42 results on '"Paul, V."'
Search Results
2. Speckle tracking echocardiography-derived left ventricular global longitudinal strain in ex-thalassaemics
- Author
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Paul, Amal, primary, Kulkarni, Uday, additional, Yadav, Bijesh, additional, Aboobacker, Fouzia N., additional, Devasia, Anup J., additional, Korula, Anu, additional, Abraham, Aby, additional, George, Biju, additional, George, Paul V., additional, and Srivastava, Alok, additional
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- 2023
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3. Fiber alignment drives changes in architectural and mechanical features in collagen matrices.
- Author
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Paul V Taufalele, Jacob A VanderBurgh, Adam Muñoz, Matthew R Zanotelli, and Cynthia A Reinhart-King
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Medicine ,Science - Abstract
Aligned collagen architecture is a characteristic feature of the tumor extracellular matrix (ECM) and has been shown to facilitate cancer metastasis using 3D in vitro models. Additional features of the ECM, such as pore size and stiffness, have also been shown to influence cellular behavior and are implicated in cancer progression. While there are several methods to produce aligned matrices to study the effect on cell behavior in vitro, it is unclear how the alignment itself may alter these other important features of the matrix. In this study, we have generated aligned collagen matrices and characterized their pore sizes and mechanical properties at the micro- and macro-scale. Our results indicate that collagen alignment can alter pore-size of matrices depending on the polymerization temperature of the collagen. Furthermore, alignment does not affect the macro-scale stiffness but alters the micro-scale stiffness in a temperature independent manner. Overall, these results describe the manifestation of confounding variables that arise due to alignment and the importance of fully characterizing biomaterials at both micro- and macro-scales.
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- 2019
- Full Text
- View/download PDF
4. Genome annotation improvements from cross-phyla proteogenomics and time-of-day differences in malaria mosquito proteins using untargeted quantitative proteomics.
- Author
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Lisa Imrie, Thierry Le Bihan, Áine O'Toole, Paul V Hickner, W Augustine Dunn, Benjamin Weise, and Samuel S C Rund
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Medicine ,Science - Abstract
The malaria mosquito, Anopheles stephensi, and other mosquitoes modulate their biology to match the time-of-day. In the present work, we used a non-hypothesis driven approach (untargeted proteomics) to identify proteins in mosquito tissue, and then quantified the relative abundance of the identified proteins from An. stephensi bodies. Using these quantified protein levels, we then analyzed the data for proteins that were only detectable at certain times-of-the day, highlighting the need to consider time-of-day in experimental design. Further, we extended our time-of-day analysis to look for proteins which cycle in a rhythmic 24-hour ("circadian") manner, identifying 31 rhythmic proteins. Finally, to maximize the utility of our data, we performed a proteogenomic analysis to improve the genome annotation of An. stephensi. We compare peptides that were detected using mass spectrometry but are 'missing' from the An. stephensi predicted proteome, to reference proteomes from 38 other primarily human disease vector species. We found 239 such peptide matches and reveal that genome annotation can be improved using proteogenomic analysis from taxonomically diverse reference proteomes. Examination of 'missing' peptides revealed reading frame errors, errors in gene-calling, overlapping gene models, and suspected gaps in the genome assembly.
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- 2019
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5. In patients with unilateral pleural effusion, restricted lung inflation is the principal predictor of increased dyspnoea.
- Author
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Luke A Garske, Kuhan Kunarajah, Paul V Zimmerman, Lewis Adams, and Ian B Stewart
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Medicine ,Science - Abstract
BACKGROUND AND OBJECTIVE:The mechanism of dyspnoea associated with pleural effusion is uncertain. A cohort of patients requiring thoracoscopy for unilateral exudative effusion were investigated for associations between dyspnoea and suggested predictors: impaired ipsilateral diaphragm movement, effusion volume and restricted lung inflation. METHODS:Baseline Dyspnoea Index, respiratory function, and ultrasound assessment of ipsilateral diaphragm movement were assessed prior to thoracoscopy, when effusion volume was measured. Transitional Dyspnoea Index (change from baseline) was assessed 4 and 8 weeks after thoracoscopy. Pearson product moment assessed bivariate correlations and a general linear model examined how well total lung capacity (measuring restricted lung inflation), effusion volume and impaired diaphragm movement predicted Baseline Dyspnoea Index. Un-paired t tests compared the groups with normal and impaired diaphragm movement. RESULTS:19 patients were studied (14 malignant etiology). Total lung capacity was associated with Baseline Dyspnoea Index (r = 0.68, P = 0.003). Effusion volume (r = -0.138, P = 0.60) and diaphragm movement (P = 0.09) were not associated with Baseline Dyspnoea Index. Effusion volume was larger with impaired diaphragm movement compared to normal diaphragm movement (2.16 ±SD 0.95 vs.1.16 ±0.92 L, P = 0.009). Total lung capacity was lower with impaired diaphragm movement compared to normal diaphragm movement (65.4 ±10.3 vs 78.2 ±8.6% predicted, P = 0.011). The optimal general linear model to predict Baseline Dyspnoea Index used total lung capacity alone (adjusted R2 = 0.42, P = 0.003). In nine participants with controlled effusion, baseline effusion volume (r = 0.775, P = 0.014) and total lung capacity (r = -0.690, P = 0.040) were associated with Transitional Dyspnoea Index. CONCLUSIONS:Restricted lung inflation was the principal predictor of increased dyspnoea prior to thoracoscopic drainage of effusion, with no independent additional association with either effusion volume or impaired ipsilateral diaphragm movement. Restricted lung inflation may be an important determinant of the dyspnoea associated with pleural effusion.
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- 2018
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6. Downscaling of national crop area statistics using drivers of cropland productivity measured at fine resolutions.
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Jingyu Song, Michael S Delgado, Paul V Preckel, and Nelson B Villoria
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Medicine ,Science - Abstract
Despite substantial research and policy interest in pixel level cropland allocation data, few sources are available that span a large geographic area. The data used for much of this research are derived from complex modeling techniques that may include model simulation and other data processing. We develop a transparent econometric framework that uses pixel level biophysical measurements and aggregate cropland statistics to develop pixel level cropland allocation predictions. Such pixel level land use data can be used to investigate the impact of human activities on the environment. Validation exercises show that our approach is effective at downscaling cropland allocation to multiple levels of resolution.
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- 2018
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7. Sustained virological response halts fibrosis progression: A long-term follow-up study of people with chronic hepatitis C infection.
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Swee Lin G Chen Yi Mei, Alexander J Thompson, Britt Christensen, Georgina Cunningham, Lucy McDonald, Sally Bell, David Iser, Tin Nguyen, and Paul V Desmond
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Medicine ,Science - Abstract
Long-term follow-up studies validating the clinical benefit of sustained virological response (SVR) in people with chronic hepatitis C (CHC) infection are lacking. Our aim was to identify rates and predictors of liver fibrosis progression in a large, well characterized cohort of CHC patients in whom paired liver fibrosis assessments were performed more than 10 years apart.CHC patients who had undergone a baseline liver biopsy pre-2004 and a follow up liver fibrosis assessment more than 10 years later (biopsy or liver stiffness measurement (LSM) using transient elastography [FibroScan]) were identified. Subjects who had undergone a baseline liver biopsy but had no follow up fibrosis assessment were recalled for LSM. Fibrosis was categorised as mild-moderate (METAVIR F0-2 / LSM result of ≤ 9.5 kPa) or advanced (METAVIR F3-4/ LSM >9.5 kPa). The primary objective was to assess the association between SVR and the rate of liver fibrosis progression over at least 10 years, defined as an increase from mild-moderate fibrosis at baseline liver biopsy (METAVIR F0-2) to advanced fibrosis at follow-up liver fibrosis assessment.131 subjects were included in this analysis: 69% male, 82% Caucasian, 60% G1 HCV, 25% G3 HCV. The median age at F/U fibrosis staging was 57 (IQR 54-62) years with median estimated duration of infection 33-years (IQR 29-38). At F/U, liver fibrosis assessment was performed by LSM in 86% and liver biopsy in 14%. The median period between fibrosis assessments was 14-years (IQR 12-17). 109 (83%) participants had received interferon-based antiviral therapy. 40% attained SVR. At F/U, there was a significant increase in the proportion of subjects with advanced liver fibrosis: 27% at baseline vs. 46% at F/U (p = 0.002). The prevalence of advanced fibrosis did not change among subjects who attained SVR, 30% at B/L vs 25% at F/U (p = 0.343). However, advanced fibrosis became more common at F/U among subjects with persistent viremia: 10% at B/L vs 31% at F/U (p = 0.0001). SVR was independently associated with protection from liver fibrosis progression after adjustment for other variables including baseline ALT (p = 0.011), duration of HCV infection and mode of acquisition.HCV eradication is associated with lower rates of liver fibrosis progression. The data support early treatment to prevent long-term liver complications of HCV infection.
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- 2017
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8. Environmental Drivers of Benthic Flux Variation and Ecosystem Functioning in Salish Sea and Northeast Pacific Sediments.
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Rénald Belley, Paul V R Snelgrove, Philippe Archambault, and S Kim Juniper
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Medicine ,Science - Abstract
The upwelling of deep waters from the oxygen minimum zone in the Northeast Pacific from the continental slope to the shelf and into the Salish Sea during spring and summer offers a unique opportunity to study ecosystem functioning in the form of benthic fluxes along natural gradients. Using the ROV ROPOS we collected sediment cores from 10 sites in May and July 2011, and September 2013 to perform shipboard incubations and flux measurements. Specifically, we measured benthic fluxes of oxygen and nutrients to evaluate potential environmental drivers of benthic flux variation and ecosystem functioning along natural gradients of temperature and bottom water dissolved oxygen concentrations. The range of temperature and dissolved oxygen encountered across our study sites allowed us to apply a suite of multivariate analyses rarely used in flux studies to identify bottom water temperature as the primary environmental driver of benthic flux variation and organic matter remineralization. Redundancy analysis revealed that bottom water characteristics (temperature and dissolved oxygen), quality of organic matter (chl a:phaeo and C:N ratios) and sediment characteristics (mean grain size and porosity) explained 51.5% of benthic flux variation. Multivariate analyses identified significant spatial and temporal variation in benthic fluxes, demonstrating key differences between the Northeast Pacific and Salish Sea. Moreover, Northeast Pacific slope fluxes were generally lower than shelf fluxes. Spatial and temporal variation in benthic fluxes in the Salish Sea were driven primarily by differences in temperature and quality of organic matter on the seafloor following phytoplankton blooms. These results demonstrate the utility of multivariate approaches in differentiating among potential drivers of seafloor ecosystem functioning, and indicate that current and future predictive models of organic matter remineralization and ecosystem functioning of soft-muddy shelf and slope seafloor habitats should consider bottom water temperature variation. Bottom temperature has important implications for estimates of seasonal and spatial benthic flux variation, benthic-pelagic coupling, and impacts of predicted ocean warming at high latitudes.
- Published
- 2016
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9. Striking Phenotypic Variation yet Low Genetic Differentiation in Sympatric Lake Trout (Salvelinus namaycush).
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Kia Marin, Andrew Coon, Robert Carson, Paul V Debes, and Dylan J Fraser
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Medicine ,Science - Abstract
The study of population differentiation in the context of ecological speciation is commonly assessed using populations with obvious discreteness. Fewer studies have examined diversifying populations with occasional adaptive variation and minor reproductive isolation, so factors impeding or facilitating the progress of early stage differentiation are less understood. We detected non-random genetic structuring in lake trout (Salvelinus namaycush) inhabiting a large, pristine, postglacial lake (Mistassini Lake, Canada), with up to five discernible genetic clusters having distinctions in body shape, size, colouration and head shape. However, genetic differentiation was low (FST = 0.017) and genetic clustering was largely incongruent between several population- and individual-based clustering approaches. Genotype- and phenotype-environment associations with spatial habitat, depth and fish community structure (competitors and prey) were either inconsistent or weak. Striking morphological variation was often more continuous within than among defined genetic clusters. Low genetic differentiation was a consequence of relatively high contemporary gene flow despite large effective population sizes, not migration-drift disequilibrium. Our results suggest a highly plastic propensity for occupying multiple habitat niches in lake trout and a low cost of morphological plasticity, which may constrain the speed and extent of adaptive divergence. We discuss how factors relating to niche conservatism in this species may also influence how plasticity affects adaptive divergence, even where ample ecological opportunity apparently exists.
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- 2016
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10. Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus.
- Author
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Jeffrey C Boyington, M Gordon Joyce, Mallika Sastry, Guillaume B E Stewart-Jones, Man Chen, Wing-Pui Kong, Joan O Ngwuta, Paul V Thomas, Yaroslav Tsybovsky, Yongping Yang, Baoshan Zhang, Lei Chen, Aliaksandr Druz, Ivelin S Georgiev, Kiyoon Ko, Tongqing Zhou, John R Mascola, Barney S Graham, and Peter D Kwong
- Subjects
Medicine ,Science - Abstract
Respiratory syncytial virus (RSV) is a significant cause of severe respiratory illness worldwide, particularly in infants, young children, and the elderly. Although no licensed vaccine is currently available, an engineered version of the metastable RSV fusion (F) surface glycoprotein-stabilized in the pre-fusion (pre-F) conformation by "DS-Cav1" mutations-elicits high titer RSV-neutralizing responses. Moreover, pre-F-specific antibodies, often against the neutralization-sensitive antigenic site Ø in the membrane-distal head region of trimeric F glycoprotein, comprise a substantial portion of the human response to natural RSV infection. To focus the vaccine-elicited response to antigenic site Ø, we designed a series of RSV F immunogens that comprised the membrane-distal head of the F glycoprotein in its pre-F conformation. These "head-only" immunogens formed monomers, dimers, and trimers. Antigenic analysis revealed that a majority of the 70 engineered head-only immunogens displayed reactivity to site Ø-targeting antibodies, which was similar to that of the parent RSV F DS-Cav1 trimers, often with increased thermostability. We evaluated four of these head-only immunogens in detail, probing their recognition by antibodies, their physical stability, structure, and immunogenicity. When tested in naïve mice, a head-only trimer, half the size of the parent RSV F trimer, induced RSV titers, which were statistically comparable to those induced by DS-Cav1. When used to boost DS-Cav1-primed mice, two head-only RSV F immunogens, a dimer and a trimer, boosted RSV-neutralizing titers to levels that were comparable to those boosted by DS-Cav1, although with higher site Ø-directed responses. Our results provide proof-of-concept for the ability of the smaller head-only RSV F immunogens to focus the vaccine-elicited response to antigenic site Ø. Decent primary immunogenicity, enhanced physical stability, potential ease of manufacture, and potent immunogenicity upon boosting suggest these head-only RSV F immunogens, engineered to retain the pre-fusion conformation, may have advantages as candidate RSV vaccines.
