bluuebunny/crossref_metadata_2025 huggingface dataset:
Consistent Land- and Atmosphere-Based U.S. Carbon Sink Estimates
Authors: Pacala S. W. , Hurtt G. C. , Baker D. , Peylin P. , Houghton R. A. , Birdsey R. A. , Heath L. , Sundquist E. T. , Stallard R. F. , Ciais P. , Moorcroft P. , Caspersen J. P. , Shevliakova E. , Moore B. , Kohlmaier G. , Holland E. , Gloor M. , Harmon M. E. , Fan S.-M. , Sarmiento J. L. , Goodale C. L. , Schimel D. , Field C. B.
Published: July 2002

For the period 1980–89, we estimate a carbon sink in the coterminous United States between 0.30 and 0.58 petagrams of carbon per year (petagrams of carbon = 10
15
grams of carbon). The net carbon flux from the atmosphere to the land was higher, 0.37 to 0.71 petagrams of carbon per year, because a net flux of 0.07 to 0.13 petagrams of carbon per year was exported by rivers and commerce and returned to the atmosphere elsewhere. These land-based estimates are larger than those from previous studies (0.08 to 0.35 petagrams of carbon per year) because of the inclusion of additional processes and revised estimates of some component fluxes. Although component estimates are uncertain, about one-half of the total is outside the forest sector. We also estimated the sink using atmospheric models and the atmospheric concentration of carbon dioxide (the tracer-transport inversion method). The range of results from the atmosphere-based inversions contains the land-based estimates. Atmosphere- and land-based estimates are thus consistent, within the large ranges of uncertainty for both methods. Atmosphere-based results for 1980–89 are similar to those for 1985–89 and 1990–94, indicating a relatively stable U.S. sink throughout the period.
Strand-Specific Postreplicative Processing of Mammalian Telomeres
Authors: Bailey S. M. , Cornforth M. N. , Kurimasa A. , Chen D. J. , Goodwin E. H.
Published: July 2002

Telomeres are specialized nucleoprotein structures that stabilize the ends of linear eukaryotic chromosomes. In mammalian cells, abrogation of telomeric repeat binding factor TRF2 or DNA-dependent protein kinase (DNA-PK) activity causes end-to-end chromosomal fusion, thus establishing an essential role for these proteins in telomere function. Here we show that TRF2-mediated end-capping occurs after telomere replication. The postreplicative requirement for TRF2 and DNA-PKcs, the catalytic subunit of DNA-PK, is confined to only half of the telomeres, namely, those that were produced by leading-strand DNA synthesis. These results demonstrate a crucial difference in postreplicative processing of telomeres that is linked to their mode of replication.
A DNA Microarray-Based Genetic Screen for Nonhomologous End-Joining Mutants in
Saccharomyces cerevisiae
Authors: Ooi Siew Loon , Shoemaker Daniel D. , Boeke Jef D.
Published: July 2002

We describe a microarray-based screen performed by imposing different genetic selections on thousands of yeast mutants in parallel, representing most genes in the yeast genome. The presence or absence of mutants was detected by oligonucleotide arrays that hybridize to 20-nucleotide “barcodes.” We used this method to screen for components of the nonhomologous end-joining (NHEJ) pathway. Known components of the pathway were identified, as well as a gene not previously known to be involved in NHEJ,
NEJ1
. Nej1 protein interacts with the amino terminus of LIF1/XRCC4, a recently recognized “guardian of the genome” against cancer.
Redox Regulation of Forkhead Proteins Through a
p66shc
-Dependent Signaling Pathway
Authors: Nemoto Shino , Finkel Toren
Published: July 2002

Genetic determinants of longevity include the forkhead-related transcription factor DAF-16 in the worm
Caenorhabditis elegans
and the
p66shc
locus in mice. We demonstrate that
p66shc
regulates intracellular oxidant levels in mammalian cells and that hydrogen peroxide can negatively regulate forkhead activity. In
p66shc
–/–
cells, the activity of the mammalian forkhead homolog FKHRL1 is increased and redox-dependent forkhead inactivation is reduced. In addition, expression of FKHRL1 results in an increase in both hydrogen peroxide scavenging and oxidative stress resistance. These results demonstrate an important functional relation between three distinct elements linked to aging: forkhead proteins,
p66shc
, and intracellular oxidants.
Noble Gas-Actinide Compounds: Complexation of the CUO Molecule by Ar, Kr, and Xe Atoms in Noble Gas Matrices
Authors: Li Jun , Bursten Bruce E. , Liang Binyong , Andrews Lester
Published: July 2002

The CUO molecule, formed from the reaction of laser-ablated U atoms with CO in a noble gas, exhibits very different stretching frequencies in a solid argon matrix [804.3 and 852.5 wave numbers (cm
−1
)] than in a solid neon matrix (872.2 and 1047.3 cm
−1
). Related experiments in a matrix consisting of 1% argon in neon suggest that the argon atoms are interacting directly with the CUO molecule. Relativistic density functional calculations predict that CUO can bind directly to one argon atom (U-Ar = 3.16 angstroms; binding energy = 3.2 kilocalories per mole), accompanied by a change in the ground state from a singlet to a triplet. Our experimental and theoretical results also suggest that multiple argon atoms can bind to a single CUO molecule.
Preferential Formation of Benzo[
a
]pyrene Adducts at Lung Cancer Mutational Hotspots in
P53
Authors: Denissenko Mikhail F. , Pao Annie , Tang Moon-shong , Pfeifer Gerd P.
Published: July 2002

