bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of chiral indices of individual single- and double-walled boron nitride nanotubes by electron diffraction
Authors: Arenal R. , Kociak M. , Loiseau A. , Miller D.-J.
Published: August 2006

The intensities of electron diffraction patterns from individual (single-, double-walled) boron nitride nanotubes (BNNTs) as well as from bundles of these tubes have been recorded. The helicities have been systematically measured, and the diameter and the chiral indices have been determined. The analysis of 121 nanotubes reveals that 12% of the tubes are zigzag, while the distribution of the other helicities is uniform. The large value of the intertube distance and the significant difference of the chiral angle between the two constituent tubes in double-walled BNNTs indicate a lower interaction between the BN sheets than in bulk hexagonal BN.
Shear-strain induced decomposition of 1,1-diamino-2,2-dinitroethylene
Authors: Kuklja M. M. , Rashkeev S. N. , Zerilli F. J.
Published: August 2006

The structural and electronic features of shear strains in the molecular crystal 1,1-diamino-2,2-dinitroethylene and their effect on decomposition of the material are investigated. The authors demonstrate that shear strains lower the decomposition barrier and narrow the band gap of the solid and thus facilitate thermal chemistry in molecular materials. The appearance of defect-related electronic states in the band gap is consistent with previous results for dislocation modeling in molecular solids and with experiments on energetic materials. The dynamic behavior of the band gap contains a rich variety of information about the details of the decomposition processes at the initiation stage.
Self-driven formation and structure of single crystal platelets of Zn3As2
Authors: Kouklin N. , Sen S. , Gajdardziska-Josifovska M.
Published: August 2006

In this work the authors introduce and provide details on the stoichiometrically controlled self-driven formation of freestanding single crystal platelets in Zn3As2 by a direct self-catalytic vapor-solid growth mechanism. The platelets feature dimensions of up to ∼1cm and mirrorlike microscopically flat top surfaces. A coherent formation of pyramids and wires has been further observed on some of the platelet top surfaces, the growth mechanism of which is discussed. This study might open pathways for facile engineering of high-performance semiconductor via a direct vapor-solid conversion of polycrystalline semiconductor powders into single crystal substrates on a large scale and with low cost.
On the solute coupling at the moving solid/liquid interface during equiaxed solidification
Authors: Yao X.
Published: August 2006

Integral mass conservation was widely accepted for the solute coupling to solve solute redistribution during equiaxed solidification so far. The present study revealed that the integral form was invalid for moving boundary problems as it could not represent the mass balance at the moving interface. Accordingly, differential mass conservation at the solid/liquid interface was used to solve solute diffusion for spherical geometry. The model was applied for hydrogen diffusion in solidification to validate that the hydrogen enrichment was significant and depended on the growth rate.
Enhanced spectral coverage in tandem organic solar cells
Authors: Dennler Gilles , Prall Hans-Jürgen , Koeppe Robert , Egginger Martin , Autengruber Robert , Sariciftci Niyazi Serdar
Published: August 2006

In order to realize enhanced spectral coverage in organic photovoltaic devices, the authors have stacked a zinc phthalocyanine:C60 based cell on the top of a poly-3-hexyl-thiophene:[6,6]-phenyl C61-butyric acid methyl ester layer using a 1nm thick Au intermediate recombination layer. Such tandem devices comprising active materials with complementary absorption spectra exhibit a short circuit current (Isc) of 4.8mAcm−2, an open circuit voltage (Voc) of 1020mV, and a fill factor of 0.45. Measurements of the photocurrent versus wavelength of the incident light show that photons are converted into charge carriers from 400 to more than 800nm. Further optimization of the respective layer thicknesses may lead to high efficiency devices.
Ordering of metallic quantum dots
Authors: Salac David , Lu Wei
Published: August 2006

This letter proposes a mechanism for the ordering of metallic quantum dots without coherent lattice or lattice mismatch with the substrate so that elasticity may not account for the phenomena. The authors show that contact potential induces repulsive charge clouds in the substrate. The size-dependent repulsion and van der Waals attraction lead to ordered nanoscale structures.
Two-dimension full array high-speed ink-jet print head
Authors: Einat M. , Einat N.
Published: August 2006

An ink-jet print head in a structure, similar to a liquid crystal display, is suggested. It is based on a segment, containing a microink reservoir, feeding one or a few nozzles. The segment is autonomous and unlimitedly duplicable to form a large ink-jet print head. The microreservoirs are open to the atmospheric pressure, and pressure regulation in the nozzle is accomplished by capillary action. The microreservoirs are replenished by slow wiper smearing action. Experiments with a 57600 nozzle matrix print head showed good results for the design. Printing speed of ∼1000pagesmin, and even more, is achievable.
Dielectric behavior of a metal-polymer composite with low percolation threshold
Authors: Li Yun-Jia , Xu Man , Feng Jun-Qiang , Dang Zhi-Min
Published: August 2006

