bluuebunny/crossref_metadata_2025 huggingface dataset:
Understudied populations with hepatitis C
Authors: Strader Doris B.
Published: October 2002

Managing patients with hepatitis C virus (HCV) infection consists primarily of antiviral treatment, currently with peginterferon and ribavirin. Unfortunately, treatment recommendations derive largely from trials that have focused on highly selected patient populations. As a consequence of the strict inclusion and exclusion criteria in these studies, more than half of all HCV-infected patients would be ineligible for enrollment. Even among the selected patients enrolled into studies, only 50% achieve a sustained virological response (SVR). Patients not eligible for current therapies include those with mild disease and normal alanine aminotransferase (ALT) levels, patients with advanced and decompensated liver disease, children, the elderly, patients with ongoing or recent alcohol and substance abuse, renal disease, human immunodeficiency virus (HIV) infection, severe psychiatric or neurologic illness, autoimmune disorders, solid organ transplant, and other significant comorbid conditions. Because these patients have been excluded from most clinical trials, little is known about the safety or efficacy of therapy in these populations. The expense and side effects of therapy are also an impediment to treatment of patients who are on public assistance, in prisons, and in institutions. Clearly, new efforts and new approaches are needed to expand the eligibility for antiviral therapy of hepatitis C and make treatment more available for understudied populations with this disease.
Development of a four-element conical electron lens dedicated to high resolution Auger electron–ion(s) coincidence experiments
Authors: Le Guen K. , Céolin D. , Guillemin R. , Miron C. , Leclercq N. , Bougeard M. , Simon M. , Morin P. , Mocellin A. , Burmeister F. , Naves de Brito A. , Sorensen S. L.
Published: October 2002

A four-element conical electron lens has been developed in view of its integration to a double toroidal electron energy analyzer (DTA) dedicated to Auger electron–ion coincidence measurements. The lens design, using electron trajectory numerical simulations, was entirely guided by the perspective of analyzing energetic electrons with high resolution in the multicoincidence regime. The design, construction, and experimental characterization stages of this electron optics system are described in this article. Emphasis is put on the importance of third generation synchrotron radiation sources when performing such multicoincidence experiments.
Properties of polyelectrolyte chains from analysis of angular correlation functions
Authors: Cannavacciuolo Luigi , Pedersen Jan Skov
Published: October 2002

An empirical expression for the angular correlation function (ACF) of charged (Debye–Hückel) wormlike chains (WLC) with excluded volume (EV) is introduced. It reproduces the Monte Carlo (MC) data of a previous study very well. Using this expression analytical calculations for the persistence length (Lp), radius of gyration (Rg), and end-to-end distance (R) are given in the form of Taylor series. It is shown that the above quantities can be expressed as a weighted sum over the corresponding quantities (Lph, Rgh, Rh) of a set of ideal wormlike chains {Ch} h=0,1,… . Both the set {Ch} and the coefficients in the Taylor expansions are defined as functions of three parameters which are determined by fitting the ACF expression to the MC data. A comparison of the calculated Rg and R shows excellent agreement with the corresponding sampled values. The persistence length Lp is in good agreement with the values determined by fitting the sampled scattering functions by model expressions for neutral chains with excluded volume interactions, provided that a contribution due to EV is subtracted from Lp. Moreover, the method here proposed allows one to determine the persistence length of very short chains which is not possible by fitting the scattering function. The new expression for the angular correlation function, as well as the expressions derived for Rg and R are a natural generalization of well known results for ideal WLC, when EV and/or electrostatic interactions are present.
A new method of molecular dynamic computer simulation at constant temperature and pressure
Authors: Landau A. I.
Published: October 2002

A new method of molecular dynamic computer simulation at constant temperature T and pressure P has been proposed. Unlike the earlier techniques of this sort, the new approach does not assume the volume V of the crystal to be an independent variable but the one that can be estimated from the coordinates of the atoms in the crystal. The new method was carefully tested on a finite hcp crystal whose Lennard-Jones potential of the two-atom interaction is known. The test proved the efficiency of the new method under different conditions including T=0 and P>0.
Isotopic krypton mixtures revisited: Vapor pressure isotope effects
Authors: Lopes J. N. Canongia , Rebelo L. P. N. , Bigeleisen Jacob
Published: October 2002

The theory of nonideal, multicomponent, isotopic mixtures is used to calculate the vapor pressures of pure Kr80(l) and Kr84(l) from data on isotopic mixtures. The correction to ideal solution behavior, Δ, is found to be much smaller than the statistical deviations in the experimental data on the isotopic mixtures. It amounts to about 0.0005 and 0.0007 mmHg for the absolute vapor pressures of the pure isotopes at 116 and 123 K, respectively. The vapor pressure difference between pure isotopes is calculated to be 0.5572 mmHg at 116 K after correction for nonideality compared with 0.5573 mmHg based on ideal solution behavior. The corresponding differences are 0.8381 and 0.8382 mmHg, respectively, at 123 K. The theoretically important quantity, ln(p80Kr(l)/p84Kr(l)), shows a decrease (almost irrespective of temperature) of about 0.01% if nonideality is taken into account. The pressure–temperature data for normal krypton given by Lee, Eshelman, and Bigeleisen [J. Chem. Phys. 56, 4585 (1972)], in the temperature range 123.93–129.89 K cannot be reconciled with their vapor pressure equation for the normal liquid. We conclude that the Δ-correction can be safely discarded in the case of the vapor pressure isotope effect (VPIE) studies involving isotopic mixtures of krypton. Moreover, one can infer from this study that, in the case of the rare gases family, the borderline between still measurable and totally negligible nonideal behavior lies between the VPIEs found in mixtures of argon and those in mixtures of krypton, respectively. We anticipate that the case of neon isotopes deserve investigation since the deviations from ideality are expected to be about 400 times greater than those here predicted for krypton.
Hardness of metals from electron transfer reactions at electrode surfaces
Authors: Harinipriya S. , Sangaranarayanan M. V.
Published: October 2002

