bluuebunny/crossref_metadata_2025 huggingface dataset:
First Reported Infections Caused by Three Newly Described Genera in the Family
Xanthomonadaceae
Authors: LaSala P. Rocco , Segal Jonathan , Han Faye S. , Tarrand Jeffrey J. , Han Xiang Y.
Published: November 2006

Members of the family of
Xanthomonadaceae
are typically characterized as environmental organisms. With the exception of
Stenotrophomonas maltophilia
, these organisms are infrequently implicated as human pathogens. We describe three cases of central venous catheter-associated bloodstream infections caused by
Dokdonella koreensis
,
Aquimonas voraii
, and a
Luteibacter
sp., all newly named genera within the family
Xanthomonadaceae
. The three patients all had histories of underlying hematological disorders, presented with fever, and recovered fully following treatment. These isolates required 16S rRNA gene sequencing for identification and, unlike
S. maltophilia
, demonstrated susceptibility to most antibiotics tested. This report represents the first description of human infections caused by these organisms.
Distribution of
Mycoplasma pneumoniae
and
Mycoplasma salivarium
in the Synovial Fluid of Arthritis Patients
Authors: Johnson Sheena M. , Bruckner Felix , Collins David
Published: November 2006

By use of a very sensitive nested PCR method targeting part of the strongly conserved mycoplasmal 16S RNA genes,
Mycoplasma pneumoniae
was found in the synovial fluid of 19/24 (79%) of rheumatoid arthritis patients, 6/6 (100%) of patients with nonrheumatoid inflammatory arthritis, and 8/10 (80%) of osteoarthritis patients attending the rheumatology clinic for drainage of joint effusions. It was not found in the synovial exudates of 13 people attending the orthopedic clinic with traumatic knee injuries or undergoing surgery for knee replacement. However,
M. pneumoniae
was detected in 2/4 synovial biopsy specimens from orthopedic patients with traumatic knee injuries.
M. pneumoniae
was associated with the increased synovial fluids found in arthritic flares but was not found in the synovial fluids of trauma patients.
Mycoplasma salivarium
occurred sporadically.
Mycoplasma fermentans
had previously been isolated from patients with inflammatory cellular infiltrates, such as rheumatoid arthritis, but it was not detected for osteoarthritic patients from either clinic. It is possible that these organisms may contribute to chronic inflammation within the joints.
Identification of Group A Porcine Rotavirus Strains Bearing a Novel VP4 (P) Genotype in Italian Swine Herds
Authors: Martella V. , Ciarlet M. , Bányai K. , Lorusso E. , Arista S. , Lavazza A. , Pezzotti G. , Decaro N. , Cavalli A. , Lucente M. S. , Corrente M. , Elia G. , Camero M. , Tempesta M. , Buonavoglia C.
Published: November 2006

The VP4 gene of a G5 Italian porcine rotavirus strain, 344/04-1, was nontypeable by PCR genotyping. The amino acid sequence of the full-length VP4 protein had low identity (≤76.6%) with the homologous sequences of representative strains of the remaining P genotypes, providing evidence for a novel P genotype.
Inhibition of the Secretory Pathway by Foot-and-Mouth Disease Virus 2BC Protein Is Reproduced by Coexpression of 2B with 2C, and the Site of Inhibition Is Determined by the Subcellular Location of 2C
Authors: Moffat Katy , Knox Caroline , Howell Gareth , Clark Sarah J. , Yang H. , Belsham Graham J. , Ryan Martin , Wileman Thomas
Published: November 2006

Infection of cells with picornaviruses can lead to a block in protein secretion. For poliovirus this is achieved by the 3A protein, and the consequent reduction in secretion of proinflammatory cytokines and surface expression of major histocompatibility complex class I proteins may inhibit host immune responses in vivo. Foot-and-mouth disease virus (FMDV), another picornavirus, can cause persistent infection of ruminants, suggesting it too may inhibit immune responses. Endoplasmic reticulum (ER)-to-Golgi apparatus transport of proteins is blocked by the FMDV 2BC protein. The observation that 2BC is processed to 2B and 2C during infection and that individual 2B and 2C proteins are unable to block secretion stimulated us to study the effects of 2BC processing on the secretory pathway. Even though 2BC was processed rapidly to 2B and 2C, protein transport to the plasma membrane was still blocked in FMDV-infected cells. The block could be reconstituted by coexpression of 2B and 2C, showing that processing of 2BC did not compromise the ability of FMDV to slow secretion. Under these conditions, 2C was located to the Golgi apparatus, and the block in transport also occurred in the Golgi apparatus. Interestingly, the block in transport could be redirected to the ER when 2B was coexpressed with a 2C protein fused to an ER retention element. Thus, for FMDV a block in secretion is dependent on both 2B and 2C, with the latter determining the site of the block.
Physiological Levels of Virion-Associated Human Immunodeficiency Virus Type 1 Envelope Induce Coreceptor-Dependent Calcium Flux
Authors: Melar Marta , Ott David E. , Hope Thomas J.
Published: November 2006

