bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for Autoregulation of Cystathionine γ-Synthase mRNA Stability in
Arabidopsis
Authors: Chiba Yukako , Ishikawa Mari , Kijima Fumiko , Tyson R. Huw , Kim Jungsup , Yamamoto Ayako , Nambara Eiji , Leustek Thomas , Wallsgrove Roger M. , Naito Satoshi
Published: July 2002

Control of messenger RNA (mRNA) stability serves as an important mechanism for regulating gene expression. Analysis of
Arabidopsis
mutants that overaccumulate soluble methionine (Met) revealed that the gene for cystathionine γ-synthase (CGS), the key enzyme in Met biosynthesis, is regulated at the level of mRNA stability. Transfection experiments with wild-type and mutant forms of the CGS gene suggest that an amino acid sequence encoded by the first exon of CGS acts in cis to destabilize its own mRNA in a process that is activated by Met or one of its metabolites.
Molecular Architecture of the Rotary Motor in ATP Synthase
Authors: Stock Daniela , Leslie Andrew G. W. , Walker John E.
Published: July 2002

Adenosine triphosphate (ATP) synthase contains a rotary motor involved in biological energy conversion. Its membrane-embedded F
0
sector has a rotation generator fueled by the proton-motive force, which provides the energy required for the synthesis of ATP by the F
1
domain. An electron density map obtained from crystals of a subcomplex of yeast mitochondrial ATP synthase shows a ring of 10 c subunits. Each c subunit forms an α-helical hairpin. The interhelical loops of six to seven of the c subunits are in close contact with the γ and δ subunits of the central stalk. The extensive contact between the c ring and the stalk suggests that they may rotate as an ensemble during catalysis.
Core Rotational Dynamics and Geological Events
Authors: Greff-Lefftz Marianne , Legros Hilaire
Published: July 2002

A study of Earth's fluid core oscillations induced by lunar-solar tidal forces, together with tidal secular deceleration of Earth's axial rotation, shows that the rotational eigenfrequency of the fluid core and some solar tidal waves were in resonance around 3.0 × 10
9
, 1.8 × 10
9
, and 3 × 10
8
years ago. The associated viscomagnetic frictional power at the core boundaries may be converted into heat and would destabilize the D" thermal layer, leading to the generation of deep-mantle plumes, and would also increase the temperature at the fluid core boundaries, perturbing the core dynamo process. Such phenomena could account for large-scale episodes of continental crust formation, the generation of flood basalts, and abrupt changes in geomagnetic reversal frequency.
Satellite Evidence for an Arctic Sea Ice Cover in Transformation
Authors: Johannessen Ola M. , Shalina Elena V. , Miles Martin W.
Published: July 2002

Recent research using microwave satellite remote sensing data has established that there has been a reduction of about 3 percent per decade in the areal extent of the Arctic sea ice cover since 1978, although it is unknown whether the nature of the perennial ice pack has changed. These data were used to quantify changes in the ice cover's composition, revealing a substantial reduction of about 14 percent in the area of multiyear ice in winter during the period from 1978 to 1998. There also appears to be a strong correlation between the area of multiyear ice and the spatially averaged thickness of the perennial ice pack, which suggests that the satellite-derived areal decreases represent substantial rather than only peripheral changes. If this apparent transformation continues, it may lead to a markedly different ice regime in the Arctic, altering heat and mass exchanges as well as ocean stratification.
Use of the Cell Wall Precursor Lipid II by a Pore-Forming Peptide Antibiotic
Authors: Breukink E. , Wiedemann I. , Kraaij C. van , Kuipers O. P. , Sahl H.-G. , de Kruijff B.
Published: July 2002

Resistance to antibiotics is increasing in some groups of clinically important pathogens. For instance, high vancomycin resistance has emerged in enterococci. Promising alternative antibiotics are the peptide antibiotics, abundant in host defense systems, which kill their targets by permeabilizing the plasma membrane. These peptides generally do not act via specific receptors and are active in the micromolar range. Here it is shown that vancomycin and the antibacterial peptide nisin Z use the same target: the membrane-anchored cell wall precursor Lipid II. Nisin combines high affinity for Lipid II with its pore-forming ability, thus causing the peptide to be highly active (in the nanomolar range).
Reduced MAP Kinase Phosphatase-1 Degradation After p42/p44
MAPK
-Dependent Phosphorylation
Authors: Brondello Jean-Marc , Pouysségur Jacques , McKenzie Fergus R.
Published: July 2002

The mitogen-activated protein (MAP) kinase cascade is inactivated at the level of MAP kinase by members of the MAP kinase phosphatase (MKP) family, including MKP-1. MKP-1 was a labile protein in CCL39 hamster fibroblasts; its degradation was attenuated by inhibitors of the ubiquitin-directed proteasome complex. MKP-1 was a target in vivo and in vitro for p42
MAPK
or p44
MAPK
, which phosphorylates MKP-1 on two carboxyl-terminal serine residues, Serine 359 and Serine 364. This phosphorylation did not modify MKP-1's intrinsic ability to dephosphorylate p44
MAPK
but led to stabilization of the protein. These results illustrate the importance of regulated protein degradation in the control of mitogenic signaling.
Evidence for Crystalline Water and Ammonia Ices on Pluto's Satellite Charon
Authors: Brown Michael E. , Calvin Wendy M.
Published: July 2002

