bluuebunny/crossref_metadata_2025 huggingface dataset:
A Pair of Related Genes with Antagonistic Roles in Mediating Flowering Signals
Authors: Kobayashi Yasushi , Kaya Hidetaka , Goto Koji , Iwabuchi Masaki , Araki Takashi
Published: July 2002

Flowering in
Arabidopsis
is promoted via several interacting pathways. A photoperiod-dependent pathway relays signals from photoreceptors to a transcription factor gene,
CONSTANS
(
CO
), which activates downstream meristem identity genes such as
LEAFY
(
LFY
).
FT
, together with
LFY
, promotes flowering and is positively regulated by
CO
. Loss of
FT
causes delay in flowering, whereas overexpression of
FT
results in precocious flowering independent of
CO
or photoperiod.
FT
acts in part downstream of
CO
and mediates signals for flowering in an antagonistic manner with its homologous gene,
TERMINAL FLOWER1
(
TFL1
).
Organogenic Role of B Lymphocytes in Mucosal Immunity
Authors: Golovkina Tatyana V. , Shlomchik Mark , Hannum Lynn , Chervonsky Alexander
Published: July 2002

Follicle-associated epithelium (FAE) in the intestinal Peyer's patches contains M cells that deliver pathogens to organized lymphoid tissue. Development of Peyer's patches, FAE, and M cells was found to be impaired in mice that had no B cells. Transgenic expression of membrane-bound immunoglobulin M restored B cells and FAE development. The lack of M cells abrogated infection with a milk-borne retrovirus. Thus, in addition to secretion of antibodies and presentation of antigens, B cells are important for organogenesis of the mucosal immune barriers.
Biological and Chemical Response of the Equatorial Pacific Ocean to the 1997-98 El Niño
Authors: Chavez F. P. , Strutton P. G. , Friederich G. E. , Feely R. A. , Feldman G. C. , Foley D. G. , McPhaden M. J.
Published: July 2002

During the 1997–98 El Niño, the equatorial Pacific Ocean retained 0.7 × 10
15
grams of carbon that normally would have been lost to the atmosphere as carbon dioxide. The surface ocean became impoverished in plant nutrients, and chlorophyll concentrations were the lowest on record. A dramatic recovery occurred in mid-1998, the system became highly productive, analogous to coastal environments, and carbon dioxide flux out of the ocean was again high. The spatial extent of the phytoplankton bloom that followed recovery from El Niño was the largest ever observed for the equatorial Pacific. These chemical and ecological perturbations were linked to changes in the upwelling of nutrient-enriched waters. The description and explanation of these dynamic changes would not have been possible without an observing system that combines biological, chemical, and physical sensors on moorings with remote sensing of chlorophyll.
Zener Model Description of Ferromagnetism in Zinc-Blende Magnetic Semiconductors
Authors: Dietl T. , Ohno H. , Matsukura F. , Cibert J. , Ferrand D.
Published: July 2002

Ferromagnetism in manganese compound semiconductors not only opens prospects for tailoring magnetic and spin-related phenomena in semiconductors with a precision specific to III-V compounds but also addresses a question about the origin of the magnetic interactions that lead to a Curie temperature (
T
C
) as high as 110 K for a manganese concentration of just 5%. Zener's model of ferromagnetism, originally proposed for transition metals in 1950, can explain
T
C
of Ga
1−

x

Mn

x

As and that of its II-VI counterpart Zn
1−

x

Mn

x

Te and is used to predict materials with
T
C
exceeding room temperature, an important step toward semiconductor electronics that use both charge and spin.
Superplastic Extensibility of Nanocrystalline Copper at Room Temperature
Authors: Lu L. , Sui M. L. , Lu K.
Published: July 2002

A bulk nanocrystalline (nc) pure copper with high purity and high density was synthesized by electrodeposition. An extreme extensibility (elongation exceeds 5000%) without a strain hardening effect was observed when the nc copper specimen was rolled at room temperature. Microstructure analysis suggests that the superplastic extensibility of the nc copper originates from a deformation mechanism dominated by grain boundary activities rather than lattice dislocation, which is also supported by tensile creep studies at room temperature. This behavior demonstrates new possibilities for scientific and technological advancements with nc materials.
Translocation of
C. elegans
CED-4 to Nuclear Membranes During Programmed Cell Death
Authors: Chen Fangli , Hersh Bradley M. , Conradt Barbara , Zhou Zheng , Riemer Dieter , Gruenbaum Yosef , Horvitz H. Robert
Published: July 2002

The
Caenorhabditis elegans
Bcl-2–like protein CED-9 prevents programmed cell death by antagonizing the Apaf-1–like cell-death activator CED-4. Endogenous CED-9 and CED-4 proteins localized to mitochondria in wild-type embryos, in which most cells survive. By contrast, in embryos in which cells had been induced to die, CED-4 assumed a perinuclear localization. CED-4 translocation induced by the cell-death activator EGL-1 was blocked by a gain-of-function mutation in
ced-9
but was not dependent on
ced-3
function, suggesting that CED-4 translocation precedes caspase activation and the execution phase of programmed cell death. Thus, a change in the subcellular localization of CED-4 may drive programmed cell death.
Mid-Pleistocene Acheulean-like Stone Technology of the Bose Basin, South China
Authors: Yamei Hou , Potts Richard , Baoyin Yuan , Zhengtang Guo , Deino Alan , Wei Wang , Clark Jennifer , Guangmao Xie , Weiwen Huang
Published: July 2002