The standard exchange current densities pertaining to electron transfer processes at electrodes are employed to estimate chemical hardness of various metals. This is accomplished by deriving a new parametric relation for hardness in terms of the work function and surface potential of electrons. Hydrogen evolution and ferric/ferrous redox reactions are considered as examples to extract chemical hardness from electrode kinetic data. The surface potential is calculated for a large number of metals using phenomenological thermodynamic considerations. The significance of the methodology is also illustrated by calculating the potential of zero charge of metal/solution interfaces, thus demonstrating that equilibrium as well as kinetic studies in electrochemistry are capable of yielding the hardness of metals.
Single chain elasticity and thermoelasticity of polyethylene
Authors: Titantah John T. , Pierleoni Carlo , Ryckaert Jean-Paul
Published: October 2002

Single-chain elasticity of polyethylene at θ point up to 90% of stretching with respect to its contour length is computed by Monte Carlo simulation of an atomistic model in continuous space. The elasticity law together with the free-energy and the internal energy variations with stretching are found to be very well represented by the wormlike chain model up to 65% of the chain elongation, provided the persistence length is treated as a temperature-dependent parameter. Beyond this value of elongation simple ideal chain models are not able to describe the Monte Carlo data in a thermodynamic consistent way. This study reinforces the use of the wormlike chain model to interpret experimental data on the elasticity of synthetic polymers in the finite extensibility regime, provided the chain is not yet in its fully stretched regime. Specific solvent effects on the elasticity law and the partition between energetic and entropic contributions to single chain elasticity are investigated.
Determination of a flexible (12D) water dimer potential via direct inversion of spectroscopic data
Authors: Leforestier Claude , Gatti Fabien , Fellers Raymond S. , Saykally Richard J.
Published: October 2002

We report the determination of two dimer water potential energy surfaces via direct inversion of spectroscopic data. The first surface, rigid, employs the MCY functional form originally fitted by Clementi and co-workers from ab initio calculations, modified by adjunction of a fifth, uncharged, site to improve the dispersion component. The vibration-rotation-tunneling energy levels were computed by means of the pseudospectral split Hamiltonian method that we developed previously. The fitted surface shows considerable improvement as compared to the original one: transitions among the ground-state manifold are in error by at most 0.2 cm−1, and excited state band origins (up to 150 cm−1) are reproduced to within 0.5 to 3 cm−1. For the second surface, flexible, we used the same modified MCY functional form, considered now to depend on the 12 internal degrees of freedom, and augmented by the monomer potential energy terms. The water dimer is described in its full dimensionality by collision-type coordinates in order to access the whole configuration sampled by this floppy system. Internal motions of the monomers (stretches and bends) are explicitly considered by invoking an adiabatic separation between the slow (intermonomeric) and fast (intramonomeric) modes. This (6+6)d adiabatic formulation allows us to recast the calculations into an equivalent six-dimensional dynamics problem (∼pseudorigid monomers) on an effective potential energy surface. The resulting, fitted, fully flexible dimer potential leads to a much better agreement with experiment than does the rigid version, as examplified by the standard deviation on all observed frequencies being reduced by a factor of 3. It is shown that monomer flexibility is essential in order to reproduce the experimental transitions.
Coherent integration of 0.5 GHz spectral holograms at 1536 nm using dynamic biphase codes
Authors: Cole Z. , Böttger T. , Mohan R. Krishna , Reibel R. , Babbitt W. R. , Cone R. L. , Merkel K. D.
Published: October 2002

Spectral hole-burning-based optical processing devices are proposed for coherent integration of multiple high-bandwidth interference patterns in a spectral hole-burning medium. In this implementation, 0.5 GHz spectral holographic gratings are dynamically accumulated in Er3+:Y2SiO5 at 4.2 K using a 1536 nm laser frequency stabilized to a spectral hole, along with commercial off-the-shelf components. The processed data, representing time delays over 0.5–2.0 μs, were optically read out using a frequency-swept probe; this approach makes possible the use of low-bandwidth, large-dynamic-range detectors and digitizers and enables competitive processing for applications such as radar, lidar, and radio astronomy. Coherent integration dynamics and material advances are reported.
Room-temperature single-electron tunneling in conducting polypyrrole nanotube
Authors: Saha S. K.
Published: October 2002

