bluuebunny/crossref_metadata_2025 huggingface dataset:
Process control of high volume pseudomorphic high electron mobility transistor and metal–semiconductor field effect transistor molecular beam epitaxy production using temperature-dependent photoluminescence
Authors: Liu W. , Lin M. E.
Published: July 2002

In this article we report the nondestructive photoluminescence (PL) techniques to monitor and control high volumes of pseudomorphic high electron mobility transistors (PHEMT) and metal–semiconductor field effect transistors (MESFETS) molecular beam epitaxy (MBE) production. By studying the PL line-shape we found that the correlation between the intensity or the peak position and the doping level is much poorer than that between full width at half maximum (FWHM) and doping level. For the bulk doping layer the minimum detectable level is around 5×1016 cm−3 by 77 K PL. The FWHM correlation between bulk doping and the active doping layer from product wafers has been determined. Furthermore, a three-sigma PL control chart of the MESFET product wafer, which monitors nondestructively with about 5% accuracy, has been setup. After a detailed analysis of the variations of different parameters against PHEMT structure information obtained using x-ray diffraction and Hall effect, we found a close correlation between the PL spectra and the PHEMT structures. The successful PL monitoring of AlGaAs, which is a key factor in determining PHEMT quality and device performance, shows useful information on AlGaAs quality and doping level to guide PHEMT production. By applying the process control method the mass production and device performance shows that the quantum well thickness can be controlled within 1.0%, charge density within 1.5% and the Al and In compositions within 0.2% with over 98% production wafer line yield and over 85% device package yield.
Fabrication of GaAs quantum wires by natural selective doping and its characterization by electrostatic force microscope
Authors: Yoh Kanji , Takabayashi Shingo
Published: July 2002

We report an in situ fabrication method of self-organized quantum wire structures on patterned GaAs substrates by molecular beam epitaxy. The present method is based upon a selective doping mechanism of amphoteric silicon dopant both on patterned (311)A and on (100) GaAs substrates. The surface electrostatic potential distribution on these patterns was investigated by electrostatic force microscope (EFM) and quantum wire structures were verified. A minimum wire width of ≈80 nm was obtained for samples based on both substrate orientations. Good agreement of the wire width estimation by the EFM estimation and the magnetoresistance measurement on modulation-doped heterojunction single quantum wire transistor confirms the validity of the present approach to fabricate self-assembled quantum wires.
The Detection of Large HNO
3
-Containing Particles in the Winter Arctic Stratosphere
Authors: Fahey D. W. , Gao R. S. , Carslaw K. S. , Kettleborough J. , Popp P. J. , Northway M. J. , Holecek J. C. , Ciciora S. C. , McLaughlin R. J. , Thompson T. L. , Winkler R. H. , Baumgardner D. G. , Gandrud B. , Wennberg P. O. , Dhaniyala S. , McKinney K. , Peter Th. , Salawitch R. J. , Bui T. P. , Elkins J. W. , Webster C. R. , Atlas E. L. , Jost H. , Wilson J. C. , Herman R. L. , Kleinböhl A. , von König M.
Published: July 2002

Large particles containing nitric acid (HNO
3
) were observed in the 1999/2000 Arctic winter stratosphere. These in situ observations were made over a large altitude range (16 to 21 kilometers) and horizontal extent (1800 kilometers) on several airborne sampling flights during a period of several weeks. With diameters of 10 to 20 micrometers, these sedimenting particles have significant potential to denitrify the lower stratosphere. A microphysical model of nitric acid trihydrate particles is able to simulate the growth and sedimentation of these large sizes in the lower stratosphere, but the nucleation process is not yet known. Accurate modeling of the formation of these large particles is essential for understanding Arctic denitrification and predicting future Arctic ozone abundances.
Selective Cleavage of D-Ala-D-Lac by Small Molecules: Re-Sensitizing Resistant Bacteria to Vancomycin
Authors: Chiosis Gabriela , Boneca Ivo G.
Published: July 2002

Pathogenic enterococci are becoming resistant to currently available antibiotics, including vancomycin, the drug of last resort for Gram-positive infections. Enterococci pose a significant public health threat, not least because of the risk of transferring vancomycin resistance to the ubiquitous
Staphylococcus aureus
. Vancomycin resistance is manifested by cell wall peptidoglycan precursors with altered termini that cannot bind the antibiotic. Small molecules with well-oriented nucleophile-electrophile assembly and complementary chirality to the peptidoglycan termini were identified as catalytic and selective cleavers of the peptidoglycan precursor depsipeptide. These molecules were tested in combination with vancomycin and were found to re-sensitize vancomycin-resistant bacteria to the antibiotic.
Restricting Dislocation Movement in Transition Metal Carbides by Phase Stability Tuning
Authors: Hugosson Håkan W. , Jansson Ulf , Johansson Börje , Eriksson Olle
Published: July 2002

A mechanism to enhance hardness in multilayer coatings is proposed. Using the technologically important hard transition metal carbides as prototypes, although the principle is transferable also to other systems, we demonstrate, from first-principles calculations, that by suitable alloying the energy difference between several competing structures in the transition metal carbides is small or tunable. This creates multiphase/polytypic compounds with a random or controllable layer stacking sequence, systems in which the propagation of dislocations can be strongly suppressed by a large number of interfaces between structures with different glide systems, accordingly allowing the possibility of a greatly enhanced hardness. With modern thin-film technologies, it should therefore be possible to deposit such materials that will express multilayer characteristics with only minor changes in the chemical constitution of the material, which is in contrast to conventional superlattices.
Midbrain Control of Three-Dimensional Head Orientation
Authors: Klier Eliana M. , Wang Hongying , Constantin Alina G. , Crawford J. Douglas
Published: July 2002