Stone artifacts from the Bose basin, South China, are associated with tektites dated to 803,000 ± 3000 years ago and represent the oldest known large cutting tools (LCTs) in East Asia. Bose toolmaking is compatible with Mode 2 (Acheulean) technologies in Africa in its targeted manufacture and biased spatial distribution of LCTs, large-scale flaking, and high flake scar counts. Acheulean-like tools in the mid-Pleistocene of South China imply that Mode 2 technical advances were manifested in East Asia contemporaneously with handaxe technology in Africa and western Eurasia. Bose lithic technology is associated with a tektite airfall and forest burning.
An Archaeal Iron-Oxidizing Extreme Acidophile Important in Acid Mine Drainage
Authors: Edwards Katrina J. , Bond Philip L. , Gihring Thomas M. , Banfield Jillian F.
Published: July 2002

A new species of Archaea grows at pH ∼0.5 and ∼40°C in slime streamers and attached to pyrite surfaces at a sulfide ore body, Iron Mountain, California. This iron-oxidizing Archaeon is capable of growth at pH 0. This species represents a dominant prokaryote in the environment studied (slimes and sediments) and constituted up to 85% of the microbial community when solution concentrations were high (conductivity of 100 to 160 millisiemens per centimeter). The presence of this and other closely related
Thermoplasmales
suggests that these acidophiles are important contributors to acid mine drainage and may substantially impact iron and sulfur cycles.
Mechanism-Based Target Identification and Drug Discovery in Cancer Research
Authors: Gibbs Jackson B.
Published: July 2002

Cancer as a disease in the human population is becoming a larger health problem, and the medicines used as treatments have clear limitations. In the past 20 years, there has been a tremendous increase in our knowledge of the molecular mechanisms and pathophysiology of human cancer. Many of these mechanisms have been exploited as new targets for drug development in the hope that they will have greater antitumor activity with less toxicity to the patient than is seen with currently used medicines. The fruition of these efforts in the clinic is just now being realized with a few encouraging results.
Age of Neoproterozoic Bilatarian Body and Trace Fossils, White Sea, Russia: Implications for Metazoan Evolution
Authors: Martin M. W. , Grazhdankin D. V. , Bowring S. A. , Evans D. A. D. , Fedonkin M. A. , Kirschvink J. L.
Published: July 2002

A uranium-lead zircon age for a volcanic ash interstratified with fossil-bearing, shallow marine siliciclastic rocks in the Zimnie Gory section of the White Sea region indicates that a diverse assemblage of body and trace fossils occurred before 555.3 ± 0.3 million years ago. This age is a minimum for the oldest well-documented triploblastic bilaterian
Kimberella
. It also makes co-occurring trace fossils the oldest that are reliably dated. This determination of age implies that there is no simple relation between Ediacaran diversity and the carbon isotopic composition of Neoproterozoic seawater.
Rapid Flooding of the Sunda Shelf: A Late-Glacial Sea-Level Record
Authors: Hanebuth Till , Stattegger Karl , Grootes Pieter M.
Published: July 2002

The increase in sea level from the last glacial maximum has been derived from a siliciclastic system on the tectonically stable Sunda Shelf in Southeast Asia. The time from 21 to 14 thousand calendar years before the present has been poorly covered in other records. The record generally confirms sea-level reconstructions from coral reefs. The rise of sea level during meltwater pulse 1A was as much as 16 meters within 300 years (14.6 to 14.3 thousand years ago).
Influenza B Virus in Seals
Authors: Osterhaus A. D. M. E. , Rimmelzwaan G. F. , Martina B. E. E. , Bestebroer T. M. , Fouchier R. A. M.
Published: July 2002

Influenza B virus is a human pathogen whose origin and possible reservoir in nature are not known. An influenza B virus was isolated from a naturally infected harbor seal (
Phoca vitulina
) and was found to be infectious to seal kidney cells in vitro. Sequence analyses and serology indicated that influenza virus B/Seal/Netherlands/1/99 is closely related to strains that circulated in humans 4 to 5 years earlier. Retrospective analyses of sera collected from 971 seals showed a prevalence of antibodies to influenza B virus in 2% of the animals after 1995 and in none before 1995. This animal reservoir, harboring influenza B viruses that have circulated in the past, may pose a direct threat to humans.
Overpressure and Fluid Flow in the New Jersey Continental Slope: Implications for Slope Failure and Cold Seeps
Authors: Dugan Brandon , Flemings Peter B.
Published: July 2002

Miocene through Pleistocene sediments on the New Jersey continental slope (Ocean Drilling Program Site 1073) are undercompacted (porosity between 40 and 65%) to 640 meters below the sea floor, and this is interpreted to record fluid pressures that reach 95% of the lithostatic stress. A two-dimensional model, where rapid Pleistocene sedimentation loads permeable sandy silt of Miocene age, successfully predicts the observed pressures. The model describes how lateral pressure equilibration in permeable beds produces fluid pressures that approach the lithostatic stress where overburden is thin. This transfer of pressure may cause slope failure and drive cold seeps on passive margins around the world.
Low-Friction Nanoscale Linear Bearing Realized from Multiwall Carbon Nanotubes
Authors: Cumings John , Zettl A.
Published: July 2002

We demonstrate the controlled and reversible telescopic extension of multiwall carbon nanotubes, thus realizing ultralow-friction nanoscale linear bearings and constant-force nanosprings. Measurements performed in situ on individual custom-engineered nanotubes inside a high-resolution transmission electron microscope demonstrated the anticipated van der Waals energy–based retraction force and enabled us to place quantitative limits on the static and dynamic interwall frictional forces between nested nanotubes. Repeated extension and retraction of telescoping nanotube segments revealed no wear or fatigue on the atomic scale. Hence, these nanotubes may constitute near perfect, wear-free surfaces.
Rapid Kimberlite Ascent and the Significance of Ar-Ar Ages in Xenolith Phlogopites
Authors: Kelley S. P. , Wartho J-A.
Published: July 2002

