bluuebunny/crossref_metadata_2025 huggingface dataset:
Infectious Molecular Clones from a Simian Immunodeficiency Virus-Infected Rapid-Progressor (RP) Macaque: Evidence of Differential Selection of RP-Specific Envelope Mutations In Vitro and In Vivo
Authors: Kuwata Takeo , Dehghani Houman , Brown Charles R. , Plishka Ronald , Buckler-White Alicia , Igarashi Tatsuhiko , Mattapallil Joseph , Roederer Mario , Hirsch Vanessa M.
Published: January 2006

A minor fraction of simian immunodeficiency virus (SIV)-infected macaques progress rapidly to AIDS in the absence of SIV-specific immune responses. Common mutations in conserved residues of
env
in three SIVsmE543-3-infected rapid-progressor (RP) macaques suggest the evolution of a common viral variant in RP macaques. The goal of the present study was to analyze the biological properties of these variants in vitro and in vivo through the derivation of infectious molecular clones. Virus isolated from a SIVsmE543-3-infected RP macaque, H445 was used to inoculate six naive rhesus macaques. Although RP-specific mutations dominated in H445 tissues, they represented only 10% of the population of the virus stock, suggesting a selective disadvantage in vitro. Only one of these macaques (H635) progressed rapidly to AIDS. Plasma virus during primary infection of H635 was similar to the inoculum. However, RP-specific mutations were apparently rapidly reselected by 4 to 9 weeks postinfection. Terminal plasma from H635 was used as a source of viral RNA to generate seven full-length, infectious molecular clones. With the exception of one clone, which was similar to SIVsmE543-3, clones with RP-specific mutations replicated with delayed kinetics in rhesus peripheral blood mononuclear cells and human T-cell lines. None of the clones replicated in monocyte-derived or alveolar macrophages, and all used CCR5 as their major coreceptor. RP variants appear to be well adapted to replicate in vivo in RP macaques but are at a disadvantage in tissue culture compared to their parent, SIVsmE543-3. Therefore, tissue culture may not provide a good surrogate for replication of RP variants in macaques. These infectious clones will provide a valuable reagent to study the roles of specific viral variants in rapid progression in vivo.
Herpes Simplex Virus 1-Encoded Protein Kinase UL13 Phosphorylates Viral Us3 Protein Kinase and Regulates Nuclear Localization of Viral Envelopment Factors UL34 and UL31
Authors: Kato Akihisa , Yamamoto Mayuko , Ohno Takashi , Tanaka Michiko , Sata Tetsutaro , Nishiyama Yukihiro , Kawaguchi Yasushi
Published: January 2006

UL13 and Us3 are protein kinases encoded by herpes simplex virus 1. We report here that Us3 is a physiological substrate for UL13 in infected cells, based on the following observations. (i) The electrophoretic mobility, in denaturing gels, of Us3 isoforms from Vero cells infected with wild-type virus was slower than that of isoforms from cells infected with a UL13 deletion mutant virus (ΔUL13). After treatment with phosphatase, the electrophoretic mobility of the Us3 isoforms from cells infected with wild-type virus changed, with one isoform migrating as fast as one of the Us3 isoforms from ΔUL13-infected cells. (ii) A recombinant protein containing a domain of Us3 was phosphorylated by UL13 in vitro. (iii) The phenotype of ΔUL13 resembles that of a recombinant virus lacking the Us3 gene (ΔUs3) with respect to localization of the viral envelopment factors UL34 and UL31, whose localization has been shown to be regulated by Us3. UL34 and UL31 are localized in a smooth pattern throughout the nuclei of cells infected with wild-type virus, whereas their localization in ΔUL13- and ΔUs3-infected cells appeared as nuclear punctate patterns. These results indicate that UL13 phosphorylates Us3 in infected cells and regulates UL34 and UL31 localization, either by phosphorylating Us3 or by a Us3-independent mechanism.
Canine Adenovirus Vectors for Lung-Directed Gene Transfer: Efficacy, Immune Response, and Duration of Transgene Expression Using Helper-Dependent Vectors
Authors: Keriel Anne , René Céline , Galer Chad , Zabner Joseph , Kremer Eric J.
Published: January 2006

A major hurdle to the successful clinical use of some viral vectors relates to the innate, adaptive, and memory immune responses that limit the efficiency and duration of transgene expression. Some of these drawbacks may be circumvented by using vectors derived from nonhuman viruses such as canine adenovirus type 2 (CAV-2). Here, we evaluated the potential of CAV-2 vectors for gene transfer to the respiratory tract. We found that CAV-2 transduction was efficient in vivo in the mouse respiratory tract, and ex vivo in well-differentiated human pulmonary epithelia. Notably, the in vivo and ex vivo efficiency was poorly inhibited by sera from mice immunized with a human adenovirus type 5 (HAd5, a ubiquitous human pathogen) vector or by human sera containing HAd5 neutralizing antibodies. Following intranasal instillation in mice, CAV-2 vectors also led to a lower level of inflammatory cytokine secretion and cellular infiltration compared to HAd5 vectors. Moreover, CAV-2 transduction efficiency was increased in vitro in human pulmonary cells and in vivo in the mouse respiratory tract by FK228, a histone deacetylase inhibitor. Finally, by using a helper-dependent CAV-2 vector, we increased the in vivo duration of transgene expression to at least 3 months in immunocompetent mice without immunosuppression. Our data suggest that CAV-2 vectors may be efficient and safe tools for long-term clinical gene transfer to the respiratory tract.
High-Resolution Molecular and Antigen Structure of the VP8* Core of a Sialic Acid-Independent Human Rotavirus Strain
Authors: Monnier Nilah , Higo-Moriguchi Kyoko , Sun Zhen-Yu J. , Prasad B. V. Venkataram , Taniguchi Koki , Dormitzer Philip R.
Published: January 2006

