4,121 results on '"S. Graham"'
Search Results
102. Data from Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [64Cu]Cu-NOTA-anti-CD8 PET
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Jason S. Lewis, Ingo K. Mellinghoff, Andrea Schietinger, Neeta Pandit-Taskar, Luis F. Parada, Carl Campos, Maya S. Graham, Charli Ann J. Hertz, Kelly E. Henry, and Veronica L. Nagle
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Purpose:Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8+) T cells using PET.Experimental Design:We generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8+ T cells by flow cytometry relative to the [64Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8+ tumor-infiltrating lymphocytes by IHC. To determine whether [64Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8+ T cells.Results:Nontumor-bearing NOG mice injected with human PBMCs showed prominent [64Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8+ T cells. Radiotracer retention correlated with CD8+ T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [64Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8+ T cells in brain tumors.Conclusions:Human CD8+ T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [64Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8+ T cells.
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- 2023
103. Development of the ESRA CubeSat Mission to GTO
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Carlos A. Maldonado, Jonathan Deming, Brooke N. Mosley, Justin McGlown, Anthony Nelson, Phil A. Fernandes, Anthony J. Rogers, Douglas Patrick, Martin Kroupa, Michael Caffrey, Susan Mendel, Kerry Boyd, August Gula, Kim Katko, Markus P. Hehlen, Daniel Arnold, Jonathan Barney, Ted Schultz, Dan Reisenfeld, Ruth Skoug, Angus Guider, Michael Holloway, Heidi Morning, John T. Steinberg, Erik Krause, Andrew Kirby, Darrel Beckman, Justin Tripp, Keith S. Morgan, Zachary Miller, Rob Merl, Paul S. Graham, Bradley Hoose, Joshua Ortner, Quinn Cole, Chuck Clanton, Brian A. Larsen, Tom Fairbanks, Jeff George, Rory Scobie, Kasidit Subsomboon, Kristina McKeown, Katherine Alano, and John Michel
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- 2023
104. Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later
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Emma C. Milligan, Katherine Olstad, Caitlin A. Williams, Michael Mallory, Patricio Cano, Kaitlyn A. Cross, Jennifer E. Munt, Carolina Garrido, Lisa Lindesmith, Jennifer Watanabe, Jodie L. Usachenko, Lincoln Hopkins, Ramya Immareddy, Yashavanth Shaan Lakshmanappa, Sonny R. Elizaldi, Jamin W. Roh, Rebecca L. Sammak, Rachel E. Pollard, JoAnn L. Yee, Savannah Herbek, Trevor Scobey, Dieter Miehlke, Genevieve Fouda, Guido Ferrari, Hongmei Gao, Xiaoying Shen, Pamela A. Kozlowski, David Montefiori, Michael G. Hudgens, Darin K. Edwards, Andrea Carfi, Kizzmekia S. Corbett, Barney S. Graham, Christopher B. Fox, Mark Tomai, Smita S. Iyer, Ralph Baric, Rachel Reader, Dirk P. Dittmer, Koen K.A. Van Rompay, Sallie R. Permar, and Kristina De Paris
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General Medicine - Abstract
The U.S. Food and Drug Administration only gave emergency use authorization of the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet questions regarding the durability of vaccine efficacy, especially against emerging variants, in this age group remain. We demonstrated previously that a two-dose regimen of stabilized prefusion Washington SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or purified S-2P mixed with 3M-052, a synthetic Toll-like receptor (TLR) 7/8 agonist, in a squalene emulsion (Protein+3M-052-SE) was safe and immunogenic in infant rhesus macaques. Here, we demonstrate that broadly neutralizing and spike-binding antibodies against variants of concern (VOCs), as well as T cell responses, persisted for 12 months. At 1 year, corresponding to human toddler age, we challenged vaccinated rhesus macaques and age-matched nonvaccinated controls intranasally and intratracheally with a high dose of heterologous SARS-CoV-2 B.1.617.2 (Delta). Seven of eight control rhesus macaques exhibited severe interstitial pneumonia and high virus replication in the upper and lower respiratory tract. In contrast, vaccinated rhesus macaques had faster viral clearance with mild to no pneumonia. Neutralizing and binding antibody responses to the B.1.617.2 variant at the day of challenge correlated with lung pathology and reduced virus replication. Overall, the Protein+3M-052-SE vaccine provided superior protection to the mRNA-LNP vaccine, emphasizing opportunities for optimization of current vaccine platforms. The observed efficacy of both vaccines 1 year after vaccination supports the implementation of an early-life SARS-CoV-2 vaccine.
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- 2023
105. Transcriptomic Analysis Reveals Host miRNAs Correlated with Immune Gene Dysregulation during Fatal Disease Progression in the Ebola Virus Cynomolgus Macaque Disease Model
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Christopher P. Stefan, Catherine E. Arnold, Charles J. Shoemaker, Elizabeth E. Zumbrun, Louis A. Altamura, Christina E. Douglas, Cheryl L. Taylor-Howell, Amanda S. Graham, Korey L. Delp, Candace D. Blancett, Keersten M. Ricks, Scott P. Olschner, Joshua D. Shamblin, Suzanne E. Wollen, Justine M. Zelko, Holly A. Bloomfield, Thomas R. Sprague, Heather L. Esham, and Timothy D. Minogue
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Ebola virus ,non-human primate ,pathogenesis ,transcriptome ,immunology ,miRNA ,Biology (General) ,QH301-705.5 - Abstract
Ebola virus is a continuing threat to human populations, causing a virulent hemorrhagic fever disease characterized by dysregulation of both the innate and adaptive host immune responses. Severe cases are distinguished by an early, elevated pro-inflammatory response followed by a pronounced lymphopenia with B and T cells unable to mount an effective anti-viral response. The precise mechanisms underlying the dysregulation of the host immune system are poorly understood. In recent years, focus on host-derived miRNAs showed these molecules to play an important role in the host gene regulation arsenal. Here, we describe an investigation of RNA biomarkers in the fatal Ebola virus disease (EVD) cynomolgus macaque model. We monitored both host mRNA and miRNA responses in whole blood longitudinally over the disease course in these non-human primates (NHPs). Analysis of the interactions between these classes of RNAs revealed several miRNA markers significantly correlated with downregulation of genes; specifically, the analysis revealed those involved in dysregulated immune pathways associated with EVD. In particular, we noted strong interactions between the miRNAs hsa-miR-122-5p and hsa-miR-125b-5p with immunological genes regulating both B and T-cell activation. This promising set of biomarkers will be useful in future studies of severe EVD pathogenesis in both NHPs and humans and may serve as potential prognostic targets.
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- 2021
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106. Realistic simulation of artefacts in diffusion MRI for validating post-processing correction techniques.
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Mark S. Graham, Ivana Drobnjak, and Hui Zhang 0005
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- 2016
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107. Incorporating outlier detection and replacement into a non-parametric framework for movement and distortion correction of diffusion MR images.
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Jesper L. R. Andersson, Mark S. Graham, Eniko Zsoldos, and Stamatios N. Sotiropoulos
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- 2016
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108. Evidence for Integrated Visual Face and Body Representations in the Anterior Temporal Lobes.
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Bronson B. Harry, Katja Umla-Runge, Andrew D. Lawrence, Kim S. Graham, and Paul E. Downing
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- 2016
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109. Improved cell tracking via automated removal of particulates.
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Alireza Nejati Javaremi, Charles P. Unsworth, and Euan S. Graham
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- 2014
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110. Rotation-invariant cell shape representation and modeling with level sets and graphical models.