Observations have resolved the satellite Charon from its parent planet Pluto, giving separate spectra of the two objects from 1.0 to 2.5 micrometers. The spectrum of Charon is found to be different from that of Pluto, with water ice in crystalline form covering most of the surface of the satellite. In addition, an absorption feature in Charon's spectrum suggests the presence of ammonia ices. Ammonia ice–water ice mixtures have been proposed as the cause of flowlike features observed on the surfaces of many icy satellites. The existence of such ices on Charon may indicate geological activity in the satellite's past.
Rutile-Bearing Refractory Eclogites: Missing Link Between Continents and Depleted Mantle
Authors: Rudnick Roberta L. , Barth Matthias , Horn Ingo , McDonough William F.
Published: July 2002

A mass imbalance exists in Earth for Nb, Ta, and possibly Ti: continental crust and depleted mantle both have subchondritic Nb/Ta, Nb/La, and Ti/Zr, which requires the existence of an additional reservoir with superchondritic ratios, such as refractory eclogite produced by slab melting. Trace element compositions of minerals in xenolithic eclogites derived from cratonic lithospheric mantle show that rutile dominates the budget of Nb and Ta in the eclogites and imparts a superchondritic Nb/Ta, Nb/La, and Ti/Zr to the whole rocks. About 1 to 6 percent by weight of eclogite is required to solve the mass imbalance in the silicate Earth, and this reservoir must have an Nb concentration ≥ 2 parts per million, Nb/La ≥ 1.2, and Nb/Ta between 19 and 37—values that overlap those of the xenolithic eclogites. As the mass of eclogite in the continental lithosphere is significantly lower than this, much of this material may reside in the lower mantle, perhaps as deep as the core-mantle boundary.
Regulation of Area Identity in the Mammalian Neocortex by
Emx2
and
Pax6
Authors: Bishop Kathie M. , Goudreau Guy , O'Leary Dennis D. M.
Published: July 2002

The contribution of extrinsic and genetic mechanisms in determining areas of the mammalian neocortex has been a contested issue. This study analyzes the roles of the regulatory genes
Emx2
and
Pax6
, which are expressed in opposing gradients in the neocortical ventricular zone, in specifying areas. Changes in the patterning of molecular markers and area-specific connections between the cortex and thalamus suggest that arealization of the neocortex is disproportionately altered in
Emx2
and
Pax6
mutant mice in opposing manners predicted from their countergradients of expression: rostral areas expand and caudal areas contract in
Emx2
mutants, whereas the opposite effect is seen in
Pax6
mutants. These findings suggest that
Emx2
and
Pax6
cooperate to regulate arealization of the neocortex and to confer area identity to cortical cells.
Orbital Physics in Transition-Metal Oxides
Authors: Tokura Y. , Nagaosa N.
Published: July 2002

An electron in a solid, that is, bound to or nearly localized on the specific atomic site, has three attributes: charge, spin, and orbital. The orbital represents the shape of the electron cloud in solid. In transition-metal oxides with anisotropic-shaped d-orbital electrons, the Coulomb interaction between the electrons (strong electron correlation effect) is of importance for understanding their metal-insulator transitions and properties such as high-temperature superconductivity and colossal magnetoresistance. The orbital degree of freedom occasionally plays an important role in these phenomena, and its correlation and/or order-disorder transition causes a variety of phenomena through strong coupling with charge, spin, and lattice dynamics. An overview is given here on this “orbital physics,” which will be a key concept for the science and technology of correlated electrons.
Template Boundary in a Yeast Telomerase Specified by RNA Structure
Authors: Tzfati Yehuda , Fulton Tracy B. , Roy Jagoree , Blackburn Elizabeth H.
Published: July 2002

The telomerase ribonucleoprotein has a phylogenetically divergent RNA subunit, which contains a short template for telomeric DNA synthesis. To understand how telomerase RNA participates in mechanistic aspects of telomere synthesis, we studied a conserved secondary structure adjacent to the template. Disruption of this structure caused DNA synthesis to proceed beyond the normal template boundary, resulting in altered telomere sequences, telomere shortening, and cellular growth defects. Compensatory mutations restored normal telomerase function. Thus, the RNA structure, rather than its sequence, specifies the template boundary. This study reveals a specific function for an RNA structure in the enzymatic action of telomerase.
Light-Driven Motion of Liquids on a Photoresponsive Surface
Authors: Ichimura Kunihiro , Oh Sang-Keun , Nakagawa Masaru
Published: July 2002

The macroscopic motion of liquids on a flat solid surface was manipulated reversibly by photoirradiation of a photoisomerizable monolayer covering the surface. When a liquid droplet several millimeters in diameter was placed on a substrate surface modified with a calix[4]resorcinarene derivative having photochromic azobenzene units, asymmetrical photoirradiation caused a gradient in surface free energy due to the photoisomerization of surface azobenzenes, leading to the directional motion of the droplet. The direction and velocity of the motion were tunable by varying the direction and steepness of the gradient in light intensity. The light-driven motion of a fluid substance in a surface-modified glass tube suggests potential applicability to microscale chemical process systems.
Essential Role for Cholesterol in Entry of Mycobacteria into Macrophages
Authors: Gatfield John , Pieters Jean
Published: July 2002