Kimberlite eruptions bring exotic rock fragments and minerals, including diamonds, from deep within the mantle up to the surface. Such fragments are rapidly absorbed into the kimberlite magma so their appearance at the surface implies rapid transport from depth. High spatial resolution Ar-Ar age data on phlogopite grains in xenoliths from Malaita in the Solomon Islands, southwest Pacific, and Elovy Island in the Kola Peninsula, Russia, indicate transport times of hours to days depending upon the magma temperature. In addition, the data show that the phlogopite grains preserve Ar-Ar ages recorded at high temperature in the mantle, 700°C above the conventional closure temperature.
The Response of Two Contrasting Limestone Grasslands to Simulated Climate Change
Authors: Grime J. Philip , Brown Valerie K. , Thompson Ken , Masters Gregory J. , Hillier Susan H. , Clarke Ian P. , Askew Andrew P. , Corker David , Kielty Jonathan P.
Published: July 2002

Two different UK limestone grasslands were exposed to simulated climate change with the use of nonintrusive techniques to manipulate local climate over 5 years. Resistance to climate change, defined as the ability of a community to maintain its composition and biomass in response to environmental stress, could be explained by reference to the functional composition and successional status of the grasslands. The more fertile, early-successional grassland was much more responsive to climate change. Resistance could not be explained by the particular climates experienced by the two grasslands. Productive, disturbed landscapes created by modern human activity may prove more vulnerable to climate change than older, traditional landscapes.
The Complete Atomic Structure of the Large Ribosomal Subunit at 2.4 Å Resolution
Authors: Ban Nenad , Nissen Poul , Hansen Jeffrey , Moore Peter B. , Steitz Thomas A.
Published: July 2002

The large ribosomal subunit catalyzes peptide bond formation and binds initiation, termination, and elongation factors. We have determined the crystal structure of the large ribosomal subunit from
Haloarcula marismortui
at 2.4 angstrom resolution, and it includes 2833 of the subunit's 3045 nucleotides and 27 of its 31 proteins. The domains of its RNAs all have irregular shapes and fit together in the ribosome like the pieces of a three-dimensional jigsaw puzzle to form a large, monolithic structure. Proteins are abundant everywhere on its surface except in the active site where peptide bond formation occurs and where it contacts the small subunit. Most of the proteins stabilize the structure by interacting with several RNA domains, often using idiosyncratically folded extensions that reach into the subunit's interior.
Quantized Phonon Spectrum of Single-Wall Carbon Nanotubes
Authors: Hone J. , Batlogg B. , Benes Z. , Johnson A. T. , Fischer J. E.
Published: July 2002

The electronic spectra of carbon nanotubes and other nanoscale systems are quantized because of their small radii. Similar quantization in the phonon spectra has been difficult to observe because of the far smaller energy scale. We probed this regime by measuring the temperature-dependent specific heat of purified single-wall nanotubes. The data show direct evidence of one-dimensional quantized phonon subbands. Above 4 kelvin, they are in excellent agreement with model calculations of individual nanotubes and differ markedly from the specific heat of two-dimensional graphene or three-dimensional graphite. Detailed modeling yields an energy of 4.3 millielectron volts for the lowest quantized phonon subband and a tube-tube (or “lattice”) Debye energy of 1.1 millielectron volts, implying a small intertube coupling in bundles.
Scanometric DNA Array Detection with Nanoparticle Probes
Authors: Taton T. Andrew , Mirkin Chad A. , Letsinger Robert L.
Published: July 2002

A method for analyzing combinatorial DNA arrays using oligonucleotide-modified gold nanoparticle probes and a conventional flatbed scanner is described here. Labeling oligonucleotide targets with nanoparticle rather than fluorophore probes substantially alters the melting profiles of the targets from an array substrate. This difference permits the discrimination of an oligonucleotide sequence from targets with single nucleotide mismatches with a selectivity that is over three times that observed for fluorophore-labeled targets. In addition, when coupled with a signal amplification method based on nanoparticle-promoted reduction of silver(I), the sensitivity of this scanometric array detection system exceeds that of the analogous fluorophore system by two orders of magnitude.
Evidence That the Reactivity of the Martian Soil Is Due to Superoxide Ions
Authors: Yen A. S. , Kim S. S. , Hecht M. H. , Frant M. S. , Murray B.
Published: July 2002

The Viking Landers were unable to detect evidence of life on Mars but, instead, found a chemically reactive soil capable of decomposing organic molecules. This reactivity was attributed to the presence of one or more as-yet-unidentified inorganic superoxides or peroxides in the martian soil. Using electron paramagnetic resonance spectroscopy, we show that superoxide radical ions (O
2
–
) form directly on Mars-analog mineral surfaces exposed to ultraviolet radiation under a simulated martian atmosphere. These oxygen radicals can explain the reactive nature of the soil and the apparent absence of organic material at the martian surface.
Requirement of NAD and
SIR2
for Life-Span Extension by Calorie Restriction in
Saccharomyces cerevisiae
Authors: Lin Su-Ju , Defossez Pierre-Antoine , Guarente Leonard
Published: July 2002

Calorie restriction extends life-span in a wide variety of organisms. Although it has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species produced during respiration, the mechanism by which this regimen slows aging is uncertain. Here, we mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in life-span. This extension was not observed in strains mutant for
SIR2
(which encodes the silencing protein Sir2p) or
NPT1
(a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide). These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD.
Transgene and Transposon Silencing in
Chlamydomonas reinhardtii
by a DEAH-Box RNA Helicase
Authors: Wu-Scharf Dancia , Jeong Byeong-ryool , Zhang Chaomei , Cerutti Heriberto
Published: July 2002

