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Search Results: 1 - 10 of 168831 matches for " Kate E. Broderick "
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Elucidating the Kinetics of Expression and Immune Cell Infiltration Resulting from Plasmid Gene Delivery Enhanced by Surface Dermal Electroporation
Janess M. Mendoza,Dinah H. Amante,Gleb Kichaev,Christine L. Knott,William B. Kiosses,Trevor R. F. Smith,Niranjan Y. Sardesai,Kate E. Broderick
Vaccines , 2013, DOI: 10.3390/vaccines1030384
Abstract: The skin is an attractive tissue for vaccination in a clinical setting due to the accessibility of the target, the ease of monitoring and most importantly the immune competent nature of the dermal tissue. While skin electroporation offers an exciting and novel future methodology for the delivery of DNA vaccines in the clinic, little is known about the actual mechanism of the approach and the elucidation of the resulting immune responses. To further understand the mechanism of this platform, the expression kinetics and localization of a reporter plasmid delivered via a surface dermal electroporation (SEP) device as well as the effect that this treatment would have on the resident immune cells in that tissue was investigated. Initially a time course (day 0 to day 21) of enhanced gene delivery with electroporation (EP) was performed to observe the localization of green fluorescent protein (GFP) expression and the kinetics of its appearance as well as clearance. Using gross imaging, GFP expression was not detected on the surface of the skin until 8 h post treatment. However, histological analysis by fluorescent microscopy revealed GFP positive cells as early as 1 h after plasmid delivery and electroporation. Peak GFP expression was observed at 24 h and the expression was maintained in skin for up to seven days. Using an antibody specific for a keratinocyte cell surface marker, reporter gene positive keratinocytes in the epidermis were identified. H&E staining of treated skin sections demonstrated an influx of monocytes and granulocytes at the EP site starting at 4 h and persisting up to day 14 post treatment. Immunological staining revealed a significant migration of lymphocytic cells to the EP site, congregating around cells expressing the delivered antigen. In conclusion, this study provides insights into the expression kinetics following EP enhanced DNA delivery targeting the dermal space. These findings may have implications in the future to design efficient DNA vaccination strategies for the clinic.
Enhanced Delivery and Potency of Self-Amplifying mRNA Vaccines by Electroporation in Situ
Yen Cu,Kate E. Broderick,Kaustuv Banerjee,Julie Hickman,Gillis Otten,Susan Barnett,Gleb Kichaev,Niranjan Y. Sardesai,Jeffrey B. Ulmer,Andrew Geall
Vaccines , 2013, DOI: 10.3390/vaccines1030367
Abstract: Nucleic acid-based vaccines such as viral vectors, plasmid DNA (pDNA), and mRNA are being developed as a means to address limitations of both live-attenuated and subunit vaccines. DNA vaccines have been shown to be potent in a wide variety of animal species and several products are now licensed for commercial veterinary but not human use. Electroporation delivery technologies have been shown to improve the generation of T and B cell responses from synthetic DNA vaccines in many animal species and now in humans. However, parallel RNA approaches have lagged due to potential issues of potency and production. Many of the obstacles to mRNA vaccine development have recently been addressed, resulting in a revival in the use of non-amplifying and self-amplifying mRNA for vaccine and gene therapy applications. In this paper, we explore the utility of EP for the in vivo delivery of large, self-amplifying mRNA, as measured by reporter gene expression and immunogenicity of genes encoding HIV envelope protein. These studies demonstrated that EP delivery of self-amplifying mRNA elicited strong and broad immune responses in mice, which were comparable to those induced by EP delivery of pDNA.
Enhanced Efficacy of a Codon-Optimized DNA Vaccine Encoding the Glycoprotein Precursor Gene of Lassa Virus in a Guinea Pig Disease Model When Delivered by Dermal Electroporation
Kathleen A. Cashman,Kate E. Broderick,Eric R. Wilkinson,Carl I. Shaia,Todd M. Bell,Amy C. Shurtleff,Kristin W. Spik,Catherine V. Badger,Mary C. Guttieri,Niranjan Y. Sardesai,Connie S. Schmaljohn
Vaccines , 2013, DOI: 10.3390/vaccines1030262
Abstract: Lassa virus (LASV) causes a severe, often fatal, hemorrhagic fever endemic to West Africa. Presently, there are no FDA-licensed medical countermeasures for this disease. In a pilot study, we constructed a DNA vaccine (pLASV-GPC) that expressed the LASV glycoprotein precursor gene (GPC). This plasmid was used to vaccinate guinea pigs (GPs) using intramuscular electroporation as the delivery platform. Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls. However, vaccinated GPs experienced transient viremia after challenge, although lower than the mock-vaccinated controls. In a follow-on study, we developed a new device that allowed for both the vaccine and electroporation pulse to be delivered to the dermis. We also codon-optimized the GPC sequence of the vaccine to enhance expression in GPs. Together, these innovations resulted in enhanced efficacy of the vaccine. Unlike the pilot study where neutralizing titers were not detected until after virus challenge, modest neutralizing titers were detected in guinea pigs before challenge, with escalating titers detected after challenge. The vaccinated GPs were never ill and were not viremic at any timepoint. The combination of the codon-optimized vaccine and dermal electroporation delivery is a worthy candidate for further development.
