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Search Results: 1 - 10 of 17248 matches for " Andrew Freywald "
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Transgene IL-21-Engineered T Cell-Based Vaccine Potently Converts CTL Exhaustion via the Activation of the mTORC1 Pathway in Chronic Infection  [PDF]
Aizhang Xu, Xueying Zhang, Rajni Chibbar, Andrew Freywald, Suresh Tikoo, Changyu Zheng, Jim Xiang
World Journal of Vaccines (WJV) , 2019, DOI: 10.4236/wjv.2019.91001
Abstract: CD8+ cytotoxic T lymphocyte (CTL) exhaustion is one of the major obstacles for the effectiveness of virus control in chronic infectious diseases. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing OVA-TEXO and human immunodeficiency virus (HIV-1) Gag-specific Gag-TEXO vaccines, inducing therapeutic immunity in wild-type C57BL/6 (B6) mice, and converting CTL exhaustion in recombinant OVA-specific adenovirus AdVOVA-infected B6 (AdVOVA-B6) mice with chronic infection. IL-21 cytokine plays an important role in controlling chronic infections. Therefore, in this study, we constructed recombinant transgene IL-21-expressing AdVIL-21, and generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines, or control vaccines (OVA-TEXO/Null and Gag-TEXO/Null) by infecting OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull, lacking transgene, and assessed their effects in B6 or AdVOVA-B6 mice. We demonstrate that both OVA-TEXO/IL-21 and control OVA-TEXO/Null vaccines are capable of converting CTL exhaustion in chronic infection. However, the OVA-TEXO/IL-21 vaccine more efficiently rescues exhausted CTLs by increasing stronger CTL proliferation and effector cytokine IFN-γ expression than the control OVA-TEXO/Null vaccine in AdVOVA-B6 mice with chronic infection, though both vaccines stimulated comparable OVA-specific CTL responses and protective immunity against OVA-expressing BL6-10OVA melanoma lung metastasis in wild-type B6 mice. In vivo, the OVA-TEXO/IL-21-stimulated CTLs more efficiently up-regulate phosphorylation of mTORC1-controlled EIF4E and expression of mTORC1- regulated T-bet molecule than the control OVA-TEXO/Null-stimulated ones. Importantly, the Gag-TEXO/IL21 vaccine induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10Gag melanoma lung metastases than the control Gag-TEXO/Null vaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic vaccines for patients with chronic infections.
CD154 and IL-2 Signaling of CD4+ T Cells Play a Critical Role in Multiple Phases of CD8+ CTL Responses Following Adenovirus Vaccination
Channakeshava Sokke Umeshappa, Roopa Hebbandi Nanjundappa, Yufeng Xie, Andrew Freywald, Yulin Deng, Hong Ma, Jim Xiang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047004
Abstract: Adenoviral (AdV) vectors represent most commonly utilized viral vaccines in clinical studies. While the role of CD8+ cytotoxic T lymphocyte (CTL) responses in mediating AdV-induced protection is well understood, the involvement of CD4+ T cell-provided signals in the development of functional CD8+ CTL responses remain unclear. To explore CD4+ T helper signals required for AdVova-stimulated CTL responses, we established an adoptive transfer system by transferring CD4+ T cells derived from various knock out and transgenic mice into wild-type and/or CD4-deficient animals, followed by immunizing with recombinant ovalbumin (OVA)-expressing AdVova vector. Without CD4+ T help, both primary and memory CTL responses were greatly reduced in this model, and were associated with increased PD-1 expression. The provision of OVA-specific CD4+ T help in CD4+ T cell-deficient mice restored AdVova-induced primary CTL responses, and supported survival and recall responses of AdVova-stimulated memory CTLs. These effects were specifically mediated by CD4+ T cell-produced IL-2 and CD154 signals. Adoptive transfer of “helped” or “unhelped” effector and memory CTLs into na?ve CD4+ T cell-deficient or -sufficient mice also revealed an additional role for polyclonal CD4+ T cell environment in the survival of AdVova-stimulated CTLs, partially explaining the extension of CTL contraction phase. Finally, during recall responses, CD4+ T cell environment, particularly involving memory CD4+ T cells, greatly enhanced expansion of memory CTLs. Collectively, our data strongly suggest a critical role for CD4+ T help in multiple phases of AdV-stimulated CTL responses, and could partially explain certain failures in AdV-based immunization trials targeting malignant tumors and chronic diseases that are often associated with compromised CD4+ T cell population and function.