Little is known about the neural mechanisms controlling head posture and why they fail in clinical syndromes like torticollis. It is well established, however, that the brain controls eye position by integrating eye velocity commands. By electrically stimulating and reversibly inactivating midbrain sites in the head-free (nonimmobilized) monkey, we found that the interstitial nucleus of Cajal functions as a neural integrator for head posture. We suggest that a bilateral imbalance in this structure, through either direct damage or inappropriate input, could be one of the mechanisms underlying torticollis.
Involvement of Pre- and Postsynaptic Mechanisms in Posttetanic Potentiation at
Aplysia
Synapses
Authors: Bao Jian-Xin , Kandel Eric R. , Hawkins Robert D.
Published: July 2002

Posttetanic potentiation (PTP) is a common form of short-term synaptic plasticity that is generally thought to be entirely presynaptic. Consistent with that idea, PTP of evoked excitatory postsynaptic potentials at
Aplysia
sensory-motor neuron synapses in cell culture was reduced by presynaptic injection of a slow calcium chelator and was accompanied by an increase in the frequency but not the amplitude of spontaneous excitatory postsynaptic potentials. However, PTP was also reduced by postsynaptic injection of a rapid calcium chelator or postsynaptic hyperpolarization. Thus, PTP at these synapses is likely to involve a postsynaptic induction mechanism in addition to the known presynaptic mechanisms.
Organic Synthesis in Experimental Impact Shocks
Authors: McKay Christopher P. , Borucki William J.
Published: July 2002

Laboratory simulations of shocks created with a high-energy laser demonstrate that the efficacy of organic production depends on the molecular, not just the elemental composition of the shocked gas. In a methane-rich mixture that simulates a low-temperature equilibrium mixture of cometary material, hydrogen cyanide and acetylene were produced with yields of 5 × 10
17
molecules per joule. Repeated shocking of the methane-rich mixture produced amine groups, suggesting the possible synthesis of amino acids. No organic molecules were produced in a carbon dioxide–rich mixture, which is at odds with thermodynamic equilibrium approaches to shock chemistry and has implications for the modeling of shock-produced organic molecules on early Earth.
NMR Perspectives
Authors: Warren Warren S.
Published: July 2002

Spin Choreography.
Basic Steps in High Resolution NMR. RAY FREEMAN. Spektrum, Oxford, UK, and University Science Books, Sausalito, CA, 1997. xii, 391 pp., illus. $58.50 or £30. ISBN 0-935702-95-4.
Abscisic Acid Signaling Through Cyclic ADP-Ribose in Plants
Authors: Wu Yan , Kuzma Jennifer , Maréchal Eric , Graeff Richard , Lee Hon Cheung , Foster Randy , Chua Nam-Hai
Published: July 2002

Abscisic acid (ABA) is the primary hormone that mediates plant responses to stresses such as cold, drought, and salinity. Single-cell microinjection experiments in tomato were used to identify possible intermediates involved in ABA signal transduction. Cyclic ADP–ribose (cADPR) was identified as a signaling molecule in the ABA response and was shown to exert its effects by way of calcium. Bioassay experiments showed that the amounts of cADPR in
Arabidopsis thaliana
plants increased in response to ABA treatment and before ABA-induced gene expression.
Roles for ORC in M Phase and S Phase
Authors: Dillin Andrew , Rine Jasper
Published: July 2002

The origin recognition complex (ORC), a six-subunit protein, functions as the replication initiator in the yeast
Saccharomyces cerevisiae
. Initiation depends on the assembly of the prereplication complex in late M phase and activation in S phase. One subunit of ORC, Orc5p, was required at G
1
/S and in early M phase. Asynchronous cells with a temperature-sensitive
orc5-1
allele arrested in early M phase. In contrast, cells that were first synchronized in M phase, shifted to the restrictive temperature, and then released from the block arrested at the G
1
/S boundary. The G
1
/S arrest phenotype could not be suppressed by introducing wild-type Orc5p during G
1
. Although all
orc2
and
orc5
mutations were recessive in the conventional sense, this dominant phenotype was shared with other
orc5
alleles and an
orc2
allele. The dominant inhibition to cell-cycle progression exhibited by the
orc
mutants was restricted to the nucleus, suggesting that chromosomes with mutant ORC complexes were capable of sending a signal that blocked initiation on chromosomes containing functional origins.
MR Imaging Contrast Enhancement Based on Intermolecular Zero Quantum Coherences
Authors: Warren Warren S. , Ahn Sangdoo , Mescher Marlene , Garwood Michael , Ugurbil Kamil , Richter Wolfgang , Rizi Rahim R. , Hopkins Jeff , Leigh John S.
Published: July 2002

A new method for magnetic resonance imaging (MRI) based on the detection of relatively strong signal from intermolecular zero-quantum coherences (iZQCs) is reported. Such a signal would not be observable in the conventional framework of magnetic resonance; it originates in long-range dipolar couplings (10 micrometers to 1 millimeter) that are traditionally ignored. Unlike conventional MRI, where image contrast is based on variations in spin density and relaxation times (often with injected contrast agents), contrast with iZQC images comes from variations in the susceptibility over a distance dictated by gradient strength. Phantom and in vivo (rat brain) data confirm that iZQC images give contrast enhancement. This contrast might be useful in the detection of small tumors, in that susceptibility correlates with oxygen concentration and in functional MRI.
Energetics of Amino Acid Synthesis in Hydrothermal Ecosystems
Authors: Amend J. P. , Shock E. L.
Published: July 2002

Thermodynamic calculations showed that the autotrophic synthesis of all 20 protein-forming amino acids was energetically favored in hot (100°C), moderately reduced, submarine hydrothermal solutions relative to the synthesis in cold (18°C), oxidized, surface seawater. The net synthesis reactions of 11 amino acids were exergonic in the hydrothermal solution, but all were endergonic in surface seawater. The synthesis of the requisite amino acids of nine thermophilic and hyperthermophilic proteins in a 100°C hydrothermal solution yielded between 600 and 8000 kilojoules per mole of protein, which is energy that is available to drive the intracellular synthesis of enzymes and other biopolymers in hyperthermophiles thriving in these ecosystems.
Convergence of Transforming Growth Factor-β and Vitamin D Signaling Pathways on SMAD Transcriptional Coactivators
Authors: Yanagisawa Junn , Yanagi Yasuo , Masuhiro Yoshikazu , Suzawa Miyuki , Watanabe Michiko , Kashiwagi Kouji , Toriyabe Takeshi , Kawabata Masahiro , Miyazono Kohei , Kato Shigeaki
Published: July 2002