Mycobacteria are intracellular pathogens that can invade and survive within host macrophages, thereby creating a major health problem worldwide. The molecular mechanisms involved in mycobacterial entry are still poorly characterized. Here we report that cholesterol is essential for uptake of mycobacteria by macrophages. Cholesterol accumulated at the site of mycobacterial entry, and depleting plasma membrane cholesterol specifically inhibited mycobacterial uptake. Cholesterol also mediated the phagosomal association of TACO, a coat protein that prevents degradation of mycobacteria in lysosomes. Thus, by entering host cells at cholesterol-rich domains of the plasma membrane, mycobacteria may ensure their subsequent intracellular survival in TACO-coated phagosomes.
Mantle Convection and Plate Tectonics: Toward an Integrated Physical and Chemical Theory
Authors: Tackley Paul J.
Published: July 2002

Plate tectonics and convection of the solid, rocky mantle are responsible for transporting heat out of Earth. However, the physics of plate tectonics is poorly understood; other planets do not exhibit it. Recent seismic evidence for convection and mixing throughout the mantle seems at odds with the chemical composition of erupted magmas requiring the presence of several chemically distinct reservoirs within the mantle. There has been rapid progress on these two problems, with the emergence of the first self-consistent models of plate tectonics and mantle convection, along with new geochemical models that may be consistent with seismic and dynamical constraints on mantle structure.
Earth's Core and the Geodynamo
Authors: Buffett Bruce A.
Published: July 2002

Earth's magnetic field is generated by fluid motion in the liquid iron core. Details of how this occurs are now emerging from numerical simulations that achieve a self-sustaining magnetic field. Early results predict a dominant dipole field outside the core, and some models even reproduce magnetic reversals. The simulations also show how different patterns of flow can produce similar external fields. Efforts to distinguish between the various possibilities appeal to observations of the time-dependent behavior of the field. Important constraints will come from geological records of the magnetic field in the past.
Role of CD47 as a Marker of Self on Red Blood Cells
Authors: Oldenborg Per-Arne , Zheleznyak Alex , Fang Yi-Fu , Lagenaur Carl F. , Gresham Hattie D. , Lindberg Frederik P.
Published: July 2002

The immune system recognizes invaders as foreign because they express determinants that are absent on host cells or because they lack “markers of self” that are normally present. Here we show that CD47 (integrin-associated protein) functions as a marker of self on murine red blood cells. Red blood cells that lacked CD47 were rapidly cleared from the bloodstream by splenic red pulp macrophages. CD47 on normal red blood cells prevented this elimination by binding to the inhibitory receptor signal regulatory protein alpha (SIRPα). Thus, macrophages may use a number of nonspecific activating receptors and rely on the presence or absence of CD47 to distinguish self from foreign. CD47-SIRPα may represent a potential pathway for the control of hemolytic anemia.
Signature of Superfluid Density in the Single-Particle Excitation Spectrum of Bi
2
Sr
2
CaCu
2
O
8+δ
Authors: Feng D. L. , Lu D. H. , Shen K. M. , Kim C. , Eisaki H. , Damascelli A. , Yoshizaki R. , Shimoyama J.-i. , Kishio K. , Gu G. D. , Oh S. , Andrus A. , O'Donnell J. , Eckstein J. N. , Shen Z.-X.
Published: July 2002

We report that the doping and temperature dependence of photoemission spectra near the Brillouin zone boundary of Bi
2
Sr
2
CaCu
2
O
8+δ
exhibit unexpected sensitivity to the superfluid density. In the superconducting state, the photoemission peak intensity as a function of doping scales with the superfluid density and the condensation energy. As a function of temperature, the peak intensity shows an abrupt behavior near the superconducting phase transition temperature where phase coherence sets in, rather than near the temperature where the gap opens. This anomalous manifestation of collective effects in single-particle spectroscopy raises important questions concerning the mechanism of high-temperature superconductivity.
Inhibition of Adipogenesis by Wnt Signaling
Authors: Ross Sarah E. , Hemati Nahid , Longo Kenneth A. , Bennett Christina N. , Lucas Peter C. , Erickson Robin L. , MacDougald Ormond A.
Published: July 2002

Wnts are secreted signaling proteins that regulate developmental processes. Here we show that Wnt signaling, likely mediated by Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator- activated receptor γ (PPARγ). When Wnt signaling in preadipocytes is prevented by overexpression of Axin or dominant-negative TCF4, these cells differentiate into adipocytes. Disruption of Wnt signaling also causes transdifferentiation of myoblasts into adipocytes in vitro, highlighting the importance of this pathway not only in adipocyte differentiation but also in mesodermal cell fate determination.
A Quantum State-Resolved Insertion Reaction: O(
1
D) + H
2
(
J
= 0) → OH(
2
∏,
v
,
N
) + H(
2
S)
Authors: Liu Xianghong , Lin Jim J. , Harich Steven , Schatz George C. , Yang Xueming
Published: July 2002

The O(
1
D) + H
2
→ OH + H reaction, which proceeds mainly as an insertion reaction at a collisional energy of 1.3 kilocalories per mole, has been investigated with the high-resolution H atom Rydberg “tagging” time-of-flight technique and the quasiclassical trajectory (QCT) method. Quantum state–resolved differential cross sections were measured for this prototype reaction. Different rotationally-vibrationally excited OH products have markedly different angular distributions, whereas the total reaction products are roughly forward and backward symmetric. Theoretical results obtained from QCT calculations indicate that this reaction is dominated by the insertion mechanism, with a small contribution from the collinear abstraction mechanism through quantum tunneling.
Respiration and Parturition Affected by Conditional Overexpression of the Ca
2+
-Activated K
+
Channel Subunit, SK3
Authors: Bond Chris T. , Sprengel Rolf , Bissonnette John M. , Kaufmann Walter A. , Pribnow David , Neelands Torben , Storck Thorsten , Baetscher Manfred , Jerecic Jasna , Maylie James , Knaus Hans-Günther , Seeburg Peter H. , Adelman John P.
Published: July 2002

