bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal stability and tribological properties of CrZr–Si–N films synthesized by closed field unbalanced magnetron sputtering
Authors: Lee Sang Yul , Kim Young Su , Kim Gwang Seok
Published: June 2009

In this work, CrZr–Si–N films with various Si contents (⩽6.4at.%) were synthesized by closed field unbalanced magnetron sputtering with vertical magnetron sources. The characteristics such as hardness, surface morphology, and friction coefficient of the films as a function of the Si content after annealing up to 500°C in air were evaluated. Results revealed that the as-deposited films showed very similar characteristics irrespective of the Si content. However, after annealing at 500°C, the film characteristics showed a strong dependency upon the Si content. After annealing at 500°C, the hardness of the Cr39.4Zr12.3N48.3 film decreased significantly to approximately 24GPa and the surface roughness value increased approximately 3.5 times more than that of the as-deposited film. The Cr34.6Zr10.6–Si6.4–N48.4 film, however, was observed to have a hardness of approximately 30GPa, which is close to that of the as-deposited film, 32GPa. In addition, as the wear test temperature increased from room temperature to 500°C, the average friction coefficient of the Cr39.4Zr12.3N48.3 film increased significantly from approximately 0.23 to 0.81, but the average friction coefficient of the Cr34.6Zr10.6–Si6.4–N48.4 film was not changed extensively, measuring approximately 0.43. These results could be attributed to the improvement of the thermal stability by adding Si into the Cr–Zr–N films.
Collisionless gas flows over a flat cryogenic pump plate
Authors: Cai Chunpei , Khasawneh Khaleel
Published: June 2009

This article concerns collisionless gas flows over a flat cryogenic pump plate with a specific sticking probability. It presents exact density, velocity, temperature, and pressure solutions which are useful in determining the plate sticking probability. At any point off the plate, the local velocity distribution function (VDF) consists of several pieces of Maxwellian VDFs, one is characterized by free stream flow properties and the others by plate surface properties. Integrating the VDFs with different moments leads to these exact solutions, which are further validated by simulations with the direct simulation Monte Carlo (DSMC) method. We use these solutions to derive several useful expressions, based on special measured flow field properties at specific locations off the plate, to evaluate the pump sticking probability. Also, the exact solutions complement past studies of aerodynamic coefficients and heat transfer rate for collisionless gas flowing over a flat plate. They explicitly express the physical and geometrical factors. Evaluations of those solutions are much faster than DSMC simulations. This study can find other useful applications, e.g., cold gas spray for thin film depositions inside a vacuum chamber, and spacecraft plume impingement estimations.
Co
Si
x
contact resistance after etching and ashing plasma exposure
Authors: Katahira Ken , Fukasawa Masanaga , Kobayashi Shoji , Takizawa Toshifumi , Isobe Michio , Hamaguchi Satoshi , Nagahata Kazunori , Tatsumi Tetsuya
Published: June 2009

The authors investigated the contact resistance fluctuation caused by CoSix damage in plasma etching and ashing processes. They found that CoSix layers damaged by plasma process exposure are readily oxidized when exposed to air resulting in increased resistance. They also found that the contact resistance increases more when CH3F is used instead of CF4 during etching process. The lower the mass number of dominant ions becomes, the deeper the ions penetrate. Molecular dynamics simulation revealed that dissociated species from lighter ions penetrate deeper and that this stimulates deeper oxidation. They also found that contact resistance further increased by using postetch ashing plasma even in an H2∕N2 ashing process in which O2 was not used. Here, too, the reason for this is that the ion penetration causes deep oxidation. They observed that the contact resistance has a linear relationship with the oxide concentration in CoSix. This leads to the conclusion that it is essential to precisely control the ion energy as well as to properly select the ion species in the plasma process in the fabrication of next-generation semiconductor devices.
Surface characterization of hydrophobic thin films deposited by inductively coupled and pulsed plasmas
Authors: Kim Youngsoo , Lee Ji-Hye , Kim Kang-Jin , Lee Yeonhee
Published: June 2009

Different fluorocarbon thin films were deposited on Si substrates using a plasma-polymerization method. Fluorine-containing hydrophobic thin films were obtained by inductively coupled plasma (ICP) and pulsed plasma (PP) with a mixture of fluorocarbon precursors C2F6, C3F8, and c-C4F8 and the unsaturated hydrocarbons of C2H2. The influence on the fluorocarbon surfaces of the process parameters for plasma polymerization, including the gas ratio and the plasma power, were investigated under two plasma-polymerized techniques with different fluorocarbon gas precursors. The hydrophobic properties, surface morphologies, and chemical compositions were elucidated using water contact angle measurements, field emission-scanning electron microscope, x-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR), and time-of-flight secondary ion mass spectrometry (TOF-SIMS). In this study, the ICP technique provides coarser grained films and more hydrophobic surfaces as well as a higher deposition rate compared to the PP technique. XPS, FT-IR, and TOF-SIMS analyses indicated that the ICP technique produced more fluorine-related functional groups, including CF2 and CF3, on the surface. From the curve-fitted XPS results, fluorocarbon films grown under ICP technique exhibited less degree of cross-linking and higher CF2 concentrations than those grown under PP technique.
Structural, electrical, and optical properties of antimony-doped tin oxide films prepared at room temperature by radio frequency magnetron sputtering for transparent electrodes
Authors: Lee Sung Uk , Hong Byungyou , Choi Won Seok
Published: June 2009

