bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular phylogeny of Scaphopoda (Mollusca) inferred from 18S rDNA sequences: support for a Scaphopoda–Cephalopoda clade
Authors: Steiner Gerhard , Dreyer Hermann
Published: June 2003

The phylogenetic relationships of the Scaphopoda, one of the ‘lesser’ molluscan classes, with the other conchiferan taxa are far from clear. They appear either as the sister‐group to the Bivalvia (Diasoma concept) or to a Gastropoda–Cephalopoda clade or to the Cephalopoda alone (helcionellid concept). We compiled a 18S rDNA sequence dataset of 48 molluscan species containing 17 scaphopods to test these hypotheses and to address questions regarding high‐level relationships with the Scaphopoda. Both parsimony and maximum likelihood trees show low branch support at the base of the Conchifera, except for the robust clade uniting Scaphopoda and Cephalopoda. This result is corroborated by spectral analysis and likelihood mapping. We also tested alternative topologies which scored significantly worse both in tree length and in likelihood. The 18S rDNA data thus reject the Diasoma in favour of a Scaphopoda–Cephalopoda clade as proposed in the helcionellid concept. When plotted on the molecular tree, the pivotal morphological characters associated with the burrowing life style of the Bivalvia and Scaphopoda, i.e. mantle/shell enclosure of the body and the burrowing foot with true pedal ganglia, appear convergent in these groups. In contrast, the prominent and tilted dorsoventral body axes, multiple cephalic tentacles and a ring‐shaped muscle attachment on the shell are potential synapomorphies of Scaphopoda and Cephalopoda. Most of the higher taxa within the Scaphopoda are supported by the molecular data. However, there is no support for the families Dentaliidae and Gadilidae. The basal position of the Fustiariidae within the Dentaliida is confirmed.
Prograde, peak, and retrograde P–T paths from aluminium in orthopyroxene: High‐temperature contact metamorphism in the aureole of the Makhavinekh Lake Pluton, Nain Plutonic Suite, Labrador
Authors: McFarlane C. R. M. , Carlson W. D. , Connelly J. N.
Published: June 2003

Static heating during intrusion of the Makhavinekh Lake Pluton (MLP) caused replacement of garnet in the adjacent country rocks (Tasiuyak Gneiss) by coronal assemblages of orthopyroxene + cordierite. Thermometry based on Al solubility in orthopyroxene, applied to relict garnet and neighbouring orthopyroxene, preserves a temperature gradient from 700 to 900 °C at distances between 5750 and 20 m from the intrusion, reaffirming the robustness of this thermometry technique. Intracrystalline and intergranular variations of Al zoning in orthopyroxene are well‐preserved, suggesting that little diffusional modification of Al growth zoning occurred. Maximum Al2O3 in orthopyroxene ranges from c. 2.0 wt% at 5750 m from the intrusion to a maximum of 4.3 wt% at the contact. Individual orthopyroxene grains show decreasing Al from core to rim in samples < 500 m from the intrusion, while those at greater distances show an increase from core to rim. These features are interpreted with the aid of numerical models for conductive heat flow in the aureole. Coronas in samples close to the intrusion grew at high temperatures and along T‐t paths dominated by cooling, so maximum Al content in orthopyroxene in these samples occurs in the cores of grains that grew during the earliest stages of garnet consumption. In contrast, the corona‐forming reactions in rocks further from the contact proceeded along prograde heating paths, so maximum Al content in orthopyroxene occurs in the rims of grains that grew during the final stages of garnet consumption. These results document the ability of Al‐in‐orthopyroxene thermometry to preserve a detailed record of thermal histories in contact‐metamorphic granulites; they suggest that similar intracrystalline and intergranular variations of Al zoning in orthopyroxene in regional granulites may also preserve portions of both the prograde and peak‐T evolution.
A mineral equilibria study of the hydrothermal alteration in mafic greenschist facies rocks at Kalgoorlie, Western Australia
Authors: White R. W. , Powell R. , Phillips G. N.
Published: June 2003

The influx of a H2O–CO2‐dominated fluid into actinolite‐bearing metabasic rocks during greenschist facies metamorphism in the Kalgoorlie area of Western Australia resulted in a zoned alteration halo around inferred fluid conduits that contain gold mineralisation. The alteration halo is divided into two outer zones, the chlorite zone and the carbonate zone, and an inner pyrite zone adjacent to the inferred fluid conduits. Reaction between the fluid and the protolith resulted in the breakdown of actinolite and the development of chlorite, dolomite, calcite and siderite. In addition, rocks in the pyrite zone developed muscovite‐bearing assemblages as a consequence of the introduction of potassium by the fluid. Mineral equilibria calculations undertaken using the computer software thermocalc in the model system Na2O–CaO–K2O–FeO–MgO–Al2O3–SiO2–H2O–CO2 show that mineral assemblages in the outer zones of the alteration halo are consistent with equilibrium of the protoliths with a fluid of composition XCO2 = CO2/(CO2 + H2O) = 0.1–0.25 for temperatures of 315–320 °C. The inner zone of the alteration halo reflect equilibrium with a fluid of composition XCO2≈ 0.25. Fluid‐rock buffering calculations show that the alteration halo is consistent with interaction with a single fluid composition and that the zoned structure of the halo reflects the volume of this fluid with which the rocks reacted. This fluid is likely to have also been the one responsible for the gold mineralisation at Kalgoorlie.
The preservation potential of microstructures during static grain growth
Authors: Jessell M. W. , Kostenko O. , Jamtveit B.
Published: June 2003

