bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral ulcerations are associated with the loss of response to infliximab in Crohn's disease
Authors: Sánchez A. R. , Rogers R. S. , Sheridan P. J.
Published: December 2004

We describe a 25‐year‐old Caucasian man with a 13‐year history of inflammatory Crohn's disease (CD) who was suffering recurrent severe oral and esophageal ulcerations for the past 3 years. His CD had been treated with infliximab infusions among other medications. The loss of efficacy was confirmed by antibodies to infliximab (ATI) and serum infliximab tests that showed high levels of ATIs and undetectable levels of infliximab respectively. These findings were consistent with significant immunogenic response to infliximab leading to loss of effect. Infliximab infusions and prednisone were discontinued and treatment of the CD was instituted with adalimumab, a human anti‐tumor necrosis factor (TNF)‐α biologic agent, to control the inflammatory small intestinal disease and dapsone for the oral and esophageal CD ulcerations. The patient's oral and esophageal lesions as well as the enteric CD are under control after 5 months of therapy.
HIV/AIDS and Cross‐National Convergence in Life Expectancy
Authors: Neumayer Eric
Published: December 2004

This article analyzes the effect of HIV/AIDS on the cross‐national convergence in life expectancy as well as infant and child survival rates by comparing three scenarios. One is based on historical and future best‐guess estimated values given the existence of the epidemic. The second scenario assumes that the effect of the epidemic is much worse than expected. The final scenario is based on hypothetical values derived from estimations where the mortality caused by the epidemic is removed. For life expectancy, convergence becomes stalled in the late 1980s (without weighting by country population size) or 1990s (with weighting). Convergence in infant and child survival rates does not become stalled, but slows down. These results are mainly attributable to the epidemic since all signs of stalled convergence or even divergence disappear in the “No AIDS scenario.” Given the existence of the epidemic, however, the reduced degree of inequality in life expectancy attained by 1985 is only expected to be achieved again by 2015 at the earliest. If the epidemic turns out much worse than expected, divergence could continue to 2050. No divergence is to be expected in infant and child survival rates in any of the scenarios.
A Case Report of the Effect of Plasma Exchange on Reactive Hemophagocytic Syndrome Associated with Toxic Shock Syndrome
Authors: Sanada Satoru , Ookawara Susumu , Shindo Tetsurou , Morino Kazuma , Ishikawa Hiroyasu , Suzuki Masayuki
Published: December 2004

Abstract:  We report here the case of a patient suffering from hemophagocytic syndrome (HPS) associated with toxic shock syndrome (TSS). A 50‐year‐old man was admitted because of fever, watery diarrhea and shortness of breath. Clinical analysis revealed systemic cyanosis, sunburn‐like erythema and septic shock. Staphylococcus aureus was identified from both blood and sputum culture and the serum enterotoxin A antibody test was positive, suggesting that this was a case of TSS. Though the respiratory and hemodynamic status improved by the mechanical ventilation, fluid resuscitation with catecholamine and antibiotic therapy, the platelet count decreased rapidly. Bone marrow aspiration revealed a large quantity of hemophagocytosis by macrophages. This reactive HPS was treated not with immunosuppressive drugs but with therapeutic plasma exchange in order to prevent worsening of S. aureus infection. After plasma exchange, the circulating macrophage colony‐stimulating factor (M‐CSF) level was reduced and the platelet count increased rapidly. Bacteria associated HPS remains a difficult diagnosis with high mortality and there is a crucial question of whether this should be treated with immunosuppressive drugs. The patient's clinical course would suggest that the therapeutic plasma exchange should be considered as a therapeutic tool for the bacteria associated HPS instead of immunosuppressive drugs.
Human Amygdala Responsivity to Masked Fearful Eye Whites
Authors: Whalen Paul J. , Kagan Jerome , Cook Robert G. , Davis F. Caroline , Kim Hackjin , Polis Sara , McLaren Donald G. , Somerville Leah H. , McLean Ashly A. , Maxwell Jeffrey S. , Johnstone Tom
Published: December 2004

The amygdala was more responsive to fearful (larger) eye whites than to happy (smaller) eye whites presented in a masking paradigm that mitigated subjects' awareness of their presence and aberrant nature. These data demonstrate that the amygdala is responsive to elements of biologically relevant configural stimuli.
Methylation of Tat by PRMT6 Regulates Human Immunodeficiency Virus Type 1 Gene Expression
Authors: Boulanger Marie-Chloé , Liang Chen , Russell Rodney S. , Lin Rongtuan , Bedford Mark T. , Wainberg Mark A. , Richard Stéphane
Published: December 2004

The human immunodeficiency virus (HIV) transactivator protein, Tat, stimulates transcription from the viral long terminal repeats via an arginine-rich transactivating domain. Since arginines are often known to be methylated, we investigated whether HIV type 1 (HIV-1) Tat was a substrate for known protein arginine methyltransferases (PRMTs). Here we identify Tat as a substrate for the arginine methyltransferase, PRMT6. Tat is specifically associated with and methylated by PRMT6 within cells. Overexpression of wild-type PRMT6, but not a methylase-inactive PRMT6 mutant, decreased Tat transactivation of an HIV-1 long terminal repeat luciferase reporter plasmid in a dose-dependent manner. Knocking down PRMT6 consistently increased HIV-1 production in HEK293T cells and also led to increased viral infectiousness as shown in multinuclear activation of a galactosidase indicator assays. Our study demonstrates that arginine methylation of Tat negatively regulates its transactivation activity and that PRMT6 acts as a restriction factor for HIV replication.
The Unique Stacked Rings in the Nucleocapsid of the White Spot Syndrome Virus Virion Are Formed by the Major Structural Protein VP664, the Largest Viral Structural Protein Ever Found
Authors: Leu Jiann-Horng , Tsai Jyh-Ming , Wang Han-Ching , Wang Andrew H.-J. , Wang Chung-Hsiung , Kou Guang-Hsiung , Lo Chu-Fang
Published: December 2004

