bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Adenovirus Serotype 5 Hexon Regions That Interact with Scavenger Receptors
Authors: Khare Reeti , Reddy Vijay S. , Nemerow Glen R. , Barry Michael A. 
Published: December 2011

ABSTRACT

Most of an intravenous dose of species C adenovirus serotype 5 (Ad5) is destroyed by liver Kupffer cells. In contrast, another species C virus, Ad6, evades these cells to mediate more efficient liver gene delivery. Given that this difference in Kupffer cell interaction is mediated by the hypervariable (HVR) loops of the virus hexon protein, we genetically modified each of the seven HVRs of Ad5 with a cysteine residue to enable conditional blocking of these sites with polyethylene glycol (PEG). We show that these modifications do not affect
in vitro
virus transduction. In contrast, after intravenous injection, targeted PEGylation at HVRs 1, 2, 5, and 7 increased viral liver transduction up to 20-fold. Elimination or saturation of liver Kupffer cells did not significantly affect this increase in the liver transduction.
In vitro
, PEGylation blocked uptake of viruses via the Kupffer cell scavenger receptor SRA-II. These data suggest that HVRs 1, 2, 5, and 7 of Ad5 may be involved in Kupffer cell recognition and subsequent destruction. These data also demonstrate that this conditional genetic-chemical mutation strategy is a useful tool for investigating the interactions of viruses with host tissues.
Development of a Novel Nonhuman Primate Model for Rift Valley Fever
Authors: Smith Darci R. , Bird Brian H. , Lewis Bridget , Johnston Sara C. , McCarthy Sarah , Keeney Ashley , Botto Miriam , Donnelly Ginger , Shamblin Joshua , Albariño César G. , Nichol Stuart T. , Hensley Lisa E. 
Published: December 2011

ABSTRACTRift Valley fever (RVF) virus (RVFV) can cause severe human disease characterized by either acute-onset hepatitis, delayed-onset encephalitis, retinitis and blindness, or a hemorrhagic syndrome. The existing nonhuman primate (NHP) model for RVF utilizes an intravenous (i.v.) exposure route in rhesus macaques (Macaca mulatta). Severe disease in these animals is infrequent, and large cohorts are needed to observe significant morbidity and mortality. To overcome these drawbacks, we evaluated the infectivity and pathogenicity of RVFV in the common marmoset (Callithrix jacchus) by i.v., subcutaneous (s.c.), and intranasal exposure routes to more closely mimic natural exposure. Marmosets were more susceptible to RVFV than rhesus macaques and experienced higher rates of morbidity, mortality, and viremia and marked aberrations in hematological and chemistry values. An overwhelming infection of hepatocytes was a major consequence of infection of marmosets by the i.v. and s.c. exposure routes. Additionally, these animals displayed signs of hemorrhagic manifestations and neurological impairment. Based on our results, the common marmoset model more closely resembles severe human RVF disease and is therefore an ideal model for the evaluation of potential vaccines and therapeutics.
High-Mannose Glycan-Dependent Epitopes Are Frequently Targeted in Broad Neutralizing Antibody Responses during Human Immunodeficiency Virus Type 1 Infection
Authors: Lavine Christy L. , Lao Socheata , Montefiori David C. , Haynes Barton F. , Sodroski Joseph G. , Yang Xinzhen ,   the NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
Published: December 2011

ABSTRACT

Broad and potent neutralizing antibody (BNAb) responses are rare in people infected by human immunodeficiency virus type 1 (HIV-1). Clearly defining the nature of BNAb epitopes on HIV-1 envelope glycoproteins (Envs) targeted
in vivo
is critical for future directions of anti-HIV-1 vaccine development. Conventional techniques are successful in defining neutralizing epitopes in a small number of individual subjects but fail in studying large groups of subjects. Two independent methods were employed to investigate the nature of NAb epitopes targeted in 9 subjects, identified by the NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI) 001 and 008 clinical teams, known to make a strong BNAb response. Neutralizing activity from 8/9 subjects was enhanced by enriching high-mannose N-linked glycan (HM-glycan) of HIV-1 glycoproteins on neutralization target viruses and was sensitive to specific glycan deletion mutations of HIV-1 glycoproteins, indicating that HM-glycan-dependent epitopes are targeted by BNAb responses in these subjects. This discovery adds to accumulating evidence supporting the hypothesis that glycans are important targets on HIV-1 glycoproteins for BNAb responses
in vivo
, providing an important lead for future directions in developing NAb-based anti-HIV-1 vaccines.
Risks of ignoring fish population spatial structure in fisheries management
Authors: Ying Yiping , Chen Yong , Lin Longshan , Gao Tianxian 
Published: December 2011