Grain growth simulations using the microstructure simulation system Elle have been performed in materials with a pre‐existing grain shape foliation. As might be expected, the foliation is destroyed by the end of the experiment, and grain areas have increased by a factor of seven. The area of material swept by the migrating grain boundaries was monitored, and it was found that at every stage, virtually all of the grains which survived the grain growth process contain one and only one core of ‘unswept’ material. Remarkably these remnant unswept cores preserve a useable record of the initial grain size and the orientation of the grain shape foliation. This work suggests that, even for samples where no equivalent protolith can be found, it may be possible to see past a grain growth episode to estimate the original grain shape and grain size of the rock, and perhaps even reconstruct the grain boundary kinematics. In addition the identification of unswept cores has the potential to help unravel the evolution of grain boundary chemistry in rocks during metamorphism.

As an example of a natural system showing these microstructures, we describe a peridotite from Almklovdalen, Norway. This peridotite was infiltrated by aqueous fluids at several stages during late Caledonian exhumation and retrogressive metamorphism. Grain boundary migration associated with the last of these infiltration events swept off abundant intragranular fluid inclusions in the original chlorite‐peridotite. At the grain scale, microstructural mapping of the fluid inclusion rich areas shows that, as with the numerical simulations, many of the grains retain exactly one core of unswept material. Examples of other natural systems discussed include dislocation density distributions and trace element zoning.
Orthopyroxene–sillimanite–quartz assemblages: distribution, petrology, quantitative P–T–X constraints and P–T paths
Authors: Kelsey D. E. , White R. W. , Powell R.
Published: June 2003

Granulite facies magnesian metapelites commonly preserve a wide array of mineral assemblages and reaction textures that are useful for deciphering the metamorphic evolution of a terrane. Quantitative pressure, temperature and bulk composition constraints on the development and preservation of characteristic peak granulite facies mineral assemblages such as orthopyroxene + sillimanite + quartz are assessed with reference to calculated phase diagrams. In NCKFMASH and its chemical subsystems, peak assemblages form mainly in high‐variance fields, and most mineral assemblage changes reflect multivariant equilibria. The rarity of orthopyroxene–sillimanite–quartz‐bearing assemblages in granulite facies rocks reflects the need for bulk rock XMg of greater than approximately 0.60–0.65, with pressures and temperatures exceeding c. 8 kbar and 850 °C, respectively. Cordierite coronas mantling peak minerals such as orthopyroxene, sillimanite and quartz have historically been used to infer isothermal decompression P–T paths in ultrahigh‐temperature granulite facies terranes. However, a potentially wide range of P–T paths from a given peak metamorphic condition facilitate retrograde cordierite growth after orthopyroxene + sillimanite + quartz, indicating that an individual mineral reaction texture is unable to uniquely define a P–T vector. Therefore, the interpretation of P–T paths in high‐grade rocks as isothermal decompression or isobaric cooling may be overly simplistic. Integration of quantitative data from different mineral reaction textures in rocks with varying bulk composition will provide the strongest constraints on a P–T path, and in turn on tectonic models derived from these paths.
Headaches and Papilledema Secondary to Dural Arteriovenous Malformation
Authors: Adelman James U.
Published: June 2003

A 21‐year‐old developed progressive headaches and pulsatile tinnitus. He was found to have papilledema and a pulsatile bruit. A dural arteriovenous malformation was not recognized on brain CT or MRI, but was well documented on magnetic resonance angiography and cerebral angiography. Dural malformations draining into the superior sagittal sinus can cause increased intracranial venous pressure and secondarily increase intracranial pressure even without a mass effect.
Subacute Angle‐Closure Glaucoma as a Cause of Headache in the Presence of a White Eye
Authors: Lewis Jacqueline , Fourman Stuart
Published: June 2003

Three patients, initially diagnosed with headache syndromes, were subsequently found to have subacute angle‐closure glaucoma. In each case, the eye appeared grossly normal and there were no visual symptoms.A comprehensive ophthalmologic examination, including gonioscopy, confirmed the diagnosis. Laser iridotomy was curative with complete resolution of head and face pain. Subacute angle‐closure glaucoma is an exception to the maxim that a white eye is not the cause of a painful eye.
Daily Sumatriptan for Detoxification From Rebound
Authors: Drucker Peggy , Tepper Stewart
Published: June 2003

Medications which provide symptomatic relief from headache can transform episodic migraine into chronic daily headache by propagating the daily headache, causing “rebound.” It is possible to restore the episodic migraine pattern by using an inpatient course of intravenous dihydroergotamine.

This study was undertaken to explore whether it was possible to use oral sumatriptan in the outpatient setting as a bridge to detoxification for patients with chronic daily headache due to medication overuse. All patients had previously met International Headache Society (IHS) criteria for episodic migraine and currently had greater than 15 days of headache per month for greater than 1 month. These patients were advised to take 25 mg sumatriptan by mouth three times a day for 10 days or until they were headache‐free for 24 hours.