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- 2016
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11. Mapping Above- and Below-Ground Carbon Pools in Boreal Forests: The Case for Airborne Lidar.
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Terje Kristensen, Erik Næsset, Mikael Ohlson, Paul V Bolstad, and Randall Kolka
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Medicine ,Science - Abstract
A large and growing body of evidence has demonstrated that airborne scanning light detection and ranging (lidar) systems can be an effective tool in measuring and monitoring above-ground forest tree biomass. However, the potential of lidar as an all-round tool for assisting in assessment of carbon (C) stocks in soil and non-tree vegetation components of the forest ecosystem has been given much less attention. Here we combine the use airborne small footprint scanning lidar with fine-scale spatial C data relating to vegetation and the soil surface to describe and contrast the size and spatial distribution of C pools within and among multilayered Norway spruce (Picea abies) stands. Predictor variables from lidar derived metrics delivered precise models of above- and below-ground tree C, which comprised the largest C pool in our study stands. We also found evidence that lidar canopy data correlated well with the variation in field layer C stock, consisting mainly of ericaceous dwarf shrubs and herbaceous plants. However, lidar metrics derived directly from understory echoes did not yield significant models. Furthermore, our results indicate that the variation in both the mosses and soil organic layer C stock plots appears less influenced by differences in stand structure properties than topographical gradients. By using topographical models from lidar ground returns we were able to establish a strong correlation between lidar data and the organic layer C stock at a stand level. Increasing the topographical resolution from plot averages (~2000 m2) towards individual grid cells (1 m2) did not yield consistent models. Our study demonstrates a connection between the size and distribution of different forest C pools and models derived from airborne lidar data, providing a foundation for future research concerning the use of lidar for assessing and monitoring boreal forest C.
- Published
- 2015
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12. Decline in an Atlantic Puffin Population: Evaluation of Magnitude and Mechanisms.
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Will T S Miles, Roddy Mavor, Nick J Riddiford, Paul V Harvey, Roger Riddington, Deryk N Shaw, David Parnaby, and Jane M Reid
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Medicine ,Science - Abstract
Determining which demographic and ecological parameters contribute to variation in population growth rate is crucial to understanding the dynamics of declining populations. This study aimed to evaluate the magnitude and mechanisms of an apparent major decline in an Atlantic Puffin Fratercula arctica population. This was achieved using a 27-year dataset to estimate changes in population size and in two key demographic rates: adult survival and breeding success. Estimated demographic variation was then related to two ecological factors hypothesised to be key drivers of demographic change, namely the abundance of the main predator at the study site, the Great Skua Stercorarius skua, and Atlantic Puffin chick food supply, over the same 27-year period. Using a population model, we assessed whether estimated variation in adult survival and reproductive success was sufficient to explain the population change observed. Estimates of Atlantic Puffin population size decreased considerably during the study period, approximately halving, whereas Great Skua population estimates increased, approximately trebling. Estimated adult Atlantic Puffin survival remained high across all years and did not vary with Great Skua abundance; however, Atlantic Puffin breeding success and quantities of fish prey brought ashore by adults both decreased substantially through the period. A population model combining best possible demographic parameter estimates predicted rapid population growth, at odds with the long-term decrease observed. To simulate the observed decrease, population models had to incorporate low immature survival, high immature emigration, or increasingly high adult non-breeding rates. We concluded that reduced recruitment of immatures into the breeding population was the most likely cause of population decrease. This study showed that increase in the size of a predator population does not always impact on the survival of adult prey and that reduced recruitment can be a crucial determinant of seabird population size but can easily go undetected.
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- 2015
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13. Reduced IL-17A Secretion Is Associated with High Levels of Pneumococcal Nasopharyngeal Carriage in Fijian Children.
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Edwin Hoe, Laura K Boelsen, Zheng Quan Toh, Guang Wen Sun, Ghee Chong Koo, Anne Balloch, Rachel Marimla, Eileen M Dunne, Lisi Tikoduadua, Fiona M Russell, Catherine Satzke, E Kim Mulholland, and Paul V Licciardi
- Subjects
Medicine ,Science - Abstract
Streptococcus pneumonia (the pneumococcus) is the leading vaccine preventable cause of serious infections in infants under 5 years of age. The major correlate of protection for pneumococcal infections is serotype-specific IgG antibody. More recently, antibody-independent mechanisms of protection have also been identified. Preclinical studies have found that IL-17 secreting CD4+ Th17 cells in reducing pneumococcal colonisation. This study assessed IL-17A levels in children from Fiji with high and low pneumococcal carriage density, as measured by quantitative real-time PCR (qPCR). We studied Th17 responses in 54 children who were designated as high density carriers (N=27, >8.21x10(5) CFU/ml) or low density carriers (N=27,
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- 2015
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14. A Cysteine Zipper Stabilizes a Pre-Fusion F Glycoprotein Vaccine for Respiratory Syncytial Virus.
- Author
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Guillaume B E Stewart-Jones, Paul V Thomas, Man Chen, Aliaksandr Druz, M Gordon Joyce, Wing-Pui Kong, Mallika Sastry, Cinque Soto, Yongping Yang, Baoshan Zhang, Lei Chen, Gwo-Yu Chuang, Ivelin S Georgiev, Jason S McLellan, Sanjay Srivatsan, Tongqing Zhou, Ulrich Baxa, John R Mascola, Barney S Graham, and Peter D Kwong
- Subjects
Medicine ,Science - Abstract
Recombinant subunit vaccines should contain minimal non-pathogen motifs to reduce potential off-target reactivity. We recently developed a vaccine antigen against respiratory syncytial virus (RSV), which comprised the fusion (F) glycoprotein stabilized in its pre-fusion trimeric conformation by "DS-Cav1" mutations and by an appended C-terminal trimerization motif or "foldon" from T4-bacteriophage fibritin. Here we investigate the creation of a cysteine zipper to allow for the removal of the phage foldon, while maintaining the immunogenicity of the parent DS-Cav1+foldon antigen. Constructs without foldon yielded RSV F monomers, and enzymatic removal of the phage foldon from pre-fusion F trimers resulted in their dissociation into monomers. Because the native C terminus of the pre-fusion RSV F ectodomain encompasses a viral trimeric coiled-coil, we explored whether introduction of cysteine residues capable of forming inter-protomer disulfides might allow for stable trimers. Structural modeling indicated the introduced cysteines to form disulfide "rings", with each ring comprising a different set of inward facing residues of the coiled-coil. Three sets of rings could be placed within the native RSV F coiled-coil, and additional rings could be added by duplicating portions of the coiled-coil. High levels of neutralizing activity in mice, equivalent to that of the parent DS-Cav1+foldon antigen, were elicited by a 4-ring stabilized RSV F trimer with no foldon. Structure-based alteration of a viral coiled-coil to create a cysteine zipper thus allows a phage trimerization motif to be removed from a candidate vaccine antigen.
- Published
- 2015
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15. Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs
- Author
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Kenneth C. Bagley, Nika Hajari, Deborah H. Fuller, Debra Bratt, Megan A. O'Connor, Hillary C. Tunggal, Sandra Dross, James T. Fuller, and Paul V. Munson
- Subjects
0301 basic medicine ,T-Lymphocytes ,medicine.medical_treatment ,Simian Acquired Immunodeficiency Syndrome ,Monkeys ,White Blood Cells ,Medical Conditions ,0302 clinical medicine ,Animal Cells ,Medicine and Health Sciences ,Vaccines, DNA ,Medicine ,Cytotoxic T cell ,Public and Occupational Health ,030212 general & internal medicine ,Mammals ,Vaccines ,Multidisciplinary ,T Cells ,Viral Vaccine ,Eukaryota ,Viral Load ,Vaccination and Immunization ,Vaccination ,Infectious Diseases ,medicine.anatomical_structure ,Anti-Retroviral Agents ,Vertebrates ,Simian Immunodeficiency Virus ,Cellular Types ,Viral load ,Adjuvant ,Macaque ,Research Article ,Primates ,Infectious Disease Control ,Science ,Immune Cells ,T cell ,Immunology ,Antiretroviral Therapy ,Cytotoxic T cells ,Microbiology ,DNA vaccination ,03 medical and health sciences ,Antiviral Therapy ,Virology ,Old World monkeys ,Animals ,Blood Cells ,business.industry ,HIV vaccines ,Organisms ,Biology and Life Sciences ,Viral Vaccines ,Cell Biology ,Macaca mulatta ,Viral Replication ,030104 developmental biology ,Viral replication ,Amniotes ,Preventive Medicine ,business ,Zoology ,Viral Transmission and Infection - Abstract
A therapeutic vaccine that induces lasting control of HIV infection could eliminate the need for lifelong adherence to antiretroviral therapy. This study investigated a therapeutic DNA vaccine delivered with a single adjuvant or a novel combination of adjuvants to augment T cell immunity in the blood and gut-associated lymphoid tissue in SIV-infected rhesus macaques. Animals that received DNA vaccines expressing SIV proteins, combined with plasmids expressing adjuvants designed to increase peripheral and mucosal T cell responses, including the catalytic subunit of the E. coli heat-labile enterotoxin, IL-12, IL-33, retinaldehyde dehydrogenase 2, soluble PD-1 and soluble CD80, were compared to mock-vaccinated controls. Following treatment interruption, macaques exhibited variable levels of viral rebound, with four animals from the vaccinated groups and one animal from the control group controlling virus at median levels of 103 RNA copies/ml or lower (controllers) and nine animals, among all groups, exhibiting immediate viral rebound and median viral loads greater than 103 RNA copies/ml (non-controllers). Although there was no significant difference between the vaccinated and control groups in protection from viral rebound, the variable virological outcomes during treatment interruption enabled an examination of immune correlates of viral replication in controllers versus non-controllers regardless of vaccination status. Lower viral burden in controllers correlated with increased polyfunctional SIV-specific CD8+ T cells in mesenteric lymph nodes and blood prior to and during treatment interruption. Notably, higher frequencies of colonic CD4+ T cells and lower Th17/Treg ratios prior to infection in controllers correlated with improved responses to ART and control of viral rebound. These results indicate that mucosal immune responses, present prior to infection, can influence efficacy of antiretroviral therapy and the outcome of immunotherapeutic vaccination, suggesting that therapies capable of modulating host mucosal responses may be needed to achieve HIV cure.
- Published
- 2021
16. Fiber alignment drives changes in architectural and mechanical features in collagen matrices
- Author
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Adam Muñoz, Matthew R. Zanotelli, Jacob A. VanderBurgh, Paul V. Taufalele, and Cynthia A. Reinhart-King
- Subjects
0301 basic medicine ,Fibrillar Collagens ,02 engineering and technology ,Microscopy, Atomic Force ,Biochemistry ,Stiffness ,Polymerization ,Extracellular matrix ,Matrix (mathematics) ,Collagen matrices ,Cell Movement ,Neoplasms ,Fiber ,Microscopy ,Multidisciplinary ,Chemical Reactions ,021001 nanoscience & nanotechnology ,Extracellular Matrix ,Cancer Cell Migration ,Atomic Force Microscopy ,Chemistry ,Cell Motility ,Aspect Ratio ,Physical Sciences ,Disease Progression ,Medicine ,medicine.symptom ,Cellular Structures and Organelles ,0210 nano-technology ,Algorithms ,Research Article ,Pore size ,Materials science ,Science ,Materials Science ,Material Properties ,Temperature independent ,Cancer metastasis ,Geometry ,Cell Migration ,Research and Analysis Methods ,03 medical and health sciences ,medicine ,Humans ,Mechanical Properties ,Scanning Probe Microscopy ,Biology and Life Sciences ,Proteins ,Cell Biology ,Polymer Chemistry ,030104 developmental biology ,Biophysics ,Collagens ,Mathematics ,Developmental Biology - Abstract
Aligned collagen architecture is a characteristic feature of the tumor extracellular matrix (ECM) and has been shown to facilitate cancer metastasis using 3D in vitro models. Additional features of the ECM, such as pore size and stiffness, have also been shown to influence cellular behavior and are implicated in cancer progression. While there are several methods to produce aligned matrices to study the effect on cell behavior in vitro, it is unclear how the alignment itself may alter these other important features of the matrix. In this study, we have generated aligned collagen matrices and characterized their pore sizes and mechanical properties at the micro- and macro-scale. Our results indicate that collagen alignment can alter pore-size of matrices depending on the polymerization temperature of the collagen. Furthermore, alignment does not affect the macro-scale stiffness but alters the micro-scale stiffness in a temperature independent manner. Overall, these results describe the manifestation of confounding variables that arise due to alignment and the importance of fully characterizing biomaterials at both micro- and macro-scales.