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Alireza Nejati, Charles P. Unsworth, and Euan S. Graham
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- 2014
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111. Recurrent Respiratory Syncytial Virus Infection in a CD14-Deficient Patient
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Sjanna B Besteman, Emily Phung, Henriette H M Raeven, Gimano D Amatngalim, Matevž Rumpret, Juliet Crabtree, Rutger M Schepp, Lisa W Rodenburg, Susanna G Siemonsma, Nile Verleur, Rianne van Slooten, Karen Duran, Gijs W van Haaften, Jeffrey M Beekman, Lauren A Chang, Linde Meyaard, Tjomme van der Bruggen, Guy A M Berbers, Nicole Derksen, Stefan Nierkens, Kaitlyn M Morabito, Tracy J Ruckwardt, Evelyn A Kurt-Jones, Douglas Golenbock, Barney S Graham, and Louis J Bont
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Infectious Diseases ,Toll-like receptor ,Respiratory Syncytial Virus, Human ,monocyte ,Leukocytes, Mononuclear ,Lipopolysaccharide Receptors ,Cytokines ,Humans ,Immunology and Allergy ,Respiratory Syncytial Virus Infections ,Respiratory syncytial virus ,CD14 ,epithelium - Abstract
Background Recurrent respiratory syncytial virus (RSV) infection requiring hospitalization is rare and the underlying mechanism is unknown. We aimed to determine the role of CD14-mediated immunity in the pathogenesis of recurrent RSV infection. Methods We performed genotyping and longitudinal immunophenotyping of the first patient with a genetic CD14 deficiency who developed recurrent RSV infection. We analyzed gene expression profiles and interleukin (IL)-6 production by patient peripheral blood mononuclear cells in response to RSV pre- and post-fusion (F) protein. We generated CD14-deficient human nasal epithelial cells cultured at air-liquid interface (HNEC-ALI) of patient-derived cells and after CRISPR-based gene editing of control cells. We analyzed viral replication upon RSV infection. Results Sanger sequencing revealed a homozygous single-nucleotide deletion in CD14, resulting in absence of the CD14 protein in the index patient. In vitro, viral replication was similar in wild-type and CD14−/− HNEC-ALI. Loss of immune cell CD14 led to impaired cytokine and chemokine responses to RSV pre- and post-F protein, characterized by absence of IL-6 production. Conclusions We report an association of recurrent RSV bronchiolitis with a loss of CD14 function in immune cells. Lack of CD14 function led to defective immune responses to RSV pre- and post-F protein without a change in viral replication.
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- 2022
112. Comparison of Illumina and Oxford Nanopore Sequencing Technologies for Pathogen Detection from Clinical Matrices Using Molecular Inversion Probes
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Christopher P. Stefan, Adrienne T. Hall, Amanda S. Graham, and Timothy D. Minogue
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Nanopore Sequencing ,Nanopores ,Bacteria ,Molecular Probes ,High-Throughput Nucleotide Sequencing ,Humans ,Molecular Medicine ,Pathology and Forensic Medicine - Abstract
Next-generation sequencing is rapidly finding footholds in numerous microbiological fields, including infectious disease diagnostics. Here, we describe a molecular inversion probe panel for the identification of bacterial, viral, and parasitic pathogens. We describe the ability of Illumina and Oxford Nanopore Technologies (ONT) to sequence small amplicons originating from this panel for the identification of pathogens in complex matrices. The panel correctly classified 31 bacterial pathogens directly from positive blood culture bottles with a genus-level concordance of 96.7% and 90.3% on the Illumina and ONT platforms, respectively. Both sequencing platforms detected 18 viral and parasitic organisms directly from mock clinical samples of plasma and whole blood at concentrations of 10
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- 2022
113. Tectal Hemorrhage in the Setting of COVID-19 Infection
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Patrick F. O’Brien, Erica C. Johnson, and Robert S. Graham
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Adult ,Male ,COVID-19 ,Humans ,Intracranial Hemorrhages ,Cerebral Hemorrhage ,Ventriculostomy - Abstract
Coronavirus disease 2019 (COVID-19) has emerging evidence of a relationship to intracranial hemorrhage. The hemorrhages described to date often affect patients on anticoagulation, of advanced age, of nonwhite race, and requiring mechanical ventilation. Unusual or rare hemorrhage patterns have not as yet been described in the literature as being associated with COVID-19.A 36-year-old Hispanic male with no significant past medical history presented with isolated tectal intraparenchymal hemorrhage with intraventricular hemorrhage in the setting of no identifiable risk factors other than COVID-19. His management required temporizing with external ventricular drainage and subsequent endoscopic third ventriculostomy for ongoing obstruction of the cerebral aqueduct following the hemorrhage. He was discharged and did clinically well. To our knowledge, this is the first report of an intraparenchymal hematoma of the brain isolated to the midbrain tectum with only COVID-19 as a risk factor.COVID-19 may predispose patients to rare types of intraparenchymal hematomas which remain amenable to standard management algorithms.
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- 2022
114. Low pKa of Lys promotes glycation at one complementarity-determining region of a bispecific antibody
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Xiaobin Xu, Jessica Ann O'Callaghan, Zachary Guarnero, Haibo Qiu, Ning Li, Terra Potocky, Douglas E. Kamen, Kenneth S. Graham, Mohammed Shameem, and Teng-Chieh Yang
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Biophysics - Published
- 2022
115. Noninvasive Imaging of CD4+ T Cells in Humanized Mice
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Veronica L. Nagle, Charli Ann J. Hertz, Kelly E. Henry, Maya S. Graham, Carl Campos, Nagavarakishore Pillarsetty, Andrea Schietinger, Ingo K. Mellinghoff, and Jason S. Lewis
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CD4-Positive T-Lymphocytes ,Mice ,Cancer Research ,Copper Radioisotopes ,Oncology ,Cell Line, Tumor ,Positron-Emission Tomography ,Animals ,Humans ,Article - Abstract
Antibody-based PET (immunoPET) with radiotracers that recognize specific cells of the immune system provides an opportunity to monitor immune cell trafficking at the organismal scale. We previously reported the visualization of human CD8+ T cells, including CD8+ tumor-infiltrating lymphocytes (TIL), in mice using a humanized CD8-targeted minibody. Given the important role of CD4+ T cells in adaptive immune responses of health and disease including infections, tumors, and autoimmunity, we explored immunoPET using an anti-human-CD4 minibody. We assessed the ability of [64Cu]Cu-NOTA-IAB41 to bind to various CD4+ T-cell subsets in vitro. We also determined the effect of the CD4-targeted minibody on CD4+ T-cell abundance, proliferation, and activation state in vitro. We subsequently evaluated the ability of the radiotracer to visualize CD4+ T cells in T-cell rich organs and orthotopic brain tumors in vivo. For the latter, we injected the [64Cu]Cu-NOTA-IAB41 radiotracer into humanized mice that harbored intracranial patient-derived glioblastoma (GBM) xenografts and performed in vivo PET, ex vivo autoradiography, and anti-CD4 IHC on serial brain sections. [64Cu]Cu-NOTA-IAB41 specifically detects human CD4+ T cells without impacting their abundance, proliferation, and activation. In humanized mice, [64Cu]Cu-NOTA-IAB41 can visualize various peripheral tissues in addition to orthotopically implanted GBM tumors. [64Cu]Cu-NOTA-IAB41 is able to visualize human CD4+ T cells in humanized mice and can provide noninvasive quantification of CD4+ T-cell distribution on the organismal scale.
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- 2022
116. Newcastle Disease Virus-Like Particles Displaying Prefusion-Stabilized SARS-CoV-2 Spikes Elicit Potent Neutralizing Responses
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Yongping Yang, Wei Shi, Olubukola M. Abiona, Alexandra Nazzari, Adam S. Olia, Li Ou, Emily Phung, Tyler Stephens, Yaroslav Tsybovsky, Raffaello Verardi, Shuishu Wang, Anne Werner, Christina Yap, David Ambrozak, Tatsiana Bylund, Tracy Liu, Richard Nguyen, Lingshu Wang, Baoshan Zhang, Tongqing Zhou, Gwo-Yu Chuang, Barney S. Graham, John R. Mascola, Kizzmekia S. Corbett, and Peter D. Kwong
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neutralizing antibody ,Newcastle disease virus ,prefusion-stabilized spike ,SARS-CoV-2 ,S-2P stabilization ,vaccine ,Medicine - Abstract
The COVID-19 pandemic highlights an urgent need for vaccines that confer protection from SARS-CoV-2 infection. One approach to an effective COVID-19 vaccine may be through the display of SARS-CoV-2 spikes on the surface of virus-like particles, in a manner structurally mimicking spikes on a native virus. Here we report the development of Newcastle disease virus-like particles (NDVLPs) displaying the prefusion-stabilized SARS-CoV-2 spike ectodomain (S2P). Immunoassays with SARS-CoV-2-neutralizing antibodies revealed the antigenicity of S2P-NDVLP to be generally similar to that of soluble S2P, and negative-stain electron microscopy showed S2P on the NDVLP surface to be displayed with a morphology corresponding to its prefusion conformation. Mice immunized with S2P-NDVLP showed substantial neutralization titers (geometric mean ID50 = 386) two weeks after prime immunization, significantly higher than those elicited by a molar equivalent amount of soluble S2P (geometric mean ID50 = 17). Neutralizing titers at Week 5, two weeks after a boost immunization with S2P-NDVLP doses ranging from 2.0 to 250 μg, extended from 2125 to 4552, and these generally showed a higher ratio of neutralization versus ELISA than observed with soluble S2P. Overall, S2P-NDVLP appears to be a promising COVID-19 vaccine candidate capable of eliciting substantial neutralizing activity.
