a severe block in proliferation but still differentiated into mature T cells. GADS
–
thymocytes failed to respond to CD3 cross-linking in vivo and were impaired in positive and negative selection. Immunoprecipitation experiments revealed that the association between SLP-76 and LAT was uncoupled in GADS
–
thymocytes. These observations indicate that GADS is a critical adaptor for CD3 signaling.
Distinguishing Inchworm and Hand-Over-Hand Processive Kinesin Movement by Neck Rotation Measurements
Authors: Hua Wei , Chung Johnson , Gelles Jeff
Published: July 2002

The motor enzyme kinesin makes hundreds of unidirectional 8-nanometer steps without detaching from or freely sliding along the microtubule on which it moves. We investigated the kinesin stepping mechanism by immobilizing a
Drosophila
kinesin derivative through the carboxyl-terminal end of the neck coiled-coil domain and measuring orientations of microtubules moved by single enzyme molecules at submicromolar adenosine triphosphate concentrations. The kinesin-mediated microtubule-surface linkage was sufficiently torsionally stiff (≥2.0 ± 0.9 × 10
−20
Newton meters per radian
2
) that stepping by the hypothesized symmetric hand-over-hand mechanism would produce 180° rotations of the microtubule relative to the immobilized kinesin neck. In fact, there were no rotations, a finding that is inconsistent with symmetric hand-over-hand movement. An alternative “inchworm” mechanism is consistent with our experimental results.
The Water Dipole Moment in Water Clusters
Authors: Gregory J. K. , Clary D. C. , Liu K. , Brown M. G. , Saykally R. J.
Published: July 2002

The average dipole moment of a water molecule in the condensed phase is enhanced by around 40 percent relative to that of an isolated monomer. This enhancement results from the large polarization caused by the electric field induced by surrounding monomers. A quantitative molecular description of this polarization is essential for modeling aqueous solvation phenomena. This combined theoretical and experimental study of dipole moments in small water clusters provides such a description and also gives insights into the structure of liquid water.
Direct Measurement of Angles Between Bond Vectors in High-Resolution NMR
Authors: Reif Bernd , Hennig Mirko , Griesinger Christian
Published: July 2002

Angles between two interatomic vectors are measured for structure elucidation in solution nuclear magnetic resonance (NMR). The angles can be determined directly by using the effects of dipole-dipole cross-correlated relaxation of double-quantum and zero-quantum coherences. The measured rates can be directly related to the angular geometry without need for calibration of a Karplus-type curve, as is the case for scalar coupling measurements, and depend only on the rotational correlation time of the molecule as an empirical parameter. This makes the determination of torsional angles independent from the measurement of coupling constants. The two interatomic vectors can in principle be arbitrarily far apart. The method was demonstrated on the measurement of the peptide backbone angle ψ in the protein rhodniin, which is difficult to determine in solution by NMR spectroscopy.
Oxygen on Ganymede: Laboratory Studies
Authors: Vidal R. A. , Bahr D. , Baragiola R. A. , Peters M.
Published: July 2002

To test proposals for the origin of oxygen absorption bands in the visible reflectance spectrum of Ganymede, the reflectance of condensed films of pure oxygen (O
2
) and O
2
-water mixtures and the evolution of O
2
from the films as a function of temperature were determined. Absorption band shapes and positions for oxygen at 26 kelvin were similar to those reported for Ganymede, whereas those for the mixtures were slightly shifted. The band intensity dropped by more than two orders of magnitude when the ice mixture was warmed to 100 kelvin, although about 20 percent of the O
2
remained trapped in the ice, which suggested that at these temperatures O
2
molecules dissolve in the ice rather than aggregate in clusters or bubbles. The experiments suggest that the absorption bands in Ganymede's spectrum were not produced in the relatively warm surface of the satellite but in a much colder source. Solid O
2
may exist in a cold subsurface layer or in an atmospheric haze.
A Mound Complex in Louisiana at 5400-5000 Years Before the Present
Authors: Saunders Joe W. , Mandel Rolfe D. , Saucier Roger T. , Allen E. Thurman , Hallmark C. T. , Johnson Jay K. , Jackson Edwin H. , Allen Charles M. , Stringer Gary L. , Frink Douglas S. , Feathers James K. , Williams Stephen , Gremillion Kristen J. , Vidrine Malcolm F. , Jones Reca
Published: July 2002