Stainless steel fiber (SSF)/poly(vinylidene fluoride) composite is prepared via simple blending and hot pressing route. The dependence of the dielectric properties of the composite on both volume fraction of the fillers and frequency is investigated. The percolation threshold of the composite, 9.4vol% (0.094 volume fraction), is much lower than that of the common two phase metal particle-polymer composite. A dielectric constant of 427 is observed at 50Hz with 10vol% of SSF. Large enhancements of the ac conductivity and loss tangent are also observed near the percolation threshold. The dielectric properties are explained by percolation theory while the dielectric anomalies are attributed to the high slenderness ratio of the SSF fillers.
Bright-field imaging of lattice distortions using x rays
Authors: Yi J. M. , Je J. H. , Chu Y. S. , Zhong Y. , Hwu Y. , Margaritondo G.
Published: August 2006

Can x rays yield bright-field images of crystalline systems similar to those of transmission electron microscopy? So far, the response was negative, but the authors present here a positive case: bright-field x-ray images carrying information both from diffraction/scattering phenomena and from absorption and phase contrast. Specifically, synchrotron x-ray transmission micrographs simultaneously yielded diffraction-based information on strain effects and information on structural inhomogeneities when (0001) 4H-SiC wafers were set for a strong reflection in the Laue geometry. This approach offers interesting advantages with respect to the separate study of strain and inhomogeneity effects for a variety of crystalline systems.
Visual Form-Processing Deficits in Autism
Authors: Spencer Janine V , O'Brien Justin M D
Published: August 2006

People with autism have a number of reported deficits in object recognition and global processing. Is there a low-level spatial integration deficit associated with this? We measured spatial-form-coherence detection thresholds using a Glass stimulus in a field of random dots, and compared performance to a similar motion-coherence task. A coherent visual patch was depicted by dots separated by a rotational transformation in space (form) or space - time (motion). To measure parallel visual integration, stimuli were presented for only 250 ms. We compared detection thresholds for children with autism, children with Asperger syndrome, and a matched control group. Children with autism showed a significant form-coherence deficit and a significant motion-coherence deficit, while the performance of the children with Asperger syndrome did not differ significantly from that of controls on either task.
Featural and Configural Face Processing in Adults and Infants: A Behavioral and Electrophysiological Investigation
Authors: Scott Lisa S , Nelson Charles A
Published: August 2006

We sought to elucidate the behavioral and electrophysiological correlates of face processing, in adults and infants, by manipulating either the featural or configural information within the face. Two different experiments are reported. In these experiments, event-related potentials (ERPs) were recorded from the scalp while adult, 8-month-old, and 4-month-old participants completed configural-change and featural-change face tasks. The infants also completed a behavioral visual paired-comparison task with featural and configural face changes. ERP results reveal hemispheric differences in processing featural but not configural changes for the N170 in adults. Furthermore, featural and configural changes are processed differently within the right and left hemispheres. The right hemisphere N170 is significantly greater for configural compared to featural changes. The left hemisphere N170, however, exhibits the opposite effect. Infant data suggest that similar to adults, 8-month-old, but not 4-month-old participants, exhibit similar hemispheric differences between featural and configural changes for the P400 component. Behavioral results suggest increased sensitivity to both featural and configural face changes in 8-month-olds compared to 4-month-olds.
The Role of Part Structure in the Perceptual Localization of a Shape
Authors: Denisova Kristina , Singh Manish , Kowler Eileen
Published: August 2006

The process of object localization may be accomplished with respect to a particular reference location, such as the center of gravity, COG (eg Vishwanath and Kowler, 2003 Vision Research43 1637 – 1653). Here, we investigated how part structure affects an object's reference location. The reference location was evaluated with a measure of the illusory displacement of an internal target element embedded within a larger object (Morgan et al, 1990 Vision Research30 1793 – 1810). To examine whether the reference location is different for shapes with part structure, two shapes were tested: circle (small and large; no part structure) and bell (shape with two parts, one larger than the other). Results were examined with respect to two predictions: either the location of an object is based on its shape as a whole, disregarding part structure (ie a single, overall COG), or the parts are processed separately (different COGs).

With the circles, the results showed a systematic illusory displacement of the internal target toward the COG. With the bell, the illusion was significantly weaker than with both circles—even though the main part of the bell had the same size as the small circle, and its horizontal axis had the same extent as the large circle. Moreover, the distance judgments for the bell were consistent with a (weaker) reference point being located at the COG of the larger part, rather than at the COG of the entire bell. These results show that the part structure of a shape plays a role in the representation of its location, and that for complex shapes the perceived location of an embedded element depends more on the parts within which it is embedded, rather than on the whole shape.
Direct Evidence for the Existence of Energy-Based Texture Mechanisms
Authors: Prins Nicolaas , Kingdom Frederick A A
Published: August 2006