One unique feature of the shrimp white spot syndrome virus (WSSV) genome is the presence of a giant open reading frame (ORF) of 18,234 nucleotides that encodes a long polypeptide of 6,077 amino acids with a hitherto unknown function. In the present study, by applying proteomic methodology to analyze the sodium dodecyl sulfate-polyacrylamide gel electrophoresis profile of purified WSSV virions by liquid chromatography-mass spectrometry (LC-MS/MS), we found that this giant polypeptide, designated VP664, is one of the viral structural proteins. The existence of the corresponding 18-kb transcript was confirmed by sequencing analysis of reverse transcription-PCR products, which also showed that
vp664
was intron-less. A time course analysis showed that this transcript was actively transcribed at the late stage, suggesting that this gene product should contribute primarily to the assembly and morphogenesis of the virion. Several polyclonal antisera against this giant protein were prepared, and one of them was successfully used for immunoelectron microscopy analysis to localize the protein in the virion. Immunoelectron microscopy with a gold-labeled secondary antibody showed that the gold particles were regularly distributed around the periphery of the nucleocapsid with a periodicity that matched the characteristic stacked ring subunits that appear as striations. From this and other evidence, we argue that this giant ORF in fact encodes the major WSSV nucleocapsid protein.
Silencing the Morphogenesis of Rotavirus
Authors: López Tomas , Camacho Minerva , Zayas Margarita , Nájera Rebeca , Sánchez Rosana , Arias Carlos F. , López Susana
Published: December 2004

The morphogenesis of rotaviruses follows a unique pathway in which immature double-layered particles (DLPs) assembled in the cytoplasm bud across the membrane of the endoplasmic reticulum (ER), acquiring during this process a transient lipid membrane which is modified with the ER resident viral glycoproteins NSP4 and VP7; these enveloped particles also contain VP4. As the particles move towards the interior of the ER cisternae, the transient lipid membrane and the nonstructural protein NSP4 are lost, while the virus surface proteins VP4 and VP7 rearrange to form the outermost virus protein layer, yielding mature infectious triple-layered particles (TLPs). In this work, we have characterized the role of NSP4 and VP7 in rotavirus morphogenesis by silencing the expression of both glycoproteins through RNA interference. Silencing the expression of either NSP4 or VP7 reduced the yield of viral progeny by 75 to 80%, although the underlying mechanism of this reduction was different in each case. Blocking the synthesis of NSP4 affected the intracellular accumulation and the cellular distribution of several viral proteins, and little or no virus particles (neither DLPs nor TLPs) were assembled. VP7 silencing, in contrast, did not affect the expression or distribution of other viral proteins, but in its absence, enveloped particles accumulated within the lumen of the ER, and no mature infectious virus was produced. Altogether, these results indicate that during a viral infection, NSP4 serves as a receptor for DLPs on the ER membrane and drives the budding of these particles into the ER lumen, while VP7 is required for removing the lipid envelope during the final step of virus morphogenesis.
Mouse Cytomegalovirus Early M112/113 Proteins Control the Repressive Effect of IE3 on the Major Immediate-Early Promoter
Authors: Tang Qiyi , Li Luge , Maul Gerd G.
Published: December 2004

The mouse cytomegalovirus major immediate-early (IE) transcript is differentially spliced to produce two IE proteins: IE1, which functions partly to maintain its own promoter, the major IE promoter (MIEP), free from repression, and IE3, which functions partly as a repressor of MIEP. Paradoxically, the site where transcription of the viral genome occurs is also the site where the greatest amounts of IE3 accumulate. This raises the question of how the repression capabilities of IE3 are controlled so soon after infection. We detected IE3, an activator of early proteins, contemporaneously with gene products of the early M112/113 locus. Both IE3 and the early M112/113 gene products colocalize and coimmunoprecipitate. Protein interaction most likely occurs between IE3 and the 87-kDa splice form of M112/113, because only the 87-kDa component coimmunoprecipitated with IE3. The complex also includes PML. Transiently expressed M112/113 can form large domains alone, even in the absence of full viral genomes or PML. Coexpression of M112/113 products and IE3 results in segregation of IE3 into newly formed M112/113-based domains. Importantly, coexpression eliminates the IE3-based repressive effect on MIEP, as determined by MIEP-driven reporter assays. The consequence of segregating IE3 into the M112/113-containing prereplication domains appears to make IE3 unavailable for binding and repressing MIEP during the earliest stages of infection. These findings establish a new feedback mechanism between IE and early proteins, a new mechanism of promoter control via segregation of the repressor, and a new function for proteins from the M112/113 locus.
The Infectivity and Lytic Activity of Minute Virus of Mice Wild-Type and Derived Vector Particles Are Strikingly Different
Authors: Lang Susanne I. , Boelz Stephanie , Stroh-Dege Alexandra Y. , Rommelaere Jean , Dinsart Christiane , Cornelis Jan J.
Published: December 2004