Human immunodeficiency virus (HIV) entry into target cells requires the engagement of receptor and coreceptor by envelope glycoprotein (Env). Coreceptors CCR5 and CXCR4 are chemokine receptors that generate signals manifested as calcium fluxes in response to binding of the appropriate ligand. It has previously been shown that engagement of the coreceptors by HIV Env can also generate Ca2+fluxing. Since the sensitivity and therefore the physiological consequence of signaling activation in target cells is not well understood, we addressed it by using a microscopy-based approach to measure Ca2+levels in individual CD4+T cells in response to low Env concentrations. Monomeric Env subunit gp120 and virion-bound Env were able to activate a signaling cascade that is qualitatively different from the one induced by chemokines. Env-mediated Ca2+fluxing was coreceptor mediated, coreceptor specific, and CD4 dependent. Comparison of the observed virion-mediated Ca2+fluxing with the exact number of viral particles revealed that the viral threshold necessary for coreceptor activation of signaling in CD4+T cells was quite low, as few as two virions. These results indicate that the physiological levels of virion binding can activate signaling in CD4+T cells in vivo and therefore might contribute to HIV-induced pathogenesis.
Microglial Cell Line Established from Prion Protein-Overexpressing Mice Is Susceptible to Various Murine Prion Strains
Authors: Iwamaru Yoshifumi , Takenouchi Takato , Ogihara Kazumasa , Hoshino Megumi , Takata Masuhiro , Imamura Morikazu , Tagawa Yuichi , Hayashi-Kato Hiroko , Ushiki-Kaku Yuko , Shimizu Yoshihisa , Okada Hiroyuki , Shinagawa Morikazu , Kitani Hiroshi , Yokoyama Takashi
Published: November 2006

Several lines of evidence suggest that microglia have important roles in the pathogenesis of prion diseases. Here, we establish a novel microglial cell line (MG20) from neonatal
tga20
mice that overexpress murine prion protein. After exposure to Chandler scrapie, we observed the replication and accumulation of disease-associated forms of the prion protein in MG20 cells up to the 15th passage. Furthermore, MG20 cells were susceptible to ME7, Obihiro scrapie, and bovine spongiform encephalopathy agents. Thus, MG20 cell lines persistently infected with various murine prion strains provide a useful model for the study of the pathogenesis of prion diseases.
A Single-Nucleotide Synonymous Mutation in the
gag
Gene Controlling Human Immunodeficiency Virus Type 1 Virion Production
Authors: Hamano Takaichi , Matsuo Kazuhiro , Hibi Yurina , Victoriano Ann Florence B. , Takahashi Naoko , Mabuchi Yosio , Soji Tsuyoshi , Irie Shinji , Sawanpanyalert Pathom , Yanai Hideki , Hara Takashi , Yamazaki Shudo , Yamamoto Naoki , Okamoto Takashi
Published: November 2006

Viral factors as well as host ones play major roles in the disease progression of human immunodeficiency virus type 1 (HIV-1) infection. We have examined cytotoxic T-lymphocyte activity and HIV-1 DNA PCR results of 312 high-risk seronegative drug users in northern Thailand and identified four seronegative cases positive for both assays. Furthermore, we have identified a synonymous mutation in nucleotide position 75 of the
gag
p17 gene (A426G) of HIV-1 that belongs to the CRF01_AE virus circulating in Thailand. The replication-competent HIV-1 clone containing the A426G mutation demonstrated a dramatic reduction of virion production and perturbation of viral morphogenesis without affecting viral protein synthesis in cells.
The Cytomegalovirus Homolog of Interleukin-10 Requires Phosphatidylinositol 3-Kinase Activity for Inhibition of Cytokine Synthesis in Monocytes
Authors: Spencer Juliet V.
Published: November 2006

Human cytomegalovirus (CMV) has evolved numerous strategies for evading host immune defenses, including piracy of cellular cytokines. A viral homolog of interleukin-10, designated cmvIL-10, binds to the cellular IL-10 receptor and effects potent immune suppression. The signaling pathways employed by cmvIL-10 were investigated, and the classic IL-10R/JAK1/Stat3 pathway was found to be activated in monocytes. However, inhibition of JAK1 had little effect on cmvIL-10-mediated suppression of tumor necrosis factor alpha (TNF-α) production. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway had a more significant impact on TNF-α levels but did not completely relieve the immune suppression, demonstrating that cmvIL-10 stimulates multiple signaling pathways to modulate cell function.
Amelioration of Influenza Virus Pathogenesis in Chickens Attributed to the Enhanced Interferon-Inducing Capacity of a Virus with a Truncated NS1 Gene
Authors: Cauthen Angela N. , Swayne David E. , Sekellick Margaret J. , Marcus Philip I. , Suarez David L.
Published: November 2006

Avian influenza virus (AIV) A/turkey/Oregon/71-SEPRL (TK/OR/71-SEPRL) (H7N3) encodes a full-length NS1 protein and is a weak inducer of interferon (IFN). A variant, TK/OR/71-delNS1 (H7N3), produces a truncated NS1 protein and is a strong inducer of IFN. These otherwise genetically related variants differ 20-fold in their capacities to induce IFN in primary chicken embryo cells but are similar in their sensitivities to the action of IFN. Furthermore, the weak IFN-inducing strain actively suppresses IFN induction in cells that are otherwise programmed to produce it. These phenotypic differences are attributed to the enhanced IFN-inducing capacity that characterizes type A influenza virus strains that produce defective NS1 protein. The pathogenesis of these two variants was evaluated in 1-day-old and 4-week-old chickens. The cell tropisms of both viruses were similar. However, the lesions in chickens produced by the weak IFN inducer were more severe and differed somewhat in character from those observed for the strong IFN inducer. Differences in lesions included the nature of inflammation, the rate of resolution of the infection, and the extent of viral replication and/or virus dissemination. The amelioration of pathogenesis is attributed to the higher levels of IFN produced by the variant encoding the truncated NS1 protein and the antiviral state subsequently induced by that IFN. The high titer of virus observed in kidney tissue (≈10
9
50% embryo lethal doses/g) from 1-day-old chickens infected intravenously by the weak IFN-inducing strain is attributed to the capacity of chicken kidney cells to activate the hemagglutinin fusion peptide along with their unresponsiveness to inducers of IFN as measured in vitro. Thus, the IFN-inducing capacity of AIV appears to be a significant factor in regulating the pathogenesis, virulence, and viral transmission of AIV in chickens. This suggests that the IFN-inducing and IFN induction suppression phenotypes of AIV should be considered when characterizing strains of influenza virus.
Silencing of both β-TrCP1 and HOS (β-TrCP2) Is Required To Suppress Human Immunodeficiency Virus Type 1 Vpu-Mediated CD4 Down-Modulation
Authors: Butticaz Christophe , Michielin Olivier , Wyniger Josiane , Telenti Amalio , Rothenberger Sylvia
Published: November 2006