Two classes of models have been proposed to explain how the visual system processes texture modulations. In ‘feature models’, abstract representations of the featural properties of local texture regions (eg orientation, spatial frequency, contrast) are first generated, after which differences in individual feature properties across space are detected. In ‘energy models’, on the other hand, differences across space in the response energies of linear simple-cell-like filters are detected. This model thus processes the existing differences between texture regions directly without generating a full representation of the individual texture regions. We provide here direct evidence for the existence of the second, energy model, using an adaptation paradigm in conjunction with textures simultaneously modulated in two dimensions—orientation and spatial frequency. We found that the mechanism that processed the conjoint modulation was tuned to orientations and spatial frequencies that could not be predicted by any feature model, but which were precisely predicted by the energy model.
Information Processing during Face Recognition: The Effects of Familiarity, Inversion, and Morphing on Scanning Fixations
Authors: Barton Jason J S , Radcliffe Nathan , Cherkasova Mariya V , Edelman Jay , Intriligator James M
Published: August 2006

Where we make ocular fixations when viewing an object likely reflects interactions between ‘external’ object properties and internal ‘top - down’ factors, as our perceptual system tests hypotheses and attempts to make decisions about our environment. These scanning fixation patterns can tell us how and where the visual system gathers information critical to specific tasks. We determined the effects of the internal factors of expertise, experience, and ambiguity on scanning during a face-recognition task, in eight subjects. To assess the effects of expertise, we compared upright with inverted faces, since it is hypothesized that inverted faces do not access an orientation-dependent face-expert processor. To assess the effects of experience, we compared famous with novel faces, as famous faces would have stronger internal representations than anonymous ones. Ambiguity in matching seen and remembered faces was manipulated with morphed faces. We measured three classes of variables: (i) total scanning time and fixations; (ii) the spatial distribution of scanning; and (iii) the sequence of scanning, using first-order Markov matrices for local scan structure and string editing for global scan structure. We found that, with inverted faces, subjects redistributed fixations to the mouth and lower face, and their local and global scan structure became more random. With novel or morphed faces, they scanned the eyes and upper face more. Local scan structure was not affected by familiarity, but global scan structure was least random (most stereotyped) for novel upright faces. We conclude that expertise (upright faces) leads to less lower-face scanning and more predictable global patterns of information gathering. Experience (famous faces) leads to less upper-face scanning and more idiosyncratic global scan structures, suggesting a superseding influence of facial memories. With morphed faces, subjects return to the upper face to resolve ambiguity, implying a greater importance of this region in face recognition.
Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor
Authors: Rossi Ferdinand , Ehlers Imke , Agosti Valter , Socci Nicholas D. , Viale Agnes , Sommer Gunhild , Yozgat Yasemin , Manova Katia , Antonescu Cristina R. , Besmer Peter
Published: August 2006

Kit receptor-activating mutations are critical in the pathogenesis of gastrointestinal stromal tumors (GIST). We investigated mechanisms of oncogenic Kit signaling and the consequences of therapeutic intervention in a mouse model of human GIST. Treatment of GIST mice with imatinib decreased cell proliferation and increased apoptosis in the tumor. Analysis of tumor tissue from imatinib-treated mice showed diminished phosphatidylinositol 3-kinase (PI3-kinase) and mammalian target of rapamycin (mTOR) signaling suggesting that oncogenic Kit signaling critically contributes to the translational response in GIST. Treatment with RAD001 (everolimus), an mTOR inhibitor, diminished the translational response and cell proliferation in tumor lesions, pointing to mTOR inhibition as a therapeutic approach for imatinib-resistant GIST. Analysis of RNA expression profiles in GIST lesions with and without imatinib treatment showed changes in expression of IFN-inducible genes and cell cycle regulators. These results convincingly show that Kit
V558Δ/+
mice represent a unique faithful mouse model of human familial GIST, and they demonstrate the utility of these mice for preclinical investigations and to elucidate oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention.
Climate variability has a stabilizing effect on the coexistence of prairie grasses
Authors: Adler Peter B. , HilleRisLambers Janneke , Kyriakidis Phaedon C. , Guan Qingfeng , Levine Jonathan M.
Published: August 2006

How expected increases in climate variability will affect species diversity depends on the role of such variability in regulating the coexistence of competing species. Despite theory linking temporal environmental fluctuations with the maintenance of diversity, the importance of climate variability for stabilizing coexistence remains unknown because of a lack of appropriate long-term observations. Here, we analyze three decades of demographic data from a Kansas prairie to demonstrate that interannual climate variability promotes the coexistence of three common grass species. Specifically, we show that (i) the dynamics of the three species satisfy all requirements of “storage effect” theory based on recruitment variability with overlapping generations, (ii) climate variables are correlated with interannual variation in species performance, and (iii) temporal variability increases low-density growth rates, buffering these species against competitive exclusion. Given that environmental fluctuations are ubiquitous in natural systems, our results suggest that coexistence based on the storage effect may be underappreciated and could provide an important alternative to recent neutral theories of diversity. Field evidence for positive effects of variability on coexistence also emphasizes the need to consider changes in both climate means and variances when forecasting the effects of global change on species diversity.
Evidence from meimechites and other low-degree mantle melts for redox controls on mantle-crust fractionation of platinum-group elements
Authors: Mungall James E. , Hanley Jacob J. , Arndt Nicholas T. , Debecdelievre Anne
Published: August 2006

