bluuebunny/crossref_metadata_2025 huggingface dataset:
Solution Structure of a Cisplatin-Induced DNA Interstrand Cross-Link
Authors: Huang Huifang , Zhu Leiming , Reid Brian R. , Drobny Gary P. , Hopkins Paul B.
Published: October 2006

The widely used antitumor drug
cis
-diamminedichloroplatinum(II) (cisplatin or
cis
-DDP) reacts with DNA, cross-linking two purine residues through the N7 atoms, which reside in the major groove in B-form DNA. The solution structure of the short duplex [d(CATAGCTATG)]
2
cross-linked at the GC:GC site was determined by nuclear magnetic resonance (NMR). The deoxyguanosine-bridging
cis
-diammineplatinum(II) lies in the minor groove, and the complementary deoxycytidines are extrahelical. The double helix is locally reversed to a left-handed form, and the helix is unwound and bent toward the minor groove. These findings were independently confirmed by results from a phase-sensitive gel electrophoresis bending assay. The NMR structure differs markedly from previously proposed models but accounts for the chemical reactivity, the unwinding, and the bending of
cis
-DDP interstrand cross-linked DNA and may be important in the formation and repair of these cross-links in chromatin.
Complexity of Holocene Climate as Reconstructed from a Greenland Ice Core
Authors: O'Brien S. R. , Mayewski P. A. , Meeker L. D. , Meese D. A. , Twickler M. S. , Whitlow S. I.
Published: October 2006

Glaciochemical time series developed from Summit, Greenland, indicate that the chemical composition of the atmosphere was dynamic during the Holocene epoch. Concentrations of sea salt and terrestrial dusts increased in Summit snow during the periods 0 to 600, 2400 to 3100, 5000 to 6100, 7800 to 8800, and more than 11,300 years ago. The most recent increase, and also the most abrupt, coincides with the Little Ice Age. These changes imply that either the north polar vortex expanded or the meridional air flow intensified during these periods, and that temperatures in the mid to high northern latitudes were potentially the coldest since the Younger Dryas event.
High-Resolution Microcoil
1
H-NMR for Mass-Limited, Nanoliter-Volume Samples
Authors: Olson Dean L. , Peck Timothy L. , Webb Andrew G. , Magin Richard L. , Sweedler Jonathan V.
Published: October 2006

High-resolution, proton nuclear magnetic resonance (NMR) spectra of 5-nanoliter samples have been obtained with much higher mass sensitivity [signal-to-noise ratio (S/N) per micromole] than with traditional methods. Arginine and sucrose show a mean sensitivity enhancement of 130 compared to 278-microliter samples run in a 5-millimeter tube in a conventional, commercial probe. This can reduce data acquisition time by a factor of >16,000 or reduce the needed sample mass by a factor of about 130. A linewidth of 0.6 hertz was achieved on a 300-megahertz spectrometer by matching the magnetic susceptibility of the medium that surrounds the detection cell to that of the copper coil. For sucrose, the limit of detection (defined at S/N = 3) was 19 nanograms (56 picomoles) for a 1-minute data acquisition. This technique should prove useful with mass-limited samples and for use as a detector in capillary separations.
A Subclass of bHLH Proteins Required for Cardiac Morphogenesis
Authors: Srivastava Deepak , Cserjesi Peter , Olson Eric N.
Published: October 2006

Skeletal muscle development is controlled by a family of muscle-specific basic helix-loop-helix (bHLH) transcription factors. Two bHLH genes,
dHAND
and
eHAND
, have now been isolated that are expressed in the bilateral heart primordia and subsequently throughout the primitive tubular heart and its derivatives during chick and mouse embryogenesis. Incubation of stage 8 chick embryos with
dHAND
and
eHAND
antisense oligonucleotides revealed that either oligonucleotide alone had no effect on embryonic development, whereas together they arrested development at the looping heart tube stage. Thus,
dHAND
and
eHAND
may play redundant roles in the regulation of the morphogenetic events of vertebrate heart development.
Gene Transfer into the Medfly,
Ceratitis capitata
, with a
Drosophila hydei
Transposable Element
Authors: Loukeris Thanasis G. , Livadaras Ioannis , Arcà Bruno , Zabalou Sophia , Savakis Charalambos
Published: October 2006

Exogenous functional DNA was introduced into the germline chromosomes of the Mediterranean fruit fly (medfly)
Ceratitis capitata
with a germline transformation system based on the transposable element
Minos
from
Drosophila hydei
. Transformants were identified as phenotypic revertants of a white-eyed mutation carried by the recipient strain. Clusters of transformants were detected among the progeny of 390 individuals screened for germline transformation. Five independent and phenotypically active integration events were identified, in each of which a single copy of the transposon was inserted into a different site of the medfly genome. Molecular analysis indicates that they represent transposase-mediated insertions of the transposon into medfly chromosomes.
Identification of a Member of the MAPKKK Family as a Potential Mediator of TGF-β Signal Transduction
Authors: Yamaguchi Kyoko , Shirakabe Kyoko , Shibuya Hiroshi , Irie Kenji , Oishi Isao , Ueno Naoto , Taniguchi Tadatsugu , Nishida Eisuke , Matsumoto Kunihiro
Published: October 2006

The mitogen-activated protein kinase (MAPK) pathway is a conserved eukaryotic signaling module that converts receptor signals into various outputs. MAPK is activated through phosphorylation by MAPK kinase (MAPKK), which is first activated by MAPKK kinase (MAPKKK). A genetic selection based on a MAPK pathway in yeast was used to identify a mouse protein kinase (TAK1) distinct from other members of the MAPKKK family. TAK1 was shown to participate in regulation of transcription by transforming growth factor-β (TGF-β). Furthermore, kinase activity of TAK1 was stimulated in response to TGF-β and bone morphogenetic protein. These results suggest that TAK1 functions as a mediator in the signaling pathway of TGF-β superfamily members.
Giving Language Skills a Boost
Authors: Barinaga Marcia
Published: October 2006

