bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Authors: Kussie Paul H. , Gorina Svetlana , Marechal Vincent , Elenbaas Brian , Moreau Jacque , Levine Arnold J. , Pavletich Nikola P.
Published: July 2002

The MDM2 oncoprotein is a cellular inhibitor of the p53 tumor suppressor in that it can bind the transactivation domain of p53 and downregulate its ability to activate transcription. In certain cancers, MDM2 amplification is a common event and contributes to the inactivation of p53. The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-residue transactivation domain peptide of p53 revealed that MDM2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic α helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 α helix and, in particular, on a triad of p53 amino acids—Phe
19
, Trp
23
, and Leu
26
—which insert deep into the MDM2 cleft. These same p53 residues are also involved in transactivation, supporting the hypothesis that MDM2 inactivates p53 by concealing its transactivation domain. The structure also suggests that the amphipathic α helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors.
Controlled Deposition of Size-Selected Silver Nanoclusters
Authors: Bromann Karsten , Félix Christian , Brune Harald , Harbich Wolfgang , Monot René , Buttet Jean , Kern Klaus
Published: July 2002

Variable-temperature scanning tunneling microscopy was used to study the effect of kinetic cluster energy and rare-gas buffer layers on the deposition process of size-selected silver nanoclusters on a platinum(111) surface. Clusters with impact energies of ≤1 electron volt per atom could be landed nondestructively on the bare substrate, whereas at higher kinetic energies fragmentation and substrate damage were observed. Clusters with elevated impact energy could be soft-landed via an argon buffer layer on the platinum substrate, which efficiently dissipated the kinetic energy. Nondestructive cluster deposition represents a promising method to produce monodispersed nanostructures at surfaces.
Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt
Authors: Dudek Henryk , Datta Sandeep Robert , Franke Thomas F. , Birnbaum Morris J. , Yao Ryoji , Cooper Geoffrey M. , Segal Rosalind A. , Kaplan David R. , Greenberg Michael E.
Published: July 2002

A signaling pathway was delineated by which insulin-like growth factor 1 (IGF-1) promotes the survival of cerebellar neurons. IGF-1 activation of phosphoinositide 3-kinase (PI3-K) triggered the activation of two protein kinases, the serine-threonine kinase Akt and the p70 ribosomal protein S6 kinase (p70
S6K
). Experiments with pharmacological inhibitors, as well as expression of wild-type and dominant-inhibitory forms of Akt, demonstrated that Akt but not p70
S6K
mediates PI3-K-dependent survival. These findings suggest that in the developing nervous system, Akt is a critical mediator of growth factor-induced neuronal survival.
Controlling Polymer-Surface Interactions with Random Copolymer Brushes
Authors: Mansky P. , Liu Y. , Huang E. , Russell T. P. , Hawker C.
Published: July 2002

A simple technique for precisely controlling the interfacial energies and wetting behavior of polymers in contact with solid surfaces is described. End-functionalized statistical random copolymers of styrene and methylmethacrylate were synthesized, with the styrene fraction
f
varying from 0 to 1, and were end-grafted onto silicon substrates to create random copolymer brushes about 5 nanometers thick. For
f
< 0.7, polystyrene (PS) films (20 nanometers thick) rapidly dewet from the brushes when heated well above the glass transition temperature. The contact angle of the resulting polymer droplets increased monotonically with decreasing
f
. Similar behavior was observed for poly(methylmethacrylate) (PMMA) films but with an opposite dependence on
f
. The interfacial energies of the random copolymer brushes with PS and PMMA were equal when
f
was about 0.6. Thus, precise control of the relative surface affinities of PS and PMMA was possible, demonstrating a way to manipulate polymer-surface interactions.
Spatial Variability of Turbulent Mixing in the Abyssal Ocean
Authors: Polzin K. L. , Toole J. M. , Ledwell J. R. , Schmitt R. W.
Published: July 2002

Ocean microstructure data show that turbulent mixing in the deep Brazil Basin of the South Atlantic Ocean is weak at all depths above smooth abyssal plains and the South American Continental Rise. The diapycnal diffusivity there was estimated to be less than or approximately equal to 0.1 × 104

4 meters squared per second. In contrast, mixing rates are large throughout the water column above the rough Mid-Atlantic Ridge, and the diffusivity deduced for the bottom-most 150 meters exceeds 5 × 104

4

meters squared per second. Such patterns in vertical mixing imply that abyssal circulations have complex spatial structures that are linked to the underlying bathymetry.
Infrared Spectrum of a Molecular Ice Cube: The
S
4
and
D
2

d

Water Octamers in Benzene-(Water)
8
Authors: Gruenloh Christopher J. , Carney Joel R. , Arrington Caleb A. , Zwier Timothy S. , Fredericks Sharon Y. , Jordan Kenneth D.
Published: July 2002

Resonant two-photon ionization, ultraviolet hole-burning, and resonant ion-dip infrared (RIDIR) spectroscopy were used to assign and characterize the hydrogen-bonding topology of two conformers of the benzene-(water)
8
cluster. In both clusters, the eight water molecules form a hydrogen-bonded cube to which benzene is surface-attached. Comparison of the RIDIR spectra with density functional theory calculations is used to assign the two (water)
8
structures in benzene-(water)
8
as cubic octamers of
D
2

d

and
S
4
symmetry, which differ in the configuration of the hydrogen bonds within the cube. OH stretch vibrational fundamentals near 3550 wave numbers provide unique spectral signatures for these “molecular ice cubes.”
daf-2
, an Insulin Receptor-Like Gene That Regulates Longevity and Diapause in
Caenorhabditis elegans
Authors: Kimura Koutarou D. , Tissenbaum Heidi A. , Liu Yanxia , Ruvkun Gary
Published: July 2002