Ignorance of spatial structures in fisheries management may lead to unexpected risks of overexploitation. Based on the information about small yellow croaker ( Larimichthys polyactis ) off the coast of China, we simulated a fish population consisting of three subpopulations mixing at intermediate levels, which was considered in the “true” spatial structure of the population in this study. Three scenarios of population spatial structure were assumed in assessing and managing this simulated fishery: (i) metapopulation, which has the same structure as the “true” population; (ii) three independent subpopulations, which overlook the exchanges among the subpopulations; and (iii) unit population, which completely ignores the population spatial structure. Corresponding approaches were applied to assess and manage each of these assumed fish populations. The management time period was assumed to be 10 years with two harvesting levels (i.e., maximum sustainable yield (MSY) and f0.1). Assessing and managing the metapopulation as several independent populations could lead to a high probability of overexploitation. Managing the metapopulation as a unit population could lead to local depletion. Use of MSY as a management target may be risk prone in the existence of a metapopulation, and use of a fishing mortality lower than f0.1as a management target is more desirable.
Large-scale and long-term decrease in fish growth following the construction of hydroelectric reservoirs
Authors: Milbrink Göran , Vrede Tobias , Tranvik Lars J. , Rydin Emil 
Published: December 2011

Hydroelectric reservoirs retain large volumes of water and have a global impact on sea level, elemental cycles, and biodiversity. Using data from a total of 90 historical and recent surveys in nine regulated and eight unregulated alpine and subalpine lakes, we show an additional large effect of reservoirs, i.e., that impoundment causes drastically decreased fish growth and thereby great negative consequences for inland fisheries in Scandinavia. Following a long period (40–65 years) after impoundment, the length and mass of Arctic charr ( Salvelinus alpinus ) of the single age class 4+ years was, on average, 35% and 72% lower, respectively, in impounded versus natural lakes in northern Scandinavia. The effect was stronger at higher altitudes and can be mitigated by addition of inorganic nutrients. We suggest that the decreased fish growth is a consequence of lowered ecosystem productivity, oligotrophication, caused by impoundment, resulting in erosion and loss of the littoral ecosystem as well as delayed flooding and leakage of nutrients from the riparian zone until after the growing season.
Modeling Regular Polysemy: A Study on the Semantic Classification of Catalan Adjectives
Authors: Boleda Gemma , Schulte im Walde Sabine , Badia Toni 
Published: December 2011

We present a study on the automatic acquisition of semantic classes for Catalan adjectives from distributional and morphological information, with particular emphasis on polysemous adjectives. The aim is to distinguish and characterize broad classes, such as qualitative (gran ‘big’) and relational (pulmonar ‘pulmonary’) adjectives, as well as to identify polysemous adjectives such as econòmic (‘economic ∣ cheap’). We specifically aim at modeling regular polysemy, that is, types of sense alternations that are shared across lemmata. To date, both semantic classes for adjectives and regular polysemy have only been sparsely addressed in empirical computational linguistics.Two main specific questions are tackled in this article. First, what is an adequate broad semantic classification for adjectives? We provide empirical support for the qualitative and relational classes as defined in theoretical work, and uncover one type of adjective that has not received enough attention, namely, the event-related class. Second, how is regular polysemy best modeled in computational terms? We present two models, and argue that the second one, which models regular polysemy in terms of simultaneous membership to multiple basic classes, is both theoretically and empirically more adequate than the first one, which attempts to identify independent polysemous classes. Our best classifier achieves 69.1% accuracy, against a 51% baseline.
Building legitimacy at Sport Canada: pitfalls of public value creation?
Authors: Sam Michael P 
Published: December 2011

