bluuebunny/crossref_metadata_2025 huggingface dataset:
Electoral salience and the costs of voting at national, sub‐national and supra‐national elections in the UK: a case study of Brent, UK
Authors: Orford Scott , Rallings Colin , Thrasher Michael , Borisyuk Galina
Published: December 2008

This paper considers the impact of distance to polling station upon electoral turnout. Using polling station level data from a London borough, it examines three types of election – parliamentary, European and local elections – over a twenty year period. The UK is notable among western liberal democracies for its relatively large turnout gap – the percentage point difference between turnout at elections for the Westminster parliament compared to that for other institutions, including local councils and the supra‐national European parliament. This research considers the hypothesis that in high information, high salience elections for the national parliament the costs of voting associated with travelling to a polling station to vote in person are perceived as either low or insignificant but that in low information, low salience elections, those costs are perceived as higher and may act as a deterrent upon voting. A series of multi‐level models consider the relationships between the dependent variable, percentage turnout, and a range of independent variables, including socio‐economic characteristics, marginality as well as the spatial context. We show that there is indeed a relationship between distance and voter turnout, and other spatial and contextual variables, which are stronger for the lower salience European and local elections than for the higher salience national elections. Hence we conclude that the local geography of the polling station can have a significant impact on voter turnout and that there should be a more strategic approach to the siting of polling stations.
Systems biology of innate immunity
Authors: Zak Daniel E. , Aderem Alan
Published: December 2008

Summary:  Systems biology is the comprehensive and quantitative analysis of the interactions between all of the components of biological systems over time. Systems biology involves an iterative cycle, in which emerging biological problems drive the development of new technologies and computational tools. These technologies and tools then open new frontiers that revolutionize biology. Innate immunity is well suited for systems analysis, because the relevant cells can be isolated in various functional states and their interactions can be reconstituted in a biologically meaningful manner. Application of the tools of systems biology to the innate immune system will enable comprehensive analysis of the complex interactions that maintain the difficult balance between host defense and inflammatory disease. In this review, we discuss innate immunity in the context of the systems biology concepts, emergence, robustness, and modularity, and we describe emerging technologies we are applying in our systems‐level analyses. These technologies include genomics, proteomics, computational analysis, forward genetics screens, and analyses that link human genetic polymorphisms to disease resistance.
Functional evolution of the TICAM‐1 pathway for extrinsic RNA sensing
Authors: Seya Tsukasa , Matsumoto Misako , Ebihara Takashi , Oshiumi Hiroyuki
Published: December 2008

Summary:  The type I interferon (IFN) is a host defense factor against microbial pathogens in vertebrates. In mammals, retinoic acid‐inducible gene I (RIG‐I) and melanoma differentiation‐associated gene 5 (MDA5) in the cytoplasm are regarded as sensors for double‐stranded RNA (dsRNA) and trigger IFN regulatory factor‐3 (IRF‐3) activation followed by type I IFN induction through the mitochondrial antiviral signaling (MAVS) adapter. This intrinsic pathway appears to link the main protective responses against RNA virus infection in mammals. On the other hand, human Toll‐like receptor 3 (TLR3) is localized in the endosomal membrane or cell surface and signals the presence of extrinsic dsRNA. In response to RNA stimulation, TLR3 recruits the Toll‐interleukin 1 receptor domain (TIR)‐containing adapter molecule 1 (TICAM‐1) adapter and induces IRF‐3 activation followed by IFN‐β promoter activation. Human TLR3 is localized limitedly extent in myeloid dendritic cells, fibroblasts, and epithelial cells. The TICAM‐1 and cytoplasmic MAVS pathways converge at the IRF‐3‐activating kinase in human cells. The reason for the involvement of this extrinsic mode of IFN‐inducing pathways in the dsRNA response remains unknown. In fish, two TLRs, i.e. endoplasmic TLR3 and cell surface TLR22, participate in teleost IFN production without the activation of IRF‐3. TLR22 is distinct from mammalian TLR3 in terms of cellular localization, ligand selection, and tissue distribution. TLR22 may be a functional substitute for human cell surface TLR3 and may serve as a surveillance molecule for detecting dsRNA virus infection and alerting the immune system for antiviral protection in fish. In this review, we discuss the fundamentals of the extrinsic dsRNA recognition system, which has evolved to induce cellular effectors to cope with dsRNA virus infection across different vertebrate species.
Pattern recognition receptors and control of adaptive immunity
Authors: Palm Noah W. , Medzhitov Ruslan
Published: December 2008

Summary:  The mammalian immune system effectively fights infection through the cooperation of two connected systems, innate and adaptive immunity. Germ‐line encoded pattern recognition receptors (PRRs) of the innate immune system sense the presence of infection and activate innate immunity. Some PRRs also induce signals that lead to the activation of adaptive immunity. Adaptive immunity is controlled by PRR‐induced signals at multiple checkpoints dictating the initiation of a response, the type of response, the magnitude and duration of the response, and the production of long‐term memory. PRRs thus instruct the adaptive immune system on when and how to best respond to a particular infection. In this review, we discuss the roles of various PRRs in control of adaptive immunity.
Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases
Authors: Beutler Bruce
Published: December 2008