Results reveal that of the 26 patients who started the protocol, 58% had reverted to an episodic migraine pattern at 1 month, and 69% were no longer having chronic daily headache at 6 months. This study demonstrates that it is possible to detoxify patients with rebound headaches using oral sumatriptan during the withdrawal period in an outpatient setting.
Nukleäre Hormonrezeptoren: Interventionsmöglichkeiten jenseits von Glukokortikoiden, Retinoiden und Vitamin D
Authors: Schmuth Matthias , Elias Peter M. , Feingold, Kenneth R.
Published: June 2003

Nukleäre Hormonrezeptoren sind Transkriptionsfaktoren, deren Aktivität von Liganden reguliert wird. Zur Gruppe der nukleären Hormonrezeptoren, die mit dem Retinoid‐X‐Rezeptor heterodimerisieren, gehören für die dermatologische Therapie interessante Zielmoleküle, darunter bereits im klinischen Einsatz der Retinoic‐Acid‐Rezeptor (RAR) und der Vitamin‐D‐Rezeptor (VDR). Neu hinzu kommen kürzlich bekannt gewordene Rezeptoren wie die Peroxisome‐Proliferator‐Activated‐Rezeptoren (PPAR) und die Liver‐X‐Rezeptoren (LXR). Nach der Bindung von Liganden (häufig Lipidmetabolite) bindet der Komplex aus Ligand und Rezeptor an definierte regulatorische Sequenzen in der DNA und beeinflußt die Transkription von Genen insbesondere der Zelldifferenzierung, des Energie‐ und des Lipidstoffwechsels. Aufgrund von Fortschritten der kombinatorischen Chemie sind synthetische Liganden für PPAR und LXR verfügbar geworden, initial zur Behandlung von Diabetes, Hyperlipidämien und zur Regulierung des Gallensäurestoffwechsels. Es zeichnet sich ab, daß derartige Liganden über die Systemwirkung hinaus positive Effekte auf die kutane Homöostase und damit ein Potential für den Einsatz in der dermatologischen Therapie besitzen. In dieser Übersicht werden die für die Dermatologie wesentlichen, neueren Forschungsergebnisse auf diesem Gebiet zusammengefaßt.
Stärken‐ und Schwächen‐Analyse: Grundlage der Leistungsausrichtung im wettbewerbsorientierten Umfeld
Authors: Hensen, Peter , Wollert Silke , Schwarz Thomas , Luger Thomas , Roeder Norbert
Published: June 2003

Kliniken und Krankenhäuser sehen sich in zunehmenden Maße den Notwendigkeiten ausgesetzt, sich flexibel und innovativ mit einem sich verändernden, vor allen Dingen stärker wettbewerbsorientierten Markt auseinanderzusetzen. Der bevorstehende Wandel in der Krankenhausfinanzierung und der zunehmende Wettbewerb des zukünftigen Anbietermarkts erfordern eine genaue Organisations‐ und Standortanalyse. Mehr als andere stehen die Kliniken der Maximalversorgung bei einem unabhängig von der Versorgungsstufe gleich pauschalierenden Finanzierungsansatz unter dem Druck, dauerhaft ihre Leistungsfähigkeit zu erhalten, eine verbesserte Nutzung vorhandener Ressourcen, insbesondere der Mitarbeiterpotenziale, zu erreichen und eine Existenzsicherung auch über das Eingehen von langfristig angelegten Kooperationen zu betreiben. Nur durch eine eindeutige Positionierung und nachhaltige Leistungsausrichtung im regionalen und überregionalen Wettbewerb wird es den Kliniken der Maximalversorgung gelingen, die zunehmend verschärfenden Wettbewerbsbedingungen zu bewältigen. Vor diesem Hintergrund wird am Beispiel einer dermatologischen Universitätsklinik erläutert, wie die konstruktive Auseinandersetzung mit einem sich verändernden Markt erfolgen kann.
Pemphigoid gestationis: treatment with immunoapheresis
Authors: Wöhrl Stefan , Geusau Alexandra , Karlhofer Franz , Derfler Kurt , Stingl Georg , Zillikens Detlef
Published: June 2003

Background: Pemphigoid (herpes) gestationis is a rare blistering disease of pregnancy. Topical and systemic corticosteroids and antihistamines are usually sufficient for treatment.

Case report: A patient suffering from severe, therapy‐resistant pemphigoid gestationis was successfully treated with the additional use of six sessions of immunoapheresis. Systemic corticosteroids could be tapered and serum autoantibody levels to bullous pemphigoid antigen 2 (BPAG2 = BP180) significantly dropped during this treatment.

Conclusion: Immunoapheresis represents a helpful therapeutic option with few side effects for severe cases of pemphigoid gestationis, unresponsive to conventional treatment.
A role for Z-DNA binding in vaccinia virus pathogenesis
Authors: Kim Yang-Gyun , Muralinath Maneesha , Brandt Teresa , Pearcy Matthew , Hauns Kevin , Lowenhaupt Ky , Jacobs Bertram L. , Rich Alexander
Published: June 2003