Gene therapy vectors have been developed from autonomous rodent parvoviruses that carry a therapeutic gene or a marker gene in place of the genes encoding the capsid proteins. These vectors are currently evaluated in preclinical experiments. The infectivity of the vector particles deriving from the fibroblastic strain of minute virus of mice (MVMp) (produced by transfection in human cells) was found to be far less (approximately 50-fold-less) infectious than that of wild-type virus particles routinely produced by infection of A9 mouse fibroblasts. Similarly, wild-type MVMp produced by transfection also had a low infectivity in mouse cells, indicating that the method and producer cells influence the infectivity of the virus produced. Interestingly, producer cells made as many full vector particles as wild-type particles, arguing against deficient packaging being responsible for the low infectivity of viruses recovered from transfected cells. The hurdle to infection with full particles produced through transfection was found to take place at an early step following entry and limiting viral DNA replication and gene expression. Infections with transfection or infection-derived virus stocks normalized for their replication ability yielded similar monomer and dimer DNA amplification and gene expression levels. Surprisingly, at equivalent replication units, the capacity of parvovirus vectors to kill tumor cells was lower than that of the parental wild-type virus produced under the same transfection conditions, suggesting that beside the viral nonstructural proteins, the capsid proteins, assembled capsids, or the corresponding coding region contribute to the lytic activity of these viruses.
Herpes Simplex Virus Type 1 gK Is Required for gB-Mediated Virus-Induced Cell Fusion, While neither gB and gK nor gB and UL20p Function Redundantly in Virion De-Envelopment
Authors: Melancon Jeffrey M. , Luna Rafael E. , Foster Timothy P. , Kousoulas Konstantin G.
Published: December 2004

Multiple amino acid changes within herpes simplex virus type 1 (HSV-1) gB and gK cause extensive virus-induced cell fusion and the formation of multinucleated cells (syncytia). Early reports established that syncytial mutations in gK could not cause cell-to-cell fusion in the absence of gB. To investigate the interdependence of gB, gK, and UL20p in virus-induced cell fusion and virion de-envelopment from perinuclear spaces as well as to compare the ultrastructural phenotypes of the different mutant viruses in a syngeneic HSV-1 (F) genetic background, gB-null, gK-null, UL20-null, gB/gK double-null, and gB/UL20 double-null viruses were constructed with the HSV-1 (F) bacterial artificial chromosome pYEBac102. The gK/gB double-null virus YEbacΔgBΔgK was used to isolate the recombinant viruses gBsyn3ΔgK and gBamb1511ΔgK, which lack the gK gene and carry the gBsyn3 or gBamb1511 syncytial mutation, respectively. Both viruses formed small nonsyncytial plaques on noncomplementing Vero cells and large syncytial plaques on gK-complementing cells, indicating that gK expression was necessary for gBsyn3- and gBamb1511-induced cell fusion. Lack of virus-induced cell fusion was not due to defects in virion egress, since recombinant viruses specifying the gBsyn3 or gKsyn20 mutation in the UL19/UL20 double-null genetic background caused extensive cell fusion on UL20-complementing cells. As expected, the gB-null virus failed to produce infectious virus, but enveloped virion particles egressed efficiently out of infected cells. The gK-null and UL20-null viruses exhibited cytoplasmic defects in virion morphogenesis like those of the corresponding HSV-1 (KOS) mutant viruses. Similarly, the gB/gK double-null and gB/UL20 double-null viruses accumulated capsids in the cytoplasm, indicating that gB, gK, and UL20p do not function redundantly in membrane fusion during virion de-envelopment at the outer nuclear lamellae.
Mutations in the RNase H Primer Grip Domain of Murine Leukemia Virus Reverse Transcriptase Decrease Efficiency and Accuracy of Plus-Strand DNA Transfer
Authors: Mbisa Jean L. , Nikolenko Galina N. , Pathak Vinay K.
Published: December 2004

The RNase H primer grip of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) contacts the DNA primer strand and positions the template strand near the RNase H active site, influencing RNase H cleavage efficiency and specificity. Sequence alignments show that 6 of the 11 residues that constitute the RNase H primer grip have functional equivalents in murine leukemia virus (MLV) RT. We previously showed that a Y586F substitution in the MLV RNase H primer grip resulted in a 17-fold increase in substitutions within 18 nucleotides of adenine-thymine tracts, which are associated with a bent DNA conformation. To further determine the effects of the MLV RNase H primer grip on replication fidelity and viral replication, we performed additional mutational analysis. Using either β-galactosidase (
lacZ
) or green fluorescent protein (
GFP
) reporter genes, we found that S557A, A558V, and Q559L substitutions resulted in statistically significant increases in viral mutation rates, ranging from 2.1- to 3.8-fold. DNA sequencing analysis of nonfluorescent
GFP
clones indicated that the mutations in RNase H primer grip significantly increased the frequency of deletions between the primer-binding site (PBS) and sequences downstream of the PBS. In addition, quantitative real-time PCR analysis of reverse transcription products revealed that the mutant RTs were substantially inefficient in plus-strand DNA transfer relative to the wild-type control. These results indicate that the MLV RNase H primer grip is an important determinant of in vivo fidelity of DNA synthesis and suggest that the mutant RT was unable to copy through the DNA-RNA junction of the minus-strand DNA and the tRNA because of its bent conformation resulting in error-prone plus-strand DNA transfer.
Expression of Cellular Oncogene Bcl-xL Prevents Coronavirus-Induced Cell Death and Converts Acute Infection to Persistent Infection in Progenitor Rat Oligodendrocytes
Authors: Liu Yin , Zhang Xuming
Published: December 2004