Summary:  The molecular apparatus that protects us against infection can also injure us by causing autoimmune or autoinflammatory disease. It now seems that at times, defects within the sensing arm of innate immunity contribute to diseases of this type. The initiation of an immune response is often microbe dependent and, in many cases, Toll‐like receptor (TLR) dependent. Positive feedback loops triggering immune activation may occur when TLR signaling pathways stimulate host cells in an unchecked manner. Or, immune activation may persist because of failure to eradicate an inciting infection. Or on occasion, endogenous DNA may trigger specific immune responses that beget further responses in a TLR‐dependent autoamplification loop. Specific biochemical defects that cause loop‐related autoimmunity have been revealed by random germline mutagenesis and by gene targeting. We have also developed some insight into critical points at which feedback loops can be interrupted.
Crosstalk between components of the innate immune system: promoting anti‐microbial defenses and avoiding immunopathologies
Authors: Crozat Karine , Vivier Eric , Dalod Marc
Published: December 2008

Summary:  Because it reaches full functional efficacy rapidly upon encounter with a pathogen, the innate immune system is considered as the first line of defense against infections. The sensing of microbes or of transformed or infected cells, through innate immune recognition receptors (referred to as activating I2R2), initiates pro‐inflammatory responses and innate immune effector functions. Other I2R2 with inhibitory properties bind self‐ligands constitutively expressed in host. However, this dichotomy in the recognition of foreign or induced self versus constitutive self by I2R2 is not always respected in certain non‐infectious conditions reminiscent of immunopathologies. In this review, we discuss that immune mechanisms have evolved to avoid inappropriate inflammatory disorders in individuals. Molecular crossregulation exists between components of I2R2 signaling pathways, and intricate interactions between cells from both innate and adaptive immune systems set the bases of controlled immune responses. We also pinpoint that, like T or B cells, some cells of the innate immune system must go through education processes to prevent autoreactivity. In addition, we illustrate how gene expression profiling of immune cell types is a useful tool to find functional homologies between cell subsets of different species and to speculate about unidentified functions of these cells in the responses to pathogen infections.
Innate immunity to virus infection
Authors: Takeuchi Osamu , Akira Shizuo
Published: December 2008

Summary:  The innate immune system is essential for the initial detection of invading viruses and subsequent activation of adaptive immunity. Three classes of receptors, designated retinoic acid‐inducible gene I (RIG‐I)‐like receptors (RLRs), Toll‐like receptors (TLRs), and nucleotide oligomerization domain (NOD)‐like receptors (NLRs), sense viral components, such as double‐stranded RNA (dsRNA), single‐stranded RNA, and DNA. RLRs and TLRs play essential roles in the production of type I interferons (IFNs) and proinflammatory cytokines in cell type‐specific manners. While the RLRs play essential roles in the recognition of RNA viruses in various cells, plasmacytoid dendritic cells utilize TLRs for detecting virus invasion. NLRs play a role in the production of mature interleukin‐1β to dsRNA stimulation. Activation of innate immune cells is critical for mounting adaptive immune responses. In this review, we discuss recent advances in our understanding of the mechanisms of viral RNA recognition by these different types of receptors and its relation to acquired immune responses.
Adult–Adolescent Interaction and Adolescents’ Brain Development: Integrating Pragmatism/Interactionism and Neuroscience to Develop a Platform for Research on Adolescents’ Life Regulation
Authors: Moula Alireza , Timpka Toomas , Puddephatt Antony J.
Published: December 2008

The aim of this paper is to outline a platform for research on adolescents’ life regulation. Adolescents’ brain development is described with the help of neuroscience and integrated with pragmatist and symbolic interactionist insights about how adolescents can learn to control their impulses and act thoughtfully. The foundation for the analysis is found in American pragmatism, where a biopsychosocial perspective is built on the understanding that the developed human brain is the essential precondition of a complex and civilized society. Today's interactionists, and in general, the majority of sociologists, show little interest in brain development and function. However, there is an opportunity for sociologists and neuroscientists to collaborate in order to better understand how the brain develops in relation to biological development and social experience.
Wildlife decline in Cambodia, 1953–2005: exploring the legacy of armed conflict
Authors: Loucks Colby , Mascia Michael B. , Maxwell Andy , Huy Keavuth , Duong Kong , Chea Nareth , Long Barney , Cox Nick , Seng Teak
Published: December 2008

Armed conflict is a social phenomenon often detrimental to wildlife and wildlife habitat, but the legacy of armed conflict for wildlife in post‐conflict settings remains unexplored. We explore the effects of armed conflict on wildlife in eastern Cambodia, particularly the relationships among wildlife abundance, habitat loss, technological change, trade, governance, and local livelihood strategies. Based on ordinal‐scale measures, both relative wildlife abundance and species richness declined from pre‐1953 to 2005, with the sharpest declines occurring during the 1970s. These declines are consistent with three synergistic social processes: proliferation of guns; emergence of wildlife trade for external markets; and government policies mandating hunting by local villagers. Armed conflict officially ceased in 1991, but conflict‐induced changes in livelihoods and continuing non‐local demand for wildlife have fostered further wildlife declines. Our study demonstrates that the legacy of conflict for wildlife can be profound and destructive. To address post‐conflict challenges more effectively, conservation must be integrated within broader peace‐building processes, including disarmament, demobilization, and reintegration of combatants.
Glutathione, Cysteine, and Ascorbate Concentrations in Clinically Ill Dogs and Cats
Authors: Viviano K.R. , Lavergne S.N. , Goodman L. , VanderWielen B. , Grundahl L. , Padilla M. , Trepanier L.A.
Published: December 2008

Background: Oxidative stress plays a role in the pathogenesis of many systemic diseases. Hospitalized human patients are glutathione, cysteine, and ascorbate deficient, and antioxidant depletion has been correlated with poor clinical outcome. To date little is known about antioxidant concentrations in hospitalized veterinary patients. The purpose of this study was to determine whether ascorbate, cysteine, or glutathione depletion is present in ill dogs and cats compared with healthy controls.