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- 2021
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117. Semiparametrically efficient estimation of the average linear regression function
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Cristine Campos de Xavier Pinto and Bryan S. Graham
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Economics and Econometrics ,Average treatment effect ,Applied Mathematics ,05 social sciences ,Linear prediction ,Function (mathematics) ,01 natural sciences ,Regression ,010104 statistics & probability ,Nonlinear system ,0502 economics and business ,Linear regression ,Covariate ,Applied mathematics ,Semiparametric regression ,0101 mathematics ,050205 econometrics ,Mathematics - Abstract
Let Y be an outcome of interest, X a vector of treatment measures, and W a vector of pre-treatment control variables. Here X may include (combinations of) continuous, discrete, or non-mutually exclusive “treatments”. Consider the linear regression of Y onto X in a subpopulation homogeneous in W = w (formally a conditional linear predictor). Let b 0 w be the coefficient vector on X in this regression. We introduce a semiparametrically efficient estimate of the average β 0 = E b 0 W . When X is binary-valued (multi-valued) our procedure recovers the (a vector of) average treatment effect(s). When X is continuously-valued, or consists of multiple non-exclusive treatments, our estimand coincides with the average partial effect (APE) of X on Y when the underlying potential response function is linear in X , but otherwise heterogeneous across agents. When the potential response function takes a general nonlinear/heterogeneous form, and X is continuously-valued, our procedure recovers a weighted average of the gradient of this response across individuals and values of X . We provide a simple, and semiparametrically efficient, method of covariate adjustment for settings with complicated treatment regimes. Our method generalizes familiar methods of covariate adjustment used for program evaluation as well as methods of semiparametric regression (e.g., the partially linear regression model).
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- 2022
118. Author response for 'A Role for the Fornix in Temporal Sequence Memory'
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null Marie‐Lucie Read, null Katja Umla‐Runge, null Andrew D. Lawrence, null Alison G. Costigan, null Liang‐Tien Hsieh, null Maxime Chamberland, null Charan Ranganath, and null Kim S. Graham
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- 2023
119. Diet and lifestyle behaviour disruption related to the pandemic was varied and bidirectional among US and UK adults participating in the ZOE COVID Study
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Mohsen Mazidi, Emily R. Leeming, Jordi Merino, Long H. Nguyen, Somesh Selvachandran, Joan Capdavila Pujal, Tyler Maher, Kirstin Kadé, Benjamin Murray, Mark S. Graham, Carole H. Sudre, Jonathan Wolf, Christina Hu, David A. Drew, Claire J. Steves, Sebastien Ourselin, Christopher Gardner, Tim D. Spector, Andrew T. Chan, Paul W. Franks, Rachel Gibson, and Sarah E. Berry
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Animal Science and Zoology ,Agronomy and Crop Science ,Food Science - Abstract
Evidence of the impact of the COVID-19 pandemic on health behaviours in the general population is limited. In this retrospective longitudinal study including UK and US participants, we collected diet and lifestyle data pre-pandemic (896,286) and peri-pandemic (291,871) using a mobile health app, and we computed a bidirectional health behaviour disruption index. Disruption of health behaviour was higher in younger, female and socio-economically deprived participants. Loss in body weight was greater in highly disrupted individuals than in those with low disruption. There were large inter-individual changes observed in 46 health and diet behaviours measured peri-pandemic compared with pre-pandemic, but no mean change in the total population. Individuals most adherent to less healthy pre-pandemic health behaviours improved their diet quality and weight compared with those reporting healthier pre-pandemic behaviours, irrespective of relative deprivation; therefore, for a proportion of the population, the pandemic may have provided an impetus to improve health behaviours. Public policies to tackle health inequalities widened by the pandemic should continue to prioritize diet and physical activity for all, as well as more targeted approaches to support younger females and those living in economically deprived areas.
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- 2021
120. Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice
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Kai Wu, Carole Henry, Charis Palandjian, Sarah O’Connell, Angela Woods, Darin K. Edwards, Anna Hill, Hamilton Bennett, Naveen Nunna, Elisabeth Narayanan, Samantha Falcone, Matthew A. Koch, Andrea Carfi, Robert A. Seder, Diana Lee, Guillaume Stewart-Jones, LingZhi Ma, Barney S. Graham, Angela Choi, Tonya M. Colpitts, Kizzmekia S. Corbett, Adrian B. McDermott, Sayda Elbashir, Julian Quinones, and Hardik Jani
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PsVN, pseudovirus neutralization titer ,ID50, inhibitory dilution factor ,GMT, geometric mean titer ,Booster dose ,Disease ,Antibodies, Viral ,ns, not significant ,Neutralization ,mRNA-1273 ,Mice ,Pandemic ,SARS-CoV-2 variants of concern ,NHPs, non-human primates ,VOI, variant of interest ,Medicine ,Neutralizing antibody ,booster dose ,Vaccines, Synthetic ,Booster (rocketry) ,ACE2, angiotensin converting enzyme 2 ,LNP, lipid nanoparticle ,biology ,Vaccination ,ELISA, enzyme-linked immunosorbent assay ,Nab, neutralizing antibody ,UTR, untranslated region ,Titer ,Infectious Diseases ,Molecular Medicine ,mRNA Vaccines ,2019-nCoV Vaccine mRNA-1273 ,S, spike ,VSV, vesicular stomatitis virus ,COVID-19 Vaccines ,IgG, immunoglobulin G ,PBS, phosphate-buffered saline ,Vaccine Efficacy ,SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 ,Article ,RBD, receptor binding domain ,Immunity ,Animals ,Humans ,NTD, N-terminal domain ,VOC, variant of concern ,General Veterinary ,General Immunology and Microbiology ,SARS-CoV-2 ,business.industry ,Public Health, Environmental and Occupational Health ,TMB, tetramethylbenzidine ,COVID-19 ,primary series ,neutralization ,Vaccine efficacy ,RLUs, relative luminescence units ,Virology ,biology.protein ,business - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic that has led to more than 2.8 million deaths worldwide. Safe and effective vaccines are now available, including Moderna’s COVID-19 vaccine (mRNA-1273) that showed 94% efficacy in prevention of symptomatic COVID-19 disease in a phase 3 clinical study. mRNA-1273 encodes for a prefusion stabilized full length spike (S) protein of the Wuhan-Hu-1 isolate. However, the emergence of SARS-CoV-2 variants has led to concerns of viral escape from vaccine-induced immunity. Several emerging variants have shown decreased susceptibility to neutralization by vaccine induced immunity, most notably the B.1.351 variant, although the overall impact on vaccine efficacy remains to be determined. Here, we present the initial evaluation in mice of two updated COVID-19 mRNA vaccines designed to target emerging SARS-CoV-2 variants: (1) monovalent mRNA-1273.351 encodes for the S protein found in the B.1.351 lineage and (2) mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. Both vaccines were evaluated as a 2-dose primary series in mice; mRNA-1273.351 was also evaluated as a booster dose in animals previously vaccinated with 2-doses of mRNA-1273. The results demonstrated that a primary vaccination series of mRNA-1273.351 was effective at increasing neutralizing antibody titers against the B.1.351 lineage, while mRNA-1273.211 was most effective at providing broad cross-variant neutralization in mice. In addition, these results demonstrated a third dose of mRNA-1273.351 significantly increased both wild-type and B.1.351-specific neutralization titers. Both mRNA-1273.351 and mRNA-1273.211 are currently being evaluated in additional pre-clinical challenge models and in phase 1/2 clinical studies.