The molecular mechanism(s) responsible for posttranscriptional gene silencing and RNA interference remain poorly understood. We have cloned a gene (
Mut6
) from the unicellular green alga
Chlamydomonas reinhardtii
that is required for the silencing of a transgene and two transposon families.
Mut6
encodes a protein that is highly homologous to RNA helicases of the DEAH-box family. This protein is necessary for the degradation of certain aberrant RNAs, such as improperly processed transcripts, which are often produced by transposons and some transgenes.
Alloying at Surfaces by the Migration of Reactive Two-Dimensional Islands
Authors: Schmid A. K. , Bartelt N. C. , Hwang R. Q.
Published: July 2002

We have studied the formation kinetics of the copper-tin alloy bronze when tin is deposited on the (111) surface of copper at room temperature. Low-energy electron microscopy and atomic-resolution scanning tunneling microscopy reveal that bronze forms on the surface by a complicated, unanticipated cooperative mechanism: Ordered two-dimensional tin islands containing several hundred thousand atoms spontaneously sweep across the surface, leaving bronze alloys in their tracks. We propose that this process, driven by surface free energy, is a version of the “camphor dance” observed on liquid surfaces, and should be a general mechanism of surface alloying when surface diffusion is faster than exchange into the substrate.
The Origins of Genomic Duplications in
Arabidopsis
Authors: Vision Todd J. , Brown Daniel G. , Tanksley Steven D.
Published: July 2002

Large segmental duplications cover much of the
Arabidopsis thaliana
genome. Little is known about their origins. We show that they are primarily due to at least four different large-scale duplication events that occurred 100 to 200 million years ago, a formative period in the diversification of the angiosperms. A better understanding of the complex structural history of angiosperm genomes is necessary to make full use of
Arabidopsis
as a genetic model for other plant species.
The Bacterial Flagellar Cap as the Rotary Promoter of Flagellin Self-Assembly
Authors: Yonekura Koji , Maki Saori , Morgan David Gene , DeRosier David J. , Vonderviszt Ferenc , Imada Katsumi , Namba Keiichi
Published: July 2002

The growth of the bacterial flagellar filament occurs at its distal end by self-assembly of flagellin transported from the cytoplasm through the narrow central channel. The cap at the growing end is essential for its growth, remaining stably attached while permitting the flagellin insertion. In order to understand the assembly mechanism, we used electron microscopy to study the structures of the cap-filament complex and isolated cap dimer. Five leg-like anchor domains of the pentameric cap flexibly adjusted their conformations to keep just one flagellin binding site open, indicating a cap rotation mechanism to promote the flagellin self-assembly. This represents one of the most dynamic movements in protein structures.
Atmospheric CO
2
Concentrations over the Last Glacial Termination
Authors: Monnin Eric , Indermühle Andreas , Dällenbach André , Flückiger Jacqueline , Stauffer Bernhard , Stocker Thomas F. , Raynaud Dominique , Barnola Jean-Marc
Published: July 2002

A record of atmospheric carbon dioxide (CO
2
) concentration during the transition from the Last Glacial Maximum to the Holocene, obtained from the Dome Concordia, Antarctica, ice core, reveals that an increase of 76 parts per million by volume occurred over a period of 6000 years in four clearly distinguishable intervals. The close correlation between CO
2
concentration and Antarctic temperature indicates that the Southern Ocean played an important role in causing the CO
2
increase. However, the similarity of changes in CO
2
concentration and variations of atmospheric methane concentration suggests that processes in the tropics and in the Northern Hemisphere, where the main sources for methane are located, also had substantial effects on atmospheric CO
2
concentrations.
Evolution of Universal Grammar
Authors: Nowak Martin A. , Komarova Natalia L. , Niyogi Partha
Published: July 2002

Universal grammar specifies the mechanism of language acquisition. It determines the range of grammatical hypothesis that children entertain during language learning and the procedure they use for evaluating input sentences. How universal grammar arose is a major challenge for evolutionary biology. We present a mathematical framework for the evolutionary dynamics of grammar learning. The central result is a coherence threshold, which specifies the condition for a universal grammar to induce coherent communication within a population. We study selection of grammars within the same universal grammar and competition between different universal grammars. We calculate the condition under which natural selection favors the emergence of rule-based, generative grammars that underlie complex language.
Categorical Representation of Visual Stimuli in the Primate Prefrontal Cortex
Authors: Freedman David J. , Riesenhuber Maximilian , Poggio Tomaso , Miller Earl K.
Published: July 2002

The ability to group stimuli into meaningful categories is a fundamental cognitive process. To explore its neural basis, we trained monkeys to categorize computer-generated stimuli as “cats” and “dogs.” A morphing system was used to systematically vary stimulus shape and precisely define the category boundary. Neural activity in the lateral prefrontal cortex reflected the category of visual stimuli, even when a monkey was retrained with the stimuli assigned to new categories.
Role of ER Export Signals in Controlling Surface Potassium Channel Numbers
Authors: Ma Dzwokai , Zerangue Noa , Lin Yu-Fung , Collins Anthony , Yu Mei , Jan Yuh Nung , Jan Lily Yeh
Published: July 2002