Hypothesis: Clinically ill dogs and cats would be antioxidant depleted, and depletion would correlate with illness severity and clinical outcome.

Animals: Clinically ill client‐owned dogs (n = 61) and cats (n = 37), healthy control dogs (n = 37) and cats (n = 33).

Methods: Prospective, observational, case control study. Erythrocyte reduced glutathione, plasma cysteine, and plasma ascorbate were quantified using high‐performance liquid chromatography.

Results: Clinically ill dogs had significantly lower erythrocyte glutathione concentrations (1.22 mM, range 0.55–3.61) compared with controls (1.91 mM, range 0.87–3.51; P = .0004), and glutathione depletion correlated with both illness severity (P = .038) and mortality (P = .010). Cats had higher ascorbate concentrations when ill (10.65 μM, range 1.13–25.26) compared with controls (3.68 μM, range 0.36–13.57; P = .0009).

Conclusions and Clinical Importance: Clinically ill dogs had decreased erythrocyte glutathione concentrations, which could be a marker of illness severity and prognostic of a poor outcome. Clinically ill cats had an unexpectedly high plasma ascorbate, which could represent a unique species response to oxidative stress.
Foal Monocyte-Derived Dendritic Cells Become Activated uponRhodococcus equiInfection
Authors: Flaminio M. Julia B. F. , Nydam Daryl V. , Marquis Hélène , Matychak Mary Beth , Giguère Steeve
Published: December 2008

Susceptibility of foals toRhodococcus equipneumonia is exclusive to the first few months of life. The objective of this study was to investigate the immediate immunologic response of foal and adult horse antigen-presenting cells (APCs) upon infection withR. equi. We measured the activation of the antigen-presenting major histocompatibility complex (MHC) class II molecule, costimulatory molecules CD40 and CD86, the cytokine interleukin-12 (IL-12), and the transcriptional factor interferon regulatory factor 1 (IRF-1) in monocyte-derived macrophages (mMOs) and dendritic cells (mDCs) of adult horses and foals of different ages (from birth to 3 months of age) infected with virulentR. equior its avirulent, plasmid-cured derivative. Infection with virulent or avirulentR. equiinduced (P≤ 0.01) the expression of IL-12p35 and IL-12p40 mRNAs in foal mMOs and mDCs at different ages. This response was likely mediated by the higher (P= 0.008) expression of IRF-1 in foal mDCs at birth than in adult horse mDCs.R. equiinfection promoted comparable expression of costimulatory molecules CD86 and CD40 in foal and adult horse cells. The cytokine and costimulatory response by foal mDCs was not accompanied by robust MHC class II molecule expression. These data suggest that foal APCs detect the presence ofR. equiand respond with the expression of the Th1-inducing cytokine IL-12. Nevertheless, there seems to be a limitation to MHC class II molecule expression which we hypothesize may compromise the efficient priming of naïve effector cells in early life.
Streptococcus suisBacterin and Subunit Vaccine Immunogenicities and Protective Efficacies against Serotypes 2 and 9
Authors: Baums Christoph Georg , Kock Christoph , Beineke Andreas , Bennecke Katharina , Goethe Ralph , Schröder Charlotte , Waldmann Karl-Heinz , Valentin-Weigand Peter
Published: December 2008

Streptococcus suiscauses numerous diseases in pigs, most importantly, meningitis, arthritis, septicemia, and bronchopneumonia. One of the major problems in modern swine production is the lack of a vaccine protecting against more than oneS. suisserotype. The objective of this study was to determine the protective efficacy of a serotype 2 murein-associated protein (MAP) fraction subunit vaccine in comparison to that of a bacterin against experimental challenge with serotype 2 (containing muramidase-released protein [MRP], extracellular factor, and suilysin [SLY]) and serotype 9 (containing MRP variant MRP* and SLY) strains. MAP was shown to include different surface-associated proteins, such as the MRP and surface antigen one (SAO) expressed by both pathotypes used for challenge. The results of this study demonstrated that the serotype 2 bacterin induced protective immunity against homologous challenge. In contrast, the protective efficacy of the MAP subunit vaccine was low, though MAP immunization resulted in high serum immunoglobulin G2 titers against MRP and SAO. Importantly, immunization with bacterin but not with MAP induced opsonizing antibody titers against the serotype 2 strain, and these antibody titers were found to correlate with protection. However, after absorption with a nonencapsulated isogenic mutant, the sera from bacterin-immunized piglets failed to facilitate neutrophil killing, indicating that antibodies directed against capsule may not have been essential for opsonophagocytosis. Furthermore, induction of opsonizing antibodies against serotype 9 was not detectable in the group receiving bacterin or in the group receiving the MAP vaccine. In agreement, protection against the heterologous serotype 9 strain was low in both groups. Thus, identification of an antigen protecting against these two importantS. suispathotypes remains an important goal of future studies.
Epidemiological Screening for Hepatitis E Virus in Bile Specimens from Livestock in Northwest China
Authors: Shao Zhong-jun , Li Jing-hua , Zheng Ying-jie , Zhang Jing-xia , Ma Yong-hong , Ma Wen-tao , Jiang Qing-wu , Dang Rong-li
Published: December 2008