Understanding of the geochemistry of the chalcophile elements [i.e., Os, Ir, Ru, Pt, Pd (platinum-group elements), and Au, Cu, Ni] has been informed for at least 20 years by the common assumption that when crust-forming partial melts are extracted from the upper mantle, sulfide liquid in the restite sequesters chalcophile elements until the extent of partial melting exceeds ≈25% and all of the sulfide has been dissolved in silicate melt [Hamlyn, P. R. & Keays, R. R. (1985)
Geochim. Cosmochim. Acta
49, 1797–1811]. Here we document very high, unfractionated, chalcophile element concentrations in small-degree partial melts from the mantle that cannot be reconciled with the canonical residual sulfide assumption. We show that the observed high, unfractionated platinum-group element concentrations in small-degree partial melts can be attained if the melting takes place at moderately high oxygen fugacity, which will reduce the amount of sulfide due to the formation of sulfate and will also destabilize residual monosulfide solid solution by driving sulfide melts into the spinel-liquid divariant field. Magmas formed at high oxygen fugacity by small degrees of mantle melting can be important agents for the transfer of chalcophile elements from the upper mantle to the crust and may be progenitors of significant ore deposits of Pt, Pd, and Au.
Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y
Authors: Tosi Giovanna , Pilotti Elisabetta , Mortara Lorenzo , Barbaro Andrea De Lerma , Casoli Claudio , Accolla Roberto S.
Published: August 2006

The master regulator of MHC-II gene transcription, class II transactivator (CIITA), acts as a potent inhibitor of human T cell leukemia virus type 2 (HTLV-2) replication by blocking the activity of the viral Tax-2 transactivator. Here, we show that this inhibitory effect takes place at the nuclear level and maps to the N-terminal 1–321 region of CIITA, where we identified a minimal domain, from positions 64–144, that is strictly required to suppress Tax-2 function. Furthermore, we show that Tax-2 specifically cooperates with cAMP response element binding protein-binding protein (CBP) and p300, but not with p300/CBP-associated factor, to enhance transcription from the viral promoter. This finding represents a unique difference with respect to Tax-1, which uses all three coactivators to transactivate the human T cell leukemia virus type 1 LTR. Direct sequestering of CBP or p300 is not the primary mechanism by which CIITA causes suppression of Tax-2. Interestingly, we found that the transcription factor nuclear factor Y, which interacts with CIITA to increase transcription of MHC-II genes, exerts a negative regulatory action on the Tax-2-mediated HTLV-2 LTR transactivation. Thus, CIITA may inhibit Tax-2 function, at least in part, through nuclear factor Y. These findings demonstrate the dual defensive role of CIITA against pathogens: it increases the antigen-presenting function for viral determinants and suppresses HTLV-2 replication in infected cells.
Local peptide movement in the photoreaction intermediate of rhodopsin
Authors: Nakamichi Hitoshi , Okada Tetsuji
Published: August 2006

Photoactivation of the visual rhodopsin, a prototypical G protein-coupled receptor (GPCR), involves efficient conversion of the intrinsic inverse-agonist 11-
cis
-retinal to the
all
-
trans
agonist. This event leads to the rearrangement of the heptahelical transmembrane bundle, which is thought to be shared by hundreds of GPCRs. To examine this activation mechanism, we determined the x-ray crystallographic model of the photoreaction intermediate of rhodopsin, lumirhodopsin, which represents the conformational state having the nearly complete
all
-
trans
agonist form of the retinal. A difference electron density map clearly indicated that the distorted
all
-
trans
-retinal in the precedent intermediate bathorhodopsin relaxes by dislocation of the β-ionone ring in lumirhodopsin, along with significant peptide displacement in the middle of helix III, including approximately two helical turns. This local movement results in the breaking of the electrostatic interhelical restraints mediated by many of the conserved residues among rhodopsin-like GPCRs, with consequent acquisition of full activity.
Deletion of TolC orthologs in
Francisella tularensis
identifies roles in multidrug resistance and virulence
Authors: Gil Horacio , Platz Gabrielle J. , Forestal Colin A. , Monfett Michael , Bakshi Chandra Shekhar , Sellati Timothy J. , Furie Martha B. , Benach Jorge L. , Thanassi David G.
Published: August 2006

The Gram-negative bacterium
Francisella tularensis
is the causative agent of tularemia. Interest in this zoonotic pathogen has increased due to its classification as a category A agent of bioterrorism, but little is known about the molecular mechanisms underlying its virulence, and especially what secretion systems and virulence factors are present. In this study, we characterized two genes in the
F. tularensis
genome,
tolC
and a gene we term
ftlC
, whose products have high homology with the
Escherichia coli
TolC protein. TolC functions as the outer membrane channel component for both type I secretion and multidrug efflux systems. We constructed deletion mutations of these genes in the
F. tularensis
live vaccine strain by allelic replacement. Deletion of either
tolC
or
ftlC
caused increased sensitivity to various antibiotics, detergents, and dyes, indicating both genes are involved in the multidrug resistance machinery of
F. tularensis
. Complementation of the deletion mutations in trans restored drug resistance. Neither
tolC
nor
ftlC
was required for replication of the live vaccine strain in murine bone marrow-derived macrophages. However, deletion of
tolC
, but not
ftlC
, caused a significant attenuation of virulence in a mouse model of tularemia that could be complemented by addition of
tolC
in trans. Thus,
tolC
is a critical virulence factor of
F. tularensis
in addition to its role in multidrug resistance, which suggests the presence of a functional type I secretion system.
Anisotropic deformation response of single protein molecules
Authors: Dietz Hendrik , Berkemeier Felix , Bertz Morten , Rief Matthias
Published: August 2006