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- 2021
121. A prefusion-stabilized RSV F subunit vaccine elicits B cell responses with greater breadth and potency than a postfusion F vaccine
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Lauren A. Chang, Emily Phung, Michelle C. Crank, Kaitlyn M. Morabito, Tonya Villafana, Filip Dubovsky, Judith Falloon, Mark T. Esser, Bob C. Lin, Grace L. Chen, Barney S. Graham, and Tracy J. Ruckwardt
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Respiratory Syncytial Virus, Human ,Vaccines, Subunit ,Respiratory Syncytial Virus Vaccines ,Humans ,General Medicine ,Respiratory Syncytial Virus Infections ,Antigens ,Antibodies, Viral ,Viral Fusion Proteins ,Antibodies, Neutralizing - Abstract
There is currently no licensed vaccine for respiratory syncytial virus (RSV). Here, we assess the effect of RSV fusion protein (F) conformation on B cell responses in a post hoc comparison of samples from the DS-Cav1 [prefusion (pre-F)] and MEDI7510 [postfusion (post-F)] vaccine clinical trials. We compared the magnitude and quality of the serological and B cell responses across time points and vaccines. We measured RSV A and B neutralization, F-binding immunoglobulin G titers, and competition assays at week 0 (before vaccination) and week 4 (after vaccination) to evaluate antibody specificity and potency. To compare B cell specificity and activation, we used pre-F and post-F probes in tandem with a 17-color immunophenotyping flow cytometry panel at week 0 (before vaccination) and week 1 (after vaccination). Our data demonstrate that both DS-Cav1 and MEDI7510 vaccination robustly elicit F-specific antibodies and B cells, but DS-Cav1 elicited antibodies that more potently neutralized both RSV A and B. The superior potency was mediated by antibodies that bind antigenic sites on the apex of pre-F that are not present on post-F. In the memory (CD27 + ) B cell compartment, vaccination with DS-Cav1 or MEDI7510 elicited B cells with different epitope specificities. B cells preferentially binding the pre-F probe were activated in DS-Cav1–vaccinated participants but not in MEDI7510-vaccinated participants. Our findings emphasize the importance of using pre-F as an immunogen in humans because of its deterministic role in eliciting highly potent neutralizing antibodies and memory B cells.
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- 2022
122. Novel all-around diamond integration with GaN HEMTs demonstrating highly efficient device cooling
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R. Soman, M. Malakoutian, B. Shankar, D. Field, E. Akso, N. Hatui, N. J. Hines, S. Graham, U. K. Mishra, M. Kuball, and S. Chowdhury
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- 2022
123. 93. Novel recombinant measles virus vaccine prevents measles virus disease in rhesus macaques
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Jessica Rubens, Jacqueline Brockhurst, Shristi Ghimire, Rebecca Loomis, Alexandrine Derrien-Colemyn, Jason Villano, Guillaume Stewart-Jones, Tracy Ruckwardt, Michael Watson, Barney S Graham, and Diane Griffin
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Infectious Diseases ,Oncology - Abstract
Background Measles-Mumps-Rubella (MMR) is an effective live-virus vaccine against measles virus (MeV). However, use of MMR is limited by its inability to boost MeV immunity, lack of immunogenicity in infants, and contraindication in pregnant and immunocompromised persons. Methods We evaluated a novel recombinant dimeric MeV hemagglutinin protein vaccine (rMeV) in a rhesus macaque model. Sixteen macaques were primed at day 0 and boosted at day 42 by experimental group: 1) MMR x2; 2) rMeV x2; 3) MMR prime/rMeV boost; 4) control; n=4. Macaques were challenged intratracheally with Bilthoven strain wild type MeV 8 months later. Blood, bone marrow (BM), and lymph node (LN) samples were collected over 3–28 days after challenge. Replication-competent MeV was measured in peripheral blood mononuclear cells (PBMC), BM cells, and LN cells by infectious assay; MeV RNA in PBMC and BM cells was determined by quantitative reverse transcriptase polymerase chain reaction. Plasma was evaluated for MeV-specific IgG and plaque reduction neutralization titer (PRNT). Results Six months after vaccination, mean PRNT was 2,432 in rMeV x2 (standard deviation (SD) 3,840), 3,584 in MMR-prime/rMeV boost (SD 3,072) and 5,120 in MMR x2 groups (SD 3,547). Upon infectious challenge, macaques who received any MeV-containing vaccine developed no clinical signs of measles and had no detectable infectious virus in PBMC, BM cells, or LN cells. All unvaccinated macaques had virus in PBMC that peaked at day 7 (mean 3,162 TCID50/mL, SD 4.1) and resolved by day 14 post challenge, and one macaque developed an extensive rash. Macaques who received any MeV-containing vaccine had no detectable MeV RNA in PBMC or BM cells, whereas all unvaccinated macaques had detectable MeV RNA that peaked at day 7 (1.6e5 copies, SD 10.5) in PBMC. In all experimental groups, MeV-specific IgG titers increased after MeV challenge. Conclusion Macaques who received rMeV and/or MMR were protected from rash, viremia, and detection of MeV RNA in PBMC and BM cells, unlike unvaccinated macaques. These data suggest that rMeV vaccine generates protective immune responses against measles and may be a novel candidate for future measles vaccine strategies. Study of cellular responses after rMeV vaccination and MeV challenge is warranted. Disclosures Jessica Rubens, MD, Mevox: Grant/Research Support Guillaume Stewart-Jones, PhD, Moderna: Inventor of SARS-CoV-2 vaccine sequences|Moderna: Stocks/Bonds Michael Watson, MD, MEVOX Ltd: Board Member|MEVOX Ltd: Ownership Interest|MEVOX Ltd: Stocks/Bonds Barney S. Graham, MD, PhD, BSG: BSG is an inventor on patents for the stabilization of the RSV F protein (WO2014160463A1, Prefusion RSV F proteins and their use).|National Institutes of Health: Inventor on patents for RSV vaccines|National Institutes of Health: inventor on patents for measles and other paramyxovirus vaccines Diane Griffin, MD PhD, Gilead: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GreenLight Biosciences: Advisor/Consultant|Merck: Advisor/Consultant|MeVox: Grant/Research Support|Takeda Pharmaceuticals: Advisor/Consultant.
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- 2022
124. 487. Analysis of the Association between Specific Antibody Response against Respiratory Syncytial Virus Fusion Protein Conformations and Life-Threatening Infection in Previously Healthy Infants
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Florencia A Bonnin, Laura B Talarico, Emily Phung, Azad Kumar, Fausto M Ferolla, Alana B Byrne, Patricio L Acosta, Analía Toledano, Ana Caratozzolo, María M Contrini, Barney S Graham, Tracy Ruckwardt, and Eduardo L López
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Infectious Diseases ,Oncology - Abstract
Background Specific humoral response against pre-fusion (pre-F) conformation of respiratory syncytial virus (RSV) F protein has been proposed to play a role against severe infection. We aimed to analyze the association between serum IgG titers against pre-F and post-fusion (post-F) conformations of RSV F protein and life-threatening RSV disease (LTD) in previously healthy infants. Methods Prospective cohort study including previously healthy infants < 12 months, hospitalized with a first RSV infection, in 2017-2019. Patients were defined to have LTD when required intensive care and ventilatory support. Pre-F exclusive and post-F-specific antibody responses were determined by post-F competition and non-competitive immunoassays, respectively, and neutralizing activity was measured by plaque reduction neutralization test. Viral load (VL) was assessed by qRT-PCR from nasopharyngeal aspirates collected on admission. Serum samples were collected within 72 h from admission and in convalescence (between 14 to 60 days). Results Seventy-five patients were included, median age 3 months, 60% (n=45) were males; 21 patients developed LTD. Importantly, acute and convalescent post-F and pre-F exclusive IgG titers did not associate with LTD (Fig 1). There was a positive correlation between neutralizing antibody titers and pre-F exclusive IgG titers (p=0.016). Post-F and pre-F exclusive IgG titers negatively correlated with age in acute phase (p< 0.0001 and p= 0.0009). In acute phase, post-F and pre-F exclusive IgG titers were higher in patients ≤ 2 months (Fig 2). Patients > 2 months increased post-F and pre-F exclusive IgG titers in convalescence. Additionally, post-F and pre-F exclusive titers did not correlate with VL, and VL was not related to LTD. Conclusion -Pre-F exclusive and post-F IgG titers did not associate with LTD, even though pre-F exclusive IgG correlated with neutralizing antibody titers. -Infants under two months of age developed a lower humoral response, likely due to an interference by maternal antibodies and/or immunological immaturity. -These findings highlight the importance of fully characterizing the immune response against RSV and its association with disease severity for the development of preventive strategies. Disclosures Barney S. Graham, MD, PhD, BSG: BSG is an inventor on patents for the stabilization of the RSV F protein (WO2014160463A1, Prefusion RSV F proteins and their use).|National Institutes of Health: Inventor on patents for RSV vaccines|National Institutes of Health: inventor on patents for measles and other paramyxovirus vaccines.