Cell proliferation and differentiation are regulated by growth regulatory factors such as transforming growth factor–β (TGF-β) and the liphophilic hormone vitamin D. TGF-β causes activation of SMAD proteins acting as coactivators or transcription factors in the nucleus. Vitamin D controls transcription of target genes through the vitamin D receptor (VDR). Smad3, one of the SMAD proteins downstream in the TGF-β signaling pathway, was found in mammalian cells to act as a coactivator specific for ligand-induced transactivation of VDR by forming a complex with a member of the steroid receptor coactivator–1 protein family in the nucleus. Thus, Smad3 may mediate cross-talk between vitamin D and TGF-β signaling pathways.
Clinoenstatite in Alpe Arami Peridotite: Additional Evidence of Very High Pressure
Authors: Bozhilov K. N. , Green H. W. , Dobrzhinetskaya L.
Published: July 2002

Observations by transmission electron microscopy show that lamellae of clinoenstatite are present in diopside grains of the Alpe Arami garnet lherzolite of the Swiss Alps. The simplest interpretation of the orientation, crystallography, and microstructures of the lamellae and the phase relationships in this system is that the lamellae originally exsolved as the high-pressure
C
-centered form of clinoenstatite. These results imply that the rocks were exhumed from a minimum depth of 250 kilometers before or during continental collision.
Morphological Clues from Multilegged Frogs: Are Retinoids to Blame?
Authors: Sessions Stanley K. , Franssen R. Adam , Horner Vanessa L.
Published: July 2002

Morphological analysis was performed on multilegged deformed frogs representing five species from 12 different localities in California, Oregon, Arizona, and New York. The pattern of duplicated limbs was consistent with mechanical perturbation by trematode infestation but not with the effects of retinoids.
Stimulation of Microtubule Aster Formation and Spindle Assembly by the Small GTPase Ran
Authors: Wilde Andrew , Zheng Yixian
Published: July 2002

Ran, a small guanosine triphosphatase, is suggested to have additional functions beyond its well-characterized role in nuclear trafficking. Guanosine triphosphate–bound Ran, but not guanosine diphosphate–bound Ran, stimulated polymerization of astral microtubules from centrosomes assembled on
Xenopus
sperm. Moreover, a Ran allele with a mutation in the effector domain (RanL43E) induced the formation of microtubule asters and spindle assembly, in the absence of sperm nuclei, in a γTuRC (γ-tubulin ring complex)– and XMAP215 (
Xenopus
microtubule associated protein)–dependent manner. Therefore, Ran could be a key signaling molecule regulating microtubule polymerization during mitosis.
Bacterial Photoreceptor with Similarity to Photoactive Yellow Protein and Plant Phytochromes
Authors: Jiang ZeYu , Swem Lee R. , Rushing Brenda G. , Devanathan Savitha , Tollin Gordon , Bauer Carl E.
Published: July 2002

A phytochrome-like protein called Ppr was discovered in the purple photosynthetic bacterium
Rhodospirillum centenum
. Ppr has a photoactive yellow protein (PYP) amino-terminal domain, a central domain with similarity to phytochrome, and a carboxyl-terminal histidine kinase domain. Reconstitution experiments demonstrate that Ppr covalently attaches the blue light–absorbing chromophore
p
-hydroxycinnamic acid and that it has a photocycle that is spectrally similar to, but kinetically slower than, that of PYP. Ppr also regulates chalcone synthase gene expression in response to blue light with autophosphorylation inhibited in vitro by blue light. Phylogenetic analysis demonstrates that
R. centenum
Ppr may be ancestral to cyanobacterial and plant phytochromes.
Molecular Linkage Underlying Microtubule Orientation Toward Cortical Sites in Yeast
Authors: Korinek William S. , Copeland Matthew J. , Chaudhuri Amitabha , Chant John
Published: July 2002

Selective microtubule orientation toward spatially defined cortical sites is critical to polarized cellular processes as diverse as axon outgrowth and T cell cytotoxicity. In yeast, oriented cytoplasmic microtubules align the mitotic spindle between mother and bud. The cortical marker protein Kar9 localizes to the bud tip and is required for the orientation of microtubules toward this region. Here, we show that Kar9 directs microtubule orientation by acting through Bim1, a conserved microtubule-binding protein. Bim1 homolog EB1 was originally identified through its interaction with adenomatous polyposis coli (APC) tumor suppressor, raising the possibility that an APC-EB1 linkage orients microtubules in higher cells.
Malaria Parasite Development in a
Drosophila
Model
Authors: Schneider David , Shahabuddin Mohammed
Published: July 2002

Malaria is a devastating public health menace, killing over one million people every year and infecting about half a billion. Here it is shown that the protozoan
Plasmodium gallinaceum
, a close relative of the human malaria parasite
Plasmodium falciparum
, can develop in the fruit fly
Drosophila melanogaster
.
Plasmodium gallinaceum
ookinetes injected into the fly developed into sporozoites infectious to the vertebrate host with similar kinetics as seen in the mosquito host
Aedes aegypti
. In the fly, a component of the insect's innate immune system, the macrophage, can destroy
Plasmodia
. These experiments suggest that
Drosophila
can be used as a surrogate mosquito for defining the genetic pathways involved in both vector competence and part of the parasite sexual cycle.
Calcium-Aluminum-Rich Inclusions from Enstatite Chondrites: Indigenous or Foreign?
Authors: Guan Yunbin , Huss Gary R. , MacPherson Glenn J. , Wasserburg Gerald J.
Published: July 2002