Antimony-doped tin oxide (ATO) films were prepared on 7059 Corning glass substrate by the radio frequency (rf) magnetron sputtering method using SnO2 target mixed with Sb of 6 wt % at room temperature. The working pressure was varied from 0.67 to 2 Pa in steps of 0.67 Pa, and the rf power was varied from 100 to 175 W in steps of 25 W at room temperature. The thickness of the deposited ATO films was about 150 nm. X-ray diffraction (XRD) measurements showed the ATO films to be crystallized with a strong (101) preferred orientation as the rf power is increased. The spectra revealed that the deposited films were polycrystalline, retaining the tetragonal structure. The grain size was estimated from the XRD spectra using the Scherrer equation and found to decrease with a decrease in the working pressure and an increase in the rf power, while the surface roughness was observed to be smoothened. The ATO film that was deposited at a working pressure of 0.67 Pa with rf power of 175 W showed the lowest resistivity of 8.6×10−3 Ω cm, and the optical transmittance was 86.5% in the visible wavelength range from 400 to 800 nm.
Characterization of surface damage in AlSi alloys
Authors: Su J. , Nie X. , Stoilov V. , Yang Q.
Published: June 2009

Plastic deformation and damage accumulation at the contact surface are two important aspects of sliding wear of metal-matrix composite (MMC) materials such as AlSi alloys. The particular topography of the surfaces of the AlSi alloys has triggered the idea that the silicon particles form a load bearing surface over which the countersurfaces are sliding. Therefore, the wear resistance of AlSi surface is thought to originate from the high hardness of the silicon surface formed by the primary Si particles (inclusions). On the other hand, the mechanical strength of the reinforcement (Si)/matrix(Al) interface in a MMC is the primary factor determining the strength on the load bearing Si formation. In this work, the authors developed a novel method to characterize the interface strength of a MMC, combining a nano-/microindentation experiment and a finite element/atomistic analysis. The nano-/microindentation experiment was carried out by indenting individual reinforcement particles on a free surface with a nano-/microindenter. The dependence of indentation response on the interface properties was systematically studied, and the interface strength was extracted from the threshold stress for the sink in of the Si particles. With this method, the shear strength of an Al∕Si interface was measured approximately 330MPa, which compares well with the lower bound of an atomistic simulation with a modified embedded atom method potential [A. Noreyan et al., Acta Mater. 56, 3461 (2008)].
Inductively coupled plasma-reactive ion etching of InSb using CH4∕H2∕Ar plasma
Authors: Zhang Guo-Dong , Sun Wei-Guo , Xu Shu-Li , Zhao Hong-Yan , Su Hong-Yi , Wang Hai-Zhen
Published: June 2009

InSb is an important material for optoelectronic devices. Most InSb devices are currently wet etched, and the etching geometries are limited due to the isotropic nature of wet etching. Inductively coupled plasma (ICP)–reactive ion etching (RIE) is a more desirable alternative because it offers a means of producing small anisotropic structures especially needed in large format infrared focal plane arrays. This work describes the novel use of ICP-RIE for fabricating InSb mesas with CH4∕H2∕Ar plasma and presents the influences of the process parameters on the etch rate and surface morphology. The parameters investigated include bias radio frequency power (50–250W), % CH4 in H2 (10–50), argon (Ar) partial pressure (0–0.3Pa with total pressure of 1.0Pa), and total pressure (0.35–4Pa). With the process parameters optimized in this investigated ranges, good etching results have been achieved with etch rates up to 80nm∕min, and etch features with sidewall angles of about 80°, the etched surface is as smooth as before the RIE process.
Correlation of temperature response and structure of annealed VOx thin films for IR detector applications
Authors: Venkatasubramanian Chandrasekaran , Cabarcos Orlando M. , Allara David L. , Horn Mark W. , Ashok S.
Published: June 2009

The effects of thermal annealing on vanadium oxide (VOx) thin films prepared by pulsed-dc magnetron sputtering were studied to explore methods of improving the efficiency of uncooled IR imaging microbolometers, particularly with respect to maximizing the temperature coefficients of resistance (TCR) (typically ∼2%) while minimizing resistivity values (typically 0.05–5Ωcm). Since high TCR values are usually associated with high resistivities, the experiments were designed to find processing conditions that provide an optimal balance in these properties and to then determine the underlying structural correlations which would enable rational design of thin films for this specific application. VOx films of different compositions were deposited by pulsed-dc reactive sputtering from a vanadium target at different oxygen flow rates. The deposited films were further modified by annealing in inert (nitrogen) and oxidizing (oxygen) atmospheres at four different temperatures for 10, 20, or 30min at a time. The resistivities of the as-deposited films ranged from 0.2to13Ωcm and the TCR values varied from −1.6% to −2.2%. Depending on the exact annealing conditions, several orders of magnitude change in resistance and significant variations in TCR were observed. Optimal results were obtained with annealing in a nitrogen atmosphere. Structural characterization by x-ray diffraction, field emission scanning electron microscopy, atomic force microscopy, and Raman spectroscopy indicated changes in the film crystallinity and phase for annealing conditions over 300°C with the onset and extent of the changes dependent on which annealing atmosphere was used.
Structural and magnetic properties of epitaxial Fe25Pt75
Authors: Lu Z. , Walock M. J. , LeClair P. R. , Mankey G. J. , Mani P. , Lott D. , Klose F. , Ambaye H. , Lauter V. , Wolff M. , Schreyer A. , Christen H. M. , Sales B. C.
Published: June 2009