In excitable cells, small-conductance Ca
2+
-activated potassium channels (SK channels) are responsible for the slow after-hyperpolarization that often follows an action potential. Three SK channel subunits have been molecularly characterized. The SK3 gene was targeted by homologous recombination for the insertion of a gene switch that permitted experimental regulation of SK3 expression while retaining normal SK3 promoter function. An absence of SK3 did not present overt phenotypic consequences. However, SK3 overexpression induced abnormal respiratory responses to hypoxia and compromised parturition. Both conditions were corrected by silencing the gene. The results implicate SK3 channels as potential therapeutic targets for disorders such as sleep apnea or sudden infant death syndrome and for regulating uterine contractions during labor.
Interoperability of Biodiversity Databases: Biodiversity Information on Every Desktop
Authors: Edwards James L. , Lane Meredith A. , Nielsen Ebbe S.
Published: July 2002

Data about biodiversity are either scattered in many databases or reside on paper or other media not amenable to interactive searching. The Global Biodiversity Information Facility (GBIF) is a framework for facilitating the digitization of biodiversity data and for making interoperable an as-yet-unknown number of biodiversity databases that are distributed around the globe. In concert with other existing efforts, GBIF will catalyze the completion of a Catalog of the Names of Known Organisms and will develop search engines to mine the vast quantities of biodiversity data. It will be an outstanding tool for scientists, natural resource managers, and policy-makers.
Function of GATA Transcription Factors in Preadipocyte-Adipocyte Transition
Authors: Tong Qiang , Dalgin Gökhan , Xu Haiyan , Ting Chao-Nan , Leiden Jeffrey M. , Hotamisligil Gökhan S.
Published: July 2002

Genes that control the early stages of adipogenesis remain largely unknown. Here, we show that murine GATA-2 and GATA-3 are specifically expressed in white adipocyte precursors and that their down-regulation sets the stage for terminal differentiation. Constitutive GATA-2 and GATA-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. This effect is mediated, at least in part, through the direct suppression of peroxisome proliferator–activated receptor γ. GATA-3–deficient embryonic stem cells exhibit an enhanced capacity to differentiate into adipocytes, and defective GATA-2 and GATA-3 expression is associated with obesity. Thus, GATA-2 and GATA-3 regulate adipocyte differentiation through molecular control of the preadipocyte-adipocyte transition.
Genomic Analysis of Gene Expression in
C. elegans
Authors: Hill A. A. , Hunter C. P. , Tsung B. T. , Tucker-Kellogg G. , Brown †E. L.
Published: July 2002

Until now, genome-wide transcriptional profiling has been limited to single-cell organisms. The nematode
Caenorhabditis elegans
is a well-characterized metazoan in which the expression of all genes can be monitored by oligonucleotide arrays. We used such arrays to quantitate the expression of
C. elegans
genes throughout the development of this organism. The results provide an estimate of the number of expressed genes in the nematode, reveal relations between gene function and gene expression that can guide analysis of uncharacterized worm genes, and demonstrate a shift in expression from evolutionarily conserved genes to worm-specific genes over the course of development.
Autophagy as a Regulated Pathway of Cellular Degradation
Authors: Klionsky Daniel J. , Emr Scott D.
Published: July 2002

Macroautophagy is a dynamic process involving the rearrangement of subcellular membranes to sequester cytoplasm and organelles for delivery to the lysosome or vacuole where the sequestered cargo is degraded and recycled. This process takes place in all eukaryotic cells. It is highly regulated through the action of various kinases, phosphatases, and guanosine triphosphatases (GTPases). The core protein machinery that is necessary to drive formation and consumption of intermediates in the macroautophagy pathway includes a ubiquitin-like protein conjugation system and a protein complex that directs membrane docking and fusion at the lysosome or vacuole. Macroautophagy plays an important role in developmental processes, human disease, and cellular response to nutrient deprivation.
Susceptibility Locus for Alzheimer's Disease on Chromosome 10
Authors: Myers Amanda , Holmans Peter , Marshall Helen , Kwon Jennifer , Meyer David , Ramic Dzanan , Shears Shantia , Booth Jeremy , DeVrieze Fabienne Wavrant , Crook Richard , Hamshere Marian , Abraham Richard , Tunstall Nigel , Rice Francis , Carty Stephanie , Lillystone Sara , Kehoe Pat , Rudrasingham Varuni , Jones Lesley , Lovestone Simon , Perez-Tur Jordi , Williams Julie , Owen Michael J. , Hardy John , Goate Alison M.
Published: July 2002

The apolipoprotein E (
APOE
) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an
APOE4
allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of
APOE
genotype.
Magnetohydrodynamic Production of Relativistic Jets
Authors: Meier David L. , Koide Shinji , Uchida Yutaka
Published: July 2002