Observation of room-temperature single-electron tunneling (SET) in a conjugated polymer is reported. It is observed that conjugated polymers in the high doping level are composed of some ordered (metallic) and disordered (semiconducting) regions. This property has been exploited in conducting polypyrrole nanotubes to form some ordered regions separated by disordered regions. The nonlinear current–voltage and positive temperature coefficient of resistance in the high-temperature limit confirm the desired morphology of the tubes. Isolated metallic islands, which are necessary to observe SET have been formed disrupting the nanotube in the semiconducting (disordered) portions by applying a voltage pulse.
Breakdown-induced negative charge in ultrathin SiO2 films measured by atomic force microscopy
Authors: Porti M. , Nafrı́a M. , Blüm M. C. , Aymerich X. , Sadewasser S.
Published: October 2002

Atomic-force-microscopy-based techniques have been used to investigate at a nanometer scale the dielectric breakdown (BD) of ultrathin (<6 nm) SiO2 films of metal-oxide-semiconductor devices. The results show that BD leads to negative charge at the BD location and the amount of created charge has been estimated. Moreover, the comparison of the charge magnitude generated during current-limited stresses and stresses without current limit demonstrates that the observed BD induced negative charge is related to the structural damage created by the oxide BD.
Amplified spontaneous emission and efficient tunable laser emission from a substituted thiophene-based oligomer
Authors: Pisignano Dario , Anni Marco , Gigli Giuseppe , Cingolani Roberto , Zavelani-Rossi Margherita , Lanzani Guglielmo , Barbarella Giovanna , Favaretto Laura
Published: October 2002

We investigated gain and lasing in spin-coated films of a soluble substituted oligothiophene. With increasing excitation power, the photoluminescence spectra show a clear line narrowing due to amplified spontaneous emission. We measure a low threshold (20 μJ cm−2) for line narrowing and a large gain cross section (6×10−16 cm2), indicating that this molecule is a promising active material for organic solid-state lasers. As a demonstrator, we realize a transverse electromagnetic (TEM00) single-mode laser with tunable emission from the yellow to the red (a range of 37 nm), with a pump threshold as low as 18 μJ cm−2 and efficiency of 1.9%. These results are among the best so far reported for organic lasers.
Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo
Authors: Dresser George K. , Wacher Vincent , Wong Susan , Wong Harrison T. , Bailey David G.
Published: October 2002

Objectives

Our study was designed to determine the effect of peppermint oil and ascorbyl palmitate on cytochrome P4503A4 (CYP3A4) activity in vitro and oral bioavailability of felodipine in humans.

Methods

Reversible and mechanism‐based inhibitions of nifedipine oxidation were studied in human liver microsomes. The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined in 12 healthy volunteers after administration of felodipine, 10‐mg extended‐release tablet, with grapefruit juice (300 mL), peppermint oil (600 mg), ascorbyl palmitate (500 mg), or water in a randomized 4‐way crossover study.

Results

Peppermint oil (inhibition constant [Ki] = 35.9 ± 3.3 μg/mL, mean ± SEM) and 2 constituents, menthol (Ki = 87.0 ± 7.0 μmol/L), and menthyl acetate (Ki = 124.0 ± 7.0 μmol/L), produced reversible inhibition of nifedipine oxidation. Ascorbyl palmitate was more potent (Ki = 12.3 ± 0.5 μmol/L). None of these substances were mechanism‐based inhibitors. Grapefruit juice and peppermint oil increased the area under the curve (AUC) values of felodipine to 173% (range, 94%‐280%; P < .01) and 140% (range, 77%‐262%; P < .05), respectively, of those with water. They augmented the peak plasma concentration (Cmax) of felodipine and the AUC and Cmax of dehydrofelodipine but did not alter the half‐life (t½) of either substance. Grapefruit juice decreased the dehydrofelodipine/felodipine AUC ratio, but peppermint oil did not. Ascorbyl palmitate did not change the pharmacokinetics of felodipine or dehydrofelodipine compared with water.

Conclusions

Peppermint oil, menthol, menthyl acetate, and ascorbyl palmitate were moderately potent reversible inhibitors of in vitro CYP3A4 activity. Grapefruit juice increased the oral bioavailability of felodipine by inhibition of CYP3A4‐mediated presystemic drug metabolism. Peppermint oil may also have acted by this mechanism. However, this requires further investigation. Ascorbyl palmitate did not inhibit CYP3A4 activity in vivo.

Clinical Pharmacology & Therapeutics (2002) 72, 247–255; doi: 10.1067/mcp.2002.126409
Equivalence approaches*
Authors: Williams Roger L. , Chen Mei‐Ling , Hauck Walter W.
Published: October 2002

Clinical Pharmacology & Therapeutics (2002) 72, 229–237; doi: 10.1067/mcp.2002.126705
Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea
Authors: Xie Rujia , Mathijssen Ron H. J. , Sparreboom Alex , Verweij Jaap , Karlsson Mats O.
Published: October 2002

Objectives

Our objective was to build population pharmacokinetic models that describe plasma concentrations of irinotecan (CPT‐11) and its metabolites 7‐ethyl‐10‐hydroxycamptothecin (SN‐38) and SN‐38 glucuronide (SN‐38G) and to investigate the pharmacokinetic‐pharmacodynamic relationships between drug exposure and diarrhea, the major dose‐limiting toxicity.

Methods

Data were obtained from 109 patients (65 men and 44 women) who received 1.5‐hour (range, 0.75‐ to 2.25‐hour) intravenous infusions of irinotecan at doses that ranged from 100 to 350 mg/m2; 44 patients had a second course. The population pharmacokinetic models were developed to describe plasma concentration‐time profiles. The area under the concentration‐time curve from time zero to 60 hours [AUC (0–60)] was used as a measure of drug exposure to model the probabilities of diarrhea with use of a logistic regression model.