A
C. elegans
neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage.
daf-2
, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member. Decreases in DAF-2 signaling induce metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor. Decreased DAF-2 signaling also causes an increase in life-span. Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity.
Ecological Effects of an Insect Introduced for the Biological Control of Weeds
Authors: Louda S. M. , Kendall D. , Connor J. , Simberloff D.
Published: July 2002

Few data exist on the environmental risks of biological control. The weevil
Rhinocyllus conicus
Froeh., introduced to control exotic thistles, has exhibited an increase in host range as well as continuing geographic expansion. Between 1992 and 1996, the frequency of weevil damage to native thistles consistently increased, reaching 16 to 77 percent of flowerheads per plant. Weevils significantly reduced the seed production of native thistle flowerheads. The density of native tephritid flies was significantly lower at high weevil density. Such ecological effects need to be better addressed in future evaluation and regulation of potential biological control agents.
Computational Design of Hierarchically Structured Materials
Authors: Olson G. B.
Published: July 2002

A systems approach that integrates processing, structure, property, and performance relations has been used in the conceptual design of multilevel-structured materials. For high-performance alloy steels, numerical implementation of materials science principles provides a hierarchy of computational models defining subsystem design parameters that are integrated, through computational thermodynamics, in the comprehensive design of materials as interactive systems. Designed properties combine strength, toughness, and resistance to impurity embrittlement. The methods have also been applied to nonferrous metals, ceramics, and polymers.
Mitotic and G
2
Checkpoint Control: Regulation of 14-3-3 Protein Binding by Phosphorylation of Cdc25C on Serine-216
Authors: Peng Cheng-Yuan , Graves Paul R. , Thoma Richard S. , Wu Zhiqi , Shaw Andrey S. , Piwnica-Worms Helen
Published: July 2002

Human Cdc25C is a dual-specificity protein phosphatase that controls entry into mitosis by dephosphorylating the protein kinase Cdc2. Throughout interphase, but not in mitosis, Cdc25C was phosphorylated on serine-216 and bound to members of the highly conserved and ubiquitously expressed family of 14-3-3 proteins. A mutation preventing phosphorylation of serine-216 abrogated 14-3-3 binding. Conditional overexpression of this mutant perturbed mitotic timing and allowed cells to escape the G
2
checkpoint arrest induced by either unreplicated DNA or radiation-induced damage. Chk1, a fission yeast kinase involved in the DNA damage checkpoint response, phosphorylated Cdc25C in vitro on serine-216. These results indicate that serine-216 phosphorylation and 14-3-3 binding negatively regulate Cdc25C and identify Cdc25C as a potential target of checkpoint control in human cells.
Direct Observation of Cooling of Heme Upon Photodissociation of Carbonmonoxy Myoglobin
Authors: Mizutani Yasuhisa , Kitagawa Teizo
Published: July 2002

The formation of vibrationally excited heme upon photodissociation of carbonmonoxy myoglobin and its subsequent vibrational energy relaxation was monitored by picosecond anti-Stokes resonance Raman spectroscopy. The anti-Stokes intensity of the ν
4
band showed immediate generation of vibrationally excited hemes and biphasic decay of the excited populations. The best fit to double exponentials gave time constants of 1.9 ± 0.6 and 16 ± 9 picoseconds for vibrational population decay and 3.0 ± 1.0 and 25 ± 14 picoseconds for temperature relaxation of the photolyzed heme when a Boltzmann distribution was assumed. The decay of the ν
4
anti-Stokes intensity was accompanied by narrowing and frequency upshift of the Stokes counterpart. This direct monitoring of the cooling dynamics of the heme cofactor within the globin matrix allows the characterization of the vibrational energy flow through the protein moiety and to the water bath.
Reversible Polymers Formed from Self-Complementary Monomers Using Quadruple Hydrogen Bonding
Authors: Sijbesma Rint P. , Beijer Felix H. , Brunsveld Luc , Folmer Brigitte J. B. , Hirschberg J. H. K. Ky , Lange Ronald F. M. , Lowe Jimmy K. L. , Meijer E. W.
Published: July 2002

Units of 2-ureido-4-pyrimidone that dimerize strongly in a self-complementary array of four cooperative hydrogen bonds were used as the associating end group in reversible self-assembling polymer systems. The unidirectional design of the binding sites prevents uncontrolled multidirectional association or gelation. Linear polymers and reversible networks were formed from monomers with two and three binding sites, respectively. The thermal and environmental control over lifetime and bond strength makes many properties, such as viscosity, chain length, and composition, tunable in a way not accessible to traditional polymers. Hence, polymer networks with thermodynamically controlled architectures can be formed, for use in, for example, coatings and hot melts, where a reversible, strongly temperature-dependent rheology is highly advantageous.
Extension of Life-Span by Introduction of Telomerase into Normal Human Cells
Authors: Bodnar Andrea G. , Ouellette Michel , Frolkis Maria , Holt Shawn E. , Chiu Choy-Pik , Morin Gregg B. , Harley Calvin B. , Shay Jerry W. , Lichtsteiner Serge , Wright Woodring E.
Published: July 2002

Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomerase catalytic subunit. In contrast to telomerase-negative control clones, which exhibited telomere shortening and senescence, telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced staining for β-galactosidase, a biomarker for senescence. Notably, the telomerase-expressing clones have a normal karyotype and have already exceeded their normal life-span by at least 20 doublings, thus establishing a causal relationship between telomere shortening and in vitro cellular senescence. The ability to maintain normal human cells in a phenotypically youthful state could have important applications in research and medicine.
Induced Responses to Herbivory and Increased Plant Performance
Authors: Agrawal Anurag A.
Published: July 2002