Epitaxial films of Fe25Pt75 have a number of different magnetic phases as a function of temperature and chemical order. For example, chemically ordered epitaxial films have two distinct antiferromagnetic phases at temperatures below ∼160K and exhibit paramagnetism above that temperature. In sharp contrast, chemically disordered epitaxial films are ferromagnetic with a Curie temperature that is greater than 400K. It is demonstrated that by varying the substrate temperature during growth, epitaxial films with varying degrees of chemical order can be produced and it is possible to produce an alloy with the same composition throughout the film with a modified magnetic structure. The authors used polarized neutron reflectivity to gauge the magnetism of a Fe25Pt75 sample produced with a periodic variation in the growth temperature and showed that the sample exhibits a reduced Curie temperature of approximately 300K as compared to bulk Fe25Pt75.
Effect of Ar and N2 addition on CH4–H2 based chemistry inductively coupled plasma etching of HgCdTe
Authors: Boulard F. , Baylet J. , Cardinaud C.
Published: June 2009

Mercury cadmium telluride (MCT) CH4–H2 based chemistry inductively coupled plasma (ICP) etching mechanisms are investigated. The effect of Ar and N2 addition in the mixture on plasma and MCT surface characteristics are studied by Langmuir probe, mass spectrometry, and x-ray photoelectron spectroscopy (XPS). In the authors’ conditions, the HgTe faster removal than CdTe leads to the formation of a CdTe rich layer in the first 30s of plasma exposure. Ion flux intensity and composition are only slightly influenced by N2 addition while a strong effect is shown on neutral species by the formation of NH3, HCN, and the increase in CH3 radical density. At the opposite, Ar addition to the gas mixture leads to a total ion flux increase and promote CH3+ formation while small changes are observed on neutral species. In our low pressure and high density conditions, same order of magnitude of ion and neutral CH3 flux on MCT surface is found, suggesting a chemical contribution of CH3+ ions in MCT etching. This is confirmed by a strong correlation of the MCT etching yield versus total (neutral and ionic) CH3 flux. These results suggest that the etching is limited by the supply of CH3 to the surface.
Characterization of microwave plasmas for deposition of polyparylene
Authors: Franz Gerhard , Rauter Florian , Dribinskiy Stanislav F.
Published: June 2009

Polyparylene, a noncritical, nontoxic layer material well suited for long-term applications in the human body, has been deposited by plasma-enhanced chemical vapor deposition of the monomeric species. For that end, a microwave discharge in a pulsed mode has been applied. Important plasma parameters have been evaluated by simultaneous application of Langmuir probe and trace rare gas optical emission spectroscopy. Plasma densities and electron temperature have been found to cover values from an almost Langmuir plasma up to some 1010∕cm3 and between 1 and 3.5eV, respectively. The differences in electron temperature between the two methods clearly show the efficiency of microwave fields to excite the high-energy tail of the electron energy distribution function. Due to diffusion loss, the plasma is spatially inhomogenous which has been taken care of by measuring at four different radial positions and different pressures with the Langmuir probe. This holds true for both ambients: argon and parylene-C. However, the plasma density in parylene is lower by a factor of almost 10, indicating that this molecule and/or its fragments exhibit a strong power for electronic attachment or that the process of ionization must compete with other, parasitic reaction paths.
Thin films by metal-organic precursor plasma spray
Authors: Schulz Douglas L. , Sailer Robert A. , Payne Scott , Leach James , Molz Ronald J.
Published: June 2009

While most plasma spray routes to coatings utilize solids as the precursor feedstock, metal-organic precursor plasma spray (MOPPS) is an area that the authors have investigated recently as a novel route to thin film materials. Very thin films are possible via MOPPS and the technology offers the possibility of forming graded structures by metering the liquid feed. The current work employs metal-organic compounds that are liquids at standard temperature-pressure conditions. In addition, these complexes contain chemical functionality that allows straightforward thermolytic transformation to targeted phases of interest. Toward that end, aluminum 3,5-heptanedionate (Al(hd)3), triethylsilane (HSi(C2H5)3 or HSiEt3), and titanium tetrakisdiethylamide (Ti(N(C2H5)2)4 or Ti(NEt2)4) were employed as precursors to aluminum oxide, silicon carbide, and titanium nitride, respectively. In all instances, the liquids contain metal-heteroatom bonds envisioned to provide atomic concentrations of the appropriate reagents at the film growth surface, thus promoting phase formation (e.g., Si–C bond in triethylsilane, Ti–N bond in titanium amide, etc.). Films were deposited using a Sulzer Metco TriplexPro-200 plasma spray system under various experimental conditions using design of experiment principles. Film compositions were analyzed by glazing incidence x-ray diffraction and elemental determination by x-ray spectroscopy. MOPPS films from HSiEt3 showed the formation of SiC phase but Al(hd)3-derived films were amorphous. The Ti(NEt2)4 precursor gave MOPPS films that appear to consist of nanosized splats of TiOCN with spheres of TiO2 anatase. While all films in this study suffered from poor adhesion, it is anticipated that the use of heated substrates will aid in the formation of dense, adherent films.
Large-scale production and metrology of vertically aligned carbon nanotube films
Authors: Dai Lei , Wang Peter , Bosnick Ken
Published: June 2009

The authors have produced carbon nanotube (CNT) films on a large scale in a commercial chemical vapor deposition (CVD) reactor. The reactor (built by Tystar, Inc) is the first of its kind and is capable of handling up to 50 150mm wafers simultaneously with industry standard process control. Electron microscopy reveals that the CNT films consist of densely packed and vertically aligned multiwalled CNTs. A variety of catalysts and reaction conditions were systematically tested. Both Fe films and Cr∕Ni∕Fe film stacks have been found favorable for the growth of aligned CNT films. While electron microscopy provides invaluable information, it is qualitative and unsuitable for process optimization and industrial quality control. A quantitative metrology standard is required for these purposes, but has to date not been explicitly defined. They report on their initial developments toward this metrology standard, considering such factors as film thickness (or CNT length), CNT wall number and diameter, amorphous carbon content, and uniformity. Various measurement techniques have been investigated and are discussed. The developed metrology will facilitate quality control and process optimization necessary for industry applications of CNT films.
Capillary jet injection of SiH4 in the high density plasma chemical vapor deposition of SiO2
Authors: Botha R. , Novikova T. , Bulkin P.
Published: June 2009