The human immunodeficiency virus type 1 (HIV-1) Vpu protein interacts with CD4 within the endoplasmic reticula of infected cells and targets CD4 for degradation through interaction with β-TrCP1. Mammals possess a homologue of β-TrCP1, HOS, which is also named β-TrCP2. We show by coimmunoprecipitation experiments that β-TrCP2 binds Vpu and is able to induce CD4 down-modulation as efficiently as β-TrCP1. In two different cell lines, HeLa CD4
+
and Jurkat, Vpu-mediated CD4 down-modulation could not be reversed through the individual silencing of endogenous β-TrCP1 or β-TrCP2 but instead required the two genes to be silenced simultaneously.
E6AP-Dependent Degradation of DLG4/PSD95 by High-Risk Human Papillomavirus Type 18 E6 Protein
Authors: Handa Keisuke , Yugawa Takashi , Narisawa-Saito Mako , Ohno Shin-ichi , Fujita Masatoshi , Kiyono Tohru
Published: November 2006

In most cervical cancers, DNAs of high-risk mucosotropic human papillomaviruses (HPVs), such as types 16 and 18, are maintained so as to express two viral proteins, E6 and E7, suggesting that they play important roles in carcinogenesis. The carboxy-terminal PDZ domain-binding motif of the E6 proteins is in fact essential for transformation of rodent cells and induction of hyperplasia in E6-transgenic mouse skin. To date, seven PDZ domain-containing proteins, including DLG1/hDLG, which is a human homologue of the
Drosophila
discs large tumor suppressor (Dlg), have been identified as targets of high-risk HPV E6 proteins. Here, we describe DLG4/PSD95, another human homologue of Dlg, as a novel E6 target. DLG4 was found to be expressed in normal human cells, including cervical keratinocytes, but only to a limited extent in both HPV-positive and HPV-negative cervical cancer cell lines. Expression of HPV18 E6 in HCK1T decreased DLG4 levels more strongly than did HPV16 E6, the carboxy-terminal motif of the proteins being critical for binding and degradation of DLG4 in vitro. DLG4 levels were restored by expression of either E6AP-specific short hairpin RNA or bovine papillomavirus type 1 E2 in HeLa but not CaSki or SiHa cells, reflecting downregulation of DLG4 mRNA as opposed to protein by an HPV-independent mechanism in HPV16-positive cancer lines. The tumorigenicity of CaSki cells was strongly inhibited by forced expression of DLG4, while growth in culture was not inhibited at all. These results suggest that DLG4 may function as a tumor suppressor in the development of HPV-associated cancers.
Functional p53 Signaling in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas: Implications for Therapy
Authors: Petre Christin E. , Sin Sang-Hoon , Dittmer Dirk P.
Published: November 2006

The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is associated with Kaposi's sarcoma (KS) as well as primary effusion lymphomas (PEL). The expression of viral proteins capable of inactivating the p53 tumor suppressor protein has been implicated in KSHV oncogenesis. However, DNA-damaging drugs such as doxorubicin are clinically efficacious against PEL and KS, suggesting that p53 signaling remains intact despite the presence of KSHV. To investigate the functionality of p53 in PEL, we examined the response of a large number of PEL cell lines to doxorubicin. Two out of seven (29%) PEL cell lines harbored a mutant p53 allele (BCBL-1 and BCP-1) which led to doxorubicin resistance. In contrast, all other PEL containing wild-type p53 showed DNA damage-induced cell cycle arrest, p53 phosphorylation, and p53 target gene activation. These data imply that p53-mediated DNA damage signaling was intact. Supporting this finding, chemical inhibition of p53 signaling in PEL led to doxorubicin resistance, and chemical activation of p53 by the Hdm2 antagonist Nutlin-3 led to unimpaired induction of p53 target genes as well as growth inhibition and apoptosis.
Involvement of Hsp90 in Assembly and Nuclear Import of Influenza Virus RNA Polymerase Subunits
Authors: Naito Tadasuke , Momose Fumitaka , Kawaguchi Atsushi , Nagata Kyosuke
Published: November 2006