Plant resistance to herbivores was induced in a field experiment to evaluate the consequences of induced responses for subsequent herbivory and plant fitness. Induction early in the season resulted in halving of herbivory by chewing herbivores and a reduction in the abundance of phloem-feeding aphids when compared with controls. A correlate of lifetime plant fitness, seed mass, was enhanced by over 60 percent for individuals that were induced.
Making Nonmagnetic Semiconductors Ferromagnetic
Authors: Ohno H.
Published: July 2002

REVIEW

Semiconductor devices generally take advantage of the charge of electrons, whereas magnetic materials are used for recording information involving electron spin. To make use of both charge and spin of electrons in semiconductors, a high concentration of magnetic elements can be introduced in nonmagnetic III-V semiconductors currently in use for devices. Low solubility of magnetic elements was overcome by low-temperature nonequilibrium molecular beam epitaxial growth, and ferromagnetic (Ga,Mn)As was realized. Magnetotransport measurements revealed that the magnetic transition temperature can be as high as 110 kelvin. The origin of the ferromagnetic interaction is discussed. Multilayer heterostructures including resonant tunneling diodes (RTDs) have also successfully been fabricated. The magnetic coupling between two ferromagnetic (Ga,Mn)As films separated by a nonmagnetic layer indicated the critical role of the holes in the magnetic coupling. The magnetic coupling in all semiconductor ferromagnetic/nonmagnetic layered structures, together with the possibility of spin filtering in RTDs, shows the potential of the present material system for exploring new physics and for developing new functionality toward future electronics.
Quantum Dot Bioconjugates for Ultrasensitive Nonisotopic Detection
Authors: Chan Warren C. W. , Nie Shuming
Published: July 2002

Highly luminescent semiconductor quantum dots (zinc sulfide–capped cadmium selenide) have been covalently coupled to biomolecules for use in ultrasensitive biological detection. In comparison with organic dyes such as rhodamine, this class of luminescent labels is 20 times as bright, 100 times as stable against photobleaching, and one-third as wide in spectral linewidth. These nanometer-sized conjugates are water-soluble and biocompatible. Quantum dots that were labeled with the protein transferrin underwent receptor-mediated endocytosis in cultured HeLa cells, and those dots that were labeled with immunomolecules recognized specific antibodies or antigens.
Mitochondrial Evolution
Authors: Gray Michael W. , Burger Gertraud , Lang B. Franz
Published: July 2002

The serial endosymbiosis theory is a favored model for explaining the origin of mitochondria, a defining event in the evolution of eukaryotic cells. As usually described, this theory posits that mitochondria are the direct descendants of a bacterial endosymbiont that became established at an early stage in a nucleus-containing (but amitochondriate) host cell. Gene sequence data strongly support a monophyletic origin of the mitochondrion from a eubacterial ancestor shared with a subgroup of the α-Proteobacteria. However, recent studies of unicellular eukaryotes (protists), some of them little known, have provided insights that challenge the traditional serial endosymbiosis–based view of how the eukaryotic cell and its mitochondrion came to be. These data indicate that the mitochondrion arose in a common ancestor of all extant eukaryotes and raise the possibility that this organelle originated at essentially the same time as the nuclear component of the eukaryotic cell rather than in a separate, subsequent event.
Storage and Executive Processes in the Frontal Lobes
Authors: Smith Edward E. , Jonides John
Published: July 2002

The human frontal cortex helps mediate working memory, a system that is used for temporary storage and manipulation of information and that is involved in many higher cognitive functions. Working memory includes two components: short-term storage (on the order of seconds) and executive processes that operate on the contents of storage. Recently, these two components have been investigated in functional neuroimaging studies. Studies of storage indicate that different frontal regions are activated for different kinds of information: storage for verbal materials activates Broca's area and left-hemisphere supplementary and premotor areas; storage of spatial information activates the right-hemisphere premotor cortex; and storage of object information activates other areas of the prefrontal cortex. Two of the fundamental executive processes are selective attention and task management. Both processes activate the anterior cingulate and dorsolateral prefrontal cortex.
Linear Differentiation of Cytotoxic Effectors into Memory T Lymphocytes
Authors: Opferman Joseph T. , Ober Bertram T. , Ashton-Rickardt Philip G.
Published: July 2002

A central question in immunology is the origin of long-lived T cell memory that confers protection against recurrent infection. The differentiation of naı̈ve T cell receptor transgenic CD8
+
cells into effector cytotoxic T lymphocytes (CTLs) and memory CD8
+
cells was studied. Memory CD8
+
cells that were generated after strong antigenic stimulation were the progeny of cytotoxic effectors and retained antigen-specific cytolytic activity 10 weeks after adoptive transfer to antigen-free recipient mice. Thus, potential vaccines based on CTL memory will require the differentiation of naı̈ve cells into post-effector memory T cells.
Digital Logic Gate Using Quantum-Dot Cellular Automata
Authors: Amlani Islamshah , Orlov Alexei O. , Toth Geza , Bernstein Gary H. , Lent Craig S. , Snider Gregory L.
Published: July 2002

A functioning logic gate based on quantum-dot cellular automata is presented, where digital data are encoded in the positions of only two electrons. The logic gate consists of a cell, composed of four dots connected in a ring by tunnel junctions, and two single-dot electrometers. The device is operated by applying inputs to the gates of the cell. The logic AND and OR operations are verified using the electrometer outputs. Theoretical simulations of the logic gate output characteristics are in excellent agreement with experiment.
Two-Dimensional Photonic Band-Gap Defect Mode Laser
Authors: Painter O. , Lee R. K. , Scherer A. , Yariv A. , O'Brien J. D. , Dapkus P. D. , Kim I.
Published: July 2002