Single-molecule methods have given experimental access to the mechanical properties of single protein molecules. So far, access has been limited to mostly one spatial direction of force application. Here, we report single-molecule experiments that explore the mechanical properties of a folded protein structure in precisely controlled directions by applying force to selected amino acid pairs. We investigated the deformation response of GFP in five selected directions. We found fracture forces widely varying from 100 pN up to 600 pN. We show that straining the GFP structure in one of the five directions induces partial fracture of the protein into a half-folded intermediate structure. From potential widths we estimated directional spring constants of the GFP structure and found values ranging from 1 N/m up to 17 N/m. Our results show that classical continuum mechanics and simple mechanistic models fail to describe the complex mechanics of the GFP protein structure and offer insights into the mechanical design of protein materials.
The E3 ubiquitin ligase Itch controls the protein stability of p63
Authors: Rossi Mario , Aqeilan Rami I. , Neale Michael , Candi Eleonora , Salomoni Paolo , Knight Richard A. , Croce Carlo M. , Melino Gerry
Published: August 2006

p63, a member of the p53 family of transcription factors, plays an important role in epithelial development, regulating both cell cycle and apoptosis. Even though p63 activity is regulated mainly at the posttranslational level, the control of p63 protein stability is far from being fully understood. Here, we show that the Hect (homologous to the E6-associated protein C terminus)-containing Nedd4-like ubiquitin protein ligase Itch binds, ubiquitylates, and promotes the degradation of p63. The physical interaction occurs at the border between the PY and the SAM (sterile α motif) domains; a single Y504F mutation significantly affects p63 degradation. Itch and p63 are coexpressed in the epidermis and in primary keratinocytes where Itch controls the p63 protein steady-state level. Accordingly, p63 protein levels are significantly increased in Itch knockout keratinocytes. These data suggest that Itch has a fundamental role in the mechanism that controls endogenous p63 protein levels and therefore contributes to regulation of p63 in physiological conditions.
Dystroglycan down-regulation links EGF receptor signaling and anterior–posterior polarity formation in the
Drosophila
oocyte
Authors: Poulton John S. , Deng Wu-Min
Published: August 2006

Anterior–posterior axis formation in the
Drosophila
oocyte requires activation of the EGF receptor (EGFR) pathway in the posterior follicle cells (PFC), where it also redirects them from the default anterior to the posterior cell fate. The relationship between EGFR activity in the PFC and oocyte polarity is unclear, because no EGFR-induced changes in the PFC have been observed that subsequently affect oocyte polarity. Here, we show that an extracellular matrix receptor, Dystroglycan, is down-regulated in the PFC by EGFR signaling, and this down-regulation is necessary for proper localization of posterior polarity determinants in the oocyte. Failure to down-regulate Dystroglycan disrupts apicobasal polarity in the PFC, which includes mislocalization of the extracellular matrix component Laminin. Our data indicate that Dystroglycan links EGFR-induced repression of the anterior follicle cell fate and anterior–posterior polarity formation in the oocyte.
Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles
Authors: Naccache Samia N. , Hasson Tama , Horowitz Arie
Published: August 2006

Myosin VI (myo6) is the only actin-based molecular motor that translocates along actin filaments toward the minus end. Myo6 participates in two steps of endocytic trafficking; it is recruited to both clathrin-coated pits and to ensuing uncoated endocytic vesicles (UCV). Although there is evidence suggesting that the PDZ adaptor protein GIPC/synectin is involved in the association of myo6 with UCV, the recruitment mechanism is unknown. We show that GIPC/synectin is required for both internalization of cell surface receptors and for coupling of myo6 to UCV. This coupling occurs via a mechanism wherein engagement of the GIPC/synectin PDZ domain by C termini of internalized receptors facilitates
in trans
myo6 binding to the GIPC/synectin C terminus located outside of the PDZ domain. Analysis of megalin, a prototypical GIPC/synectin-binding receptor, revealed that deletion of its PDZ-binding motif drastically reduced GIPC/synectin and myo6 recruitment to UCV. Furthermore, interaction with GIPC/synectin was required for megalin’s function, as megalin was mistargeted in the renal proximal tubules of GIPC/synectin-null mice and these mice exhibited proteinuria, a condition consistent with defective megalin trafficking.
What do eye movements reveal about the role of memory in visual search?
Authors: Geyer Thomas , Von Mühlenen Adrian , Müller Hermann J.
Published: August 2006