Cigarette smoke carcinogens such as benzo[
a
]pyrene are implicated in the development of lung cancer. The distribution of benzo[
a
]pyrene diol epoxide (BPDE) adducts along exons of the
P53
gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct formation occurred at guanine positions in codons 157, 248, and 273. These same positions are the major mutational hotspots in human lung cancers. Thus, targeted adduct formation rather than phenotypic selection appears to shape the
P53
mutational spectrum in lung cancer. These results provide a direct etiological link between a defined chemical carcinogen and human cancer.
Basic Science Spending to Jump in 1997
Authors: Normile Dennis
Published: July 2002

Tokyo—Science is set to grow faster in 1997 than most other government activities, as a draft budget shows an 8% increase for basic science programs. That's in line with a 5-year plan adopted last summer to use science and technology as an economic driver.
Diameter-Selective Raman Scattering from Vibrational Modes in Carbon Nanotubes
Authors: Rao A. M. , Richter E. , Bandow Shunji , Chase Bruce , Eklund P. C. , Williams K. A. , Fang S. , Subbaswamy K. R. , Menon M. , Thess A. , Smalley R. E. , Dresselhaus G. , Dresselhaus M. S.
Published: July 2002

Single wall carbon nanotubes (SWNTs) that are found as close-packed arrays in crystalline ropes have been studied by using Raman scattering techniques with laser excitation wavelengths in the range from 514.5 to 1320 nanometers. Numerous Raman peaks were observed and identified with vibrational modes of armchair symmetry (
n
,
n
) SWNTs. The Raman spectra are in good agreement with lattice dynamics calculations based on C-C force constants used to fit the two-dimensional, experimental phonon dispersion of a single graphene sheet. Calculated intensities from a nonresonant, bond polarizability model optimized for
sp
2
carbon are also in qualitative agreement with the Raman data, although a resonant Raman scattering process is also taking place. This resonance results from the one-dimensional quantum confinement of the electrons in the nanotube.
A Functional Model Related to Cytochrome c Oxidase and Its Electrocatalytic Four-Electron Reduction of O
2
Authors: Collman James P. , Fu Lei , Herrmann Paul C. , Zhang Xumu
Published: July 2002

A cytochrome c oxidase model that consists of a cobalt(II) porphyrin with a copper(I) triazacyclononane macrocycle fastened on the distal face and an imidazole covalently attached to the proximal face has been synthesized and characterized. Redox titrations with molecular oxygen (O
2
) and cobaltocene were carried out, and O
2
was found to bind irreversibly in a 1:1 ratio to the model compound. This O
2
adduct (a bridged peroxide) can be fully reduced to the deoxygenated form with four equivalents of cobaltocene. The model compound was adsorbed on an edge-plane graphite electrode, and rotating ring-disk voltammetry was used to monitor the electrocatalytic reduction of O
2
. Four-electron reduction of O
2
was observed at physiological pH.
Modeling of Cometary X-rays Caused by Solar Wind Minor Ions
Authors: Häberli Roman M. , Gombosi Tamas I. , De Zeeuw Darren L. , Combi Michael R. , Powell Kenneth G.
Published: July 2002

X-ray emission was discovered in comet Hyakutake (C/1996 B2) by the Röntgen satellite in 1996, and these emissions were attributed to the excitation of high charge state solar wind ions due to electron capture from cometary molecules or atoms. Using the plasma flow in the coma of Hyakutake calculated by a three-dimensional adaptive magnetohydrodynamic model, the density distribution of solar wind ions in the coma and the resulting x-ray emission were computed. The calculated High Resolution Imager count rate of 4.4 per second and the spatial distribution of the x-ray emission agree with the observations. A detailed energy spectrum of cometary x-rays is predicted in the 80 to 2000 electronvolt energy range. Cometary x-rays present a sensitive tool to monitor cometary activity and solar wind ion composition.
Advances from Japan
Authors: Nathan Marshall I.
Published: July 2002

The Blue Laser Diode.
GaN Based Light Emitters and Lasers. SHUJI NAKAMURA and GERHARD FASOL. Springer-Verlag, New York, 1997. xvi, 343 pp., illus. $69.96 or DM 98. ISBN 3-540-61590-3.
Biomass Collapse in Amazonian Forest Fragments
Authors: Laurance William F. , Laurance Susan G. , Ferreira Leandro V. , Rankin-de Merona Judy M. , Gascon Claude , Lovejoy Thomas E.
Published: July 2002

Rain forest fragments in central Amazonia were found to experience a dramatic loss of above-ground tree biomass that is not offset by recruitment of new trees. These losses were largest within 100 meters of fragment edges, where tree mortality is sharply increased by microclimatic changes and elevated wind turbulence. Permanent study plots within 100 meters of edges lost up to 36 percent of their biomass in the first 10 to 17 years after fragmentation. Lianas (climbing woody vines) increased near edges but usually compensated for only a small fraction of the biomass lost as a result of increased tree mortality.
A Model for the Mechanism of Human Topoisomerase I
Authors: Stewart Lance , Redinbo Matthew R. , Qiu Xiayang , Hol Wim G. J. , Champoux James J.
Published: July 2002