The most intensively studied rotavirus strains initially attach to cells when the “heads” of their protruding spikes bind cell surface sialic acid. Rotavirus strains that cause disease in humans do not bind this ligand. The structure of the sialic acid binding head (the VP8* core) from the simian rotavirus strain RRV has been reported, and neutralization epitopes have been mapped onto its surface. We report here a 1.6-Å resolution crystal structure of the equivalent domain from the sialic acid-independent rotavirus strain DS-1, which causes gastroenteritis in humans. Although the RRV and DS-1 VP8* cores differ functionally, they share the same galectin-like fold. Differences between the RRV and DS-1 VP8* cores in the region that corresponds to the RRV sialic acid binding site make it unlikely that DS-1 VP8* binds an alternative carbohydrate ligand in this location. In the crystals, a surface cleft on each DS-1 VP8* core binds N-terminal residues from a neighboring molecule. This cleft may function as a ligand binding site during rotavirus replication. We also report an escape mutant analysis, which allows the mapping of heterotypic neutralizing epitopes recognized by human monoclonal antibodies onto the surface of the VP8* core. The distribution of escape mutations on the DS-1 VP8* core indicates that neutralizing antibodies that recognize VP8* of human rotavirus strains may bind a conformation of the spike that differs from those observed to date.
Two Domains That Control Prefusion Stability and Transport Competence of the Measles Virus Fusion Protein
Authors: Doyle Joshua , Prussia Andrew , White Laura K. , Sun Aiming , Liotta Dennis C. , Snyder James P. , Compans Richard W. , Plemper Richard K.
Published: January 2006

Most viral glycoproteins mediating membrane fusion adopt a metastable native conformation and undergo major conformational changes during fusion. We previously described a panel of compounds that specifically prevent fusion induced by measles virus (MV), most likely by interfering with conformational rearrangements of the MV fusion (F) protein. To further elucidate the basis of inhibition and better understand the mechanism of MV glycoprotein-mediated fusion, we generated and characterized resistant MV variants. Spontaneous mutations conferring drug resistance were confirmed in transient assays and in the context of recombinant virions and were in all cases located in the fusion protein. Several mutations emerged independently at F position 462, which is located in the C-terminal heptad repeat (HR-B) domain. In peptide competition assays, all HR-B mutants at residue 462 revealed reduced affinity for binding to the HR-A core complex compared to unmodified HR-B. Combining mutations at residue 462 with mutations in the distal F head region, which we had previously identified as mediating drug resistance, causes intracellular retention of the mutant proteins. The transport competence and activity of the mutants can be restored, however, by incubation at reduced temperature or in the presence of the inhibitory compounds, indicating that the F escape mutants have a reduced conformational stability and that the inhibitors stabilize a transport-competent conformation of the F trimer. The data support the conclusion that residues located in the head domain of the F trimer and the HR-B region contribute jointly to controlling F conformational stability.
Mutational Analysis of the Herpes Simplex Virus Triplex Protein VP19C
Authors: Adamson Walt E. , McNab David , Preston Valerie G. , Rixon Frazer J.
Published: January 2006

Herpes simplex virus type 1 (HSV-1) capsids have an icosahedral structure with capsomers formed by the major capsid protein, VP5, linked in groups of three by distinctive structures called triplexes. Triplexes are heterotrimers formed by two proteins in a 1:2 stoichiometry. The single-copy protein is called VP19C, and the dimeric protein is VP23. We have carried out insertional and deletional mutagenesis on VP19C and have examined the effects of the mutations on virus growth and capsid assembly. Insertional mutagenesis showed that the N-terminal ∼100 amino acids of the protein, which correspond to a region that is poorly conserved among herpesviruses, are insensitive to disruption and that insertions into the rest of the protein had various effects on virus growth. Some, but not all, severely disabled mutants were compromised in the ability to bind VP23 or VP5. Analysis of deletion mutants revealed the presence of a nuclear localization signal (NLS) near the N terminus of VP19C, and this was mapped to a 33-amino-acid region by fusion of specific sequences to a green fluorescent protein marker. By replacing the endogenous NLS with that from the simian virus 40 large T antigen, we were able to show that the first 45 amino acids of VP19C were not essential for assembly of functional capsids and infectious virus particles. However, removing the first 63 amino acids resulted in formation of aberrant capsids and prevented virus growth, suggesting that the poorly conserved N-terminal sequences have some as-yet-unidentified function.
A Genetic System for Rhesus Monkey Rhadinovirus: Use of Recombinant Virus To Quantitate Antibody-Mediated Neutralization
Authors: Bilello John P. , Morgan Jennifer S. , Damania Blossom , Lang Sabine M. , Desrosiers Ronald C.
Published: January 2006