In this article, the authors compare the thickness profiles and OH content of SiO2 films deposited using capillary jet injection of silane in a high density plasma chemical vapor deposition (HDP CVD) system with the results of phenomenological modeling using direct simulation Monte Carlo (DSMC) gas flow calculations. A tube with an internal diameter of 1mm is located vertically at 3cm in front of the substrate surface and is used for the injection of the silane. The deposition plasma is characterized using optical emission spectroscopy (OES) and differentially pumped quadrupole mass spectrometry (QMS). Studying the thickness-normalized OH absorption in the deposited film at various points on the substrate, the authors gain insight into the contribution of the water flux to the OH content in the deposited SiO2 film. Gas flow simulations using the DSMC technique are used to study the fluxes of the species onto the substrate plane. From the results the authors conclude that (i) the flux of the H2O onto the substrate holder is uniform, while the SiH4 flux varies considerably along the substrate holder, which leads to a lower level of hydroxyl incorporated into the deposited film in regions of high deposition rate; (ii) HDP CVD systems cannot be considered as well mixed when using SiH4 because its reaction products have high sticking coefficients and the ground-state molecules have the possibility to be consumed on the surface through reactions with oxygen radicals and ions when depositing SiO2; (iii) the primary beamlike flux of undissociated SiH4 onto the substrate surface has an important influence on the film’s deposition rate; and (iv) the SiH4 reactive sticking coefficient is estimated to be between 0.01 and 0.03.
Transparent conducting Si-codoped Al-doped ZnO thin films prepared by magnetron sputtering using Al-doped ZnO powder targets containing SiC
Authors: Nomoto Jun-ichi , Miyata Toshihiro , Minami Tadatsugu
Published: June 2009

Transparent conducting Al-doped ZnO (AZO) thin films codoped with Si, or Si-codoped AZO (AZO:Si), were prepared by radio-frequency magnetron sputtering using a powder mixture of ZnO, Al2O3, and SiC as the target; the Si content (Si∕[Si+Zn] atomic ratio) was varied from 0to1at.%, but the Al content (Al∕[Al+Zn] atomic ratio) was held constant. To investigate the effect of carbon on the electrical properties of AZO:Si thin films prepared using the powder targets containing SiC, the authors also prepared thin films using a mixture of ZnO, Al2O3, and SiO2 or SiO powders as the target. They found that when AZO:Si thin films were deposited on glass substrates at about 200°C, both Al and Si doped into ZnO acted as effective donors and the atomic carbon originating from the sputtered target acted as a reducing agent. As a result, sufficient improvement was obtained in the spatial distribution of resistivity on the substrate surface in AZO:Si thin films prepared with a Si content (Si∕[Si+Zn] atomic ratio) of 0.75at.% using powder targets containing SiC. The improvement in resistivity distribution was mainly attributed to increases in both carrier concentration and Hall mobility at locations on the substrate corresponding to the target erosion region. In addition, the resistivity stability of AZO: Si thin films exposed to air for 30min at a high temperature was found to improve with increasing Si content.
Physical and optical properties of room temperature microwave plasma anodically grown TiO2
Authors: Busani T. , Devine R. A. B.
Published: June 2009

A dense, amorphous form of TiO2 produced by plasma assisted anodic oxidation of Ti was identified using infrared absorption, x-ray diffraction, x-ray reflectivity, atomic force microscopy, and ellipsometry. The films were grown by nominally room temperature processing. Comparison of the physical properties of the material is made with respect to existing data on plasma enhanced chemical vapor deposited TiO2 and new data obtained on electron beam evaporated TiO2. Anodic TiO2 is found to be amorphous with a refractive index of the order of 2.33 as compared to 2.2 for plasma enhanced chemical vapor deposited films and 1.89 for electron beam evaporated TiO2 films. The density is measured to be 4.1g∕cm3. Samples annealed up to 600°C in a N2 atmosphere for 1h remained amorphous, the refractive index increasing to 2.38 and the density to 4.25g∕cm3. The surface roughness remained almost unchanged consistent with the amorphicity. No evidence for the presence of crystalline rutile or anatase phases was detected. Furthermore, unlike plasma assisted chemical vapor deposited and electron beam evaporated TiO2 films, annealed anodic TiO2 showed no observable interaction with the Si substrate either during growth or following annealing.
Comparative studies on the thermal stability and corrosion resistance of CrN, CrSiN, and CrSiN∕AlN coatings
Authors: Kim Gwang Seok , Kim Sung Min , Lee Sang Yul , Lee Bo Young
Published: June 2009