The primary mineral assemblages and initial
26
Al/
27
Al ratios of rare calcium-aluminum–rich inclusions (CAIs) from enstatite (E) chondrites are similar to those of CAIs from other chondrite classes. CAIs from all chondrite classes formed under oxidizing conditions that are much different from the reducing conditions under which the E chondrites formed. Either CAIs formed at an earlier, more oxidizing epoch in the region where E chondrites ultimately formed, or they formed at a different place in the solar nebula and were transported into the E chondrite formation region.
Role of
Bacillus subtilis
SpoIIIE in DNA Transport Across the Mother Cell-Prespore Division Septum
Authors: Bath Jonathan , Wu Ling Juan , Errington Jeffery , Wang James C.
Published: July 2002

The SpoIIIE protein of
Bacillus subtilis
is required for chromosome segregation during spore formation. The COOH-terminal cytoplasmic part of SpoIIIE was shown to be a DNA-dependent adenosine triphosphatase (ATPase) capable of tracking along DNA in the presence of ATP, and the NH
2
-terminal part of the protein was found to mediate its localization to the division septum. Thus, during sporulation, SpoIIIE appears to act as a DNA pump that actively moves one of the replicated pair of chromosomes into the prespore. The presence of SpoIIIE homologs in a broad range of bacteria suggests that this mechanism for active transport of DNA may be widespread.
Activity of ABT-773 against
Mycobacterium avium
Complex in the Beige Mouse Model
Authors: Cynamon M. H. , Carter J. L. , Shoen C. M.
Published: July 2002

ABT-773, a new ketolide antimicrobial agent, was evaluated in comparison to clarithromycin (CLA) in vitro against
Mycobacterium avium
complex (MAC) and in a beige mouse model of disseminated MAC infection. The MICs at which 50 and 90% of the isolates tested were inhibited were 2 and 4 μg/ml, respectively, for CLA and 8 and 16 μg/ml, respectively, for ABT-773. Eight CLA-resistant isolates were found to be resistant to ABT-773 (MICs > 64 μg/ml). In the in vivo study mice were treated with ABT-773 (50, 100, and 200 mg/kg of body weight) or CLA (200 mg/kg). Both ABT-773 (100 and 200 mg/kg) and CLA significantly decreased the viable cell counts in spleens and lungs. ABT-773 (200 mg/kg) and CLA had similar activities in lungs, but the former was more active in spleens.
In Vitro Activity of the New Ketolide Telithromycin Compared with Those of Macrolides against
Streptococcus pyogenes
: Influences of Resistance Mechanisms and Methodological Factors
Authors: Bemer-Melchior Pascale , Juvin Marie-Emmanuelle , Tassin Sandrine , Bryskier Andre , Schito Gian Carlo , Drugeon Henri-B.
Published: July 2002

One hundred and seven clinical isolates of
Streptococcus pyogenes
, 80 susceptible to macrolides and 27 resistant to erythromycin A (MIC >0.5 μg/ml), were examined. The erythromycin A-lincomycin double-disk test assigned 7 resistant strains to the M-phenotype, 8 to the inducible macrolide, lincosamide, and streptogramin B resistance (iMLS
B
) phenotype, and 12 to the constitutive MLS
B
resistance (cMLS
B
) phenotype. MICs of erythromycin A, clarithromycin, azithromycin, roxithromycin, and clindamycin were determined by a broth microdilution method. MICs of telithromycin were determined by three different methods (broth microdilution, agar dilution, and E-test methods) in an ambient air atmosphere and in a 5 to 6% CO
2
atmosphere. Erythromycin A resistance genes were investigated by PCR in the 27 erythromycin A-resistant isolates. MICs of erythromycin A and clindamycin showed six groups of resistant strains, groups A to F. iMLS
B
strains (A, B, and D groups) are characterized by two distinct patterns of resistance correlated with genotypic results. A- and B-group strains were moderately resistant to 14- and 15-membered ring macrolides and highly susceptible to telithromycin. All A- and B-group isolates harbored
erm TR
gene, D-group strains, highly resistant to macrolides and intermediately resistant to telithromycin (MICs, 1 to 16 μg/ml), were all characterized by having the
ermB
gene. All M-phenotype isolates (C group), resistant to 14- and 15-membered ring macrolides and susceptible to clindamycin and telithromycin, harbored the
mefA
gene. All cMLS
B
strains (E and F groups) with high level of resistance to macrolides, lincosamide, and telithromycin had the
ermB
gene. The effect of 5 to 6% CO
2
was remarkable on resistant strains, by increasing MICs of telithromycin from 1 to 6 twofold dilutions against D-E- and F-group isolates.
Mechanisms and Frequency of Resistance to Premafloxacin in
Staphylococcus aureus
: Novel Mutations Suggest Novel Drug-Target Interactions
Authors: Ince Dilek , Hooper David C.
Published: July 2002

Premafloxacin is a novel 8-methoxy fluoroquinolone with enhanced activity against
Staphylococcus aureus
. We found premafloxacin to be 32-fold more active than ciprofloxacin against wild-type
S. aureus
. Single mutations in either subunit of topoisomerase IV caused a four- to eightfold increase in the MICs of both quinolones. A double mutation (
gyrA
and either
grlA
or
grlB
) caused a 32-fold increase in the MIC of premafloxacin, while the MIC of ciprofloxacin increased 128-fold. Premafloxacin appeared to be a poor substrate for NorA, with NorA overexpression causing an increase of twofold or less in the MIC of premafloxacin in comparison to a fourfold increase in the MIC of ciprofloxacin. The frequency of selection of resistant mutants was 6.4 × 10
−10
to 4.0 × 10
−7
at twofold the MIC of premafloxacin, 2 to 4 log
10
less than that with ciprofloxacin. Single-step mutants could not be selected at higher concentrations of premafloxacin. In five single-step mutants, only one previously described uncommon mutation (Ala116Glu), and four novel mutations (Arg43Cys, Asp69Tyr, Ala176Thr, and Pro157Leu), three of which were outside the quinolone resistance-determining region (QRDR) were found. Genetic linkage studies, in which incross of
grlA
+
and outcross of mutations were performed, showed a high correlation between the mutations and the resistance phenotypes, and allelic exchange experiments confirmed the role of the novel mutations in
grlA
in resistance. Our results suggest that although topoisomerase IV is the primary target of premafloxacin, premafloxacin appears to interact with topoisomerase IV in a manner different from that of other quinolones and that the range of the QRDR of
grlA
should be expanded.
Activities of Sordarins in Experimental Models of Candidiasis, Aspergillosis, and Pneumocystosis
Authors: Martinez Antonio , Aviles Pablo , Jimenez Elena , Caballero Jesus , Gargallo-Viola Domingo
Published: July 2002