The N-terminal domain of the E3L protein of vaccinia virus has sequence similarity to a family of Z-DNA binding proteins of defined three-dimensional structure and it is necessary for pathogenicity in mice. When other Z-DNA-binding domains are substituted for the similar E3L domain, the virus retains its lethality after intracranial inoculation. Mutations decreasing Z-DNA binding in the chimera correlate with decreases in viral pathogenicity, as do analogous mutations in wild-type E3L. A chimeric virus incorporating a related protein that does not bind Z-DNA is not pathogenic, but a mutation that creates Z-DNA binding makes a lethal virus. The ability to bind the Z conformation is thus essential to E3L activity. This finding may allow the design of a class of antiviral agents, including agents against variola (smallpox), which has an almost identical E3L.
Folding and misfolding of the papillomavirus E6 interacting peptide E6ap
Authors: Cui Bianxiao , Shen Min-Yi , Freed Karl F.
Published: June 2003

All-atom Langevin dynamics simulations have been performed to study the folding pathways of the 18-residue binding domain fragment E6ap of the human papillomavirus E6 interacting peptide. Six independent folding trajectories, with a total duration of nearly 2 μs, all lead to the same native state in which the E6ap adopts a fluctuating α-helix structure in the central portion (Ser-4–Leu-13) but with very flexible N and C termini. Simulations starting from different core configurations exhibit the E6ap folding dynamics as either a two- or three-state folder with an intermediate misfolded state. The essential leucine hydrophobic core (Leu-9, Leu-12, and Leu-13) is well conserved in the native-state structure but absent in the intermediate structure, suggesting that the leucine core is not only essential for the binding activity of E6ap but also important for the stability of the native structure. The free energy landscape reveals a significant barrier between the basins separating the native and misfolded states. We also discuss the various underlying forces that drive the peptide into its native state.
Redirection of B cell responsiveness by transforming growth factor β receptor
Authors: Roes Jürgen , Choi B. Ken , Cazac Balthazar B.
Published: June 2003

The multifunctional transforming growth factor β receptor (TβR) ligand pair plays a central role in the regulation of lymphocyte homeostasis and prevention of autoimmunity. Although the mechanisms underlying the induction of transcriptional modulators by TβR have been studied in considerable detail, relatively little is known about the regulatory pathways targeted. To shed light on the mechanisms involved in negative regulation of B cell responses we identified TβR-dependent transcriptome changes by comparative gene expression profiling of normal and TβR-deficient primary B cells. The data reveal TβR-mediated induction of inhibitors of antigen receptor signaling (Ship-1, CD72) as well as inhibitors of the Jak/Stat pathway and signaling by means of Toll-like receptors (SOCS1,3). These inhibitory effects are complemented by induction of antiproliferative transcription factors. In contrast to this inhibition, G protein-coupled receptors such as CXCR4 and agonists mediating Ca2+flux (inositol trisphosphate receptor subtype 2) are induced by TβR, indicating enhancement of the Ca2+storage/ release system and chemotactic responses. Suppression of proapoptotic genes suggests support of cell survival. Confirming the shift in B cell responsiveness, antigen-receptor-mediated activation of Syk and phospholipase C-γ2, as well as Stat6 phosphorylation, is inhibited, whereas chemotaxis, Ca2+release, and cell survival are enhanced in transforming growth factor-β-sensitive B cells. The data provide a molecular basis for TβR-mediated inhibition of B cell responsiveness and indicate that TβR maintains homeostasis not only through inhibition of the cell cycle but also by delivering a coherent instructive signal that redirects responsiveness to microenvironmental cues.
Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy
Authors: Dombeck Daniel A. , Kasischke Karl A. , Vishwasrao Harshad D. , Ingelsson Martin , Hyman Bradley T. , Webb Watt W.
Published: June 2003

Microtubule (MT) ensemble polarity is a diagnostic determinant of the structure and function of neuronal processes. Here, polarized MT structures are selectively imaged with second-harmonic generation (SHG) microscopy in native brain tissue. This SHG is found to colocalize with axons in both brain slices and cultured neurons. Because SHG arises only from noninversion symmetric structures, the uniform polarity of axonal MTs leads to the observed signal, whereas the mixed polarity in dendrites leads to destructive interference. SHG imaging provides a tool to investigate the kinetics and function of MT ensemble polarity in dynamic native brain tissue structures and other subcellular motility structures based on polarized MTs.
Peripheral heme substituents control the hydrogen-atom abstraction chemistry in cytochromes P450
Authors: Guallar Victor , Baik Mu-Hyun , Lippard Stephen J. , Friesner Richard A.
Published: June 2003

We elucidate the hydroxylation of camphor by cytochrome P450 with the use of density functional and mixed quantum mechanics/molecular mechanics methods. Our results reveal that the enzyme catalyzes the hydrogen-atom abstraction step with a remarkably low free-energy barrier. This result provides a satisfactory explanation for the experimental failure to trap the proposed catalytically competent high-valent heme Fe(IV) oxo (oxyferryl) species responsible for this hydroxylation chemistry. The primary and previously unappreciated contribution to stabilization of the transition state is the interaction of positively charged residues in the active-site cavity with carboxylate groups on the heme periphery. A similar stabilization found in dioxygen binding to hemerythrin, albeit with reversed polarity, suggests that this mechanism for controlling the relative energetics of redox-active intermediates and transition states in metalloproteins may be widespread in nature.
3D electron microscopy reveals the variable deposition and protein dynamics of the peripheral pyruvate dehydrogenase component about the core
Authors: Gu Yingqi , Zhou Z. Hong , McCarthy Diane B. , Reed Lester J. , Stoops James K.
Published: June 2003