An 11-mound site in Louisiana predates other known mound complexes with earthen enclosures in North America by 1900 years. Radiometric, luminescence, artifactual, geomorphic, and pedogenic data date the site to over 5000 calendar years before present. Evidence suggests that the site was occupied by hunter-gatherers who seasonally exploited aquatic resources and collected plant species that later became the first domesticates in eastern North America.
Reversible Nanocontraction and Dilatation in a Solid Induced by Polarized Light
Authors: Krecmer P. , Moulin A. M. , Stephenson R. J. , Rayment T. , Welland M. E. , Elliott S. R.
Published: July 2002

Reversible, controllable optical nanocontraction and dilatation in a chalcogenide glass film was induced by polarized light, and a direct correlation of this optomechanical effect with the reversible optical-induced optical anisotropy (dichroism) also exhibited by the chalcogenide glass was observed. A microscopic model of the photoinduced, reversible structural phenomenon responsible for the optomechanical behavior is presented. The ability to induce an anisotropic optomechanical effect could form the basis of a number of applications, including polarized light-dependent optical nanoactuators, optomechanical diaphragm micropumps, and even motors driven by polarized light.
Geological Evolution of Venus: Rises, Plains, Plumes, and Plateaus
Authors: Phillips Roger J. , Hansen Vicki L.
Published: July 2002

Crustal plateaus and volcanic rises, major physiographic features on Venus, both formed over mantle plumes. Crustal plateaus were produced by large degrees of plume melting beneath thin lithosphere. The oldest tectonic features in crustal plateaus are ribbon-like troughs indicating early uplift and tensile stretching; their shallow depths suggest that surface temperature there was higher in the past. Widespread volcanic plains, derived from the broad upwellings of internally heated mantle convection, were continually erupted during the time of crustal plateau formation. Discrete volcanic rises, younger than crustal plateaus, formed over a thicker lithosphere, with less plume partial melting. The presence of only one transitional form indicates that the lithosphere thickened rapidly. Thermal and magmatic models show that the formation of these major features can be tied to an expected change in mantle convective style about 1 billion years ago.
Micromechanical "Trampoline" Magnetometers for Use in Large Pulsed Magnetic Fields
Authors: Aksyuk V. , Balakirev F. F. , Boebinger G. S. , Gammel P. L. , Haddon R. C. , Bishop D. J.
Published: July 2002

A silicon micromechanical magnetometer was constructed and successfully used in 60-tesla pulsed magnetic fields of less than 100-millisecond duration. The device is small, inexpensive to fabricate, and easy to use. It features a fast mechanical response (up to 50,000 hertz) and extremely high sensitivity yet is relatively robust against electrical and mechanical noise. Quantum oscillations in the magnetization of a 1-microgram sample of an organic superconductor, κ-[bis(ethylenedithio)tetrathiafulvalene]
2
Cu(NCS)
2
, have been observed with this device.
An Unusual Mechanism for Ligand Antagonism
Authors: Torigoe Chikako , Inman John K. , Metzger Henry
Published: July 2002

The ratio of late to early events stimulated by the mast cell receptor for immunoglobulin E (IgE) correlated with the affinity of a ligand for the receptor-bound IgE. Because excess receptors clustered by a weakly binding ligand could hoard a critical initiating kinase, they prevented the outnumbered clusters engendered by the high-affinity ligands from launching the more complete cascade. A similar mechanism could explain the antagonistic action of some peptides on the activation of T cells.
Differential Clustering of CD4 and CD3ζ During T Cell Recognition
Authors: Krummel Matthew F. , Sjaastad Michael D. , Wülfing Christoph , Davis Mark M.
Published: July 2002

Whereas T helper cells recognize peptide–major histocompatibility complex (MHC) class II complexes through their T cell receptors (TCRs), CD4 binds to an antigen-independent region of the MHC. Using green fluorescent protein–tagged chimeras and three-dimensional video microscopy, we show that CD4 and TCR-associated CD3ζ cluster in the interface coincident with increases in intracellular calcium. Signaling-, costimulation-, and cytoskeleton-dependent processes then stabilize CD3ζ in a single cluster at the center of the interface, while CD4 moves to the periphery. Thus, the CD4 coreceptor may serve primarily to “boost” recognition of ligand by the TCR and may not be required once activation has been initiated.
Clarithromycin-Resistant
Mycobacterium avium
Is Still Susceptible to Treatment with Clarithromycin and Is Virulent in Mice
Authors: Bermudez Luiz E. , Nash Kevin , Petrofsky Mary , Young Lowell S. , Inderlied Clark B.
Published: July 2002