Little is known about the identity of endoplasmic reticulum (ER) export signals and how they are used to regulate the number of proteins on the cell surface. Here, we describe two ER export signals that profoundly altered the steady-state distribution of potassium channels and were required for channel localization to the plasma membrane. When transferred to other potassium channels or a G protein–coupled receptor, these ER export signals increased the number of functional proteins on the cell surface. Thus, ER export of membrane proteins is not necessarily limited by folding or assembly, but may be under the control of specific export signals.
Surface-Directed Liquid Flow Inside Microchannels
Authors: Zhao Bin , Moore Jeffrey S. , Beebe David J.
Published: July 2002

Self-assembled monolayer chemistry was used in combination with either multistream laminar flow or photolithography to pattern surface free energies inside microchannel networks. Aqueous liquids introduced into these patterned channels are confined to the hydrophilic pathways, provided the pressure is maintained below a critical value. The maximum pressure is determined by the surface free energy of the liquid, the advancing contact angle of the liquid on the hydrophobic regions, and the channel depth. Surface-directed liquid flow was used to create pressure-sensitive switches inside channel networks. The ability to confine liquid flow inside microchannels with only two physical walls is expected to be useful in applications where a large gas-liquid interface is critical, as demonstrated here by a gas-liquid reaction.
Glycosylation and the Immune System
Authors: Rudd Pauline M. , Elliott Tim , Cresswell Peter , Wilson Ian A. , Dwek Raymond A.
Published: July 2002

Almost all of the key molecules involved in the innate and adaptive immune response are glycoproteins. In the cellular immune system, specific glycoforms are involved in the folding, quality control, and assembly of peptide-loaded major histocompatibility complex (MHC) antigens and the T cell receptor complex. Although some glycopeptide antigens are presented by the MHC, the generation of peptide antigens from glycoproteins may require enzymatic removal of sugars before the protein can be cleaved. Oligosaccharides attached to glycoproteins in the junction between T cells and antigen-presenting cells help to orient binding faces, provide protease protection, and restrict nonspecific lateral protein-protein interactions. In the humoral immune system, all of the immunoglobulins and most of the complement components are glycosylated. Although a major function for sugars is to contribute to the stability of the proteins to which they are attached, specific glycoforms are involved in recognition events. For example, in rheumatoid arthritis, an autoimmune disease, agalactosylated glycoforms of aggregated immunoglobulin G may induce association with the mannose-binding lectin and contribute to the pathology.
Age, Sex, Density, Winter Weather, and Population Crashes in Soay Sheep
Authors: Coulson T. , Catchpole E. A. , Albon S. D. , Morgan B. J. T. , Pemberton J. M. , Clutton-Brock T. H. , Crawley M. J. , Grenfell B. T.
Published: July 2002

Quantifying the impact of density, extrinsic climatic fluctuations, and demography on population fluctuations is a persistent challenge in ecology. We analyzed the effect of these processes on the irregular pattern of population crashes of Soay sheep on the St. Kilda archipelago, United Kingdom. Because the age and sex structure of the population fluctuates independently of population size, and because animals of different age and sex respond in different ways to density and weather, identical weather conditions can result in different dynamics in populations of equal size. In addition, the strength of density-dependent processes is a function of the distribution of weather events. Incorporating demographic heterogeneities into population models can influence dynamics and their response to climate change.
Neutral Macroecology
Authors: Bell Graham
Published: July 2002

The central themes of community ecology—distribution, abundance, and diversity—display strongly marked and very general patterns. These include the log-normal distribution of abundance, the relation between range and abundance, the species-area law, and the turnover of species composition. Each pattern is the subject of a large literature that interprets it in terms of ecological processes, typically involving the sorting of differently specialized species onto heterogeneous landscapes. All of these patterns can be shown to arise, however, from neutral community models in which all individuals have identical properties, as the consequence of local dispersal alone. This implies, at the least, that functional interpretations of these patterns must be reevaluated. More fundamentally, neutral community models provide a general theory for biodiversity and conservation biology capable of predicting the fundamental processes and patterns of community ecology.
Hepatitis B or Hepatitis C Virus Infection Is a Risk Factor for Severe Hepatic Cytolysis after Initiation of a Protease Inhibitor-Containing Antiretroviral Regimen in Human Immunodeficiency Virus-Infected Patients
Authors: Savès Marianne , Raffi François , Clevenbergh Philippe , Marchou Bruno , Waldner-Combernoux Anne , Morlat Philippe , Le Moing Vincent , Rivière Catherine , Chêne Geneviève , Leport Catherine ,   The APROCO Study Group
Published: July 2002

In a cohort of 1,047 human immunodeficiency virus type 1-infected patients started on protease inhibitors (PIs), the incidence of severe hepatic cytolysis (alanine aminotransferase concentration five times or more above the upper limit of the normal level ≥ 5N) was 5% patient-years after a mean follow-up of 5 months. Only positivity for hepatitis C virus antibodies (hazard ratio [HR], 7.95;P< 10−3) or hepatitis B virus surface antigen (HR, 6.67;P< 10−3) was associated with severe cytolysis. Before starting patients on PIs, assessment of liver enzyme levels and viral coinfections is necessary.
Role of the PDR Gene Network in Yeast Susceptibility to the Antifungal Antibiotic Mucidin
Authors: Michalkova-Papajova Dana , Obernauerova Margita , Subik Julius
Published: July 2002

Yeast strains disrupted in the
PDR1
,
PDR3
, or
PDR5
gene, but not in
SNQ2
, exhibited higher sensitivity to mucidin (strobilurin A) than did the isogenic wild-type strains. Different gain-of-function mutations in the
PDR1
and
PDR3
genes rendered yeast mutants resistant to this antibiotic. Mucidin induced
PDR5
expression, but the changes in the expression of
SNQ2
were only barely detectable. The results indicate that
PDR5
provides the link between transcriptional regulation by
PDR1
and
PDR3
and mucidin resistance of yeast.
A Convenient Assay for Estimating the Possible Involvement of Efflux of Fluoroquinolones by
Streptococcus pneumoniae
and
Staphylococcus aureus
: Evidence for Diminished Moxifloxacin, Sparfloxacin, and Trovafloxacin Efflux
Authors: Beyer Rebecca , Pestova Ekaterina , Millichap John J. , Stosor Valentina , Noskin Gary A. , Peterson Lance R.
Published: July 2002