Horowitz and Wolfe (1998, 2003) have challenged the view that serial visual search involves memory processes that keep track of already inspected locations. The present study used a search paradigm similar to Horowitz and Wolfe's (1998), comparing a standard static search condition with a dynamic condition in which display elements changed locations randomly every 111 ms. In addition to measuring search reaction times, observers’ eye movements were recorded. For target-present trials, the search rates were near-identical in the two search conditions, replicating Horowitz and Wolfe's findings. However, the number of fixations and saccade amplitude were larger in the static than in the dynamic condition, whereas fixation duration and the latency of the first saccade were longer in the dynamic condition. These results indicate that an active, memory-guided search strategy was adopted in the static condition, and a passive “sit-and-wait” strategy in the dynamic condition.
A dose-dependent requirement for the proline motif of CD28 in cellular and humoral immunity revealed by a targeted knockin mutant
Authors: Friend Lindzy D. , Shah Dulari D. , Deppong Christine , Lin Joseph , Bricker Traci L. , Juehne Twyla I. , Rose Christine M. , Green Jonathan M.
Published: August 2006

Activation of naive T cells requires the integration of signals through the antigen receptor and CD28. Although there is agreement on the importance of CD28, there remains controversy on the mechanism by which CD28 regulates T cell function. We have generated a gene-targeted knockin mouse expressing a mutation in the C-terminal proline-rich region of the cytoplasmic tail of CD28. Our analysis conclusively showed that this motif is essential for CD28-dependent regulation of interleukin 2 secretion and proliferation. In vivo analysis revealed that mutation of this motif-dissociated CD28-dependent regulation of cellular and humoral responses in an allergic airway inflammation model. Furthermore, we find an important gene dosage effect on the phenotype of the mutation and provide a mechanistic explanation for the conflicting data on the significance of this motif in CD28 function.
Carbon monoxide reverses established pulmonary hypertension
Authors: Zuckerbraun Brian S. , Chin Beek Yoke , Wegiel Barbara , Billiar Timothy R. , Czsimadia Eva , Rao Jayashree , Shimoda Larissa , Ifedigbo Emeka , Kanno Shin , Otterbein Leo E.
Published: August 2006

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by a progressive increase in pulmonary vascular resistance leading to right heart failure. Carbon monoxide (CO) has emerged as a potently protective, homeostatic molecule that prevents the development of vascular disorders when administered prophylactically. The data presented in this paper demonstrate that CO can also act as a therapeutic (i.e., where exposure to CO is initiated after pathology is established). In three rodent models of PAH, a 1 hour/day exposure to CO reverses established PAH and right ventricular hypertrophy, restoring right ventricular and pulmonary arterial pressures, as well as the pulmonary vascular architecture, to near normal. The ability of CO to reverse PAH requires functional endothelial nitric oxide synthase (eNOS/NOS3) and NO generation, as indicated by the inability of CO to reverse chronic hypoxia-induced PAH in eNOS-deficient (nos3−/−) mice versus wild-type mice. The restorative function of CO was associated with a simultaneous increase in apoptosis and decrease in cellular proliferation of vascular smooth muscle cells, which was regulated in part by the endothelial cells in the hypertrophied vessels. In conclusion, these data demonstrate that CO reverses established PAH dependent on NO generation supporting the use of CO clinically to treat pulmonary hypertension.
Enhancing immunogenicity by limiting susceptibility to lysosomal proteolysis
Authors: Delamarre Lélia , Couture Rachael , Mellman Ira , Trombetta E. Sergio
Published: August 2006

T cells recognize protein antigens as short peptides processed and displayed by antigen-presenting cells. However, the mechanism of peptide selection is incompletely understood, and, consequently, the differences in the immunogenicity of protein antigens remain largely unpredictable and difficult to manipulate. In this paper we show that the susceptibility of protein antigens to lysosomal proteolysis plays an important role in determining immunogenicity in vivo. We compared the immunogenicity of proteins with the same sequence (same T cell epitopes) and structure (same B cell epitopes) but with different susceptibilities to lysosomal proteolysis. After immunizing mice with each of the proteins adsorbed onto aluminum hydroxide as adjuvant, we measured serum IgG responses as a physiological measure of the antigen's ability to be presented on major histocompatibility complex class II molecules and to prime CD4+ T cells in vivo. For two unrelated model antigens (RNase and horseradish peroxidase), we found that only the less digestible forms were immunogenic, inducing far more efficient T cell priming and antibody responses. These findings suggest that stability to lysosomal proteolysis may be an important factor in determining immunogenicity, with potential implications for vaccine design.
Acceleration of Stretch Activation in Murine Myocardium due to Phosphorylation of Myosin Regulatory Light Chain
Authors: Stelzer Julian E. , Patel Jitandrakumar R. , Moss Richard L.
Published: August 2006