Children who are severely impaired in oral language, it seems, are unable to recognize the very short duration sounds of speech. Based on that idea, researchers have now developed a training program that uses computer games to improve the children's ability to understand and respond to spoken language. (The results are also described in Reports on pp.
77
and
81
.) The researchers suggest that similar training may improve the children's reading skills, and perhaps those of the larger population of children who have dyslexia, although that idea is controversial.
Putting a New Spin on Spider Silk
Authors: Tirrell David A.
Published: October 2006

The dragline silk spun by spiders exhibits unusual tensile strength and the energy required to break it can be higher than that of Kevlar. In his Perspective, Tirrell comments on a research report in the same issue by Simmons
et al
. (
p. 84
) that elucidates some of the structural properties that give spider silk its impressive characteristics.
Electrochemically Tunable Magnetic Phase Transition in a High-
T
c
Chromium Cyanide Thin Film
Authors: Sato O. , Iyoda T. , Fujishima A. , Hashimoto K.
Published: October 2006

Molecular-based ferrimagnetic thin films with high critical temperatures (
T
c
) composed of mixed-valence chromium cyanides were synthesized by means of a simple electrochemical route. The highest
T
c
was 270 K, obtained for Cr
2.12
(CN)
6
. The
T
c
values were easily controlled by changing the preparation conditions. Moreover, a reversible shift of
T
c
could be electrochemically induced. As a result of such electrochemical control, these cyanides can be switched reversibly back and forth between ferrimagnetism and paramagnetism. These magnets thus represent materials in which magnetic properties are combined with electrical functions.
Low-Compressibility Carbon Nitrides
Authors: Teter David M. , Hemley Russell J.
Published: October 2006

First-principles calculations of the relative stability, structure, and physical properties of carbon nitride polymorphs predict a cubic form of C
3
N
4
with a zero-pressure bulk modulus exceeding that of diamond. Like diamond, this new phase could potentially be synthesized at high pressure and quenched to ambient pressure for use as a superhard material. The calculations also predict that α-C
3
N
4
and graphite-C
3
N
4
are energetically favored relative to β-C
3
N
4
and that published diffraction data can be re-indexed as α-C
3
N
4
with lower error.
Quantifying Hydrogen Bond Cooperativity in Water: VRT Spectroscopy of the Water Tetramer
Authors: Cruzan J. D. , Braly L. B. , Liu Kun , Brown M. G. , Loeser J. G. , Saykally R. J.
Published: October 2006

Measurement of the far-infrared vibration-rotation tunneling spectrum of the perdeuterated water tetramer is described. Precisely determined rotational constants and relative intensity measurements indicate a cyclic quasi-planar minimum energy structure, which is in agreement with recent ab initio calculations. The O-O separation deduced from the data indicates a rapid exponential convergence to the ordered bulk value with increasing cluster size. Observed quantum tunneling splittings are interpreted in terms of hydrogen bond rearrangements connecting two degenerate structures.
Role of Mutant CFTR in Hypersusceptibility of Cystic Fibrosis Patients to Lung Infections
Authors: Pier Gerald B. , Grout Martha , Zaidi Tanweer S. , Olsen John C. , Johnson Larry G. , Yankaskas James R. , Goldberg Joanna B.
Published: October 2006

Cystic fibrosis (CF) patients are hypersusceptible to chronic
Pseudomonas aeruginosa
lung infections. Cultured human airway epithelial cells expressing the ΔF508 allele of the cystic fibrosis transmembrane conductance regulator (CFTR) were defective in uptake of
P. aeruginosa
compared with cells expressing the wild-type allele.
Pseudomonas aeruginosa
lipopolysaccharide (LPS)-core oligosaccharide was identified as the bacterial ligand for epithelial cell ingestion; exogenous oligosaccharide inhibited bacterial ingestion in a neonatal mouse model, resulting in increased amounts of bacteria in the lungs. CFTR may contribute to a host-defense mechanism that is important for clearance of
P. aeruginosa
from the respiratory tract.
Temporal Processing Deficits of Language-Learning Impaired Children Ameliorated by Training
Authors: Merzenich Michael M. , Jenkins William M. , Johnston Paul , Schreiner Christoph , Miller Steven L. , Tallal Paula
Published: October 2006

Children with language-based learning impairments (LLIs) have major deficits in their recognition of some rapidly successive phonetic elements and nonspeech sound stimuli. In the current study, LLI children were engaged in adaptive training exercises mounted as computer “games” designed to drive improvements in their “temporal processing” skills. With 8 to 16 hours of training during a 20-day period, LLI children improved markedly in their abilities to recognize brief and fast sequences of nonspeech and speech stimuli.
The Effect of Quantum and Thermal Fluctuations on the Structure of the Floppy Molecule C
2
H
3
+
Authors: Marx Dominik , Parrinello Michele
Published: October 2006

The structure of protonated acetylene C
2
H
3
+
was investigated through a series of ab initio simulations that treat all nuclei as either classical or quantum particles. This makes it possible to probe separately the effects of quantum and thermal fluctuations on the molecular structure of this floppy molecule. The simulations show that the quantum ground state of C
2
H
3
+
is best pictured as a quasi-planar bridged structure with anisotropic delocalization of the protons due to zero-point quantum effects. Comparison with high-temperature simulations suggests that recent Coulomb explosion imaging data that led to a different conclusion did not probe the ground state of the fluxional molecule C
2
H
3
+
.
Permian Vessel Elements
Authors: Li Hongqi , Taylor Edith L. , Taylor Thomas N.
Published: October 2006