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- 2022
125. Assessment of a quadrivalent nucleoside-modified mRNA vaccine that protects against group 2 influenza viruses
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Meagan McMahon, George O’Dell, Jessica Tan, András Sárközy, Máté Vadovics, Juan Manuel Carreño, Eduard Puente-Massaguer, Hiromi Muramatsu, Csaba Bajusz, Willemijn Rijnink, Mitchell Beattie, Ying K. Tam, Ericka Kirkpatrick Roubidoux, Isabel Francisco, Shirin Strohmeier, Masaru Kanekiyo, Barney S. Graham, Florian Krammer, and Norbert Pardi
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Multidisciplinary ,Vaccination ,Nucleosides ,Hemagglutinin Glycoproteins, Influenza Virus ,Antibodies, Viral ,Mice ,Influenza A Virus, H1N1 Subtype ,Hemagglutinins ,Orthomyxoviridae Infections ,Influenza Vaccines ,Influenza, Human ,Animals ,Humans ,Vaccines, Combined ,RNA, Messenger - Abstract
Combined vaccine formulations targeting not only hemagglutinin but also other influenza virus antigens could form the basis for a universal influenza virus vaccine that has the potential to elicit long-lasting, broadly cross-reactive immune responses. Lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) vaccines can be utilized to efficiently target multiple antigens with a single vaccine. Here, we assessed the immunogenicity and protective efficacy of nucleoside-modified mRNA-LNP vaccines that contain four influenza A group 2 virus antigens (hemagglutinin stalk, neuraminidase, matrix protein 2, and nucleoprotein) in mice. We found that all vaccine components induced antigen-specific cellular and humoral immune responses after administration of a single dose. While the monovalent formulations were not exclusively protective, the combined quadrivalent formulation protected mice from all challenge viruses, including a relevant H1N1 influenza virus group 1 strain, with minimal weight loss. Importantly, the combined vaccine protected from morbidity at a dose of 125 ng per antigen after a single vaccination in mice. With these findings, we confidently conclude that the nucleoside-modified mRNA-LNP platform can be used to elicit protection against a large panel of influenza viruses.
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- 2022
126. Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy
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Maya S. Graham and Ingo K. Mellinghoff
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pediatric high-grade glioma ,diffuse midline glioma ,oncohistone ,H3K27M ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children. Despite histologic similarities, it has recently become apparent that this disease is molecularly distinct from its adult counterpart. Specific hallmark oncogenic histone mutations within pediatric malignant gliomas divide these tumors into subgroups with different neuroanatomic and chronologic predilections. In this review, we will summarize the characteristic molecular alterations of pediatric high-grade gliomas, with a focus on how preclinical models of these alterations have furthered our understanding of their oncogenicity as well as their potential impact on developing targeted therapies for this devastating disease.
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- 2020
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127. The Cibola Flight Experiment.
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Heather M. Quinn, Diane Roussel-Dupre, Michael P. Caffrey, Paul S. Graham, Michael J. Wirthlin, Keith Morgan, Anthony Salazar, Tony Nelson, William Howes, Darrel Eric Johnson, Jonathan M. Johnson, Brian H. Pratt, Nathan Rollins, and Jim Krone
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- 2015
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128. Low cost, patterning of human hNT brain cells on parylene-C with UV & IR laser machining.
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Brad J. Raos, C. P. Unsworth, J. L. Costa, C. A. Rohde, C. S. Doyle, Evangelos Delivopoulos, Alan F. Murray, M. E. Dickinson, M. Cather Simpson, Euan S. Graham, and A. S. Bunting
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- 2013
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129. Rapid antibiotic susceptibility testing from blood culture bottles with species agnostic real-time polymerase chain reaction.
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Tucker Maxson, Candace D Blancett, Amanda S Graham, Christopher P Stefan, and Timothy D Minogue
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Medicine ,Science - Abstract
Development and implementation of rapid antimicrobial susceptibility testing is critical for guiding patient care and improving clinical outcomes, especially in cases of sepsis. One approach to reduce the time-to-answer for antimicrobial susceptibility is monitoring the inhibition of DNA production, as differences in DNA concentrations are more quickly impacted compared to optical density changes in traditional antimicrobial susceptibility testing. Here, we use real-time PCR to rapidly determine antimicrobial susceptibility after short incubations with antibiotic. Application of this assay to a collection of 144 isolates in mock blood culture, covering medically relevant pathogens displaying high rates of resistance, provided susceptibility data in under 4 hours. This assay provided categorical agreement with a reference method in 96.3% of cases across all species. Sequencing of a subset of PCR amplicons showed accurate genus level identification. Overall, implementation of this method could provide accurate susceptibility results with a reduced time-to-answer for a number of medically relevant bacteria commonly isolated from blood culture.
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- 2018
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130. DNA vaccine priming for seasonal influenza vaccine in children and adolescents 6 to 17 years of age: A phase 1 randomized clinical trial.
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Katherine V Houser, Galina V Yamshchikov, Abbie R Bellamy, Jeanine May, Mary E Enama, Uzma Sarwar, Brenda Larkin, Robert T Bailer, Richard Koup, Myeisha Paskel, Kanta Subbarao, Edwin Anderson, David I Bernstein, Buddy Creech, Harry Keyserling, Paul Spearman, Peter F Wright, Barney S Graham, Julie E Ledgerwood, and VRC 702 study team
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Medicine ,Science - Abstract
BACKGROUND:Children are susceptible to severe influenza infections and facilitate community transmission. One potential strategy to improve vaccine immunogenicity in children against seasonal influenza involves a trivalent hemagglutinin DNA prime-trivalent inactivated influenza vaccine (IIV3) boost regimen. METHODS:Sites enrolled adolescents, followed by younger children, to receive DNA prime (1 mg or 4 mg) intramuscularly by needle-free jet injector (Biojector), followed by split virus 2012/13 seasonal IIV3 boost by needle and syringe approximately 18 weeks later. A comparator group received IIV3 prime and boost at similar intervals. Primary study objectives included evaluation of the safety and tolerability of the vaccine regimens, with secondary objectives of measuring antibody responses at four weeks post boost by hemagglutination inhibition (HAI) and neutralization assays. RESULTS:Seventy-five children ≥6 to ≤17 years old enrolled. Local reactogenicity was higher after DNA prime compared to IIV3 prime (p
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- 2018
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131. The Modern Family Business: Relationships, Succession and Transition
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L. Collins, L. Grisoni, J. Tucker, C. Seaman, S. Graham, R. Fakoussa, D. Otten and L. Collins, L. Grisoni, J. Tucker, C. Seaman, S. Graham, R. Fakoussa, D. Otten
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- 2016
132. Improving active contour methods for tracking endothelial cells by the removal of low-confidence edge segments.
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Alireza Nejati, Charles P. Unsworth, and Euan S. Graham
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- 2012
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133. Sodium hyperaccumulators in the Caryophyllales are characterized by both abnormally large shoot sodium concentrations and [Na]shoot/[Na]root quotients greater than unity
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Jacqueline Thompson, Gladys Wright, Hamed A. El-Serehy, Timothy S. George, Martin R. Broadley, Konrad Neugebauer, Philip J. White, and Neil S. Graham
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Nutrient solution ,Caryophyllales ,biology ,Sodium ,chemistry.chemical_element ,Original Articles ,Plant Science ,Mineral composition ,biology.organism_classification ,Positive correlation ,Plant Roots ,Magnoliopsida ,chemistry ,Botany ,Shoot ,Hyperaccumulator ,Plant Shoots ,Ionomics - Abstract
Background and Aims Some Caryophyllales species accumulate abnormally large shoot sodium (Na) concentrations in non-saline environments. It is not known whether this is a consequence of altered Na partitioning between roots and shoots. This paper tests the hypotheses (1) that Na concentrations in shoots ([Na]shoot) and in roots ([Na]root) are positively correlated among Caryophyllales, and (2) that shoot Na hyperaccumulation is correlated with [Na]shoot/[Na]root quotients. Methods Fifty two genotypes, representing 45 Caryophyllales species and 4 species from other angiosperm orders, were grown hydroponically in a non-saline, complete nutrient solution. Concentrations of Na in shoots and in roots were determined using inductively coupled plasma mass spectrometry (ICP-MS). Key Results Sodium concentrations in shoots and roots were not correlated among Caryophyllales species with normal [Na]shoot, but were positively correlated among Caryophyllales species with abnormally large [Na]shoot. In addition, Caryophyllales species with abnormally large [Na]shoot had greater [Na]shoot/[Na]root than Caryophyllales species with normal [Na]shoot. Conclusions Sodium hyperaccumulators in the Caryophyllales are characterized by abnormally large [Na]shoot, a positive correlation between [Na]shoot and [Na]root, and [Na]shoot/[Na]root quotients greater than unity.