A laser cavity formed from a single defect in a two-dimensional photonic crystal is demonstrated. The optical microcavity consists of a half wavelength–thick waveguide for vertical confinement and a two-dimensional photonic crystal mirror for lateral localization. A defect in the photonic crystal is introduced to trap photons inside a volume of 2.5 cubic half-wavelengths, approximately 0.03 cubic micrometers. The laser is fabricated in the indium gallium arsenic phosphide material system, and optical gain is provided by strained quantum wells designed for a peak emission wavelength of 1.55 micrometers at room temperature. Pulsed lasing action has been observed at a wavelength of 1.5 micrometers from optically pumped devices with a substrate temperature of 143 kelvin.
Integrin Signaling
Authors: Giancotti Filippo G. , Ruoslahti Erkki
Published: July 2002

Cells reside in a protein network, the extracellular matrix (ECM), which they secrete and mold into the intercellular space. The ECM exerts profound control over cells. The effects of the matrix are primarily mediated by integrins, a family of cell surface receptors that attach cells to the matrix and mediate mechanical and chemical signals from it. These signals regulate the activities of cytoplasmic kinases, growth factor receptors, and ion channels and control the organization of the intracellular actin cytoskeleton. Many integrin signals converge on cell cycle regulation, directing cells to live or die, to proliferate, or to exit the cell cycle and differentiate.
Global Optimization of Clusters, Crystals, and Biomolecules
Authors: Wales David J. , Scheraga Harold A.
Published: July 2002

Finding the optimal solution to a complex optimization problem is of great importance in many fields, ranging from protein structure prediction to the design of microprocessor circuitry. Some recent progress in finding the global minima of potential energy functions is described, focusing on applications of the simple “basin-hopping” approach to atomic and molecular clusters and more complicated hypersurface deformation techniques for crystals and biomolecules. These methods have produced promising results and should enable larger and more complex systems to be treated in the future.
Continuous Deformation Versus Faulting Through the Continental Lithosphere of New Zealand
Authors: Molnar Peter , Anderson Helen J. , Audoine Etienne , Eberhart-Phillips Donna , Gledhill Ken R. , Klosko Eryn R. , McEvilly Thomas V. , Okaya David , Savage Martha Kane , Stern Tim , Wu Francis T.
Published: July 2002

Seismic anisotropy and
P
-wave delays in New Zealand imply widespread deformation in the underlying mantle, not slip on a narrow fault zone, which is characteristic of plate boundaries in oceanic regions. Large magnitudes of shear-wave splitting and orientations of fast polarization parallel to the Alpine fault show that pervasive simple shear of the mantle lithosphere has accommodated the cumulative strike-slip plate motion. Variations in
P
-wave residuals across the Southern Alps rule out underthrusting of one slab of mantle lithosphere beneath another but permit continuous deformation of lithosphere shortened by about 100 kilometers since 6 to 7 million years ago.
Global Warming and Northern Hemisphere Sea Ice Extent
Authors: Vinnikov Konstantin Y. , Robock Alan , Stouffer Ronald J. , Walsh John E. , Parkinson Claire L. , Cavalieri Donald J. , Mitchell John F. B. , Garrett Donald , Zakharov Victor F.
Published: July 2002

Surface and satellite-based observations show a decrease in Northern Hemisphere sea ice extent during the past 46 years. A comparison of these trends to control and transient integrations (forced by observed greenhouse gases and tropospheric sulfate aerosols) from the Geophysical Fluid Dynamics Laboratory and Hadley Centre climate models reveals that the observed decrease in Northern Hemisphere sea ice extent agrees with the transient simulations, and both trends are much larger than would be expected from natural climate variations. From long-term control runs of climate models, it was found that the probability of the observed trends resulting from natural climate variability, assuming that the models' natural variability is similar to that found in nature, is less than 2 percent for the 1978–98 sea ice trends and less than 0.1 percent for the 1953–98 sea ice trends. Both models used here project continued decreases in sea ice thickness and extent throughout the next century.
Nanotube Molecular Wires as Chemical Sensors
Authors: Kong Jing , Franklin Nathan R. , Zhou Chongwu , Chapline Michael G. , Peng Shu , Cho Kyeongjae , Dai Hongjie
Published: July 2002

Chemical sensors based on individual single-walled carbon nanotubes (SWNTs) are demonstrated. Upon exposure to gaseous molecules such as NO
2
or NH
3
, the electrical resistance of a semiconducting SWNT is found to dramatically increase or decrease. This serves as the basis for nanotube molecular sensors. The nanotube sensors exhibit a fast response and a substantially higher sensitivity than that of existing solid-state sensors at room temperature. Sensor reversibility is achieved by slow recovery under ambient conditions or by heating to high temperatures. The interactions between molecular species and SWNTs and the mechanisms of molecular sensing with nanotube molecular wires are investigated.
Europe Confronts the Embryonic Stem Cell Research Challenge
Authors: Lenoir Noëlle
Published: July 2002

Europe's historic plurality and the lack of a commonly accepted definition of the moral status of the embryo have led to varying regulation in European countries. Council of Europe and European Union legislation, based on fundamental ethical principles, does exist for specific issues, such as prohibition against producing embryos solely for research. Such principles have recently been elucidated by the European Group on Ethics in Science and New Technologies. Newly emerging research techniques are beginning to cause reconsideration of the regulation of embryo research in Europe.
Translating Stem and Progenitor Cell Biology to the Clinic: Barriers and Opportunities
Authors: Weissman Irving L.
Published: July 2002