- Published
- 2019
17. Correction: Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation
- Author
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Paul V. Munson, Anne Messer, Merika Treants Koday, Michael Koday, Yuhui Hu, Steven J. Gray, Jeremy Smedley, Debbie Bratt, Deborah H. Fuller, Andrew A. Reilly, Robert D. Murnane, and Arlene I. Ramsingh
- Subjects
0301 basic medicine ,Central Nervous System ,Physiology ,lcsh:Medicine ,Antibody Response ,Gene Expression ,Monkeys ,Nervous System ,Autoantigens ,Viral Packaging ,Animals, Genetically Modified ,White Blood Cells ,Random Allocation ,Animal Cells ,Transduction, Genetic ,Immune Physiology ,Medicine and Health Sciences ,Medicine ,Transgenes ,Enzyme-Linked Immunoassays ,lcsh:Science ,Immune Response ,Cerebrospinal Fluid ,Mammals ,Innate Immune System ,Multidisciplinary ,T Cells ,Gene Transfer Techniques ,Eukaryota ,Dependovirus ,Cell biology ,Body Fluids ,Expression (architecture) ,Vertebrates ,Self-protein ,Cytokines ,Cellular Types ,Anatomy ,Macaque ,Research Article ,Primates ,Immune Cells ,Immunology ,Genetic Vectors ,Green Fluorescent Proteins ,Research and Analysis Methods ,Microbiology ,Immunomodulation ,03 medical and health sciences ,Virology ,Old World monkeys ,Animals ,Immunoassays ,Blood Cells ,business.industry ,lcsh:R ,fungi ,Organisms ,Biology and Life Sciences ,Correction ,Cell Biology ,Molecular Development ,Viral Replication ,Macaca fascicularis ,030104 developmental biology ,Immune System ,Amniotes ,Immunologic Techniques ,lcsh:Q ,business ,Developmental Biology - Abstract
A critical issue in transgene delivery studies is immune reactivity to the transgene- encoded protein and its impact on sustained gene expression. Here, we test the hypothesis that immunomodulation by rapamycin can decrease immune reactivity after intrathecal AAV9 delivery of a transgene (GFP) in non-human primates, resulting in sustained GFP expression in the CNS. We show that rapamycin treatment clearly reduced the overall immunogenicity of the AAV9/GFP vector by lowering GFP- and AAV9-specific antibody responses, and decreasing T cell responses including cytokine and cytolytic effector responses. Spinal cord GFP protein expression was sustained for twelve weeks, with no toxicity. Immune correlates of robust transgene expression include negligible GFP-specific CD4 and CD8 T cell responses, absence of GFP-specific IFN-γ producing T cells, and absence of GFP-specific cytotoxic T cells, which support the hypothesis that decreased T cell reactivity results in sustained transgene expression. These data strongly support the use of modest doses of rapamycin to modulate immune responses for intrathecal gene therapies, and potentially a much wider range of viral vector-based therapeutics.
- Published
- 2018
18. Genome annotation improvements from cross-phyla proteogenomics and time-of-day differences in malaria mosquito proteins using untargeted quantitative proteomics
- Author
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Lisa, Imrie, Thierry, Le Bihan, Áine, O'Toole, Paul V, Hickner, W Augustine, Dunn, Benjamin, Weise, and Samuel S C, Rund
- Subjects
Proteomics ,Arthropoda ,Proteomes ,Anopheles Gambiae ,India ,Gene Expression ,Mosquito Vectors ,Disease Vectors ,Research and Analysis Methods ,Biochemistry ,Mosquitoes ,Mass Spectrometry ,Database and Informatics Methods ,parasitic diseases ,Anopheles ,Genetics ,Medicine and Health Sciences ,Animals ,Humans ,Proteogenomics ,Proteomic Databases ,fungi ,Organisms ,Biology and Life Sciences ,Proteins ,Computational Biology ,Eukaryota ,Sequence Analysis, DNA ,Genomics ,Genome Analysis ,Genome Annotation ,Invertebrates ,Malaria ,Insect Vectors ,Insects ,Species Interactions ,Biological Databases ,Infectious Diseases ,Insect Proteins ,Peptides ,Protein Abundance ,Research Article - Abstract
The malaria mosquito, Anopheles stephensi, and other mosquitoes modulate their biology to match the time-of-day. In the present work, we used a non-hypothesis driven approach (untargeted proteomics) to identify proteins in mosquito tissue, and then quantified the relative abundance of the identified proteins from An. stephensi bodies. Using these quantified protein levels, we then analyzed the data for proteins that were only detectable at certain times-of-the day, highlighting the need to consider time-of-day in experimental design. Further, we extended our time-of-day analysis to look for proteins which cycle in a rhythmic 24-hour (“circadian”) manner, identifying 31 rhythmic proteins. Finally, to maximize the utility of our data, we performed a proteogenomic analysis to improve the genome annotation of An. stephensi. We compare peptides that were detected using mass spectrometry but are ‘missing’ from the An. stephensi predicted proteome, to reference proteomes from 38 other primarily human disease vector species. We found 239 such peptide matches and reveal that genome annotation can be improved using proteogenomic analysis from taxonomically diverse reference proteomes. Examination of ‘missing’ peptides revealed reading frame errors, errors in gene-calling, overlapping gene models, and suspected gaps in the genome assembly.
- Published
- 2018
19. Genome annotation improvements from cross-phyla proteogenomics and time-of-day differences in malaria mosquito proteins using untargeted quantitative proteomics
- Author
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Imrie, Lisa, primary, Le Bihan, Thierry, additional, O'Toole, Áine, additional, Hickner, Paul V., additional, Dunn, W. Augustine, additional, Weise, Benjamin, additional, and Rund, Samuel S. C., additional
- Published
- 2019
- Full Text
- View/download PDF
20. Fiber alignment drives changes in architectural and mechanical features in collagen matrices
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Taufalele, Paul V., primary, VanderBurgh, Jacob A., additional, Muñoz, Adam, additional, Zanotelli, Matthew R., additional, and Reinhart-King, Cynthia A., additional
- Published
- 2019
- Full Text
- View/download PDF
21. Multigenic DNA vaccine induces protective cross-reactive T cell responses against heterologous influenza virus in nonhuman primates
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Deborah H. Fuller, Michael G. Katze, Juliet Morrison, Kelly Stefano-Cole, Shulin Qin, Karen M. Duus, James T. Fuller, Jolie A. Leonard, Todd A. Reinhart, Debra Bratt, Merika Treants Koday, Michael Koday, Robert D. Murnane, Paul V. Munson, Adriana Forero, Amy L. Hartman, Ilhem Messaoudi, and Krammer, Florian
- Subjects
0301 basic medicine ,and promotion of well-being ,Viral Diseases ,Physiology ,T-Lymphocytes ,lcsh:Medicine ,Antibody Response ,Monkeys ,medicine.disease_cause ,DNA vaccination ,Biochemistry ,White Blood Cells ,0302 clinical medicine ,Influenza A Virus, H1N1 Subtype ,Animal Cells ,Immune Physiology ,Influenza A virus ,Influenza A Virus ,Medicine and Health Sciences ,Vaccines, DNA ,030212 general & internal medicine ,Enzyme-Linked Immunoassays ,Neutralizing antibody ,lcsh:Science ,Neutralizing ,Immune Response ,Mammals ,Vaccines ,Multidisciplinary ,Immune System Proteins ,biology ,T Cells ,Immunogenicity ,Antibody titer ,Eukaryota ,3. Good health ,Infectious Diseases ,3.4 Vaccines ,5.1 Pharmaceuticals ,Influenza Vaccines ,Vertebrates ,Pneumonia & Influenza ,Vaccination and immunization ,Development of treatments and therapeutic interventions ,Cellular Types ,Infection ,Viral load ,Macaque ,Biotechnology ,Research Article ,Primates ,Infectious Disease Control ,General Science & Technology ,Immune Cells ,Immunology ,Heterologous ,Cross Reactions ,Research and Analysis Methods ,Virus ,Antibodies ,Vaccine Related ,03 medical and health sciences ,Biodefense ,MD Multidisciplinary ,Old World monkeys ,medicine ,Animals ,H1N1 Subtype ,Vaccine Related (AIDS) ,Immunoassays ,Preventive medicine ,Blood Cells ,Biology and life sciences ,Prevention ,lcsh:R ,Organisms ,Proteins ,DNA ,Cell Biology ,Prevention of disease and conditions ,Virology ,Antibodies, Neutralizing ,Influenza ,Macaca fascicularis ,030104 developmental biology ,Emerging Infectious Diseases ,Public and occupational health ,Amniotes ,biology.protein ,Immunologic Techniques ,Immunization ,lcsh:Q - Abstract
Recent avian and swine-origin influenza virus outbreaks illustrate the ongoing threat of influenza pandemics. We investigated immunogenicity and protective efficacy of a multi-antigen (MA) universal influenza DNA vaccine consisting of HA, M2, and NP antigens in cynomolgus macaques. Following challenge with a heterologous pandemic H1N1 strain, vaccinated animals exhibited significantly lower viral loads and more rapid viral clearance when compared to unvaccinated controls. The MA DNA vaccine induced robust serum and mucosal antibody responses but these high antibody titers were not broadly neutralizing. In contrast, the vaccine induced broadly-reactive NP specific T cell responses that cross-reacted with the challenge virus and inversely correlated with lower viral loads and inflammation. These results demonstrate that a MA DNA vaccine that induces strong cross-reactive T cell responses can, independent of neutralizing antibody, mediate significant cross-protection in a nonhuman primate model and further supports development as an effective approach to induce broad protection against circulating and emerging influenza strains.
- Published
- 2017
22. Quality of Vitamin K Antagonist Control and 1-Year Outcomes in Patients with Atrial Fibrillation: A Global Perspective from the GARFIELD-AF Registry
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Faria Neto, J., Steffens, A., Yim, K. H., Yoo, K. M., Yoon, E. J., Yun, S. Y., Angchaisuksiri, P., Chawanadelert, S., Mongkolwongroj, P., Kanokphatcharakun, K., Cheewatanakornkul, S., Laksomya, T., Pattanaprichakul, S., Chantrarat, T., Rungaramsin, S., Silaruks, S., Wongcharoen, W., Siriwattana, K., Likittanasombat, K., Katekangplu, P., Boonyapisit, W., Cholsaringkarl, D., Chatlaong, B., Chattranukulchai, P., Santanakorn, Y., Hutayanon, P., Khunrong, P., Bunyapipat, T., Jai-Aue, S., Kaewsuwanna, P., Bamungpong, P., Gunaparn, S., Hongsuppinyo, S., Inphontan, R., Khattaroek, R., Khunkong, K., Kitmapawanont, U., Kongsin, C., Naratreekoon, B., Ninwaranon, S., Phangyota, J., Phrommintikul, A., Phunpinyosak, P., Pongmorakot, K., Poomiphol, S., Pornnimitthum, N., Pumprueg, S., Ratchasikaew, S., Sanit, K., Sawanyawisuth, K., Silaruks, B., Sirichai, R., Sriwichian, A., Suebjaksing, W., Sukklad, P., Suttana, T., Vensentini, N., Ingaramo, A. C., Sambadaro, G. A., Fernandez Caputi, V, Berman, S. G., Dragotto, P., Kleiban, A. J., Centurion, N., Giacomi, G., Ahuad Guerrero, R. A., Conde, D., Zapata, G., Di Paola, L. A., Ramos, J. L., Dran, R. D., Egido, J., Fernandez, A. A., Fosco, M. J., Sassone, S., Sinisi, V. A., Cartasegna, L. R., Berli, M. A., Gomez Vilamajo, O. A., Ferroni, F., Alaguibe, E. D., Alvarez D'Amelio, A., Arabetti, C., Arias, L., Belardi, J. A., Bergesio, L., Berli, F., Berli, M., Borchowiec, S., Buzzetti, C., Cabrini, R., Campisi, V, Cappi, A. L., Carrizo, R., Colombo Berra, F., Costabel, J. P., Costamagna, O. J. A., Damonte, A. A., De Urquiza, I. N., Diez, F., Eden, M. F., Fanuele, M., Fernandez Voena, F., Foa Torres, M., Funosas, C., Giacomi, M. P., Gimenez, C. H., Gurfinkel, E. P., Had, M. de L. M., Hansen, V, Hrabar, A. D., Ingratta, M., Lopez, A., Maehara, G., Maffei, L., Martinelli, A., Martinelli, C., Matkovich, J., Mautner, B., Meirino, A., Munguia, R., Navarro, A., Novas, V, Perez Prados, G., Pontoriero, J., Potito, R. N., Ricotti, C., Rodriguez, M. A., Mairesse, G., Boussy, T., Godart, P., De