The three-dimensional structure of a 70-kilodalton amino terminally truncated form of human topoisomerase I in complex with a 22–base pair duplex oligonucleotide, determined to a resolution of 2.8 angstroms, reveals all of the structural elements of the enzyme that contact DNA. The linker region that connects the central core of the enzyme to the carboxyl-terminal domain assumes a coiled-coil configuration and protrudes away from the remainder of the enzyme. The positively charged DNA-proximal surface of the linker makes only a few contacts with the DNA downstream of the cleavage site. In combination with the crystal structures of the reconstituted human topoisomerase I before and after DNA cleavage, this information suggests which amino acid residues are involved in catalyzing phosphodiester bond breakage and religation. The structures also lead to the proposal that the topoisomerization step occurs by a mechanism termed “controlled rotation.”
Polyolefin Spheres from Metallocenes Supported on Noninteracting Polystyrene
Authors: Roscoe Stephen B. , Fréchet Jean M. J. , Walzer John F. , Dias Anthony J.
Published: July 2002

To obviate the destructive interaction of highly reactive metallocene catalysts with classical silica-based supports while retaining the advantage of supported catalysts, a noninteracting polystyrene support was developed. Supported catalysts for the polymerization of α-olefins are prepared by treating lightly cross-linked, chloromethylated polystyrene beads consecutively with a secondary amine, an ammonium salt of a weakly coordinating anion, and a neutral dialkylmetallocene. Catalytic sites are distributed homogeneously throughout the support particle, and the polymerization occurs within the bead, in contrast to traditional surface-supported metallocene catalysts. The copolymerization of ethylene and 1-hexene at 40°C affords discrete spherical polyolefin beads with a size (0.3 to 1.4 millimeters) that varies according to the polymerization time.
An Inverted Hexagonal Phase of Cationic Liposome-DNA Complexes Related to DNA Release and Delivery
Authors: Koltover Ilya , Salditt Tim , Rädler Joachim O. , Safinya Cyrus R.
Published: July 2002

A two-dimensional columnar phase in mixtures of DNA complexed with cationic liposomes has been found in the lipid composition regime known to be significantly more efficient at transfecting mammalian cells in culture compared to the lamellar (L
α
C
) structure of cationic liposome–DNA complexes. The structure, derived from synchrotron x-ray diffraction, consists of DNA coated by cationic lipid monolayers and arranged on a two-dimensional hexagonal lattice (H
II
C
). Two membrane-altering pathways induce the L
α
C
→ H
II
C
transition: one where the spontaneous curvature of the lipid monolayer is driven negative, and another where the membrane bending rigidity is lowered with a new class of helper-lipids. Optical microscopy revealed that the L
α
C
complexes bind stably to anionic vesicles (models of cellular membranes), whereas the more transfectant H
II
C
complexes are unstable and rapidly fuse and release DNA upon adhering to anionic vesicles.
A Matter of Life and Cell Death
Authors: Evan Gerard , Littlewood Trevor
Published: July 2002

In multicellular organisms, mutations in somatic cells affecting critical genes that regulate cell proliferation and survival cause fatal cancers. Repair of the damage is one obvious option, although the relative inconsequence of individual cells in metazoans means that it is often a “safer” strategy to ablate the offending cell. Not surprisingly, corruption of the machinery that senses or implements DNA damage greatly predisposes to cancer. Nonetheless, even when oncogenic mutations do occur, there exist potent mechanisms that limit the expansion of affected cells by suppressing their proliferation or triggering their suicide. Growing understanding of these innate mechanisms is suggesting novel therapeutic strategies for cancer.
Solar Wind Outflow and the Chromospheric Magnetic Network
Authors: Hassler Donald M. , Dammasch Ingolf E. , Lemaire Philippe , Brekke Pål , Curdt Werner , Mason Helen E. , Vial Jean-Claude , Wilhelm Klaus
Published: July 2002

Observations of outflow velocities in coronal holes (regions of open coronal magnetic field) have recently been obtained with the Solar and Heliospheric Observatory (SOHO) spacecraft. Velocity maps of Ne
7+
from its bright resonance line at 770 angstroms, formed at the base of the corona, show a relationship between outflow velocity and chromospheric magnetic network structure, suggesting that the solar wind is rooted at its base to this structure, emanating from localized regions along boundaries and boundary intersections of magnetic network cells. This apparent relation to the chromospheric magnetic network and the relatively large outflow velocity signatures will improve understanding of the complex structure and dynamics at the base of the corona and the source region of the solar wind.
Phase Separation Scenario for Manganese Oxides and Related Materials
Authors: Moreo Adriana , Yunoki Seiji , Dagotto Elbio
Published: July 2002

Recent computational studies of models for manganese oxides have revealed a rich phase diagram, which was not anticipated in early calculations in this context performed in the 1950s and 1960s. In particular, the transition between the antiferromagnetic insulator state of the hole-undoped limit and the ferromagnetic metal at finite hole density was found to occur through a mixed-phase process. When extended Coulomb interactions are included, a microscopically charged inhomogeneous state should be stabilized. These phase separation tendencies, also present at low electronic densities, influence the properties of the ferromagnetic region by increasing charge fluctuations. Experimental data reviewed here by applying several techniques for manganites and other materials are consistent with this scenario. Similarities with results previously discussed in the context of cuprates are clear from this analysis, although the phase segregation tendencies in manganites appear stronger.
Complexity in Biological Signaling Systems
Authors: Weng Gezhi , Bhalla Upinder S. , Iyengar Ravi
Published: July 2002

Biological signaling pathways interact with one another to form complex networks. Complexity arises from the large number of components, many with isoforms that have partially overlapping functions; from the connections among components; and from the spatial relationship between components. The origins of the complex behavior of signaling networks and analytical approaches to deal with the emergent complexity are discussed here.
The Magnetic Excitation Spectrum and Thermodynamics of High-
T
c
Superconductors
Authors: Dai Pengcheng , Mook H. A. , Hayden S. M. , Aeppli G. , Perring T. G. , Hunt R. D. , Doğan F.
Published: July 2002