Stem cells are the natural units of embryonic generation, and also adult regeneration, of a variety of tissues. Recently, the list of tissues that use the model of differentiation from stem to progenitor to mature cell has increased from blood to include a variety of tissues, including both central and peripheral nervous systems and skeletal muscle; it is also possible that all organs and tissues are derived from, and still contain, stem cells. Because the number and activities of stem cells and their progeny are homeostatically regulated, clinical stem cell transplantation could greatly add to the physician's armamentarium against degenerative diseases.
A
Drosophila
Mechanosensory Transduction Channel
Authors: Walker Richard G. , Willingham Aarron T. , Zuker Charles S.
Published: July 2002

Mechanosensory transduction underlies a wide range of senses, including proprioception, touch, balance, and hearing. The pivotal element of these senses is a mechanically gated ion channel that transduces sound, pressure, or movement into changes in excitability of specialized sensory cells. Despite the prevalence of mechanosensory systems, little is known about the molecular nature of the transduction channels. To identify such a channel, we analyzed
Drosophila melanogaster
mechanoreceptive mutants for defects in mechanosensory physiology. Loss-of-function mutations in the
no mechanoreceptor potential C
(
nompC
) gene virtually abolished mechanosensory signaling.
nompC
encodes a new ion channel that is essential for mechanosensory transduction. As expected for a transduction channel,
D. melanogaster
NOMPC and a
Caenorhabditis elegans
homolog were selectively expressed in mechanosensory organs.
Giant Birefringent Optics in Multilayer Polymer Mirrors
Authors: Weber Michael F. , Stover Carl A. , Gilbert Larry R. , Nevitt Timothy J. , Ouderkirk Andrew J.
Published: July 2002

Multilayer mirrors that maintain or increase their reflectivity with increasing incidence angle can be constructed using polymers that exhibit large birefringence in their indices of refraction. The most important feature of these multilayer interference stacks is the index difference in the thickness direction (
z
axis) relative to the in-plane directions of the film. This
z
-axis refractive index difference provides a variable that determines the existence and value of the Brewster's angle at layer interfaces, and it controls both the interfacial Fresnel reflection coefficient and the phase relations that determine the optics of multilayer stacks. These films can yield optical results that are difficult or impossible to achieve with conventional multilayer optical designs. The materials and processes necessary to fabricate such films are amenable to large-scale manufacturing.
The Archean Sulfur Cycle and the Early History of Atmospheric Oxygen
Authors: Canfield Donald E. , Habicht Kirsten S. , Thamdrup Bo
Published: July 2002

The isotope record of sedimentary sulfides can help resolve the history of oxygen accumulation into the atmosphere. We measured sulfur isotopic fractionation during microbial sulfate reduction up to 88°C and show how sulfate reduction rate influences the preservation of biological fractionations in sediments. The sedimentary sulfur isotope record suggests low concentrations of seawater sulfate and atmospheric oxygen in the early Archean (3.4 to 2.8 billion years ago). The accumulation of oxygen and sulfate began later, in the early Proterozoic (2.5 to 0.54 billion years ago).
Posttranslational N-Myristoylation of BID as a Molecular Switch for Targeting Mitochondria and Apoptosis
Authors: Zha Jiping , Weiler Solly , Oh Kyoung Joon , Wei Michael C. , Korsmeyer Stanley J.
Published: July 2002

Many apoptotic molecules relocate subcellularly in cells undergoing apoptosis. The pro-apoptotic protein BID underwent posttranslational (rather than classic cotranslational) N-myristoylation when cleavage by caspase 8 caused exposure of a glycine residue. N-myristoylation enabled the targeting of a complex of p7 and myristoylated p15 fragments of BID to artificial membranes bearing the lipid composition of mitochondria, as well as to intact mitochondria. This post-proteolytic N-myristoylation serves as an activating switch, enhancing BID-induced release of cytochrome c and cell death.
Genome-Wide Location and Function of DNA Binding Proteins
Authors: Ren Bing , Robert François , Wyrick John J. , Aparicio Oscar , Jennings Ezra G. , Simon Itamar , Zeitlinger Julia , Schreiber Jörg , Hannett Nancy , Kanin Elenita , Volkert Thomas L. , Wilson Christopher J. , Bell Stephen P. , Young Richard A.
Published: July 2002

Understanding how DNA binding proteins control global gene expression and chromosomal maintenance requires knowledge of the chromosomal locations at which these proteins function in vivo. We developed a microarray method that reveals the genome-wide location of DNA-bound proteins and used this method to monitor binding of gene-specific transcription activators in yeast. A combination of location and expression profiles was used to identify genes whose expression is directly controlled by Gal4 and Ste12 as cells respond to changes in carbon source and mating pheromone, respectively. The results identify pathways that are coordinately regulated by each of the two activators and reveal previously unknown functions for Gal4 and Ste12. Genome-wide location analysis will facilitate investigation of gene regulatory networks, gene function, and genome maintenance.
Molecular Analysis of Commensal Host-Microbial Relationships in the Intestine
Authors: Hooper Lora V. , Wong Melissa H. , Thelin Anders , Hansson Lennart , Falk Per G. , Gordon Jeffrey I.
Published: July 2002

Human beings contain complex societies of indigenous microbes, yet little is known about how resident bacteria shape our physiology. We colonized germ-free mice with
Bacteroides thetaiotaomicron
, a prominent component of the normal mouse and human intestinal microflora. Global intestinal transcriptional responses to colonization were observed with DNA microarrays, and the cellular origins of selected responses were established by laser-capture microdissection. The results reveal that this commensal bacterium modulates expression of genes involved in several important intestinal functions, including nutrient absorption, mucosal barrier fortification, xenobiotic metabolism, angiogenesis, and postnatal intestinal maturation. These findings provide perspectives about the essential nature of the interactions between resident microorganisms and their hosts.
Evidence for a Large-Scale Remnant of Subducted Lithosphere Beneath Fiji
Authors: Chen Wang-Ping , Brudzinski Michael R.
Published: July 2002