Resistance to clarithromycin in breakthrough
Mycobacterium avium
complex (MAC) isolates typically occurs 3 to 4 months after the initiation of monotherapy in bacteremic AIDS patients. It has been suggested that continuation of clarithromycin therapy still results in clinical and microbiological improvement. To study this paradox, C57BL/6 beige mice were infected with a clarithromycin-resistant (MIC, ≥128 μg/ml) strain of MAC 101 (CLA-R MAC 101) and treated with 200 mg of clarithromycin per kg of body weight/day alone or in combination with ethambutol (100 mg/kg/day) for 2 weeks. Mice infected with a clarithromycin-susceptible strain of MAC 101 had bacterial loads reduced by 90% in the liver and 91% in the spleen (
P
< 0.05, compared with the control). Clarithromycin treatment of CLA-R MAC 101 resulted in a 65% reduction of bacterial loads in the liver (
P
= 0.009) and a 71% reduction in the spleen (
P
= 0.009), compared with the results for the untreated control. CLA-R MAC 101 and MAC 101 (isogenic strains) had comparable growth rates in murine tissue, ruling out a loss of virulence of CLA-R MAC 101. Strains of MAC currently defined as macrolide resistant may still respond to treatment with an agent such as clarithromycin within infected tissues.
Efficacy of the Echinocandin Caspofungin against Disseminated Aspergillosis and Candidiasis in Cyclophosphamide-Induced Immunosuppressed Mice
Authors: Abruzzo George K. , Gill Charles J. , Flattery Amy M. , Kong Li , Leighton Claire , Smith Jeffrey G. , Pikounis V. Bill , Bartizal Ken , Rosen Hugh
Published: July 2002

The in vivo efficacy of the echinocandin antifungal caspofungin acetate (caspofungin; MK-0991) was evaluated in models of disseminated aspergillosis and candidiasis in mice with cyclophosphamide (CY)-induced immunosuppression. Caspofungin is a 1,3-β-
d
-glucan synthesis inhibitor efficacious against a number of clinically relevant fungi including
Aspergillus
and
Candida
species. Models of CY-induced transient or chronic leukopenia were used with once daily administration of therapy initiated 24 h after microbial challenge. Caspofungin was effective in treating disseminated aspergillosis in mice that were transiently leukopenic (significant prolongation of survival at doses of ≥0.125 mg/kg of body weight and a 50% protective dose [PD
50
] of 0.245 mg/kg/day at 28 days after challenge) or chronically leukopenic (50 to 100% survival at doses of ≥0.5 mg/kg and PD
50
s ranging from 0.173 to 0.400 mg/kg/day). Caspofungin was effective in the treatment and sterilization of
Candida
infections in mice with transient leukopenia with a 99% effective dose based on reduction in log
10
CFU of
Candida albicans
/gram of kidneys of 0.119 mg/kg and 80 to 100% of the caspofungin-treated mice having sterile kidneys at caspofungin doses from 0.25 to 2.0 mg/kg. In
Candida
-infected mice with chronic leukopenia, caspofungin was effective at all dose levels tested (0.25 to 1.0 mg/kg), with the log
10
CFU of
C. albicans
/gram of kidneys of caspofungin-treated mice being significantly lower (>99% reduction) than that of sham-treated mice from day 4 to day 28 after challenge. Also, 70 to 100% of the caspofungin-treated, chronic leukopenic mice had sterile kidneys at caspofungin doses of 0.5 to 1.0 mg/kg from day 8 to 28 after challenge. Sterilization of
Candida
infections by caspofungin in the absence of host leukocytes provides compelling in vivo evidence for fungicidal activity against
C. albicans
. Further human clinical trials with caspofungin against serious fungal infections are in progress.
Animal Pharmacokinetics and Interspecies Scaling of Sordarin Derivatives following Intravenous Administration
Authors: Aviles P. , Pateman A. , San Roman R. , Guillén M. J. , Gómez De Las Heras F. , Gargallo-Viola D.
Published: July 2002