Th Cells Promote CTL Survival and Memory via Acquired pMHC-I and Endogenous IL-2 and CD40L Signaling and by Modulating Apoptosis-Controlling Pathways
Channakeshava Sokke Umeshappa, Yufeng Xie, Shulin Xu, Roopa Hebbandi Nanjundappa, Andrew Freywald, Yulin Deng, Hong Ma, Jim Xiang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064787
Abstract: Involvement of CD4+ helper T (Th) cells is crucial for CD8+ cytotoxic T lymphocyte (CTL)-mediated immunity. However, CD4+ Th’s signals that govern CTL survival and functional memory are still not completely understood. In this study, we assessed the role of CD4+ Th cells with acquired antigen-presenting machineries in determining CTL fates. We utilized an adoptive co-transfer into CD4+ T cell-sufficient or -deficient mice of OTI CTLs and OTII Th cells or Th cells with various gene deficiencies pre-stimulated in vitro by ovalbumin (OVA)-pulsed dendritic cell (DCova). CTL survival was kinetically assessed in these mice using FITC-anti-CD8 and PE-H-2Kb/OVA257-264 tetramer staining by flow cytometry. We show that by acting via endogenous CD40L and IL-2, and acquired peptide-MHC-I (pMHC-I) complex signaling, CD4+ Th cells enhance survival of transferred effector CTLs and their differentiation into the functional memory CTLs capable of protecting against highly-metastasizing tumor challenge. Moreover, RT-PCR, flow cytometry and Western blot analysis demonstrate that increased survival of CD4+ Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2) and down-regulation of proapoptotic (Bcl-10, Casp-3, Casp-4, Casp-7) molecules. Taken together, our results reveal a previously unexplored mechanistic role for CD4+ Th cells in programming CTL survival and memory recall responses. This knowledge could also aid in the development of efficient adoptive CTL cancer therapy.
Can a Massive Graviton be a Stable Particle  [PDF]
Andrew Beckwith
Journal of Modern Physics (JMP) , 2011, DOI: 10.4236/jmp.2011.25043
Abstract: This document is based on a question asked in the Dark Side of the Universe 2010 conference in Leon, Mexico, when a researcher from India asked the author about how to obtain a stability analysis of massive gravitons. The answer to this question involves an extension of the usual Pauli_Fiertz Langrangian as written by Ortin, with non- zero graviton mass contributing to a relationship between the trace of a revised GR stress-energy tensor (assuming non- zero graviton mass), and the trace of a revised symmetric tensor times a tiny mass for a 4 dimensional graviton. The resulting analysis makes use of Visser’s treatment of a stress en-ergy tensor, with experimental applications discussed in the resulting analysis. If the square of frequency of a massive graviton is real valued and greater than zero, stability can be possibly confirmed experimentally.
Octonionic Gravity Formation, Its Connections to Micro Physics  [PDF]
Andrew Beckwith
Open Journal of Microphysics (OJM) , 2011, DOI: 10.4236/ojm.2011.11002
Abstract: We ask if Octonionic quantum gravity is a relevant consideration near the Planck scale. Furthermore, we examine whether gravitational waves would be generated during the initial phase, , of the universe when triggered by changes in spacetime geometry; i.e. what role would an increase in degrees of freedom have in setting the conditions during , so that the result of these conditions can be observed and analyzed by a gravitational detector. The micro physics interaction is due to the formation of a pre Planckian to Planckian space time transition in spatial dimensions at and near the Planck dimensional values, i.e. 10–33 centimeters in spatial dimensions. This transition would be abrupt and arising in micro physics regimes of space time.
Detailing Coherent, Minimum Uncertainty States of Gravitons, as Semi Classical Components of Gravity Waves, and How Squeezed States Affect Upper Limits To Graviton Mass  [PDF]
Andrew Beckwith
Journal of Modern Physics (JMP) , 2011, DOI: 10.4236/jmp.2011.27086
Abstract: We present what is relevant to squeezed states of initial space time and how that affects both the composition of relic GW, and also gravitons. A side issue to consider is if gravitons can be configured as semi classical "particles", which is akin to the Pilot model of Quantum Mechanics as embedded in a larger non linear "deterministic" background.