Wolf, A., Voet, J., Heyse, A., Hollanders, G., Ann, W., Vercammen, J., Purnode, P., Blankoff, I, Faes, D., Balthazar, Y., Beutels, M., Marechal, P., Verstraete, S., Xhaet, O., Striekwold, H., Thoeng, J., Hermans, K., Alzand, B., Ascoop, A-K, Banaeian, F., Barbuto, A-M, Billiaux, A. C., Blockmans, M., Bouvy, C., Brike, C., Capiau, H., Casier, T., Conde Y Bolado, A., De Cleen, D., De Coninck, M., de Vos, M., de Weerdt, N., Delforge, M., Delvigne, M., Denie, D., Derycker, K., Deweerd, E., Dormal, F., Drieghe, S., Everaert, M., Eykerman, T., Feys, E., Ghekiere, M., Gits, F., Hellemans, S., Helvasto, L., Jacobs, C., Lips, S., Mestdagh, I, Nimmegeers, J., Piamonte, V, Pollet, P., Postolache, A., Raepers, M., Raymenants, E., Richa, J., Rombouts, H., Salembier, J., Scheurwegs, C., Semeraro, O., Simons, N., Smessaert, C., Smolders, W., Stockman, I, Tahon, S., Thyssen, V, Tincani, G., Van Durme, F., Van Lier, D., Vandekerckhove, H., Vandekerckhove, Y., Vandenbroeck, D., Vandorpe, A., Vanhalst, E., Vanhauwaert, B., Vantomme, C., Vergauwen, L., Verloove, H., Vydt, T., Weyn, T., Jansky, P., Reichert, P., Spacek, R., Machova, V, Zidkova, E., Ludka, O., Olsr, J., Kotik, L., Plocova, K., Racz, B., Ferkl, R., Hubac, J., Kotik, I, Monhart, Z., Burianova, H., Jerabek, O., Pisova, J., Petrova, I, Dedek, V, Honkova, M., Podrazil, P., Spinar, J., Vitovec, J., Novak, M., Lastuvka, J., Durdil, V, Antonova, P., Bockova, L., Bultas, J., Chlumsky, J., Dastychova, L., Drasnar, T., Honek, J., Horejsi, M., Hubacova, V, Janska, L., Kopeckova, I, Kratochvilova, R., Krcova, E., Labrova, R., Lindourkova, A., Lipoldova, J., Lubanda, H., Ludkova, A., Mahdalikova, L., Majernikova, M., Michalik, D., Potuznik, P., Prochazkova, E., Sulc, A., Sveceny, J., Valtova, M., Zidek, M., D'Avino, M., Bongiorni, M. G., Severi, S., Capucci, A., Lodigiani, C., Salomone, E., Serviddio, G., Tondo, C., Golino, P., Mazzone, C., Iacopino, S., Pengo, V, Galvani, M., Moretti, L., Ambrosino, P., Banfi, E., Biagioli, V, Bianchi, A., Boggian, G., Breschi, M., Brusorio, S., Calcagnoli, F., Campagna, G., Carpenedo, M., Ciabatta, C., Ciliberti, G., Cimmino, G., D'Arienzo, C., Di Gennaro, L., Fedele, M., Ferrini, P. M., Granzow, K., Guazzaloca, G., Guerra, F., Lo Buglio, A., Longo, S., Macellari, F., Mesolella, E., Rolandi, F., Said Palladino, M. E., Salinger, M., Sanziani, L. S., Schygiel, P. O., Sossich, A., Tinto, J. F., Tonelli, L., Tufare, A. L., Vallejo, M., Yunis, M. E., Zillo, M., Zurbrigk, F. J., Barretto, A. C. P., Sobral Filho, D. C., Jaber, J., Armaganijan, D., Kakkar, Ajay K., Worthy, V, Verdi, C., Tripti, T., Treasure, L., Thompson, N., Theobald, H., Thatcher, A., Stephanie, B., Smith, K., Shoemaker, J., Shaw, P., Sanghera, T., Sage, A., Robertson, C., Richardson, T., Richard, C., Raziano, S., Raynor, J., Purcell, T., Pickelsimer, N., Peterson, J., Pearl, G., Paserchia, S., Parrott, T., Parker, M., Palumbo, V, Orosco, C., Minardo, J., Merritt, D., Merliss, A., Malone, E., Lincoln, T., Lee, J. A., Lay, M., Langdon, J., Knowles, P., Kerr, J., Keeling, M., Karl, S., Jones, P., Jones, L., Jones, A., Jasinski, S., Hicks, T., Hawkins, B., Hartranft, E., Harbour, T., Hakimi, F., Haideri, A., Gentry, P., Fielder, D., Ferdinand, K., Felpel, S., Evans, L., Eley, M., Dickerson, A., DePauw, J., Congal, S., Cervellione, K., Cassidy, D., Canova, M., Cameron-Watts, J., Browne, A., Brown, A., Bowers, S., Bentley, M., Bartlett, M., Ball, K., Asafu-Adjaye, N., Treasure, C., Nishijima, D., Pitta, S., Duffy, P., Noveck, H., Ison, R., Alberts, M., Remmel, K., Theodoro, D., Diercks, D., Delafontaine, P., Ahmed, W., Reddy, R., Haque, I, Gutowski, T., Alfieri, A., Beach, S., Miller, S., Williams, M., Mendelson, R., Falkowski, S., Franco, M., Cox, M., Kutayli, W. M., Ferrick, K., Quick, A., Wilson, V, Mullen, P., Garcia, J., Blumberg, E., Rama, P., Canosa, R., Goldhaber, S. Z., Thanzeel, M., Sharma, R., Sharma, N., Mohamed, R., Maqsood, I, Makdad, M., Magdaluyo, K., Jadhav, S., Haridas, P., El Bardisy, S., Al Mulla, A., Abdul, A., Subbaraman, B., Khan, M., Gupta, R., Wassef, A., Bazargani, N., Maruthanayagam, R., Al Naeemi, A., Al Omairi, M., Abu-Mahfouz, M., Naguib, A., Singh, R., Esheiba, E. M., Ibrahim, M., Nathani, M., Agrawal, A., Yousef, G., Al Mahmeed, W., van Zyl, F., Tau, T., Tarr, G., Smith, L., Skein, A., Shaik, F., Sasto, J., Salie, M., Rikhotso, L., Page, A., Mostert, M., Mavhusa, L., Marks, J., Loyd, E., Karsten, M., Henley, L., Ellis, T., Du Plessis, G., de Meyer, L., Davids, A., Conway, G., Chami, C., Cassimjee, S., Cannon, C., Boshoff, C., Booysen, M., Bester, C., Angel, G., Oosthuysen, W., Maharajh, S., Ramdass, A., Engelbrecht, J., Ahmed, F., Ismail, S., Loghdey, R., Ueckermann, V, Mntla, P., Greyling, D., Louw, R., Murray, A., Theron, H., van Zyl, L., Guerra, M., Pillay, T., Garda, R., Kelfkens, Y., Horak, A., Siebert, H., Bayat, J., Kettles, D., Zaatout, E., Tawfik, M., Taha, N., Soliman, A., Sobhy, M., Setiha, M., Samir, S., Sami, N., Salem, H., Reda, M., Reda, A., Ohanissian, A., Nawar, M., Mowafy, A., Khairy, T., Katta, A., Elkhadem, M., El-Etreby, A., Elbahry, A., El Etriby, S., El Din, M. G., Abou Seif, S. K., Abd El-Aziz, A., Ragy, H., Wright, D., Wong, S., Trahey, T., Stevenson, J., Spearson, S., Snell, L., Schulman, S., Sas, G., Robinson, M., Roberts, P., Raines, M., Pinter, A., Petrie, F., Pandey, M., Otis, R., Otis, J., Neas, I, Navratil, J., Moor, R., Mangat, I, Lewis, S., Lewis, C., Largy, J., Kwan, L., Kornder, J., Korley, V, Kim, R., Kelly, S., Kahlon, R., Jethoo, G., Jean, C., Jackson, A. M., Hines, K., Hines, C., Haveman, K., Gulliver, W., Grenier, M-C, Fox, B., Fournier, D., Ferleyko, L., Fearon, A., Farquhar, D., Ewert, A., Dunnigan, J., Douglass, S., Dorian, P., Djaidani, Z., Denis, I, Dehghani, P., Daheb, S., Cleveland, T., Clarke, B., Carroll, L., Burke, E., Breakwell, L., Bignell, N., Bigcanoe, J., Bergeron, C., Mooso, B., Beaudry, K., Aves, T., Aro, L., Ahmad, K., Bonet, J., Ramjattan, B., Cha, J., Lavoie, A., Parkash, R., Fikry, S., Vizel, S., MacDonald, P., Angaran, P., Coutu, B., Schweitzer, B., Hruczkowski, T., Dhillon, R., Dresser, G., Nadeau, R., Du Preez, M., Poirier, G., Heath, J., Berlingieri, J., Ayala-Paredes, F., Beaudry, P., Leader, R., Cheung, S., Pandey, A. S., Gupta, M., Luton, R., Eikelboom, J., Spyropoulos, A., Connolly, S. J., Wong, K., Wilford, E., Wallis, L., Waldman, A., Vorster, M., Tsay, I. M., Thompson, S., Tarrant, J., Swaraj, K., Sutcliffe, S., Stoyanov, N., Singleton, C., Singh, C., Shrestha, P., Shone, S., Setio, H., Seremetkoska, M., Sanders, L., Rose, J., Raynes, S., Ratcliffe, M., Rashad, H., Preston, S., Plotz, M., Paul, V, Patching, T., Patching, K., Parsons, L., Palmer, J., O'May, V, Oldfield, G., Nagalingam, V, Myers, J-D, Mussap, C., Morrison, H., McKeon, L., McIntosh, C., McCarthy, C., MacKenzie, M., Fitzpatrick, D., Fetahovic, T., Ferreira-Jardim, A., Eslick, R., Eskandari, M., Duroux, M., Dolman, M., Dixon, S., Dimitri, H., Cresp, D., Conway, B., Connelly, A., Carlton, L., Campo, M., Buckley, E., Boys, J., Bonner, M., Black, A., Beveridge, R., Batta, C., Barry, L., Aggarwala, A., Faunt, J., Carroll, P., Starmer, G., Rogers, J., Lee, A., Binnekamp, M., Jepson, N., Arstall, M., Astridge, P., Choi, A., O'Donnell, D., Crimmins, D., Blombery, P., Phan, T., Ayres, B., Zimmett, L., French, J., Eccleston, D., Kiat, H., Colquhoun, D., Catanchin, A., Coulshed, D., Kilian, J., Roberts-Thomson, P., Lehman, R., Abhayaratna, W., Van Gaal, W., Singh, B., Blenkhorn, A., Gibbs, H., Thomson, A., Thomas, N., Sword, A., Stoddart, H., Simper, H., Simmons, P., Shewring, J., Seamark, C., Saunders, P. B., Rogers, G., Rickenbach, M., Reed, R., Redpath, D., Randfield, S., Powell, K., Nadaph, M., Muvva, R., Munro, I, Lomax, L., Jeffers, L., Jacobs, P., Hay, A., Halpin, A., Goram, J., Fox, R., Flynn, A., Dooldeniya, C., Dobson, S., Cartwright, S., Bennett, J., Ayers, J., A'Court, C., Ahmad, S., Pugsley, M., Gunasegaram, J., Wong, M., Cooke, P., Beattie, A., McEleny, P., Wastling, R., McGinty, P., Bandrapalli, M., Liley, C., Vinson, P., Zaman, K., Davies, T., Forshaw, K., Veale, R., Wilkinson, J., Geatch, D., Estifano, S., Myhill, T., Lucraft, L., Batson, R., Choi, H., Stephenson, T., Hargreaves, N., Schatzberger, T., Davies, S., Baron, R. T., Haria-Shah, R., Bunney, R., Boon, M., Wong, T., Sterry, M., Shepherd, D., Walton, S., Jackson, D., Ward, B., Coates, S., Heer, A., Roberts, N., Coulson, W., Peters, S., Wilson, A., Khalaque, S., Choudhary, F., Sabir, A., Rothwell, A. 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N., Burns, G., Conn, P., Warke, A., Mulholland, C., Poland, K., Korneeva, O., Konyushenko, D., Kolesova, T., Ivanova, Y., Gurmach, M., Gubanov, A., Gorshkova, T., Gorbunova, E., Erofeeva, S., Dumikyan, A., Chugunnaya, S., Bitakova, F., Belenkova, Y., Batalov, R., Agakhanyan, A., Edin, A., Nagibovich, O., Shapovalova, Y., Zubeeva, G., Rossovskaya, M., Sobolev, K., Polkanova, E., Moiseeva, Y., Kostenko, V, Novikova, T., Zrazhevskiy, K., Mazur, E., Shutemova, E., Sergeev, M., Chizhov, P., Aleksandrova, E., Miller, O., Barbarash, O., Vishnevsky, A., Drapkina, O., Zateyshchikov, D., Poltavskaya, M., Yakupov, E., Khokhlov, A., Egorova, L., Nikolaev, K., Kolesnikova, A., Kropacheva, E., Zateyshchikova, A., Belenky, D., Kamalov, G., Popov, S., Tereshchenko, S., Libis, R., Eltishcheva, V, Panchenko, E., Zyczynska-Szmon, M., Zakutynska-Kowalczyk, K., Wrobel, M., Wojnowski, L., Wojewoda, P., Wilgat-Szecowka, M., Wilczewski, P., Wierzbicka, A., Wieczorek, W., Wesolowska, K., Wegrzynowska, M., Walasik, P., Tybura, S., Trzcinski, G., Troszczynska, M., Traczyk, T., Szwoch, M., Szumczyk-Muszytowska, G., Szulowska, A., Szuchnik, E., Szkrobka, W., Cieszynska, A., Cieslak, K., Cichomski, R., Chojnowski, P., Chmielowski, A., Bzymek, R., Brzustowska, M., Brzozowski, W., Broton, E., Blaszczyk, D., Biernacka, A., Biedrzycki, L., Bernat, L., Bekieszczuk, E., Basiak, M., Bartnik, J., Bartkowiak, R., Barszcz, A., Araminowicz, J., Andrzejewski, D., Ambicka, M., Lesnik, J., Nessler, J., Domanska, E., Raczak, G., Rusicka-Piekarz, T., Baszak, J., Lysek, R., Mazur, S., Myszka, W., Miekus, P., Jurowiecki, J., Cymerman, K., Galbas, K., Wozniak-Skowerska, I, Kukla, P., Okopien, B., Sciborski, R., Jaworska, K., Ruszkowski, P., Glanowska, G., Ogorek, M. (Michal), Bronisz, M., Opolski, G., Trusz-Gluza, M., Chmielnicka-Pruszczynska, M., Karczmarczyk, A., Zinka, E., Lewczuk, J., Ostrowska-Pomian, B., Lajkowski, Z., Krzciuk, M., Kania, G., Olszewski, M., Minc, P., Gruchala, M., Kucharski, L., Swiatkowska-Byczynska, L., Hiczkiewicz, J., Zaluska, R., Kuzniar, J., Supinski, W., Kosior, J., Loboz-Grudzien, K., Wozakowska-Kaplon, B., Ogorek, M. (Marcin), Biedrzycka, M., Gieroba, A., Korzeniak, R., Stepinska, J., Strand, S., Ringdalen, K., O'Donovan, M., Nilsen, V, Lensebraaten, A. B., Jekthammer, A., Dominguez, I, Claussen, H., Ausen, K., Antonsen, H., Otterstad, J. E., Berg-Johansen, J., Koval, O., Ushakov, O., Mostovoy, Y., Serediuk, N., Kupnovytska, I, Kraiz, I, Zhurba, S., Karpenko, O., Tseluyko, V, Rudyk, I, Parkhomenko, A., Winnik, S., Saga, E., Henriette, I, Guinand, A., Grau, A., Elise, G., Bruegger, J., Amstutz, D., Debrunner, J., Beer, J. 