A number of astronomical systems have been discovered that generate collimated flows of plasma with velocities close to the speed of light. In all cases, the central object is probably a neutron star or black hole and is either accreting material from other stars or is in the initial violent stages of formation. Supercomputer simulations of the production of relativistic jets have been based on a magnetohydrodynamic model, in which differential rotation in the system creates a magnetic coil that simultaneously expels and pinches some of the infalling material. The model may explain the basic features of observed jets, including their speed and amount of collimation, and some of the details in the behavior and statistics of different jet-producing sources.
First Solvation Shell of the Cu(II) Aqua Ion: Evidence for Fivefold Coordination
Authors: Pasquarello Alfredo , Petri Ingrid , Salmon Philip S. , Parisel Olivier , Car Roberto , Tóth Éva , Powell D. Hugh , Fischer Henry E. , Helm Lothar , Merbach André E.
Published: July 2002

We determined the structure of the hydrated Cu(II) complex by both neutron diffraction and first-principles molecular dynamics. In contrast with the generally accepted picture, which assumes an octahedrally solvated Cu(II) ion, our experimental and theoretical results favor fivefold coordination. The simulation reveals that the solvated complex undergoes frequent transformations between square pyramidal and trigonal bipyramidal configurations. We argue that this picture is also consistent with experimental data obtained previously by visible near-infrared absorption, x-ray absorption near-edge structure, and nuclear magnetic resonance methods. The preference of the Cu(II) ion for fivefold instead of sixfold coordination, which occurs for other cations of comparable charge and size, results from a Jahn-Teller destabilization of the octahedral complex.
Alignment of Liquid Crystals with Patterned Isotropic Surfaces
Authors: Lee Baek-woon , Clark Noel A.
Published: July 2002

The molecules of a nematic liquid crystal exposed to an isotropic surface adopt a mean tilt relative to the normal but have no in-plane alignment—that is, they are free to have any azimuthal orientation in the surface plane. Pursuing the theoretical suggestion by Meyer that, in spite of this azimuthal degeneracy, spatially inhomogeneous isotropic surfaces combine with liquid crystal elastic anisotropy to produce alignment, we show that a boundary line between two isotropic regions that differ in mean tilt does indeed align the liquid crystal. The boundaries on a patterned surface of distinct isotropic regions thus act as a system of lines that the molecular orientation locally follows. This enables the development of liquid crystal alignment surfaces based on printing or lithographic patterning.
Paleobotanical Evidence for Near Present-Day Levels of Atmospheric CO
2
During Part of the Tertiary
Authors: Royer Dana L. , Wing Scott L. , Beerling David J. , Jolley David W. , Koch Paul L. , Hickey Leo J. , Berner Robert A.
Published: July 2002

Understanding the link between the greenhouse gas carbon dioxide (CO
2
) and Earth's temperature underpins much of paleoclimatology and our predictions of future global warming. Here, we use the inverse relationship between leaf stomatal indices and the partial pressure of CO
2
in modern
Ginkgo biloba
and
Metasequoia glyptostroboides
to develop a CO
2
reconstruction based on fossil
Ginkgo
and
Metasequoia
cuticles for the middle Paleocene to early Eocene and middle Miocene. Our reconstruction indicates that CO
2
remained between 300 and 450 parts per million by volume for these intervals with the exception of a single high estimate near the Paleocene/Eocene boundary. These results suggest that factors in addition to CO
2
are required to explain these past intervals of global warmth.
Comparative Pharmacodynamic Analysis of Q-T Interval Prolongation Induced by the Macrolides Clarithromycin, Roxithromycin, and Azithromycin in Rats
Authors: Ohtani Hisakazu , Taninaka Chieko , Hanada Erika , Kotaki Hajime , Sato Hitoshi , Sawada Yasufumi , Iga Tatsuji
Published: July 2002

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms · ml/μg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.
Distribution and Antimicrobial Activity of Fosfomycin in the Interstitial Fluid of Human Soft Tissues
Authors: Frossard Martin , Joukhadar Christian , Erovic Boban M. , Dittrich Peter , Mrass Paulus E. , Van Houte Michael , Burgmann Heinz , Georgopoulos Apostolos , Müller Markus
Published: July 2002

Fosfomycin is a broad-spectrum antibiotic which is established as therapy for uncomplicated lower urinary tract infections. In addition, preliminary data indicate that fosfomycin has a potential role in the treatment of soft tissue infections. However, the use of fosfomycin has not been established for this condition, and it is unclear whether the level of fosfomycin penetration into human soft tissues is high enough to eradicate relevant pathogens. To better characterize the antibiotic potential of fosfomycin, we applied a combined in vivo pharmacokinetic-in vitro pharmacodynamic model to human volunteers. For this purpose fosfomycin concentrations in vivo in the fluid of the interstitial space of human soft tissues were measured by microdialysis following intravenous infusion of 4 or 8 g of fosfomycin (
n
= 6). Subsequently, bacterial isolates with relevance for soft tissue infections were exposed to concentrations according to the in vivo pharmacokinetic profile in the interstitial space fluid obtained by microdialysis. Our experiments indicated a high degree of soft tissue penetration for fosfomycin, with ratios of the area under the concentration-time curve from 0 to 8 h for muscle (AUC