Inelastic neutron scattering was used to study the wave vector– and frequency-dependent magnetic fluctuations in single crystals of superconducting YBa
2
Cu
3
O
6+

x

. The spectra contain several important features, including a gap in the superconducting state, a pseudogap in the normal state, and the much-discussed resonance peak. The appearance of the pseudogap determined from transport and nuclear resonance coincides with formation of the resonance in the magnetic excitations. The exchange energy associated with the resonance has the temperature and doping dependences as well as the magnitude to describe approximately the electronic specific heat near the superconducting transition temperature (
T
c
).
Structure of Human Pro-Matrix Metalloproteinase-2: Activation Mechanism Revealed
Authors: Morgunova Ekaterina , Tuuttila Ari , Bergmann Ulrich , Isupov Mikhail , Lindqvist Ylva , Schneider Gunter , Tryggvason Karl
Published: July 2002

Matrix metalloproteinases (MMPs) catalyze extracellular matrix degradation. Control of their activity is a promising target for therapy of diseases characterized by abnormal connective tissue turnover. MMPs are expressed as latent proenzymes that are activated by proteolytic cleavage that triggers a conformational change in the propeptide (cysteine switch). The structure of proMMP-2 reveals how the propeptide shields the catalytic cleft and that the cysteine switch may operate through cleavage of loops essential for propeptide stability.
Neuronal Protection in Stroke by an sLe
x
-Glycosylated Complement Inhibitory Protein
Authors: Huang Judy , Kim Louis J. , Mealey Richard , Marsh Henry C. , Zhang Yuan , Tenner Andrea J. , Connolly E. Sander , Pinsky David J.
Published: July 2002

Glycoprotein adhesion receptors such as selectins contribute to tissue injury in stroke. Ischemic neurons strongly expressed C1q, which may target them for complement-mediated attack or C1qRp-mediated clearance. A hybrid molecule was used to simultaneously inhibit both complement activation and selectin-mediated adhesion. The extracellular domain of soluble complement receptor–1 (sCR1) was sialyl Lewis x glycosylated (sCR1sLe
x
) to inhibit complement activation and endothelial-platelet-leukocyte interactions. sCR1 and sCR1sLe
x
colocalized to ischemic cerebral microvessels and C1q-expressing neurons, inhibited neutrophil and platelet accumulation, and reduced cerebral infarct volumes. Additional benefit was conferred by sialyl Lewis x glycosylation of the unmodified parent sCR1 molecule.
Phonon- Versus Electron-Mediated Desorption and Oxidation of CO on Ru(0001)
Authors: Bonn M. , Funk S. , Hess Ch. , Denzler D. N. , Stampfl C. , Scheffler M. , Wolf M. , Ertl G.
Published: July 2002

Heating of a ruthenium surface on which carbon monoxide and atomic oxygen are coadsorbed leads exclusively to desorption of carbon monoxide. In contrast, excitation with femtosecond infrared laser pulses enables also the formation of carbon dioxide. The desorption is caused by coupling of the adsorbate to the phonon bath of the ruthenium substrate, whereas the oxidation reaction is initiated by hot substrate electrons, as evidenced by the observed subpicosecond reaction dynamics and density functional calculations. The presence of this laser-induced reaction pathway allows elucidation of the microscopic mechanism and the dynamics of the carbon monoxide oxidation reaction.
Modulation of Respiratory Frequency by Peptidergic Input to Rhythmogenic Neurons in the PreBötzinger Complex
Authors: Gray Paul A. , Rekling Jens C. , Bocchiaro Christopher M. , Feldman Jack L.
Published: July 2002

Neurokinin-1 receptor (NK1R) and μ-opioid receptor (μOR) agonists affected respiratory rhythm when injected directly into the preBötzinger Complex (preBötC), the hypothesized site for respiratory rhythmogenesis in mammals. These effects were mediated by actions on preBötC rhythmogenic neurons. The distribution of NK1R
+
neurons anatomically defined the preBötC. Type 1 neurons in the preBötC, which have rhythmogenic properties, expressed both NK1Rs and μORs, whereas type 2 neurons expressed only NK1Rs. These findings suggest that the preBötC is a definable anatomic structure with unique physiological function and that a subpopulation of neurons expressing both NK1Rs and μORs generate respiratory rhythm and modulate respiratory frequency.
A Role for Histone Acetylation in the Developmental Regulation of V(D)J Recombination
Authors: McMurry Michelle Taylor , Krangel Michael S.
Published: July 2002

V(D)J recombination is developmentally regulated in vivo by enhancer-dependent changes in the accessibility of chromosomal recombination signal sequences to the recombinase, but the molecular nature of these changes is unknown. Here histone H3 acetylation was measured along versions of a transgenic V(D)J recombination reporter and the endogenous T cell receptor α/δ locus. Enhancer activity was shown to impart long-range, developmentally regulated changes in H3 acetylation, and H3 acetylation status was tightly linked to V(D)J recombination. H3 hyperacetylation is proposed as a molecular mechanism coupling enhancer activity to accessibility for V(D)J recombination.
Lunar Impact History from
40
Ar/
39
Ar Dating of Glass Spherules
Authors: Culler Timothy S. , Becker Timothy A. , Muller Richard A. , Renne Paul R.
Published: July 2002