Results

A 3‐compartment pharmacokinetic model best described the disposition of irinotecan, whereas SN‐38 and SN‐38G showed 2‐compartmental characteristics. The population estimate of clearance for irinotecan was 31.6 L/h, and the volume of distribution at steady‐state (VSS) was 263 L. The clearance divided by formation fraction (Fm) was 712 L/h and 66.8 L/h for SN‐38 and SN‐38G, respectively. The VSS/Fm was 72,000 L for SN‐38 and 85.4 L for SN‐38G. The frequencies of diarrhea scores in this study were 46% (grade 0), 28% (grade 1), 20% (grade 2), 4% (grade 3), and 2% (grade 4). Significant correlations between AUC(0–60) and diarrhea scores were found for irinotecan (P < .05) and SN‐38G (P < .01) but not for SN‐38 or the biliary index.

Conclusions

In this population analysis, irinotecan and SN‐38G AUC values were appropriate predictors of the risk for diarrhea, and SN‐38G AUC showed the stronger relationship of the two. The developed population models may be useful in further clinical development of this agent.

Clinical Pharmacology & Therapeutics (2002) 72, 265–275; doi: 10.1067/mcp.2002.126741
Cytochrome P450 phenotypic ratios for predicting herb‐drug interactions in humans
Authors: Gurley Bill J. , Gardner Stephanie F. , Hubbard Martha A. , Williams D. Keith , Gentry W. Brooks , Cui Yanyan , Ang Catharina Y. W.
Published: October 2002

Objectives

Phytochemical‐mediated modulation of cytochrome P450 (CYP) activity may underlie many herb‐drug interactions. Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of St John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.

Methods

Twelve healthy volunteers (6 females) were randomly assigned to receive either St John's wort, garlic oil, P ginseng, or G biloba for 28 days. For each subject, a 30‐day washout period was interposed between each supplementation phase. Probe‐drug cocktails of midazolam, caffeine, chlorzoxazone, and debrisoquin (INN, debrisoquine) were administered before supplementation (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 with the use of 1‐hydroxymidazolam/midazolam serum ratios (1‐hour sample), paraxanthine/caffeine serum ratios (6‐hour sample), 6‐hydroxychlorzoxazone/chlorzoxazone serum ratios (2‐hour sample), and debrisoquin urinary recovery ratios (8‐hour collection), respectively.

Results

Comparisons of presupplementation and postsupplementation ratios indicated that St John's wort significantly induced the activity of CYP2E1 and CYP3A4 (P < .0001). Among female subjects, St John's wort produced significantly greater increases in CYP3A4 phenotypic ratios that appeared to be unrelated to body mass index. This finding is suggestive of a sexual dimorphism in CYP3A4 inducibility. Garlic oil reduced CYP2E1 activity by 39% (P = .030), whereas no significant effect on CYP activity was observed for P ginseng and G biloba.

Conclusions

Single‐time point phenotypic metabolic ratios may provide a practical means of predicting CYP‐mediated herb‐drug interactions in humans.

Clinical Pharmacology & Therapeutics (2002) 72, 276–287; doi: 10.1067/mcp.2002.126913
Losartan and lercanidipine attenuate low‐density lipoprotein oxidation in patients with hypertension and type 2 diabetes mellitus: A randomized, prospective crossover study
Authors: Rachmani Rita , Levi Zohar , Zadok Bat‐Sheva , Ravid Mordchai
Published: October 2002

Objectives

Lipoprotein oxidation, dyslipidemia, and hypertension are important underlying causes of accelerated atherosclerosis in patients with diabetes mellitus. The potential of antihypertensive medications to reduce lipid oxidation is, therefore, an important determinant in the choice of agents for patients with diabetes mellitus. The aim of this study was to compare the lowering effect of a new dihydropyridine calcium antagonist, lercanidipine, with that of the first angiotensin‐receptor blocker, losartan, on low‐density lipoprotein (LDL) oxidation.

Methods

Forty patients in metabolically stable condition who had type 2 diabetes mellitus with hypertension were studied in this single‐blind, randomized, prospective crossover study, comprising 2 treatment periods of 16 weeks each, separated by a 4‐week washout period. LDL oxidation was evaluated by dialdehyde analysis by means of the thiobarbituric acid‐reactive substances assay with and without cupric sulfate, as well as determination of conjugated dienes in the LDL lipid extract.

Results

Lercanidipine and losartan both significantly reduced the propensity of the serum to oxidize LDL (P = .001). With one method of estimation (conjugated dienes), the effect of lercanidipine was superior to that of losartan (P = .04). Losartan lowered urinary albumin excretion but lercanidipine did not.

Conclusions

Both lercanidipine and losartan attenuate LDL oxidation in patients with type 2 diabetes mellitus and hypertension. This observation may offer insight into the mechanisms of the therapeutic effects of these agents in patients with diabetes mellitus.