Transcription
and replication of the influenza virus RNA genome occur in the nuclei
of infected cells through the viral RNA-dependent RNA polymerase
consisting of PB1, PB2, and PA. We previously identified a
host factor designated RAF-1 (RNA polymerase activating factor 1) that
stimulates viral RNA synthesis. RAF-1 is found to be identical to
Hsp90. Here, we examined the intracellular localization of Hsp90 and
viral RNA polymerase subunits and their molecular interaction. Hsp90
was found to interact with PB2 and PB1, and it was relocalized to the
nucleus upon viral infection. We found that the nuclear transport of
Hsp90 occurs in cells expressing PB2 alone. The nuclear transport of
Hsp90 was in parallel with that of the viral RNA polymerase binary
complexes, either PB1 and PB2 or PB1 and PA, as well as with that of
PB2 alone. Hsp90 also interacted with the binary RNA polymerase complex
PB1-PB2, and it was dissociated from the PB1-PB2 complex upon its
association with PA. Furthermore, Hsp90 could form a stable
PB1-PB2-Hsp90 complex prior to the formation of a ternary polymerase
complex by the assembly of PA in the infected cells. These results
suggest that Hsp90 is involved in the assembly and nuclear transport of
viral RNA polymerase subunits, possibly as a molecular chaperone for
the polymerase subunits prior to the formation of a mature ternary
polymerase
complex.
Adenovirus Infection Triggers a Rapid, MyD88-Regulated Transcriptome Response Critical to Acute-Phase and Adaptive Immune Responses In Vivo
Authors: Hartman Zachary C. , Kiang Anne , Everett Ruth S. , Serra Delila , Yang Xiao Y. , Clay Timothy M. , Amalfitano Andrea
Published: November 2006

Nearly 50 years ago, the discovery of interferon prompted the notion that host cells innately respond to viral invasion. Since that time, technological advances have allowed this response to be extensively characterized and dissected in vitro. However, these advances have only recently been applied to highly complex, in vivo biological systems. To this end, we exploited high-titer adenovirus (Ad) vectors to globally investigate the innate immune response to nonenveloped viral infection in vivo. Our results indicated a potent cellular transcriptome response shortly after infection, with global assessments revealing significant dysregulation in ∼15% of the measured transcripts derived from Ad vector-transduced tissue. Bioinformatics-based transcriptome analysis revealed a complex innate response to Ad infection, with induction of proinflammatory responses (and suppression of metabolism and mitochondrial genes) akin to those observed when mice are challenged with lipopolysaccharide. Despite this commonality, there were many unique aspects of the Ad-dependent transcriptome response, including the upregulation of several RNA regulatory mechanisms and apoptosis-related pathways, accompanied by the suppression of lysosomal and endocytic genes. Our results also implicated the Toll-like receptors (TLRs) in these responses, prompting specific investigations into this pathway. By using MyD88KO mice, our results confirmed that Ad-induced dysregulation of five functionally related gene clusters are significantly dependent on this TLR adaptor gene. MyD88 deficiency also resulted in significantly diminished, although not abolished, adaptive and acute-phase immune responses to Ad, confirming the transcriptome data, as well as specifically identifying MyD88 as a significant Ad immunity amplifier and regulator in vivo.
Type-Specific Epitopes Targeted by Monoclonal Antibodies with Exceptionally Potent Neutralizing Activities for Selected Strains of Human Immunodeficiency Virus Type 1 Map to a Common Region of the V2 Domain of gp120 and Differ Only at Single Positions from the Clade B Consensus Sequence
Authors: Honnen W. J. , Krachmarov C. , Kayman S. C. , Gorny M. K. , Zolla-Pazner S. , Pinter A.
Published: November 2006

Only a few monoclonal antibodies (MAbs) have been isolated that recognize conserved sites in human immunodeficiency virus type 1 (HIV-1) Env proteins and possess broad neutralizing activities. Other MAbs directed against targets in various domains of Env have been described that are strongly neutralizing, but they possess limited breadth. One such MAb, 2909, possesses a uniquely potent neutralizing activity specific for a quaternary epitope on SF162 Env that requires the presence of both the V2 and the V3 domains. We now show that replacement of the SF162 V3 sequence with consensus V3 sequences of multiple subtypes led to attenuated but still potent neutralization by 2909 and that the main determinants for the type specificity of 2909 reside in the V2 domain. A substitution at position 160 completely eliminated 2909 reactivity, and mutations at position 167 either attenuated or potentiated neutralization by this antibody. Different substitutions at the same positions in V2 were previously shown to introduce epitopes recognized by MAbs 10/76b and C108g and to allow potent neutralization by these MAbs. Two substitutions at key positions in the V2 domain of JR-FL Env also allowed potent expression of the 2909 epitope, and single substitutions in YU2 V2 were sufficient for expression of the 2909, C108g, and 10/76b epitopes. These results demonstrate that the minimal epitopes for 2909, C108g, and 10/76b differed from that of the clade B consensus sequence only at single positions and suggest that all three MAbs recognize distinct variants of a relatively conserved sequence in V2 that is a particularly sensitive mediator of HIV-1 neutralization.
Effect of Rotavirus Strain on the Murine Model of Biliary Atresia
Authors: Allen Steven R. , Jafri Mubeen , Donnelly Bryan , McNeal Monica , Witte David , Bezerra Jorge , Ward Richard , Tiao Gregory M.
Published: November 2006

Biliary atresia is a devastating disorder of the newborn in which afflicted infants develop inflammation and fibrosis of the extrahepatic biliary tract, resulting in cirrhosis and end-stage liver disease. Infection with a virus is thought to be a contributing factor in the etiology of biliary atresia. In the murine model of biliary atresia, perinatal exposure to rhesus rotavirus (RRV) results in biliary epithelial cell infection causing bile duct obstruction. The purpose of this study was to determine if tropism for the biliary epithelial cell was unique to RRV. Newborn mice underwent intraperitoneal injection with five strains of rotavirus: RRV (simian), SA11-FM (simian/bovine), SA11-SM (simian), EDIM (murine), and Wa (human). RRV and SA11-FM caused clinical manifestations of bile duct obstruction and high mortality. SA11-SM caused clinical signs of hepatobiliary injury but the mortality was markedly reduced. EDIM and Wa caused no sign of hepatobiliary disease. The systemic and temporal distribution of viral protein and live virus varied according to the injected strain. Immunohistochemistry revealed that RRV and SA11-FM targeted the biliary epithelial cells. In contrast, SA11-SM was found in the liver but in not in the biliary epithelium. These results indicate that strain-specific characteristics dictate tropism for cells of hepatobiliary origin which in turn impact the ability to induce the murine model of biliary atresia.
PTP-H2 and PTP-H3 fromMicroplitis demolitorBracovirus Localize to Focal Adhesions and Are Antiphagocytic in Insect Immune Cells
Authors: Pruijssers Andrea J. , Strand Michael R.
Published: November 2006