0–8
muscle

)/AUC

0–8
serum

of 0.48 ± 0.08 and 0.53 ± 0.04 and ratios of AUC

0–8
adipose tissue

/AUC

0–8
serum

of 0.74 ± 0.12 and 0.71 ± 0.11 following administration of 4 and 8 g, respectively. In corresponding in vitro simulation experiments with selected isolates of
Staphylococcus aureus
,
Enterobacter cloacae
, and
Serratia marcescens
for which MICs were 16 μg/ml, organisms were undetectable after a single dosing interval. Fosfomycin exhibits a strong ability to penetrate into the fluid of the interstitial space of soft tissues and reaches levels sufficient to substantially inhibit the growth of relevant bacteria at the target site. We therefore conclude that fosfomycin might qualify as an alternative candidate for the therapy of soft tissue infections.
Itraconazole-Amphotericin B Antagonism in
Aspergillus fumigatus
: an E-Test-Based Strategy
Authors: Kontoyiannis Dimitrios P. , Lewis Russell E. , Sagar Namita , May Gregory , Prince Randall A. , Rolston Kenneth V. I.
Published: July 2002

We examined an E-test-based strategy for testing the combination of itraconazole and amphotericin B, the latter given either sequentially or concomitantly, in isolates of
Aspergillus fumigatus
. An antagonistic interaction between the two drugs was noted, especially with the sequential administration of amphotericin B. This in vitro antagonism was reversible.
In Vitro Activities of Novel
trans
-3,5-Disubstituted Pyrrolidinylthio-1β-Methylcarbapenems with Potent Activities against Methicillin-Resistant
Staphylococcus aureus
and
Pseudomonas aeruginosa
Authors: Nagano Rie , Shibata Kaneyoshi , Adachi Yuka , Imamura Hideaki , Hashizume Terutaka , Morishima Hajime
Published: July 2002

The in vitro activities of the novel 1β-methylcarbapenems J-111,225, J-114,870, and J-114,871, which have a structurally unique side chain that consists of a
trans
-3,5-disubstituted 5-arylpyrrolidin-3-ylthio moiety at the C-2 position, were compared with those of reference antibiotics. Among isolates of both methicillin-resistant
Staphylococcus aureus
(MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS), 90% were inhibited by J-111,347 (prototype), J-111,225, J-114,870, and J-114,871 at concentrations of 2, 4, 4, and 4 μg/ml (MICs at which 90% of isolates are inhibited [MIC
90
s]), respectively, indicating that these agents were 32- to 64-fold more potent than imipenem, which has an MIC
90
of 128 μg/ml. Although these drugs were less active in vitro than vancomycin, which had MIC
90
s of 1 and 2 μg/ml for MRSA and MRCoNS, respectively, the new carbapenems displayed better killing kinetics than vancomycin. The potent anti-MRSA activity was ascribed to the excellent affinities of the new carbapenems for penicillin-binding protein 2a of MRSA. Since the new carbapenems also exhibited good activity against gram-positive and -negative bacteria including clinically important pathogens such as penicillin-resistant
Streptococcus pneumoniae
,
Haemophilus influenzae
, members of the family
Enterobacteriaceae
,
Pseudomonas aeruginosa
, and
Clostridium difficile
, as well as MRSA, the novel carbapenems are worthy of further evaluation.
vanC
Cluster of Vancomycin-Resistant
Enterococcus gallinarum
BM4174
Authors: Arias Cesar A. , Courvalin Patrice , Reynolds Peter E.
Published: July 2002

Glycopeptide-resistant enterococci of the VanC type synthesize UDP-muramyl-pentapeptide[
d
-Ser] for cell wall assembly and prevent synthesis of peptidoglycan precursors ending in
d
-Ala. The
vanC
cluster of
Enterococcus gallinarum
BM4174 consists of five genes:
vanC-1
,

vanXY
C

,
vanT
,

vanR
C

, and

vanS
C

. Three genes are sufficient for resistance:
vanC-1
encodes a ligase that synthesizes the dipeptide
d
-Ala-
d
-Ser for addition to UDP-MurNAc-tripeptide,

vanXY
C

encodes a
d
,
d
-dipeptidase–carboxypeptidase that hydrolyzes
d
-Ala-
d
-Ala and removes
d
-Ala from UDP-MurNAc-pentapeptide[
d
-Ala], and
vanT
encodes a membrane-bound serine racemase that provides
d
-Ser for the synthetic pathway. The three genes are clustered: the start codons of

vanXY
C

and
vanT
overlap the termination codons of
vanC-1
and

vanXY
C

, respectively. Two genes which encode proteins with homology to the VanS-VanR two-component regulatory system were present downstream from the resistance genes. The predicted amino acid sequence of VanR
C
exhibited 50% identity to VanR and 33% identity to VanR
B
. VanS
C
had 40% identity to VanS over a region of 308 amino acids and 24% identity to VanS
B
over a region of 285 amino acids. All residues with important functions in response regulators and histidine kinases were conserved in VanR
C
and VanS
C
, respectively. Induction experiments based on the determination of
d
,
d
-carboxypeptidase activity in cytoplasmic extracts confirmed that the genes were expressed constitutively. Using a promoter-probing vector, regions upstream from the resistance and regulatory genes were identified that have promoter activity.
Antiviral Therapy Reduces Viral Burden but Does Not Prevent Thymic Involution in Young Cats Infected with Feline Immunodeficiency Virus
Authors: Hayes Kathleen A. , Phipps Andrew J. , Francke Sabine , Mathes Lawrence E.
Published: July 2002