Hepatitis E has been hypothesized as a zoonosis. However, there is no definite conclusion about which animal species contribute to hepatitis E virus (HEV) infection in humans. In this study, HEV RNA was detected only in swine bile specimens and not in bile specimens collected from cattle, goats, or dogs. We postulate that swine are the main animal reservoir for HEV.
Development and Evaluation of a Real-Time Reverse Transcription-Loop-Mediated Isothermal Amplification Assay for Rapid Detection of Rift Valley Fever Virus in Clinical Specimens
Authors: Le Roux C. A. , Kubo T. , Grobbelaar A. A. , van Vuren P. Jansen , Weyer J. , Nel L. H. , Swanepoel R. , Morita K. , Paweska J. T.
Published: December 2008

This paper reports on the development and validation of a real-time reverse transcription-loop-mediated isothermal amplification assay (RT-LAMP) targeting the genomic large RNA segment of Rift Valley fever virus (RVFV). The set of six designed RT-LAMP primers identified strains of RVFV isolated in geographically distinct areas over a period of 50 years; there was no cross-reactivity with other genetically related and unrelated arboviruses. When testing serial sera and plasma from sheep experimentally infected with wild-type RVFV, there was 100% agreement between results of the RT-LAMP, a TaqMan-based real-time PCR, and virus isolation. Similarly, the assay had very high levels of diagnostic sensitivity and specificity when testing various clinical specimens from humans and animals naturally infected with the virus during recent outbreaks of the disease in Africa. The detection of specific viral genome targets in positive clinical specimens was achieved in less than 30 min. As a highly accurate, rapid, and very simple nucleic acid detection format, the RT-LAMP has the potential to be used in less-well-equipped laboratories in Africa and as a portable device during RVF outbreaks in remote areas, and it can be a valuable tool for the differential diagnosis of viral hemorrhagic fevers.
Utilization of Microsatellite Polymorphism for Differentiating Herpes Simplex Virus Type 1 Strains
Authors: Deback C. , Boutolleau D. , Depienne C. , Luyt C. E. , Bonnafous P. , Gautheret-Dejean A. , Garrigue I. , Agut H.
Published: December 2008

The herpes simplex virus type 1 (HSV-1) genome is a linear double-stranded DNA of 152 kpb. It is divided into long and short regions of unique sequences termed U
L
and U
S
, respectively, and these are flanked by regions of inverted internal and terminal repeats. Microsatellites are short tandem repeats of 1- to 6-nucleotide motifs; they are often highly variable and polymorphic within the genome, which raises the question of whether they may be used as molecular markers for the precise differentiation of HSV-1 strains. In this study, 79 different microsatellites (mono-, di-, and trinucleotide repeats) in the HSV-1 complete genome were identified by in silico analysis. Among those microsatellites, 45 were found to be distributed in intergenic or noncoding inverted repeat regions, while 34 were in open reading frames. Length polymorphism analysis of the PCR products was used to investigate a set of 12 distinct HSV-1 strains and allowed the identification of 23 polymorphic and 6 monomorphic microsatellites, including two polymorphic trinucleotide repeats (CGT and GGA) within the UL46 and US4 genes, respectively. A multiplex PCR method that amplified 10 polymorphic microsatellites was then developed for the rapid and accurate genetic characterization of HSV-1 strains. Each HSV-1 strain was characterized by its own microsatellite haplotype, which proved to be stable over time in cell culture. This relevant innovative tool was successfully applied both to confirm the close relationship between sequential HSV-1 isolates collected from patients with multiple recurrent infections and to investigate putative nosocomial infections.
Isolation and Characterization of a New Fungal Species,
Chrysosporium ophiodiicola
, from a Mycotic Granuloma of a Black Rat Snake (
Elaphe obsoleta obsoleta
)
Authors: Rajeev S. , Sutton D. A. , Wickes B. L. , Miller D. L. , Giri D. , Van Meter M. , Thompson E. H. , Rinaldi M. G. , Romanelli A. M. , Cano J. F. , Guarro J.
Published: December 2008

Isolation and characterization of the new species
Chrysosporium ophiodiicola
from a mycotic granuloma of a black rat snake (
Elaphe obsoleta obsoleta
) are reported. Analysis of the sequences of different fragments of the ribosomal genes demonstrated that this species belongs to the Onygenales and that this species is genetically different from other morphologically similar species of
Chrysosporium
. This new species is unique in having both narrow and cylindrical-to-slightly clavate conidia and a strong, pungent odor.
Reovirus μ2 Protein Inhibits Interferon Signaling through a Novel Mechanism Involving Nuclear Accumulation of Interferon Regulatory Factor 9
Authors: Zurney Jennifer , Kobayashi Takeshi , Holm Geoffrey H. , Dermody Terence S. , Sherry Barbara
Published: December 2008