Legitimacy building is an increasingly recognized feature of bureaucratic practice under networked governance. Mark Moore's (1995) model of ‘public value creation’ captures the strategic imperative to build credibility, legitimacy and support for policies and programmes in this context. As an emerging ‘narrative’ in public organizations, it combines perspectives on managerial and political leadership and is therefore useful to explain bureaucratic experiences with legitimacy building and their implications for policy. This article investigates the efforts of Canada's federal sport agency to secure legitimacy and explores the implications of public value creation on future policy-making. Drawing from interview data as well as public and internal documents, the study outlines Sport Canada's initiatives to establish sport's ‘benefits’, collaborate widely and add value in terms of equity and ethics. Two related implications (or storylines) are considered and discussed: (a) the tendency for public value creation to reduce the policy sector to anecdotal understandings in the eyes of political authorizers, and (b) the propensity for building public value to result in over-commitment due to the accumulation and embedding of new collaborations, mandates and target populations. Points for practitioners Mark Moore's ‘public value’ approach resonates with practitioners because of its realist portrayal of politics in public administration. Generating support and legitimacy for existing or proposed policies and programmes is acknowledged to be particularly important in contexts where networks are prevalent. This article investigates legitimacy building within federal sport, a sector which has been reliant on networked governance since its inception and where substantive efforts have been aimed at raising its profile. The case cautions against persistent case-building and public value creation because continuous justifications may ultimately raise questions regarding the credibility of bureaucratic advice and of the likely success of programme commitments.
An ‘institutional turn’ in integrity management in China
Authors: Gong Ting 
Published: December 2011

Previous unsuccessful attempts at controlling corruption have led the Chinese government to change its strategy from campaign-style anti-corruption enforcement to institutionalized integrity management, referred to as an ‘institutional turn’ in this article. The ‘turn’ is characterized by rule-guided integrity building and manifests itself in the growth of various local integrity initiatives. Drawing on a particular case – the declaration of assets by local government officials – this article details the characteristics and mechanisms of the institutional change towards integrity management in China. In addition to a conceptual discussion of the institutional turn, the broad social and political implications beyond the turn itself are examined. As the findings of the article show, China's ongoing institutional turn towards integrity management implies a paradigm shift in understanding corruption and its changing patterns. Points for practitioners The institutional turn towards integrity management in China has practical implications. First, integrity management is an institutionalized and rule-guided process, rather than a process of mere ideological inspiration. Second, whether covering certain specific aspects of concrete action or providing a general schema to be applied to particular circumstances, integrity management programmes should detail how a requirement is to be implemented and assessed, and what sanctions are to be imposed in cases of non-compliance. Third, integrity management relies not only on rules but also on important values, such as accountability, responsibility, transparency, and public engagement, which ensure good management of probity risks.
Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia
Authors: Paterson Alex , Mockridge C. Ian , Adams Jemimah E. , Krysov Sergey , Potter Kathleen N. , Duncombe Andrew S. , Cook Simon J. , Stevenson Freda K. , Packham Graham 
Published: December 2011

Abstract
B-cell receptor and microenvironment-derived signals promote accumulation of chronic lymphocytic leukemia (CLL) cells through increased proliferation and/or decreased apoptosis. In this study, we investigated the regulation of BIM, a proapoptotic BCL2-related protein, which is tightly regulated by phosphorylation. Surface IgM stimulation increased phosphorylation of 2 BIM isoforms, BIMEL and BIML, in a subset of CLL samples. In contrast, in normal B cells, anti-IgM triggered selective phosphorylation of BIMEL only. In CLL, anti-IgM–induced BIM phosphorylation correlated with unmutated IGHV gene status and with progressive disease. Strikingly, it was also associated with progressive disease within the mutated IGHV gene subset. BIM phosphorylation was dependent on MEK1/2 kinase activity, and we identified BIMEL serine 69, previously linked to pro-survival responses, as the major site of phosphorylation in CLL and in Ramos cells. BIMEL/BIML phosphorylation was associated with release of the pro-survival protein MCL1. Coculture of CLL cells with HK cells, a model of the CLL microenvironment, promoted CLL cell survival and was associated with MEK1/2 activation and BIMEL phosphorylation. Hence, BIM phosphorylation appears to play a key role in apoptosis regulation in CLL cells, potentially coordinating antigen and microenvironment-derived survival signals. Antigen-mediated effects on BIM may be an important determinant of clinical behavior.
Are prescribing doctors sensitive to the price that their patients have to pay in the Spanish National Health System?
Authors: González López-Valcárcel Beatriz , Librero Julián , Sanfélix-Gimeno Gabriel , Peiró Salvador ,   The Group for Drug Utilization Research in the Spanish National Health System (IUM-SNS Group)
Published: December 2011