Rhesus monkey rhadinovirus (RRV), a simian gamma-2 herpesvirus closely related to the Kaposi sarcoma-associated herpesvirus, replicates lytically in cultured rhesus monkey fibroblasts and establishes persistence in B cells. Overlapping cosmid clones were generated that encompass the entire 130-kilobase-pair genome of RRV strain 26-95, including the terminal repeat regions required for its replication. Cloned RRV that was produced by cotransfection of overlapping cosmids spanning the entire RRV26-95 genome replicated with growth kinetics and to titers similar to those of the parental, uncloned, wild-type RRV26-95. Expression cassettes for secreted-engineered alkaline phosphatase (SEAP) and green fluorescent protein (GFP) were inserted upstream of the R1 gene, and the cosmid-based system for RRV genome reconstitution was used to generate replication-competent, recombinant RRV that expressed either the SEAP or GFP reporter gene. Using the SEAP and GFP recombinant RRVs, assays were developed to monitor RRV infection, neutralization, and replication. Heat-inactivated sera from rhesus monkeys that were naturally or experimentally infected with RRV were assayed for their ability to neutralize RRV-SEAP and RRV-GFP infectivity using rhesus monkey fibroblasts. Sera from RRV-positive monkeys, but not RRV-negative monkeys, were consistently able to neutralize RRV infectivity when assayed by the production of SEAP activity or by the ability to express GFP. The neutralizing activity was present in the immunoglobulin fraction. Of the 17 rhesus monkeys tested, sera from rhesus monkey 26-95, i.e., the monkey that yielded the RRV 26-95 isolate, had the highest titer of neutralizing activity against RRV26-95. This cosmid-based genetic system and the reporter virus neutralization assay will facilitate study of the contribution of individual RRV glycoproteins to entry into different cell types, particularly fibroblasts and B cells.
Host-Selected Amino Acid Changes at the Sialic Acid Binding Pocket of the Parvovirus Capsid Modulate Cell Binding Affinity and Determine Virulence
Authors: López-Bueno Alberto , Rubio Mari-Paz , Bryant Nathan , McKenna Robert , Agbandje-McKenna Mavis , Almendral José M.
Published: January 2006

The role of receptor recognition in the emergence of virulent viruses was investigated in the infection of severe combined immunodeficient (SCID) mice by the apathogenic prototype strain of the parvovirus minute virus of mice (MVMp). Genetic analysis of isolated MVMp viral clones (
n
= 48) emerging in mice, including lethal variants, showed only one of three single changes (V325M, I362S, or K368R) in the common sequence of the two capsid proteins. As was found for the parental isolates, the constructed recombinant viruses harboring the I362S or the K368R single substitutions in the capsid sequence, or mutations at both sites, showed a large-plaque phenotype and lower avidity than the wild type for cells in the cytotoxic interaction with two permissive fibroblast cell lines in vitro and caused a lethal disease in SCID mice when inoculated by the natural oronasal route. Significantly, the productive adsorption of MVMp variants carrying any of the three mutations selected through parallel evolution in mice showed higher sensitivity to the treatment of cells by neuraminidase than that of the wild type, indicating a lower affinity of the viral particle for the sialic acid component of the receptor. Consistent with this, the X-ray crystal structure of the MVMp capsids soaked with sialic acid (
N
-acetyl neuraminic acid) showed the sugar allocated in the depression at the twofold axis of symmetry (termed the dimple), immediately adjacent to residues I362 and K368, which are located on the wall of the dimple, and approximately 22 Å away from V325 in a threefold-related monomer. This is the first reported crystal structure identifying an infectious receptor attachment site on a parvovirus capsid. We conclude that the affinity of the interactions of sialic-acid-containing receptors with residues at or surrounding the dimple can evolutionarily regulate parvovirus pathogenicity and adaptation to new hosts.
Mass Spectrometric Analyses of Purified Rhesus Monkey Rhadinovirus Reveal 33 Virion-Associated Proteins
Authors: O'Connor Christine M. , Kedes Dean H.
Published: January 2006

The repertoire of proteins that comprise intact gammaherpesviruses, including the human pathogen Kaposi's sarcoma-associated herpesvirus (KSHV), is likely to have critical functions not only in viral structure and assembly but also in the early stages of infection and evasion of the host's rapidly deployed antiviral defenses. To develop a better understanding of these proteins, we analyzed the composition of rhesus monkey rhadinovirus (RRV), a close phylogenetic relative of KSHV. Unlike KSHV, RRV replicates to high titer in cell culture and thus serves as an effective model for studying primate gammaherpesvirus structure and virion proteomics. We employed two complementary mass spectrometric approaches and found that RRV contains at least 33 distinct virally encoded proteins. We have assigned 7 of these proteins to the capsid, 17 to the tegument, and 9 to the envelope. Of the five gammaherpesvirus-specific tegument proteins, three have no known function. We also found three proteins not previously associated with a purified herpesvirus and an additional seven that represent new findings for a member of the gamma-2 herpesviruses. Detergent extraction resulted in particles that contained six distinct tegument proteins in addition to the expected capsid structural proteins, suggesting that this subset of tegument components may interact more directly with or with higher affinity for the underlying capsid and, in turn, may play a role in assembly or transport of viral or subviral particles during entry or egress.
Papillomavirus E1 Protein Binds to and Stimulates Human Topoisomerase I
Authors: Clower Randolph V. , Fisk John C. , Melendy Thomas
Published: January 2006