Sordarin derivatives constitute a new group of synthetic antifungal agents that selectively inhibit fungal protein synthesis. They have demonstrated in vitro activity against the most important fungal pathogens, both yeast and filamentous. This new family of compounds has also shown in vivo activity against murine
Candida albicans, Histoplasma capsulatum
, and
Coccidioides immitis
experimental infections, as well as against
Pneumocystis carinii
pneumonia in rats. After intravenous dosing in animals, both the area under the concentration-time curve and the elimination half-life were highest in
Cynomolgus
monkeys, followed by those in rats, mice, and rabbits. The volume of distribution at steady state for sordarin derivatives was similar in all species tested. The clearance in rats and mice was higher than for other species. GM 237354, a sordarin derivative, was characterized by high serum protein binding in mouse, rat, and monkey serum (unbound fraction, ≤5%). An indirect evaluation of the effect of liver function upon the metabolism of this class of compounds has been made in animals with impaired liver function such as Gunn rats, as well as in allometric studies that showed better correlations of half-life to liver blood flow than to animal body weight. Linearity of the main pharmacokinetic parameters was demonstrated after intravenous dosing of the representative compound GM 193663 at 10 and 20 mg/kg of body weight in rats. Allometry was used to determine whether human pharmacokinetic parameters can be predicted from animal data by regression analysis against body weight and liver blood flow. All these results have demonstrated that the human pharmacokinetics of sordarin derivatives can be forecast from animal data.
Activities of Newer Fluoroquinolones against Ciprofloxacin-Resistant
Streptococcus pneumoniae
Authors: Coyle Elizabeth A. , Kaatz Glenn W. , Rybak Michael J.
Published: July 2002

The incidence of ciprofloxacin resistance in
Streptococcus pneumoniae
is low but steadily increasing, which raises concerns regarding the clinical impact of potential cross-resistance with newer fluoroquinolones. To investigate this problem, we utilized an in vitro pharmacodynamic model and compared the activities of gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin to that of ciprofloxacin against two laboratory-derived, ciprofloxacin-resistant derivatives of
S. pneumoniae
(strains R919 and R921). Ciprofloxacin resistance in these strains involved the activity of a multidrug efflux pump and possibly, for R919, a mutation resulting in an amino acid substitution in GyrA. Gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin achieved 99.9% killing of both R919 and R921 in ≤28 h. With respect to levofloxacin, significant regrowth of both mutants was observed at 48 h (
P
< 0.05). For gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin, regrowth was minimal at 48 h, with each maintaining 99.9% killing against both mutants. No killing of either R919 or R921 was observed with exposure to ciprofloxacin. During model experiments, resistance to gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin did not develop but the MICs of ciprofloxacin and levofloxacin increased 1 to 2 dilutions for both R919 and R921. Although specific area under the concentration-time curve from 0 to 24 h (AUC
0–24
)/MIC and maximum concentration of drug in serum (
C
max
)/MIC ratios have not been defined for the fluoroquinolones with respect to gram-positive organisms, our study revealed that significant regrowth and/or resistance was associated with AUC
0–24
/MIC ratios of ≤31.7 and
C
max
/MIC ratios of ≤3.1. It is evident that the newer fluoroquinolones tested possess improved activity against
S. pneumoniae
, including strains for which ciprofloxacin MICs were elevated.
In Vitro and In Vivo Activities of Syn2836, Syn2869, Syn2903, and Syn2921: New Series of Triazole Antifungal Agents
Authors: Salama S. M. , Atwal H. , Gandhi A. , Simon J. , Poglod M. , Montaseri H. , Khan J. K. , Furukawa T. , Saito H. , Nishida K. , Higashitani F. , Uji T. , Unemi N. , Daneshtalab M. , Micetich R. G.
Published: July 2002