The regulatory light chains (RLCs) of vertebrate muscle myosins bind to the neck region of the heavy chain domain and are thought to play important structural roles in force transmission between the cross-bridge head and thick filament backbone. In vertebrate striated muscles, the RLCs are reversibly phosphorylated by a specific myosin light chain kinase (MLCK), and while phosphorylation has been shown to accelerate the kinetics of force development in skeletal muscle, the effects of RLC phosphorylation in cardiac muscle are not well understood. Here, we assessed the effects of RLC phosphorylation on force, and the kinetics of force development in myocardium was isolated in the presence of 2,3-butanedione monoxime (BDM) to dephosphorylate RLC, subsequently skinned, and then treated with MLCK to phosphorylate RLC. Since RLC phosphorylation may be an important determinant of stretch activation in myocardium, we recorded the force responses of skinned myocardium to sudden stretches of 1% of muscle length both before and after treatment with MLCK. MLCK increased RLC phosphorylation, increased the Ca2+ sensitivity of isometric force, reduced the steepness of the force–pCa relationship, and increased both Ca2+-activated and Ca2+-independent force. Sudden stretch of myocardium during an otherwise isometric contraction resulted in a concomitant increase in force that quickly decayed to a minimum and was followed by a delayed redevelopment of force, i.e., stretch activation, to levels greater than pre-stretch force. MLCK had profound effects on the stretch activation responses during maximal and submaximal activations: the amplitude and rate of force decay after stretch were significantly reduced, and the rate of delayed force recovery was accelerated and its amplitude reduced. These data show that RLC phosphorylation increases force and the rate of cross-bridge recruitment in murine myocardium, which would increase power generation in vivo and thereby enhance systolic function.
Molecular Template for a Voltage Sensor in a Novel K+ Channel. I. Identification and Functional Characterization of KvLm, a Voltage-gated K+ Channel from Listeria monocytogenes
Authors: Santos Jose S. , Lundby Alicia , Zazueta Cecilia , Montal Mauricio
Published: August 2006

The fundamental principles underlying voltage sensing, a hallmark feature of electrically excitable cells, are still enigmatic and the subject of intense scrutiny and controversy. Here we show that a novel prokaryotic voltage-gated K+ (Kv) channel from Listeria monocytogenes (KvLm) embodies a rudimentary, yet robust, sensor sufficient to endow it with voltage-dependent features comparable to those of eukaryotic Kv channels. The most conspicuous feature of the KvLm sequence is the nature of the sensor components: the motif is recognizable; it appears, however, to contain only three out of eight charged residues known to be conserved in eukaryotic Kv channels and accepted to be deterministic for folding and sensing. Despite the atypical sensor sequence, flux assays of KvLm reconstituted in liposomes disclosed a channel pore that is highly selective for K+ and is blocked by conventional Kv channel blockers. Single-channel currents recorded in symmetric K+ solutions from patches of enlarged Escherichia coli (spheroplasts) expressing KvLm showed that channel open probability sharply increases with depolarization, a hallmark feature of Kv channels. The identification of a voltage sensor module in KvLm with a voltage dependence comparable to that of other eukaryotic Kv channels yet encoded by a sequence that departs significantly from the consensus sequence of a eukaryotic voltage sensor establishes a molecular blueprint of a minimal sequence for a voltage sensor.
Meta-analysis based on control of false discovery rate: combining yeast ChIP-chip datasets
Authors: Pyne Saumyadipta , Futcher Bruce , Skiena Steve
Published: August 2006

Motivation: High-throughput microarray technology can be used to examine thousands of features, such as all the genes of an organism, and measure their expression. Two important issues of microarray bioinformatics are first, how to combine the significance values for each feature across experiments with high statistical power, and second, how to control the proportion of false positives. Existing methods address these issues separately, in spite of their linked usage.

Results: We present a novel method (ESP) to address the two requirements in an interdependent way. It generalizes the truncated product method of Zaykin et al. to combine only those significance values which clear their respective experiment-specific false discovery restrictive thresholds, thus allowing us to control the false discovery rate (FDR) for the final combined result. Further, we introduce several concepts that together offer FDR control, high power, quality control and speed-up in meta-analysis as done by our algorithm. Computational and statistical methods of research synthesis like the one described here will be increasingly important as additional genome-wide datasets accumulate in databases.

We apply our method to combine three well-known ChIP-chip transcription factor binding datasets for budding yeast to identify significant intergenic regulatory sequences for nine cell cycle regulating transcription factors, both with high power and controlled FDR.

Contact:  spyne@cs.sunysb.edu

Supplementary Materials and Appendices:
Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle
Authors: Riley Brigit E. , Orr Harry T
Published: August 2006

The polyglutamine disorders are a class of nine neuro-degenerative disorders that are inherited gain-of-function diseases caused by expansion of a translated CAG repeat. Even though the disease-causing proteins are widely expressed, specific collections of neurons are more susceptible in each disease, resulting in characteristic patterns of pathology and clinical symptoms. One hypothesis poses that altered protein function is fundamental to pathogenesis, with protein context of the expanded polyglutamine having key roles in disease-specific processes. This review will focus on the role of the disease-causing polyglutamine proteins in gene transcription and the extent to which the mutant proteins induce disruption of transcription.
Full and partial genome-wide assembly and disassembly of the yeast transcription machinery in response to heat shock
Authors: Zanton Sara J. , Pugh B. Franklin
Published: August 2006