We combine spatial variations of
P
- and
S
-wave speeds, 1000 fault plane solutions, and 6600 well-determined hypocenters to investigate the nature of subducted lithosphere and deep earthquakes beneath the Tonga back-arc. We show that perplexing patterns in seismicity and fault plane solutions can be accounted for by the juxtaposition of a steep-dipping Wadati-Benioff zone and a subhorizontal remnant of slab that is no longer attached to the actively subducting lithosphere. The detached slab may be from a previous episode of subduction along the fossil Vitiaz trench about 5 to 8 million years ago. The juxtaposition of slabs retains a large amount of subducted material in the transition zone of the mantle. Such a configuration, if common in the past, would allow the preservation of a primordial component in the lower mantle.
A Novel Class A Extended-Spectrum β-Lactamase (BES-1) in
Serratia marcescens
Isolated in Brazil
Authors: Bonnet R. , Sampaio J. L. M. , Chanal C. , Sirot D. , De Champs C. , Viallard J. L. , Labia R. , Sirot J.
Published: July 2002

Serratia marcescens
Rio-5, one of 18 extended-spectrum β-lactamase (ESBL)-producing strains isolated in several hospitals in Rio de Janeiro (Brazil) in 1996 and 1997, exhibited a high level of resistance to aztreonam (MIC, 512 μg/ml) and a distinctly higher level of resistance to cefotaxime (MIC, 64 μg/ml) than to ceftazidime (MIC, 8 μg/ml). The strain produced a plasmid-encoded ESBL with a pI of 7.5 whose
bla
gene was not related to those of other plasmid-mediated Ambler class A ESBLs. Cloning and sequencing revealed a
bla
gene encoding a novel class A β-lactamase in functional group 2be, designated BES-1 (Brazil extended-spectrum β-lactamase). This enzyme had 51% identity with chromosomal class A penicillinase of
Yersinia enterocolitica
Y56, which was the most closely related enzyme and 47 to 48% identity with CTX-M-type β-lactamases, which were the most closely related ESBLs. In common with CTX-M enzymes, BES-1 exhibited high cefotaxime-hydrolyzing activity (
k
cat
, 425 s
−1
). However, BES-1 differed from CTX-M enzymes by its significant ceftazidime-hydrolyzing activity (
k
cat
, 25 s
−1
), high affinity for aztreonam (

K
i

, 1 μM), and lower susceptibility to tazobactam (50% inhibitory concentration [IC
50
], 0.820 μM) than to clavulanate (IC
50
, 0.045 μM). Likewise, certain characteristic structural features of CTX-M enzymes, such as Phe-160, Ser-237, and Arg-276, were observed for BES-1, which, in addition, harbored different residues (Ala-104, Ser-171, Arg-220, Gly-240) and six additional residues at the end of the sequence. BES-1, therefore, may be an interesting model for further investigations of the structure-function relationships of class A ESBLs.
In Vitro and In Vivo Activities of LB 10827, a New Oral Cephalosporin, against Respiratory Pathogens
Authors: Paek Kyong-Sook , Kim Mu-Yong , Lee Chang-Seok , Youn Hasik
Published: July 2002

The in vitro antibacterial activities of LB 10827, a new oral cephalosporin, against common respiratory tract pathogens were compared with those of six β-lactams (cefdinir, cefuroxime, cefprozil, penicillin G, amoxicillin-clavulanate, and ampicillin), two quinolones (trovafloxacin and ciprofloxacin), and one macrolide (clarithromycin). The MIC of LB 10827 at which 90% of the penicillin-resistant strains of
Streptococcus pneumoniae
tested were inhibited was 0.5 μg/ml, and the drug was 4- to 32-fold more active than the compared β-lactams. The potent activity of LB 10827 against
Haemophilus influenzae
and
Moraxella catarrhalis
was retained, and the presence of β-lactamase in both strains had little effect on the in vitro activity of the compound. Time-kill studies revealed that LB 10827 had bactericidal activity against these respiratory pathogens. This agent reduced original counts of all pathogens tested by ≥3 log
10
CFU/ml at the MIC, and the regrowth was completely prevented for 12 h. The potent in vitro antibacterial activity of LB 10827 against respiratory pathogens has been proved in both mouse pneumonia and neutropenic rat models. These results strongly suggest that this agent has potential for the treatment of respiratory tract infections.
Postantibiotic Effects and Bactericidal Activities of Clarithromycin–14-Hydroxy-Clarithromycin, versus Those of Amoxicillin-Clavulanate, against Anaerobes
Authors: Jung Rose , Messick Chad R. , Pendland Susan L. , Tesoro Eljim P. , Losendahl Karen J. , Schriever Christopher A. , Danziger Larry H.
Published: July 2002

The bactericidal activities and postantibiotic effects (PAE) of clarithromycin–14-hydroxy-clarithromycin and amoxicillin-clavulanate against
Bacteroides fragilis
and
Peptostreptococcus anaerobius
were determined. A concentration of twice the MIC resulted in bactericidal activity against four of four and three of four organisms at 24 h with clarithromycin–14-hydroxy-clarithromycin and amoxicillin-clavulanate, respectively. The PAE of clarithromycin–14-hydroxy-clarithromycin was 1.44 to 3.20 h, compared to the less than 1 h of amoxicillin-clavulanate. Clarithromycin–14-hydroxy-clarithromycin possesses good activity against susceptible anaerobes.
Susceptibilities of Oral and Nasal Isolates of
Streptococcus mitis
and
Streptococcus oralis
to Macrolides and PCR Detection of Resistance Genes
Authors: Ono Tsuneko , Shiota Sumiko , Hirota Katsuhiko , Nemoto Ken , Tsuchiya Tomofusa , Miyake Yoichiro
Published: July 2002