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B., Kumar, S., Jain, D., Abraham, S., Adak, D., Barai, A., Begum, H., Bhattacharjee, P., Dargude, M., Davies, D., Deshpande, B., Dhakrao, P., Dhyani, V, Duhan, S., Earath, M., Ganatra, A., Giradkar, S., Jain, V, Karthikeyan, R., Kasala, L., Kaur, S., Krishnappa, S., Lawande, A., Lokesh, B., Madarkar, N., Meena, R., More, P., Naik, D., Prashanth, K., Rao, M., Rao, N. M., Sadhu, N., Shah, D., Sharma, M., Shiva, P., Singhal, S., Suresh, S., Vanajakshamma, V., Panse, S. G., Koretsune, Y., Kanamori, S., Yamamoto, K., Kumagai, K., Katsuda, Y., Sadamatsu, K., Toyota, F., Mizuno, Y., Misumi, I, Noguchi, H., Ando, S., Suetsugu, T., Minamoto, M., Oda, H. (Hiroshi), Shiraishi, K., Adachi, S., Chiba, K., Norita, H., Tsuruta, M., Koyanagi, T., Ando, H., Higashi, T., Okada, K., Azakami, S., Komaki, S., Kumeda, K., Murayama, T., Matsumura, J., Oba, Y., Sonoda, R., Goto, K., Minoda, K., Haraguchi, Y., Suefuji, H., Miyagi, H., Kato, H., Nakamura, T. (Tadashi), Nakamura, T. (Tsugihiro), Nandate, H., Zaitsu, R., Fujiura, Y. (Yoshihisa), Yoshimura, A., Numata, H., Ogawa, J., Tatematsu, H., Kamogawa, Y., Murakami, K., Wakasa, Y., Yamasawa, M., Maekawa, H., Abe, S., Kihara, H., Tsunoda, S., Saito, K. (Katsumi), Saito, K. (Kazuyuki), Fudo, T., Obunai, K., Tachibana, H., Oba, I, Kuwahata, T., Higa, S., Gushiken, M., Eto, T., Yoshida, H., Ikeda, D., Fujiura, Y. (Yoshitake), Ishizawa, M., Headlee, M., Henson, L., Herrick, C., Haas, Sylvia, ten Cate, Hugo, Accetta, Gabriele, Angchaisuksiri, Pantep, Bassand, Jean-Pierre, Camm, A. John, Corbalan, Ramon, Darius, Harald, Fitzmaurice, David A., Goldhaber, Samuel Z., Yilmaz, MEHMET BİRHAN, Goto, Shinya, Jacobson, Barry, Kayani, Gloria, Mantovani, Lorenzo G., Misselwitz, Frank, Pieper, Karen, Schellong, Sebastian M., Stepinska, Janina, Turpie, Alexander G. 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S., Li, X., Wu, T. G., Cheng, X. S., Yan, X. W., Zhao, R. P., Chen, M. S., Xiong, L. G., Chen, P., Jiao, Y., Guo, Y., Xue, L., Wang, F. Z., Li, H., Yang, Z. M., Bai, C. L., Chen, J., Chen, J. Y., Chen, X., Feng, S., Fu, Q. H., Gao, X. J., Guo, W. N., He, R. H., He, X. A., Hu, X. S., Huang, X. F., Li, B., Li, J., Li, L., Li, Y. H., Liu, T. T., Liu, W. L., Liu, Y. Y., Lu, Z. C., Luo, X. L., Ma, T. Y., Peng, J. Q., Sheng, X., Shi, X. J., Sun, Y. H., Tian, G., Wang, K., Wang, L., Wu, R. N., Xie, Q., Xu, R. Y., Yang, J. S., Yang, L. L., Yang, Q., Ye, Y., Yu, H. Y., Yu, J. H., Yu, T., Zhai, H., Zhan, Q., Zhang, G. S., Zhang, Q., Zhang, R., Zhang, Y., Akutsu, M., Takamura, I, Hoshino, F., Yokota, N., Iwao, T., Tsuchida, K., Takeuchi, M., Hatori, Y., Kitami, Y., Nakamura, Y. (Yoichi), Oyama, R., Ageta, M., Oda, H. (Hiroyuki), Go, Y., Mishima, K., Unoki, T., Morii, S., Shiga, Y. 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Y., Seker, T., Alkan, D. Uzun, Yildirim, E., Yildirim, R., Yilmaz, F., Yuksekdag, V, Luciardi, H. L., Ono, T., Pearce, Y. Onuki, Oriso, S., Ota, A., Otaki, E., Saito, Y., Sakai, H., Sakamoto, N., Sakamoto, Y., Samejima, Y., Sasagawa, Y., Sasaguri, H., Sasaki, A., Sasaki, T., Sato, K. (Kazuki), Sato, K. (Kiyoharu), Sawano, M., Seki, S., Sekine, Y., Seta, Y., Sezaki, K., Shibata, N., Shiina, Y., Shimono, H., Shimoyama, Y., Shindo, T., Shinohara, H., Shinohe, R., Shinozuka, T., Shirai, T., Shiraiwa, T., Shozawa, Y., Suga, T., Sugimoto, C., Suzuki, K. (Kazuo), Suzuki, K. (Keita), Suzuki, S. (Shu), Suzuki, S. (Shunji), Suzuki, S. 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M., Accogli, M., Ciampani, N., Malengo, S., Feola, M., Raisaro, A., Fattore, L., Grilli, P., Germini, F., Settimi, M., Alunni, M., Duranti, G., Tedeschi, L., Baglioni, G., Avanzino, G., Berardi, M., Pannacci, V, Giombolini, A., Nicoli, S., Scarponi, T., Allasia, B., Ricciarini, P., Nasorri, R., Argena, A., Bossolasco, P., Ronchini, P., Filippi, A., Tradati, F., Bulla, C., Donzelli, L., Foppa, L., Bottarelli, M. L., Tomasello, A., Mauric, A., Femiano, C., Reggio, R., Lillo, F., Mariani, A., Forcignano, F., Volpe, M., Lee, H. Y., Lee, H-Y, Lee, K. H., Lee, K. R., Lee, M. S., Lee, M-Y, Lee, R. W., Lee, S. E., Lee, S. H., Lee, S., Lee, W. Y., Noh, I. K., Park, A. R., Park, B. R., Park, H. N., Park, J. H., Park, M., Park, Y., Seo, S-Y, Shim, J., Sim, J. H., Sohn, Y. M., Son, W. S., Son, Y. S., Song, H. J., Wi, H. K., Woo, J. J., Ye, S., Haas, S., Cate, H. T., Accetta, G., Angchaisuksiri, P., Bassand, J. -P., John Camm, A., Corbalan, R., Darius, H., Fitzmaurice, D. A., Goldhaber, S. Z., Goto, S., Jacobson, B., Kayani, G., Mantovani, L. G., Misselwitz, F., Pieper, K., Schellong, S. M., Stepinska, J., Turpie, A. G. G., Eickels, M. V., Kakkar, A. K., Hacke, W., Gersh, B. J., Luciardi, H. L., Gibbs, H., Brodmann, M., Cools, F., Barretto, A. C. P., Connolly, S. J., Spyropoulos, A., Eikelboom, J., Hu, D., Jansky, P., Nielsen, J. D., Ragy, H., Raatikainen, P., Le Heuzey, J. -Y., Keltai, M., Kakkar, S., Sawhney, J. P. S., Agnelli, G., Ambrosio, G., Koretsune, Y., Diaz, C. J. S., Atar, D., Panchenko, E., Lim, T. W., Oh, S., Vinolas, X., Rosenqvist, M., Steffel, J., Parkhomenko, A., Al Mahmeed, W., Chen, K. N., Zhao, Y. S., Zhang, H. Q., Chen, J. Z., Cao, S. P., Wang, D. W., Yang, Y. J., Li, W. H., Yin, Y. H., Tao, G. Z., Yang, P., Chen, Y. M., He, S. H., Wang, Y., Fu, G. S., Li, X., Wu, T. G., Cheng, X. S., Yan, X. W., Zhao, R. P., Chen, M. S., Xiong, L. G., Chen, P., Jiao, Y., Guo, Y., Xue, L., Wang, F. Z., Li, H., Yang, Z. M., Bai, C. L., Chen, J., Chen, J. Y., Chen, X., Feng, S., Fu, Q. H., Gao, X. J., Guo, W. N., He, R. H., He, X. A., Hu, X. S., Huang, X. F., Li, B., Li, J., Li, L., Li, Y. H., Liu, T. T., Liu, W. L., Liu, Y. Y., Lu, Z. C., Luo, X. L., Ma, T. Y., Peng, J. Q., Sheng, X., Shi, X. J., Sun, Y. H., Tian, G., Wang, K., Wang, L., Wu, R. N., Xie, Q., Xu, R. Y., Yang, J. S., Yang, L. L., Yang, Q., Ye, Y., Yu, H. Y., Yu, J. H., Yu, T., Zhai, H., Zhan, Q., Zhang, G. S., Zhang, Q., Zhang, R., Zhang, Y., Zheng, W. Y., Zhou, B., Zhou, Z. H., Zhu, X. Y., Jadhav, P., Durgaprasad, R., Ravi Shankar, A. G., Rajput, R. K., Bhargava, K., Sarma, R., Srinivas, A., Roy, D., Nagamalesh, U. M., Chopda, M., Kishore, R., Kulkarni, G., Chandwani, P., Pothiwala, R. A., Padinhare Purayil, M., Shah, S., Chawla, K., Kothiwale, V. A., Raghuraman, B., Vijayaraghavan, G., Vijan, V. M., Bantwal, G., Bisne, V., Khan, A., Gupta, J. 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G., Kanamori, S., Yamamoto, K., Kumagai, K., Katsuda, Y., Sadamatsu, K., Toyota, F., Mizuno, Y., Misumi, I., Noguchi, H., Ando, S., Suetsugu, T., Minamoto, M., Oda, H., Shiraishi, K., Adachi, S., Chiba, K., Norita, H., Tsuruta, M., Koyanagi, T., Ando, H., Higashi, T., Okada, K., Azakami, S., Komaki, S., Kumeda, K., Murayama, T., Matsumura, J., Oba, Y., Sonoda, R., Goto, K., Minoda, K., Haraguchi, Y., Suefuji, H., Miyagi, H., Kato, H., Nakamura, T., Nandate, H., Zaitsu, R., Fujiura, Y., Yoshimura, A., Numata, H., Ogawa, J., Tatematsu, H., Kamogawa, Y., Murakami, K., Wakasa, Y., Yamasawa, M., Maekawa, H., Abe, S., Kihara, H., Tsunoda, S., Saito, K., Fudo, T., Obunai, K., Tachibana, H., Oba, I., Kuwahata, T., Higa, S., Gushiken, M., Eto, T., Yoshida, H., Ikeda, D., Ishizawa, M., Nakatsuka, M., Murata, K., Ogurusu, C., Shimoyama, M., Akutsu, M., Takamura, I., Hoshino, F., Yokota, N., Iwao, T., Tsuchida, K., Takeuchi, M., Hatori, Y., Kitami, Y., Nakamura, Y., Oyama, R., Ageta, M., Go, Y., Mishima, K., Unoki, T., Morii, S., Shiga, Y., Sumi, H., Nagatomo, T., Sanno, K., Fujisawa, K., Atsuchi, Y., Nagoshi, T., Seto, T., Tabuchi, T., Kameko, M., Nii, K., Oshiro, K., Takezawa, H., Nagano, S., Miyamoto, N., Iwaki, M., Fujii, M., Okawa, M., Abe, M., Saito, T., Mito, T., Nagao, K., Minami, J., Mita, T., Sakuma, I., Taguchi, T., Marusaki, S., Doi, H., Tanaka, M., Fujito, T., Matsuta, M., Kusumoto, T., Kakinoki, S., Ashida, K., Yoshizawa, N., Agata, J., Arasaki, O., Manita, M., Ikemura, M., Fukuoka, S., Murakami, H., Matsukawa, S., Hata, Y., Taniguchi, T., Ko, T., Kubo, H., Imamaki, M., Akiyama, M., Inagaki, M., Odakura, H., Ueda, T., Katsube, Y., Nakata, A., Watanabe, H., Techigawara, M., Igarashi, M., Taga, K., Kimura, T., Tomimoto, S., Shibuya, M., Nakano, M., Ito, K., Seo, T., Hiramitsu, S., Hosokawa, H., Hoshiai, M., Hibino, M., Miyagawa, K., Horie, H., Sugishita, N., Soma, A., Neya, K., Yoshida, T., Mizuguchi, M., Ishiguro, M., Minagawa, T., Wada, M., Mukawa, H., Okuda, F., Nagasaka, S., Abe, Y., Adachi, T., Akahane, K., Amano, T., Aoki, K., Aoyama, T., Arai, H., Arima, S., Arino, T., Asano, H., Asano, T., Azuma, J., Baba, T., Betsuyaku, T., Chibana, H., Date, H., Doiuchi, J., Emura, Y., Endo, M., Fujii, Y., Fujiki, R., Fujisawa, A., Fujisawa, Y., Fukuda, T., Fukui, T., Furukawa, N., Furukawa, T., Furumoto, W., Goto, T., Hamaoka, M., Hanazono, N., Hasegawa, K., Hatsuno, T., Hayashi, Y., Higuchi, K., Hirasawa, K., Hirayama, H., Hirose, M., Hirota, S., Honda, M., Ido, T., Iiji, O., Ikeda, H., Ikeda, K., Ikeoka, K., Imaizumi, M., Inaba, H., Inoue, T., Iseki, F., Ishihara, A., Ishioka, N., Ito, N., Iwase, T., Kakuda, H., Kamata, J., Kanai, H., Kanda, H., Kaneko, M., Kano, H., Kasai, T., Kato, T., Kato, Y., Kawada, Y., Kawai, K., Kawakami, K., Kawakami, S., Kawamoto, T., Kawano, S., Kim, J., Kira, T., Kitazawa, H., Kitazumi, H., Kito, T., Kobayashi, T., Koeda, T., Kojima, J., Komatsu, H., Komatsu, I., Koshibu, Y., Kotani, T., Kozuka, T., Kumai, Y., Kumazaki, T., Maeda, I., Maeda, K., Maruyama, Y., Matsui, S., Matsushita, K., Matsuura, Y., Mineoi, K., Mitsuhashi, H., Miura, N., Miyaguchi, S., Miyajima, S., Miyamoto, H., Miyashita, A., Miyata, S., Mizuguchi, I., Mizuno, A., Mori, T., Moriai, O., Morishita, K., Murai, O., Nagai, S., Nagata, E., Nagata, H., Nakagomi, A., Nakahara, S., Nakamura, M., Nakamura, R., Nakanishi, N., Nakayama, T., Nakazato, R., Nanke, T., Nariyama, J., Niijima, Y., Niinuma, H., Nishida, Y., Nishihata, Y., Nishino, K., Nishioka, H., Nishizawa, K., Niwa, I., Nomura, K., Nomura, S., Nozoe, M., Ogawa, T., Ohara, N., Okada, M., Okamoto, K., Okita, H., Okuyama, M., Ono, H., Ono, T., Pearce, Y. 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S., Pickavance, G., Mcdonnell, J., Williams, A., Gooding, T., Wagner, H., Suryani, S., Singal, A., Sircar, S., Bilas, R., Hutchinson, P., Wakeman, A., Stokes, M., Paul, N., Aziz, M., Ramesh, C., Wilson, P., Franklin, S., Fairhead, S., Thompson, J., St Joseph, V., Taylor, G., Tragen, D., Seamark, D., Paul, C., Richardson, M., Jefferies, A., Sharp, H., Jones, H., Giles, C., Page, M., Oginni, O., Aldegather, J., Wetherwell, S., Lumb, W., Evans, P., Scouller, F., Macey, N., Stipp, Y., West, R., Thurston, S., Wadeson, P., Matthews, J., Pandya, P., Gallagher, A., Railton, T., Sinha, B., Russell, D., Davies, J. A., Ainsworth, P., Jones, C. P., Weeks, P., Eden, J., Kernick, D., Murdoch, W., Lumley, L., Patel, R. P., Wong, S. W., Saigol, M., Ladha, K., Douglas, K., Cumberlidge, D. F., Bradshaw, C., Van Zon, G., Jones, K. P., Thomas, M. J., Watson, E., Sarai, B., Ahmad, N., Willcock, W., Cairns, J., Sathananthan, S., de Kare-Silver, N., Gilliland, A., Strieder, E., Howitt, A., Vishwanathan, B., Bird, N., Gray, D., Clark, M., Bisatt, J., Litchfield, J., Fisher, E., Fooks, T., Kelsall, A. R., Alborough, E., Wakeling, J., Parfitt, M., Milne, K., Rogers, S., Priyadharshan, R., Oliver, J. L., Davies, E., Abushal, S., Jacobs, M., Hutton, C., Walls, N. I., Thompson, R., Chigbo, C., Zaidi, S. M. A., Howard, M., Butter, K. C., Barrow, S., Little, H., Haq, I. U., Gibbons, L., Glencross, S., Mcleod, A. J., Poland, K., Mulholland, C., Warke, A., Conn, P., Burns, G., Smith, R. N., Lowe, S., Kamath, R., Dau, H. S., Webster, J., Hodgins, I., Vercoe, S., Roome, P. C., Pinnock, H., Patel, J. R. A., Ali, A., Hart, N., Davies, R., Stuart, E., Neden, C. A., Danielsen, M., Heath, R., Sharma, P., Galloway, S., Hawkins, C., Oliver, R., Aylward, M., Mannion, S., Braddick, M., Edwards, D., Rothwell, A. C., Sabir, A., Choudhary, F., Khalaque, S., Wilson, A., Peters, S., Coulson, W., Roberts, N., Heer, A., Coates, S., Ward, B., Jackson, D., Walton, S., Shepherd, D., Sterry, M., Wong, T., Boon, M., Bunney, R., Haria-Shah, R., Baron, R. T., Davies, S., Schatzberger, T., Hargreaves, N., Stephenson, T., Choi, H., Batson, R., Lucraft, L., Myhill, T., Estifano, S., Geatch, D., Wilkinson, J., Veale, R., Forshaw, K., Davies, T., Zaman, K., Vinson, P., Liley, C., Bandrapalli, M., Mcginty, P., Wastling, R., Mceleny, P., Beattie, A., Cooke, P., Wong, M., Gunasegaram, J., Pugsley, M., Ahmad, S., A'Court, C., Ayers, J., Bennett, J., Cartwright, S., Dobson, S., Dooldeniya, C., Flynn, A., Fox, R., Goram, J., Halpin, A., Hay, A., Jacobs, P., Jeffers, L., Lomax, L., Munro, I., Muvva, R., Nadaph, M., Powell, K., Randfield, S., Redpath, D., Reed, R., Rickenbach, M., Rogers, G., Saunders, P. B., Seamark, C., Shewring, J., Simmons, P., Simper, H., Stoddart, H., Sword, A., Thomas, N., Thomson, A., Blenkhorn, A., Singh, B., Van