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- 2021
134. Host response transcriptomic analysis of Crimean-Congo hemorrhagic fever pathogenesis in the cynomolgus macaque model
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Charles J. Shoemaker, Darci R. Smith, Amanda S. Graham, Christina E. Douglas, Catherine E. Arnold, Timothy D. Minogue, and Candace D. Blancett
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Crimean–Congo hemorrhagic fever ,Science ,Adaptive Immunity ,Macaque ,Article ,Virus ,Pathogenesis ,biology.animal ,medicine ,Animals ,Gene ,Multidisciplinary ,biology ,Interferon-stimulated gene ,Infectious-disease diagnostics ,RNA virus ,Viral host response ,biology.organism_classification ,medicine.disease ,Virology ,Disease Models, Animal ,Macaca fascicularis ,Viral infection ,Hemorrhagic Fever Virus, Crimean-Congo ,Medicine ,Hemorrhagic Fever, Crimean ,Sample collection ,Transcriptome - Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne RNA virus prevalent in Asia, Europe, and Africa, and can cause a hemorrhagic disease (CCHF) in humans with mortality rates as high as 60%. A general lack of both effective medical countermeasures and a comprehensive understanding of disease pathogenesis is partly driven by an historical lack of viable CCHF animal models. Recently, a cynomolgous macaque model of CCHF disease was developed. Here, we document the targeted transcriptomic response of non-human primates (NHP) to two different CCHFV strains; Afghan09-2990 and Kosova Hoti that both yielded a mild CCHF disease state. We utilized a targeted gene panel to elucidate the transcriptomic changes occurring in NHP whole blood during CCHFV infection; a first for any primate species. We show numerous upregulated genes starting at 1 day post-challenge through 14 days post-challenge. Early gene changes fell predominantly in the interferon stimulated gene family with later gene changes coinciding with an adaptive immune response to the virus. There are subtle differences between viral strains, namely duration of the differentially expressed gene response and biological pathways enriched. After recovery, NHPs showed no lasting transcriptomic changes at the end of sample collection.
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- 2021
135. Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial
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Peifeng Chen, Anita Arthur, Kaitlyn M. Morabito, Kristin Leach, Xiaolin Wang, Grace L. Chen, Attila Nagy, Lauren A. Chang, Jon Cooper, Amy L. Chamberlain, Janel Holland-Linn, Olga Vasilenko, Alicia T. Widge, Shufeng Bai, Judith A Stein, LaSonji A. Holman, Cristina Carter, Iris Pittman, Deepika Gollapudi, Lisa A. Kueltzo, Colleen Fridley, Michelle C. Crank, Amritha Menon, William Whalen, Mridul Ghosh, Cynthia S. Hendel, Martha Nason, Amy Liu, Althaf Hussain, Laura Novik, Pernell Williams, Maria Burgos Florez, Robert T. Bailer, Thuy Nguyen, Brenda Larkin, Tracy J. Ruckwardt, Pamela Costner, Lam Le, Zhong Zhao, Elizabeth Carey, Vera Ivleva, Jennifer Walters, John R. Mascola, Jennifer Cunningham, Olga Trofymenko, Ya-chen Chang, Somia P. Hickman, Martin R. Gaudinski, Richard M. Schwartz, Slobodanka D. Manceva, Kevin Carlton, Barney S. Graham, Rahul Ragunathan, Jason G. D. Gall, Ana M. Ortega-Villa, Colin Tran, Sarah H. Plummer, Abidemi Ola, Ro Shauna S Rothwell, Ingelise J. Gordon, Mingzhong Chen, Jamie G. Saunders, Aba Mensima Eshun, Bob C. Lin, Azad Kumar, Nina M. Berkowitz, Xun Liu, Cora Trelles Cartagena, Emily Phung, Galina Yamshchikov, Joe Horwitz, Sarah O’Connell, Florence Kaltovich, Floreliz Mendoza, LaShawn Requilman, Man Chen, Preeti Apte, Christopher Lee, and Renunda Hicks
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Adult ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Allergy ,Adolescent ,medicine.medical_treatment ,Phases of clinical research ,Antibodies, Viral ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,Respiratory Syncytial Virus Vaccines ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,business.industry ,Immunogenicity ,Infant ,Middle Aged ,medicine.disease ,Antibodies, Neutralizing ,Respiratory Syncytial Viruses ,Clinical trial ,Vaccination ,030228 respiratory system ,Tolerability ,Vaccines, Subunit ,business ,Adjuvant - Abstract
Multiple active vaccination approaches have proven ineffective in reducing the substantial morbidity and mortality caused by respiratory syncytial virus (RSV) in infants and older adults (aged ≥65 years). A vaccine conferring a substantial and sustainable boost in neutralising activity is required to protect against severe RSV disease. To that end, we evaluated the safety and immunogenicity of DS-Cav1, a prefusion F subunit vaccine.In this randomised, open-label, phase 1 clinical trial, the stabilised prefusion F vaccine DS-Cav1 was evaluated for dose, safety, tolerability, and immunogenicity in healthy adults aged 18-50 years at a single US site. Participants were assigned to receive escalating doses of either 50 μg, 150 μg, or 500 μg DS-Cav1 at weeks 0 and 12, and were randomly allocated in a 1:1 ratio within each dose group to receive the vaccine with or without aluminium hydroxide (AlOH) adjuvant. After 71 participants had been randomised, the protocol was amended to allow some participants to receive a single vaccination at week 0. The primary objectives evaluated the safety and tolerability at every dose within 28 days following each injection. Neutralising activity and RSV F-binding antibodies were evaluated from week 0 to week 44 as secondary and exploratory objectives. Safety was assessed in all participants who received at least one vaccine dose; secondary and exploratory immunogenicity analysis included all participants with available data at a given visit. The trial is registered with ClinicalTrials.gov, NCT03049488, and is complete and no longer recruiting.Between Feb 21, 2017, and Nov 29, 2018, 244 participants were screened for eligibility and 95 were enrolled to receive DS-Cav1 at the 50 μg (n=30, of which n=15 with AlOH), 150 μg (n=35, of which n=15 with AlOH), or 500 μg (n=30, of which n=15 with AlOH) doses. DS-Cav1 was safe and well tolerated and no serious vaccine-associated adverse events deemed related to the vaccine were identified. DS-Cav1 vaccination elicited robust neutralising activity and binding antibodies by 4 weeks after a single vaccination (p0·0001 for F-binding and neutralising antibodies). In analyses of exploratory endpoints at week 44, pre-F-binding IgG and neutralising activity were significantly increased compared with baseline in all groups. At week 44, RSV A neutralising activity was 3·1 fold above baseline in the 50 μg group, 3·8 fold in the 150 μg group, and 4·5 fold in the 500 μg group (p0·0001). RSV B neutralising activity was 2·8 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 3·7 fold in the 500 μg group (p0·0001). Pre-F-binding IgG remained significantly 3·2 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 4·0 fold in the 500 μg group (p0·0001). Pre-F-binding serum IgA remained 4·1 fold above baseline in the 50 μg group, 4·3 fold in the 150 μg group, and 4·8 fold in the 500 μg group (p0·0001). Although a higher vaccine dose or second immunisation elicited a transient advantage compared with lower doses or a single immunisation, neither significantly impacted long-term neutralisation. There was no long-term effect of dose, number of vaccinations, or adjuvant on neutralising activity.In this phase 1 study, DS-Cav1 vaccination was safe and well tolerated. DS-Cav1 vaccination elicited a robust boost in RSV F-specific antibodies and neutralising activity that was sustained above baseline for at least 44 weeks. A single low-dose of pre-F immunisation of antigen-experienced individuals might confer protection that extends throughout an entire RSV season.The National Institutes of Allergy and Infectious Diseases.