Anatomically preserved stems from the Late Permian (250 to 270 million years ago) of China have been discovered that contain vessels. The stems possess several features commonly found in vines, including tendril-like appendages, and are associated with large leaves assignable to the Gigantopteridales, an enigmatic group of Permian plants. The individual vessel elements contain foraminate perforation plates in their end walls and are anatomically similar to the conducting elements of modern gnetophytes and of some extant flowering plants.
Origin of High Mountains in the Continents: The Southern Sierra Nevada
Authors: Wernicke Brian , Clayton Robert , Ducea Mihai , Jones Craig H. , Park Stephen , Ruppert Stan , Saleeby Jason , Snow J. Kent , Squires Livia , Fliedner Moritz , Jiracek George , Keller Randy , Klemperer Simon , Luetgert James , Malin Peter , Miller Kate , Mooney Walter , Oliver Howard , Phinney Robert
Published: October 2006

Active and passive seismic experiments show that the southern Sierra, despite standing 1.8 to 2.8 kilometers above its surroundings, is underlain by crust of similar seismic thickness, about 30 to 40 kilometers. Thermobarometry of xenolith suites and magnetotelluric profiles indicate that the upper mantle is eclogitic to depths of 60 kilometers beneath the western and central parts of the range, but little subcrustal lithosphere is present beneath the eastern High Sierra and adjacent Basin and Range. These and other data imply the crust of both the High Sierra and Basin and Range thinned by a factor of 2 since 20 million years ago, at odds with purported late Cenozoic regional uplift of some 2 kilometers.
Fluorination of Diamond Surfaces by Irradiation of Perfluorinated Alkyl Iodides
Authors: Smentkowski V. S. , Yates John T.
Published: October 2006

A facile method for chemically functionalizing diamond surfaces has been developed using x-ray irradiation of perfluoroalkyl iodide layers on the surface. Perfluoroalkyl radicals chemically bond to the diamond surface and can be thermally decomposed to produce strongly bound surface C-F bonds that are stable at high temperatures.
A Role for CD81 in Early T Cell Development
Authors: Boismenu Richard , Rhein Maria , Fischer Wolfgang H. , Havran Wendy L.
Published: October 2006

Early stages of T cell development are thought to include a series of coordinated interactions between thymocytes and other cells of the thymus. A monoclonal antibody specific for mouse CD81 was identified that blocked the appearance of αβ but not γδ T cells in fetal organ cultures initiated with day 14.5 thymus lobes. In reaggregation cultures with CD81-transfected fibroblasts, CD4
−
CD8
−
thymocytes differentiated into CD4
+
CD8
+
T cells. Thus, interactions between immature thymocytes and stromal cells expressing CD81 are required and may be sufficient to induce early events associated with T cell development.
Structure of the Heat Shock Protein Chaperonin-10 of
Mycobacterium leprae
Authors: Mande Shekhar C. , Mehra Vijay , Bloom Barry R. , Hol Wim G. J.
Published: October 2006

Members of the chaperonin-10 (cpn10) protein family, also called heat shock protein 10 and in
Escherichia coli
GroES, play an important role in ensuring the proper folding of many proteins. The crystal structure of the
Mycobacterium leprae
cpn10 (Ml-cpn10) oligomer has been elucidated at a resolution of 3.5 angstroms. The architecture of the Ml-cpn10 heptamer resembles a dome with an oculus in its roof. The inner surface of the dome is hydrophilic and highly charged. A flexible region, known to interact with cpn60, extends from the lower rim of the dome. With the structure of a cpn10 heptamer now revealed and the structure of the
E. coli
GroEL previously known, models of cpn10:cpn60 and GroEL:GroES complexes are proposed.
Direct Physical Measure of Conformational Rearrangement Underlying Potassium Channel Gating
Authors: Mannuzzu Lidia M. , Moronne Mario M. , Isacoff Ehud Y.
Published: October 2006

In response to membrane depolarization, voltage-gated ion channels undergo a structural rearrangement that moves charges or dipoles in the membrane electric field and opens the channel-conducting pathway. By combination of site-specific fluorescent labeling of the
Shaker
potassium channel protein with voltage clamping, this gating conformational change was measured in real time. During channel activation, a stretch of at least seven amino acids of the putative transmembrane segment S4 moved from a buried position into the extracellular environment. This movement correlated with the displacement of the gating charge, providing physical evidence in support of the hypothesis that S4 is the voltage sensor of voltage-gated ion channels.
Plasmodium Hemozoin Formation Mediated by Histidine-Rich Proteins
Authors: Sullivan David J. , Gluzman Ilya Y. , Goldberg Daniel E.
Published: October 2006

The digestive vacuole of
Plasmodium falciparum
is the site of hemoglobin degradation, heme polymerization into crystalline hemozoin, and antimalarial drug accumulation. Antibodies identified histidine-rich protein II (HRP II) in purified digestive vacuoles. Recombinant or native HRP II promoted the formation of hemozoin, and chloroquine inhibited the reaction. The related HRP III also polymerized heme, and an additional HRP was identified in vacuoles. It is proposed that after secretion by the parasite into the host erythrocyte cytosol, HRPs are brought into the acidic digestive vacuole along with hemoglobin. After hemoglobin proteolysis, HRPs bind the liberated heme and mediate hemozoin formation.
New Tumor Suppressor Found in Pancreatic Cancer
Authors: O'Brien Claire
Published: October 2006