Cryo-electron microscopy was exploited to reveal and study the influence of pyruvate dehydrogenase (E
1
) occupancy on the conformational states of the
Saccharomyces cerevisiae
pyruvate dehydrogenase complex (PDC). Structures representative of PDC preparations with ≈40% and full E
1
occupancy were determined after the electron microscopy images from each preparation were classified according to their sizes. The reconstructions derived from two size groups showed that the deposition of the E
1
molecules associated with the larger complex is, unexpectedly, not icosahedrally arranged, whereas in the smaller complex the E
1
molecules have an arrangement and architecture similar to their more ordered deposition in the WT bovine kidney PDC. This study also shows that the linker of dihydrolipamide acetyltransferase (E
2
) that tethers E
1
to the E
2
core increases in length from ≈50 to 75 Å, accounting largely for the size difference of the smaller and larger structures, respectively. Extensive E
1
occupancy of its 60 E
2
binding sites favors the extended conformation of the linker associated with the larger complex and appears to be related to the loss of icosahedral symmetry of the E
1
molecules. However, the presence of a significant fraction of larger molecules also in the WT PDC preparation with low E
1
occupancy indicates that the conformational variability of the linker contributes to the overall protein dynamics of the PDC and the variable deposition of E
1
. The flexibility of the complex may enhance the catalytic proficiency of this macromolecular machine by promoting the channeling of the intermediates of catalysis between the active sites.
Mapping the genetic variation of executive attention onto brain activity
Authors: Fan Jin , Fossella John , Sommer Tobias , Wu Yanghong , Posner Michael I.
Published: June 2003

Brain imaging data have repeatedly shown that the anterior cingulate cortex is an important node in the brain network mediating conflict. We previously reported that polymorphisms in dopamine receptor (
DRD4
) and monoamine oxidase A (
MAOA
) genes showed significant associations with efficiency of handling conflict as measured by reaction time differences in the Attention Network Test (ANT). To examine whether this genetic variation might contribute to differences in brain activation within the anterior cingulate cortex, we genotyped 16 subjects for the
DRD4
and
MAOA
genes who had been scanned during the ANT. In each of the two genes previously associated with more efficient handling of conflict in reaction time experiments, we found a polymorphism in which persons with the allele associated with better behavioral performance showed significantly more activation in the anterior cingulate while performing the ANT than those with the allele associated with worse performance. The results demonstrate how genetic differences among individuals can be linked to individual differences in neuromodulators and in the efficiency of the operation of an appropriate attentional network.
A global view of the selectivity of zinc deprivation and excess on genes expressed in human THP-1 mononuclear cells
Authors: Cousins Robert J. , Blanchard Raymond K. , Popp Michael P. , Liu Li , Cao Jay , Moore J. Bernadette , Green Calvert L.
Published: June 2003

Among the micronutrients required by humans, zinc has particularly divergent modes of action. cDNA microarray and quantitative PCR technologies were used to investigate the zinc responsiveness of known genes that influence zinc homeostasis and to identify, through global screening, genes that may relate to phenotypic outcomes of altered dietary zinc intake. Human monocytic/macrophage THP-1 cells were either acutely zinc depleted, using a cell-permeable zinc-specific chelator, or were supplemented with zinc to alter intracellular zinc concentrations. Initially, genes associated with zinc homeostasis were evaluated by quantitative PCR to establish ranges for fold changes in transcript abundance that might be expected with global screening. Zinc transporter-1 and zinc transporter-7 expression increased when cellular zinc increased, whereas Zip-2 expression, the most zinc-responsive gene examined, was markedly increased by zinc depletion. Microarrays composed of ≈22,000 elements were used to identify those genes responsive to either zinc depletion, zinc supplementation, or both conditions. Hierarchal clustering and ANOVA revealed that ≈5% or 1,045 genes were zinc responsive. Further sorting based on this pattern of the zinc responsiveness of these genes into seven groups revealed that 104 genes were linearly zinc responsive in a positive mode (i.e., increased expression as cellular zinc increases) and 86 genes that were linearly zinc responsive in a negative mode (i.e., decreased expression as cellular zinc increases). Expression of some genes was responsive to only zinc depletion or supplementation. Categorization by function revealed numerous genes needed for host defense were among those identified as zinc responsive, including cytokine receptors and genes associated with amplification of the Th1 immune response.
Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles
Authors: Hsu Mayla , Zhang Jie , Flint Mike , Logvinoff Carine , Cheng-Mayer Cecilia , Rice Charles M. , McKeating Jane A.
Published: June 2003

HIV pseudotypes bearing native hepatitis C virus (HCV) glycoproteins (strain H and Con1) are infectious for the human hepatoma cell lines Huh-7 and PLC/PR5. Infectivity depends on coexpression of both E1 and E2 glycoproteins, is pH-dependent, and can be neutralized by mAbs mapping to amino acids 412–447 within E2. Cell-surface expression of one or all of the candidate receptor molecules (CD81, low-density lipoprotein receptor, scavenger receptor class B type 1, and dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin) failed to confer permissivity to HIV–HCV pseudotype infection. However, HIV–HCV pseudotype infectivity was inhibited by a recombinant soluble form of CD81 and a mAb specific for CD81, suggesting that CD81 may be a component of a receptor complex.
Spatial parasite transmission, drug resistance, and the spread of rare genes
Authors: Cornell S. J. , Isham V. S. , Smith G. , Grenfell B. T.
Published: June 2003