Altered Response Hierarchy and Increased T-Cell Breadth upon HIV-1 Conserved Element DNA Vaccination in Macaques
Viraj Kulkarni, Antonio Valentin, Margherita Rosati, Candido Alicea, Ashish K. Singh, Rashmi Jalah, Kate E. Broderick, Niranjan Y. Sardesai, Sylvie Le Gall, Beatriz Mothe, Christian Brander, Morgane Rolland, James I. Mullins, George N. Pavlakis, Barbara K. Felber
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086254
Abstract: HIV sequence diversity and potential decoy epitopes are hurdles in the development of an effective AIDS vaccine. A DNA vaccine candidate comprising of highly conserved p24gag elements (CE) induced robust immunity in all 10 vaccinated macaques, whereas full-length gag DNA vaccination elicited responses to these conserved elements in only 5 of 11 animals, targeting fewer CE per animal. Importantly, boosting CE-primed macaques with DNA expressing full-length p55gag increased both magnitude of CE responses and breadth of Gag immunity, demonstrating alteration of the hierarchy of epitope recognition in the presence of pre-existing CE-specific responses. Inclusion of a conserved element immunogen provides a novel and effective strategy to broaden responses against highly diverse pathogens by avoiding decoy epitopes, while focusing responses to critical viral elements for which few escape pathways exist.
HIV-1 Env DNA Vaccine plus Protein Boost Delivered by EP Expands B- and T-Cell Responses and Neutralizing Phenotype In Vivo
Kar Muthumani, Megan C. Wise, Kate E. Broderick, Natalie Hutnick, Jonathan Goodman, Seleeke Flingai, Jian Yan, Chaoran B. Bian, Janess Mendoza, Colleen Tingey, Christine Wilson, Krzysztof Wojtak, Niranjan Y. Sardesai, David B. Weiner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084234
Abstract: An effective HIV vaccine will most likely require the induction of strong T-cell responses, broadly neutralizing antibodies (bNAbs), and the elicitation of antibody-dependent cellular cytotoxicity (ADCC). Previously, we demonstrated the induction of strong HIV/SIV cellular immune responses in macaques and humans using synthetic consensus DNA immunogens delivered via adaptive electroporation (EP). However, the ability of this improved DNA approach to prime for relevant antibody responses has not been previously studied. Here, we investigate the immunogenicity of consensus DNA constructs encoding gp140 sequences from HIV-1 subtypes A, B, C and D in a DNA prime-protein boost vaccine regimen. Mice and guinea pigs were primed with single- and multi-clade DNA via EP and boosted with recombinant gp120 protein. Sera were analyzed for gp120 binding and induction of neutralizing antibody activity. Immunization with recombinant Env protein alone induced low-titer binding antibodies with limited neutralization breath. In contrast, the synthetic DNA prime-protein boost protocol induced significantly higher antibody binding titers. Furthermore, sera from DNA prime-protein boost groups were able to neutralize a broader range of viruses in a panel of tier 1 clade B viruses as well as multiple tier 1 clade A and clade C viruses. Further investigation of synthetic DNA prime plus adaptive EP plus protein boost appears warranted.
Signatures of Relativistic Helical Motion in the Rotation Measures of AGN Jets
Avery E Broderick,Abraham Loeb
Physics , 2009, DOI: 10.1088/0004-637X/703/2/L104
Abstract: Polarization has proved an invaluable tool for probing magnetic fields in relativistic jets. Maps of the intrinsic polarization vectors have provided the best evidence to date for uniform, toroidally dominated magnetic fields within jets. More recently, maps of the rotation measure (RM) in jets have for the first time probed the field geometry of the cool, moderately relativistic surrounding material. In most cases, clear signatures of toroidal magnetic field are detected, corresponding to gradients in RM profiles transverse to the jet. However, in many objects these profiles also display marked asymmetries which are difficult to explain in simple helical jet models. Furthermore, in some cases the RM profiles are strongly frequency and/or time dependent. Here we show that these features may be naturally accounted for by including relativistic helical motion in the jet model. In particular, we are able to reproduce bent RM profiles observed in a variety of jets, frequency dependent RM profile morphologies and even the time dependence of the RM profiles of knots in 3C 273. Finally, we predict that some sources may show reversals in their RM profiles at sufficiently high frequencies, depending upon the the ratio of the components of jet sheath velocity transverse and parallel to the jet. Thus, multi-frequency RM maps promise a novel way in which to probe the velocity structure of relativistic outflows.