Pancreatic cancer is one of the most dangerous cancers, killing half its victims within 6 weeks and having a 5-year survival rate of only 1%. Within the past few years, researchers have begun getting a handle on what makes this tumor so dangerous. Most of the cancers show loss or inactivation of two major tumor suppressor genes (
p 53
and
p 16
), and now another major tumor suppressor gene for pancreatic cancer has been identified (see Report on
p. 350
). The gene, which is called
DPC4,
may encode a component of the pathway by which transforming growth factor- inhibits cell growth. If so, that could help explain how loss of
DPC4
contributes to the runaway growth of pancreatic cancers.
Covalent Fullerene Chemistry
Authors: Diederich François , Thilgen Carlo
Published: October 2006

The covalent functionalization of C
60
has developed vigorously over the past 5 years. Several methods are now available for the formation of C
60
monoadducts. Regioselective formation of multiple adducts has allowed study of the changes in chemical and physical properties that occur when the conjugated fullerene chromophore is reduced during an increase in functionalization. The systematic development of covalent fullerene chemistry provides an unprecedented diversity of tailor-made three-dimensional building blocks for technologically interesting materials.
Recent Changes in Eastern Mediterranean Deep Waters
Authors: Roether Wolfgang , Manca Beniamino B. , Klein Birgit , Bregant Davide , Georgopoulos Dimitrios , Beitzel Volker , Kovačević Vedrana , Luchetta Anna
Published: October 2006

Results from a recent hydrographic survey show that an influx of Aegean Sea water has replaced 20 percent of the deep and bottom waters of the eastern Mediterranean. Previously, the only source of such waters was the Adriatic Sea, and the waters of the eastern Mediterranean were in near-steady state. The flux changed the water characteristics and displaced older waters upward. Its cause was increasing Aegean Sea salinity, resulting from changes in either the circulation pattern or the large-scale freshwater balance. Current deepwater studies may be affected by the intrusion, but effects might be found also at shallower depths and over a larger region.
Mineralization of Chlorofluorocarbons and Aromatization of Saturated Fluorocarbons by a Convenient Thermal Process
Authors: Burdeniuc Juan , Crabtree Robert H.
Published: October 2006

A chemical reaction has been discovered that mineralizes chlorofluorocarbons (CFCs) and enables the complete destruction of these environmentally hazardous species. The reaction products are easily handled solids, including recyclable alkali metal halides. Under milder conditions, the same reaction causes partial defluorination of cyclic perfluoroalkanes to yield perfluoroarenes, which are valuable chemical intermediates. The vaporized substrates are passed over a packed bed of heated sodium oxalate; heating at 270° to 290°C causes mineralization, whereas heating at 230°C causes aromatization.
Design of a Monomeric 23-Residue Polypeptide with Defined Tertiary Structure
Authors: Struthers Mary D. , Cheng Richard P. , Imperiali Barbara
Published: October 2006

Small proteins or protein domains generally require disulfide bridges or metal sites for their stabilization. Here it is shown that the ββα architecture of zinc fingers can be reproduced in a 23-residue polypeptide in the absence of metal ions. The sequence was obtained through an iterative design process. A key feature of the final design is the incorporation of a type II' β turn to aid in β-hairpin formation. Nuclear magnetic resonance analysis reveals that the α helix and β hairpin are held together by a defined hydrophobic core. The availability of this structural template has implications for the development of functional polypeptides.
Mutant Enzyme Provides New Insights Into the Cause of ALS
Authors: Marx Jean
Published: October 2006

Although neurobiologists have known for 3 years that mutations in the
SOD1
gene cause some cases of familial amyotrophic lateral sclerosis (FALS), finding out exactly how those mutations cause the deadly neurodegeneration of the disease has proved tougher than expected. But two reports, one appearing on page
page 515
of this issue and the other in the February
Annals of Neurology
, now suggest that one way the mutations act is by increasing the ability of the enzyme encoded by
SOD1
to carry out peroxidation, a potentially toxic reaction that may lead to membrane degeneration and neuronal cell death. If so, then it may be possible to design better ALS therapies aimed at blocking the peroxidation reaction.
Thiyl Radicals in Ribonucleotide Reductases
Authors: Licht Stuart , Gerfen Gary J. , Stubbe JoAnne
Published: October 2006

The ribonucleoside triphosphate reductase (RTPR) from
Lactobacillus leichmannii
catalyzes adenosylcobalamin (AdoCbl)-dependent nucleotide reduction, as well as exchange of the 5′ hydrogens of AdoCbl with solvent. A protein-based thiyl radical is proposed as an intermediate in both of these processes. In the presence of RTPR containing specifically deuterated cysteine residues, the electron paramagnetic resonance (EPR) spectrum of an intermediate in the exchange reaction and the reduction reaction, trapped by rapid freeze quench techniques, exhibits narrowed hyperfine features relative to the corresponding unlabeled RTPR. The spectrum was interpreted to represent a thiyl radical coupled to cob(II)alamin. Another proposed intermediate, 5′-deoxyadenosine, was detected by rapid acid quench techniques. Similarities in mechanism between RTPR and the
Escherichia coli
ribonucleotide reductase suggest that both enzymes require a thiyl radical for catalysis.
Energy Dissipation During Rupture of Adhesive Bonds
Authors: Baljon Arlette R. C. , Robbins Mark O.
Published: October 2006