Murine coronavirus mouse hepatitis virus (MHV) causes persistent infection of the central nervous system (CNS) in rodents, which has been associated with demyelination. However, the precise mechanism of MHV persistence in the CNS remains elusive. Here we show that the progenitor oligodendrocytes (central glial 4 [CG-4] cells) derived from newborn rat brain were permissive to MHV infection, which resulted in cell death, although viral replication was restricted. Interestingly, treatment with fetal bovine serum or exogenous expression of cellular oncogene Bcl-xL prevented CG-4 cells from MHV-induced cell death. Significantly, overexpression of Bcl-xL alone was sufficient to convert acute to persistent, nonproductive infection in CG-4 cells. This finding indicates that intracellular factors rather than viral components play a critical role in establishing viral persistence in CNS cells. Although viral genomic RNAs continuously persisted in Bcl-xL-expressing CG-4 cells over 10 passages, infectious virus could no longer be isolated beyond 2 passages of the cell. Such a phenomenon resembles the persistent MHV infection in animal CNS. Thus, the establishment of a persistent, nonproductive infection in CG-4 cells may provide a useful in vitro model for studying viral persistence in animal CNS. The data also suggest that direct virus-host cell interaction is one of the underlying mechanisms that regulate viral persistence in CNS cells.
Short Internal Sequences Involved in Replication and Virion Accumulation in a Subviral RNA of
Turnip Crinkle Virus
Authors: Sun Xiaoping , Zhang Guohua , Simon Anne E.
Published: December 2004

cis
-acting sequences and structural elements in untranslated regions of viral genomes allow viral RNA-dependent RNA polymerases to correctly initiate and transcribe asymmetric levels of plus and minus strands during replication of plus-sense RNA viruses. Such elements include promoters, enhancers, and transcriptional repressors that may require interactions with distal RNA sequences for function. We previously determined that a non-sequence-specific hairpin (M1H) in the interior of a subviral RNA (satC) associated with
Turnip crinkle virus
is required for fitness and that its function might be to bridge flanking sequences (X. Sun and A. E. Simon, J. Virol. 77:7880-7889, 2003). To establish the importance of the flanking sequences in replication and satC-specific virion repression, segments on both sides of M1H were randomized and subjected to in vivo functional selection (in vivo SELEX). Analyses of winning (functional) sequences revealed three different conserved elements within the segments that could be specifically assigned roles in replication, virion repression, or both. One of these elements was also implicated in the molecular switch that releases the 3′ end from its interaction with the repressor hairpin H5, which is possibly involved in controlling the level of minus-strand synthesis.
Human Cytomegalovirus Tegument Protein pp71 Directs Long-Term Gene Expression from Quiescent Herpes Simplex Virus Genomes
Authors: Preston Chris M. , Nicholl Mary Jane
Published: December 2004

The human cytomegalovirus tegument protein pp71 is important for transactivation of immediate-early (IE) gene expression and for the efficient initiation of virus replication. We have analyzed the properties of pp71 by assaying its effects on gene expression from the genome of
in
1312, a herpes simplex virus type 1 (HSV-1) mutant devoid of functional VP16, ICP0, and ICP4. Upon infection of human fibroblasts,
in
1312-derived viruses are repressed and retained in a quiescent state, but the presence of pp71 prevented the quiescent state from being attained. Reporter gene cassettes cloned into the
in
1312 genome, in addition to the endogenous IE promoters, remained active for at least 12 days postinfection, and infected cells were viable and morphologically normal. Cells expressing pp71 remained responsive to the HSV-1 transactivating factors VP16 and ICP4 and to trichostatin A. The C-terminal 61 amino acids, but not the LACSD motif, were required for pp71 activity. In addition to preventing attainment of quiescence, pp71 was able to disrupt the quiescent state of
in
1312 derivatives and promote the resumption of viral gene expression after a lag of approximately 3 days. The results extend the functional analysis of pp71 and suggest a degree of similarity with the HSV-1 IE protein ICP0. The ability to provoke slow reactivation of quiescent genomes, in conjunction with cell survival, represents a novel property for a viral structural protein.
Viral Transport of DNA Damage That Mimics a Stalled Replication Fork
Authors: Jurvansuu Jaana , Raj Kenneth , Stasiak Andrzej , Beard Peter
Published: December 2004