Gaal, W., Abhayaratna, W., Lehman, R., Roberts-Thomson, P., Kilian, J., Coulshed, D., Catanchin, A., Colquhoun, D., Kiat, H., Eccleston, D., French, J., Zimmett, L., Ayres, B., Phan, T., Blombery, P., Crimmins, D., O'Donnell, D., Choi, A., Astridge, P., Arstall, M., Jepson, N., Binnekamp, M., Lee, A., Rogers, J., Starmer, G., Carroll, P., Faunt, J., Aggarwala, A., Barry, L., Batta, C., Beveridge, R., Black, A., Bonner, M., Boys, J., Buckley, E., Campo, M., Carlton, L., Connelly, A., Conway, B., Cresp, D., Dimitri, H., Dixon, S., Dolman, M., Duroux, M., Eskandari, M., Eslick, R., Ferreira-Jardim, A., Fetahovic, T., Fitzpatrick, D., Geraghty, R., Gibbs, J., Grabek, T., Modi, M. H., Hayes, K., Hegde, M. P., Hesketh, L., Hoffmann, B., Johnson, K., Juergens, C., Kassam, I., Lawlor, V., Lehman, M., Lehman, S., Leung, D., Mackay, S., Mackenzie, M., Mccarthy, C., Mcintosh, C., Mckeon, L., Morrison, H., Mussap, C., Myers, J. -D., Nagalingam, V., Oldfield, G., O'May, V., Palmer, J., Parsons, L., Patching, K., Patching, T., Paul, V., Plotz, M., Preston, S., Rashad, H., Ratcliffe, M., Raynes, S., Rose, J., Sanders, L., Seremetkoska, M., Setio, H., Shone, S., Shrestha, P., Singh, C., Singleton, C., Stoyanov, N., Sutcliffe, S., Swaraj, K., Tarrant, J., Thompson, S., Tsay, I. M., Vorster, M., Waldman, A., Wallis, L., Wilford, E., Wong, K., Luton, R., Gupta, M., Pandey, A. S., Cheung, S., Leader, R., Beaudry, P., Ayala-Paredes, F., Berlingieri, J., Heath, J., Poirier, G., Du Preez, M., Nadeau, R., Dresser, G., Dhillon, R., Hruczkowski, T., Schweitzer, B., Coutu, B., Angaran, P., Macdonald, P., Vizel, S., Fikry, S., Parkash, R., Lavoie, A., Cha, J., Ramjattan, B., Bonet, J., Ahmad, K., Aro, L., Aves, T., Beaudry, K., Bergeron, C., Bigcanoe, J., Bignell, N., Breakwell, L., Burke, E., Carroll, L., Clarke, B., Cleveland, T., Daheb, S., Dehghani, P., Denis, I., Djaidani, Z., Dorian, P., Douglass, S., Dunnigan, J., Ewert, A., Farquhar, D., Fearon, A., Ferleyko, L., Fournier, D., Fox, B., Grenier, M. -C., Gulliver, W., Haveman, K., Hines, C., Hines, K., Jackson, A. M., Jean, C., Jethoo, G., Kahlon, R., Kelly, S., Kim, R., Korley, V., Kornder, J., Kwan, L., Largy, J., Lewis, C., Lewis, S., Mangat, I., Moor, R., Navratil, J., Neas, I., Otis, J., Otis, R., Pandey, M., Petrie, F., Pinter, A., Raines, M., Roberts, P., Robinson, M., Sas, G., Schulman, S., Snell, L., Spearson, S., Stevenson, J., Trahey, T., Wong, S., Wright, D., El-Aziz, A. A., Seif, S. K. A., El Din, M. G., El Etriby, S., Elbahry, A., El-Etreby, A., Elkhadem, M., Katta, A., Khairy, T., Mowafy, A., Nawar, M., Ohanissian, A., Reda, A., Reda, M., Salem, H., Sami, N., Samir, S., Setiha, M., Sobhy, M., Soliman, A., Taha, N., Tawfik, M., Zaatout, E., Kettles, D., Bayat, J., Siebert, H., Horak, A., Kelfkens, Y., Garda, R., Pillay, T., Guerra, M., van Zyl, L., Theron, H., Murray, A., Louw, R., Greyling, D., Mntla, P., Ueckermann, V., Loghdey, R., Ismail, S., Ahmed, F., Engelbrecht, J., Ramdass, A., Maharajh, S., Oosthuysen, W., Angel, G., Bester, C., Booysen, M., Boshoff, C., Cannon, C., Cassimjee, S., Chami, C., Conway, G., Davids, A., de Meyer, L., Du Plessis, G., Ellis, T., Henley, L., Karsten, M., Loyd, E., Marks, J., Mavhusa, L., Mostert, M., Page, A., Rikhotso, L., Salie, M., Sasto, J., Shaik, F., Skein, A., Smith, L., Tarr, G., Tau, T., van Zyl, F., Yousef, G., Agrawal, A., Nathani, M., Ibrahim, M., Esheiba, E. M., Singh, R., Naguib, A., Abu-Mahfouz, M., Al Omairi, M., Al Naeemi, A., Maruthanayagam, R., Bazargani, N., Wassef, A., Gupta, R., Khan, M., Subbaraman, B., Abdul, A., Al Mulla, A., El Bardisy, S., Haridas, P., Jadhav, S., Magdaluyo, K., Makdad, M., Maqsood, I., Mohamed, R., Sharma, N., Sharma, R., Thanzeel, M., Canosa, R., Rama, P., Blumberg, E., Garcia, J., Mullen, P., Wilson, V., Quick, A., Ferrick, K., Kutayli, W. M., Cox, M., Franco, M., Falkowski, S., Mendelson, R., Williams, M., Miller, S., Beach, S., Alfieri, A., Gutowski, T., Haque, I., Reddy, R., Ahmed, W., Delafontaine, P., Diercks, D., Theodoro, D., Remmel, K., Alberts, M., Ison, R., Noveck, H., Duffy, P., Pitta, S., Nishijima, D., Treasure, C., Asafu-Adjaye, N., Ball, K., Bartlett, M., Bentley, M., Bowers, S., Brown, A., Browne, A., Cameron-Watts, J., Canova, M., Cassidy, D., Cervellione, K., Congal, S., Depauw, J., Dickerson, A., Eley, M., Evans, L., Felpel, S., Ferdinand, K., Fielder, D., Gentry, P., Haideri, A., Hakimi, F., Harbour, T., Hartranft, E., Hawkins, B., Headlee, M., Henson, L., Herrick, C., Hicks, T., Jasinski, S., Jones, A., Jones, L., Jones, P., Karl, S., Keeling, M., Kerr, J., Knowles, P., Langdon, J., Lay, M., Lee, J. A., Lincoln, T., Malone, E., Merliss, A., Merritt, D., Minardo, J., Mooso, B., Orosco, C., Palumbo, V., Parker, M., Parrott, T., Paserchia, S., Pearl, G., Peterson, J., Pickelsimer, N., Purcell, T., Raynor, J., Raziano, S., Richard, C., Richardson, T., Robertson, C., Sage, A., Sanghera, T., Shaw, P., Shoemaker, J., Smith, K., Stephanie, B., Thatcher, A., Theobald, H., Thompson, N., Treasure, L., Tripti, T., Verdi, C., Worthy, V., RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: MA Alg Interne Geneeskunde (9), Interne Geneeskunde, Biochemie, Haas, S, Cate, H, Accetta, G, Angchaisuksiri, P, Bassand, J, John Camm, A, Corbalan, R, Darius, H, Fitzmaurice, D, Goldhaber, S, Goto, S, Jacobson, B, Kayani, G, Mantovani, L, Misselwitz, F, Pieper, K, Schellong, S, Stepinska, J, Turpie, A, Eickels, M, Kakkar, A, Ten Cate, Hugo [0000-0001-7796-4463], Accetta, Gabriele [0000-0002-3794-6620], and Apollo - University of Cambridge Repository
- Subjects
Male ,Registrie ,Vitamin K ,Organic chemistry ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Pathology and Laboratory Medicine ,Antiplatelet Therapy ,Vascular Medicine ,Geographical Locations ,0302 clinical medicine ,Risk Factors ,Atrial Fibrillation ,Medicine and Health Sciences ,030212 general & internal medicine ,Prospective Studies ,Registries ,lcsh:Science ,Prospective cohort study ,Stroke ,education.field_of_study ,Multidisciplinary ,Pharmaceutics ,Mortality rate ,Atrial fibrillation ,Vitamins ,Vitamin K antagonist ,Middle Aged ,ddc ,Physical sciences ,Hemorrhagic Stroke ,Chemistry ,Treatment Outcome ,Neurology ,Female ,Arrhythmia ,Research Article ,Human ,medicine.medical_specialty ,endocrine system ,Asia ,Death Rates ,medicine.drug_class ,Cerebrovascular Diseases ,B vitamins ,Population ,Cardiology ,Hemorrhage ,Chemical compounds ,03 medical and health sciences ,Antiplatyhelmintic Agents ,Signs and Symptoms ,Drug Therapy ,Population Metrics ,Diagnostic Medicine ,Internal medicine ,Organic compounds ,medicine ,Humans ,International Normalized Ratio ,education ,Demography ,Ischemic Stroke ,Biochemistry, Genetics and Molecular Biology (all) ,Population Biology ,business.industry ,Risk Factor ,lcsh:R ,Anticoagulant ,Biology and Life Sciences ,Anticoagulants ,ta3121 ,medicine.disease ,Antiplatyhelmintic Agent ,Prospective Studie ,People and Places ,Attributable risk ,Physical therapy ,lcsh:Q ,business ,RC - Abstract
Aims Vitamin K antagonists (VKAs) need to be individually dosed. International guidelines recommend a target range of international normalised ratio (INR) of 2.0–3.0 for stroke prevention in atrial fibrillation (AF). We analysed the time in this therapeutic range (TTR) of VKA-treated patients with newly diagnosed AF in the ongoing, global, observational registry GARFIELD-AF. Taking TTR as a measure of the quality of patient management, we analysed its relationship with 1-year outcomes, including stroke/systemic embolism (SE), major bleeding, and all-cause mortality. Methods and Results TTR was calculated for 9934 patients using 136,082 INR measurements during 1-year follow-up. The mean TTR was 55.0%; values were similar for different VKAs. 5851 (58.9%) patients had TTR
- Published
- 2016
23. Downscaling of national crop area statistics using drivers of cropland productivity measured at fine resolutions
- Author
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Song, Jingyu, primary, Delgado, Michael S., additional, Preckel, Paul V., additional, and Villoria, Nelson B., additional
- Published
- 2018
- Full Text
- View/download PDF
24. In patients with unilateral pleural effusion, restricted lung inflation is the principal predictor of increased dyspnoea
- Author
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Garske, Luke A., primary, Kunarajah, Kuhan, additional, Zimmerman, Paul V., additional, Adams, Lewis, additional, and Stewart, Ian B., additional
- Published
- 2018
- Full Text
- View/download PDF
25. Striking Phenotypic Variation yet Low Genetic Differentiation in Sympatric Lake Trout (Salvelinus namaycush)
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Paul V. Debes, Robert Spencer Carson, Kia Marin, Dylan J. Fraser, and Andrew Coon
- Subjects
0106 biological sciences ,0301 basic medicine ,Heredity ,Trout ,Speciation ,lcsh:Medicine ,Population genetics ,Marine and Aquatic Sciences ,01 natural sciences ,Effective population size ,Limnology ,lcsh:Science ,Freshwater Ecology ,education.field_of_study ,Multidisciplinary ,Ecology ,Fishes ,Reproductive isolation ,Freshwater Fish ,Sympatric speciation ,Osteichthyes ,Vertebrates ,Research Article ,Freshwater Environments ,Gene Flow ,Evolutionary Processes ,Population ,Biology ,010603 evolutionary biology ,Ecological speciation ,03 medical and health sciences ,Genetics ,Animals ,education ,Salvelinus ,Ecological niche ,Evolutionary Biology ,Population Biology ,lcsh:R ,Ecology and Environmental Sciences ,Organisms ,Aquatic Environments ,Biology and Life Sciences ,Bodies of Water ,biology.organism_classification ,Lakes ,030104 developmental biology ,Genetic Loci ,Earth Sciences ,ta1181 ,lcsh:Q ,Population Genetics - Abstract
The study of population differentiation in the context of ecological speciation is commonly assessed using populations with obvious discreteness. Fewer studies have examined diversifying populations with occasional adaptive variation and minor reproductive isolation, so factors impeding or facilitating the progress of early stage differentiation are less understood. We detected non-random genetic structuring in lake trout (Salvelinus namaycush) inhabiting a large, pristine, postglacial lake (Mistassini Lake, Canada), with up to five discernible genetic clusters having distinctions in body shape, size, colouration and head shape. However, genetic differentiation was low (FST = 0.017) and genetic clustering was largely incongruent between several population- and individual-based clustering approaches. Genotype- and phenotype-environment associations with spatial habitat, depth and fish community structure (competitors and prey) were either inconsistent or weak. Striking morphological variation was often more continuous within than among defined genetic clusters. Low genetic differentiation was a consequence of relatively high contemporary gene flow despite large effective population sizes, not migration-drift disequilibrium. Our results suggest a highly plastic propensity for occupying multiple habitat niches in lake trout and a low cost of morphological plasticity, which may constrain the speed and extent of adaptive divergence. We discuss how factors relating to niche conservatism in this species may also influence how plasticity affects adaptive divergence, even where ample ecological opportunity apparently exists.