The papillomavirus (PV) E1 helicase plays a direct role in recruiting cellular DNA replication factors, such as replication protein A or polymerase α-primase, to replicate PV genomes. Here, E1 is shown to bind to human topoisomerase I and stimulate its relaxation activity up to sevenfold. The interaction between E1 and topoisomerase I was mapped to the E1 DNA binding domain and C terminus. These findings imply a mechanism for the recruitment of topoisomerase I to PV DNA replication forks and for stimulating topoisomerase I to allow for efficient relaxation of the torsional stress induced by replication fork progression.
Direct Stimulation of Translation by the Multifunctional Herpesvirus ICP27 Protein
Authors: Larralde Osmany , Smith Richard W. P. , Wilkie Gavin S. , Malik Poonam , Gray Nicola K. , Clements J. Barklie
Published: January 2006

Herpes simplex virus type 1 (HSV-1) ICP27 protein is an essential regulator of viral gene expression with roles at various levels of RNA metabolism in the nucleus. Using the tethered function assay, we showed a cytoplasmic activity for ICP27 in directly enhancing mRNA translation in vivo in the absence of other viral factors. The region of ICP27 required for translational stimulation maps to the C terminus. Furthermore, in infected cells, ICP27 is associated with polyribosomes, indicating a function in translation during the lytic cycle.
A Gammaherpesvirus 68 Gene 50 Null Mutant Establishes Long-Term Latency in the Lung but Fails To Vaccinate against a Wild-Type Virus Challenge
Authors: Moser Janice M. , Farrell Michael L. , Krug Laurie T. , Upton Jason W. , Speck Samuel H.
Published: January 2006

The gammaherpesvirus immediate-early genes are critical regulators of virus replication and reactivation from latency. Rta, encoded by gene 50, serves as the major transactivator of the lytic program and is highly conserved among all the gammaherpesviruses, including Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, and murine gammaherpesvirus 68 (γHV68). Introduction of a translation stop codon in γHV68 gene 50 (gene 50.stop γHV68) demonstrated that Rta is essential for virus replication in vitro. To investigate the role that virus replication plays in the establishment and maintenance of latency, we infected mice with gene 50.stop γHV68. Notably, the gene 50.stop virus established a long-term infection in lung B cells following intranasal infection of mice but was unable to establish latency in the spleen. This complete block in the establishment of latency in the spleen was also seen when lytic virus production was inhibited by treating mice infected with wild-type virus with the antiviral drug cidofovir, implicating virus replication and not an independent function of Rta in the establishment of splenic latency. Furthermore, we showed that gene 50.stop γHV68 was unable to prime the immune system and was unable to protect against a challenge with wild-type γHV68, despite its ability to chronically infect lung B cells. These data indicate gammaherpesviruses that are unable to undergo lytic replication in vivo may not be viable vaccine candidates despite the detection of cells harboring viral genome at late times postinfection.
Rapid Expression of Human Immunodeficiency Virus following Activation of Latently Infected Cells
Authors: Arlen Philip A. , Brooks David G. , Gao Lian Y. , Vatakis Dimitrios , Brown Helen J. , Zack Jerome A.
Published: January 2006

The host cell activation state impacts the nature of human immunodeficiency virus infection. Activated cells facilitate productive infections; quiescent cells enable the virus to enter a latent state, the major obstacle to viral clearance. We wanted to understand how these differences affected viral gene expression. In quiescent cells activated prior to infection, viral RNA was seen 12 h postinfection; when cells were stimulated postinfection, viral RNA was not seen until 36 h postinfection. Up-regulation of viral RNA in latently infected cells occurred within 2 h poststimulation. This hierarchy also held true for viral protein production. These results may explain the rapid reemergence of viremia following termination of therapy.
Identification and Characterization of Two Internal Cleavage and Polyadenylation Sites of Parvovirus B19 RNA
Authors: Yoto Yuko , Qiu Jianming , Pintel David J.
Published: January 2006

Polyadenylation of B19 pre-mRNAs at the major internal site, (pA)p1, is programmed by the nonconsensus core cleavage and polyadenylation specificity factor-binding hexanucleotide AUUAAA. Efficient use of this element requires both downstream and upstream
cis
-acting elements and is further influenced by an adjacent AAUAAC motif. The primary hexanucleotide element must be nonconsensus to allow efficient readthrough of P6-generated pre-mRNAs into the capsid-coding region. An additional cleavage and polyadenylation site, (pA)p2, 296 nucleotides downstream of (pA)p1 was shown to be used following both B19 infection and transfection of a genomic clone. RNAs polyadenylated at (pA)p2 comprise approximately 10% of B19 RNAs that are polyadenylated internally.
REVISITING e-e- SWITCHOVER IN THE NLC LINAC
Authors: LARSEN R. S.
Published: January 2006

This paper is an extension of a talk given in December 1999 which discussed various options for reconfiguring magnets and power sources to convert the NLC to e-e- operation. At that time three different configurations were examined and a Directional Reversal model was recommended in order to avoid the difficulties of polarity reversal with permanent magnets anticipated in the main linac at that time. Since permanent magnets are no longer in the baseline, a Polarity Reversal scheme becomes more attractive.
HEAVY MESON PRODUCTION AT A LOW-ENERGY PHOTON COLLIDER
Authors: ASZTALOS STEPHEN
Published: January 2006