Molecular dynamics simulations were used to study energy-dissipation mechanisms during the rupture of a thin adhesive bond formed by short chain molecules. The degree of dissipation and its velocity dependence varied with the state of the film. When the adhesive was in a liquid phase, dissipation was caused by viscous loss. In glassy films, dissipation occurred during a sequence of rapid structural rearrangements. Roughly equal amounts of energy were dissipated in each of three types of rapid motion: cavitation, plastic yield, and bridge rupture. These mechanisms have similarities to nucleation, plastic flow, and crazing in commercial polymeric adhesives.
Th-Pb and U-Pb Dating of Ore-Stage Calcite and Paleozoic Fluid Flow
Authors: Brannon Joyce C. , Cole Susan C. , Podosek Frank A. , Ragan Virginia M. , Coveney Raymond M. , Wallace Malcolm W. , Bradley Alison J.
Published: October 2006

Thorium-232-lead-208 and uranium-238-lead-206 radiometric ages for ore-stage calcite show that Mississippi Valley-type (MVT) ore deposits can form in distinct tectonic settings. An age of 251 ± 11 million years for the Jumbo Mine in Kansas, United States, is in agreement with other ages for MVT deposits in the midcontinent of North America. The similarity of ages of these deposits supports the concept that they formed in response to fluid flow during the late Paleozoic Alleghenian-Ouachita orogeny. An age of 351 ± 15 million years for Twelve Mile Bore and Bloodwood-Kapok deposits in Australia indicates that these MVT ores were deposited in a rifting environment.
Reduction of HIV Concentration During Acute Infection: Independence from a Specific Immune Response
Authors: Phillips Andrew N.
Published: October 2006

After infection with the human immunodeficiency virus (HIV), the concentration of the virus in the person's plasma increases. The subsequent decrease in concentration a few weeks later was thought to result from an HIV-specific immune response. This purported causal relation is investigated with a model of the dynamics of early HIV infection that incorporates no increase in the rate of removal of free virions or virus-infected cells. A pattern of changes in virus concentration similar to that observed in patients is predicted by the model. Thus, the reduction in virus concentration during acute infection may not reflect the ability of the HIV-specific immune response to control virus replication.
Angiotensin II-Forming Activity in a Reconstructed Ancestral Chymase
Authors: Chandrasekharan Unnikrishnan M. , Sanker Subramaniam , Glynias Manuel J. , Karnik Sadashiva S. , Husain Ahsan
Published: October 2006

The current model of serine protease diversity theorizes that the earliest protease molecules were simple digestive enzymes that gained complex regulatory functions and restricted substrate specificities through evolution. Among the chymase group of serine proteases are enzymes that convert angiotensin I to angiotensin II, as well as others that simply degrade angiotensins. An ancestral chymase reconstructed with the use of phylogenetic inference, total gene synthesis, and protein expression had efficient and specific angiotensin II-forming activity (turnover number, about 700 per second). Thus, angiotensin II-forming activity is the more primitive state for chymases, and the loss of such activity occurred later in the evolution of some of these serine proteases.
Activation by Attention of the Human Reticular Formation and Thalamic Intralaminar Nuclei
Authors: Kinomura Shigeo , Larsson Jonas , Gulyás Balázs , Roland Per E.
Published: October 2006

It has been known for over 45 years that electrical stimulation of the midbrain reticular formation and of the thalamic intralaminar nuclei of the brain alerts animals. However, lesions of these sectors fail to impair arousal and vigilance in some cases, making the role of the ascending activating reticular system controversial. Here, a positron emission tomographic study showed activation of the midbrain reticular formation and of thalamic intralaminar nuclei when human participants went from a relaxed awake state to an attention-demanding reaction-time task. These results confirm the role of these areas of the brain and brainstem in arousal and vigilance.
Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis
Authors: Wiedau-Pazos Martina , Goto Joy J. , Rabizadeh Shahrooz , Gralla Edith B. , Roe James A. , Lee Michael K. , Valentine Joan S. , Bredesen Dale E.
Published: October 2006

A subset of individuals with familial amyotrophic lateral sclerosis (FALS) possesses dominantly inherited mutations in the gene that encodes copper-zinc superoxide dismutase (CuZnSOD). A4V and G93A, two of the mutant enzymes associated with FALS, were shown to catalyze the oxidation of a model substrate (spin trap 5,5′-dimethyl-1-pyrroline
N
-oxide) by hydrogen peroxide at a higher rate than that seen with the wild-type enzyme. Catalysis of this reaction by A4V and G93A was more sensitive to inhibition by the copper chelators diethyldithiocarbamate and penicillamine than was catalysis by wild-type CuZnSOD. The same two chelators reversed the apoptosis-inducing effect of mutant enzymes expressed in a neural cell line. These results suggest that oxidative reactions catalyzed by mutant CuZnSOD enzymes initiate the neuropathologic changes in FALS.
Catalysis of Amide Proton Exchange by the Molecular Chaperones GroEL and SecB
Authors: Zahn Ralph , Perrett Sarah , Stenberg Gun , Fersht Alan R.
Published: October 2006

Hydrogen-deuterium exchange of 39 amide protons of
Bacillus amyloliquefaciens
ribonuclease (barnase) was analyzed by two-dimensional nuclear magnetic resonance in the presence of micromolar concentrations of the molecular chaperones GroEL and SecB. Both chaperones bound to native barnase under physiological conditions and catalyzed exchange of deeply buried amide protons with solvent. Such exchange required complete unfolding of barnase, which occurred in the complex with the chaperones. Subsequent collapse of unfolded barnase to the exchange-protected folding intermediate was markedly slowed in the presence of GroEL or SecB. Thus, both chaperones have the potential to correct misfolding in proteins by annealing.
Protein Kinase N (PKN) and PKN-Related Protein Rhophilin as Targets of Small GTPase Rho
Authors: Watanabe Go , Saito Yuji , Madaule Pascal , Ishizaki Toshimasa , Fujisawa Kazuko , Morii Narito , Mukai Hideyuki , Ono Yoshitaka , Kakizuka Akira , Narumiya Shuh
Published: October 2006