Clinical Pharmacology & Therapeutics (2002) 72, 302–307; doi: 10.1067/mcp.2002.127110
Ischemic stroke in a user of Thermadrene: A case study in alternative medicine
Authors: Kaberi‐Otarod Jila , Conetta Rick , Kundo Krzysztof K. , Farkash Arthur
Published: October 2002

A case of a young user of Thermadrene (SportPharma USA, Inc, Concord, Calif), an herbal remedy for weight loss, was studied. We believe that Thermadrene can cause serious complications such as ischemic stroke. Because these remedies are available over the counter and are not regulated by the Food and Drug Administration or similar organizations, there is a need for critical scrutiny of their content and side effects, as is performed for other pharmaceuticals.

Clinical Pharmacology & Therapeutics (2002) 72, 343–346; doi: 10.1067/mcp.2002.127942
Service quality in Internet banking: the importance of customer role
Authors: Broderick Anne J. , Vachirapornpuk Supattra
Published: October 2002

One of the key challenges of the Internet as a service delivery channel is how service firms can manage service quality as these remote formats bring significant change in customer interaction and behaviour. Drawing on theoretical frameworks of service quality and adapting these to particularly reflect the remote delivery format of the Internet, this study proposes and tests a service quality model of Internet banking. The research uses participant observation and narrative analysis of a UK Internet banking Web site community to explore how Internet banking customers perceive and interpret the elements of the model. Findings show that the level and nature of customer participation had the greatest impact on the quality of the service experience and issues such as customers’ zone of tolerance, the degree of role understanding by customers and emotional response potentially determined, expected and perceived service quality.
Direct-to-reverberant energy ratio sensitivity
Authors: Zahorik Pavel
Published: October 2002

Although the ratio of direct-to-reverberant sound energy is known to be an important acoustic cue to sound source distance, human sensitivity to changes in this cue is largely unknown. Here, direct-to-reverberant energy discrimination thresholds were measured for six listeners using virtual sound source techniques that allow for convenient and precise control of this stimulus parameter. Four different types of source stimuli were tested: a 50 ms noise burst with abrupt onset/offset, a 300 ms duration noise burst with gradual onset/offset, a speech syllable, and an impulse. Over a range of direct-to-reverberant ratios from 0 to 20 dB, an adaptive 2AFC procedure (3-down, 1-up) was used to measure discrimination thresholds. For all stimuli, these thresholds ranged from 5 to 6 dB. A post hoc fitting procedure confirmed that slopes of the psychometric functions were homogeneous across stimulus conditions and listeners. These threshold results suggest that direct-to-reverberant energy ratio by itself provides only a course coding of sound source distance, because threshold values correspond to greater than 2-fold changes in physical distance for the acoustic environment under examination.
Modal analysis of a drumlike silencer
Authors: Huang Lixi
Published: October 2002

Low-frequency duct noise is difficult to deal with by passive methods such as porous duct lining. Reactive methods like expansion chamber are rather bulky, while compact resonators are too narrow banded. This study shows that a suitably stretched thin membrane backed by a slender cavity can achieve a satisfactory performance from low to medium frequencies over an octave band. The present paper focuses on the details of the modal behavior of the fully coupled membrane-cavity system, and examples are given with parameters set in a practical range. Typically, the membrane has a structure to air mass ratio of unity, and is stretched towards the elastic stress limit for a material like aluminum. The backing cavity has a depth equal to the duct height and a length five times the duct height. Three resonant peaks are found in the low to medium frequency range while the transmission loss between adjacent peaks remain above 10 dB. For the first peak, almost complete sound reflection occurs as a result of an out-of-phase combination of the first and second in vacuo modes of simply supported membranes. The second peak is solely contributed to by the first mode, while the third peak features mainly the second mode vibration.
Two-frequency driven single-bubble sonoluminescence
Authors: Krefting Dagmar , Mettin Robert , Lauterborn Werner
Published: October 2002

Sonoluminescing single bubbles driven simultaneously by two harmonic frequencies were recently reported to increase the maximum light output up to a factor of 3 with respect to single mode excitation. In this paper, experimental and numerical results on single-bubble sonoluminescence (SBSL) in an air/water system using the fundamental mode of 25 kHz and the second harmonic at 50 kHz are presented. The region of light emission is mapped in the three-dimensional parameter space spanned by the two driving pressure amplitudes and their relative phase. Good agreement was seen between measured light output, maximum bubble radius, and stability boundaries and the numerical model which is based on spherical bubble oscillations regarding diffusive and shape stability. The maximum brightness was enhanced by a factor up to 2.5 with respect to single mode SBSL. However, long-term measurements reveal great variation of the emission at fundamental mode driven SBSL and of the boost factor reached with two frequencies. The overall brightness maxima of both excitation methods within a period of several hours turn out to show little difference.
Cytoprotective Role of Ca
2+
- Activated K
+
Channels in the Cardiac Inner Mitochondrial Membrane
Authors: Xu Wenhong , Liu Yongge , Wang Sheng , McDonald Todd , Van Eyk Jennifer E. , Sidor Agnieszka , O'Rourke Brian
Published: October 2002

Ion channels on the mitochondrial inner membrane influence cell function in specific ways that can be detrimental or beneficial to cell survival. At least one type of potassium (K
+
) channel, the mitochondrial adenosine triphosphate–sensitive K
+
channel (mitoK
ATP
), is an important effector of protection against necrotic and apoptotic cell injury after ischemia. Here another channel with properties similar to the surface membrane calcium-activated K
+
channel was found on the mitochondrial inner membrane (mitoK
Ca
) of guinea pig ventricular cells. MitoK
Ca
significantly contributed to mitochondrial K
+
uptake of the myocyte, and an opener of mitoK
Ca
protected hearts against infarction.
Guest Transport in a Nonporous Organic Solid via Dynamic van der Waals Cooperativity
Authors: Atwood Jerry L. , Barbour Leonard J. , Jerga Agoston , Schottel Brandi L.
Published: October 2002