Viruses in the familyPolydnaviridaeare symbiotically associated with parasitoid wasps. Wasps inject polydnaviruses (PDVs) when laying an egg into their insect host, and expression of viral gene products causes several physiological alterations, including immunosuppression, that allow the wasp's progeny to develop. As with other PDVs, mostMicroplitis demolitorbracovirus (MdBV) genes are related variants that form gene families. The largest MdBV gene family includes 13 members that encode predicted proteins related to protein tyrosine phosphatases (PTPs). Sequence analysis during the present study indicated that five PTP family members (PTP-H2, -H3, -N1, and -N2) have fully conserved catalytic domains, whereas other family members exhibited replacements, deletions, or rearrangements of amino acids considered essential for tyrosine phosphatase activity. Expression studies indicated that most MdBV PTP genes are expressed in virus-infected host insects, with transcript abundance usually being highest in hemocytes. MdBV-infected hemocytes also exhibited higher levels of tyrosine phosphatase activity than noninfected hemocytes. We produced expression constructs for four of the most abundantly expressed PTP family members and conducted functional studies with hemocyte-likeDrosophilaS2 cells. These experiments suggested that recombinant PTP-H2 and PTP-H3 are functional tyrosine phosphatases whereas PTP-H1 and PTP-J1 are not. PTP-H2 and -H3 localized to focal adhesions in S2 cells, and coexpression with another MdBV gene product, Glc1.8, resulted in complete inhibition of phagocytosis.
Rhinovirus Activates Interleukin-8 Expression via a Src/p110β Phosphatidylinositol 3-Kinase/Akt Pathway in Human Airway Epithelial Cells
Authors: Bentley J. Kelley , Newcomb Dawn C. , Goldsmith Adam M. , Jia Yue , Sajjan Uma S. , Hershenson Marc B.
Published: November 2006

Rhinovirus (RV) is responsible for the majority of common colds and triggers exacerbations of asthma and chronic obstructive lung disease. We have shown that RV serotype 39 (RV39) infection activates phosphatidylinositol 3 (PI 3)-kinase and the serine threonine kinase Akt minutes after infection and that the activation of PI 3-kinase and Akt is required for maximal interleukin-8 (IL-8) expression. Here, we further examine the contributions of Src and PI 3-kinase activation to RV-induced Akt activation and IL-8 expression. Confocal fluorescent microscopy of 16HBE14o− human bronchial epithelial cells showed rapid (10-min) colocalization of RV39 with Src, p85α PI 3-kinase, p110β PI 3-kinase, Akt and Cit-Akt-PH, a fluorescent Akt pleckstrin homology domain which binds PI(3,4,5)P
3
. The chemical Src inhibitor PP2 {4-amino-5-(4-chlorophenyl)-7-(
t
-butyl)pyrazolo [3,4-
d
]pyrimidine} and the PI 3-kinase inhibitor LY294002 each inhibited Akt phosphorylation and the colocalization of RV39 with Akt. Digoxigenin-tagged RV coprecipitated with a Crosstide kinase likely to be Akt, and inhibition of Src blocked kinase activity. Digoxigenin-tagged RV39 colocalized with the lipid raft marker ceramide. In 16HBE14o− and primary mucociliary differentiated human bronchial epithelial cells, inhibition of Src kinase activity with the Src family chemical inhibitor PP2, dominant-negative Src (K297R), and Src small interfering RNA (siRNA) each inhibited RV39-induced IL-8 expression. siRNA against p110β PI 3-kinase also inhibited IL-8 expression. These data demonstrate that, in the context of RV infection, Src and p110β PI 3-kinase are upstream activators of Akt and the IL-8 promoter and that RV colocalizes with Src, PI 3-kinase, and Akt in lipid rafts.
Status of Charm Flavor Physics
Authors: Shipsey Ian
Published: November 2006

The role of charm in testing the Standard Model description of quark mixing and CP violation through measurements of lifetimes, decay constants and semileptonic form factors is reviewed. Together with Lattice QCD, charm has the potential this decade to maximize the sensitivity of the entire flavor physics program to new physics and pave the way for understanding physics beyond the Standard Model at the LHC in the coming decade. The status of indirect searches for physics beyond the Standard Model through charm mixing, CP-violation and rare decays is also reported.
$D^0 \bar{D}^0$ Quantum Correlations, Mixing, and Strong Phases
Authors:   For the CLEO Collaboration., Asner David M.
Published: November 2006

Because of the quantum correlation between the pair-produced D0 and [Formula: see text] from the decay of the ψ(3770), the time-integrated single and double tag decay rates depend on charm mixing amplitudes, doubly-Cabibbo-suppressed amplitudes, and the relative strong phase δ between D0 and [Formula: see text] decays to identical final states. Using 281 pb-1 collected with the CLEO-c detector on the ψ(3770) resonance, we measure the absolute branching fractions of D0 decays to hadronic flavored states, CP eigenstates, and semileptonic final states to determine the relative strong phase cos δ and to limit the mixing amplitude y.
Charm Dalitz Analyses at BABAR
Authors:   Representing the BABAR collaboration., PAPPAGALLO MARCO
Published: November 2006