A low-energy γγ collider has been discussed in the context of a testbed for a γγ interaction region at the Next Linear Collider (NLC). We consider the production of heavy mesons at such a testbed using Compton-backscattered photons and demonstrate that their production rivals or exceeds those by BELLE, BABAR or LEP where they are produced indirectly via virtual γγ luminosities.
HIGH ENERGY PHOTON–PHOTON COLLISIONS AT A LINEAR COLLIDER
Authors: BRODSKY STANLEY J.
Published: January 2006

High intensity back-scattered laser beams will allow the efficient conversion of a substantial fraction of the incident lepton energy into high energy photons, thus significantly extending the physics capabilities of an e-e± linear collider. The annihilation of two photons produces C = + final states in virtually all angular momentum states. An important physics measurement is the measurement of the Higgs coupling to two photons. The annihilation of polarized photons into the Higgs boson determines its fundamental H0γγ coupling as well as determining its parity. Other novel two-photon processes include the two-photon production of charged pairs τ+τ-, W+W-, [Formula: see text], and supersymmetric squark and slepton pairs. The one-loop box diagram leads to the production of pairs of neutral particles such as γγ → Z0Z0, γZ0, and γγ. At the next order one can study Higgstrahlung processes, such as γγ → W+W-W-H. Since each photon can be resolved into a W+W- pair, high energy photon-photon collisions can also provide a remarkably background-free laboratory for studying possibly anomalous WW collisions and annihilation. In the case of QCD, each photon can materialize as a quark anti-quark pair which interact via multiple gluon exchange. The diffractive channels in photon-photon collisions allow a novel look at the QCD pomeron and odderon. The C = - odderon exchange contribution can be identified by looking at the heavy quark asymmetry. In the case of eγ → e′ collisions, one can measure the photon structure functions and its various components. Exclusive hadron production processes in photon-photon collisions provide important tests of QCD at the amplitude level, particularly as measures of hadron distribution amplitudes which are also important for the analysis of exclusive semi-leptonic and two-body hadronic B-decays.
Reaching Confidence in Photon Collider Technology
Authors: Gronberg J.
Published: January 2006

The technology for a photon collider experiment will ultimately be judged by its ability to deliver sustained luminosity. Attaining high luminosity requires the production of large amounts of laser power and tightly focusing it onto the oncoming electron beam. This paper describes the development and testing program required to have confidence that the laser and optics technology designed for the warm X-band machine will be able to deliver its design luminosity.
The Search for New Physics Phenomena using e-e- Collisions in the CLIC Energy Range
Authors: Heusch Clemens A.
Published: January 2006

The International Linear Collider project, now no longer on the back burner, finds its natural sequel in the several-TeV realm by relying on CLIC technology. We briefly home in on a few of those physics processes initiated by e-e- collision where the extension to that higher energy region is likely to be of major importance.
PHOTON STRUCTURE AND DEEPLY VIRTUAL COMPTON SCATTERING IN ELECTRON-PHOTON COLLISION
Authors: HWANG DAE SUNG , UEMATSU TSUNEO
Published: January 2006

We study the deeply virtual Compton scattering on the photon target. The light-cone wavefunctions and the axial vector form factors of the photon are analyzed.
Electroweak Radiative Corrections to Parity-Violating Asymmetry in Møller Scattering
Authors: Kolomensky Yury G. , Shumeiko Nikolai M. , Suarez Juan G. , Zykunov Vladimir A.
Published: January 2006

We have computed the lowest-order electroweak radiative corrections (sans vacuum polarization contribution) to parity-violating observables in polarized Møller scattering. A covariant method of removing infrared divergences is applied, which allows to compute the corrections without introducing any unphysical parameters. When applied to the kinematics of SLAC E158 experiment, the considered radiative corrections reduce the parity-violating asymmetry by about 13%.
INTERACTION REGION LAYOUT AND e+e- PAIR BACKGROUNDS IN e-e- COLLISIONS
Authors: MARKIEWICZ THOMAS W. , MARUYAMA TAKASHI
Published: January 2006

The production of soft e+e- pairs through the interactions of beamstrahlung photons is the major expected background at the next generation of high energy e+e- and e-e- colliders. This process has been simulated and the resulting distributions of particles in the very forward 5-25 mrad pair luminosity monitor are shown.
MODEL-INDEPENDENT TESTS OF LEPTON CONTACT INTERACTIONS IN BHABHA AND MØLLER SCATTERING AT A POLARIZED LINEAR COLLIDER
Authors: PANKOV ALEXANDER A. , PAVER NELLO
Published: January 2006

We discuss the sensitivity to electron-electron contact-interactions of the processes e+e- → e+e- and e-e- → e-e- at a Linear Collider running in both e+e- and e-e- modes, with both longitudinally polarized beams. We emphasize the crucial role of polarized cross section measurements in deriving model-independent constraints on the new coupling constants, and the complementarity of the two processes as regards the different chiralities involved. We assess the reach on the values of contact-couplings expected at the planned Linear Collider.
SEARCH FOR THE NMSSM HIGGS BOSONS AT THE PHOTON COLLIDER
Authors: SZLEPER MICHAŁ
Published: January 2006