A well-known organic host compound undergoes single-crystal–to–single-crystal phase transitions upon guest uptake and release. Despite a lack of porosity of the material, guest transport through the solid occurs readily until a thermodynamically stable structure is achieved. In order to actively facilitate this dynamic process, the host molecules undergo significant positional and/or orientational rearrangement. This transformation of the host lattice is triggered by weak van der Waals interactions between the molecular components. In order for the material to maintain its macroscopic integrity, extensive cooperativity must exist between the molecules throughout the crystal, such that rearrangement can occur in a well-orchestrated fashion. We demonstrate here that even weak dispersive forces can exert a profound influence over solid-state dynamics.
Membrane Fusion Tropism and Heterotypic Functional Activities of theNipah VirusandHendra VirusEnvelope Glycoproteins
Authors: Bossart Katharine N. , Wang Lin-Fa , Flora Michael N. , Chua Kaw Bing , Lam Sai Kit , Eaton Bryan T. , Broder Christopher C.
Published: October 2002

Nipah virus(NiV) andHendra virus(HeV) are novel paramyxoviruses from pigs and horses, respectively, that are responsible for fatal zoonotic infections of humans. The unique genetic and biological characteristics of these emerging agents has led to their classification as the prototypic members of a new genus within theParamyxovirinaesubfamily calledHenipavirus. These viruses are most closely related to members of the genusMorbillivirusand infect cells through a pH-independent membrane fusion event mediated by the actions of their attachment (G) and fusion (F) glycoproteins. Understanding their cell biological features and exploring the functional characteristics of the NiV and HeV glycoproteins will help define important properties of these emerging viruses and may provide new insights into paramyxovirus membrane fusion mechanisms. Using a recombinant vaccinia virus system and a quantitative assay for fusion, we demonstrate NiV glycoprotein function and the same pattern of cellular tropism recently reported for HeV-mediated fusion, suggesting that NiV likely uses the same cellular receptor for infection. Fusion specificity was verified by inhibition with a specific antiserum or peptides derived from the α-helical heptads of NiV or HeV F. Like that of HeV, NiV-mediated fusion also requires both F and G. Finally, interactions between the glycoproteins of the paramyxoviruses have not been well defined, but here we show that the NiV and HeV glycoproteins are capable of highly efficient heterotypic functional activity with each other. However, no heterotypic activity was observed with envelope glycoproteins of the morbillivirusesMeasles virusandCanine distemper virus.
Identification of the Orthopoxvirus
p4c
Gene, Which Encodes a Structural Protein That Directs Intracellular Mature Virus Particles into A-Type Inclusions
Authors: McKelvey Terry A. , Andrews Stanley C. , Miller Sara E. , Ray Caroline A. , Pickup David J.
Published: October 2002

The orthopoxvirus gene
p4c
has been identified in the genome of the vaccinia virus strain Western Reserve. This gene encodes the 58-kDa structural protein P4c present on the surfaces of the intracellular mature virus (IMV) particles. The gene is disrupted in the genome of cowpox virus Brighton Red (BR), demonstrating that although the P4c protein may be advantageous for virus replication in vivo, it is not essential for virus replication in vitro. Complementation and recombination analyses with the
p4c
gene have shown that the P4c protein is required to direct the IMV into the A-type inclusions (ATIs) produced by cowpox virus BR. The
p4c
gene is highly conserved among most members of the orthopoxvirus genus, including viruses that produce ATIs, such as cowpox, ectromelia, and raccoonpox viruses, as well as those such as variola, monkeypox, vaccinia, and camelpox viruses, which do not. The conservation of the
p4c
gene among the orthopoxviruses, irrespective of their capacities to produce ATIs, suggests that the P4c protein provides functions in addition to that of directing IMV into ATIs. These findings, and the presence of the P4c protein in IMV but not extracellular enveloped virus (D. Ulaeto, D. Grosenbach, and D. E. Hruby, J. Virol. 70:3372-3377, 1996), suggest a model in which the P4c protein may play a role in the retrograde movement of IMV particles, thereby contributing to the retention of IMV particles within the cytoplasm and within ATIs when they are present. In this way, the P4c protein may affect both viral morphogenesis and processes of virus dissemination.
Tsg101, an Inactive Homologue of Ubiquitin Ligase E2, Interacts Specifically with Human Immunodeficiency Virus Type 2 Gag Polyprotein and Results in Increased Levels of Ubiquitinated Gag
Authors: Myers Erin L. , Allen Jane F.
Published: October 2002