Sordarin derivatives represent a new class of antifungal agents that act as potent inhibitors of fungal protein synthesis and possess a broad spectrum of activity. The in vivo activity of GM193663 and GM237354 was studied in mouse models of disseminated candidiasis and aspergillosis and in a rat model of pneumocystosis. The pharmacokinetic behavior of both sordarin derivatives was studied in mice and rats. In all studies, compounds were administered by the subcutaneous route. After a subcutaneous dose of 50 mg/kg of body weight to mice, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for GM193663 and GM237354 were 51.8 and 23 μg/ml, 79.5 and 46 μg · h/ml, 0.8 and 0.85 h, and 21 and 25 ml/h, respectively. Systemic candidiasis and aspergillosis were established in CD-1 male mice infected with
Candida albicans
or
Aspergillus fumigatus
. For systemic candidiasis, compounds were given three times per day for seven consecutive days at 15, 30, 60, or 120 mg/kg/day. GM193663 and GM237354 showed dose-related efficacy against
C. albicans
, with 50% effective doses, 1 month after infection, of 25.2 and 10.7 mg/kg/dose, respectively. In experimental infections with
A. fumigatus
, GM237354 was given three times per day at 30, 60, or 120 mg/kg/day for five consecutive days. Animals treated with GM237354 demonstrated irregular responses. The survival of animals treated with GM237354 was 0, 30, and 0% at 30, 60, and 120 mg/kg/day, respectively. The therapeutic efficacy of GM193663 and GM237354 against
Pneumocystis carinii
was studied in an experimental
P. carinii
pneumonia (PCP) rat model. After a subcutaneous dose of 10 mg/kg given to rats, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for GM193663 and GM237354 were 6.6 and 7.2 μg/ml, 8.5 and 11.8 μg · h/ml, 0.7 and 0.8 h, and 230 and 133 ml/h, respectively. To induce spontaneous PCP, rats were chronically immunosuppressed with dexamethasone. Infected animals were treated twice daily for 10 days at 0.2, 2, or 10 mg/kg/day. The therapeutic effect was estimated by the reduction in the number of cysts in the lungs of treated versus untreated animals. GM193663 and GM237354 significantly reduced the mean (± standard deviation) log number of cysts from 7.6 ± 0.2 in the untreated group to 4.7 ± 0.2 and 4.6 ± 0.1, respectively, when the drugs were administered at a dose of 2 mg/kg/day. The log number of cysts was also reduced in infected animals given lower doses of the compounds (0.2 mg/kg/day). In summary, GM193663 and GM237354 are new sordarin derivatives that may potentially play a major role in the treatment of candidiasis and PCP. Further testing with
Aspergillus
in other animal models is warranted.
Morphological Changes and Lysis Induced by β-Lactams Associated with the Characteristic Profiles of Affinities of Penicillin-Binding Proteins in
Actinobacillus pleuropneumoniae
Authors: Inui Takashi , Endo Toshio , Matsushita Tadahiro
Published: July 2002

Actinobacillus pleuropneumoniae
, which was formerly classified in the genus
Haemophilus
, is a pathogen causing swine pleuropneumonia. We found that aspoxicillin showed strong activity and that meropenem had better lytic activity against this pathogen. In the present study, we for the first time identified penicillin-binding proteins (PBPs) of
A. pleuropneumoniae
in order to elucidate the relationship between the antibacterial and lytic activities of β-lactam antibiotics and affinities of the PBPs. The competitive assay using
3
H-labeled benzylpenicillin revealed seven PBPs in
A. pleuropneumoniae
; they were determined to be PBPs 1a, 1b, 2, 3, 4, 5, and 6, and the molecular masses of these PBPs were estimated to be 92, 80, 76, 72, 50, 44, and 30 kDa, respectively, by comparison with those of
Haemophilus influenzae
. Our detailed analysis of the affinities of the PBPs of
A. pleuropneumoniae
and of the bacterial lysis kinetics for several β-lactam antibiotics revealed that the strong antibacterial activity of aspoxicillin against this strain could be related to the higher affinity of PBP 3 and that preferential inactivation of PBP 1b could cause rapid lysis.
Depletion of the Squalene Synthase (
ERG9
) Gene Does Not Impair Growth of
Candida glabrata
in Mice
Authors: Nakayama Hironobu , Izuta Miho , Nakayama Noboru , Arisawa Mikio , Aoki Yuko
Published: July 2002

Squalene synthase (farnesyl-diphosphate farnesyltransferase, EC
2.5.1.21
) is the first committed enzyme of the sterol biosynthesis pathway. Inhibitors of this enzyme have been intensively studied as potential antifungal agents. To assess the effect of deactivating squalene synthase on the growth of fungi in mice, we isolated the squalene synthase (
ERG9
) gene from the pathogenic fungus
Candida glabrata
and generated strains in which the
CgERG9
gene was under the control of the tetracycline-regulatable promoter. Depletion of the
ERG9
gene by doxycycline (DOX), a derivative of tetracycline, decreased the cell viability in laboratory media, whereas it did not affect cell growth in mice at all. The growth defect caused by DOX in laboratory media was suppressed by the addition of serum. Analyses of the sterol composition of the restored cells in serum-containing media suggest that the defect of ergosterol biosynthesis can be complemented by the incorporation of exogenous cholesterol into the cells. Thus, deactivation of squalene synthase did not affect fungal growth in mice, presumably because the cells were able to incorporate cholesterol from the serum. These results showed that squalene synthase could not be a suitable target of antifungals for the treatment of
C. glabrata
infection.
Efficacy of Ampicillin plus Arbekacin in Experimental Rabbit Endocarditis Caused by an
Enterococcus faecalis
Strain with High-Level Gentamicin Resistance
Authors: Kak Vivek , Donabedian Susan M. , Zervos Marcus J. , Kariyama Reiko , Kumon Hiromi , Chow Joseph W.
Published: July 2002