The Rho guanosine 5′-triphosphatase (GTPase) cycles between the active guanosine triphosphate (GTP)-bound form and the inactive guanosine diphosphate-bound form and regulates cell adhesion and cytokinesis, but how it exerts these actions is unknown. The yeast two-hybrid system was used to clone a complementary DNA for a protein (designated Rhophilin) that specifically bound to GTP-Rho. The Rho-binding domain of this protein has 40 percent identity with a putative regulatory domain of a protein kinase, PKN. PKN itself bound to GTP-Rho and was activated by this binding both in vitro and in vivo. This study indicates that a serine-threonine protein kinase is a Rho effector and presents an amino acid sequence motif for binding to GTP-Rho that may be shared by a family of Rho target proteins.
Use-Dependent Blockers and Exit Rate of the Last Ion from the Multi-Ion Pore of a K
+
Channel
Authors: Baukrowitz Thomas , Yellen Gary
Published: October 2006

Quaternary ammonium blockers inhibit many voltage-activated potassium (K
+
) channels from the intracellular side. When applied to
Drosophila
Shaker potassium channels expressed in mammalian cells, these rapidly reversible blockers produced use-dependent inhibition through an unusual mechanism-they promoted an intrinsic conformational change known as C-type inactivation, from which recovery is slow. The blockers did so by cutting off potassium ion flow to a site in the pore, which then emptied at a rate of 10
5
ions per second. This slow rate probably reflected the departure of the last ion from the multi-ion pore: Permeation of ions (at 10
7
per second) occurs rapidly because of ion-ion repulsion, but the last ion to leave would experience no such repulsion.
Horizontal Cells of the Primate Retina: Cone Specificity Without Spectral Opponency
Authors: Dacey Dennis M. , Lee Barry B. , Stafford Donna K. , Pokorny Joel , Smith Vivianne C.
Published: October 2006

The chromatic dimensions of human color vision have a neural basis in the retina. Ganglion cells, the output neurons of the retina, exhibit spectral opponency; they are excited by some wavelengths and inhibited by others. The hypothesis that the opponent circuitry emerges from selective connections between horizontal cell interneurons and cone photoreceptors sensitive to long, middle, and short wavelengths (L-, M-, and S-cones) was tested by physiologically and anatomically characterizing cone connections of horizontal cell mosaics in macaque monkeys. H1 horizontal cells received input only from L- and M-cones, whereas H2 horizontal cells received a strong input from S-cones and a weaker input from L- and M-cones. All cone inputs were the same sign, and both horizontal cell types lacked opponency. Despite cone type selectivity, the horizontal cell cannot be the locus of an opponent transformation in primates, including humans.
Molecular Detection of Primary Bladder Cancer by Microsatellite Analysis
Authors: Mao Li , Schoenberg Mark P. , Scicchitano Marshall , Erozan Yener S. , Merlo Adrian , Schwab Donna , Sidransky David
Published: October 2006

Microsatellite DNA markers have been widely used as a tool for the detection of loss of heterozygosity and genomic instability in primary tumors. In a blinded study, urine samples from 25 patients with suspicious bladder lesions that had been identified cystoscopically were analyzed by this molecular method and by conventional cytology. Microsatellite changes matching those in the tumor were detected in the urine sediment of 19 of the 20 patients (95 percent) who were diagnosed with bladder cancer, whereas urine cytology detected cancer cells in 9 of 18 (50 percent) of the samples. These results suggest that microsatellite analysis, which in principle can be performed at about one-third the cost of cytology, may be a useful addition to current screening methods for detecting bladder cancer.
Expression of a
Plasmodium
Gene Introduced into Subtelomeric Regions of
Plasmodium berghei
Chromosomes
Authors: van Dijk Melissa R. , Janse Chris J. , Waters Andrew P.
Published: October 2006

Targeted integration of exogenous DNA into the genome of malaria parasites will allow their phenotype to be modulated by means of gene disruption or the stable expression of foreign and mutated genes. Described here is the site-specific integration through reciprocal exchange, and subsequent expression, of a selectable marker gene into the genome of the pathogenic, bloodstage forms of the rodent malaria parasite
Plasmodium berghei
. Stable integration of a single copy of the marker gene (retained for more than 70 generations in the absence of drug pressure) into a nontranscribed subtelomeric repeat array of different chromosomes was observed. Expression of the gene within the subtelomeres indicated that the previously recorded absence of transcription in these regions could be due to a corresponding absence of genes rather than active silencing mechanisms.
Human Appropriation of Renewable Fresh Water
Authors: Postel Sandra L. , Daily Gretchen C. , Ehrlich Paul R.
Published: October 2006

Humanity now uses 26 percent of total terrestrial evapotranspiration and 54 percent of runoff that is geographically and temporally accessible. Increased use of evapotranspiration will confer minimal benefits globally because most land suitable for rain-fed agriculture is already in production. New dam construction could increase accessible runoff by about 10 percent over the next 30 years, whereas population is projected to increase by more than 45 percent during that period.
DNA: An Extensible Molecule
Authors: Cluzel Philippe , Lebrun Anne , Heller Christoph , Lavery Richard , Viovy Jean-Louis , Chatenay Didier , Caron François
Published: October 2006