We developed a simplified assay for estimating efflux by measuring the effect of reserpine on the growth of
Streptococcus pneumoniae
and
Staphylococcus aureus
over 7 h. Reserpine enhanced ciprofloxacin and levofloxacin 17 to 68%. The hydrophobic drug trovafloxacin and the drug moxifloxacin, with a bulky C-7 substituent but hydrophilicity similar to that of levofloxacin, showed little (0 to 11%) reserpine-enhancing effect. The ease of resistant mutant strain selection correlated with efflux susceptibility.
In Vitro Activities of Telithromycin (HMR 3647) against
Rickettsia rickettsii
,
Rickettsia conorii
,
Rickettsia africae
,
Rickettsia typhi
,
Rickettsia prowazekii
,
Coxiella burnetii
,
Bartonella henselae
,
Bartonella quintana
,
Bartonella bacilliformis
, and
Ehrlichia chaffeensis
Authors: Rolain Jean-Marc , Maurin Max , Bryskier André , Raoult Didier
Published: July 2002

In vitro activities of telithromycin compared to those of erythromycin against
Rickettsia
spp.,
Bartonella
spp.,
Coxiella burnetii
, and
Ehrlichia chaffeensis
were determined. Telithromycin was more active than erythromycin against
Rickettsia
,
Bartonella
, and
Coxiella burnetii
, with MICs of 0.5 μg/ml, 0.003 to 0.015 μg/ml, and 1 μg/ml, respectively, but was inactive against
Ehrlichia chaffeensis
.
Pharmacokinetic Interaction of Abacavir (1592U89) and Ethanol in Human Immunodeficiency Virus-Infected Adults
Authors: McDowell James A. , Chittick Gregory E. , Stevens Cristina Pilati , Edwards Kathleen D. , Stein Daniel S.
Published: July 2002

While in vitro results at clinically relevant concentrations do not predict abacavir (1592U89) interactions with drugs highly metabolized by cytochrome P450, the potential does exist for a pharmacokinetic interaction between abacavir and ethanol, as both are metabolized by alcohol dehydrogenase. Twenty-five subjects were enrolled in an open-label, randomized, three-way-crossover, phase I study of human immunodeficiency virus-infected male subjects. The three treatments were administration of (i) 600 mg of abacavir, (ii) 0.7 g of ethanol per kg of body weight, and (iii) 600 mg of abacavir and 0.7 g of ethanol per kg. Twenty-four subjects completed the study with no unexpected adverse events reported. Ethanol pharmacokinetic parameters were unchanged with abacavir coadministration. The geometric least squares mean area under the concentration curve extrapolated to infinite time for abacavir increased 41% (from 11.07 to 15.62 μg · h/ml), and the half-life increased 26% (from 1.42 to 1.79 h) in the presence of ethanol (mean ethanol maximum concentration in plasma of 498 μg/ml). The percentages of abacavir dose recovered in urine as abacavir and its two major metabolites were each altered in the presence of ethanol, but there was no change in the total percentage (≈50%) of administered dose recovered in the 12-h collection interval. In conclusion, while a single 600-mg dose of abacavir does not alter blood ethanol concentration, ethanol does increase plasma abacavir concentrations.
Quantitation of
Candida albicans
Ergosterol Content Improves the Correlation between In Vitro Antifungal Susceptibility Test Results and In Vivo Outcome after Fluconazole Treatment in a Murine Model of Invasive Candidiasis
Authors: Arthington-Skaggs Beth A. , Warnock David W. , Morrison Christine J.
Published: July 2002

MIC end point determination for the most commonly prescribed azole antifungal drug, fluconazole, can be complicated by “trailing” growth of the organism during susceptibility testing by the National Committee for Clinical Laboratory Standards approved M27-A broth macrodilution method and its modified broth microdilution format. To address this problem, we previously developed the sterol quantitation method (SQM) for in vitro determination of fluconazole susceptibility, which measures cellular ergosterol content rather than growth inhibition after exposure to fluconazole. To determine if SQM MICs of fluconazole correlated better with in vivo outcome than M27-A MICs, we used a murine model of invasive candidiasis and analyzed the capacity of fluconazole to treat infections caused by
C. albicans
isolates which were trailers (M27-A MICs at 24 and 48 h, ≤1.0 and ≥64 μg/ml, respectively; SQM MIC, ≤1.0 μg/ml), as well as those which were fluconazole sensitive (M27-A and SQM MIC, ≤1.0 μg/ml) and fluconazole resistant (M27-A MIC, ≥64 μg/ml; SQM MIC, 54 μg/ml). Compared with the untreated controls, fluconazole therapy increased the survival of mice infected with a sensitive isolate and both trailing isolates but did not increase the survival of mice infected with a resistant isolate. These results indicate that the SQM is more predictive of in vivo outcome than the M27-A method for isolates that give unclear MIC end points due to trailing growth in fluconazole.
BMS-232632, a Highly Potent Human Immunodeficiency Virus Protease Inhibitor That Can Be Used in Combination with Other Available Antiretroviral Agents
Authors: Robinson Brett S. , Riccardi Keith A. , Gong Yi-fei , Guo Qi , Stock David A. , Blair Wade S. , Terry Brian J. , Deminie Carol A. , Djang Fred , Colonno Richard J. , Lin Pin-fang
Published: July 2002