The in vitro and in vivo activities of four azole compounds belonging to a new series of 2(2,4-difluorophenyl)-3-(4-substituted piperazin-1-yl)-1-(1,2,4-triazol-1-yl) butanol antifungal agents is described. The compounds were selected from a library of azole compounds synthesized by our group. The in vitro activities of Syn2869, Syn2836, Syn2903, and Syn2921 against a panel of over 240 recently collected clinical isolates of yeast and molds were determined, and the results were compared with those obtained with fluconazole (FLC), itraconazole (ITC), and amphotericin B (AMB). The MICs at which 90% of the isolates were inhibited (MIC
90
s) for the four test compounds for strains of
Candida
spp. ranged from <0.048 to 0.78 μg/ml. All compounds were also active against FLC-resistant
Candida albicans
and other
Candida
sp. strains. Moreover, MIC
90
s for strains of
Cryptococcus neoformans
,
Aspergillus
spp.,
Trichophyton
spp., and
Microsporum
spp. were also low and ranged from <0.048 to 0.39 μg/ml. The test compounds produced a fungistatic pattern during the time-kill kinetic studies. In vivo studies indicated that all four test compounds have good efficacies against
C. albicans
in a murine systemic infection model and significantly improved the survival rates of the infected mice. The results for Syn2903 were similar to those for FLC, while the other compounds were slightly less effective but had ranges of activities similar to the range of activity of ITC. The compounds were also evaluated against an
Aspergillus fumigatus
systemic infection. Syn2903 was also superior to ITC, whereas the efficacy data for the other compounds were similar to those for ITC. It was concluded from the data generated for this new series of azole compounds in the studies described above that further pharmacokinetic and toxicologic evaluations are warranted prior to selection of a candidate compound for preclinical testing.
Drug Interactions with Clinafloxacin
Authors: Randinitis Edward J. , Alvey Christine W. , Koup Jeffery R. , Rausch George , Abel Robert , Bron Nicola J. , Hounslow Neil J. , Vassos Artemios B. , Sedman Allen J.
Published: July 2002

Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration.
Glutathione Derivatives Active against
Trypanosoma brucei rhodesiense
and
T.
brucei brucei
In Vitro
Authors: Daunes Sylvie , D'Silva Claudius
Published: July 2002

Diesters based on
N
-benzyloxycarbonyl-
S
-(2,4-dinitrophenyl) GSH (CBzGSDNP) containing linear alcohols 3 to 9, branched alcohols 10 to 20, or heteroatom linear alcohols 21 to 25, were investigated as in vitro inhibitors of pathogenic parasites. Diesters 3 to 25 were better inhibitors of
Trypanosoma brucei rhodesiense
than of
T. brucei brucei
and had low cytotoxicities. The most active compound had a 50% effective dose (ED
50
) of 0.2 μM. A quantitative structure activity regression equation relating the log (1/ED
50
) versus the hydrophobicity parameter (log
P
), Taft's steric parameter (

E
s

), molecular weight (MW), and the WienI descriptor (
W
) was determined, and the species difference was found to be related to membrane penetration and steric effects.
Effects of Metronidazole, Tetracycline, and Bismuth-Metronidazole-Tetracycline Triple Therapy in the
Helicobacter pylori
SS1 Mouse Model after 1 Day of Dosing: Development of an
H. pylori
Lead Selection Model
Authors: Sizemore Christine F. , Quispe Joel D. , Amsler Karen M. , Modzelewski Todd C. , Merrill Jayson J. , Stevenson D. Andrew , Foster Lorie A. , Slee Andrew M.
Published: July 2002

We evaluated the effect of optimized doses and dosing schedules of metronidazole, tetracycline, and bismuth-metronidazole-tetracycline (BMT) triple therapy with only 1 day of dosing on
Helicobacter pylori
SS1 titers in a mouse model. A reduction of bacterial titers was observable with 22.5 and 112.5 mg of metronidazole per kg of body weight (as well as BMT) given twice daily and four times daily (QID). Two hundred milligrams of tetracycline per kilogram, given QID, resulted in only a slight reduction of
H. pylori
titers in the stomach. We argue that optimization of doses based on antimicrobial drug levels in the animal and shortened (1 or 2 days) drug administration can be used to facilitate early evaluation of putative anti-
H. pylori
drug candidates in lieu of using human doses and extended schedules (7 to 14 days), as can be deduced from the results seen with these antimicrobial agents.
Purification and Properties of an Enzyme Capable of Degrading the Sheath of
Sphaerotilus natans
Authors: Takeda Minoru , Iohara Keishi , Shinmaru Sachie , Suzuki Ichiro , Koizumi Jun-Ichi
Published: July 2002