Lunar spherules are small glass beads that are formed mainly as a result of small impacts on the lunar surface; the ages of these impacts can be determined by the
40
Ar/
39
Ar isochron technique. Here, 155 spherules separated from 1 gram of Apollo 14 soil were analyzed using this technique. The data show that over the last ∼3.5 billion years, the cratering rate decreased by a factor of 2 to 3 to a low about 500 to 600 million years ago, then increased by a factor of 3.7 ± 1.2 in the last 400 million years. This latter period coincided with rapid biotic evolutionary radiation on Earth.
A Brief History of
Drosophila
's Contributions to Genome Research
Authors: Rubin Gerald M. , Lewis Edward B.
Published: July 2002

The sequence of the
Drosophila melanogaster
genome presented in this issue of
Science
is the latest milestone in nine decades of research on this organism. Genetic and physical mapping, whole-genome mutational screens, and functional alteration of the genome by gene transfer were pioneered in metazoans with the use of this small fruit fly. Here we look at some of the instances in which work on
Drosophila
has led to major conceptual or technical breakthroughs in our understanding of animal genomes.
Cooperation Through Image Scoring in Humans
Authors: Wedekind Claus , Milinski Manfred
Published: July 2002

The “tragedy of the commons,” that is, the selfish exploitation of resources in the public domain, is a reason for many of our everyday social conflicts. However, humans are often more helpful to others than evolutionary theory would predict, unless indirect reciprocity takes place and is based on image scoring (which reflects the way an individual is viewed by a group), as recently shown by game theorists. We tested this idea under conditions that control for confounding factors. Donations were more frequent to receivers who had been generous to others in earlier interactions. This shows that image scoring promotes cooperative behavior in situations where direct reciprocity is unlikely.
Evidence for the Evolution of Bdelloid Rotifers Without Sexual Reproduction or Genetic Exchange
Authors: Mark Welch David B. , Meselson Matthew
Published: July 2002

The Class Bdelloidea of the Phylum Rotifera is the largest metazoan taxon in which males, hermaphrodites, and meiosis are unknown. We conducted a molecular genetic test of this indication that bdelloid rotifers may have evolved without sexual reproduction or genetic exchange. The test is based on the expectation that after millions of years without these processes, genomes will no longer contain pairs of closely similar haplotypes and instead will contain highly divergent descendants of formerly allelic nucleotide sequences. We find that genomes of individual bdelloid rotifers, representing four different species, appear to lack pairs of closely similar sequences and contain representatives of two ancient lineages that began to diverge before the bdelloid radiation many millions of years ago when sexual reproduction and genetic exchange may have ceased.
High Magma Storage Rates Before the 1983 Eruption of Kilauea, Hawaii
Authors: Cayol Valérie , Dieterich James H. , Okamura Arnold T. , Miklius Asta
Published: July 2002

After a magnitude 7.2 earthquake in 1975 and before the start of the ongoing eruption in 1983, deformation of Kilauea volcano was the most rapid ever recorded. Three-dimensional numerical modeling shows that this deformation is consistent with the dilation of a dike within Kilauea's rift zones coupled with creep over a narrow area of a low-angle fault beneath the south flank. Magma supply is estimated to be 0.18 cubic kilometers per year, twice that of previous estimates. The 1983 eruption may be a direct consequence of the high rates of magma storage within the rift zone that followed the 1975 earthquake.
Altered Nociceptive Neuronal Circuits After Neonatal Peripheral Inflammation
Authors: Ruda M. A. , Ling Qing-Dong , Hohmann Andrea G. , Peng Yuan Bo , Tachibana Toshiya
Published: July 2002

Nociceptive neuronal circuits are formed during embryonic and postnatal times when painful stimuli are normally absent or limited. Today, medical procedures for neonates with health risks can involve tissue injury and pain for which the long-term effects are unknown. To investigate the impact of neonatal tissue injury and pain on development of nociceptive neuronal circuitry, we used an animal model of persistent hind paw peripheral inflammation. We found that, as adults, these animals exhibited spinal neuronal circuits with increased input and segmental changes in nociceptive primary afferent axons and altered responses to sensory stimulation.
A Basal Transcription Factor That Activates or Represses Transcription
Authors: Willy Patricia J. , Kobayashi Ryuji , Kadonaga James T.
Published: July 2002

We have identified an activity that is required for transcription of downstream promoter element (DPE)–containing core promoters in vitro. The purified factor was found to be the
Drosophila
homolog of the transcriptional repressor known as NC2 or Dr1-Drap1. Purified recombinant dNC2 activates DPE-driven promoters and represses TATA-driven promoters. A mutant version of dNC2 can activate DPE promoters but is unable to repress TATA promoters. Thus, the activation and repression functions are distinct. These studies reveal that NC2 (Dr1-Drap1) is a bifunctional basal transcription factor that differentially regulates gene transcription through DPE or TATA box motifs.
Down-Regulation of the Macrophage Lineage Through Interaction with OX2 (CD200)
Authors: Hoek Robert M. , Ruuls Sigrid R. , Murphy Craig A. , Wright Gavin J. , Goddard Ruth , Zurawski Sandra M. , Blom Bianca , Homola Margit E. , Streit Wolfgang J. , Brown Marion H. , Barclay A. Neil , Sedgwick Jonathon D.
Published: July 2002

OX2 (CD200) is a broadly expressed membrane glycoprotein, shown here to be important for regulation of the macrophage lineage. In mice lacking CD200, macrophage lineage cells, including brain microglia, exhibited an activated phenotype and were more numerous. Upon facial nerve transection, damaged CD200-deficient neurons elicited an accelerated microglial response. Lack of CD200 resulted in a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Outside the brain, disruption of CD200-CD200 receptor interaction precipitated susceptibility to collagen-induced arthritis (CIA) in mice normally resistant to this disease. Thus, in diverse tissues OX2 delivers an inhibitory signal for the macrophage lineage.
The Neurobiology of Slow Synaptic Transmission
Authors: Greengard Paul
Published: July 2002