Adeno-associated virus type 2 (AAV2) infection incites cells to arrest with 4N DNA content or die if the p53 pathway is defective. This arrest depends on AAV2 DNA, which is single stranded with inverted terminal repeats that serve as primers during viral DNA replication. Here, we show that AAV2 DNA triggers damage signaling that resembles the response to an aberrant cellular DNA replication fork. UV treatment of AAV2 enhances the G
2
arrest by generating intrastrand DNA cross-links which persist in infected cells, disrupting viral DNA replication and maintaining the viral DNA in the single-stranded form. In cells, such DNA accumulates into nuclear foci with a signaling apparatus that involves DNA polymerase delta, ATR, TopBP1, RPA, and the Rad9/Rad1/Hus1 complex but not ATM or NBS1. Focus formation and damage signaling strictly depend on ATR and Chk1 functions. Activation of the Chk1 effector kinase leads to the virus-induced G
2
arrest. AAV2 provides a novel way to study the cellular response to abnormal DNA replication without damaging cellular DNA. By using the AAV2 system, we show that in human cells activation of phosphorylation of Chk1 depends on TopBP1 and that it is a prerequisite for the appearance of DNA damage foci.
Nonhepatic Cell Lines HeLa and 293 Support Efficient Replication of the Hepatitis C Virus Genotype 2a Subgenomic Replicon
Authors: Kato Takanobu , Date Tomoko , Miyamoto Michiko , Zhao Zijiang , Mizokami Masashi , Wakita Takaji
Published: December 2004

The hepatitis C virus (HCV) genotype 2a subgenomic replicon can replicate in two human non-hepatocyte-derived cell lines, HeLa and 293, with in vitro-transcribed replicon RNA. Sequencing analysis revealed that mutations in HCV-derived regions were not essential for replication in these cells, as some clones displayed no mutations.
Evolutionary Spread and Recombination of Porcine Endogenous Retroviruses in the
Suiformes
Authors: Niebert Marcus , Tönjes Ralf R.
Published: December 2004

Different
Suiformes
with increasing phylogenetic distance to the common pig (
Sus scrofa
) were assayed for the presence of porcine endogenous retroviruses (PERV) in general (
pol
gene), while the distribution of long terminal repeat (LTR) types (with or without repeats in U3) and
env
genes (classes A, B, and C) were determined in detail. PERV was not detectable in the most distantly related species, while classes PERV-A and PERV-B are present in
Suiformes
originating in the Pliocene epoch, and class PERV-C was detectable only in
S. scrofa
and in closely related species originating in the Holocene epoch. This distribution pattern of PERV classes is in line with our previous study on the age of PERV (45) and suggests an African origin of about 7.5 million years ago (MYA) and a gradual spread of PERV through the
Suiformes
. It seems likely that PERV-C originated more recently (1.5 to 3.5 MYA) by recombination with a homologue of unknown descent, while the origin of the repeatless LTR was a separate event approximately 3.5 MYA.
Natural Killer Cells Utilize both Perforin and Gamma Interferon To Regulate Murine Cytomegalovirus Infection in the Spleen and Liver
Authors: Loh Joy , Chu Dortha T. , O'Guin Andrew K. , Yokoyama Wayne M. , Virgin Herbert W.
Published: December 2004

Natural killer (NK) cells are critical for innate regulation of the acute phase of murine cytomegalovirus (MCMV) infection and have been reported to utilize perforin (Pfp)- and gamma interferon (IFN-γ)-dependent effector mechanisms in an organ-specific manner to regulate MCMV infection in the spleen and liver. In this study, we further examined the roles of NK cells, Pfp, and IFN-γ in innate immunity to MCMV infection. With the recently described NK cell-deficient (NKD) mouse, we confirmed previous findings that NK cells, but not NKT cells, are required for control of the acute phase of MCMV infection in spleen and liver cells. Interestingly, we found that Pfp and IFN-γ are each important for regulating MCMV replication in both the spleen and the liver. Moreover, NK cells can regulate MCMV infection in the spleens and livers of Pfp−/−mice in a Pfp-independent manner and can use an IFN-γ-independent mechanism to control MCMV infection in IFN-γ−/−mice. Thus, contrary to previous reports, NK cells utilize both Pfp and IFN-γ to control MCMV infection in the spleen and liver.
Improved Enzootic Nasal Tumor Virus Pseudotype Packaging Cell Lines Reveal Virus Entry Requirements in Addition to the Primary Receptor Hyal2
Authors: Van Hoeven Neal S. , Miller A. Dusty
Published: December 2004

Enzootic nasal tumor virus (ENTV) and jaagsiekte sheep retrovirus (JSRV) are closely related retroviruses that cause epithelial cancers of the respiratory tract in sheep and goats. Both viruses use the glycosylphosphatidylinositol (GPI)-anchored cell surface protein hyaluronidase 2 (Hyal2) as a receptor for cell entry, and entry is mediated by the envelope (Env) proteins encoded by these viruses. Retroviral vectors bearing JSRV Env can transduce cells from a wide range of species, with the exception of rodent cells. Because of the low titer of vectors bearing ENTV Env, it has been difficult to determine the tropism of ENTV vectors, which appeared to transduce cells from sheep and humans only. Here we have developed high-titer ENTV packaging cells and confirm that ENTV has a restricted host range compared to that of JSRV. Most cells that are not transduced by JSRV or ENTV vectors can be made susceptible following expression of human Hyal2 on the cells. However, five rat cell lines from different rat strains and different tissues that were engineered to express human Hyal2 were still only poorly infected by ENTV vectors, even though the ENTV Env protein could bind well to human Hyal2 expressed on four of these cell lines. These results indicate the possibility of a coreceptor requirement for these viruses.
A brief history of the development of mannequin simulators for clinical education and training
Authors: Cooper J B , Taqueti V R
Published: December 2004