The susceptibility of viridans group streptococci to macrolides was determined. Thirteen isolates (17%) were resistant to erythromycin. Five strains carried an
erm
gene that was highly homologous to that in Tn
917
. Four strains had
mefE
genes that coded erythromycin efflux ability.
Interspecies Comparison of Pharmacokinetics of the Novel Triazole Antifungal Agent SYN-2869 and Its Derivatives
Authors: Khan Jehangir K. , Montaseri Hashem , Poglod Marzena , Bu Hai-Zhi , Zuo Zhong , Salama Sameeh M. , Daneshtalab Mohsen , Micetich Ronald G.
Published: July 2002

The pharmacokinetics and distribution in tissue of several novel triazole antifungal agents were studied in different animal species in order to select an appropriate lead compound. The purpose of the study was also to determine species differences in pharmacokinetics for SYN azoles to select the most appropriate species for secondary efficacy and toxicological evaluation of the selected compound. SYN-2836, SYN-2869, SYN-2903, and SYN-2921 were rapidly absorbed into the systemic circulation and reached maximum concentrations (
C
max
s) of 7.31 ± 2.53, 6.29 ± 0.85, 6.16 ± 0.39, and 3.41 ± 0.34 μg/ml, respectively, in BALB/c mice after administration of an oral dose of 50 mg/kg of body weight, with bioavailability being greater than 45% in all mice. The areas under the concentration-time curve from time zero to infinity (AUC
0–∞
s) after administration of a single intravenous dose of 20 mg/kg to mice varied between 25.0 and 63.6 μg · h/ml. The half-life was in the range of 4.5 to 6 h. In Sprague-Dawley rats there was no significant difference in AUC
0–∞
after administration of a single intravenous dose of 20 mg/kg, but on oral administration, the bioavailability of SYN-2836 was extremely low, while that of SYN-2869 was only 14.7%. In New Zealand White rabbits the
C
max
and the time to reach
C
max
for SYN-2836 and SYN-2869 after administration of a single oral dose of 50 mg/kg were similar. There were significant differences in AUC
0–∞
and half-life between SYN-2836 and SYN-2869. On the other hand, in beagle dogs the
C
max
and AUC
0–∞
of SYN-2836 after administration of a single oral dose of 30 mg/kg were 4.82 ± 1.54 μg/ml and 41.8 ± 15.7 μg · h/ml, respectively, which were threefold higher than those of SYN-2869. The concentrations of the SYN compounds in tissue indicated that the AUC
0–∞
s of SYN-2836, SYN-2869, SYN-2903, and SYN-2921 in mouse lungs were significantly different from each other. The ratios of the concentrations of the SYN azoles in lungs to those in plasma were also significantly different from those for itraconazole. Among the SYN azoles the highest concentration in the lungs was found for SYN-2869. The higher level of distribution of SYN-2869 into lung tissue was considered to contribute to the potent efficacy in respiratory tract infection models compared with the potency of itraconazole. Significant differences in the pharmacokinetics of these compounds were observed in different animal species, and selection of an animal model for further evaluation was based on results obtained from these studies.
Influence of Resistance to Streptogramin A Type Antibiotics on the Activity of Quinupristin-Dalfopristin In Vitro and in Experimental Endocarditis Due to
Staphylococcus aureus
Authors: Zarrouk Virginie , Bozdogan Bülent , Leclercq Roland , Garry Louis , Carbon Claude , Fantin Bruno
Published: July 2002

We evaluated the activity of quinupristin-dalfopristin (Q-D) against three clinical strains of
Staphylococcus aureus
susceptible to Q (MIC, 8 μg/ml) and Q-D (MICs, 0.5 to 1 μg/ml) but displaying various levels of susceptibility to D. D was active against
S. aureus
HM 1054 (MIC, 4 μg/ml) and had reduced activity against
S. aureus
RP 13 and
S. aureus
N 95 (MICs, 32 and 64 μg/ml, respectively). In vitro, Q-D at a concentration two times the MIC (2×MIC) produced reductions of 4.3, 3.9, and 5.8 log
10
CFU/ml after 24 h of incubation for HM 1054, RP 13, and N 95, respectively. Comparable killing was obtained at 8×MIC. Q-D-resistant mutants were selected in vitro at a frequency of 2 × 10
−8
to 2 × 10
−7
for the three strains on agar containing 2×MIC of Q-D; no resistant bacteria were detected at 4×MIC. Rabbits with aortic endocarditis were treated for 4 days with Q-D at 30 mg/kg of body weight intramuscularly (i.m.) three times a day (t.i.d.) or vancomycin at 50 mg/kg i.m. t.i.d. In vivo, Q-D and vancomycin were similarly active and bactericidal against the three tested strains compared to the results for control animals (
P
< 0.01). Among animals infected with RP 13 and treated with Q-D, one rabbit retained Q-D-resistant mutants that were resistant to Q and to high levels of D (MICs, 64, >256, and 8 μg/ml for Q, D, and Q-D, respectively). We conclude that the bactericidal activity of Q-D against strains with reduced susceptibility to D and susceptible to Q-D is retained and is comparable to that of vancomycin. Acquisition of resistance to both Q and D is necessary to select resistance to Q-D.
Carbapenemases of
Chryseobacterium
(
Flavobacterium
)
meningosepticum
: Distribution of
blaB
and Characterization of a Novel Metallo-β-Lactamase Gene,
blaB3
, in the Type Strain, NCTC 10016
Authors: Woodford Neil , Palepou Marie-France I. , Babini Gioia S. , Holmes Barry , Livermore David M.
Published: July 2002