Enterococcus faecalis
LC40 is an ampicillin-susceptible clinical isolate with high-level gentamicin resistance due to the
aac(6′)-Ie-aph(2")-Ia
aminoglycoside resistance gene. The combination of ampicillin plus arbekacin reduced mean bacterial vegetation counts significantly more than ampicillin alone or ampicillin plus gentamicin in a rabbit model of aortic-valve endocarditis caused by
E. faecalis
LC40.
Successful Trovafloxacin Prophylaxis against Experimental Streptococcal Aortic Valve Endocarditis
Authors: Katsarolis Ioannis , Pefanis Angelos , Iliopoulos Dimitrios , Siaperas Peter , Karayiannakos Panagiotis , Giamarellou Helen
Published: July 2002

Single-dose trovafloxacin (15 mg/kg given intravenously [i.v.]) and ampicillin (40 mg/kg given i.v.) protected 38 and 33% of animals challenged with an ampicillin-tolerant strain of
Streptococcus oralis
, respectively. As a double-dose regimen, trovafloxacin afforded total protection (100%;
P
< 0.001 versus controls). Trovafloxacin is the first fluoroquinolone effective in preventing experimental streptococcal endocarditis.
SHV-14, a Novel β-Lactamase Variant in
Klebsiella pneumoniae
Isolates from Nijmegen, The Netherlands
Authors: Yuan Meifang , Hall Lucinda M. C. , Hoogkamp-Korstanje Jaa , Livermore David M.
Published: July 2002

Four ceftazidime-resistant isolates of a
Klebsiella pneumoniae
strain were collected from intensive care unit patients in Nijmegen, The Netherlands. These isolates had TEM-29 and SHV-14 β-lactamases. SHV-14 is a novel variant, with two substitutions compared with the sequence of SHV-1: Ile8Phe and Arg43Ser. Its gene also had a silent C→T mutation at nucleotide 481. The SHV-14 enzyme had slightly higher
V
max
rates than SHV-1 for oxyimino-aminothiazolyl cephalosporins, but this activity was insufficient for the enzyme to count as an extended-spectrum β-lactamase.
In Vitro Antibiotic Susceptibility of
Neisseria gonorrhoeae
in Jakarta, Indonesia
Authors: Lesmana Murad , Lebron Carlos I. , Taslim Djufri , Tjaniadi Periska , Subekti Decy , Wasfy Momtaz O. , Campbell James R. , Oyofo Buhari A.
Published: July 2002

Antibiotic susceptibilities were determined for 122
Neisseria gonorrheae
isolates obtained from 400 sex workers in Jakarta, Indonesia, and susceptibilities to ciprofloxacin, cefuroxime, cefoxitin, cefotaxime, ceftriaxone, chloramphenicol, and spectinomycin were found. All isolates were resistant to tetracycline. A number of the isolates demonstrated decreased susceptibilities to erythromycin (MIC ≥ 1.0 μg/ml), thiamphenicol (MIC ≥ 1.0 μg/ml), kanamycin (MIC ≥ 16.0 μg/ml), penicillin (MIC ≥ 2.0 μg/ml), gentamicin (MIC ≥ 16.0 μg/ml), and norfloxacin (MIC = 0.5 μg/ml). These data showed that certain antibiotics previously used in the treatment of gonorrhea are no longer effective.
Effects of New Quinolones on Transepithelial Electrical Potential Difference of Tracheal Mucosa In Vivo
Authors: Kanoh Soichiro , Tamaoki Jun , Kondo Mitsuko , Nagano Yuko , Nagai Atsushi
Published: July 2002

Superfusion of canine tracheal mucosa with 100 μg each of grepafloxacin and ciprofloxacin per ml reduced the electrical transepithelial potential difference in vivo by more than 50%. This effect was dose dependent, specific for new quinolones, and inhibited by Cl channel blockers, indicating that new quinolones attenuate Cl secretion across the airway epithelium.
New Model of Oropharyngeal Candidiasis in Mice
Authors: Kamai Yasuki , Kubota Mikie , Kamai Yoko , Hosokawa Tsunemichi , Fukuoka Takashi , Filler Scott G.
Published: July 2002

We established a straightforward murine model of oropharyngeal candidiasis. Mice were immunosuppressed with cortisone acetate, anesthetized, and then inoculated by placing cotton wool balls saturated with
Candida albicans
sublingually for 2 h. A prolonged, reproducible infection was induced. This model may be useful for antifungal screening or pathogenesis studies.
Fungal Phospholipase Activity and Susceptibility to Lipid Preparations of Amphotericin B
Authors: Gottfredsson Magnus , Jessup Chad J. , Cox Gary M. , Perfect John R. , Ghannoum Mahmoud A.
Published: July 2002

It has been postulated that phospholipases of fungal origin can affect in vitro susceptibility testing of amphotericin B lipid complex (ABLC). We used specific phospholipase-deficient mutants of
Candida albicans
and
Cryptococcus neoformans
in susceptibility testing and demonstrated that extracellular fungal phospholipase activity does not influence the in vitro susceptibilities of these two fungi to ABLC.
In Vitro and In Vivo Effects of Quinupristin-Dalfopristin against
Pneumocystis carinii
Authors: Walzer Peter D. , Ashbaugh Alan , Collins Margaret , Cushion Melanie T.
Published: July 2002