Simulation for medical and healthcare applications, although still in a relatively nascent stage of development, already has a history that can inform the process of further research and dissemination. The development of mannequin simulators used for education, training, and research is reviewed, tracing the motivations, evolution to commercial availability, and efforts toward assessment of efficacy of those for teaching cardiopulmonary resuscitation, cardiology skills, anaesthesia clinical skills, and crisis management. A brief overview of procedural simulators and part-task trainers is also presented, contrasting the two domains and suggesting that a thorough history of the 20+ types of simulator technologies would provide a useful overview and perspective. There has been relatively little cross fertilisation of ideas and methods between the two simulator domains. Enhanced interaction between investigators and integration of simulation technologies would be beneficial for the dissemination of the concepts and their applications.
QUANTUM COMPUTATION BASED PROBABILITY DENSITY FUNCTION ESTIMATION
Authors: BALÁZS FERENC , IMRE SÁNDOR
Published: December 2004

Signal processing techniques will lean on blind methods in the near future, where no redundant, resource allocating information will be transmitted through the channel. To achieve a proper decision, however, it is essential to know at least the probability density function (PDF), which to estimate is classically a time consumpting and/or less accurate hard task that may make decisions to fail. This paper describes the design of a quantum assisted PDF estimation method also by way of an example, which promises to achieve the exact PDF by proper setting of parameters in a very rapid way.
TESTING PRIMALITY DETERMINISTICALLY
Authors: TOFFALORI CARLO
Published: December 2004

We introduce and discuss the recent Agrawal–Kayal–Saxena deterministic algorithm solving primality in polynomial time.
TRANSFORMATIONS IN WORLD POLITICS: The Intellectual Contributions of Ernst B. Haas
Authors: Gerard Ruggie John , Katzenstein Peter J. , Keohane Robert O. , Schmitter Philippe C.
Published: December 2004

▪ Abstract  For half a century, Ernst B. Haas was an extraordinarily prolific contributor to theoretical debates in international relations. His work focused on the question of continuity and transformation in the system of states. His substantive writings are extremely diverse and can be difficult, so no overall appreciation has ever been attempted. This essay pulls together the major strands of Haas' theoretical work into a coherent whole and seeks to make it accessible to the broadest possible audience of IR scholars. The first section locates Haas in the overall theoretical milieu in which his thinking evolved, and it identifies some core intellectual choices he made. The next three sections summarize Haas' main theoretical contributions to the fields of European integration, the study of change at the level of the world polity, and nationalism.
Chemoreflex and metaboreflex control during static hypoxic exercise
Authors: Houssiere Anne , Najem Boutaina , Ciarka Agniezka , Velez-Roa Sonia , Naeije Robert , van de Borne Philippe
Published: December 2004

To investigate the effects of muscle metaboreceptor activation during hypoxic static exercise, we recorded muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, ventilation, and blood lactate in 13 healthy subjects (22 ± 2 yr) during 3 min of three randomized interventions: isocapnic hypoxia (10% O2) (chemoreflex activation), isometric handgrip exercise in normoxia (metaboreflex activation), and isometric handgrip exercise during isocapnic hypoxia (concomitant metaboreflex and chemoreflex activation). Each intervention was followed by a forearm circulatory arrest to allow persistent metaboreflex activation in the absence of exercise and chemoreflex activation. Handgrip increased blood pressure, MSNA, heart rate, ventilation, and lactate (all P < 0.001). Hypoxia without handgrip increased MSNA, heart rate, and ventilation (all P < 0.001), but it did not change blood pressure and lactate. Handgrip enhanced blood pressure, heart rate, MSNA, and ventilation responses to hypoxia (all P < 0.05). During circulatory arrest after handgrip in hypoxia, heart rate returned promptly to baseline values, whereas ventilation decreased but remained elevated ( P < 0.05). In contrast, MSNA, blood pressure, and lactate returned to baseline values during circulatory arrest after hypoxia without exercise but remained markedly increased after handgrip in hypoxia ( P < 0.05). We conclude that metaboreceptors and chemoreceptors exert differential effects on the cardiorespiratory and sympathetic responses during exercise in hypoxia.
Salinity acclimation affects the somatotropic axis in rainbow trout
Authors: Shepherd Brian S. , Drennon Katherine , Johnson Jaime , Nichols Joel W. , Playle Richard C. , Singer Thomas D. , Vijayan Mathilakath M.
Published: December 2004

In this study, we set out to examine the role of the somatotropic axis in the ion-regulation process in rainbow trout. Specifically, our objective was to examine whether plasma insulin-like growth factor-binding proteins (IGFBPs) are modulated by gradual salinity exposure. To this end, freshwater (FW)-adapted rainbow trout were subjected to gradual salinity increases, up to 66% seawater, over a period of 5 days. During this acclimation process, minimal elevations in plasma Ca2+ and Cl− were seen in the salinity-acclimated groups compared with FW controls. There were no changes in plasma Na+ levels, and only a minor transient change in plasma cortisol levels was seen with salinity exposure. The salinity challenged animals responded with elevations in plasma growth hormone (GH) and IGF-I levels and gill Na+-K+-ATPase activity. We identified IGFBPs of 21, 32, 42, and 50 kDa in size in the plasma of these animals, and they were consistently higher with salinity. Despite the overall increase in IGFBPs with salinity, transient changes in individual BPs over the 5-day period were noted in the FW and salinity-exposed fish. Specifically, the transient changes in plasma levels of the 21-, 42-, and 50-kDa IGFBPs were different between the FW and salinity groups, while the 32-kDa IGFBP showed a similar trend (increases with sampling time) in both groups. Considered together, the elevated plasma IGFBPs suggest a key role for these binding proteins in the regulation of IGF-I during salinity acclimation in salmonids.
Activation of Postsynaptic Ca2+Stores Modulates Glutamate Receptor Cycling in Hippocampal Neurons
Authors: Maher Brady J. , MacKinnon Roger L. , Bai Jihong , Chapman Edwin R. , Kelly Paul T.
Published: December 2004