Nerve cells communicate with each other through two mechanisms, referred to as fast and slow synaptic transmission. Fast-acting neurotransmitters, e.g., glutamate (excitatory) and γ-aminobutyric acid (GABA) (inhibitory), achieve effects on their target cells within one millisecond by virtue of opening ligand-operated ion channels. In contrast, all of the effects of the biogenic amine and peptide neurotransmitters, as well as many of the effects of glutamate and GABA, are achieved over hundreds of milliseconds to minutes by slow synaptic transmission. This latter process is mediated through an enormously more complicated sequence of biochemical steps, involving second messengers, protein kinases, and protein phosphatases. Slow-acting neurotransmitters control the efficacy of fast synaptic transmission by regulating the efficiency of neurotransmitter release from presynaptic terminals and by regulating the efficiency with which fast-acting neurotransmitters produce their effects on postsynaptic receptors.
Comparative In Vitro Activities of GAR-936 against Aerobic and Anaerobic Animal and Human Bite Wound Pathogens
Authors: Goldstein Ellie J. C. , Citron Diane M. , Merriam C. Vreni , Warren Yumi , Tyrrell Kerin
Published: July 2002

GAR-936 is a new semisynthetic glycylcycline with a broad antibacterial spectrum, including tetracycline-resistant strains. The in vitro activities of GAR-936, minocycline, doxycycline, tetracycline, moxifloxacin, penicillin G, and erythromycin were determined by agar dilution methods against 268 aerobic and 148 anaerobic strains of bacteria (including
Pasteurella
,
Eikenella
,
Moraxella
,
Bergeyella
,
Neisseria
, EF-4,
Bacteroides
,
Prevotella
,
Porphyromonas
,
Fusobacterium
,
Staphylococcus
,
Streptococcus
,
Enterococcus
,
Corynebacterium
,
Propionibacterium
,
Peptostreptococcus
, and
Actinomyces
) isolated from infected human and animal bite wounds in humans, including strains resistant to commonly used antimicrobials. GAR-936 was very active, with an MIC at which 90% of the strains are inhibited (MIC
90
) of ≤0.25 μg/ml, against all aerobic gram-positive and -negative strains, including tetracycline-resistant strains of
Enterococcus
,
Streptococcus
, and coagulase-negative staphylococci, except for
Eikenella corrodens
(MIC
90
, ≤4 μg/ml). GAR-936 was also very active against all anaerobic species, including tetracycline-, doxycycline-, and minocycline-resistant strains of
Prevotella
spp.,
Porphyromonas
spp.,
Bacteroides tectum
, and
Peptostreptococcus
spp., with an MIC
90
of ≤0.25 μg/ml. Erythromycin- and moxifloxacin-resistant fusobacteria were susceptible to GAR-936, with an MIC
90
of 0.06 μg/ml.
In Vitro Activities of Sitafloxacin (DU-6859a) and Six Other Fluoroquinolones against 8,796 Clinical Bacterial Isolates
Authors: Milatovic Dana , Schmitz Franz-Josef , Brisse Sylvain , Verhoef Jan , Fluit Ad C.
Published: July 2002

The in vitro activities of sitafloxacin, ciprofloxacin, trovafloxacin, levofloxacin, clinafloxacin, gatifloxacin, and moxifloxacin against 5,046 gram-negative bacteria, 3,344 gram-positive cocci, and 406 anaerobes were determined. Sitafloxacin was the most active agent against gram-positive cocci and anaerobes. Against
Enterobacteriaceae
and nonfermenters, its activity was either equivalent to or better than that of clinafloxacin.
Correlation between Pretreatment Levels of Interferon Response Genes and Clinical Responses to an Immune Response Modifier (Imiquimod) in Genital Warts
Authors: Arany I. , Tyring S. K. , Brysk M. M. , Stanley M. A. , Tomai M. A. , Miller R. L. , Smith M. H. , McDermott D. J. , Slade H. B.
Published: July 2002

Imiquimod (IQ) has been successfully used in treatment of genital warts. In clinical settings, patients responded well but wart reduction rates varied. Our aim was to find a correlation between clinical responses and pretreatment (constitutive) levels of genes that might be involved in the molecular action of IQ. Since IQ is a cytokine inducer, we analyzed levels of expression of genes of the JAK/STAT signaling pathway and their inhibitors as well as interferon response factors (IRFs) in pretreatment biopsy specimens from complete responders (99 to 100% wart reduction rate) versus incomplete responders (75 to 92% wart reduction rate) by reverse transcription-PCR. We found that mRNA levels of signal transducer and activator of transcription 1 (STAT1) and IRF1 were higher in complete responders than in incomplete responders. Incomplete responders expressed larger amounts of STAT3, IRF2, and protein inhibitor of activated STAT1 (PIAS1) mRNAs compared to complete responders before IQ treatment. We hypothesize that high-level expression of STAT1 and IRF1 is advantageous for a better IQ response. The observed differences in constitutive mRNA levels of these genes may be the consequence of alterations in cellular differentiation and/or variable expression of endogenous interferons. Previous in vitro studies showed that keratinocyte differentiation coordinates the balance between positive and negative signals along the JAK/STAT pathway by regulating the IRF1:IRF2 and STAT1:PIAS1 ratios and thus affecting induction of IQ-inducible genes. Specifically, differentiation supports constitutive expression of STAT1 and IRF1 mRNAs but not expression of IRF2 and PIAS1. Our data are in good agreement with studies that showed the importance of STAT1 in cytokine induction and activation of interferon-responsive genes by IQ.
Mechanism of Metronidazole Resistance in
Helicobacter pylori
: Comparison of the
rdxA
Gene Sequences in 30 Strains
Authors: Solcà Nadia Maggi , Bernasconi Marco Valerio , Piffaretti Jean-Claude
Published: July 2002