Quinupristin-dalfopristin (Q-D), which is active against bacteria and
Toxoplasma gondii
, was examined for its activity against
Pneumocystis carinii
. After 72 h of incubation with rat
P. carinii
in an ATP cytotoxicity assay, the 50% inhibitory concentration of Q-D was 10.6 μg/ml, a level that can be achieved in serum with high-dose administration. Q-D administered intraperitoneally at doses of 50 to 200 mg per kg of body weight per day in the treatment and 100 mg/kg/day three times per week in the prophylaxis of pneumocystosis in immunosuppressed mice reduced the organism burden up to 15- and 302-fold, respectively. We conclude that Q-D has activity against
P. carinii
in vitro and in vivo.
Evolution of TEM-Related Extended-Spectrum β-Lactamases in Korea
Authors: Pai Hyunjoo , Lee Hoan-Jong , Choi Eun-Hwa , Kim Jungmin , Jacoby George A.
Published: July 2002

TEM-52, differing from TEM-1 by having the substitutions Glu-104→Lys, Met-182→Thr, and Gly-238→Ser, has previously been described as the most prevalent extended-spectrum β-lactamase (ESBL) in Korea. In a further survey, we discovered the ESBLs TEM-15, which is like TEM-52 but lacks the substitution at residue 182, and TEM-88, which is like TEM-52 with an additional Gly-196→Asp substitution. TEM-88 retained the activity of TEM-52 against moxalactam. Otherwise, the kinetic properties of the three ESBLs failed to show an advantage to this evolution.
Optimal Susceptibility Testing Conditions for Detection of Azole Resistance in
Aspergillus
spp.: NCCLS Collaborative Evaluation
Authors: Espinel-Ingroff A. , Bartlett M. , Chaturvedi V. , Ghannoum M. , Hazen K. C. , Pfaller M. A. , Rinaldi M. , Walsh T. J.
Published: July 2002

The most important role of susceptibility testing is to identify potentially resistant isolates for the agent being evaluated. Standard testing guidelines recently have been proposed for antifungal susceptibility testing of filamentous fungi (molds). This collaborative (eight centers) study evaluated further newly proposed guidelines (NCCLS, proposed standard M38-P, 1998) and other testing conditions for antifungal susceptibility testing of
Aspergillus
spp. to itraconazole and three new triazoles, posaconazole (SCH56592), ravuconazole (BMS-207147), and voriconazole. MICs of itraconazole, posaconazole, ravuconazole, and voriconazole for 15 selected isolates of three species of
Aspergillus
(
A. fumigatus, A. flavus
, and
A. terreus
) with well documented in vitro, clinical, or animal data were determined in each center by using four medium formulations (standard RPMI-1640 [RPMI], RPMI with 2% dextrose, antibiotic medium 3 [M3], and M3 with 2% dextrose) and two criteria of MIC determination (complete [MIC-0s] and prominent [MIC-2s] growth inhibition) at 24, 48, and 72 h. The highest reproducibility (92 to 99%) was seen with the standard RPMI and M3 media. Moreover, the distinction between itraconazole-resistant (MICs of >8 μg/ml for clinically resistant strains) and -susceptible (MICs of 0.03 to 1 μg/ml) isolates, as well as between a voriconazole-resistant laboratory mutant and other isolates (voriconazole MICs of 2 to >8 versus 0.12 to 2 μg/ml), was more consistently evident with the standard RPMI medium and when MIC-0s were determined at 48 h. These results provide further refinement of the testing guidelines for susceptibility testing of
Aspergillus
spp. and warrant consideration for inclusion in the future NCCLS document M38-A.
Evaluation of Susceptibility Testing To Detect Fluoroquinolone Resistance Mechanisms in
Streptococcus pneumoniae
Authors: Richardson David C. , Bast Darrin , McGeer Allison , Low Donald E.
Published: July 2002

To determine if susceptibility testing of
Streptococcus pneumoniae
could detect those isolates that had one of the recognized mechanisms of fluoroquinolone resistance, 101 isolates were selected; the levofloxacin MIC for 28 of these isolates was ≥4 μg/ml. Only isolates with both
parC
and
gyrA
mutations or with no recognized resistance mechanisms were reliably identified by using these results. Isolates with only a
parC
mutation could not be detected reliably using any susceptibility testing method.
Macrolide-Resistant
Streptococcus pneumoniae
in Canada during 1998–1999: Prevalence of
mef
(A) and
erm
(B) and Susceptibilities to Ketolides
Authors: Hoban Daryl J. , Wierzbowski Aleksandra K. , Nichol Kim , Zhanel George G.
Published: July 2002

In this study (1998–1999), we collected 215 macrolide-resistant
Streptococcus pneumoniae
isolates from an ongoing Canadian Respiratory Organism Surveillance Study involving 23 centers representing all regions of Canada. The prevalence of erythromycin-resistant
S. pneumoniae
was 8% (215 of 2,688). Of the 215 isolates, 48.8% (105 of 215) were PCR positive for
mef
(A) and 46.5% (100 of 215) were PCR positive for
erm
(B). The ketolides telithromycin and ABT-773 demonstrated excellent activity against both
mef
(A) (MIC for 90% of strains [MIC
90
], 0.06 and 0.03 μg/ml, respectively) and
erm
(B) (MIC
90
, 0.06 and 0.03 μg/ml, respectively) strains of
S. pneumoniae
.
In Vitro Activities of MK-0826 and 16 Other Antimicrobials against
Bacteroides fragilis
Group Strains
Authors: Betriu Carmen , Sánchez Ana , Palau Marı́a Luisa , Gómez Marı́a , Picazo Juan J.
Published: July 2002

The activity of MK-0826, a new carbapenem, against 309
Bacteroides fragilis
group strains was investigated and compared with that of 11 other β-lactam and 5 non-β-lactam agents. MK-0826 showed excellent activity (MICs ranged from ≤0.06 to 4 μg/ml). The new carbapenem may be useful in the treatment of mixed anaerobic infections involving
B. fragilis
group strains.
Efficacies of BMS 284756 against Penicillin-Sensitive, Penicillin-Resistant, and Quinolone-Resistant Pneumococci in Experimental Meningitis
Authors: Cottagnoud Philippe , Acosta Fernando , Cottagnoud Marianne , Pfister Marc , Täuber Martin G.
Published: July 2002