We show that activation of postsynaptic inositol 1,4,5-tris-phosphate receptors (IP3Rs) with the IP3R agonist adenophostin A (AdA) produces large increases in AMPA receptor (AMPAR) excitatory postsynaptic current (EPSC) amplitudes at hippocampal CA1 synapses. Co-perfusion of the Ca2+chelator bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid strongly inhibited AdA-enhanced increases in EPSC amplitudes. We examined the role of AMPAR insertion/anchoring in basal synaptic transmission. Perfusion of an inhibitor of synaptotagmin-soluble n-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor SNARE-mediated exocytosis depressed basal EPSC amplitudes, whereas a peptide that inhibits GluR2/3 interactions with postsynaptic density-95 (PDZ) domain proteins glutamate receptor interacting protein (GRIP)/protein interacting with C-kinase-1 (PICK1) enhanced basal synaptic transmission. These results suggest that constitutive trafficking and anchoring of AMPARs help maintain basal synaptic transmission. The regulation of postsynaptic AMPAR trafficking involves synaptotagmin-SNARE-mediated vesicle exocytosis and interactions between AMPARs and the PDZ domains in GRIP/PICK1. We show that inhibitors of synaptotagmin-SNARE-mediated exocytosis, or interactions between AMPARs and GRIP/PICK1, attenuated AdA-enhanced increases in EPSC amplitudes. These results suggest that IP3R-mediated Ca2+release can enhance AMPAR EPSC amplitudes through mechanisms that involve AMPAR-PDZ interactions and/or synaptotagmin-SNARE-mediated receptor trafficking.
Spinal Micturition Reflex Mediated by Afferents in the Deep Perineal Nerve
Authors: Boggs Joseph W. , Wenzel Brian J. , Gustafson Kenneth J. , Grill Warren M.
Published: December 2004

Reflexes mediated by urethral sensory pathways are integral to urinary function. This study investigated the changes in bladder pressure and urethral sphincter activity resulting from electrical stimulation of afferents in the deep perineal nerve (DP), which innervates the urethra and surrounding muscles, before and after acute spinal cord transection (SCT) in cats anesthetized with α-chloralose monitored by blood pressure and heart rate. DP stimulation elicited bladder contractions before and after SCT but only if the bladder contained a sufficient volume of fluid (78% of the volume needed to cause distention-evoked reflex contractions). The volume dependency was mediated by a neuronal mechanism in the lumbosacral spinal cord and was not attributable to length-tension properties of the detrusor muscle. Stimulation at 2–40 Hz initiated bladder contractions, but 20–40 Hz was more effective than lower frequencies in evoking and sustaining bladder contractions for the duration of the stimulus train. Decreases in urethral sphincter activity occurred during sustained bladder contractions evoked by 20- to 40-Hz stimulation before and within 16 h after SCT. After SCT, average bladder pressure increases evoked by DP stimulation were smaller than those evoked before SCT, but in some animals, bladder pressures elicited by DP stimulation continued to increase as time after SCT increased and reached pretransection amplitudes at 8–16 h posttransection. These data confirm the presence of a spinal circuit that can mediate coordinated bladder–sphincter responses and show that afferents from the DP can activate this circuit under appropriate conditions.
The UNDESA/IASIA initiative for public sector leadership capacity enhancement
Authors: Bertucci Guido
Published: December 2004

The United Nations Millennium Declaration lays out an important development agenda for the next 15 years. Governmental leaders in many countries must have the skills and knowledge necessary to provide the kind of leadership necessary for successfully implementing the Declaration and achieving the Millennium Development Goals. The joint UNDESA/IASIA initiative is a four-year effort to improve the quality of education and training in public administration worldwide but with particular emphasis on Africa, Asia, Central and Eastern Europe, Latin America and the Middle East. One track will be to focus on the education and training needs of the current generation of government leaders; the second on the next generation of leaders. The initiative will assist top-level government leaders to adapt effectively to the many complex problems facing contemporary government in a globalizing world.
Integration of Immigrants
Authors: Delander Lennart , Hammarstedt Mats , MÅnsson Jonas , Nyberg Erik
Published: December 2004

In this article, the authors evaluate a Swedish pilot scheme that targeted immigrants with weak Swedish-language skills registered as unemployed at public employment offices. By sandwiching work-oriented language teaching and practical workplace training, the project aimed at enhancing the employability of project participants but also at alerting them to and preparing them for available training and further education opportunities. For the evaluation, a comparison group of nonparticipants was selected using a propensity score methodology. The results show that participation in the pilot scheme project resulted in much speedier transfers from open unemployment to employment, training, and education.
Motivations Underlying Career Decision-Making Activities: The Career Decision-Making Autonomy Scale (CDMAS)
Authors: Guay Frédéric
Published: December 2004