The force-displacement response of a single duplex DNA molecule was measured. The force saturates at a plateau around 70 piconewtons, which ends when the DNA has been stretched about 1.7 times its contour length. This behavior reveals a highly cooperative transition to a state here termed S-DNA. Addition of an intercalator suppresses this transition. Molecular modeling of the process also yields a force plateau and suggests a structure for the extended form. These results may shed light on biological processes involving DNA extension and open the route for mechanical studies on individual molecules in a previously unexplored range.
Activation of BTK by a Phosphorylation Mechanism Initiated by SRC Family Kinases
Authors: Rawlings David J. , Scharenberg Andrew M. , Park Hyunsun , Wahl Matthew I. , Lin Siqi , Kato Roberta M. , Fluckiger Anne-Catherine , Witte Owen N. , Kinet Jean-Pierre
Published: October 2006

Bruton's tyrosine kinase (BTK) is pivotal in B cell activation and development through its participation in the signaling pathways of multiple hematopoietic receptors. The mechanisms controlling BTK activation were studied here by examination of the biochemical consequences of an interaction between BTK and SRC family kinases. This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation. BTK then autophosphorylated at a second site. The same two sites were phosphorylated upon B cell antigen receptor cross-linking. The activated BTK was predominantly membrane-associated, which suggests that BTK integrates distinct receptor signals resulting in SRC kinase activation and BTK membrane targeting.
A Lower Limit on the Age of the Universe
Authors: Chaboyer Brian , Demarque Pierre , Kernan Peter J. , Krauss Lawrence M.
Published: October 2006

A detailed numerical study was designed and conducted to estimate the absolute age and the uncertainty in age (with confidence limits) of the oldest globular clusters in our galaxy, and hence to put a robust lower bound on the age of the universe. Estimates of the uncertainty range and distribution in the input parameters of stellar evolution codes were used to produce 1000 Monte Carlo realizations of stellar isochrones, which were then used to derive ages for the 17 oldest globular clusters. A probability distribution for the mean age of these systems was derived by incorporating the observational uncertainties in the measured color-magnitude diagrams for these systems and the predicted isochrones. The dominant contribution to the width of the distribution (approximately ± 5 percent) resulted from the observational uncertainty in RR-Lyrae variable absolute magnitudes. Subdominant contributions came from the choice of the color table used to translate theoretical luminosities and temperatures to observed magnitudes and colors, as well as from theoretical uncertainties in heavy element abundances and mixing length. The one-sided 95 percent confidence limit lower bound for this distribution occurs at an age of 12.07 × 10
9
years, and the median age for the distribution is 14.56 × 10
9
years. These age limits, when compared with the Hubble age estimate, put powerful constraints on cosmology.
Dust: A Diagnostic of the Hydrologic Cycle During the Last Glacial Maximum
Authors: Yung Yuk L. , Lee Typhoon , Wang Chung-Ho , Shieh Ying-Tzung
Published: October 2006

Dust concentrations in ice of the last glacial maximum (LGM) are high in ice cores from Greenland and Antarctica. The magnitude of the enhancements can be explained if the strength of the hydrologic cycle during the LGM was about half of that at present. This notion is consistent with a large decrease (5°C) in ocean temperature during the LGM, as recently deduced from measurements of strontium and calcium in corals.
Delivery of Molecular Medicine to Solid Tumors
Authors: Jain Rakesh K.
Published: October 2006

Molecular medicine is increasing our understanding of the molecular basis of cancer and is providing new targets for therapeutic intervention. But at present we do not have appropriate ways to deliver these agents to the tumor, and without this ability their potential will not be realized. Jain proposes a three-part strategy for overcoming this obstacle to successful treatment of tumors.
The Galvanization of Biology: A Growing Appreciation for the Roles of Zinc
Authors: Berg Jeremy M. , Shi Yigong
Published: October 2006

Zinc ions are key structural components of a large number of proteins. The binding of zinc stabilizes the folded conformations of domains so that they may facilitate interactions between the proteins and other macromolecules such as DNA. The modular nature of some of these zinc-containing proteins has allowed the rational design of site-specific DNA binding proteins. The ability of zinc to be bound specifically within a range of tetrahedral sites appears to be responsible for the evolution of the wide range of zinc-stabilized structural domains now known to exist. The lack of redox activity for the zinc ion and its binding and exchange kinetics also may be important in the use of zinc for specific functional roles.
The Immunological Evolution of Catalysis
Authors: Patten Phillip A. , Gray Nathanael S. , Yang Priscilla L. , Marks Cara B. , Wedemayer Gary J. , Boniface J. Jay , Stevens Raymond C. , Schultz Peter G.
Published: October 2006

The germline genes used by the mouse to generate the esterolytic antibody 48G7 were cloned and expressed in an effort to increase our understanding of the detailed molecular mechanisms by which the immune system evolves catalytic function. The nine replacement mutations that were fixed during affinity maturation increased affinity for the transition state analogue by a factor of 10
4
, primarily the result of a decrease in the dissociation rate of the hapten-antibody complex. There was a corresponding increase in the rate of reaction of antibody with substrate,
k
cat
/
K
m
, from 1.7 × 10
2
M
−1
min
−1
to 1.4 × 10
4
M
−1
min
−1
. The three-dimensional crystal structure of the 48G7-transition state analogue complex at 2.0 angstroms resolution indicates that none of the nine residues in which somatic mutations have been fixed directly contact the hapten. Thus, in the case of 48G7, affinity maturation appears to play a conformational role, either in reorganizing the active site geometry or limiting side-chain and backbone flexibility of the germline antibody. The crystal structure and analysis of somatic and directed active site mutants underscore the role of transition state stabilization in the evolution of this catalytic antibody.
Self-Assembling Dendrimers
Authors: Zimmerman Steven C. , Zeng Fanwen , Reichert David E. C. , Kolotuchin Sergei V.
Published: October 2006