The transmission of many parasitic worms involves aggregated movement between hosts of “packets” of infectious larvae. We use a generic metapopulation model to show that this aggregation naturally promotes the preferential spread of rare recessive genes, compared with the expectations of traditional nonspatial models. A more biologically realistic model also demonstrates that this effect could explain the rapid observed spread of recessive or weakly dominant drug-resistant genotypes in nematode parasites of sheep. This promotion of a recessive trait arises from a novel mechanism of inbreeding arising from the metapopulation dynamics of transmission.
The economic value of ecological stability
Authors: Armsworth Paul R. , Roughgarden Joan E.
Published: June 2003

Seemingly intangible ecosystem characteristics that preoccupy ecologists, like ecosystem stability and the responsiveness of populations to environmental variation, have quantifiable economic values. We show how to derive these values, and how their consideration should change environmental decision making. To illustrate these concepts, we use a simple reserve design model. When resource managers choose a particular landscape configuration, their decision affects both the mean abundance of species and the temporal variation in abundances. Population stability and related phenomena have economic value, because management actions affect the variance of ecosystem components. In our example, a larger reserve size is recommended when accounting for the stability of the managed ecosystem.
Absolute quantification of proteins and phosphoproteins from cell lysates by tandem MS
Authors: Gerber Scott A. , Rush John , Stemman Olaf , Kirschner Marc W. , Gygi Steven P.
Published: June 2003

A need exists for technologies that permit the direct quantification of differences in protein and posttranslationally modified protein expression levels. Here we present a strategy for the absolute quantification (termed AQUA) of proteins and their modification states. Peptides are synthesized with incorporated stable isotopes as ideal internal standards to mimic native peptides formed by proteolysis. These synthetic peptides can also be prepared with covalent modifications (e.g., phosphorylation, methylation, acetylation, etc.) that are chemically identical to naturally occurring posttranslational modifications. Such AQUA internal standard peptides are then used to precisely and quantitatively measure the absolute levels of proteins and posttranslationally modified proteins after proteolysis by using a selected reaction monitoring analysis in a tandem mass spectrometer. In the present work, the AQUA strategy was used to (
i
) quantify low abundance yeast proteins involved in gene silencing, (
ii
) quantitatively determine the cell cycle-dependent phosphorylation of Ser-1126 of human separase protein, and (
iii
) identify kinases capable of phosphorylating Ser-1501 of separase in an
in vitro
kinase assay. The methods described here represent focused, alternative approaches for studying the dynamically changing proteome.
Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation
Authors: Zipfel Warren R. , Williams Rebecca M. , Christie Richard , Nikitin Alexander Yu , Hyman Bradley T. , Webb Watt W.
Published: June 2003

Multicolor nonlinear microscopy of living tissue using two- and three-photon-excited intrinsic fluorescence combined with second harmonic generation by supermolecular structures produces images with the resolution and detail of standard histology without the use of exogenous stains. Imaging of intrinsic indicators within tissue, such as nicotinamide adenine dinucleotide, retinol, indoleamines, and collagen provides crucial information for physiology and pathology. The efficient application of multiphoton microscopy to intrinsic imaging requires knowledge of the nonlinear optical properties of specific cell and tissue components. Here we compile and demonstrate applications involving a range of intrinsic molecules and molecular assemblies that enable direct visualization of tissue morphology, cell metabolism, and disease states such as Alzheimer's disease and cancer.
Viral assembly of oriented quantum dot nanowires
Authors: Mao Chuanbin , Flynn Christine E. , Hayhurst Andrew , Sweeney Rozamond , Qi Jifa , Georgiou George , Iverson Brent , Belcher Angela M.
Published: June 2003

The highly organized structure of M13 bacteriophage was used as an evolved biological template for the nucleation and orientation of semiconductor nanowires. To create this organized template, peptides were selected by using a pIII phage display library for their ability to nucleate ZnS or CdS nanocrystals. The successful peptides were expressed as pVIII fusion proteins into the crystalline capsid of the virus. The engineered viruses were exposed to semiconductor precursor solutions, and the resultant nanocrystals that were templated along the viruses to form nanowires were extensively characterized by using high-resolution analytical electron microscopy and photoluminescence. ZnS nanocrystals were well crystallized on the viral capsid in a hexagonal wurtzite or a cubic zinc blende structure, depending on the peptide expressed on the viral capsid. Electron diffraction patterns showed single-crystal type behavior from a polynanocrystalline area of the nanowire formed, suggesting that the nanocrystals on the virus were preferentially oriented with their [001] perpendicular to the viral surface. Peptides that specifically directed CdS nanocrystal growth were also engineered into the viral capsid to create wurtzite CdS virus-based nanowires. Lastly, heterostructured nucleation was achieved with a dual-peptide virus engineered to express two distinct peptides within the same viral capsid. This work represents a genetically controlled biological synthesis route to a semiconductor nanoscale heterostructure.
Transcriptional profiling of the Sonic hedgehog response: A critical role for N-myc in proliferation of neuronal precursors
Authors: Oliver Trudy G. , Grasfeder Linda L. , Carroll Audra L. , Kaiser Constanze , Gillingham Christine L. , Lin Simon M. , Wickramasinghe Rasika , Scott Matthew P. , Wechsler-Reya Robert J.
Published: June 2003