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- 2021
136. THE ET INTERVIEW: PROFESSOR GARY CHAMBERLAIN
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Guido W. Imbens, Bryan S. Graham, and Keisuke Hirano
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Economics and Econometrics ,Art history ,Social Sciences (miscellaneous) ,Mathematics - Published
- 2021
137. Anosmia, ageusia, and other COVID-19-like symptoms in association with a positive SARS-CoV-2 test, across six national digital surveillance platforms: an observational study
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Hagai Rossman, Jonathan Wolf, Smadar Shilo, Joan Capdevila Pujol, Marc Modat, Tomer Meir, Long H. Nguyen, Christina M Astley, Michela Antonelli, Benjamin J. Murray, Amit Joshi, Kerstin Klaser, Liane D Canas, Andrew T. Chan, John S. Brownstein, Carole H. Sudre, Eran Segal, Claire J. Steves, Sajaysurya Ganesh, Ayya Keshet, David A. Drew, Tim D. Spector, Sebastien Ourselin, Erika Molteni, and Mark S. Graham
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Fever ,Anosmia ,Population ,Medicine (miscellaneous) ,Health Informatics ,Corrections ,Young Adult ,Health Information Management ,Public health surveillance ,Epidemiology ,Odds Ratio ,Humans ,Medicine ,Decision Sciences (miscellaneous) ,Israel ,education ,Pandemics ,Aged ,Aged, 80 and over ,Digital Technology ,education.field_of_study ,SARS-CoV-2 ,business.industry ,Public health ,COVID-19 ,Articles ,Odds ratio ,Middle Aged ,United Kingdom ,United States ,Test (assessment) ,Dyspnea ,Cough ,Population Surveillance ,Population study ,Female ,Observational study ,Ageusia ,business ,Demography - Abstract
Summary Background Multiple voluntary surveillance platforms were developed across the world in response to the COVID-19 pandemic, providing a real-time understanding of population-based COVID-19 epidemiology. During this time, testing criteria broadened and health-care policies matured. We aimed to test whether there were consistent associations of symptoms with SARS-CoV-2 test status across three surveillance platforms in three countries (two platforms per country), during periods of testing and policy changes. Methods For this observational study, we used data of observations from three volunteer COVID-19 digital surveillance platforms (Carnegie Mellon University and University of Maryland Facebook COVID-19 Symptom Survey, ZOE COVID Symptom Study app, and the Corona Israel study) targeting communities in three countries (Israel, the UK, and the USA; two platforms per country). The study population included adult respondents (age 18–100 years at baseline) who were not health-care workers. We did logistic regression of self-reported symptoms on self-reported SARS-CoV-2 test status (positive or negative), adjusted for age and sex, in each of the study cohorts. We compared odds ratios (ORs) across platforms and countries, and we did meta-analyses assuming a random effects model. We also evaluated testing policy changes, COVID-19 incidence, and time scales of duration of symptoms and symptom-to-test time. Findings Between April 1 and July 31, 2020, 514 459 tests from over 10 million respondents were recorded in the six surveillance platform datasets. Anosmia–ageusia was the strongest, most consistent symptom associated with a positive COVID-19 test (robust aggregated rank one, meta-analysed random effects OR 16·96, 95% CI 13·13–21·92). Fever (rank two, 6·45, 4·25–9·81), shortness of breath (rank three, 4·69, 3·14–7·01), and cough (rank four, 4·29, 3·13–5·88) were also highly associated with test positivity. The association of symptoms with test status varied by duration of illness, timing of the test, and broader test criteria, as well as over time, by country, and by platform. Interpretation The strong association of anosmia–ageusia with self-reported positive SARS-CoV-2 test was consistently observed, supporting its validity as a reliable COVID-19 signal, regardless of the participatory surveillance platform, country, phase of illness, or testing policy. These findings show that associations between COVID-19 symptoms and test positivity ranked similarly in a wide range of scenarios. Anosmia, fever, and respiratory symptoms consistently had the strongest effect estimates and were the most appropriate empirical signals for symptom-based public health surveillance in areas with insufficient testing or benchmarking capacity. Collaborative syndromic surveillance could enhance real-time epidemiological investigations and public health utility globally. Funding National Institutes of Health, National Institute for Health Research, Alzheimer's Society, Wellcome Trust, and Massachusetts Consortium on Pathogen Readiness.
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- 2021
138. mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates
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Kai Wu, Ian N. Moore, Bridget Bart, John-Paul Todd, Elham Bayat Mokhtari, Gabriela S. Alvarado, Swagata Kar, Jaclyn Wear, Manjari Sriparna, Kathryn E. Foulds, Matthew Gagne, Mario Roederer, Kizzmekia S. Corbett, Seyhan Boyoglu-Barnum, Darin K. Edwards, Barbara J. Flynn, Katelyn Steingrebe, Adrian B. McDermott, Samantha J. Provost, Angela Choi, Shayne F. Andrew, Eli Boritz, Sayda Elbashir, Zackery Flinchbaugh, Timothy S. Johnston, Martha Nason, Sarah O’ Connell, Anthony Cook, Bianca M. Nagata, Mahnaz Minai, Prakriti Mudvari, Mark G. Lewis, Andrew Pekosz, Amy R. Henry, Farida Laboune, Dillon R. Flebbe, Becky Chang, Alex Van Ry, Nancy J. Sullivan, Juan I. Moliva, Saule T. Nurmukhambetova, Laurent Pessaint, Lilin Lai, Matthew A. Koch, Barney S. Graham, Hanne Leth Andersen, Maciel Porto, Kevin W. Bock, Daniel C. Douek, Anne P. Werner, Mehul S. Suthar, Evan Lamb, Alan Dodson, Andrea Carfi, and Robert A. Seder
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biology ,business.industry ,Immunology ,biology.organism_classification ,Virology ,Neutralization ,Titer ,Immunization ,biology.protein ,Vero cell ,Immunology and Allergy ,Medicine ,Antibody ,business ,Neutralizing antibody ,Mesocricetus ,Subgenomic mRNA - Abstract
B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log10 reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log10 reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.
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- 2021
139. Level of maternal respiratory syncytial virus (RSV) F antibodies in hospitalized children and correlates of protection
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Mohamed A. Elrayess, Sara Taleb, Gheyath K. Nasrallah, Asmaa Althani, Barney S. Graham, Tracy J. Ruckwardt, Khalid Alansari, Alexandrine Derrien-Colemyn, and Hadi M. Yassine
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Microbiology (medical) ,F-protein ,Respiratory Syncytial Virus Infections ,Infectious and parasitic diseases ,RC109-216 ,Antibodies, Viral ,medicine.disease_cause ,Virus ,Antibodies ,Pregnancy ,Respiratory Syncytial Virus Vaccines ,medicine ,Humans ,Respiratory system ,Child ,Lower respiratory infection ,Protection ,biology ,business.industry ,RSV ,Neonates ,General Medicine ,medicine.disease ,Antibodies, Neutralizing ,In vitro ,Titer ,Infectious Diseases ,Respiratory syncytial virus (RSV) ,Bronchiolitis ,Respiratory Syncytial Virus, Human ,Immunology ,biology.protein ,Female ,Antibody ,business ,Child, Hospitalized ,Viral Fusion Proteins ,Vaccine - Abstract
Background: Respiratory syncytial virus (RSV) is a major cause of lower respiratory infection among children and no vaccine is available. The stabilized form of the fusion (F) protein – pre-F – is a leading vaccine candidate to target different populations, including pregnant women. This study aimed to determine the magnitude and nature of RSV-directed maternal antibodies (matAbs) in hospitalized children with RSV infection. Methods: Sixty-five paired blood samples were collected from RSV-infected children aged
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- 2021
140. Accelerated COVID-19 vaccine development: milestones, lessons, and prospects
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Karin Bok, Sandra Sitar, John R. Mascola, and Barney S. Graham
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Models, Molecular ,Economic growth ,COVID-19 Vaccines ,Vaccination Coverage ,Coronavirus disease 2019 (COVID-19) ,Immunology ,Bioengineering ,Biology ,Public health surveillance ,Pandemic ,Health care ,Outcome Assessment, Health Care ,Immunology and Allergy ,Humans ,Public Health Surveillance ,Government ,business.industry ,SARS-CoV-2 ,Research ,COVID-19 ,Private sector ,United States ,Vaccinology ,Infectious Diseases ,Preparedness ,General partnership ,Perspective ,business ,Biotechnology - Abstract
The development of effective vaccines to combat infectious diseases is a complex multi-year and multi-stakeholder process. To accelerate the development of vaccines for coronavirus disease 2019 (COVID-19), a novel pathogen emerging in late 2019 and spreading globally by early 2020, the United States government (USG) mounted an operation bridging public and private sector expertise and infrastructure. The success of the endeavor can be seen in the rapid advanced development of multiple vaccine candidates, with several demonstrating efficacy and now being administered around the globe. Here, we review the milestones enabling the USG-led effort, the methods utilized, and ensuing outcomes. We discuss the current status of COVID-19 vaccine development and provide a perspective for how partnership and preparedness can be better utilized in response to future public-health pandemic emergencies.