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- 2016
26. Environmental Drivers of Benthic Flux Variation and Ecosystem Functioning in Salish Sea and Northeast Pacific Sediments
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S. Kim Juniper, Philippe Archambault, Rénald Belley, and Paul V. R. Snelgrove
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0106 biological sciences ,Chlorophyll ,Geologic Sediments ,Time Factors ,010504 meteorology & atmospheric sciences ,Effects of global warming on oceans ,lcsh:Medicine ,Marine and Aquatic Sciences ,Oxygen minimum zone ,01 natural sciences ,Water Quality ,lcsh:Science ,Sedimentary Geology ,Multidisciplinary ,geography.geographical_feature_category ,Ecology ,Geography ,Temperature ,Geology ,16. Peace & justice ,Chemistry ,Oceanography ,Benthic zone ,Physical Sciences ,Porosity ,Ecosystem Functioning ,Research Article ,Chemical Elements ,Materials Science ,Material Properties ,Ecosystems ,Phosphates ,Bottom water ,Sea Water ,Phytoplankton ,Ecosystem ,14. Life underwater ,Dissolved Oxygen ,0105 earth and related environmental sciences ,Petrology ,geography ,Nitrates ,Pacific Ocean ,Continental shelf ,010604 marine biology & hydrobiology ,Chlorophyll A ,lcsh:R ,Ecology and Environmental Sciences ,Chemical Compounds ,Biology and Life Sciences ,Water ,15. Life on land ,Oxygen ,13. Climate action ,Multivariate Analysis ,Earth Sciences ,Linear Models ,Upwelling ,lcsh:Q ,Sediment ,Hydrology - Abstract
The upwelling of deep waters from the oxygen minimum zone in the Northeast Pacific from the continental slope to the shelf and into the Salish Sea during spring and summer offers a unique opportunity to study ecosystem functioning in the form of benthic fluxes along natural gradients. Using the ROV ROPOS we collected sediment cores from 10 sites in May and July 2011, and September 2013 to perform shipboard incubations and flux measurements. Specifically, we measured benthic fluxes of oxygen and nutrients to evaluate potential environmental drivers of benthic flux variation and ecosystem functioning along natural gradients of temperature and bottom water dissolved oxygen concentrations. The range of temperature and dissolved oxygen encountered across our study sites allowed us to apply a suite of multivariate analyses rarely used in flux studies to identify bottom water temperature as the primary environmental driver of benthic flux variation and organic matter remineralization. Redundancy analysis revealed that bottom water characteristics (temperature and dissolved oxygen), quality of organic matter (chl a:phaeo and C:N ratios) and sediment characteristics (mean grain size and porosity) explained 51.5% of benthic flux variation. Multivariate analyses identified significant spatial and temporal variation in benthic fluxes, demonstrating key differences between the Northeast Pacific and Salish Sea. Moreover, Northeast Pacific slope fluxes were generally lower than shelf fluxes. Spatial and temporal variation in benthic fluxes in the Salish Sea were driven primarily by differences in temperature and quality of organic matter on the seafloor following phytoplankton blooms. These results demonstrate the utility of multivariate approaches in differentiating among potential drivers of seafloor ecosystem functioning, and indicate that current and future predictive models of organic matter remineralization and ecosystem functioning of soft-muddy shelf and slope seafloor habitats should consider bottom water temperature variation. Bottom temperature has important implications for estimates of seasonal and spatial benthic flux variation, benthic-pelagic coupling, and impacts of predicted ocean warming at high latitudes.
- Published
- 2016
27. Laparoscopic Technique for Serial Collection of Para-Colonic, Left Colic, and Inferior Mesenteric Lymph Nodes in Macaques
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Rhonda Macalister, Jeremy Smedley, Deborah H. Fuller, Jeff Lifson, Michael Koday, Paul V. Munson, Solomon Wangari, Mercy Gathuka, Joel Ahrens, Debbie Bratt, Drew May, Naoto Iwayama, and Megan A. O'Connor
- Subjects
0301 basic medicine ,Pathology ,Biopsy ,Gut-associated lymphoid tissue ,lcsh:Medicine ,Gene Expression ,Monkeys ,Pathogenesis ,0302 clinical medicine ,Inferior mesenteric lymph nodes ,Medicine and Health Sciences ,Mesenteric lymph nodes ,Mesentery ,030212 general & internal medicine ,Lymphocytes ,lcsh:Science ,Immune Response ,Mammals ,Multidisciplinary ,medicine.diagnostic_test ,3. Good health ,medicine.anatomical_structure ,Vertebrates ,Anatomy ,Macaque ,Research Article ,Primates ,medicine.medical_specialty ,Cell Survival ,Colon ,Immunology ,Surgical and Invasive Medical Procedures ,Biology ,Anesthesia, General ,Research and Analysis Methods ,Virus ,Immunophenotyping ,Lymphatic System ,03 medical and health sciences ,Immune system ,Antigens, CD ,Old World monkeys ,medicine ,Animals ,Molecular Biology Techniques ,Molecular Biology ,lcsh:R ,Organisms ,Biology and Life Sciences ,Correction ,Endoscopy ,Gastrointestinal Tract ,030104 developmental biology ,Amniotes ,Lymph Node Excision ,Macaca ,lcsh:Q ,Laparoscopy ,Lymph Nodes ,Digestive System ,Peripheral lymph ,Biomarkers ,Cloning - Abstract
Unlike peripheral lymph nodes (PLN), the mesenteric lymph nodes (MLN) draining the gastrointestinal (GI) tract are exposed to microbes and microbial products from the intestines and as such, are immunologically distinct. GI draining (MLN) have also been shown to be sites of early viral replication and likely impact early events that determine the course of HIV infection. They also are important reservoir sites that harbor latently-infected cells and from which the virus can emerge even after prolonged combination antiretroviral therapy (cART). Changes in the microbial flora and increased permeability of the GI epithelium associated with lentiviral infection can impact the gut associated lymphoid tissue (GALT) and induce changes to secondary lymphoid organs limiting immune reconstitution with cART. Nonhuman primate models for AIDS closely model HIV infection in humans and serial sampling of the GALT and associated secondary lymphoid organs in this model is crucial to gain a better understanding of the critical early events in infection, pathogenesis, and the role of immune responses or drugs in controlling virus at these sites. However, current techniques to sample GI draining (MLN) involve major surgery and/or necropsy, which have, to date, limited the ability to investigate mechanisms mediating the initiation, persistence and control of infection in this compartment. Here, we describe a minimally invasive laparoscopic technique for serial sampling of these sites that can be used with increased sampling frequency, yields greater cell numbers and immune cell subsets than current non-invasive techniques of the GALT and reduces the potential for surgical complications that could complicate interpretation of the results. This procedure has potential to facilitate studies of pathogenesis and evaluation of preventive and treatment interventions, reducing sampling variables that can influence experimental results, and improving animal welfare.
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- 2016
28. Sustained virological response halts fibrosis progression: A long-term follow-up study of people with chronic hepatitis C infection
- Author
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Chen Yi Mei, Swee Lin G., primary, Thompson, Alexander J., additional, Christensen, Britt, additional, Cunningham, Georgina, additional, McDonald, Lucy, additional, Bell, Sally, additional, Iser, David, additional, Nguyen, Tin, additional, and Desmond, Paul V., additional
- Published
- 2017
- Full Text
- View/download PDF
29. Decline in an Atlantic Puffin Population: Evaluation of Magnitude and Mechanisms
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Roddy A. Mavor, Roger Riddington, David Parnaby, Will T. S. Miles, Jane M. Reid, Deryk N. Shaw, Paul V. Harvey, and Nick J. Riddiford
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Male ,Food Chain ,Science ,Population ,Population Dynamics ,Zoology ,Skua ,Fratercula arctica ,Charadriiformes ,Population growth ,Animals ,education ,education.field_of_study ,Multidisciplinary ,biology ,Ecology ,Population size ,Reproduction ,biology.organism_classification ,United Kingdom ,Survival Rate ,Population model ,Demographic change ,Predatory Behavior ,Medicine ,Female ,Puffin ,Research Article - Abstract
Determining which demographic and ecological parameters contribute to variation in population growth rate is crucial to understanding the dynamics of declining populations. This study aimed to evaluate the magnitude and mechanisms of an apparent major decline in an Atlantic Puffin Fratercula arctica population. This was achieved using a 27-year dataset to estimate changes in population size and in two key demographic rates: adult survival and breeding success. Estimated demographic variation was then related to two ecological factors hypothesised to be key drivers of demographic change, namely the abundance of the main predator at the study site, the Great Skua Stercorarius skua, and Atlantic Puffin chick food supply, over the same 27-year period. Using a population model, we assessed whether estimated variation in adult survival and reproductive success was sufficient to explain the population change observed. Estimates of Atlantic Puffin population size decreased considerably during the study period, approximately halving, whereas Great Skua population estimates increased, approximately trebling. Estimated adult Atlantic Puffin survival remained high across all years and did not vary with Great Skua abundance; however, Atlantic Puffin breeding success and quantities of fish prey brought ashore by adults both decreased substantially through the period. A population model combining best possible demographic parameter estimates predicted rapid population growth, at odds with the long-term decrease observed. To simulate the observed decrease, population models had to incorporate low immature survival, high immature emigration, or increasingly high adult non-breeding rates. We concluded that reduced recruitment of immatures into the breeding population was the most likely cause of population decrease. This study showed that increase in the size of a predator population does not always impact on the survival of adult prey and that reduced recruitment can be a crucial determinant of seabird population size but can easily go undetected.
- Published
- 2015
30. Reduced IL-17A Secretion Is Associated with High Levels of Pneumococcal Nasopharyngeal Carriage in Fijian Children
- Author
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E. Kim Mulholland, Laura K. Boelsen, Edwin Hoe, Catherine Satzke, Zheng Quan Toh, Lisi Tikoduadua, Anne Balloch, Paul V. Licciardi, Guang Wen Sun, Eileen M. Dunne, Ghee Chong Koo, Fiona M. Russell, and Rachel Marimla
- Subjects
Male ,China ,medicine.medical_treatment ,Science ,Biology ,medicine.disease_cause ,Peripheral blood mononuclear cell ,Interferon-gamma ,Nasopharynx ,Streptococcal Infections ,Streptococcus pneumoniae ,medicine ,Humans ,Child ,Multidisciplinary ,Streptococcus ,Tumor Necrosis Factor-alpha ,Interleukin-17 ,medicine.disease ,Bacterial Load ,3. Good health ,Pneumococcal infections ,Cytokine ,Carriage ,Immunology ,biology.protein ,Medicine ,Female ,Interleukin 17 ,Antibody ,Research Article - Abstract
Streptococcus pneumonia (the pneumococcus) is the leading vaccine preventable cause of serious infections in infants under 5 years of age. The major correlate of protection for pneumococcal infections is serotype-specific IgG antibody. More recently, antibody-independent mechanisms of protection have also been identified. Preclinical studies have found that IL-17 secreting CD4+ Th17 cells in reducing pneumococcal colonisation. This study assessed IL-17A levels in children from Fiji with high and low pneumococcal carriage density, as measured by quantitative real-time PCR (qPCR). We studied Th17 responses in 54 children who were designated as high density carriers (N=27, >8.21x10(5) CFU/ml) or low density carriers (N=27
- Published
- 2015
31. A Cysteine Zipper Stabilizes a Pre-Fusion F Glycoprotein Vaccine for Respiratory Syncytial Virus
- Author
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Sanjay Srivatsan, Yongping Yang, Cinque Soto, M. Gordon Joyce, Aliaksandr Druz, Gwo-Yu Chuang, Man Chen, Tongqing Zhou, Paul V. Thomas, Guillaume Stewart-Jones, Mallika Sastry, Jason S. McLellan, John R. Mascola, Barney S. Graham, Ivelin S. Georgiev, Ulrich Baxa, Baoshan Zhang, Lei Chen, Peter D. Kwong, and Wing-Pui Kong
- Subjects
Stereochemistry ,Protein subunit ,Caveolin 1 ,lcsh:Medicine ,Trimer ,Biology ,Cell Line ,law.invention ,Mice ,Viral Proteins ,03 medical and health sciences ,law ,Respiratory Syncytial Virus Vaccines ,Animals ,Bacteriophage T4 ,Cysteine ,lcsh:Science ,Antigens, Viral ,030304 developmental biology ,chemistry.chemical_classification ,Mice, Inbred BALB C ,0303 health sciences ,Multidisciplinary ,C-terminus ,Immunogenicity ,030302 biochemistry & molecular biology ,lcsh:R ,Antibodies, Neutralizing ,Molecular biology ,Respiratory Syncytial Viruses ,3. Good health ,Mice, Inbred C57BL ,Ectodomain ,chemistry ,Vaccines, Subunit ,Recombinant DNA ,Immunization ,lcsh:Q ,Glycoprotein ,Viral Fusion Proteins ,Research Article - Abstract
Recombinant subunit vaccines should contain minimal non-pathogen motifs to reduce potential off-target reactivity. We recently developed a vaccine antigen against respiratory syncytial virus (RSV), which comprised the fusion (F) glycoprotein stabilized in its pre-fusion trimeric conformation by "DS-Cav1" mutations and by an appended C-terminal trimerization motif or "foldon" from T4-bacteriophage fibritin. Here we investigate the creation of a cysteine zipper to allow for the removal of the phage foldon, while maintaining the immunogenicity of the parent DS-Cav1+foldon antigen. Constructs without foldon yielded RSV F monomers, and enzymatic removal of the phage foldon from pre-fusion F trimers resulted in their dissociation into monomers. Because the native C terminus of the pre-fusion RSV F ectodomain encompasses a viral trimeric coiled-coil, we explored whether introduction of cysteine residues capable of forming inter-protomer disulfides might allow for stable trimers. Structural modeling indicated the introduced cysteines to form disulfide "rings", with each ring comprising a different set of inward facing residues of the coiled-coil. Three sets of rings could be placed within the native RSV F coiled-coil, and additional rings could be added by duplicating portions of the coiled-coil. High levels of neutralizing activity in mice, equivalent to that of the parent DS-Cav1+foldon antigen, were elicited by a 4-ring stabilized RSV F trimer with no foldon. Structure-based alteration of a viral coiled-coil to create a cysteine zipper thus allows a phage trimerization motif to be removed from a candidate vaccine antigen.