Microorganisms which can degrade and grow on the purified sheath of a sheathed bacterium
Sphaerotilus natans
were collected from soil and river water. Two bacterial strains were isolated from the soil and designated strains TB and TK. Both strains are rod shaped, negatively stained by gram staining, facultatively anaerobic, and formed ellipsoidal endospores. These characteristics suggested that the isolates belong to the genus
Paenibacillus
, according to Ash et al. (C. Ash, F. G. Priest, and M. D. Collins, Antonie Leeuwenhoek 64:253–260, 1993). Phylogenetic analysis based on the 16S rDNA supported this possibility. Purification of the sheath-degrading enzyme was carried out from the culture broth of strain TB. The molecular weight of the enzyme was calculated to be 78,000 and 50,000 by sodium dodecyl sulfate-polyacrylamide electrophoresis and gel filtration chromatography, respectively. Enzyme activity was optimized at pH 6.5 to 7.0 and 30 to 40°C. The reaction was accelerated by the addition of Mg
2+
, Ca
2+
, Fe
3+
, and iodoacetamide, whereas it was inhibited by the addition of Cu
2+
, Mn
2+
, and dithiothreitol. The enzyme acted on the polysaccharide moiety of the sheath, producing an oligosaccharide the size of which was between the sizes of maltopentaose and maltohexaose. As the reaction proceeded, the absorbance at 235 nm of the reaction mixture increased, suggesting the generation of unsaturated sugars. Incorporation of unsaturated sugars was also suggested by the thiobarbituric acid reaction. It is possible that the enzyme is not a hydrolytic enzyme but a kind of polysaccharide eliminase which acts on the basic polysaccharide.
PCR Use of Highly Conserved DNA Regions for Identification of
Sinorhizobium meliloti
Authors: Sánchez-Contreras María , Lloret Javier , Martín Marta , Villacieros Marta , Bonilla Ildefonso , Rivilla Rafael
Published: July 2002

A PCR identification method in which four primers that recognize homologous conserved regions in the
Sinorhizobium meliloti
genome are used was developed and tested. The regions used for identification were the nodbox 4 locus, which is located in one of the symbiotic megaplasmids, and the
mucR
gene, which is located in the chromosome. The new method was used to establish a collection of
S. meliloti
strains from polluted soils.
Hydrogen Peroxide Sensitivity of Catechol-2,3-Dioxygenase: a Cautionary Note on Use of
xylE
Reporter Fusions under Aerobic Conditions
Authors: Hassett Daniel J. , Ochsner Urs A. , Groce Stephanie L. , Parvatiyar Kislay , Ma Ju-Fang , Lipscomb John D.
Published: July 2002

Catechol-2,3-dioxygenase (C23O) of
Pseudomonas putida
, encoded by the
xylE
gene, was found to be sensitive to hydrogen peroxide (H
2
O
2
) when used as a reporter in gene fusion constructs. Exposure of
Pseudomonas aeruginosa katA
or
katA katB
mutants harboring
katA
- or
katB-lacZ
(encoding β-galactosidase) or -
xylE
fusion plasmids to H
2
O
2
stimulated β-galactosidase activity, while there was little or no detectable C23O activity in these strains. More than 95% of C23O activity was lost after a 5-min exposure to equimolar H
2
O
2
, while a 10,000-fold excess was required for similar inhibition of β-galactosidase. Electron paramagnetic resonance spectra of the nitrosyl complexes of C23O showed that H
2
O
2
nearly stoichiometrically oxidized the essential active-site ferrous ion, thus accounting for the loss of activity. Our results suggest using caution in interpreting data derived from
xylE
reporter fusions under aerobic conditions, especially where oxidative stress is present or when catalase-deficient strains are used.
Ectomycorrhizal Fungal Associates of
Pinus contorta
in Soils Associated with a Hot Spring in Norris Geyser Basin, Yellowstone National Park, Wyoming
Authors: Cullings Ken , Makhija Shilpa
Published: July 2002