Abstract

Background
This study aims to design an empirical test on the sensitivity of the prescribing doctors to the price afforded for the patient, and to apply it to the population data of primary care dispensations for cardiovascular disease and mental illness in the Spanish National Health System (NHS). Implications for drug policies are discussed.

Methods
We used population data of 17 therapeutic groups of cardiovascular and mental illness drugs aggregated by health areas to obtain 1424 observations ((8 cardiovascular groups * 70 areas) + (9 psychotropics groups * 96 areas)). All drugs are free for pensioners. For non-pensioner patients 10 of the 17 therapeutic groups have a reduced copayment (RC) status of only 10% of the price with a ceiling of €2.64 per pack, while the remaining 7 groups have a full copayment (FC) rate of 40%. Differences in the average price among dispensations for pensioners and non-pensioners were modelled with multilevel regression models to test the following hypothesis: 1) in FC drugs there is a significant positive difference between the average prices of drugs prescribed to pensioners and non-pensioners; 2) in RC drugs there is no significant price differential between pensioner and non-pensioner patients; 3) the price differential of FC drugs prescribed to pensioners and non-pensioners is greater the higher the price of the drugs.

Results
The average monthly price of dispensations to pensioners and non-pensioners does not differ for RC drugs, but for FC drugs pensioners get more expensive dispensations than non-pensioners (estimated difference of €9.74 by DDD and month). There is a positive and significant effect of the drug price on the differential price between pensioners and non-pensioners. For FC drugs, each additional euro of the drug price increases the differential by nearly half a euro (0.492). We did not find any significant differences in the intensity of the price effect among FC therapeutic groups.

Conclusions
Doctors working in the Spanish NHS seem to be sensitive to the price that can be afforded by patients when they fill in prescriptions, although alternative hypothesis could also explain the results found.
Azelnidipine prevents cardiac dysfunction in streptozotocin-diabetic rats by reducing intracellular calcium accumulation, oxidative stress and apoptosis
Authors: Kain Vasundhara , Kumar Sandeep , Sitasawad Sandhya L 
Published: December 2011

Abstract

Background
Numerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Therapeutic interventions to prevent calcium accumulation and oxidative stress could be therefore helpful in improving the cardiac function under diabetic condition.

Methods
This study was designed to examine the effect of long-acting calcium channel blocker (CCB), Azelnidipine (AZL) on contractile dysfunction, intracellular calcium (Ca2+) cycling proteins, stress-activated signaling molecules and apoptosis on cardiomyocytes in diabetes. Adult male Wistar rats were made diabetic by a single intraperitoneal (IP) injection of streptozotocin (STZ). Contractile functions were traced from live diabetic rats to isolated individual cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca2+ fluorescence.

Results
Diabetic heart showed significantly depressed PS, ± dL/dt, prolonged TPS, TR90 and intracellular Ca2+ clearing and showed an elevated resting intracellular Ca2+. AZL itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunction. Diabetes increased the levels of superoxide, enhanced expression of the cardiac damage markers like troponin I, p67phox NADPH oxidase subunit, restored the levels of the mitochondrial superoxide dismutase (Mn-SOD), calcium regulatory proteins RyR2 and SERCA2a, and suppressed the levels of the anti-apoptotic Bcl-2 protein. All of these STZ-induced alterations were reconciled by AZL treatment.