In this work, three kinds of Cr-based nitride coatings such as monolithic CrN, CrSiN coatings, and multilayered CrSiN∕AlN coating with bilayer period of 3.0nm were deposited on both Si (100) wafer and AISI H13 steel substrates by unbalanced magnetron sputtering. Thermal stability of these coatings was evaluated by annealing the coatings at temperatures between 600 and 1000°C for 30min in air. In addition, the corrosion behaviors of these coatings were investigated by potentiodynamic polarization tests in a deaerated 3.5wt.% NaCl solution at 40°C. Results from annealing test show the monolithic CrN and CrSiN coatings were completely oxidized after annealed at 800 and 900°C, and their cross sectional images and atomic force microscopy showed a loose and very porous morphology due to the oxidation. Also, the hardness values of the monolithic CrN and CrSiN coatings were decreased significantly from 22 and 27GPa to 8 and 14GPa, respectively. However, the multilayered CrSiN∕AlN coating still exhibited a dense microstructure without visible change after annealed at 1000°C, and moreover, the relatively high hardness of 25GPa was maintained. The superior thermal stability of the CrSiN∕AlN multilayer coating could be attributed to the formation of the dense and stable oxidation barrier consisted of the Al2O3, Cr2O3, and amorphous SiO2 phases near the surface region, which retard the diffusion of oxygen into the coating. In the potentiodynamic polarization test results, it was found that the significantly improved corrosion resistance of the multilayered CrSiN∕AlN coating was observed in comparison with those from the monolithic CrN and CrSiN coatings, and its corrosion current density (icorr) and protective efficiency were measured to be approximately 4.21μA∕cm2 and 95%, respectively.
Probing the Differential Interactions of Quinazolinedione PD 0305970 and Quinolones with Gyrase and Topoisomerase IV
Authors: Pan Xiao-Su , Gould Katherine A. , Fisher L. Mark
Published: June 2009

Quinazoline-2,4-diones, such as PD 0305970, are new DNA gyrase and topoisomerase IV (topo IV) inhibitors with potent activity against gram-positive pathogens, including quinolone-resistant isolates. The mechanistic basis of dione activity vis-à-vis quinolones is not understood. We present evidence for
Streptococcus pneumoniae
gyrase and topo IV that PD 0305970 and quinolones interact differently with the enzyme breakage-reunion and Toprim domains, DNA, and Mg
2+
-four components that are juxtaposed in the topoisomerase cleavage complex to effect DNA scission. First, PD 0305970 targets primarily gyrase in
Streptococcus pneumoniae
. However, unlike quinolones, which select predominantly for
gyrA
(or topo IV
parC
) mutations in the breakage-reunion domain, unusually the dione selected for novel mutants with alterations that map to a region of the Toprim domain of GyrB (R456H and E474A or E474D) or ParE (D435H and E475A). This “dione resistance-determining region” overlaps the GyrB quinolone resistance-determining region and the region that binds essential Mg
2+
ions, each function involving conserved EGDSA and PLRGK motifs. Second, dione-resistant gyrase and topo IV were inhibited by ciprofloxacin, whereas quinolone-resistant enzymes (GyrA S81F and ParC S79F) remained susceptible to PD 0305970. Third, dione-promoted DNA cleavage by gyrase occurred at a distinct repertoire of sites, implying that structural differences with quinolones are sensed at the DNA level. Fourth, unlike the situation with quinolones, the Mg
2+
chelator EDTA did not reverse dione-induced gyrase cleavage nor did the dione promote Mg
2+
-dependent DNA unwinding. It appears that PD 0305970 interacts uniquely to stabilize the cleavage complex of gyrase/topo IV perhaps via an altered orientation directed by the bidentate 3-amino-2,4-dione moiety.
Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives
Authors: Dardonville Christophe , Fernández-Fernández Cristina , Gibbons Sarah-Louise , Jagerovic Nadine , Nieto Lidia , Ryan Gary , Kaiser Marcel , Brun Reto
Published: June 2009

A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (
Trypanosoma brucei rhodesiense
,
Trypanosoma cruzi
,
Leishmania donovani
, and
Plasmodium falciparum
). This screening identified 29 molecules selectively active against bloodstream-form
T. b. rhodesiense
trypomastigotes, with 50% inhibitory concentrations (IC
50
) ranging from 0.12 to 10 μM, and 33 compounds active against the chloroquine- and pyrimethamine-resistant K1 strain of
P. falciparum
(IC
50
range, 0.17 to 5 μM). In addition, seven compounds displayed activity against intracellular
T. cruzi
amastigotes in the same range as the reference drug benznidazole (IC
50
, 1.97 μM) but were also cytotoxic to L-6 cells, showing little selectivity for
T. cruzi
. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of
L. donovani
. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.
Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, againstStaphylococcus aureus,Listeria monocytogenes, andLegionella pneumophilain Human THP-1 Macrophages
Authors: Lemaire Sandrine , Van Bambeke Françoise , Tulkens Paul M.
Published: June 2009

CEM-101 is a novel fluoroketolide with lower MICs than those of telithromycin and macrolides. Our aim was to assess the cellular accumulation and intracellular activity of CEM-101 using models developed for analyzing the pharmacokinetics and pharmacological properties of antibiotics against phagocytized bacteria. We used THP-1 macrophages andStaphylococcus aureus(ATCC 25923 [methicillin (meticillin) sensitive]),Listeria monocytogenes(strain EGD), andLegionella pneumophila(ATCC 33153). CEM-101 reached cellular-to-extracellular-concentration ratios of about 350 within 24 h (versus approximately 20, 30, and 160 for telithromycin, clarithromycin, and azithromycin, respectively). This intracellular accumulation was suppressed by incubation at a pH of ≤6 and by monensin (proton ionophore) and was unaffected by verapamil (P-glycoprotein inhibitor; twofold accumulation increase for azithromycin) or gemfibrozil. While keeping with the general properties of the macrolide antibiotics in terms of maximal efficacy (Emax; approximately 1-log10-CFU decrease compared to the postphagocytosis inoculum after a 24-h incubation), CEM-101 showed significantly greater potency against phagocytizedS. aureusthan telithromycin, clarithromycin, and azithromycin (for which the 50% effective concentration [EC50] and static concentrations were about 3-, 6-, and 15-fold lower, respectively). CEM-101 was also about 50-fold and 100-fold more potent than azithromycin against phagocytizedL. monocytogenesandL. pneumophila, respectively. These differences in EC50s and static concentrations between drugs were minimized when data were expressed as multiples of the MIC, demonstrating the critical role of intrinsic drug activity (MIC) in eliciting the antibacterial intracellular effects, whereas accumulation per se was unimportant. CEM-101 should show enhanced in vivo potency if used at doses similar to those of the comparators tested here.
Effect of Hemagglutinin-Neuraminidase Inhibitors BCX 2798 and BCX 2855 on Growth and Pathogenicity of Sendai/Human Parainfluenza Type 3 Chimera Virus in Mice
Authors: Watanabe Makiko , Mishin Vasiliy P. , Brown Scott A. , Russell Charles J. , Boyd Kelli , Babu Y. Sudhakara , Taylor Garry , Xiong Xiaoping , Yan Xiaowei , Portner Allen , Alymova Irina V.
Published: June 2009