The secreted cytokine alpha/beta interferon (IFN-α/β) binds its receptor to activate the Jak-STAT signal transduction pathway, leading to formation of the heterotrimeric IFN-stimulated gene factor 3 (ISGF3) transcription complex for induction of IFN-stimulated genes (ISGs) and establishment of an antiviral state. Many viruses have evolved countermeasures to inhibit the IFN pathway, thereby subverting the innate antiviral response. Here, we demonstrate that the mildly myocarditic reovirus type 1 Lang (T1L), but not the nonmyocarditic reovirus type 3 Dearing, represses IFN induction of a subset of ISGs and that this repressor function segregates with the T1L M1 gene. Concordantly, the T1L M1 gene product, μ2, dramatically inhibits IFN-β-induced reporter gene expression. Surprisingly, T1L infection does not degrade components of the ISGF3 complex or interfere with STAT1 or STAT2 nuclear translocation as has been observed for other viruses. Instead, infection with T1L or reassortant or recombinant viruses containing the T1L M1 gene results in accumulation of interferon regulatory factor 9 (IRF9) in the nucleus. This effect has not been previously described for any virus and suggests that μ2 modulates IRF9 interactions with STATs for both ISGF3 function and nuclear export. The M1 gene is a determinant of virus strain-specific differences in the IFN response, which are linked to virus strain-specific differences in induction of murine myocarditis. We find that virus-induced myocarditis is associated with repression of IFN function, providing new insights into the pathophysiology of this disease. Together, these data provide the first report of an increase in IRF9 nuclear accumulation associated with viral subversion of the IFN response and couple virus strain-specific differences in IFN antagonism to the pathogenesis of viral myocarditis.
Gag p27-Specific B- and T-Cell Responses in Simian Immunodeficiency Virus SIVagm-Infected African Green Monkeys
Authors: Lozano Reina José-Manuel , Favre David , Kasakow Zeljka , Mayau Véronique , Nugeyre Marie-Thérèse , Ka Thierno , Faye Abdourahmane , Miller Christopher J. , Scott-Algara Daniel , McCune Joseph M. , Barré-Sinoussi Françoise , Diop Ousmane M. , Müller-Trutwin Michaela C.
Published: December 2008

Nonpathogenic simian immunodeficiency virus SIVagm infection of African green monkeys (AGMs) is characterized by the absence of a robust antibody response against Gag p27. To determine if this is accompanied by a selective loss of T-cell responses to Gag p27, we studied CD4
+
and CD8
+
T-cell responses against Gag p27 and other SIVagm antigens in the peripheral blood and lymph nodes of acutely and chronically infected AGMs. Our data show that AGMs can mount a T-cell response against Gag p27, indicating that the absence of anti-p27 antibodies is not due to the absence of Gag p27-specific T cells.
Reduced Viral Replication Capacity of Human Immunodeficiency Virus Type 1 Subtype C Caused by Cytotoxic-T-Lymphocyte Escape Mutations in HLA-B57 Epitopes of Capsid Protein
Authors: Boutwell Christian L. , Rowley Christopher F. , Essex M.
Published: December 2008

Cytotoxic-T-lymphocyte (CTL) escape mutations in human immunodeficiency viruses encode amino acid substitutions in positions that disrupt CTL targeting, thereby increasing virus survival and conferring a relative fitness benefit. However, it is now clear that CTL escape mutations can also confer a fitness cost, and there is increasing evidence to suggest that in some cases, e.g., escape from HLA-B*57/B*5801-restricted responses, the costs to the escape virus may affect the clinical course of infection. To quantify the magnitude of the costs of HLA-B*57/B*5801 escape, a highly sensitive dual-infection assay that uses synonymous nucleotide sequence tags to quantify viral relative replication capacity (RRC) was developed. We then asked whether such CTL escape mutations had an impact equivalent to that seen for a benchmark mutation, the M184V antiretroviral drug resistance mutation of reverse transcriptase (RRC
V184
= 0.86). To answer the question, the RRCs were quantified for escape mutations in three immunodominant HLA-B*57/B*5801 epitopes in capsid: A146P in IW9 (RRC
P146
= 0.91), A163G in KF11 (RRC
G163
= 0.89), and T242N in TW10 (RRC
N242
= 0.86). Individually, the impact of the escape mutations on RRC was comparable to that of M184V, while coexpression of the mutations resulted in substantial further reductions, with the maximum impact observed for the triple mutant (RRC
P146-G163-N242
= 0.62). By comparison to M184V, the magnitude of the reductions in RRC caused by the escape mutations, particularly when coexpressed, suggests that the costs of escape are sufficient to affect in vivo viral dynamics and may thus play a role in the protective effect associated with HLA-B*57/B*5801.
Enhancement of Adeno-Associated Virus Infection by Mobilizing Capsids into and Out of the Nucleolus
Authors: Johnson Jarrod S. , Samulski R. Jude
Published: December 2008

Adeno-associated virus (AAV) serotypes are being tailored for numerous therapeutic applications, but the parameters governing the subcellular fate of even the most highly characterized serotype, AAV2, remain unclear. To understand how cellular conditions control capsid trafficking, we have tracked the subcellular fate of recombinant AAV2 (rAAV2) vectors using confocal immunofluorescence, three-dimensional infection analysis, and subcellular fractionation. Here we report that a population of rAAV2 virions enters the nucleus and accumulates in the nucleolus after infection, whereas empty capsids are excluded from nuclear entry. Remarkably, after subcellular fractionation, virions accumulating in nucleoli were found to retain infectivity in secondary infections. Proteasome inhibitors known to enhance transduction were found to potentiate nucleolar accumulation. In contrast, hydroxyurea, which also increases transduction, mobilized virions into the nucleoplasm, suggesting that two separate pathways influence vector delivery in the nucleus. Using a small interfering RNA (siRNA) approach, we then evaluated whether nucleolar proteins B23/nucleophosmin and nucleolin, previously shown to interact with AAV2 capsids, affect trafficking and transduction efficiency. Similar to effects observed with proteasome inhibition, siRNA-mediated knockdown of nucleophosmin potentiated nucleolar accumulation and increased transduction 5- to 15-fold. Parallel to effects from hydroxyurea, knockdown of nucleolin mobilized capsids to the nucleoplasm and increased transduction 10- to 30-fold. Moreover, affecting both pathways simultaneously using drug and siRNA combinations was synergistic and increased transduction over 50-fold. Taken together, these results support the hypothesis that rAAV2 virions enter the nucleus intact and can be sequestered in the nucleolus in stable form. Mobilization from the nucleolus to nucleoplasmic sites likely permits uncoating and subsequent gene expression or genome degradation. In summary, with these studies we have refined our understanding of AAV2 trafficking dynamics and have identified cellular parameters that mobilize virions in the nucleus and significantly influence AAV infection.
PRODUCTION FRAGMENTATION AND OUTSOURCING: GENERAL CONCERNS
Authors: JONES RONALD W.
Published: December 2008