BMS-232632 is an azapeptide human immunodeficiency virus type 1 (HIV-1) protease (Prt) inhibitor that exhibits potent anti-HIV activity with a 50% effective concentration (EC50) of 2.6 to 5.3 nM and an EC90of 9 to 15 nM in cell culture. Proof-of-principle studies indicate that BMS-232632 blocks the cleavage of viral precursor proteins in HIV-infected cells, proving that it functions as an HIV Prt inhibitor. Comparative studies showed that BMS-232632 is generally more potent than the five currently approved HIV-1 Prt inhibitors. Furthermore, BMS-232632 is highly selective for HIV-1 Prt and exhibits cytotoxicity only at concentrations 6,500- to 23,000-fold higher than that required for anti-HIV activity. To assess the potential of this inhibitor when used in combination with other antiretrovirals, BMS-232632 was evaluated for anti-HIV activity in two-drug combination studies. Combinations of BMS-232632 with either stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HIV-infected peripheral blood mononuclear cells yielded additive to moderately synergistic antiviral effects. Importantly, combinations of drug pairs did not result in antagonistic anti-HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation. Our results suggest that BMS-232632 may be an effective HIV-1 inhibitor that may be utilized in a variety of different drug combinations.
Selective Targeting of Topoisomerase IV and DNA Gyrase in
Staphylococcus aureus
: Different Patterns of Quinolone- Induced Inhibition of DNA Synthesis
Authors: Fournier Bénédicte , Zhao Xilin , Lu Tao , Drlica Karl , Hooper David C.
Published: July 2002

The effect of quinolones on the inhibition of DNA synthesis in
Staphylococcus aureus
was examined by using single resistance mutations in
parC
or
gyrA
to distinguish action against gyrase or topoisomerase IV, respectively. Norfloxacin preferentially attacked topoisomerase IV and blocked DNA synthesis slowly, while nalidixic acid targeted gyrase and inhibited replication rapidly. Ciprofloxacin exhibited an intermediate response, consistent with both enzymes being targeted. The absence of RecA had little influence on target choice by this assay, indicating that differences in rebound (repair) DNA synthesis were not responsible for the results. At saturating drug concentrations, norfloxacin and a
gyrA
mutant were used to show that topoisomerase IV-norfloxacin-cleaved DNA complexes are distributed on the
S. aureus
chromosome at intervals of about 30 kbp. If cleaved complexes block DNA replication, as indicated by previous work, such close spacing of topoisomerase-quinolone-DNA complexes should block replication rapidly (replication forks are likely to encounter a cleaved complex within a minute). Thus, the slow inhibition of DNA synthesis at growth-inhibitory concentrations suggests that a subset of more distantly distributed complexes is physiologically relevant for drug action and is unlikely to be located immediately in front of the DNA replication fork.
Biochemical-Genetic Characterization and Distribution of OXA-22, a Chromosomal and Inducible Class D β-Lactamase fromRalstonia(Pseudomonas)pickettii
Authors: Nordmann Patrice , Poirel Laurent , Kubina Maryline , Casetta Anne , Naas Thierry
Published: July 2002

From genomic DNA ofRalstonia pickettiiisolate PIC-1, a β-lactamase gene was cloned that encodes the oxacillinase OXA-22. It differs from known oxacillinases, being most closely related to OXA-9 (38% amino acid identity). The hydrolytic spectrum of OXA-22 is limited mostly to benzylpenicillin, cloxacillin, and restricted-spectrum cephalosporins. OXA-22-like genes were identified as single chromosomal copies in five otherR. pickettiiclinical isolates. The expression of OXA-22-like β-lactamases was inducible inR. pickettii.
SmeDEF Multidrug Efflux Pump Contributes to Intrinsic Multidrug Resistance in
Stenotrophomonas maltophilia
Authors: Zhang Li , Li Xian-Zhi , Poole Keith
Published: July 2002

Stenotrophomonas maltophilia
is an emerging nosocomial pathogen that displays high-level intrinsic resistance to a variety of structurally unrelated antimicrobial agents. Efflux mechanisms are known to contribute to acquired multidrug resistance in this organism, and indeed, one such multidrug efflux system, SmeDEF, was recently identified. Still, the importance of SmeDEF to intrinsic antibiotic resistance in
S. maltophilia
had not yet been determined. Reverse transcription-PCR confirmed expression of the
smeDEF
genes in wild-type
S. maltophilia
, and deletion of
smeE
or
smeF
in wild-type strains rendered the mutants hypersusceptible to several antimicrobials, suggesting that SmeDEF contributes to intrinsic antimicrobial resistance in this organism. Expression of
smeDEF
was also enhanced in an in vitro-selected multidrug-resistant mutant, although deletion of
smeF
but not of
smeE
in these mutants compromised antimicrobial resistance. Apparently, hyperexpressed SmeF is capable of functioning with additional multidrug efflux components to promote multidrug resistance in
S. maltophilia
.
Target Preference of 15 Quinolones againstStaphylococcus aureus, Based on Antibacterial Activities and Target Inhibition
Authors: Takei Masaya , Fukuda Hideyuki , Kishii Ryuta , Hosaka Masaki
Published: July 2002