Human parainfluenza virus type 3 (hPIV-3) is a major respiratory tract pathogen that affects young children, but no vaccines or antiviral drugs against it have yet been developed. We developed a mouse model to evaluate the efficacies of the novel parainfluenza virus hemagglutinin-neuraminidase (HN) inhibitors BCX 2798 and BCX 2855 against a recombinant Sendai virus (rSeV) in which the fusion (F) and HN surface glycoproteins (FHN) were replaced by those of hPIV-3 [rSeV(hPIV-3FHN)]. In the prophylaxis model, 129X1/SvJ mice were infected with a 90% or 20% lethal dose of the virus and were treated intranasally for 5 days with 10 mg/kg of body weight/day of either compound starting 4 h before infection. Prophylactic treatment of the mice with either compound did not prevent their death in a 90% lethality model of rSeV(hPIV-3FHN) infection. However, it significantly reduced the lung virus titers, the amount of weight lost, and the rate of mortality in mice infected with a 20% lethal virus dose. In the therapy model, mice were infected with a nonlethal dose of the virus (100 PFU/mouse) and were treated intranasally with 1 or 10 mg/kg/day of either compound for 5 days starting at 24 or 48 h postinfection. Treatment of the mice with either compound significantly reduced the virus titer in the lungs, subsequently causing a reduction in the number of immune cells and the levels of cytokines in the bronchoalveolar lavage fluid and histopathologic changes in the airways. Our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of hPIV-3 HN in our mouse model and may be promising candidates for the prophylaxis and treatment of hPIV-3 infection in humans.
Profound Antiviral Effect of Oral Administration of MIV-210 on Chronic Hepadnaviral Infection in a Woodchuck Model of Hepatitis B
Authors: Michalak Tomasz I. , Zhang Hong , Churchill Norma D. , Larsson Torbjörn , Johansson Nils-Gunnar , Öberg Bo
Published: June 2009

MIV-210 is a prodrug of 3′-fluoro-2′,3′-dideoxyguanosine with high oral bioavailability in humans and potent activity against hepatitis B virus (HBV). Woodchucks infected with woodchuck hepatitis virus (WHV) represent an accurate model of HBV infection that is utilized for evaluation of the efficacy and safety of novel anti-HBV agents. Oral administration of MIV-210 at 20 or 60 mg/kg of body weight/day induced a rapid virological response in chronically infected woodchucks, reducing serum WHV DNA levels by 4.75 log10and 5.72 log10, respectively, in 2 weeks. A progressive decline in WHV viremia occurred throughout the 10-week therapy, giving final reductions of 7.23 log10and 7.68 log10in the 20- and 60-mg/kg/day groups, respectively. Further, a daily dose of 10 mg/kg decreased the serum WHV load 400-fold after 4 weeks of treatment, and a dose of 5 mg/kg/day was sufficient to maintain this antiviral effect during the following 6-week period. MIV-210 at 20 or 60 mg/kg/day reduced the liver WHV DNA load 200- to 2,500-fold from pretreatment levels and, importantly, led to a 2.0 log10drop in the hepatic content of WHV covalently closed circular DNA. The treatment with 60 mg/kg/day was well tolerated. Liver biopsy specimens obtained after the 10-week treatment with 20 or 60 mg/kg/day and after the 10-week follow-up showed hepatocyte and mitochondrial ultrastructures comparable to those in the placebo-treated group. It was concluded that MIV-210 is highly effective against chronic WHV infection. These findings, together with the previously demonstrated inhibitory activity of MIV-210 against lamivudine-, adefovir-, and entecavir-resistant HBV variants, make MIV-210 a highly valuable candidate for further testing as an agent against chronic hepatitis B.
Efficacy of Iclaprim against Wild-Type and Thymidine Kinase-Deficient Methicillin-Resistant
Staphylococcus aureus
Isolates in an In Vitro Fibrin Clot Model
Authors: Entenza José M. , Haldimann Andreas , Giddey Marlyse , Lociuro Sergio , Hawser Stephen , Moreillon Philippe
Published: June 2009