BMS 284756 penetrated well into inflamed meninges (44% ± 11%) and produced good bactericidal activity (−0.82 ± 0.22 Δlog
10
CFU/ml · h) in the treatment of experimental meningitis in rabbits due to a penicillin-sensitive strain. BMS 284756 monotherapy had a greater potency than the standard regimen of ceftriaxone and vancomycin (−0.49 ± 0.08 Δlog
10
CFU/ml · h) against a penicillin-resistant strain (MIC, 4 mg/liter). Even against a penicillin- and quinolone-resistant strain, BMS 284756 showed good bactericidal activity (−0.52 ± 0.12 Δlog
10
CFU/ml · h). The antibacterial activity of BMS 284756 was confirmed by time-killing assays over 8 h in vitro.
Conversion of Oxacillin-Resistant Staphylococci from Heterotypic to Homotypic Resistance Expression
Authors: Finan J. E. , Rosato A. E. , Dickinson T. M. , Ko D. , Archer Gordon L.
Published: July 2002

Staphylococci that acquire the
mecA
gene are usually resistant to β-lactam antibiotics (methicillin or oxacillin resistance).
mecA
encodes a penicillin-binding protein (PBP 2a) that has a reduced affinity for β-lactams. In some isolates with methicillin or oxacillin resistance, only a small proportion (≤0.1%) of the population expresses resistance to ≥10 μg of oxacillin per ml (heterotypic resistance [HeR]), while in other isolates most of the population expresses resistance (homotypic resistance [HoR]). In the present study, growth of
Staphylococcus aureus
or
Staphylococcus epidermidis
strains with HeR in concentrations of oxacillin (0.3 to 0.7 μg/ml) that produced a fall or a lag in optical density converted the strains from the HeR to the HoR phenotype. The conversion from the HeR to the HoR phenotype appeared to be due to the selection of a highly resistant mutant population, as determined by fluctuation analysis and the failure of populations with HoR to revert to HeR after 60 generations of growth in antibiotic-free media. The frequencies of conversion were as high as 10
−3
to 10
−2
. Conversion to HoR required an intact
mecA
gene and an increase in the level of
mecA
transcription since no highly resistant subpopulation could be selected after growth in oxacillin when
mecA
transcription was constitutively repressed or when
mecA
had been inactivated. In addition, in both
S. epidermidis
and
S. aureus
the level of resistance to vancomycin, which also acts directly on the staphylococcal cell wall, was greater among convertants with HoR than their isogenic parents. The conversion of a population from HeR to HoR involves the selection of a mutation(s) that occurs at a high frequency and most likely requires abundant PBP 2a.
Evaluation of T-3811ME (BMS-284756), a New Des-F(6)-Quinolone, for Treatment of Meningitis Caused by Penicillin-Resistant
Streptococcus pneumoniae
in Rabbits
Authors: Takahata Masahiro , Yamada Hiroshi , Morita Teiichi , Furubou Shinichi , Minami Shinzaburo , Todo Yozo , Watanabe Yasuo , Narita Hirokazu
Published: July 2002

T-3811ME (BMS-284756) is a new des-F(6)-quinolone with high levels of activity against gram-positive bacteria, including penicillin-resistant
Streptococcus pneumoniae
(PRSP) strains. T-3811, the free base of T-3811ME, exhibited potent activity against 28 clinical strains of PRSP isolated clinically (MIC at which 90% of the isolates tested are inhibited, 0.0625 μg/ml). After the intravenous dosing of T-3811ME (20 mg/kg of body weight as T-3811) in rabbits with meningitis caused by PRSP, the area under the concentration-time curve (AUC) of T-3811 in cerebrospinal fluid (CSF) was 5.79 μg · h/ml and was 4.5-fold higher than that of T-3811in the CSF of rabbits without meningitis. In addition, the AUC/MIC for T-3811ME (20 mg/kg as T-3811) in CSF was 185, which was 4.3-fold higher than that for ceftriaxone (administered intravenously at 100 mg/kg). After the administration of any dose of T-3811ME (5, 10, and 20 mg/kg as T-3811), the viable cell counts in CSF decreased in a dose-dependent manner. In particular, after dosing of 20 mg/kg (as T-3811), the viable cell counts in CSF were significantly less than those in the nontreated group (
P
< 0.01). By histopathological evaluation, 6 h after the administration of T-3811ME (20 mg/kg as T-3811), the thickening of the cerebral meninx and the infiltration of neutrophils into the cerebral meninx were less severe in the treated group than in the nontreated group. T-3811ME (BMS-284756) may be expected to be evaluated for the management of meningitis caused by highly penicillin-resistant pneumococci.
Combinations of Lysostaphin with β-Lactams Are Synergistic against Oxacillin-Resistant
Staphylococcus epidermidis
Authors: Kiri Nandini , Archer Gordon , Climo Michael W.
Published: July 2002

Oxacillin-resistant
Staphylococcus aureus
is rapidly killed by the endopeptidase lysostaphin, and the addition of β-lactam antibiotics provides synergistic killing. We investigated the possibility that β-lactams given in combination with lysostaphin would improve the activity of lysostaphin against oxacillin-resistant
Staphylococcus epidermidis
(ORSE), which is normally less susceptible to lysostaphin. Checkerboard synergy testing was performed for lysostaphin given in combination with oxacillin against 10 ORSE isolates for which the lysostaphin MICs were ≥ 8 μg/ml. The fractional inhibitory concentration index ranged from 0.0234 to 0.2656, indicating synergy, which was confirmed in growth curve experiments. In the rabbit model of experimental aortic valve endocarditis using an ORSE strain, the combination of lysostaphin and nafcillin was as effective as vancomycin alone and significantly better than lysostaphin or nafcillin alone. We conclude that β-lactam antibiotics given in combination with lysostaphin are synergistic against many strains of ORSE.