What the Null Energy Condition (and When It May Be Violated) Tells Us about Gravitational Wave Frequencies in/for Relic Cosmology?  [PDF]
Andrew Beckwith
Journal of Modern Physics (JMP) , 2011, DOI: 10.4236/jmp.2011.29118
Abstract: We introduce a criterion as to the range of HFGW generated by early universe conditions. The 1 to 10 Giga Hertz range is constructed initially starting with what Grupen writes as far as what to expect of GW frequencies which can be detected assuming a sensitivity of 7×h~10-27 . From there we examine the implications of an earlier Hubble parameter at the start of inflation, and a phase transition treatment of pre to post Planckian inflation physics via use of inflatons. We close with an analysis of how gravitational constant G may vary with time, the tie in with the NEC condition and how to select a range of relic GW frequencies. The gravitational frequencies in turn may enable resolving a mis match between the datum that the entropy of the center of the galaxy black hole is greater than the entropy of the present four dimensional universe as we can infer and measure.
Result-Based Management in the Public Sector: A Decade of Experience for the Tanzanian Executive Agencies  [PDF]
Andrew Sulle
Journal of Service Science and Management (JSSM) , 2011, DOI: 10.4236/jssm.2011.44057
Abstract: One element of the NPM-inspired reforms is the adoption of result-based management in the Tanzanian public sector. This paper examines the implementation of this type of reform by focusing on executive agencies. Executive agencies were especially created to be result-oriented public organizations. Our empirical question is whether or not and to what extent the management of executive agencies has shifted to result-based approach as promised by NPM-reform doctrine. Our findings indicate that result-based approach has only been partially implemented in the Tanzanian public sector. There is less emphasis on managing for results and management processes have continued to be predominantly based on inputs and processes.
Can We Form Gravitinos by Something Other Than a Higgs Boson in the Electro-Weak Era?  [PDF]
Andrew Beckwith
Journal of Modern Physics (JMP) , 2012, DOI: 10.4236/jmp.2012.329162
Abstract: What is the physical nature of gravitinos? As asked before, this question was the template of how to introduce Machian Physics as a way to link gravitinos in the electro weak era and gravitons as of the present. What we wish to do now is to ask how a flaw in the Higgs equation as brought up by Comay shows a branch off from orthodox quantum physics, leading to, with the Machs principle application done earlier a way to embed the beginning of the universe as a semi classical superstructure of which Quantum Mechanics is a subset of. We argue that this will necessitate a review of the Higgs equation of state for reasons stated in the manuscript. We also finally review a proprosal for another form of mass formation mechanism as a replacement for the Higgs mass as introduced by Glinka and Beckwith, 2012, with commentary as to how suitable it may be to get a gravitino mass in fidelity to the Machian proposal introduced by Beckwith previously, to get linkage between electroweak era gravitinos and present day gravitons.
Variation of Vacuum Energy if Scale Factor Becomes Infinitely Small, with Fixed Entropy Due to a Non Pathological Big Bang Singularity Accessible to Modified Einstein Equations  [PDF]
Andrew Beckwith
Journal of Modern Physics (JMP) , 2012, DOI: 10.4236/jmp.2012.329171
Abstract: When initial radius Rinitial 0 if Stoica actually derived Einstein equations in a formalism which remove the big bang singularity pathology, then the reason for Planck length no longer holds. The implications of Rinitial 0 are the first part of this manuscript. Then the resolution is alluded to by work from Muller and Lousto, as to implications of entanglement entropy. We present entanglement entropy in the early universe with a steadily shrinking scale factor, due to work from Muller and Lousto, and show that there are consequences due to initial entanged Sentropy=0.3rH2/a2 for a time dependent horizon radius rH in cosmology, with for flat space conditions rH= for conformal time. In the case of a curved, but not flat space version of entropy, we look at vacuum energy as proportional to the inverse of scale factor squared times the inverse of initial entropy, effectively when there is no initial time in line with ~H2/G H≈a-1. The consequences for this initial entropy being entangled are elaborated in this manuscript. No matter how small the length gets, Sentropy if it is entanglement entropy, will not go to zero. The requirement is that the smallest length of time, t, re scaled does not go to zero. Even if the length goes to zero. This preserves a minimum non zero vacuum energy, and in doing so keep the bits, for computational bits cosmological evolution even if Rinitial 0.
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