Iclaprim is a novel diaminopyrimidine antibiotic that is active against methicillin-resistant
Staphylococcus aureus
(MRSA). However, it is known that the activity of diaminopyrimidines against
S. aureus
is antagonized by thymidine through uptake and conversion to thymidylate by thymidine kinase. Unlike with humans, for whom thymidine levels are low, thymidine levels in rodents are high, thus precluding the accurate evaluation of iclaprim efficacy in animal models. We have studied the bactericidal activity of iclaprim against an isogenic pair of MRSA isolates, the wild-type parent AW6 and its thymidine kinase-deficient mutant AH1252, in an in vitro fibrin clot model. Clots, which were aimed at mimicking vegetation structure, were made from human or rat plasma containing either the parent AW6 or the mutant AH1252, and they were exposed to homologous serum supplemented with iclaprim (3.5 μg/ml), trimethoprim-sulfamethoxazole (TMP-SMX; 8/40 μg/ml), vancomycin (40 μg/ml), or saline, each of which was added one time for 48 h. In rat clots, iclaprim and TMP-SMX were bacteriostatic against the parent, AW6. In contrast, they were bactericidal (≥3 log
10
CFU/clot killing of the original inoculum) against the mutant AH1252. Vancomycin was the most active drug against AW6 (
P
< 0.05), but it showed an activity similar those of iclaprim and TMP-SMX against AH1252. In human clots, iclaprim was bactericidal against both AW6 and AH1252 strains and was as effective as TMP-SMX and vancomycin (
P
> 0.05). Future studies of animals using simulated human kinetics of iclaprim and thymidine kinase-deficient MRSA, which eliminate the thymidine-induced confounding effect, are warranted to support the use of iclaprim in the treatment of severe MRSA infections in humans.
Population Pharmacokinetics of Linezolid in Adults with Pulmonary Tuberculosis
Authors: McGee Bryan , Dietze Reynaldo , Hadad David Jamil , Molino Lucilia Pereira Dutra , Maciel Ethel Leonor Noia , Boom W. Henry , Palaci Moises , Johnson John L. , Peloquin Charles A.
Published: June 2009

Nineteen adults with pulmonary tuberculosis received linezolid (600 mg) once or twice daily in an early bactericidal activity trial. A one-compartment population model produced median values for the absorption rate constant, volume of distribution, and elimination rate constant of 1.5 h
−1
, 29.6 liters, and 0.25 h
−1
(once daily) and 2.7 h
−1
, 32.1 liters, and 0.15 h
−1
(twice daily). Linezolid administered twice daily produced higher values for free drug area under the concentration-time curve (AUC)/MIC and time above MIC. Both regimens achieved free AUC/MIC ratios > 100. Median times above the MIC for free drug were 100% (twice daily) and 63% (once daily).
Analysis of the Genome of theEscherichia coliO157:H7 2006 Spinach-Associated Outbreak Isolate Indicates Candidate Genes That May Enhance Virulence
Authors: Kulasekara Bridget R. , Jacobs Michael , Zhou Yang , Wu Zaining , Sims Elizabeth , Saenphimmachak Channakhone , Rohmer Laurence , Ritchie Jennifer M. , Radey Matthew , McKevitt Matthew , Freeman Theodore Larson , Hayden Hillary , Haugen Eric , Gillett Will , Fong Christine , Chang Jean , Beskhlebnaya Viktoriya , Waldor Matthew K. , Samadpour Mansour , Whittam Thomas S. , Kaul Rajinder , Brittnacher Mitchell , Miller Samuel I.
Published: June 2009

In addition to causing diarrhea,Escherichia coliO157:H7 infection can lead to hemolytic-uremic syndrome (HUS), a severe disease characterized by hemolysis and renal failure. Differences in HUS frequency amongE. coliO157:H7 outbreaks have been noted, but our understanding of bacterial factors that promote HUS is incomplete. In 2006, in an outbreak ofE. coliO157:H7 caused by consumption of contaminated spinach, there was a notably high frequency of HUS. We sequenced the genome of the strain responsible (TW14359) with the goal of identifying candidate genetic factors that contribute to an enhanced ability to cause HUS. The TW14359 genome contains 70 kb of DNA segments not present in either of the two reference O157:H7 genomes. We identified seven putative virulence determinants, including two putative type III secretion system effector proteins, candidate genes that could result in increased pathogenicity or, alternatively, adaptation to plants, and an intact anaerobic nitric oxide reductase gene,norV. We surveyed 100 O157:H7 isolates for the presence of these putative virulence determinants. AnorVdeletion was found in over one-half of the strains surveyed and correlated strikingly with the absence ofstx1. The other putative virulence factors were found in 8 to 35% of the O157:H7 isolates surveyed, and their presence also correlated with the presence ofnorVand the absence ofstx1, indicating that the presence ofnorVmay serve as a marker of a greater propensity for HUS, similar to the correlation between the absence ofstx1and a propensity for HUS.
The NanA Neuraminidase of
Streptococcus pneumoniae
Is Involved in Biofilm Formation
Authors: Parker Dane , Soong Grace , Planet Paul , Brower Jonathan , Ratner Adam J. , Prince Alice
Published: June 2009

Streptococcus pneumoniae
remains a major cause of bacteremia, pneumonia, and otitis media despite vaccines and effective antibiotics. The neuraminidase of
S. pneumoniae
, which catalyzes the release of terminal sialic acid residues from glycoconjugates, is involved in host colonization in animal models of infection and may provide a novel target for preventing pneumococcal infection. We demonstrate that the
S. pneumoniae
neuraminidase (NanA) cleaves sialic acid and show that it is involved in biofilm formation, suggesting an additional role in pathogenesis, and that it shares this property with the neuraminidase of
Pseudomonas aeruginosa
even though we show that the two enzymes are phylogenetically divergent. Using an in vitro model of biofilm formation incorporating human airway epithelial cells, we demonstrate that small-molecule inhibitors of NanA block biofilm formation and may provide a novel target for preventative therapy. This work highlights the role played by the neuraminidase in pathogenesis and represents an important step in drug development for prevention of colonization of the respiratory tract by this important pathogen.
Sialic Acid Catabolism Confers a Competitive Advantage to Pathogenic
Vibrio cholerae
in the Mouse Intestine
Authors: Almagro-Moreno Salvador , Boyd E. Fidelma
Published: June 2009