- Published
- 2015
32. Striking Phenotypic Variation yet Low Genetic Differentiation in Sympatric Lake Trout (Salvelinus namaycush)
- Author
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Marin, Kia, primary, Coon, Andrew, additional, Carson, Robert, additional, Debes, Paul V., additional, and Fraser, Dylan J., additional
- Published
- 2016
- Full Text
- View/download PDF
33. Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus
- Author
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Boyington, Jeffrey C., primary, Joyce, M. Gordon, additional, Sastry, Mallika, additional, Stewart-Jones, Guillaume B. E., additional, Chen, Man, additional, Kong, Wing-Pui, additional, Ngwuta, Joan O., additional, Thomas, Paul V., additional, Tsybovsky, Yaroslav, additional, Yang, Yongping, additional, Zhang, Baoshan, additional, Chen, Lei, additional, Druz, Aliaksandr, additional, Georgiev, Ivelin S., additional, Ko, Kiyoon, additional, Zhou, Tongqing, additional, Mascola, John R., additional, Graham, Barney S., additional, and Kwong, Peter D., additional
- Published
- 2016
- Full Text
- View/download PDF
34. Environmental Drivers of Benthic Flux Variation and Ecosystem Functioning in Salish Sea and Northeast Pacific Sediments
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Belley, Rénald, primary, Snelgrove, Paul V. R., additional, Archambault, Philippe, additional, and Juniper, S. Kim, additional
- Published
- 2016
- Full Text
- View/download PDF
35. Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus
- Author
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Kiyoon Ko, Ivelin S. Georgiev, Yongping Yang, M. Gordon Joyce, Mallika Sastry, Joan O. Ngwuta, Paul V. Thomas, Baoshan Zhang, Lei Chen, Yaroslav Tsybovsky, Tongqing Zhou, Aliaksandr Druz, Peter D. Kwong, Wing-Pui Kong, Guillaume Stewart-Jones, Jeffrey C. Boyington, Man Chen, John R. Mascola, and Barney S. Graham
- Subjects
Male ,0301 basic medicine ,Protein Conformation ,Physiology ,Glycobiology ,Antibody Response ,lcsh:Medicine ,Antigen Processing and Recognition ,Antibodies, Viral ,Biochemistry ,Mice ,Immunogenicity, Vaccine ,Immune Physiology ,Medicine and Health Sciences ,Public and Occupational Health ,lcsh:Science ,Immune Response ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Vaccines ,Immune System Proteins ,Multidisciplinary ,Physics ,Viral Vaccine ,Immunogenicity ,Vaccination and Immunization ,Respiratory Syncytial Viruses ,3. Good health ,Physical sciences ,Chemistry ,Titer ,Female ,Antibody ,Research Article ,Chemical physics ,Immunology ,Biology ,complex mixtures ,Antibodies ,Virus ,03 medical and health sciences ,Immune system ,Antigen ,Animals ,Humans ,Antigens ,Glycoproteins ,lcsh:R ,Biology and Life Sciences ,Proteins ,Viral Vaccines ,Dimers (Chemical physics) ,Virology ,Mice, Inbred C57BL ,HEK293 Cells ,030104 developmental biology ,chemistry ,biology.protein ,lcsh:Q ,Preventive Medicine ,Glycoprotein ,Viral Fusion Proteins - Abstract
Respiratory syncytial virus (RSV) is a significant cause of severe respiratory illness worldwide, particularly in infants, young children, and the elderly. Although no licensed vaccine is currently available, an engineered version of the metastable RSV fusion (F) surface glycoprotein—stabilized in the pre-fusion (pre-F) conformation by “DS-Cav1” mutations—elicits high titer RSV-neutralizing responses. Moreover, pre-F-specific antibodies, often against the neutralization-sensitive antigenic site Ø in the membrane-distal head region of trimeric F glycoprotein, comprise a substantial portion of the human response to natural RSV infection. To focus the vaccine-elicited response to antigenic site Ø, we designed a series of RSV F immunogens that comprised the membrane-distal head of the F glycoprotein in its pre-F conformation. These “head-only” immunogens formed monomers, dimers, and trimers. Antigenic analysis revealed that a majority of the 70 engineered head-only immunogens displayed reactivity to site Ø-targeting antibodies, which was similar to that of the parent RSV F DS-Cav1 trimers, often with increased thermostability. We evaluated four of these head-only immunogens in detail, probing their recognition by antibodies, their physical stability, structure, and immunogenicity. When tested in naïve mice, a head-only trimer, half the size of the parent RSV F trimer, induced RSV titers, which were statistically comparable to those induced by DS-Cav1. When used to boost DS-Cav1-primed mice, two head-only RSV F immunogens, a dimer and a trimer, boosted RSV-neutralizing titers to levels that were comparable to those boosted by DS-Cav1, although with higher site Ø-directed responses. Our results provide proof-of-concept for the ability of the smaller head-only RSV F immunogens to focus the vaccine-elicited response to antigenic site Ø. Decent primary immunogenicity, enhanced physical stability, potential ease of manufacture, and potent immunogenicity upon boosting suggest these head-only RSV F immunogens, engineered to retain the pre-fusion conformation, may have advantages as candidate RSV vaccines.
- Published
- 2016
36. Mapping Above- and Below-Ground Carbon Pools in Boreal Forests: The Case for Airborne Lidar
- Author
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Kristensen, Terje, primary, Næsset, Erik, additional, Ohlson, Mikael, additional, Bolstad, Paul V., additional, and Kolka, Randall, additional
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- 2015
- Full Text
- View/download PDF
37. Decline in an Atlantic Puffin Population: Evaluation of Magnitude and Mechanisms
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Miles, Will T. S., primary, Mavor, Roddy, additional, Riddiford, Nick J., additional, Harvey, Paul V., additional, Riddington, Roger, additional, Shaw, Deryk N., additional, Parnaby, David, additional, and Reid, Jane M., additional
- Published
- 2015
- Full Text
- View/download PDF
38. A Cysteine Zipper Stabilizes a Pre-Fusion F Glycoprotein Vaccine for Respiratory Syncytial Virus
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Stewart-Jones, Guillaume B. E., primary, Thomas, Paul V., additional, Chen, Man, additional, Druz, Aliaksandr, additional, Joyce, M. Gordon, additional, Kong, Wing-Pui, additional, Sastry, Mallika, additional, Soto, Cinque, additional, Yang, Yongping, additional, Zhang, Baoshan, additional, Chen, Lei, additional, Chuang, Gwo-Yu, additional, Georgiev, Ivelin S., additional, McLellan, Jason S., additional, Srivatsan, Sanjay, additional, Zhou, Tongqing, additional, Baxa, Ulrich, additional, Mascola, John R., additional, Graham, Barney S., additional, and Kwong, Peter D., additional
- Published
- 2015
- Full Text
- View/download PDF
39. Reduced IL-17A Secretion Is Associated with High Levels of Pneumococcal Nasopharyngeal Carriage in Fijian Children
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Hoe, Edwin, primary, Boelsen, Laura K., additional, Toh, Zheng Quan, additional, Sun, Guang Wen, additional, Koo, Ghee Chong, additional, Balloch, Anne, additional, Marimla, Rachel, additional, Dunne, Eileen M., additional, Tikoduadua, Lisi, additional, Russell, Fiona M., additional, Satzke, Catherine, additional, Mulholland, E. Kim, additional, and Licciardi, Paul V., additional
- Published
- 2015
- Full Text
- View/download PDF
40. Recovery of Viral RNA and Infectious Foot-and-Mouth Disease Virus from Positive Lateral-Flow Devices
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Fowler, Veronica L., primary, Bankowski, Bartlomiej M., additional, Armson, Bryony, additional, Di Nardo, Antonello, additional, Valdazo-Gonzalez, Begoña, additional, Reid, Scott M., additional, Barnett, Paul V., additional, Wadsworth, Jemma, additional, Ferris, Nigel P., additional, Mioulet, Valérie, additional, and King, Donald P., additional
- Published
- 2014
- Full Text
- View/download PDF
41. Postprandial transfer of colostral extracellular vesicles and their protein and miRNA cargo in neonatal calves.
- Author
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Kirchner B, Buschmann D, Paul V, and Pfaffl MW
- Subjects
- Animals, Animals, Newborn, Cattle, Diet, Female, High-Throughput Nucleotide Sequencing, Proteins, Sequence Analysis, RNA, Colostrum, Extracellular Vesicles chemistry, MicroRNAs analysis
- Abstract
Extracellular vesicles (EVs) such as exosomes are key regulators of intercellular communication that can be found in almost all bio fluids. Although studies in the last decade have made great headway in discerning the role of EVs in many physiological and pathophysiological processes, the bioavailability and impact of dietary EVs and their cargo still remain to be elucidated. Due to its widespread consumption and high content of EV-associated microRNAs and proteins, a major focus in this field has been set on EVs in bovine milk and colostrum. Despite promising in vitro studies in recent years that show high resiliency of milk EVs to degradation and uptake of milk EV cargo in a variety of intestinal and blood cell types, in vivo experiments continue to be inconclusive and sometimes outright contradictive. To resolve this discrepancy, we assessed the potential postprandial transfer of colostral EVs to the circulation of newborn calves by analysing colostrum-specific protein and miRNAs, including specific isoforms (isomiRs) in cells, EV isolations and unfractionated samples from blood and colostrum. Our findings reveal distinct populations of EVs in colostrum and blood from cows that can be clearly separated by density, particle concentration and protein content (BTN1A1, MFGE8). Postprandial blood samples of calves show a time-dependent increase in EVs that share morphological and protein characteristics of colostral EVs. Analysis of miRNA expression profiles by Next-Generation Sequencing gave a different picture however. Although significant postprandial expression changes could only be detected for calf EV samples, expression profiles show very limited overlap with highly expressed miRNAs in colostral EVs or colostrum in general. Taken together our results indicate a selective uptake of membrane-associated protein cargo but not luminal miRNAs from colostral EVs into the circulation of neonatal calves., Competing Interests: The authors have declared that no competing interests exist.
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- 2020
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42. Effects of toxic compounds in Montipora capitata on exogenous and endogenous zooxanthellae performance and fertilization success.
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Hagedorn M, Farrell A, Carter V, Zuchowicz N, Johnston E, Padilla-Gamiño J, Gunasekera S, and Paul V
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- Animals, Complex Mixtures chemistry, Complex Mixtures toxicity, Reproduction, Anthozoa physiology, Fertilization drug effects, Marine Toxins metabolism, Marine Toxins toxicity
- Abstract
Studies have identified chemicals within the stony coral genus Montipora that have significant biological activities. For example, Montiporic acids A and B and other compounds have been isolated from the adult tissue and eggs of Montipora spp. and have displayed antimicrobial activity and cytotoxicity in cultured cells. The ecological role of these toxic compounds is currently unclear. This study examines the role these toxins play in reproduction. Toxins were found in the eggs and larvae of the coral Montipora capitata. Releasing these toxins by crushing both the eggs and larvae resulted in irreversible inhibition of photosynthesis in endogenous and exogenous zooxanthellae within minutes. Moreover, these toxins were stable, as frozen storage of eggs and larvae did not affect toxicity. Photosynthetic competency of Porites compressa zooxanthellae treated with either frozen or fresh, crushed eggs was inhibited similarly (P > 0.05, ANCOVA). Addition of toxic eggs plugs to live P. compressa fragments caused complete tissue necrosis under the exposed area on the fragments within 1 week. Small volumes of M. capitata crushed eggs added to sperm suspensions reduced in vitro fertilization success by killing the sperm. After 30 min, untreated sperm maintained 90 ± 1.9% SEM motility while those treated with crushed eggs were rendered immotile, 4 ± 1.4% SEM. Flow cytometry indicated membrane disruption of the immotile sperm. Fertilization success using untreated sperm was 79 ± 4% SEM, whereas the success rate dropped significantly after exposure to the crushed eggs, 1.3 ± 0% SEM. Unlike the eggs and the larvae, M. capitata sperm did not reduce the photosynthetic competency of P. compressa zooxanthellae, suggesting the sperm was nontoxic. The identity of the toxins, cellular mechanism of action, advantage of the toxins for M. capitata and their role on the reef are still unknown.
- Published
- 2015
- Full Text
- View/download PDF
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