The
rdxA
gene of 30 independently isolated
Helicobacter pylori
strains was sequenced. A comparison of the
rdxA
sequences revealed a higher percentage of amino acid substitutions in the corresponding protein than in other housekeeping genes. Out of 122 point mutations, 41 were missense and 4 were nonsense. A resistant strain with a nucleotide insertion in the
rdxA
sequence was also found. With the exception of the point mutations and the insertion generating a stop signal, no particular nucleotide mutation or amino acid substitution could be associated to metronidazole resistance. Moreover, phylogenetic analysis of the 30 nucleotide sequences did not demonstrate specific clusters associated with the resistance phenotype.
Regional Differences in Metronidazole Resistance and Increasing Clarithromycin Resistance among
Helicobacter pylori
Isolates from Japan
Authors: Kato Mototsugu , Yamaoka Yoshio , Kim Jae J. , Reddy Rita , Asaka Masahiro , Kashima Kei , Osato Michael S. , El-Zaatari Fouad A. K. , Graham David Y. , Kwon Dong H.
Published: July 2002

The patterns of antibiotic resistance in
Helicobacter pylori
were assessed in two different regions in Japan. Overall, prevalences of resistance to metronidazole and clarithromycin were 12.4 and 12.9%, respectively. While there was no difference in clarithromycin resistance, the prevalence of metronidazole resistance was significantly higher in Kyoto (23.8%) than in Sapporo (8.1%). From 1996 to 1999, the prevalence of metronidazole resistance did not change but the prevalence of clarithromycin resistance doubled (from 9.1 to 18.7%).
Pharmacological Basis for Concentration-Controlled Therapy with Zidovudine, Lamivudine, and Indinavir
Authors: Kakuda Thomas N. , Page Linda M. , Anderson Peter L. , Henry Keith , Schacker Timothy W. , Rhame Frank S. , Acosta Edward P. , Brundage Richard C. , Fletcher Courtney V.
Published: July 2002

Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naı̈ve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.
Disruption of an
Enterococcus faecium
Species-Specific Gene, a Homologue of Acquired Macrolide Resistance Genes of Staphylococci, Is Associated with an Increase in Macrolide Susceptibility
Authors: Singh Kavindra V. , Malathum Kumthorn , Murray Barbara E.
Published: July 2002

The complete sequence (1,479 nucleotides) of
msrC
, part of which was recently reported by others using a different strain, was determined. This gene was found in 233 of 233 isolates of
Enterococcus faecium
but in none of 265 other enterococci. Disruption of
msrC
was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of
E. faecium
relative to many streptococci. This endogenous, species-specific gene of
E. faecium
is 53% identical to
msr
(A), suggesting that it may be a remote progenitor of the acquired macrolide resistance gene found in some isolates of staphylococci.
Family of Class 1 Integrons Related to In4 from Tn
1696
Authors: Partridge Sally R. , Recchia Gavin D. , Stokes H. W. , Hall Ruth M.
Published: July 2002

The class 1 integron In28, found in the multidrug resistance transposon Tn
1403
, was found to be located in the
res
site of the backbone transposon and is flanked by a 5-bp direct duplication, indicating that it reached this position by transposition. In28 has a backbone structure related to that of In4, but has lost internal sequences, including the
sul1
gene, due to an IS
6100
-mediated deletion. In28 also lacks the partial copy of IS
6100
found in In4 and contains different gene cassettes,
blaP1, cmlA1,
and
aadA1
. In1, the class 1 integron found in the multidrug resistance plasmid R46, is also located in a putative
res
site and belongs to the In4 group. In1 has a shorter internal deletion than In28 and has also lost one end. Additional integrons with structures related to In4 were also found in databases, and most of them had also lost either one end or internal regions or both. Tn
610
belongs to this group.
Hypersusceptibility of thePseudomonas aeruginosa nfxBMutant to β-Lactams Due to Reduced Expression of the AmpC β-Lactamase
Authors: Masuda Nobuhisa , Sakagawa Eiko , Ohya Satoshi , Gotoh Naomasa , Nishino Takeshi
Published: July 2002

ThePseudomonas aeruginosa nfxBmutant lackingmexAB-oprMshowed hypersusceptibility to 9 out of 24 β-lactams tested. This hypersusceptibility was found for thenfxBmutant lackingmexAB-oprM-mexXY(N108) but not for thenfxBmutant lacking bothmexAB-oprM-mexXYandampC. The level of the AmpC β-lactamase induction was reduced in N108. Thus, the reduced AmpC induction must be the cause of the hypersusceptibility.
Metallo-β-Lactamases in Clinical
Pseudomonas
Isolates in Taiwan and Identification of VIM-3, a Novel Variant of the VIM-2 Enzyme
Authors: Yan Jing-Jou , Hsueh Po-Ren , Ko Wen-Chien , Luh Kwen-Tay , Tsai Shu-Huei , Wu Hsiu-Mei , Wu Jiunn-Jong
Published: July 2002