Sialic acids comprise a family of nine-carbon ketosugars that are ubiquitous on mammalian mucous membranes. However, sialic acids have a limited distribution among
Bacteria
and are confined mainly to pathogenic and commensal species.
Vibrio
pathogenicity island 2 (VPI-2), a 57-kb region found exclusively among pathogenic strains of
Vibrio cholerae
, contains a cluster of genes (
nan-nag
) putatively involved in the scavenging (
nanH
), transport (
dctPQM
), and catabolism (
nanA
,
nanE
,
nanK
, and
nagA
) of sialic acid. The capacity to utilize sialic acid as a carbon and energy source might confer an advantage to
V. cholerae
in the mucus-rich environment of the gut, where sialic acid availability is extensive. In this study, we show that
V. cholerae
can utilize sialic acid as a sole carbon source. We demonstrate that the genes involved in the utilization of sialic acid are located within the
nan-nag
region of VPI-2 by complementation of
E
scherichia coli
mutants and gene knockouts in
V. cholerae
N16961. We show that
nanH
,
dctP
,
nanA
, and
nanK
are highly expressed in
V. cholerae
grown on sialic acid. By using the infant mouse model of infection, we show that
V. cholerae
Δ
nanA
strain SAM1776 is defective in early intestinal colonization stages. In addition, SAM1776 shows a decrease in the competitive index in colonization-competition assays comparing the mutant strain with both O1 El Tor and classical strains. Our data indicate an important relationship between the catabolism of sialic acid and bacterial pathogenesis, stressing the relevance of the utilization of the resources found in the host's environment.
Aggregatibacter actinomycetemcomitans
Builds Mutualistic Biofilm Communities with
Fusobacterium nucleatum
and
Veillonella
Species in Saliva
Authors: Periasamy Saravanan , Kolenbrander Paul E.
Published: June 2009

Human oral bacterial pathogens grow in attached multispecies biofilm communities. Unattached cells are quickly removed by swallowing. Therefore, surface attachment is essential for growth, and we investigated multispecies community interactions resulting in mutualistic growth on saliva as the sole nutritional source. We used two model systems, saliva-coated transferable solid-phase polystyrene pegs (peg biofilms) and flow cells with saliva-coated glass surfaces. Fluorescent antibody staining and image analysis were used to quantify the biomass in flow cells, and quantitative real-time PCR with species-specific primers was used to quantify the biomass in peg biofilms.
Veillonella
sp. strain PK1910,
Aggregatibacter actinomycetemcomitans
JP2, and
Fusobacterium nucleatum
ATCC 10953 were unable to grow as single species in flow cells. Only
A. actinomycetemcomitans
grew after 36 h when peg biofilms remained submerged in saliva from the time of inoculation. Mixed-species coaggregates were used for two- and three-species inoculation. The biomass in two-species biofilms increased in both systems when
Veillonella
sp. strain PK1910 was present as one of the partners. Enhanced growth of all strains was observed in three-species biofilms in flow cells. Interestingly, in flow cells
F. nucleatum
and
A. actinomycetemcomitans
exhibited mutualism, and, although
F. nucleatum
was unable to grow with either of the other species in the peg system,
F. nucleatum
stimulated the growth of
Veillonella
sp. and together these two organisms increased the total biomass of
A. actinomycetemcomitans
in three-species peg biofilms. We propose that mutualistic two-species and multispecies oral biofilm communities form in vivo and that mutualism between commensal veillonellae and late colonizing pathogens, such as aggregatibacteria, contributes to the development of periodontal disease.
CD4+CD25+Foxp3−T-Regulatory Cells Produce both Gamma Interferon and Interleukin-10 during Acute Severe Murine Spotted Fever Rickettsiosis
Authors: Fang Rong , Ismail Nahed , Shelite Thomas , Walker David H.
Published: June 2009

Spotted fever group rickettsiae cause life-threatening human infections worldwide. Until now, the immune regulatory mechanisms involved in fatal rickettsial infection have been unknown. C3H/HeN mice infected with 3 × 105PFU ofRickettsia conoriideveloped an acute progressive disease, and all mice succumbed to this infection. A sublethal infection induced protective immunity, and mice survived. Compared to splenic T cells from sublethally infected mice, splenic T cells from lethally infected mice produced significantly lower levels of interleukin-2 (IL-2) and gamma interferon (IFN-γ) and a higher level of IL-10, but not of IL-4 or transforming growth factor β, and there was markedly suppressed CD4+T-cell proliferation in response to antigen-specific stimulation withR. conorii. Furthermore, lethal infection induced significant expansion of CD4+CD25+Foxp3−T cells in infected organs compared to the levels in naïve and sublethally infected mice. In a lethal infection, splenic CD4+CD25+Foxp3−T cells, which were CTLA-4highT-bet+and secreted both IFN-γ and IL-10, suppressed the proliferation of and IL-2 production by splenic CD4+CD25−Foxp3−T cells in vitro. Interestingly, depletion of CD25+T cells in vivo did not change the disease progression, but it increased the bacterial load in the lung and liver, significantly reduced the number of IFN-γ-producing Th1 cells in the spleen, and increased the serum levels of IFN-γ. These results suggested that CD4+CD25+T cells generated in acute murine spotted fever rickettsiosis are Th1-cell-related adaptive T-regulatory cells, which substantially contribute to suppressing the systemic immune response, possibly by a mechanism involving IL-10 and/or cytotoxic T-lymphocyte antigen 4.