The antibacterial activities and target inhibition of 15 quinolones againstgrlAandgyrAmutant strains were studied. The strains were obtained from wild-typeStaphylococcus aureusMS5935 by selection with norfloxacin and nadifloxacin, respectively. The antibacterial activities of most quinolones against both mutant strains were lower than those against the wild-type strain. The ratios of MICs for thegyrAmutant strain to those for thegrlAmutant strain (MIC ratio) varied from 0.125 to 4. The ratios of 50% inhibitory concentrations (IC50s) of quinolones against topoisomerase IV to those against DNA gyrase (IC50ratios) also varied, from 0.177 to 5.52. A significant correlation between the MIC ratios and the IC50ratios was observed (r= 0.919;P< 0.001). These results suggest that the antibacterial activities of quinolones against the wild-type strain are involved not only in topoisomerase IV inhibition but also in DNA gyrase inhibition and that the target preference in the wild-type strain can be anticipated by the MIC ratios. Based on the MIC ratios, the quinolones were classified into three categories. Type I quinolones (norfloxacin, enoxacin, fleroxacin, ciprofloxacin, lomefloxacin, trovafloxacin, grepafloxacin, ofloxacin, and levofloxacin) had MIC ratios of <1, type II quinolones (sparfloxacin and nadifloxacin) had MIC ratios of >1, and type III quinolones (gatifloxacin, pazufloxacin, moxifloxacin, and clinafloxacin) had MIC ratios of 1. Type I and type II quinolones seem to prefer topoisomerase IV and DNA gyrase, respectively. Type III quinolones seem to target both enzymes at nearly the same level in bacterial cells (a phenomenon known as the dual-targeting property), and their IC50ratios were approximately 2.
Need for Annual Surveillance of Antimicrobial Resistance in
Streptococcus pneumoniae
in the United States: 2-Year Longitudinal Analysis
Authors: Sahm Daniel F. , Karlowsky James A. , Kelly Laurie J. , Critchley Ian A. , Jones Mark E. , Thornsberry Clyde , Mauriz Yolanda , Kahn James
Published: July 2002

Although changing patterns in antimicrobial resistance in
Streptococcus pneumoniae
have prompted several surveillance initiatives in recent years, the frequency with which these studies are needed has not been addressed. To approach this issue, the extent to which resistance patterns change over a 1-year period was examined. In this study we analyzed
S. pneumoniae
antimicrobial susceptibility results produced in our laboratory with isolates obtained over 2 consecutive years (1997–1998 and 1998–1999) from the same 96 institutions distributed throughout the United States. Comparison of results revealed increases in resistant percentages for all antimicrobial agents studied except vancomycin. For four of the agents tested (penicillin, cefuroxime, trimethoprim-sulfamethoxazole, and levofloxacin), the increases were statistically significant (
P
< 0.05). Resistance to the fluoroquinolone remained low in both years (0.1 and 0.6%, respectively); in contrast, resistance to macrolides was consistently greater than 20%, and resistance to trimethoprim-sulfamethoxazole increased from 13.3 to 27.3%. Multidrug resistance, concurrent resistance to three or more antimicrobials of different chemical classes, also increased significantly between years, from 5.9 to 11%. The most prevalent phenotype was resistance to penicillin, azithromycin (representative macrolide), and trimethoprim-sulfamethoxazole. Multidrug-resistant phenotypes that included fluoroquinolone resistance were uncommon; however, two phenotypes that included fluoroquinolone resistance not found in 1997–1998 were encountered in 1998–1999. This longitudinal surveillance study of resistance in
S. pneumoniae
revealed that significant changes do occur in just a single year and supports the need for surveillance at least on an annual basis, if not continuously.
Staphylococcus aureus
Cell Extract Transcription-Translation Assay: Firefly Luciferase Reporter System for Evaluating Protein Translation Inhibitors
Authors: Murray Robert W. , Melchior Earline P. , Hagadorn Jeanne C. , Marotti Keith R.
Published: July 2002

The promoter for the
Staphylococcus aureus
capsule polysaccharide synthesis gene (
cap1A
) was cloned in front of the firefly luciferase gene for use in a cell extract
S. aureus
transcription-translation system. The assay is rapid, reproducible, and sensitive and has a lower background level than the radiolabeled amino acid incorporation translation assays. We present data evaluating a transcription inhibitor and a number of protein translation inhibitors in this system.
SmeC, an Outer Membrane Multidrug Efflux Protein of
Stenotrophomonas maltophilia
Authors: Li Xian-Zhi , Zhang Li , Poole Keith
Published: July 2002

A homologue of the
mexAB-oprM
multidrug efflux operon of
Pseudomonas aeruginosa
,
smeABC
, was cloned from
Stenotrophomonas maltophilia
by using, as a probe, a PCR product amplified from this organism with primers based on the
mexB
sequence. The
smeABC
genes were hyperexpressed in a mutant strain displaying resistance to several antimicrobials, including aminoglycosides, β-lactams, and fluoroquinolones. Deletions in
smeC
but not
smeB
compromised this resistance, suggesting that SmeC contributed to the multidrug resistance of the mutant as part of another, as-yet-unidentified multidrug efflux system. Consistent with SmeC functioning independently of SmeAB, a promoter activity was identified upstream of
smeC
. Upstream of the
smeABC
genes, a putative two-gene operon,
smeSR
, encoding homologues of bacterial two-component regulatory systems was identified. The cloned
smeR
gene activated expression of a
smeA-lacZ
fusion, indicating that SmeR positively regulates expression of the
smeABC
genes. Consistent with this, the multidrug resistance of the SmeABC-hyperexpressing mutant was compromised by deletion of
smeR
. Intriguingly, SmeC expression in
S. maltophilia
paralleled a β-lactamase activity provided by a C-terminally truncated L2 enzyme, which was apparently responsible for the β-lactam resistance of the SmeABC-hyperexpressing mutant. This represents the first report of coregulation of an efflux resistance determinant and a β-lactamase.