Eukaryotic genes are controlled by sequence-specific DNA-binding proteins, chromatin regulators, general transcription factors, and elongation factors. Here we examine the genome-wide location of representative members of these groups and their redistribution when the Saccharomyces cerevisiae genome is reprogrammed by heat shock. As expected, assembly of active transcription complexes is coupled to eviction of H2A.Z nucleosomes, and disassembly is coupled to the return of nucleosomes. Remarkably, a large number of promoters assemble into partial preinitiation complexes (partial PICs), containing TFIIA, TFIID (and/or SAGA), TFIIB, TFIIE, and TFIIF. However, RNA polymerase II and TFIIH are generally not recruited, and nucleosomes are not displaced. These promoters may be preparing for additional stress that naturally accompany heat stress. For example, we find that oxidative stress, which often occurs with prolonged exposure of cells to high temperature, converts partial PICs into full PICs. Partial PICs therefore represent novel regulated intermediates that assemble at promoters in the midst of chromatin.
The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle
Authors: Pramila Tata , Wu Wei , Miles Shawna , Noble William Stafford , Breeden Linda L.
Published: August 2006

Transcription patterns shift dramatically as cells transit from one phase of the cell cycle to another. To better define this transcriptional circuitry, we collected new microarray data across the cell cycle of budding yeast. The combined analysis of these data with three other cell cycle data sets identifies hundreds of new highly periodic transcripts and provides a weighted average peak time for each transcript. Using these data and phylogenetic comparisons of promoter sequences, we have identified a late S-phase-specific promoter element. This element is the binding site for the forkhead protein Hcm1, which is required for its cell cycle-specific activity. Among the cell cycle-regulated genes that contain conserved Hcm1-binding sites, there is a significant enrichment of genes involved in chromosome segregation, spindle dynamics, and budding. This may explain why Hcm1 mutants show 10-fold elevated rates of chromosome loss and require the spindle checkpoint for viability. Hcm1 also induces the M-phase-specific transcription factors FKH1, FKH2, and NDD1, and two cell cycle-specific transcriptional repressors, WHI5 and YHP1. As such, Hcm1 fills a significant gap in our understanding of the transcriptional circuitry that underlies the cell cycle.
Review article: thiopurines in inflammatory bowel disease
Authors: DERIJKS L. J. J. , GILISSEN L. P. L. , HOOYMANS P. M. , HOMMES D. W.
Published: August 2006

Background

In the past 10–20 years, knowledge of both thiopurine pharmacology and ‐pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity.

Aim

To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy.

Methods

To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: ‘azathioprine’, ‘6‐mercaptopurine’, ‘6‐MP’, ‘6‐thioguanine’, ‘6‐TG’, ‘thiopurine(s)’, ‘metabolites’, ‘level(s)’, ‘TDM’, ‘TMPT’, ‘ITPA’, ‘genotype(s)’, ‘phenotype(s)’, ‘inflammatory bowel disease’, ‘Crohn(’s) disease’, ‘ulcerative colitis’.

Results

Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno‐ or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S‐methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such.

Conclusions

Thiopurine S‐methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine‐ or mercaptopurine‐intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.
Inadvertent anticoagulation of a haemophiliac child with routine line flushing
Authors: LAMBERT C. , DENEYS V. , POTHEN D. , VERMYLEN C. , HERMANS C.
Published: August 2006

Summary.  We report the case of a 3‐year‐old boy with severe haemophilia A presenting with recurrent haemarthroses despite daily infusions of factor VIII delivered through a central venous access device (CVAD). Regular rinsing of the CVAD with heparin, according to a standard protocol, resulted in systemic anticoagulation, as demonstrated by prolonged thrombin time and therapeutic anti‐Xa levels. The bleeding symptoms resolved after replacing heparin with a normal saline solution. This case illustrates that heparin administered to maintain CVAD patency should be used with caution in young haemophiliacs. Prolonged thrombin time should alert the physician to this possible CVAD complication.
Variable bleeding manifestations characterize different types of surgery in patients with severe factor XI deficiency enabling parsimonious use of replacement therapy
Authors: SALOMON O. , STEINBERG D. M. , SELIGSHON U.
Published: August 2006

Summary.  Surgery performed without blood component therapy in patients with severe factor XI deficiency can be accompanied by excessive bleeding in some but not all patients. In an attempt to minimize the use of blood derivatives, we carried out a retrospective analysis of bleeding complications in 120 patients with severe FXI deficiency (level of <1–15 U dL−1) who had undergone different types of surgical procedures without replacement therapy. Procedures at tissues exhibiting fibrinolytic activity were associated with bleeding in 49–67% of the patients, while procedures involving sites with no local fibrinolytic activity were associated with bleeding in 1.5–40%. The increased bleeding tendency at fibrinolytic site was significant (P = 0.0015), but was unrelated to the genotype of the patients. Thus, parsimonious use of replacement therapy is possible in patients with severe FXI deficiency undergoing surgery predicting a decrease in the risks of volume overload, transfusion related acute lung injury, transmission of infectious diseases, thrombosis, allergic reactions and development of inhibitors to FXI.