The thymus is a major target organ in human immunodeficiency virus type 1 (HIV-1)-infected children and feline immunodeficiency virus (FIV)-infected young cats (G. A. Dean and N. C. Pedersen, J. Virol. 72:9436–9440, 1998; J. L. Heeney, Immunol. Today 16:515–520, 1995; S. M. Schnittman et al., Proc. Natl. Acad. Sci. USA 87:7727–7731, 1990; T. A. Seemayer et al., Hum. Pathol. 15:469–474, 1984; H.-J. Shuurn et al., Am. J. Pathol. 134:1329–1338, 1989; J. C. Woo et al., J. Virol. 71:8632–8641, 1997; J. C. Woo et al., AIDS Res. Hum. Retrovir. 15:1377–1388, 1999). It is likely that the accelerated disease process in children and cats is due to infection of the thymus during the time when generation of naive T lymphocytes is needed for development of the mature immune system. Zidovudine (ZDV) monotherapy, which is used to prevent and treat perinatal HIV-1 infection (R. Sperling, Infect. Dis. Obstet. Gynecol. 6:197–203, 1998), previously had been shown to reduce viral burden in FIV-infected young cats (K. A. Hayes et al., J. Acquir. Immune Defic. Syndr. 6:127–134, 1993). The purpose of this study was to evaluate the effect of drug-induced reduction of viral burden in the thymus on virus-mediated thymic involution and peripheral blood CD4 decline using FIV-infected cats as a model for pediatric HIV-1 infection. Eight-week-old cats were randomly assigned to uninfected, saline-treated; uninfected, ZDV-treated; FIV-infected, saline-treated; and FIV-infected, ZDV-treated groups. Parameters measured included blood lymphocyte numbers, viral load in blood and thymic tissue, and thymic histopathology. While the viral burden was significantly reduced by ZDV monotherapy in peripheral blood lymphocytes, plasma, and thymus, thymic lesions were similar for the treated and untreated FIV-infected cats. Further, markedly lowering the viral burden did not increase blood CD4 lymphocyte numbers or prevent their decline. The data suggest that an inflammatory process continued in spite of reduced virus replication. These observations imply that reducing virus load and limiting thymic inflammation are separate factors that must be addressed when considering therapeutic strategies aimed at preserving thymic function.
Molecular Modeling Approach to Understanding the Mode of Action ofl-Nucleosides as Antiviral Agents
Authors: Lee Kyeong , Chu Chung K.
Published: July 2002

A series of unnaturall-nucleosides such as 3TC, FTC andl-FMAU have been found to be potent antiviral agents. The mode of action ofl-nucleosides has been found to be similar to that ofd-nucleosides as antiviral agents, despite their unnatural stereochemistry, that is, nucleotide formation by kinases followed by interaction with the reverse transcriptase (RT) of HIV or DNA polymerase. To date, the mode of action of nucleoside inhibitors at the molecular level with respect to the active conformations of the 5′-triphosphates as well as the interaction with the RT is not known. Recently, the X-ray crystal structure of the RT-DNA-dTTP catalytic complex has been reported. Computer modeling has been performed for several pairs ofd- andl-nucleoside inhibitors using the HIV-1 RT model and crystal coordinate data from a subset of the protein surrounding the deoxynucleoside triphosphate (dNTP) binding pocket region. Results from our modeling studies ofd-/l-zidovudine,d-/l-3TC,d-/l-dideoxycytosine triphosphates, dTTP and dCTP show that their binding energies correlate with the reported 50% effective concentrations. Modeling results are also discussed with respect to favorable conformations of each inhibitor at the dNTP site in the polymerization process. Additionally, the clinically important M184V mutation, which confers resistance against 3TC and FTC, was studied with our modeling system. The binding energy patterns of nucleoside inhibitors at the M184V mutation site correlate with the reported antiviral data.
Pharmacodynamics of Fluoroquinolones against
Streptococcus pneumoniae
in Patients with Community-Acquired Respiratory Tract Infections
Authors: Ambrose Paul G. , Grasela Dennis M. , Grasela Thaddeus H. , Passarell Julie , Mayer Howard B. , Pierce Phillip F.
Published: July 2002

Fluoroquinolone antibiotic agents have demonstrated efficacy in the treatment of respiratory tract infections. This analysis was designed to examine the relationship between drug exposure, as measured by the free-drug area under the concentration-time curve at 24 h (AUC
24
)/MIC ratio, and clinical and microbiological responses in patients with community-acquired respiratory tract infections involving
Streptococcus pneumoniae
. The study population included 58 adult patients (34 males, 24 females) who were enrolled in either of two phase III, randomized, multicenter, double-blind studies of levofloxacin versus gatifloxacin for the treatment of community-acquired pneumonia or acute exacerbation of chronic bronchitis. Clearance equations from previously published population pharmacokinetic models were used in conjunction with dose and adjusted for protein binding to estimate individual patient free-drug AUC
24
s. In vitro susceptibility was determined in a central laboratory by broth microdilution in accordance with NCCLS guidelines. Pharmacodynamic analyses were performed on data from all evaluable patients with documented
S. pneumoniae
infection using univariate and multivariable logistic regression; pharmacodynamic breakpoints were estimated using Classification and Regression Tree analysis. A statistically significant (
P
= 0.013) relationship between microbiological response and the free-drug AUC
24
/MIC ratio was detected. At a free-drug AUC
24
/MIC ratio of <33.7, the probability of a microbiological response was 64%, and at a free-drug AUC
24
/MIC ratio of >33.7, it was 100% (
P
< 0.01). These findings may provide a minimum target free-drug AUC
24
/MIC ratio for the treatment of infections involving
S. pneumoniae
with fluoroquinolone antibiotics and provide a paradigm for the selection of fluoroquinolones to be brought forward from drug discovery into clinical development and dose selection for clinical trials. Further, when target free-drug AUC
24
/MIC ratios are used in conjunction with stochastic modeling techniques, these findings may be used to support susceptibility breakpoints for fluoroquinolone antibiotics and
S.
pneumoniae
.
In Vitro Anti-
Helicobacter pylori
Activity of the Probiotic Strain
Bacillus subtilis
3 Is Due to Secretion of Antibiotics
Authors: Pinchuk Irina V. , Bressollier Philippe , Verneuil Bernard , Fenet Bernard , Sorokulova Irina B. , Mégraud Francis , Urdaci Maria C.
Published: July 2002