Conclusion
Collectively, the data suggest beneficial effect of AZL in diabetic cardiomyopathy via altering intracellular Ca2+ handling proteins and preventing apoptosis by its antioxidant property.
Analysis of detergent-free lipid rafts isolated from CD4+ T cell line: interaction with antigen presenting cells promotes coalescing of lipid rafts
Authors: Kennedy Colleen , Nelson Matthew D , Bamezai Anil K 
Published: December 2011

Abstract

Background
Lipid rafts present on the plasma membrane play an important role in spatiotemporal regulation of cell signaling. Physical and chemical characterization of lipid raft size and assessment of their composition before, and after cell stimulation will aid in developing a clear understanding of their regulatory role in cell signaling. We have used visual and biochemical methods and approaches for examining individual and lipid raft sub-populations isolated from a mouse CD4+ T cell line in the absence of detergents.

Results
Detergent-free rafts were analyzed before and after their interaction with antigen presenting cells. We provide evidence that the average diameter of lipid rafts isolated from un-stimulated T cells, in the absence of detergents, is less than 100 nm. Lipid rafts on CD4+ T cell membranes coalesce to form larger structures, after interacting with antigen presenting cells even in the absence of a foreign antigen.

Conclusions
Findings presented here indicate that lipid raft coalescence occurs during cellular interactions prior to sensing a foreign antigen.
The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles
Authors: Nguyen Albert T , Feasley Christa L , Jackson Ken W , Nitz Theodore J , Salzwedel Karl , Air Gillian M , Sakalian Michael 
Published: December 2011

AbstractBackgroundBevirimat, the prototype Human Immunodeficiency Virus type 1 (HIV-1) maturation inhibitor, is highly potent in cell culture and efficacious in HIV-1 infected patients. In contrast to inhibitors that target the active site of the viral protease, bevirimat specifically inhibits a single cleavage event, the final processing step for the Gag precursor where p25 (CA-SP1) is cleaved to p24 (CA) and SP1.ResultsIn this study, photoaffinity analogs of bevirimat and mass spectrometry were employed to map the binding site of bevirimat to Gag within immature virus-like particles. Bevirimat analogs were found to crosslink to sequences overlapping, or proximal to, the CA-SP1 cleavage site, consistent with previous biochemical data on the effect of bevirimat on Gag processing and with genetic data from resistance mutations, in a region predicted by NMR and mutational studies to have α-helical character. Unexpectedly, a second region of interaction was found within the Major Homology Region (MHR). Extensive prior genetic evidence suggests that the MHR is critical for virus assembly.ConclusionsThis is the first demonstration of a direct interaction between the maturation inhibitor, bevirimat, and its target, Gag. Information gained from this study sheds light on the mechanisms by which the virus develops resistance to this class of drug and may aid in the design of next-generation maturation inhibitors.
Oral administration of interferon-α2b-transformed Bifidobacterium longum protects BALB/c mice against coxsackievirus B3-induced myocarditis
Authors: Yu Zhijian , Huang Zhen , Shao Chongwen , Huang Yuanjian , Zhang Fan , Yang Jin , Deng Lili , Zeng Zhongming , Deng Qiwen , Zeng Weiseng 
Published: December 2011

Abstract
Multiple reports have claimed that low-dose orally administered interferon (IFN)-α is beneficial in the treatment of many infectious diseases and provides a viable alternative to high-dose intramuscular treatment. However, research is needed on how to express IFN stably in the gut. Bifidobacterium may be a suitable carrier for human gene expression and secretion in the intestinal tract for the treatment of gastrointestinal diseases. We reported previously that Bifidobacterium longum can be used as a novel oral delivery of IFN-α. IFN-transformed B. longum can exert an immunostimulatory role in mice; however the answer to whether this recombinant B. longum can be used to treat virus infection still remains elusive. Here, we investigated the efficacy of IFN-transformed B. longum administered orally on coxsackie virus B3 (CVB3)-induced myocarditis in BALB/c mice. Our data indicated that oral administration of IFN-transformed B. longum for 2 weeks after virus infection reduced significantly the severity of virus-induced myocarditis, markedly down regulated virus titers in the heart, and induced a T helper 1 cell pattern in the spleen and heart compared with controls. Oral administration of the IFN-transformed B. longum, therefore, may play a potential role in the treatment of CVB3-induced myocarditis.