Cerebellar granule cells are the most abundant neurons in the brain, and granule cell precursors (GCPs) are a common target of transformation in the pediatric brain tumor medulloblastoma. Proliferation of GCPs is regulated by the secreted signaling molecule Sonic hedgehog (Shh), but the mechanisms by which Shh controls proliferation of GCPs remain inadequately understood. We used DNA microarrays to identify targets of Shh in these cells and found that Shh activates a program of transcription that promotes cell cycle entry and DNA replication. Among the genes most robustly induced by Shh are
cyclin D1
and
N-myc. N-myc
transcription is induced in the presence of the protein synthesis inhibitor cycloheximide, so it appears to be a direct target of Shh. Retroviral transduction of
N-myc
into GCPs induces expression of
cyclin D1, E2F1
, and
E2F2
, and promotes proliferation. Moreover, dominant-negative N-myc substantially reduces Shh-induced proliferation, indicating that
N-myc
is required for the Shh response. Finally,
cyclin D1
and
N-myc
are overexpressed in murine medulloblastoma. These findings suggest that
cyclin D1
and
N-myc
are important mediators of Shh-induced proliferation and tumorigenesis.
Competition and representation during memory retrieval: Roles of the prefrontal cortex and the posterior parietal cortex
Authors: Sohn Myeong-Ho , Goode Adam , Stenger V. Andrew , Carter Cameron S. , Anderson John R.
Published: June 2003

In this functional-MRI study we examined the hypothesis that the prefrontal cortex responds differently to the extent of competition during retrieval, whereas the parietal cortex is responsible for problem representation that should not be directly related to the competition. Participants mastered arbitrary person–location pairs, and their recognition memory was tested in a functional-MRI session. The pairs were constructed such that a person was associated with one, two, or three different locations and vice versa. The recognition time increased with the number of associations, reflecting increased competition. A confirmatory analysis of imaging data with prespecified prefrontal and parietal regions showed that, although both regions were highly involved during memory retrieval, only the prefrontal region responded to the levels of competition. This result was consistent with predictions of an information-processing model as well as with an exploratory identification of regions of interest.
A novel social polymorphism in a primitively eusocial bee
Authors: Richards Miriam H. , von Wettberg Eric J. , Rutgers Amy C.
Published: June 2003

Halictine sweat bees (Hymenoptera, Halictidae) are model organisms for the evolution of altruism, reproductive castes, and eusocial colony organization. Halictine social behavior is not only extremely variable, but also ecologically and evolutionarily labile. Among social species, colony social organization ranges from communal societies of egalitarian females to eusocial and semisocial ones with reproductive queens and more or less sterile workers. A striking aspect of halictine social variation is the mutual exclusivity of communal and eusocial types of colony social organization within the same species, these two types of social behavior being characteristic of different genera and subgenera. We report a recently discovered exception to this rule in a population ofHalictus sexcinctus(Fabricius) at Daimonia-Pyla in southern Greece, that contained both communal and eusocial colonies. Moreover, communal and eusocial females exhibit morphological differences that imply a preimaginal developmental switch, which could also underlie the two types of social behavior. That the communal and eusocial forms are not merely cryptic sister species with different social behavior is indicated by the comparison of mitochondrial DNA sequences of two sections of cytochrome oxidase I, which indicate that Greek specimens of both social types are more similar than they are to conspecifics from elsewhere in Europe. The phylogenetic position ofHalictus sexcinctussuggests that this unusual communal/eusocial polymorphism may represent an unstable intermediate step in an evolutionary reversal from eusocial to solitary behavior.
Hypergeometric generating functions for values of Dirichlet and other
L
functions
Authors: Lovejoy Jeremy , Ono Ken
Published: June 2003

Although there is vast literature on the values of
L
functions at nonpositive integers, the recent appearance of some of these values as the coefficients of specializations of knot invariants comes as a surprise. Using work of G. E. Andrews [(1981)
Adv. Math.
41, 173–185; (1986)
q-Series: Their Development and Application in Analysis, Combinatories, Physics, and Computer Algebra,
Conference Board of the Mathematical Sciences Regional Conference Series in Mathematics 66 (Am. Math. Soc, Providence, RI); (1975)
Problems and Prospects for Basic Hypergeometric Series: The Theory and Application of Special Functions
(Academic, New York); and (1992)
Illinois J. Math.
36, 251–274], we revisit this old subject and provide uniform and general results giving such generating functions as specializations of basic hypergeometric functions. For example, we obtain such generating functions for all nontrivial Dirichlet
L
functions.
Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor
Authors: Vasselli James R. , Shih Joanna H. , Iyengar Shuba R. , Maranchie Jodi , Riss Joseph , Worrell Robert , Torres-Cabala Carlos , Tabios Ray , Mariotti Andra , Stearman Robert , Merino Maria , Walther McClellan M. , Simon Richard , Klausner Richard D. , Linehan W. Marston
Published: June 2003