The final stages of budding and release of a retroviral particle from the cell require the late (L) domain of Gag. Recently, ubiquitin and ubiquitin ligases have been implicated in the late stages of retroviral budding. In a yeast two-hybrid screen of a T-cell cDNA library to identify cellular proteins that interact with human immunodeficiency virus type 2 (HIV-2) Gag polyprotein, we identified Tsg101, an inactive homologue of ubiquitin ligase E2. Tsg101 and HIV-2 Gag interact specifically in vitro and in vivo. The interaction requires the L domain PTAPP motif in the p6 domain of HIV-2 Gag and the N-terminal Ubc-conjugation homology domain of Tsg101. Tsg101 is incorporated into HIV-2 virions. Expression of the N-terminal Ubc-conjugation homology domain of Tsg101 inhibits the release of HIV-2 virus particles. Overexpression of Tsg101 results in an increase in the level of ubiquitination of HIV-2 Gag. Our results provide evidence for recruitment of the ubiquitination machinery of the cell during late stages of the viral life cycle, mediated by the viral Gag protein.
Proline Residues within Spacer Peptide p1 Are Important for Human Immunodeficiency Virus Type 1 Infectivity, Protein Processing, and Genomic RNA Dimer Stability
Authors: Hill Melissa K. , Shehu-Xhilaga Miranda , Crowe Suzanne M. , Mak Johnson
Published: October 2002

The full-length human immunodeficiency virus type 1 (HIV-1) mRNA encodes two precursor polyproteins, Gag and GagProPol. An infrequent ribosomal frameshifting event allows these proteins to be synthesized from the same mRNA in a predetermined ratio of 20 Gag proteins for each GagProPol. The RNA frameshift signal consists of a slippery sequence and a hairpin stem-loop whose thermodynamic stability has been shown in in vitro translation systems to be critical to frameshifting efficiency. In this study we examined the frameshift region of HIV-1, investigating the effects of altering stem-loop stability in the context of the complete viral genome and assessing the role of the Gag spacer peptide p1 and the GagProPol transframe (TF) protein that are encoded in this region. By creating a series of frameshift region mutants that systematically altered the stability of the frameshift stem-loop and the protein sequences of the p1 spacer peptide and TF protein, we have demonstrated the importance of stem-loop thermodynamic stability in frameshifting efficiency and viral infectivity. Multiple changes to the amino acid sequence of p1 resulted in altered protein processing, reduced genomic RNA dimer stability, and abolished viral infectivity. The role of the two highly conserved proline residues in p1 (position 7 and 13) was also investigated. Replacement of the two proline residues by leucines resulted in mutants with altered protein processing and reduced genomic RNA dimer stability that were also noninfectious. The unique ability of proline to confer conformational constraints on a peptide suggests that the correct folding of p1 may be important for viral function.
Human Immunodeficiency Virus Type 1 Recombination: Rate, Fidelity, and Putative Hot Spots
Authors: Zhuang Jianling , Jetzt Amanda E. , Sun Guoli , Yu Hong , Klarmann George , Ron Yacov , Preston Bradley D. , Dougherty Joseph P.
Published: October 2002

Previously, we reported that human immunodeficiency virus type 1 (HIV-1) recombines approximately two to three times per genome per replication cycle, an extremely high rate of recombination given the relatively small genome size of HIV-1. However, a recombination hot spot involving sequence of nonretroviral origin was identified in the vector system utilized, raising the possibility that this hot spot skewed the rate of recombination, and the rate of recombination observed was an overestimation. To address this issue, an HIV-1-derived vector system was used to examine the rate of recombination between autologous HIV-1 sequences after restricting replication to a single cycle in the absence of this hot spot. Viral DNA and RNA were analyzed by a combination of the heteroduplex tracking assay, restriction enzyme analysis, DNA sequencing, and reverse transcription-PCR. The results indicate that HIV-1 undergoes recombination at a minimum rate of 2.8 crossovers per genome per cycle. Again, this is a very high rate given the small size of the HIV-1 genome. The results also suggested that there might be local hot spots of recombination at different locations throughout the genome since 13 of the 33 strand transfers identified by DNA sequencing shared the same site of recombination with one or two other clones. Furthermore, identification of crossover segments also allowed examination of mutations at the point of recombination, since it has been predicted from some studies of cell-free systems that mutations may occur with a frequency of 30 to 50% at crossover junctions. However, DNA sequence analysis of crossover junctions indicated that homologous recombination during viral replication was not particularly mutagenic, indicating that there are other factors or conditions not yet reproduced in cell-free systems which contribute to fidelity during retroviral recombination.
Requirement of BAX for Efficient Adenovirus-Induced Apoptosis
Authors: Lomonosova Elena , Subramanian T. , Chinnadurai G.
Published: October 2002

Infection of human epithelial cells with adenoviruses induces an apoptosis paradigm that is efficiently suppressed by the expression of viral E1B-19K protein, which is a functional homolog of the cellular antiapoptosis protein BCL-2. The mechanisms of adenovirus (Ad)-induced apoptosis appear to involve the cellular BCL-2 family proapoptotic proteins. Recent genetic studies with fibroblasts derived from mutant mouse embryos indicate that a class of the BCL-2 family proapoptotic proteins (designated BH-123 or multidomain proteins) such as BAX and BAK constitutes an essential component of the core apoptosis machinery in animal cells. We have examined the role of BAX in Ad-induced apoptosis in human epithelial cells using two colon cancer cell lines, HCT116Bax (Bax
+/−
) and HCT116BaxKO (Bax
−/−
) (L. Zhang, J. Yu, B. H. Park, K. W. Kinzler, and B. Vogelstein, Science 290:989-992, 2000). Infection of Bax
+/−
cells with an Ad type 2 mutant (
dl
250) defective in expression of the E1B-19K protein resulted in enhanced cytopathic effect, large plaques on cell monolayers, fragmentation of cellular DNA, and enhanced cell death. These mutant phenotypes were not efficiently expressed in Bax
−/−
cells, suggesting that BAX is essential for Ad-induced apoptosis. Infection of Bax
+/−
cells with
dl
250 induced increased levels of an N-terminally processed form of BAX. Cells infected with the 19K mutant also contained enhanced levels of truncated BAX in membrane-inserted form. Our results suggest that at least a part of the mechanism utilized by E1B-19K to suppress apoptosis during Ad infection may involve modulation of the activities of BAX.
Human Papillomavirus Type 31b Infection of Human Keratinocytes and the Onset of Early Transcription
Authors: Ozbun Michelle A.
Published: October 2002