A total of 209 clinical isolates of
Pseudomonas
(193
Pseudomonas aeruginosa
, 10
P. putida
, 4
P. stutzeri
, and 2
P. fluorescens
isolates) with reduced susceptibilities to imipenem and/or ceftazidime were subjected to PCR assays with primers specific for
bla
IMP-1
,
bla
IMP-2
,
bla
VIM-1
, and
bla
VIM-2
and sequence analysis to identify the metallo-β-lactamases (MBLs) prevalent among these organisms in Taiwan; and 21 isolates gave positive results. Five isolates including two
P. putida
and three
P. stutzeri
isolates were found to carry
bla
IMP-1
, and six isolates including five
P. putida
and one
P. stutzeri
isolates harbored
bla
VIM-2
. The remaining 10 isolates were
P. aeruginosa
, and all were found to carry a novel variant of
bla
VIM-2
, designated
bla
VIM-3
. There are only two nucleotide differences between
bla
VIM-2
and
bla
VIM-3
, leading to two amino acid alterations. Our findings indicate that VIM-2 and its variant have become the most prevalent metalloenzymes in
Pseudomonas
in Taiwan. Southern hybridization with the
bla
VIM-2
-,
bla
VIM-3
-, and
bla
IMP-1
-specific probes revealed that only two VIM-2-producing
P. putida
isolates appeared to carry the MBL gene on plasmids. Pulsed-field gel electrophoresis showed that six VIM-3-producing
P. aeruginosa
isolates and two IMP-1-producing
P. stutzeri
isolates were genetically related, suggesting that the spread of these MBL genes in Taiwan could be due to clonal dissemination as well as genetic exchange between different clones.
Susceptibilities to Telithromycin and Six Other Agents and Prevalence of Macrolide Resistance Due to L4 Ribosomal Protein Mutation among 992 Pneumococci from 10 Central and Eastern European Countries
Authors: Nagai Kensuke , Appelbaum Peter C. , Davies Todd A. , Kelly Linda M. , Hoellman Dianne B. , Andrasevic Arjana Tambic , Drukalska Liga , Hryniewicz Waleria , Jacobs Michael R. , Kolman Jana , Miciuleviciene Jolanta , Pana Marina , Setchanova Lena , Thege Marianne Konkoly , Hupkova Helena , Trupl Jan , Urbaskova Pavla
Published: July 2002

The macrolide and levofloxacin susceptibilities of 992 isolates of
Streptococcus pneumoniae
from clinical specimens collected in 1999 and 2000 were determined in 10 centers in Central and Eastern European countries. The prevalences of penicillin G-intermediate (MICs, 0.125 to 1 μg/ml) and penicillin-resistant (MICs, ≤2 μg/ml)
Streptococcus pneumoniae
isolates were 14.3 and 16.6%, respectively. The MICs at which 50% of isolates are inhibited (MIC
50
s) and the MIC
90
s of telithromycin were 0.016 and 0.06 μg/ml, respectively; those of erythromycin were 0.06 and >64 μg/ml, respectively; those of azithromycin were 0.125 and >64 μg/ml, respectively; those of clarithromycin were 0.03 and >64 μg/ml, respectively; and those of clindamycin were 0.06 and >64 μg/ml, respectively. Erythromycin resistance was found in 180
S. pneumoniae
isolates (18.1%); the highest prevalence of erythromycin-resistant
S. pneumoniae
was observed in Hungary (35.5%). Among erythromycin-resistant
S. pneumoniae
isolates, strains harboring
erm
(B) genes (125 strains [69.4%]) were found to be predominant over strains with
mef
(E) genes (25 strains [13.4%]), L4 protein mutations (28 strains [15.6%]), and
erm
(A) genes (2 strains [1.1%]). Similar pulsed-field gel electrophoresis patterns suggested that some strains containing L4 mutations from the Slovak Republic, Bulgaria, and Latvia were clonally related. Of nine strains highly resistant to levofloxacin (MICs, >8 μg/ml) six were isolated from Zagreb, Croatia. Telithromycin at ≤0.5 μg/ml was active against 99.8% of
S. pneumoniae
isolates tested and may be useful for the treatment of respiratory tract infections caused by macrolide-resistant
S. pneumoniae
isolates.
Characterization and Movement of the Class 1 Integron Known as Tn
2521
and Tn
1405
Authors: Partridge Sally R. , Brown Heidi J. , Hall Ruth M.
Published: July 2002

Two putative transposons, Tn
2521
and Tn
1405
, carrying determinants for the PSE-4 β-lactamase and for resistance to streptomycin, spectinomycin, and sulfonamides were previously isolated from the chromosome of
Pseudomonas aeruginosa
Dalgleish. Detailed mapping and determination of the complete sequence of Tn
2521
revealed that it is a class 1 integron, here renamed In33, with a backbone structure identical to that of In4 from Tn
1696
. In33 contains two gene cassettes,
blaP1
and
aadA1
, replacing the
aacC1
-orfE-
aadA2
-
cmlA1
cassette array in In4. Although In33 does not include any transposition genes, movement of In33 (Tn
2521
) targeted to a single location in the IncP-1 plasmid R18-18 has been reported previously (M. I. Sinclair and B. W. Holloway, J. Bacteriol. 151:569-579, 1982). A 5-bp duplication of the target, which lies within the
res
site recognized by the ParA resolvase of R18-18, was present, indicating that the mechanism of movement was transposition. Together, these data indicate that class 1 integrons that are defective in self-transposition can move under appropriate circumstances. The Tn
1405
isolate studied was found to represent only the cassette array of In33, which had replaced the cassette array in the recipient plasmid R388, probably by homologous recombination.