To identify potential molecular determinants of tumor biology and possible clinical outcomes, global gene-expression patterns were analyzed in the primary tumors of patients with metastatic renal cell cancer by using cDNA microarrays. We used grossly dissected tumor masses that included tumor, blood vessels, connective tissue, and infiltrating immune cells to obtain a gene-expression “profile” from each primary tumor. Two patterns of gene expression were found within this uniformly staged patient population, which correlated with a significant difference in overall survival between the two patient groups. Subsets of genes most significantly associated with survival were defined, and vascular cell adhesion molecule-1 (VCAM-1) was the gene most predictive for survival. Therefore, despite the complex biological nature of metastatic cancer, basic clinical behavior as defined by survival may be determined by the gene-expression patterns expressed within the compilation of primary gross tumor cells. We conclude that survival in patients with metastatic renal cell cancer can be correlated with the expression of various genes based solely on the expression profile in the primary kidney tumor.
Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking
Authors: Schapira Matthieu , Raaka Bruce M. , Das Sharmistha , Fan Li , Totrov Maxim , Zhou Zhiguo , Wilson Stephen R. , Abagyan Ruben , Samuels Herbert H.
Published: June 2003

Treatment of hyperthyroidism, a common clinical condition that can have serious manifestations in the elderly, has remained essentially unchanged for >30 years. Directly antagonizing the effect of the thyroid hormone at the receptor level may be a significant improvement for the treatment of hyperthyroid patients. We built a computer model of the thyroid hormone receptor (TR) ligand-binding domain in its predicted antagonist-bound conformation and used a virtual screening algorithm to select 100 TR antagonist candidates out of a library of >250,000 compounds. We were able to obtain 75 of the compounds selected
in silico
and studied their ability to act as antagonists by using cultured cells that express TR. Fourteen of these compounds were found to antagonize the effect of T3 on TR with IC
50
s ranging from 1.5 to 30 μM. A small virtual library of compounds, derived from the highest affinity antagonist (1-850) that could be rapidly synthesized, was generated. A second round of virtual screening identified new compounds with predicted increased antagonist activity. These second generation compounds were synthesized, and their ability to act as TR antagonists was confirmed by transfection and receptor binding experiments. The extreme structural diversity of the antagonist compounds shows how receptor-based virtual screening can identify diverse chemistries that comply with the structural rules of TR antagonism.
Seaweed resistance to microbial attack: A targeted chemical defense against marine fungi
Authors: Kubanek Julia , Jensen Paul R. , Keifer Paul A. , Sullards M. Cameron , Collins Dwight O. , Fenical William
Published: June 2003

Pathogenic microbes can devastate populations of marine plants and animals. Yet, many sessile organisms such as seaweeds and sponges suffer remarkably low levels of microbial infection, despite lacking cell-based immune systems. Antimicrobial defenses of marine organisms are largely uncharacterized, although from a small number of studies it appears that chemical defenses may improve host resistance. In this study, we asked whether the common seaweed
Lobophora variegata
is chemically defended against potentially deleterious microorganisms. Using bioassay-guided fractionation, we isolated and characterized a 22-membered cyclic lactone, lobophorolide (1), of presumed polyketide origin, with sub-μM activity against pathogenic and saprophytic marine fungi. Deterrent concentrations of 1 were found in 46 of 51 samples collected from 10 locations in the Bahamas over a 4-year period. Lobophorolide (1) is structurally unprecedented, yet parts of the molecule are related to tolytoxin, the scytophycins, and the swinholides, macrolides previously isolated from terrestrial cyanobacteria and from marine sponges and gastropods. Until now, compounds of this structural class have not been associated with marine macrophytes. Our findings suggest that seaweeds use targeted antimicrobial chemical defense strategies and that secondary metabolites important in the ecological interactions between marine macroorganisms and microorganisms could be a promising source of novel bioactive compounds.
Decoding neuronal spike trains: How important are correlations?
Authors: Nirenberg Sheila , Latham Peter E.
Published: June 2003

It has been known for >30 years that neuronal spike trains exhibit correlations, that is, the occurrence of a spike at one time is not independent of the occurrence of spikes at other times, both within spike trains from single neurons and across spike trains from multiple neurons. The presence of these correlations has led to the proposal that they might form a key element of the neural code. Specifically, they might act as an extra channel for information, carrying messages about events in the outside world that are not carried by other aspects of the spike trains, such as firing rate. Currently, there is no general consensus about whether this proposal applies to real spike trains in the nervous system. This is largely because it has been hard to separate information carried in correlations from that not carried in correlations. Here we propose a framework for performing this separation. Specifically, we derive an information-theoretic cost function that measures how much harder it is to decode neuronal responses when correlations are ignored than when they are taken into account. This cost function can be readily applied to real neuronal data.
BRCA2 cooperates with histone acetyltransferases in androgen receptor-mediated transcription
Authors: Shin Sook , Verma Inder M.
Published: June 2003

Germ-line mutations of the
BRCA2
tumor suppressor gene greatly increase the risk of developing breast and ovarian cancers. Here, we show that wild-type BRCA2, but not a tumor-specific truncated mutant BRCA2, synergizes with the nuclear receptor coactivator p160 GRIP1 to enhance transcriptional activation by androgen receptor (AR). BRCA2 not only associates with AR and GRIP1 but also cooperates with both the histone acetyltransferase P/CAF and BRCA1 to enhance AR- and GRIP1-mediated transactivation. As such, BRCA2 can exert its tumor suppressor function, in part, by modulating androgen signaling, which has been shown to be antiproliferative in a subset of breast cancer cells and particularly implicated in male breast tumors.