A light, Standard Model-like Higgs scalar in the NMSSM will decay predominantly into a pair of Higgs pseudoscalars, these decaying into a four-fermion final state. We study the potential of the CLIC Higgs Experiment to detect such scenario via the search for the final states [Formula: see text] and [Formula: see text]. We find excellent prospects for the observation of the Higgs peak in both channels.
e-e- Probes of the Littlest Higgs
Authors: Wacker Jay G.
Published: January 2006

In these proceedings the "Littlest Higgs" is discussed in depth. With recent developments it is now possible to reduce the ultraviolet insenstivities of these models and make definite predictions for the masses of all particles including the Higgs. The charge structure of the model is briefly reviewed. The cross-section for e-e- → ϕ--νeνe, is calculated and 6.2 pb is found.
POLARIZED POSITRONS AT A FUTURE LINEAR COLLIDER AND THE FINAL FOCUS TEST BEAM
Authors:   For the E-166 Collaboration., WEIDEMANN ACHIM W.
Published: January 2006

Polarized positrons in addition to polarized electrons are a highly desirable feature of future linear e+e-colliders. The motivation for polarized positrons, and a demonstration experiment for the undulator-based production of polarized positrons are reviewed. This experiment ('E-166') uses the 50 GeV Final Focus Test electron beam at SLAC with a 1 m-long helical undulator to make ≈ 10MeV polarized photons. These photons are then converted in a thin (≈ 0.5 radiation length) target into positrons (and electrons) with about 50% polarization.
"CYBER-FILM": A VISUAL APPROACH THAT FACILITATES PROGRAM COMPREHENSION
Authors: ROXAS ROBERT R. , MIRENKOV NIKOLAY N.
Published: January 2006

This paper presents a visual approach that will make program comprehension easy. This visual approach employs "Cyber-Films" where a user can use them not only as a programming tool but also as a learning tool. This paper briefly describes how to use "Cyber-Films" as a programming tool, how to use them as a learning tool, and how to guarantee the absence (or at least minimize the presence) of syntax errors in programming. In order to verify that "Cyber-Films" are also useful as a learning tool, a prototype implementation was developed and an experiment was conducted. This paper presents and discusses the results of that experiment. Its goal was to evaluate whether or not the visual approach used was easy to understand even for users with no background at all. The results of that experiment showed that the majority of the respondents correctly identified each scheme of communication presented in "Cyber-Film" format by just observing the set of frames in animation either once or twice and at most thrice before understanding a given scheme. Because the respondents easily identified how a given scheme worked by observing it, this approach can also facilitate the understanding of programs written by other people.
A DECISION-MAKING SPECIFICATION LANGUAGE FOR VERIFIABLE USER-INTERFACE ADAPTATION LOGIC
Authors: SAVIDIS ANTHONY , ANTONA MARGHERITA , STEPHANIDIS CONSTANTINE
Published: January 2006

In automatic user interface adaptation, developers pursue the delivery of best-fit user interfaces according to the runtime-supplied profiles of individual end users and usage contexts. Software engineering of automatic interface adaptability entails: (a) storage and processing of user and usage-context profiles; (b) design and implementation of alternative interface components, to optimally support the various user activities and interface operations for different users and usage contexts; and (c) runtime decision-making, to choose on the fly the most appropriate alternative interface components, given the particular user and context profile. In automatic interface adaptation, the decision making process plays a key role in optimal on-the-fly interface assembly, engaging consolidated design wisdom in a computable form. A verifiable language has been designed and implemented which is particularly suited for the specification of adaptation-oriented decision-making logic, while also being easily deployable and usable by interface designers. This paper presents the language, its contextual role in adapted interface delivery and the automatic verification method. The employment of the language in an adaptation-design support tool is discussed, the latter automatically generating language rules by relying upon adaptation rule patterns. Finally, the deployment methodology of the language in supporting dynamic interface assembly is discussed, further generalizing towards dynamic software assembly, by introducing architectural contexts and polymorphic architectural containment.
SIMILARITY-BASED COMBINATION OF MULTIPLE CLUSTERINGS
Authors: HU TIANMING , XIONG JINZHI , ZHENG GENGZHONG
Published: January 2006

Consensus clustering refers to combining multiple clusterings over a common set of objects into a single consolidated partition. After introducing the distribution-based view of partitions, we propose a series of entropy-based distance functions for comparing various partitions. Given a candidate partition set, consensus clustering is then formalized as an optimization problem of searching for a centroid partition with the smallest distance to that set. In addition to directly selecting the local centroid candidate, we also present two combining methods for the global centroid based on the new similarity determined by the whole candidate set. The centroid partition is likely to be top/middle-ranked in terms of closeness to the true partition. Finally we evaluate its effectiveness on both artificial and real datasets, with candidates from either the full space or the subspace.
Cardiotoxicity Induced by Chemotherapy and Antibody Therapy
Authors: Yeh Edward T.H.
Published: January 2006

Modern cancer therapy employs a combination of chemotherapy, antibody-based therapy, radiotherapy, and surgery to prolong life and provide cure. However, many of the chemotherapy agents and antibodies, either singly or in combination, can affect the cardiovascular system. Common cardiovascular manifestations of these therapies include heart failure, ischemia, hypotension, hypertension, edema, QT prolongation, bradyarrhythmia, and thromboembolism. The patient's age, underlying cardiovascular status, and genetic background, as well as the route of drug administration and dosage, can all contribute to the development of cardiotoxicity. Strategies to monitor for and to manage these effects are discussed in this review.
Chemoprevention of Prostate Cancer
Authors: Klein Eric A.
Published: January 2006

Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. The Prostate Cancer Prevention Trial has provided the first firm evidence that this cancer can be prevented by a relatively nontoxic oral agent. Additional agents, many of which are antioxidants with antiandrogenic effects, are being tested (or soon will be) in large clinical trials. The current body of evidence is insufficient to make a routine recommendation of any dietary or nutritional supplement for the prevention of prostate cancer.
Ca2+-sensing receptor induces Rho kinase-mediated actin stress fiber assembly and altered cell morphology, but not in response to aromatic amino acids
Authors: Davies Sarah L. , Gibbons Claire E. , Vizard Thomas , Ward Donald T.
Published: January 2006

The Ca2+-sensing receptor (CaR) is a pleiotropic, type III G protein-coupled receptor (GPCR) that associates functionally with the cytoskeletal protein filamin. To investigate the effect of CaR signaling on the cytoskeleton, human embryonic kidney (HEK)-293 cells stably transfected with CaR (CaR-HEK) were incubated with CaR agonists in serum-free medium for up to 3 h. Addition of the calcimimetic NPS R-467 or exposure to high extracellular Ca2+ or Mg2+ levels elicited actin stress fiber assembly and process retraction in otherwise stellate cells. These responses were ablated by cotreatment with the calcilytic NPS 89636 and were absent in vector-transfected HEK-293 cells. Cotreatment with the Rho kinase inhibitors Y-27632 and H1152 attenuated the CaR-induced morphological change but not intracellular Ca2+ (Cai2+) mobilization or ERK activation, although transfection with a dominant-negative RhoA-binding protein also inhibited calcimimetic-induced actin stress fiber assembly. CaR effects on morphology were unaffected by inhibition of Gq/11 or Gi/o signaling, epidermal growth factor receptor, or the metalloproteinases. In contrast, CaR-induced cytoskeletal changes were not induced by the aromatic amino acids, treatments that also failed to potentiate CaR-induced ERK activation despite inducing Cai2+ mobilization. Together, these data establish that CaR can elicit Rho-mediated changes in stress fiber assembly and cell morphology, which could contribute to the receptor's physiological actions. In addition, this study provides further evidence that aromatic amino acids elicit differential signaling from other CaR agonists.
Resident stem cells are not required for exercise-induced fiber-type switching and angiogenesis but are necessary for activity-dependent muscle growth
Authors: Li Ping , Akimoto Takayuki , Zhang Mei , Williams R. Sanders , Yan Zhen
Published: January 2006

Skeletal muscle undergoes active remodeling in response to endurance exercise training, and the underlying mechanisms of this remodeling remain to be defined fully. We have recently obtained evidence that voluntary running induces cell cycle gene expression and cell proliferation in mouse plantaris muscles that undergo fast-to-slow fiber-type switching and angiogenesis after long-term exercise. To ascertain the functional role of cell proliferation in skeletal muscle adaptation, we performed in vivo 5-bromo-2′-deoxyuridine (BrdU) pulse labeling (a single intraperitoneal injection), which demonstrated a phasic increase (5- to 10-fold) in BrdU-positive cells in plantaris muscle between days 3 and 14 during 4 wk of voluntary running. Daily intraperitoneal injection of BrdU for 4 wk labeled 2.0% and 15.4% of the nuclei in plantaris muscle in sedentary and trained mice, respectively, and revealed the myogenic and angiogenic fates of the majority of proliferative cells. Ablation of resident stem cell activity by X-ray irradiation did not prevent voluntary running-induced increases of type IIa myofibers and CD31-positive endothelial cells but completely blocked the increase in muscle mass. These findings suggest that resident stem cell proliferation is not required for exercise-induced type IIb-to-IIa fiber-type switching and angiogenesis but is required for activity-dependent muscle growth. The origin of the angiogenic cells in this physiological exercise model remains to be determined.
Proteomic analysis of iron overload in human hepatoma cells
Authors: Petrak Jiri , Myslivcova Denisa , Man Petr , Cmejla Radek , Cmejlova Jana , Vyoral Daniel
Published: January 2006

Iron-mediated organ damage is common in patients with iron overload diseases, namely, hereditary hemochromatosis. Massive iron deposition in parenchymal organs, particularly in the liver, causes organ dysfunction, fibrosis, cirrhosis, and also hepatocellular carcinoma. To obtain deeper insight into the poorly understood and complex cellular response to iron overload and consequent oxidative stress, we studied iron overload in liver-derived HepG2 cells. Human hepatoma HepG2 cells were exposed to a high concentration of iron for 3 days, and protein expression changes initiated by the iron overload were studied by two-dimensional electrophoresis and mass spectrometry. From a total of 1,060 spots observed, 21spots were differentially expressed by iron overload. We identified 19 of them; 11 identified proteins were upregulated, whereas 8 identified proteins showed a decline in response to iron overload. The differentially expressed proteins are involved in iron storage, stress response and protection against oxidative stress, protein folding, energy metabolism, gene expression, cell cycle regulation, and other processes. Many of these molecules have not been previously suggested to be involved in the response to iron overload and the consequent oxidative stress.
Quantifying esophageal peristalsis with high-resolution manometry: a study of 75 asymptomatic volunteers
Authors: Ghosh Sudip K. , Pandolfino John E. , Zhang Qing , Jarosz Andrew , Shah Nimeesh , Kahrilas Peter J.
Published: January 2006