Molecular methods and comparisons of fruiting patterns (i.e., presence or absence of fungal fruiting bodies in different soil types) were used to determine ectomycorrhizal (EM) associates of
Pinus contorta
in soils associated with a thermal soil classified as ultra-acidic to extremely acidic (pH 2 to 4). EM were sampled by obtaining 36 soil cores from six paired plots (three cores each) of both thermal soils and forest soils directly adjacent to the thermal area. Fruiting bodies (mushrooms) were collected for molecular identification and to compare fruiting body (above-ground) diversity to below-ground diversity. Our results indicate (i) that there were significant decreases in both the level of EM infection (130 ± 22 EM root tips/core in forest soil; 68 ± 22 EM root tips/core in thermal soil) and EM fungal species richness (4.0 ± 0.5 species/core in forest soil; 1.2 ± 0.2 species/core in thermal soil) in soils associated with the thermal feature; (ii) that the EM mycota of thermal soils was comprised of a small set of dominant species and included very few rare species, while the EM mycota of forest soils contained a few dominant species and several rare EM fungal species; (iii) that
Dermocybe phoenecius
and a species of
Inocybe
, which was rare in forest soils, were the dominant EM fungal species in thermal soils; (iv) that other than the single
Inocybe
species, there was no overlap in the EM fungal communities of the forest and thermal soils; and (v) that the fungal species forming the majority of the above-ground fruiting structures in thermal soils (
Pisolithus tinctorius
, which is commonly used in remediation of acid soils) was not detected on a single EM root tip in either type of soil. Thus,
P. tinctorius
may have a different role in these thermal soils. Our results suggest that this species may not perform well in remediation of all acid soils and that factors such as pH, soil temperature, and soil chemistry may interact to influence EM fungal community structure. In addition, we identified at least one new species with potential for use in remediation of hot acidic soil.
Purification and Characterization of the RecombinantThermussp. Strain T2 α-Galactosidase Expressed inEscherichia coli
Authors: Ishiguro Mitsunori , Kaneko Satoshi , Kuno Atsushi , Koyama Yoshinori , Yoshida Shigeki , Park Gwi-Gun , Sakakibara Yoshikiyo , Kusakabe Isao , Kobayashi Hideyuki
Published: July 2002

The nucleotide sequence of theThermussp. strain T2 DNA coding for a thermostable α-galactosidase was determined. The deduced amino acid sequence of the enzyme predicts a polypeptide of 474 amino acids (Mr, 53,514). The observed homology between the deduced amino acid sequences of the enzyme and α-galactosidase fromThermus brockianuswas over 70%.Thermussp. strain T2 α-galactosidase was expressed in its active form inEscherichia coliand purified. Native polyacrylamide gel electrophoresis and gel filtration chromatography data suggest that the enzyme is octameric. The enzyme was most active at 75°C forp-nitrophenyl-α-d-galactopyranoside hydrolysis, and it retained 50% of its initial activity after 1 h of incubation at 70°C. The enzyme was extremely stable over a broad range of pH (pH 6 to 13) after treatment at 40°C for 1 h. The enzyme acted on the terminal α-galactosyl residue, not on the side chain residue, of the galactomanno-oligosaccharides as well as those of yeasts andMortierella vinaceaα-galactosidase I. The enzyme has only one Cys residue in the molecule.para-Chloromercuribenzoic acid completely inhibited the enzyme but did not affect the mutant enzyme which contained Ala instead of Cys, indicating that this Cys residue is not responsible for its catalytic function.
Isolation and Characterization of a Slowly Milk-Coagulating Variant of
Lactobacillus helveticus
Deficient in Purine Biosynthesis
Authors: Hebert Elvira M. , De Giori Graciela S. , Raya Raul R.
Published: July 2002

A slowly milk-coagulating variant (Fmc
−
) of
Lactobacillus helveticus
CRL 1062, designated S1, was isolated and characterized. Strain S1 possessed all the known essential components required to utilize casein as a nitrogen source, which include functional proteinase and peptidase activities as well as functional amino acid, di- and tripeptide, and oligopeptide transport systems. The amino acid requirements of strain S1 were similar to those of the parental strain. However, on a purine-free, chemically defined medium, the growth rate of the Fmc
−
strain was threefold lower than that of the wild-type strain.
L. helveticus
S1 was found to be defective in IMP dehydrogenase activity and therefore was deficient in the ability to synthesize XMP and GMP. This conclusion was further supported by the observation that the addition of guanine or xanthine to milk, a substrate poor in purine compounds, restored the Fmc
+
phenotype of
L. helveticus
S1.