Globalization has its detractors as well as supporters. Concerns have been expressed about the greater ease of fragmenting the production process so that more parts can be outsourced to a variety of countries. Highly developed regions worry about the possibility of greater unemployment or lower unskilled wage rates. Less developed regions are concerned that they may not possess a comparative advantage in the service link activities that promote fragmentation. The paper discusses these issues, with special emphasis on India and China.
THE ECONOMICS OF OFFSHORING: THEORY AND EVIDENCE WITH APPLICATIONS TO ASIA
Authors: MITRA DEVASHISH , RANJAN PRIYA
Published: December 2008

This paper is a non-technical survey of the literature on offshoring and outsourcing, with special focus on the relevance of this literature for Asia. We first see how and to what extent this new literature helps us understand firms' tradeoffs between outsourcing and integration, the variation in the mixes of organizational forms and the location of outsourced activities. We also explore what plausibly triggers offshoring and thereafter what determines its dynamics. Finally, we draw inferences from the existing theory and empirical work about the developmental impact of offshoring on Asia, with special attention to issues related to inequality and poverty.
MANAGING THE NOODLE BOWL: THE FRAGILITY OF EAST ASIAN REGIONALISM
Authors: BALDWIN RICHARD E.
Published: December 2008

The paper argues that East Asian regionalism is fragile, since (i) each nation's industrial competitiveness depends on the smooth functioning of "Factory Asia" — in particular, on intra-regional trade; (ii) the unilateral tariff-cutting that created "Factory Asia" is not subject to WTO discipline (bindings); (iii) there is no "top-level management" to substitute for WTO discipline, i.e., to ensure that bilateral trade tensions — tensions that are inevitable in East Asia — do not spillover into region-wide problems due to lack of cooperation and communication. This paper argues that the window of opportunity for East Asian "vision" was missed; what East Asia needs now is "management", not vision. East Asia should launch a "New East Asian Regional Management Effort", with a reinforced ASEAN + 3 being the most likely candidate for the job. The first priority should be to bind the region's unilateral tariff cuts in the WTO.
EXCHANGE RATE VOLATILITY AND MNCs' PRODUCTION AND DISTRIBUTION NETWORKS: THE CASE OF JAPANESE MANUFACTURING MNCs
Authors: KIYOTA KOZO , MATSUURA TOSHIYUKI , URATA SHUJIRO
Published: December 2008

This paper empirically examines the impacts of exchange rate volatility on the location choice by Japanese multinational corporations (MNCs) and their intra-firm trade. We use affiliate-level data for Japanese MNCs for 1995, 1998 and 2001. We found that high exchange rate volatility discourages the establishment of an affiliate by MNCs. Moreover, the high exchange rate volatility causes the shift from inter-firm to intra-firm transactions. These findings imply the importance of maintaining a stable exchange rate environment in order for MNCs to expand their production and distribution networks.
GELFAND–DICKEY ALGEBRA AND HIGHER SPIN SYMMETRIES ON T2 = S1 × S1
Authors: SEDRA M. B.
Published: December 2008

In this work we aim to renew the interest in higher conformal spins symmetries and their relations to quantum field theories and integrable models. We consider the extension of the conformal Frappat et al. symmetries containing the Virasoro and the Antoniadis et al. algebras as particular cases describing geometrically special diffeomorphisms of the two-dimensional torus T2. We show explicitly, in a consistent way, how one can extract these generalized symmetries from the Gelfand–Dickey algebra. The link with Liouville and Toda conformal field theories is established and various important properties are discussed.
ANALYTICAL EXPRESSIONS OF THREE- AND FOUR-LOOP SUNRISE FEYNMAN INTEGRALS AND FOUR-DIMENSIONAL LATTICE INTEGRALS
Authors: LAPORTA S.
Published: December 2008

In this paper we continue the work began in 2002 on the identification of the analytical expressions of Feynman integrals which require the evaluation of multiple elliptic integrals. We rewrite and simplify the analytical expression of the three-loop self-mass integral with three equal masses and on-shell external momentum. We collect and analyze a number of results on double and triple elliptic integrals. By using very high-precision numerical fits, for the first time we are able to identify a very compact analytical expression for the four-loop on-shell self-mass integral with four equal masses, that is one of the master integrals of the four-loop electron g-2. Moreover, we fit the analytical expressions of some integrals which appear in lattice perturbation theory, and in particular the four-dimensional generalized Watson integral.
TUNING OF PAULI-BLOCKING EFFECTS VIA FIELD-INDUCED ORIENTATIONS
Authors: CHU A. KWANG-HUA
Published: December 2008