The purpose of the present research was to develop and validate a measure of motivation toward career decision-making activities, the Career Decision-Making Autonomy Scale (CDMAS). The CDMAS is designed to assess the constructs of intrinsic motivation, identified regulation, introjected regulation, and external regulation. A longitudinal study was used to develop and validate the CDMAS. Overall, results show that the CDMAS is composed of four internally consistent factors. The construct validity of the scale is also supported by (a) a quasi-simplex pattern of correlations, (b) correlations with personality variables and vocational constructs, and (c) convergent and divergent correlations. In sum, the CDMAS represents a valid self-report measure of intrinsic motivation, identified regulation, introjected regulation, and external regulation toward career decision-making activities.
The effect of inflammation on the generation of plasma DNA from dead and dying cells in the peritoneum
Authors: Jiang Ning , Pisetsky David S
Published: December 2004

To assess the effects of inflammation on the generation of circulating DNA from dead and dying cells, plasma DNA levels were determined in BALB/c mice, administered apoptotic or necrotic Jurkat cells following induction of peritonitis by treatment with thioglycollate (TG), peptone (PT), or sodium periodate (NaIO4). In mice receiving TG or NaIO4, plasma DNA levels following intraperitoneal administration of Jurkat cells were significantly reduced compared with controls, whereas they were not affected in mice receiving PT. To determine the basis of these differences, the cellular composition of peritoneal fluids prior to the administration of the dead cells was analyzed. Among agents tested, TG administration led to the largest increase in cells, both neutrophils and monocytes. As shown by flow cytometry, the exudates contained apoptotic neutrophils and macrophages, with the highest levels in the TG-induced exudates. Analysis of DNA and caspase 3 in the fluids also showed differences. TG exudates showed increases in DNA and capase 3, while NaIO4-induced exudates had an increase only in DNA. Fluid from PT-treated mice did not have increases in DNA or caspase 3. Together, these results indicate that prior inflammation can affect the generation of blood DNA from apoptotic or necrotic cells, although this effect may vary depending on the composition of the exudates with respect to cells as well as DNA.
Slc11a1-mediated resistance toSalmonella entericaserovar Typhimurium andLeishmania donovaniinfections does not require functional inducible nitric oxide synthase or phagocyte oxidase activity
Authors: White Jacqueline K , Mastroeni Pietro , Popoff Jean-François , Evans Carlton A W , Blackwell Jenefer M
Published: December 2004

Solute carrier family 11a member 1 (Slc11a1; formerly natural resistance-associated macrophage protein 1) encodes a late endosomal/lysosomal protein/divalent cation transporter, which regulates iron homeostasis in macrophages. During macrophage activation, Slc11a1 exerts pleiotropic effects on gene regulation and function, including generation of nitric oxide (NO) via inducible NO synthase (iNOS; encoded by Nos2A) and of reactive oxygen intermediates (ROI) via the phagocyte oxidase complex. As NO and ROI have potent antimicrobial activity in macrophages, it was assumed that their activities would contribute to Slc11a1-regulated innate resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani. By intercrossing mice with gene disruptions at Nos2A and Cybb (encoding gp91phox, the heavy chain subunit of cytochrome b-245 and an essential component of phagocyte NADPH oxidase) onto equivalent Slc11a1 wild-type and mutant genetic backgrounds, we demonstrate that neither iNOS nor gp91phox activity is required for Slc11a1-mediated innate resistance to either infection. Functional gp91phox and iNOS are required to control S. enterica serovar Typhimurium in non-Slc11a1-regulated phases of infection. For L. donovani, an organ-specific requirement for iNOS to clear parasites from the spleen was observed at 50 days post-infection, but neither iNOS nor gp91phox influenced late-phase infection in the liver. This contrasted with Leishmania major infection, which caused rapid lesion growth and death in iNOS knockout mice and some exacerbation of disease with gp91phox deficiency. This highlights the adaptive differences in tissue and cellular tropisms between L. donovani and L. major and the different genes and mechanisms that regulate visceral versus cutaneous forms of the disease.
Tropical Diseases, Pathogens, and Vectors Biodiversity in Developing Countries: Need for Development of Genomics and Bioinformatics Approaches
Authors: DÁVILA ALBERTO M.R. , STEINDEL MÁRIO , GRISARD EDMUNDO C.
Published: December 2004

Abstract: The world's biodiversity, including many infectious, parasitic disease agents and their vectors whose impact on both human and animal health is significant, is largely retained in the developing countries of the tropics. Owing to the number of species involved and the relatively low‐level exploration of pathogens and vectors biodiversity, several organisms are still waiting to be discovered and consequently explored in terms of genomics. Although some parasitic species of humans and animals have been studied through genomics and bioinformatics approaches, a significant number of relevant species are still to be addressed. Through the use of modern technologies, such as genomics and bioinformatics, for assessment of biodiversity and targeting tropical diseases, other relevant advantages of these initiatives for developing countries would be technology transfer and capacity building. Consequently, these initiatives could be critical to the development of the respective countries. Moreover, intra‐ and interhemispheric scientific collaboration should be encouraged and supported to increase the chances for success. In Brazil, the Ministry of Science and Technology has stepped forward to further such initiatives, co‐supporting collaborative genomics and bioinformatics projects. The need for the establishment of working groups on genomics and bioinformatics in developing countries as well as the improvement and strengthening of collaborative research projects between developed and developing countries is discussed from our point of view. As these discussions remain open to debate, we encourage colleagues to promote further discussion on the subject.