Dalitz plot analyses of D0 events reconstructed for the hadronic decay [Formula: see text] and [Formula: see text] are presented here. The analyses are based on a data sample of 91.5 fb-1. All data have been collected with the BABAR detector at the PEP-II asymmetric-energy e+e- storage rings at SLAC running at center-of-mass energies on and 40 MeV below the ϒ(4S) resonance.
HUNTING THE SCALAR GLUEBALL: PROSPECTS FOR BES III
Authors: CHANOWITZ MICHAEL
Published: November 2006

The search for the ground state scalar glueball G0 is reviewed. Spin zero glueballs will have unique dynamical properties if the [Formula: see text] amplitude is suppressed by chiral symmetry, as it is to all orders in perturbation theory: for instance, mixing of G0 with [Formula: see text] mesons would be suppressed, radiative Ψ decay would be a filter for new physics in the spin zero channel, and the decay [Formula: see text] could be enhanced relative to G0 → ππ. These properties are consistent with the identification of f0(1710) as the largely unmixed ground state scalar glueball, while recent BES data implies that f0(1500) does not contain the dominant glueball admixture. Three hypotheses are discussed: that G0 is 1) predominantly f0(1500) or 2) predominantly f0(1710) or 3) is strongly mixed between f0(1500) and f0(1710).
THE XYZs OF CHARMONIUM AT BES
Authors: Barnes T.
Published: November 2006

In this contribution I review some recent developments in charmonium spectroscopy, and discuss related theoretical predictions. The spectrum of states, strong decays of states above open charm threshold, electromagnetic transitions, and issues related to the recent discoveries of the "XYZ" states are discussed. Contributions that BES can make to our understanding of charmonium and related states are stressed in particular.
CHARMONIA FROM LATTICE QCD
Authors: BALI GUNNAR S.
Published: November 2006

Recent lattice QCD results on charmonium properties are reviewed. I comment on molecules and hybrid states as well as on future studies of states near strong decay thresholds.
CHARM MIXING IN THE STANDARD MODEL AND BEYOND
Authors: PETROV ALEXEY A.
Published: November 2006

The motivation most often cited in searches for [Formula: see text] mixing and CP-violation in charm system lies with the possibility of observing a signal from New Physics which dominates that from the Standard Model. We review recent theoretical predictions and experimental constraints on [Formula: see text] mixing parameters, concentrating on possible effects of New Physics.
Actin disruption inhibits endosomal traffic of P-glycoprotein-EGFP and resistance to daunorubicin accumulation
Authors: Fu Dong , Roufogalis Basil D.
Published: November 2006

Intracellular traffic of human P-glycoprotein (P-gp), a membrane transporter responsible for multidrug resistance in cancer chemotherapy, was investigated using a P-gp and enhanced green fluorescent fusion protein (P-gp-EGFP) in human breast cancer MCF-7 cells. The stably expressed P-gp-EGFP from a clonal cell population was functional as a drug efflux pump, as demonstrated by the inhibition of daunorubicin accumulation and the conferring of resistance of the cells to colchicine and daunorubicin. Colocalization experiments demonstrated that a small fraction of the total P-gp-EGFP expressed was localized intracellularly and was present in early endosome and lysosome compartments. P-gp-EGFP traffic was shown to occur via early endosome transport to the plasma membrane. Subsequent movement of P-gp-EGFP away from the plasma membrane occurred by endocytosis to the early endosome and lysosome. The component of the cytoskeleton responsible for P-gp-EGFP traffic was demonstrated to be actin rather than microtubules. In functional studies it was shown that in parallel with the interruption of the traffic of P-gp-EGFP, cellular accumulation of the P-gp substrate daunorubicin was increased after cells were treated with actin inhibitors, and cell proliferation was inhibited to a greater extent than in the presence of daunorubicin alone. The actin dependence of P-gp traffic and the parallel changes in cytotoxic drug accumulation demonstrated in this study delineates the pathways of P-gp traffic and may provide a new approach to overcoming multidrug resistance in cancer chemotherapy.
Production of a uniform cellular injury by raster scanning of cells for the study of laser bioeffects
Authors: Walker K. P. , Schuschereba S. T. , Edsall P. R. , Stuck B. E. , Bowman P. D.
Published: November 2006

Efforts to understand laser bioeffects in cells and tissues have been hindered by a nonuniform cellular response of the specimen, resulting in graded biochemical effects. In addition, the small beam diameters of commonly used lasers limit the number of cells expressing a response to numbers inadequate for the study of biochemical effects. For a limited emission power, expansion of the beam diameter reduces the irradiance, thus requiring longer exposure durations to produce a cellular response. Cultured human retinal epithelial cells were exposed as a single spot (“tophat” exposure) from a carbon dioxide (CO2) laser operating at 10.6 μm or scanned with a raster system and compared with thermal injury produced with heated saline for short periods (1–9 s) at relatively high temperature (55–70°C). Cell viability and induction of the 70 kDa heat shock protein were evaluated as indicators of the cellular response. Initial attempts to use a tophat (uniform energy distribution) exposure resulted in a nonuniform cellular response (and nonuniform energy distribution) due to diffraction effects from the 2-mm selection aperture. However, raster scanning for appropriate times with the CO2 laser yielded uniform cell viability and heat shock protein synthesis that were comparable to dipping cells in heated saline. Because scanning results in a homogeneous exposure of cells, the described scanning technique may be applied to studies of cellular responses to other lasers to evaluate photochemical and photomechanical effects.
Mitochondrial superoxide production in skeletal muscle fibers of the rat and decreased fiber excitability
Authors: van der Poel Chris , Edwards Joshua N. , Macdonald William A. , Stephenson D. George
Published: November 2006