We obtain possibly valuable information about the phase diagram (tuned by the free orientation together with the Pauli blocking parameters) of rather dense matter at high fermion as well as boson number density but low temperature, which is not accessible to strong-magnetic-field experiments. The free orientation parameter we adopted could be due to the magnetic field or confined potentials. The possible coupling between the Pauli blocking and the induced (net) orientation (tuned by the strong magnetic field) is also addressed here which might be useful for the studies of very-strong magnetic fields in neutron stars.
MESON CLOUDS AND DRESSED CONSTITUENT QUARKS IN THE COMPLETE RG-IMPROVEMENT APPROACH
Authors: KESHAVARZIAN K. , MIRJALILI A. , YAZDANPANAH M. M.
Published: December 2008

Sea quark densities in the nucleon, based on the constituent quark model are analyzed. To model the asymmetry of these densities, the meson cloud or alternatively chiral quark model (χQM) is used. Valence quark densities of the meson which are required to extract the sea quark densities in the constituent quarks are obtained using the phenomenological valon model. In addition to the standard perturbative QCD approach which uses the [Formula: see text] scheme with a physical choice of renormalization scale, the calculations are also performed using the complete RG-improvement (CORGI) approach. To avoid a physically unacceptable Q2 behavior of the sea densities inside the constituent quarks, we assume that the free parameter which exists in the vertex function of the boson–quark splitting function, is Q2-dependent. Using the unsymmetrized sea densities of the nucleon which result from convoluting the constituent density in a nucleon with the quark density in the constituent quark, the Gottfried sum rule (GSR) is calculated using the standard perturbative and CORGI approaches. The CORGI result is closer to the reported experimental value for the GSR. The extracted sea and valence quark density in a nucleon, using χQM and also the CORGI approach, have been compared with available experimental data and what was obtained, based on χQM in the standard approach. This comparison confirms the anticipated better agreement of the CORGI approach with the data.
IMPLEMENTING DEUTSCH–JOZSA ALGORITHM USING SUPERCONDUCTING QUBIT NETWORK
Authors: ZHENG XIAO-HU , YANG MING , DONG PING , CAO ZHUO-LIANG
Published: December 2008

An improved architecture, which performs a universal set of gates by current biasing of coupling Josephson junction, has been proposed. This improvement is necessary to the realization of a functional and scalable quantum computer. The proposed architecture is in line with current technology. Secondly, we investigate a scheme for implementing the Deutsch–Jozsa algorithm via the improved architecture. It is a simple, scalable and feasible scheme for the implementation of the Deutsch–Jozsa algorithm based on the current-controlled superconducting charge qubit network.
MICROSTRUCTURES AND MAGNETIC PROPERTIES OF COBALT THIN FILMS
Authors: JIAO DONGMAO , LI JIANGONG , NI XIA , ZHANG XUDONG
Published: December 2008

Cobalt thin films deposited by radio frequency sputtering were investigated. Microstructures of the Co films were analyzed by XRD and TEM. The results show that films microstructure varies with the variation of the sputter gas pressure P Ar . Magnetic properties measured by VSM show that all the films possess relatively high saturation magnetization 4πMs, and strong in-plane uniaxial magnetic anisotropy field Hk. Co films deposited below 0.3 Pa show soft magnetic properties and its microwave permeability was measured by vector network analyzer in the 0.1–5 GHz range.
CLASSICAL SOLUTIONS OF GHOST CONDENSATION MODELS
Authors: MAENO MASAHIRO , ODA ICHIRO
Published: December 2008

Motivated by ideas obtained from both ghost condensation and gravitational Higgs mechanism, we attempt to find classical solutions in the unitary gauge in general ghost condensation models. It is shown that depending on the form of scalar fields in an action, there are three kinds of exact solutions, which are (anti-) de Sitter space–time, polynomially expanding universes and flat Minkowski space–time. We briefly comment on gravitational Higgs mechanism in these models where we have massive gravitons of five degrees of freedom and one unitary scalar field (Nambu–Goldstone boson) after spontaneous symmetry breakdown of general coordinate reparametrization invariance. The models at hand are free from the problem associated with the non-unitary propagating mode.
ON SIMPLE FILIPPOV SUPERALGEBRAS OF TYPE A(n, n)
Authors: Beites Patrícia D. , Pozhidaev Alexander P.
Published: December 2008

It is proved that there exist no simple finite-dimensional Filippov superalgebras of type A(n, n) over an algebraically closed field of characteristic 0.
Hyperosmotic stress induces Rho/Rho kinase/LIM kinase-mediated cofilin phosphorylation in tubular cells: key role in the osmotically triggered F-actin response
Authors: Thirone Ana C. P. , Speight Pam , Zulys Matthew , Rotstein Ori D. , Szászi Katalin , Pedersen Stine F. , Kapus András
Published: December 2008