Where are all the gravastars? Limits upon the gravastar model from accreting black holes
Avery E. Broderick,Ramesh Narayan
Physics , 2007, DOI: 10.1088/0264-9381/24/3/009
Abstract: The gravastar model, which postulates a strongly correlated thin shell of anisotropic matter surrounding a region of anti-de Sitter space, has been proposed as an alternative to black holes. We discuss constraints that present-day observations of well-known black hole candidates place on this model. We focus upon two black hole candidates known to have extraordinarily low luminosities: the supermassive black hole in the Galactic Center, Sagittarius A*, and the stellar-mass black hole, XTE J1118+480. We find that the length scale for modifications of the type discussed in Chapline et al. (2003) must be sub-Planckian.
On The Nature of the Compact Dark Mass at the Galactic Center
Avery E. Broderick,Ramesh Narayan
Physics , 2005, DOI: 10.1086/500930
Abstract: We consider a model in which Sgr A*, the 3.5x10^6 M_sun supermassive black hole candidate at the Galactic Center, is a compact object with a surface. Given the very low quiescent luminosity of Sgr A* in the near infrared, the existence of a hard surface, even in the limit in which the radius approaches the horizon, places severe constraints upon the steady mass accretion rate in the source, requiring dM/dt < 10^-12 M_sun/yr. This limit is well below the minimum accretion rate needed to power the observed submillimeter luminosity of Sgr A*. We thus argue that Sgr A* does not have a surface, i.e., it must have an event horizon. The argument could be made more restrictive by an order of magnitude with microarcsecond resolution imaging, e.g., with submillimeter VLBI.
The Evolution of Cloud Cores and the Formation of Stars
Avery E. Broderick,Eric Keto
Physics , 2010, DOI: 10.1088/0004-637X/721/1/493
Abstract: For a number of starless cores, self-absorbed molecular line and column density observations have implied the presence of large-amplitude oscillations. We examine the consequences of these oscillations on the evolution of the cores and the interpretation of their observations. We find that the pulsation energy helps support the cores and that the dissipation of this energy can lead toward instability and star formation. In this picture, the core lifetimes are limited by the pulsation decay timescales, dominated by non-linear mode-mode coupling, and on the order of ~few x 10^5--10^6 yr. Notably, this is similar to what is required to explain the relatively low rate of conversion of cores into stars. For cores with large-amplitude oscillations, dust continuum observations may appear asymmetric or irregular. As a consequence, some of the cores that would be classified as supercritical may be dynamically stable when oscillations are taken into account. Thus, our investigation motivates a simple hydrodynamic picture, capable of reproducing many of the features of the progenitors of stars without the inclusion of additional physical processes, such as large-scale magnetic fields.
Horizon-Scale Lepton Acceleration in Jets: Explaining the Compact Radio Emission in M87
Avery E Broderick,Alexander Tchekhovskoy
Physics , 2015, DOI: 10.1088/0004-637X/809/1/97
Abstract: It has now become clear that the radio jet in the giant elliptical galaxy M87 must turn on very close to the black hole. This implies the efficient acceleration of leptons within the jet at scales much smaller than feasible by the typical dissipative events usually invoked to explain jet synchrotron emission. Here we show that the stagnation surface, the separatrix between material that falls back into the black hole and material that is accelerated outward forming the jet, is a natural site of pair formation and particle acceleration. This occurs via an inverse-Compton pair catastrophe driven by unscreened electric fields within the charge-starved region about the stagnation surface and substantially amplified by a post-gap cascade. For typical estimates of the jet properties in M87, we find excellent quantitive agreement between the predicted relativistic lepton densities and those required by recent high-frequency radio observations of M87. This mechanism fails to adequately fill a putative jet from Sagittarius A* with relativistic leptons, which may explain the lack of an obvious radio jet in the Galactic center. Finally, this process implies a relationship between the kinetic jet power and the gamma-ray luminosity of blazars, produced during the post-gap cascade.
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