Hydrogen bond-mediated self-assembly is a powerful strategy for generating large structures from smaller subunits. The synthesis of molecules containing two isophthalic acid units covalently attached to a rigid aromatic spacer is described. By normal pairing of carboxylic acids into hydrogen-bonded dimers, these molecules self-assemble in organic solvents to form either a series of linear aggregates or a cyclic hexamer. These molecules were linked to the core of a family of polyether dendrimers, which caused the hexamer to be formed preferentially. The stability of the hexamer depended on the generation number of the dendrimer. The largest of these hydrogen-bonded macromolecular assemblies is roughly disk-shaped with a 9-nanometer diameter and a 2-nanometer thickness. Its size and molecular mass (34,000 daltons) are comparable to that of small proteins.
Re-Os Ages of Group IIA, IIIA, IVA, and IVB Iron Meteorites
Authors: Smoliar Michael I. , Walker Richard J. , Morgan John W.
Published: October 2006

Rhenium and osmium concentrations and osmium isotopic ratios of group IIA, IIIA, IVA, and IVB iron meteorites were determined by negative thermal ionization mass spectrometry with modified digestion and equilibration techniques. Precise isochrons are defined for all four groups. An absolute age of 4558 million years is assumed for group IIIA irons, leading to closure ages of 4537 ± 8, 4456 ± 25, and 4527 ± 29 million years for the group IIA, IVA, and IVB irons, respectively. The initial osmium-187/osmium-188 ratios of the IIA, IIIA, and IVA groups, as a function of crystallization age, suggest that the rhenium/osmium ratio of the parental materials to these asteroidal cores was similar to that of ordinary chondrites. Data for IVB irons, in contrast, indicate a different mode of formation and derivation from a distinctly nonchondritic osmium reservoir.
The Swelling of Clays: Molecular Simulations of the Hydration of Montmorillonite
Authors: Karaborni S. , Smit B. , Heidug W. , Urai J. , van Oort E.
Published: October 2006

The swelling of clay minerals on contact with an aqueous solution can produce strong adverse effects in the exploration and production of gas and oil. Molecular dynamics and Monte Carlo simulations were used to study the mechanism of swelling of sodium-montmorillonite. The simulations showed that the abundant clay mineral has four stable states at basal spacings of 9.7, 12.0, 15.5, and 18.3 angstroms, respectively. The amount of swelling and the locations of the stable states of sodium-montmorillonite are in good quantitative agreement with the experimental data.
Impact Origin of the Chesapeake Bay Structure and the Source of the North American Tektites
Authors: Koeberl Christian , Poag C. Wylie , Reimold Wolf Uwe , Brandt Dion
Published: October 2006

Seismic profiles, drill core samples, and gravity data suggest that a complex impact crater ∼35.5 million years old and 90 kilometers in diameter is buried beneath the lower Chesapeake Bay. The breccia that fills the structure contains evidence of shock metamorphism, including impact melt breccias and multiple sets of planar deformation features (shock lamellae) in quartz and feldspar. The age of the crater and the composition of some breccia clasts are consistent with the Chesapeake Bay impact structure being the source of the North American tektites.
Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4
+
T Cells
Authors: Li Wei , Whaley Carmella D. , Mondino Anna , Mueller Daniel L.
Published: October 2006

T cells activated by antigen receptor stimulation in the absence of accessory cell-derived costimulatory signals lose the capacity to synthesize the growth factor interleukin-2 (IL-2), a state called clonal anergy. An analysis of CD3- and CD28-induced signal transduction revealed reduced ERK and JNK enzyme activities in murine anergic T cells. The amounts of ERK and JNK proteins were unchanged, and the kinases could be fully activated in the presence of phorbol 12-myristate 13-acetate. Dephosphorylation of the calcineurin substrate NFATp (preexisting nuclear factor of activated T cells) also remained inducible. These results suggest that a specific block in the activation of ERK and JNK contributes to defective IL-2 production in clonal anergy.
Antigen Presentation and T Cell Development in H2-M-Deficient Mice
Authors: Fung-Leung Wai-Ping , Surh Charles D. , Liljedahl Monika , Pang Jesse , Leturcq Didier , Peterson Per A. , Webb Susan R. , Karlsson Lars
Published: October 2006

HLA-DM (DM) facilitates peptide loading of major histocompatibility complex class II molecules in human cell lines. Mice lacking functional H2-M, the mouse equivalent of DM, have normal amounts of class II molecules at the cell surface, but most of these are associated with invariant chain-derived CLIP peptides. These mice contain large numbers of CD4
+
T cells, which is indicative of positive selection in the thymus. Their CD4
+
cells were unresponsive to self H2-M-deficient antigen-presenting cells (APCs) but were hyperreactive to wild-type APCs. H2-M-deficient APCs failed to elicit proliferative responses from wild-type T cells.
Role of Lymphotoxin and the Type I TNF Receptor in the Formation of Germinal Centers
Authors: Matsumoto Mitsuru , Mariathasan Sanjeev , Nahm Moon H. , Baranyay Ferenc , Peschon Jacques J. , Chaplin David D.
Published: October 2006

In mice deficient in either lymphotoxin-α (LT-α) or the type I tumor necrosis factor (TNF) receptor, but not the type II TNF receptor, germinal centers failed to develop in peripheral lymphoid organs. Germinal center formation was restored in LT-α-deficient mice by transplantation of normal bone marrow, indicating that the LT-α-expressing cells required to establish this lymphoid structure are derived from bone marrow.