A limited number of antibiotics can be used against
Helicobacter pylori
infection, and resistance jeopardizes the success of treatment. Therefore, a search for new agents is warranted. The use of probiotics to enhance gastrointestinal health has been proposed for many years, but the scientific basis of the prophylactic and therapeutic actions of probiotics has not yet been clearly delineated. Probiotic strain
Bacillus subtilis
3, whose safety has previously been demonstrated, is known to have antagonistic properties against species of the family
Enterobacteriaceae
. In the present study, it was also found to inhibit
H. pylori
. The anti-
H. pylori
activity present in the cell-free supernatant was not related to pH or organic acid concentration. It was heat stable and protease insensitive. At least two antibiotics, detected by thin-layer chromatography (

R
f

values, 0.47 and 0.85, respectively) and confirmed by high-performance liquid chromatographic analysis, were found to be responsible for this anti-
H. pylori
activity. All
H. pylori
strains tested were sensitive to both compounds. One of these compounds was identified as amicoumacin A, an antibiotic with anti-inflammatory properties. MICs for
H. pylori
determined in solid and liquid media ranged between 1.7 and 6.8 μg/ml and 0.75 and 2.5 μg/ml, respectively. The underestimation of MICs determined in solid medium may be due to physicochemical instability of the antibiotic under these test conditions. An additive effect between amicoumacin A and the nonamicoumacin antibiotic against
H. pylori
was demonstrated.
Comparison of the Activities of Zanamivir, Oseltamivir, and RWJ-270201 against Clinical Isolates of Influenza Virus and Neuraminidase Inhibitor-Resistant Variants
Authors: Gubareva Larisa V. , Webster Robert G. , Hayden Frederick G.
Published: July 2002

RWJ-270201 is a novel cyclopentane inhibitor of influenza A and B virus neuraminidases (NAs). We compared the ability of RWJ-270201 to inhibit NA activity of clinical influenza isolates and viruses with defined resistance mutations with that of zanamivir and oseltamivir carboxylate. In NA inhibition assays with influenza A viruses, the median 50% inhibitory concentration (IC50) of RWJ-270201 (approximately 0.34 nM) was comparable to that of oseltamivir carboxylate (0.45 nM) but lower than that of zanamivir (0.95 nM). For influenza B virus isolates, the IC50of RWJ-270201 (1.36 nM) was comparable to that of zanamivir (2.7 nM) and less than that of oseltamivir carboxylate (8.5 nM). A zanamivir-resistant variant bearing a Glu119-to-Gly (Glu119→Gly) or Glu119→Ala substitution in an NA (N2) remained susceptible to RWJ-270201 and oseltamivir carboxylate. However, a zanamivir-selected variant with an Arg292→Lys substitution in an NA (N2) showed a moderate level of resistance to RWJ-270201 (IC50= 30 nM) and zanamivir (IC50= 20 nM) and a high level of resistance to oseltamivir carboxylate (IC50> 3,000 nM). The zanamivir-resistant influenza B virus variant bearing an Arg152→Lys substitution was resistant to each NA inhibitor (IC50= 100 to 750 nM). The oseltamivir-selected variant (N1) with the His274→Tyr substitution exhibited resistance to oseltamivir carboxylate (IC50= 400 nM) and to RWJ-270201 (IC50= 40 nM) but retained full susceptibility to zanamivir (IC50= 1.5 nM). Thus, drug-resistant variants with substitutions in framework residues 119 or 274 can retain susceptibility to other NA inhibitors, whereas replacement of functional residue 152 or 292 leads to variable levels of cross-resistance. We conclude that RWJ-270201 is a potent inhibitor of NAs of wild-type and some zanamivir-resistant or oseltamivir-resistant influenza A and B virus variants.
Newer Macrolides as Empiric Treatment for Acute Q Fever Infection
Authors: Gikas Achilleas , Kofteridis Diamantis P. , Manios Andreas , Pediaditis John , Tselentis Yiannis
Published: July 2002

The effectiveness of newer macrolides in acute Q fever for 113 patients was recorded. The mean times to defervescence were 2.9 days for doxycycline and 3.3, 3.9, 3.9, and 6.4 days for clarithromycin, roxithromycin, erythromycin, and β-lactams, respectively (
P
< 0.01 for macrolides versus β-lactams). We conclude that macrolides may be an adequate empirical antibiotic therapy for acute Q fever.