- Published
- 2021
141. First human hNT astrocytes patterned to single cell resolution on parylene-C/Silicon dioxide substrates.
- Author
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Charles P. Unsworth, Euan S. Graham, Evangelos Delivopoulos, and Alan F. Murray
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- 2011
- Full Text
- View/download PDF
142. An optimized messenger RNA vaccine candidate protects non-human primates from Zika virus infection
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Brooke Bollman, Naveen Nunna, Kapil Bahl, Chiaowen Joyce Hsiao, Hamilton Bennett, Scott Butler, Bryant Foreman, Katherine E. Burgomaster, Maya Aleshnick, Wing-Pui Kong, Brian E. Fisher, Tracy J. Ruckwardt, Kaitlyn M. Morabito, Barney S. Graham, Kimberly A. Dowd, Theodore C. Pierson, and Andrea Carfi
- Subjects
Pharmacology ,Infectious Diseases ,Immunology ,Pharmacology (medical) - Abstract
Zika virus (ZIKV), an arbovirus transmitted by mosquitoes, was identified as a cause of congenital disease during a major outbreak in the Americas in 2016. Vaccine design strategies relied on limited available isolate sequence information due to the rapid response necessary. The first-generation ZIKV mRNA vaccine, mRNA-1325, was initially generated and, as additional strain sequences became available, a second mRNA vaccine, mRNA-1893, was developed. Herein, we compared the immune responses following mRNA-1325 and mRNA-1893 vaccination and reported that mRNA-1893 generated comparable neutralizing antibody titers to mRNA-1325 at 1/20thof the dose and provided complete protection from ZIKV challenge in non-human primates. In depth characterization of these vaccines indicated that the observed immunologic differences could be attributed to a single amino acid residue difference that compromised mRNA-1325 virus-like particle formation.
- Published
- 2022
143. A Multivalent Polyomavirus Vaccine Elicits Durable Neutralizing Antibody Responses in Macaques
- Author
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Alberto Peretti, Diana G. Scorpio, Wing-Pui Kong, Yuk-Ying S. Pang, Michael McCarthy, Kuishu Ren, Moriah Jackson, Barney S. Graham, Christopher B. Buck, Patrick M. McTamney, and Diana V. Pastrana
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Infectious Diseases ,General Veterinary ,General Immunology and Microbiology ,Public Health, Environmental and Occupational Health ,Molecular Medicine - Abstract
In 2019, there were about 100,000 kidney transplants globally, with more than a quarter of them performed in the United States. Unfortunately, some engrafted organs are lost to polyomavirus-associated nephropathy (PyVAN) caused by BK and JC viruses (BKPyV and JCPyV). Transplant patients are routinely monitored for BKPyV viremia, which is an accepted hallmark of nascent nephropathy. If viremia is detected, a reduction in immunosuppressive therapy is standard care, but the intervention comes with increased risk of immune rejection of the engrafted organ. Recent reports have suggested that transplant recipients with high levels of polyomavirus-neutralizing antibodies are protected against PyVAN. Virus-like particle (VLP) vaccines, similar to approved human papillomaviruses vaccines, have an excellent safety record and are known to induce high levels of neutralizing antibodies associated and long-lasting protection from infection. In this study, we demonstrate that VLPs representing BKPyV genotypes I, II, and IV, as well as JCPyV genotype 2 produced in insect cells elicit robust antibody titers. In rhesus macaques, all monkeys developed neutralizing antibody titers above a previously proposed protective threshold of 10,000. A second inoculation, administered 19 weeks after priming, boosted titers to a plateau of ≥25,000 that was maintained for almost two years. No vaccine-related adverse events were observed in any macaques. A multivalent BK/JC VLP immunogen did not show inferiority compared to the single-genotype VLP immunogens. Considering these encouraging results, we believe a clinical trial administering the multivalent VLP vaccine in patients waiting to receive a kidney transplant is warranted to evaluate its ability to reduce or eliminate PyVAN.HIGHLIGHTSRecombinant virus-like particle vaccine was safely administered to rhesus macaquesVaccination generated high-titer neutralizing antibody responsesMultivalent BK/JC polyomavirus vaccine was as effective as monovalent vaccinesHigh neutralizing titers were sustained for 92 weeks without appreciable decline
- Published
- 2022
144. High Efficiency Space-Based Software Radio Architectures: A Minimum Size, Weight, and Power TeraOps Processor.
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Mark E. Dunham, Zachary K. Baker, Matthew Stettler, Michael Pigue, Paul S. Graham, Eric N. Schmierer, and John Power
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- 2009
- Full Text
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145. Noise impact of single-event upsets on an FPGA-based digital filter.
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Brian H. Pratt, Michael J. Wirthlin, Michael P. Caffrey, Paul S. Graham, and Keith Morgan
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- 2009
- Full Text
- View/download PDF
146. Proof of principle for epitope-focused vaccine design.
- Author
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Bruno E. Correia, John T. Bates, Rebecca J. Loomis, Gretchen Baneyx, Chris Carrico, Joseph G. Jardine, Peter Rupert, Colin E. Correnti, Oleksandr Kalyuzhniy, Vinayak Vittal, Mary J. Connell, Eric Stevens, Alexandria Schroeter, Man Chen, Skye MacPherson, Andreia M. Serra, Yumiko Adachi, Margaret A. Holmes, Yuxing Li, Rachel E. Klevit, Barney S. Graham, Richard T. Wyatt, David Baker, Roland K. Strong, James E. Crowe Jr., Philip R. Johnson, and William R. Schief
- Published
- 2014
- Full Text
- View/download PDF
147. TMR with More Frequent Voting for Improved FPGA Reliability.
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Brian H. Pratt, Michael P. Caffrey, Derrick Gibelyou, Paul S. Graham, Keith Morgan, and Michael J. Wirthlin
- Published
- 2008
148. An Introduction to Radiation-Induced Failure Modes and Related Mitigation Methods For Xilinx SRAM FPGAs.
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Heather Quinn, Paul S. Graham, Keith Morgan, Jim Krone, Michael P. Caffrey, and Michael J. Wirthlin
- Published
- 2008
149. Total Synthesis of Taiwaniaquinoids: A Strategic Account
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Marlowe S. Graham and Christopher S. P. McErlean
- Subjects
Chemistry ,Computational chemistry ,Organic Chemistry ,Enantioselective synthesis ,Total synthesis - Published
- 2021
150. Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries†
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Catherine L.A. Salvini, Crawford James John, Andrew Madin, James H. Hunter, Isaline F.S.F. Castan, Jessica S. Graham, Michael J. Waring, Harriet A. Stanway-Gordon, Garry Pairaudeau, and Matthew J. Anderson
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DNA synthesis ,010405 organic chemistry ,Chemistry ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Small molecule ,Micelle ,Chemical reaction ,0104 chemical sciences ,chemistry.chemical_compound ,Amide ,Reagent ,Amine gas treating ,Linker - Abstract
DNA encoded libraries (DELs) represent powerful new technology for finding small molecule ligands for proteins and are increasingly being applied to hit finding in medicinal chemistry. Crucial to the synthesis of high quality DELs is the identification of chemical reactions for their assembly that proceed with very high conversion across a range of different substrates, under conditions compatible with DNA-tagged substrates. Many current chemistries used in DEL synthesis do not meet this requirement, resulting in libraries of low fidelity. Amide couplings are the most commonly used reaction in synthesis of screening libraries and also in DELs. The ability to carry out highly efficient, widely applicable amide couplings in DEL synthesis would therefore be highly desirable. We report a method for amide coupling using micelle forming surfactants, promoted by a modified linker, that is broadly applicable across a wide range of substrates. Most significantly, this works exceptionally well for coupling of DNA-conjugated carboxylic acids (N-to-C) with amines in solution, a procedure that is currently very inefficient. The optimisation of separate procedures for coupling of DNA-conjugated acids and amines by reagent screening and statistically driven optimisation is described. The generality of the method is illustrated by the application to a wide range of examples with unprecedented levels of conversion. The utility of the (N-to-C) coupling of DNA-conjugated acids in DEL synthesis is illustrated by the three cycle synthesis of a fully DNA-encoded compound by two cycles of coupling of an aminoester, with intermediate ester hydrolysis, followed by capping with an amine. This methodology will be of great utility in the synthesis of high fidelity DELs., Highly efficient forward and reverse on-DNA amide couplings were developed exploiting hydrophobic linkers in combination with the micelle forming surfactant TPGS-750M. The method is highly effective for a wide range of substrates in the synthesis of DNA-encoded libraries.
- Published
- 2021
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