Mammalian skeletal muscles generate marked amounts of superoxide (O2·−) at 37°C, but it is not well understood which is the main source of O2·− production in the muscle fibers and how this interferes with muscle function. To answer these questions, O2·− production and twitch force responses were measured at 37°C in mechanically skinned muscle fibers of rat extensor digitorum longus (EDL) muscle. In mechanically skinned fibers, the sarcolemma is removed avoiding potential sources of O2·− production that are not intrinsically part of the muscle fibers, such as nerve terminals, blood cells, capillaries and other blood vessels in the whole muscle. O2·− production was also measured in split single EDL muscle fibers, where part of the sarcolemma remained attached, and small bundles of intact isolated EDL muscle fibers at rest, in the presence and absence of modifiers of mitochondrial function. The results lead to the conclusion that mitochondrial production of O2·− accounts for most of the O2·− measured intracellularly or extracellularly in skeletal muscle fibers at rest and at 37°C. Muscle fiber excitability at 37°C was greatly improved in the presence of a membrane permeant O2·− dismutase mimetic (Tempol), demonstrating a direct link between O2·− production in the mitochondria and muscle fiber performance. This implicates mitochondrial O2·− production in the down-regulation of skeletal muscle function, thus providing a feedback pathway for communication between mitochondria and plasma membranes that is not directly related to the main function of mitochondria as the power plant of the mammalian muscle cell.
Pituitary adenylate cyclase-activating peptide affects homeostatic sleep regulation in healthy young men
Authors: Murck Harald , Steiger Axel , Frieboes Ralf M. , Antonijevic Irina A.
Published: November 2006

Pituitary adenylate cyclase-activating peptide (PACAP) is involved in autonomous regulation, including timekeeping, by its action on the suprachiasmatic nucleus and on neuroendocrine secretion, energy metabolism, and transmitter release. In particular, the interactions between PACAP and the glutamatergic system are well recognized. We compared the effect of intravenously administered PACAP to that of placebo in eight healthy male subjects. PACAP in a concentration of 4 × 12.5 μg was administered in a pulsatile fashion hourly between 2200 and 0100. Sleep EEG was recorded from 2300 to 1000, which was also the time when subjects were allowed to sleep. Blood samples were taken every 20 min between 2200 and 0700 for the determination of cortisol, GH, and prolactin. PACAP administration led to no changes in the macro-sleep structure as assessed according to standard criteria. Spectral analysis revealed a significant reduction in the θ-frequency range in the first 4-h interval and of the spindle frequency range in the second 4-h interval of the registration period. This was accompanied by an increase in the time constant τ of the physiological δ-power decline in the course of the night, i.e., a less pronounced dynamic of the reduction of δ-power with time. This was accompanied by a trend ( P < 0.1) toward decreased prolactin secretion in the first 4-h period of the night. No other changes in endocrine secretion were observed. We concluded that PACAP leads to a reduction of the dynamics of homeostatic sleep regulation and prolactin secretion. Both effects are the opposite of those seen after sleep deprivation but similar to the changes after napping, i.e., a reduced sleep propensity. This implies that PACAP might be involved in homeostatic sleep regulation.
Acute and chronic regulation of leptin synthesis, storage, and secretion by insulin and dexamethasone in human adipose tissue
Authors: Lee Mi-Jeong , Wang Yanxin , Ricci Matthew R. , Sullivan Sean , Russell Colleen D. , Fried Susan K.
Published: November 2006

Serum leptin levels are upregulated in proportion to body fat and also increase over the short term in response to meals or insulin. To understand the mechanisms involved, we assessed leptin synthesis and secretion in samples of adipose tissue from subjects with a wide range of BMI. Tissue leptin content and relative rates of leptin biosynthesis, as determined by metabolic labeling, were highly correlated with each other and with BMI and fat cell size. To understand mechanisms regulating leptin synthesis in obesity, we used biosynthetic labeling to directly assess the effects of insulin and glucocorticoids (dexamethasone) on leptin synthesis and secretion in human adipose tissue. Chronic treatment (1–2 days in organ culture) with insulin increased relative rates of leptin biosynthesis without affecting leptin mRNA levels. In contrast, dexamethasone increased leptin mRNA and biosynthesis in parallel. Acute treatment with insulin or dexamethasone (added during 1-h preincubation and 45-min pulse labeling) did not affect relative rates of leptin biosynthesis, but pulse-chase studies showed that addition of insulin nearly doubled the release of [35S]leptin after a 1-h chase. We conclude that the higher leptin stores in adipose tissue of obese humans are maintained by chronic effects of insulin and glucocorticoids acting at pre- and posttranslational levels and that the ability of insulin to increase the release of preformed leptin may contribute to short-term variations in circulating leptin levels.
Cardiac effects of postconditioning depend critically on the duration of index ischemia
Authors: Manintveld Olivier C. , te Lintel Hekkert Maaike , van den Bos Ewout Jan , Suurenbroek Grietje M. , Dekkers Dick H. , Verdouw Pieter D. , Lamers Jos M. , Duncker Dirk J.
Published: November 2006