The vastly enhanced spatial resolution of high-resolution manometry (HRM) makes it possible to simultaneous monitor contractile activity over the entire length of the esophagus. The aim of this investigation was to define the essential features of esophageal peristalsis in novel HRM paradigms and establish their normative values. Ten 5-ml water swallows were recorded in each of 75 asymptomatic controls with a solid-state manometric assembly incorporating 36 circumferential sensors spaced at 1-cm intervals positioned to record from the hypopharynx to the stomach. The data set was then subjected to intensive computational analysis to distill out the essential characteristics of normal peristalsis. Esophageal peristalsis was conceptualized in terms of a proximal contraction, a distal contraction, and a transition zone separating the two. Each contractile segment was quantified in length and then normalized among subjects to summarize focal fluctuation of contractile amplitude and propagation velocity. Furthermore, the temporal and spatial characteristics of the transition zone separating the proximal and distal contraction were quantified. For each paradigm, graphics were developed, establishing median values along with the 5th to 95th percentile range of observed variation. In addition, the synchronization between peristalsis and esophagogastric junction relaxation was analyzed using a novel concept of the outflow permissive pressure gradient. We performed a detailed analysis of esophageal peristalsis aimed at quantifying its essential features and, in so doing, devised new paradigms for the quantification of peristaltic function that will hopefully optimize the utility of HRM in clinical and investigative studies.
Adiponectin normalizes LPS-stimulated TNF-α production by rat Kupffer cells after chronic ethanol feeding
Authors: Thakur Varsha , Pritchard Michele T. , McMullen Megan R. , Nagy Laura E.
Published: January 2006

Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of tumor necrosis factor-α (TNF-α). Adiponectin treatment protects mice from ethanol-induced liver injury. Because adiponectin has anti-inflammatory effects on macrophages, we hypothesized that adiponectin would normalize chronic ethanol-induced sensitization of Kupffer cells to LPS-mediated signals. Serum adiponectin concentrations were decreased by 45% in rats fed an ethanol-containing diet for 4 wk compared with pair-fed rats. Adiponectin dose dependently inhibited LPS-stimulated accumulation of TNF-α mRNA and peptide in Kupffer cells from both pair- and ethanol-fed rats. Kupffer cells from ethanol-fed rats were more sensitive to both globular (gAcrp) and full-length adiponectin (flAcrp) than Kupffer cells from pair-fed controls with suppression at 10 ng/ml adiponectin after chronic ethanol feeding. Kupffer cells expressed both adiponectin receptors 1 and 2; chronic ethanol feeding did not change the expression of adiponectin receptor mRNA or protein. gAcrp suppressed LPS-stimulated ERK1/2 and p38 phosphorylation as well as IκB degradation at 100–1,000 ng/ml in Kupffer cells from both pair- and ethanol-fed rats. However, only LPS-stimulated ERK1/2 phosphorylation was sensitive to 10 ng/ml gAcrp. gAcrp also normalized LPS-stimulated DNA binding activity of early growth response-1 with greater sensitivity in Kupffer cells from rats fed chronic ethanol. In conclusion, these results demonstrate that Kupffer cells from ethanol-fed rats are more sensitive to the anti-inflammatory effects of both gAcrp and flAcrp. Suppression of LPS-stimulated ERK1/2 signaling by low concentrations of gAcrp was associated with normalization of TNF-α production by Kupffer cells after chronic ethanol exposure.
Plaque-prone hemodynamics impair endothelial function in pig carotid arteries
Authors: Gambillara Veronica , Chambaz Céline , Montorzi Gabriela , Roy Sylvain , Stergiopulos Nikos , Silacci Paolo
Published: January 2006

Hemodynamic forces play an active role in vascular pathologies, particularly in relation to the localization of atherosclerotic lesions. It has been established that low shear stress combined with cyclic reversal of flow direction (oscillatory shear stress) affects the endothelial cells and may lead to an initiation of plaque development. The aim of the study was to analyze the effect of hemodynamic conditions in arterial segments perfused in vitro in the absence of other stimuli. Left common porcine carotid segments were mounted into an ex vivo arterial support system and perfused for 3 days under unidirectional high and low shear stress (6 ± 3 and 0.3 ± 0.1 dyn/cm2) and oscillatory shear stress (0.3 ± 3 dyn/cm2). Bradykinin-induced vasorelaxation was drastically decreased in arteries exposed to oscillatory shear stress compared with unidirectional shear stress. Impaired nitric oxide-mediated vasodilation was correlated to changes in both endothelial nitric oxide synthase (eNOS) gene expression and activation in response to bradykinin treatment. This study determined the flow-mediated effects on native tissue perfused with physiologically relevant flows and supports the hypothesis that oscillatory shear stress is a determinant factor in early stages of atherosclerosis. Indeed, oscillatory shear stress induces an endothelial dysfunction, whereas unidirectional shear stress preserves the function of endothelial cells. Endothelial dysfunction is directly mediated by a downregulation of eNOS gene expression and activation; consequently, a decrease of nitric oxide production and/or bioavailability occurs.