Genes encoding carbapenemases in 15 reference strains of
Chryseobacterium
(
Flavobacterium
)
meningosepticum
from the United Kingdom National Collection of Type Cultures and in one recent clinical isolate were investigated. All the strains hydrolyzed imipenem, but their levels of resistance to carbapenems varied, with imipenem and meropenem MICs ranging from 2 to >32 μg/ml. The
blaB
gene, which encodes a molecular-class B carbapenemase, was detected in only six reference strains and in clinical isolate 97/P/5448. The gene from 97/P/5448 had 98% nucleotide identity with the published sequence of
blaB
(from strain NCTC 10585) and was designated
blaB2
. A distinct carbapenemase gene, designated
blaB3
, was cloned from the type strain of
C. meningosepticum
, NCTC 10016.
blaB3
had an open reading frame of 750 bp with 82% nucleotide identity to
blaB
and
blaB2
and encoded a β-lactamase of 249 amino acids, including the putative signal peptide. This β-lactamase showed 87.6 and 86.7% amino acid homology with BlaB and BlaB2, respectively.
blaB3
was detected in one other reference strain besides NCTC 10016, but the genetic basis of the carbapenemase activity detected in the other seven reference strains was not defined. Thus, neither
blaB
nor
blaB3
was ubiquitous in the strains of
C. meningosepticum
studied, indicating that the reference strains may represent more than one bacterial species, each with its own intrinsic metallo-β-lactamase. Further taxonomic studies of
C. meningosepticum
are necessary to resolve this topic.
Chryseobacterium
spp. are environmental organisms and occasional opportunist pathogens. They apparently represent a reservoir of diverse metallo-β-lactamases, which potentially spread to gram-negative bacteria of greater clinical significance.
In Vivo Activity of Evernimicin (SCH 27899) against Methicillin-Resistant
Staphylococcus aureus
in Experimental Infective Endocarditis
Authors: Boucher Helen W. , Thauvin-Eliopoulos Claudie , Loebenberg David , Eliopoulos George M.
Published: July 2002

Currently, there exist few satisfactory alternatives to vancomycin for therapy of serious methicillin-resistant
Staphylococcus aureus
(MRSA) infections. We employed a rat model of aortic valve endocarditis to assess the potential efficacy of evernimicin (SCH 27899) compared with vancomycin against infection with a strain susceptible to both agents (MICs of 0.25 and 0.50 μg/ml, respectively). Infected animals were assigned to one of three groups: controls (no treatment), evernimicin at 60 mg/kg of body weight by intravenous (i.v.) infusion once daily, or vancomycin at 150 mg/kg of body weight per day by continuous i.v. infusion. Therapy was administered for 5.5 days. At the start of therapy, colony counts in vegetations were 6.63 ± 0.44 log
10
CFU/g. In both treatment groups, bacterial density within vegetations was significantly reduced in comparison with control animals that had not been treated. Final colony counts were as follows (mean ± standard deviation): controls, 10.12 ± 1.51 log
10
CFU/g of vegetation; evernimicin, 7.22 ± 2.91 log
10
CFU/g of vegetation; vancomycin, 5.65 ± 1.76 log
10
CFU/g of vegetation. The difference between the evernimicin and vancomycin groups was not significant. These results confirmed the bacteriostatic activity of evernimicin in vivo in an experimental model of severe MRSA infection.
In Vitro and In Vivo Efficacies of T-3811ME (BMS-284756) against
Mycoplasma pneumoniae
Authors: Takahata Masahiro , Shimakura Masako , Hori Ritsuko , Kizawa Kazuo , Todo Yozo , Minami Shinzaburo , Watanabe Yasuo , Narita Hirokazu
Published: July 2002

T-3811, the free base of T-3811ME (BMS-284756), a new des-F(6)-quinolone, showed a potent in vitro activity (MIC at which 90% of the isolates tested are inhibited [MIC
90
], 0.0313 μg/ml) against
Mycoplasma pneumoniae
. The MIC
90
of T-3811 was 4-fold higher than that of clarithromycin but was 4- to 8-fold lower than those of trovafloxacin, gatifloxacin, gemifloxacin, and moxifloxacin and was 16- to 32-fold lower than those of levofloxacin, ciprofloxacin, and minocycline. In an experimental
M. pneumoniae
pneumonia model in hamsters, after the administration of T-3811ME (20 mg/kg of body weight as T-3811, once daily, orally) for 5 days, the reduction of viable cells of
M. pneumoniae
in bronchoalveolar lavage fluid was greater than those of trovafloxacin, levofloxacin, and clarithromycin (20 and 40 mg/kg, orally) (
P
< 0.05).
In Vitro Pharmacodynamic Studies of Activities of Ketolides HMR 3647 (Telithromycin) and HMR 3004 against Extracellular or Intracellular
Helicobacter pylori
Authors: Gustafsson I. , Engstrand L. , Cars O.
Published: July 2002

The pharmacodynamic properties of the ketolides HMR 3647 (telithromycin) and HMR 3004 were studied against
Helicobacter pylori
. Both ketolides showed a pronounced concentration-dependent killing, a significant postantibiotic effect, a long postantibiotic sub-MIC effect, and a reduction of intracellular
H. pylori
.