Postconditioning (POC) is known as the phenomenon whereby brief intermittent ischemia applied at the onset of reperfusion following index ischemia limits myocardial infarct size. Whereas there is evidence that the algorithm of the POC stimulus is an important determinant of the protective efficacy, the importance of the duration of index ischemia on the outcome of the effects of POC has received little attention. Pentobarbital sodium-anesthetized Wistar rats were therefore subjected to index ischemia produced by coronary artery occlusions (CAO) of varying duration (15–120 min) followed by reperfusion, without or with postconditioning produced by three cycles of 30-s reperfusion and reocclusion (3POC30). 3POC30 limited infarct size produced by 45-min CAO (CAO45) from 45 ± 3% to 31 ± 5%, and CAO60 from 60 ± 3% to 47 ± 6% (both P ≤ 0.05). In contrast, 3POC30 increased infarct size produced by CAO15 from 3 ± 1% to 19 ± 6% and CAO30 from 36 ± 6 to 48 ± 4% (both P ≤ 0.05). This deleterious effect of 3POC30 was not stimulus sensitive because postconditioning with 3POC5 and 3POC15 after CAO30 also increased infarct size. The cardioprotection by 3POC30 after CAO60 was accompanied by an increased stimulation of Akt phosphorylation at 7 min of reperfusion and a 36% lower superoxide production, measured by dihydroethidium fluorescence, after 2 h of reperfusion. Consistent with these results, cardioprotection by 3POC30 was abolished by phosphatidylinositol-3-OH-kinase inhibition, as well as nitric oxide (NO) synthase inhibition. The deleterious effect of 3POC30 after CAO15 was accompanied by an increased superoxide production with no change in Akt phosphorylation and was not affected by NO synthase inhibition. In conclusion, the effect of cardiac POC depends critically on the duration of the index ischemia and can be either beneficial or detrimental. These paradoxical effects of POC may be related to the divergent effects on Akt phosphorylation and superoxide production.
Vascular metabolic dissipation in Murray's law
Authors: Liu Yi , Kassab Ghassan S.
Published: November 2006

The metabolic dissipation in Murray's minimum energy hypothesis includes only the blood metabolism. The metabolic dissipation of the vascular tree, however, should also include the metabolism of passive and active components of the vessel wall. In this study, we extend the metabolic dissipation to include blood metabolism, as well as passive and active components of the vessel wall. The analysis is extended to the entire vascular arterial tree rather than a single vessel as in Murray's formulation. The calculations are based on experimentally measured morphological data of coronary artery network and the longitudinal distribution of blood pressure along the tree. Whereas the model includes multiple dissipation sources, the total metabolic consumption of a complex vascular tree is found to remain approximately proportional to the cumulative arterial volume of the unit. This implies that the previously described scaling relations for the various morphological features (volume, length, diameter, and flow) remain unchanged under the generalized condition of metabolic requirements of blood and blood vessel wall.
In vivo left ventricular functional capacity is compromised in cMyBP-C null mice
Authors: Brickson S. , Fitzsimons D. P. , Pereira L. , Hacker T. , Valdivia H. , Moss R. L.
Published: November 2006

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament-associated protein that binds tightly to myosin and has a potential role for modulating myocardial contraction. We tested the hypothesis that cMyBP-C 1) contributes to the enhanced in vivo contractile state following β-adrenergic stimulation and 2) is necessary for myocardial adaptation to chronic increases in afterload. In vivo pressure-volume relations demonstrated that left ventricular (LV) systolic and diastolic function were compromised under basal conditions in cMyBP-C−/−compared with WT mice. Moreover, whereas β-adrenergic treatment significantly improved ejection fraction, peak elastance, and the time to peak elastance in WT mice, these functional indexes remained unchanged in cMyBP-C−/−mice. Morphological and functional changes were measured through echocardiography in anesthetized mice following 5 wk of aortic banding. Adaptation to pressure overload was diminished in cMyBP-C−/−mice as characterized by a lack of an increase in posterior wall thickness, increased LV diameter, deterioration of fractional shortening, and prolonged isovolumic relaxation time. These results suggest that the absence of cMyBP-C significantly diminishes in vivo LV function and markedly attenuates the increase in LV contractility following β-adrenergic stimulation or adaptation to pressure overload.
Vascular endothelial growth factor accelerates compensatory lung growth after unilateral pneumonectomy
Authors: Sakurai Maromi K. , Lee Sang , Arsenault Danielle A. , Nose Vania , Wilson Jay M. , Heymach John V. , Puder Mark
Published: November 2006

We hypothesize that compensatory lung growth after unilateral pneumonectomy in a murine model is, in part, angiogenesis dependent and can be altered using angiogenic agents, possibly through regulation of endothelial cell proliferation and apoptosis. Left pneumonectomy was performed in mice. Mice were then treated with proangiogenic factors [vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF)], VEGF receptor antibodies (MF-1, DC101), and VEGF receptor small molecule chemical inhibitors. Lung volume and mass were measured. The lungs were analyzed using immunohistochemistry by CD31 staining, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, type II pneumocytes staining, and proliferating cell nuclear antigen. Compensatory lung growth was complete by postoperative day 10 and was associated with diffuse apoptosis of endothelial cells and pneumocytes. This process was accelerated by VEGF, such that growth was complete by postoperative day 4 with similar associated apoptosis. bFGF had no effect on lung growth. MF-1 and DC101 had no effect. The VEGF receptor small molecule chemical inhibitors also had no effect. VEGF, but not bFGF, accelerates growth. VEGF receptor inhibitors do not block growth, suggesting that other proangiogenic factors play a role or can compensate for VEGF receptor blockade. Diffuse apoptosis, endothelial cell and pneumocyte, occurs at cessation of both normal compensatory and VEGF-accelerated growth. Angiogenesis modulators may control growth via regulation of endothelial cell proliferation and apoptosis, although the exact relationship between endothelial cells and pneumocytes has yet to be determined. The fact that bFGF did not accelerate growth in our model when it did accelerate regeneration in the liver model suggests that angiogenesis during organ regeneration is regulated in an organ-specific manner.