Hyperosmotic stress induces cytoskeleton reorganization and a net increase in cellular F-actin, but the underlying mechanisms are incompletely understood. Whereas de novo F-actin polymerization likely contributes to the actin response, the role of F-actin severing is unknown. To address this problem, we investigated whether hyperosmolarity regulates cofilin, a key actin-severing protein, the activity of which is inhibited by phosphorylation. Since the small GTPases Rho and Rac are sensitive to cell volume changes and can regulate cofilin phosphorylation, we also asked whether they might link osmostress to cofilin. Here we show that hyperosmolarity induced rapid, sustained, and reversible phosphorylation of cofilin in kidney tubular (LLC-PK1 and Madin-Darby canine kidney) cells. Hyperosmolarity-provoked cofilin phosphorylation was mediated by the Rho/Rho kinase (ROCK)/LIM kinase (LIMK) but not the Rac/PAK/LIMK pathway, because 1) dominant negative (DN) Rho and DN-ROCK but not DN-Rac and DN-PAK inhibited cofilin phosphorylation; 2) constitutively active (CA) Rho and CA-ROCK but not CA-Rac and CA-PAK induced cofilin phosphorylation; 3) hyperosmolarity induced LIMK-2 phosphorylation, and 4) inhibition of ROCK by Y-27632 suppressed the hypertonicity-triggered LIMK-2 and cofilin phosphorylation.We thenexamined whether cofilin and its phosphorylation play a role in the hypertonicity-triggered F-actin changes. Downregulation of cofilin by small interfering RNA increased the resting F-actin level and eliminated any further rise upon hypertonic treatment. Inhibition of cofilin phosphorylation by Y-27632 prevented the hyperosmolarity-provoked F-actin increase. Taken together, cofilin is necessary for maintaining the osmotic responsiveness of the cytoskeleton in tubular cells, and the Rho/ROCK/LIMK-mediated cofilin phosphorylation is a key mechanism in the hyperosmotic stress-induced F-actin increase.
Tumor necrosis factor-α downregulates intestinal NHE8 expression by reducing basal promoter activity
Authors: Xu Hua , Chen Huacong , Dong Jiali , Li Jing , Chen Rongji , Uno Jennifer K. , Ghishan Fayez K.
Published: December 2008

NHE8 transporter is a member of the sodium/hydrogen exchanger (NHE) family. This transporter protein is expressed at the apical membrane of epithelial cells of kidney and intestine and contributes to vectorial Na+transport in both tissues. Although NaCl absorption has been shown to be reduced in diarrhea associated with colitis and enteritis, little is known about the role of Na+/H+exchange and the involvement of NHE isoforms in the pathogenesis of inflammatory disorders and the mechanism of inflammation-associated diarrhea. This study investigated the role of NHE8 in the setting of inflammatory states. Jejunal mucosa was harvested from trinitrobenzene sulfonic acid (TNBS) colitis rats or lipopolysaccharide (LPS) rats for RNA extraction and brush-border membrane protein purification. The human NHE8 gene promoter was cloned from human genomic DNA and characterized in Caco-2 cells. The promoter was further used to study the mechanisms of TNF-α-mediated NHE8 expression downregulation in Caco-2 cells. Results from Western blot and real-time PCR indicated that NHE8 protein and mRNA were significantly reduced in TNBS rats and LPS rats. In Caco-2 cells, TNF-α produces similar reduction levels in the endogenous NHE8 mRNA expression observed in our in vivo studies. The downregulation of NHE8 expression mediated by TNF-α could be blocked by transcription inhibitor actinomycin D, suggesting the involvement of transcriptional regulation. Further studies indicated that the human NHE8 gene transcription could be activated by Sp3 transcriptional factor, and TNF-α inhibits human NHE8 expression by reducing Sp3 interaction at the minimal promoter region of the human NHE8 gene. In conclusion, our studies suggest that TNF-α decreases NHE8 expression in inflammation induced by TNBS and LPS, which may contribute to the diarrhea associated with inflammation.
Calpain-1 is required for hydrogen peroxide-induced myotube atrophy
Authors: McClung J. M. , Judge A. R. , Talbert E. E. , Powers S. K.
Published: December 2008

Recent reports suggest numerous roles for cysteine proteases in the progression of skeletal muscle atrophy due to disuse or disease. Nonetheless, a specific requirement for these proteases in the progression of skeletal muscle atrophy has not been demonstrated. Therefore, this investigation determined whether calpains or caspase-3 is required for oxidant-induced C2C12 myotube atrophy. We demonstrate that exposure to hydrogen peroxide (25 μM H2O2) induces myotube oxidative damage and atrophy, with no evidence of cell death. Twenty-four hours of exposure to H2O2 significantly reduced both myotube diameter and the abundance of numerous proteins, including myosin (−81%), α-actinin (−40%), desmin (−79%), talin (−37%), and troponin I (−80%). Myotube atrophy was also characterized by increased cleavage of the cysteine protease substrate αII-spectrin following 4 h and 24 h of H2O2 treatment. This degradation was blocked by administration of the protease inhibitor leupeptin (10 μM). Using small interfering RNA transfection of mature myotubes against the specific proteases calpain-1, calpain-2, and caspase-3, we demonstrated that calpain-1 is required for H2O2-induced myotube atrophy. Collectively, our data provide the first evidence for an absolute requirement for calpain-1 in the development of skeletal muscle myotube atrophy in response to oxidant-induced cellular stress.
Establishment of conditionally immortalized epithelial cell lines from the intestinal tissue of adult normal and transgenic mice
Authors: Whitehead Robert H. , Robinson Pamela S.
Published: December 2008

It has proved to be impossible to culture epithelial cells from the gastrointestinal tract of adult animals. Researchers have had to use either cell lines derived from newborn rat small intestine or colon carcinoma cell lines that have retained some of the properties of the gastrointestinal mucosa. We have described a method for establishing conditionally immortalized cell lines from the stomach, small intestine, colon, pancreas, and liver from tissue obtained from a transgenic mouse strain carrying a temperature-sensitive mutant of the SV40 large T gene (the “Immortomouse”). This immortalizing gene has proved to be useful for establishing cell lines from a number of transgenic mice following crossbreeding of the Immortomouse with the transgenic mouse of interest. These cell lines are being used in numerous studies. In this review we describe the methods for developing such lines and list the range of cell lines that have been developed from colon, small intestine, stomach, liver, and pancreas of a number of transgenic mice.