Human papillomaviruses (HPVs) cause a number of human tumors and malignancies, including cervical cancers. Epithelial differentiation is required for the complete HPV life cycle and can be achieved using the organotypic (raft) culture system. The CIN-612 9E cell line maintains episomal copies of HPV type 31b (HPV31b), an HPV type associated with cervical cancers. When grown in the raft system, CIN-612 9E cells form a differentiated epithelium such that infectious virions can be synthesized. Many aspects of the later stages of the HPV31b life cycle have been investigated in CIN-612 9E raft tissues. We used a biologically contained homogenization system for efficient virion extraction from raft epithelial tissues. Purified HPV31b virions were used to infect low-passage-number human foreskin keratinocytes and a variety of epithelial cell lines. Newly synthesized, spliced HPV31b transcripts were detected by reverse transcription and PCR (RT-PCR) following HPV31b infection. HPV31b infection was most efficient and reproducible in HaCaT cells. The onset of viral transcription following infection was also investigated using RT-PCR techniques. Spliced E1∗I,E2 RNAs were present as early as 4 h postinfection (p.i.), whereas the other major viral transcripts were detected by 8 to 10 h p.i. Furthermore, we characterized the structures and temporal expression of seven novel spliced early transcripts expressed following infection.
Porcine Endogenous Retrovirus Infects but Does Not Replicate in Nonhuman Primate Primary Cells and Cell Lines
Authors: Ritzhaupt Armin , van der Laan Luc J. W. , Salomon Daniel R. , Wilson Carolyn A.
Published: October 2002

Porcine endogenous retroviruses (PERV) can infect human cell lines in vitro; hence, there is a presumed risk of viral exposure to a recipient when pig cells are transplanted into humans (xenotransplantation). Nonhuman primates (NHP) are considered a potential permissive animal model to study the risk of in vivo infection of PERV after xenotransplantation. We set out to determine whether PERV can infect and replicate in NHP primary cells or established cell lines from African green monkey, rhesus macaque, and baboon. We confirm that the NHP cell lines under investigation were infected with PERV as measured by detection of viral DNA and RNA by PCR and reverse transcription (RT)-PCR, respectively, indicating that a functional receptor must be present on the cell surface. However, the load of detectable viral DNA in infected NHP cells declined over time, and the cells never had detectable reverse transcriptase activity. Utilizing quantitative real-time TaqMan PCR we found detectable levels of unintegrated DNA intermediates, but the levels were approximately 100-fold lower compared to HEK 293 cells infected with PERV. Virions released from infected NHP cells could productively infect naïve human cell lines, HEK 293 and HeLa, as shown by RT-PCR and RT assay. However, naïve NHP cells remained negative in RT-PCR and RT assay after exposure to virions from infected NHP cells. Together our data demonstrate that NHP cells are not permissive to productive replication by PERV, presumably due to inefficient cell entry and replication. In light of these observations, the appropriateness of NHP as suitable animal models to study PERV infection in vivo needs to be reevaluated.
Genetic Analysis of High-Risk E6 in Episomal Maintenance of Human Papillomavirus Genomes in Primary Human Keratinocytes
Authors: Park Regina B. , Androphy Elliot J.
Published: October 2002

Papillomaviruses possess small DNA genomes that encode five early (E) proteins. Transient DNA replication requires activities of the E1 and E2 proteins and a DNA segment containing their binding sites. The E6 and E7 proteins of cancer-associated human papillomavirus (HPV) transform cells in culture. Recent reports have shown that E6 and E7 are necessary for episomal maintenance of HPV in primary keratinocytes. The functions of E6 necessary for viral replication have not been determined, and to address this question we used a recently developed transfection system based on HPV31. To utilize a series of HPV16 E6 mutations, HPV31 E6 was replaced by its HPV16 counterpart. This chimeric genome was competent for both transient and stable replication in keratinocytes. Four HPV16 E6 mutations that do not stimulate p53 degradation were unable to support stable viral replication, suggesting this activity may be necessary for episomal maintenance. E7 has also been shown to be essential for episomal maintenance of the HPV31 genome. A point mutation in the Rb binding motif of HPV E7 has been reported to render HPV31 unable to stably replicate. Interestingly, HPV31 genomes harboring two of the three p53 degradation-defective E6 mutations combined with this E7 mutation were maintained as replicating episomes. These findings imply that the balance between E6 and E7 functions in infected cells is critical for episomal maintenance of high-risk HPV genomes. This model will be useful to dissect the activities of E6 and E7 necessary for viral DNA replication.