600 research outputs found
A Model of the THUNDER Actuator
A THUNDER actuator is a composite of three thin layers, a metal base, a piezoelectric wafer and a metal top cover, bonded together under pressure and at high temperature with the LaRC SI polyimid adhesive. When a voltage is applied between the metal layers across the PZT the actuator will bend and can generate a force. This document develops and describes an analytical model the transduction properties of THUNDER actuators. The model development is divided into three sections. First, a static model is described that relates internal stresses and strains and external displacements to the thermal pre-stress and applied voltage. Second, a dynamic energy based model is described that allows calculation of the resonance frequencies, developed force and electrical input impedance. Finally, a fully coupled electro-mechanical transducer model is described. The model development proceeds by assuming that both the thermal pre-stress and the piezoelectric actuation cause the actuator to deform in a pure bend in a single plane. It is useful to think of this as a two step process, the actuator is held flat, differential stresses induce a bending moment, the actuator is released and it bends. The thermal pre-stress is caused by the different amounts that the constituent layers shrink due to their different coefficients of thermal expansion. The adhesive between layers sets at a high temperature and as the actuator cools, the metal layers shrink more than the PZT. The PZT layer is put into compression while the metal layers are in tension. The piezoelectric actuation has a similar effect. An applied voltage causes the PZT layer to strain, which in turn strains the two metal layers. If the PZT layer expands it will put the metal layers into tension and PZT layer into compression. In both cases, if shear force effects are neglected, the actuator assembly will experience a uniform in-plane strain. As the materials each have a different elastic modulus, different stresses will develop in each layer and these stresses will induce a bending moment. When the actuator is released from its flat configuration, the differential stresses are relieved as the actuator bends
Active Control of Fan Noise by Vane Actuators
An active noise control system for ducted fan noise was built that uses actuators located in stator vanes. The actuators were piezoelectric benders manufactured using the THUNDER technology and were custom designed for the application. The active noise control system was installed in the NASA ANCF rig. Four actuator array with a total of 168 actuators in 28 stator vanes were used. Simultaneous reductions of acoustic power in both the inlet and exhaust duct were demonstrated for a fan disturbance that contained two radial mode orders in both inlet and exhaust. Total power levels in the target modes were reduced by up to 9 dB in the inlet and total tone levels by over 6 dB while exhaust power levels were reduced by up to 3 dB. Far field sound pressure level reductions of up to 17 dB were observed. A simpler control system, matched to the location of the disturbance with two radial actuator arrays, was demonstrated to control total acoustic power in four disturbance modes simultaneously in inlet and exhaust. The vane actuator met the requirements given for the ANCF, although in practice the performance of the system was limited by the constraints of the power amplifiers and the presence of control spillover. The vane actuators were robust. None of the 168 vane actuators failed during the tests
Prenatal factors contribute to the emergence of kwoshiorkor or marasmus in severe undernutrition: evidence for the predictive adaptation model
Severe acute malnutrition in childhood manifests as oedematous (kwashiorkor, marasmic kwashiorkor) and non-oedematous (marasmus) syndromes with very different prognoses. Kwashiorkor differs from marasmus in the patterns of protein, amino acid and lipid metabolism when patients are acutely ill as well as after rehabilitation to ideal weight for height. Metabolic patterns among marasmic patients define them as metabolically thrifty, while kwashiorkor patients function as metabolically profligate. Such differences might underlie syndromic presentation and prognosis. However, no fundamental explanation exists for these differences in metabolism, nor clinical pictures, given similar exposures to undernutrition. We hypothesized that different developmental trajectories underlie these clinical-metabolic phenotypes: if so this would be strong evidence in support of predictive adaptation model of developmental plasticity
A GMCSF-Neuroantigen Tolerogenic Vaccine Elicits Systemic Lymphocytosis of CD4+ CD25high FOXP3+ Regulatory T Cells in Myelin-Specific TCR Transgenic Mice Contingent Upon Low-Efficiency T Cell Antigen Receptor Recognition
Previous studies showed that single-chain fusion proteins comprised of GM-CSF and major encephalitogenic peptides of myelin, when injected subcutaneously in saline, were potent tolerogenic vaccines that suppressed experimental autoimmune encephalomyelitis (EAE) in rats and mice. These tolerogenic vaccines exhibited dominant suppressive activity in inflammatory environments even when emulsified in Complete Freund's Adjuvant (CFA). The current study provides evidence that the mechanism of tolerance was dependent upon vaccine-induced regulatory CD25+ T cells (Tregs), because treatment of mice with the Treg-depleting anti-CD25 mAb PC61 reversed tolerance. To assess tolerogenic mechanisms, we focused on 2D2-FIG mice, which have a transgenic T cell repertoire that recognizes myelin oligodendrocyte glycoprotein peptide MOG35-55 as a low-affinity ligand and the neurofilament medium peptide NFM13-37 as a high-affinity ligand. Notably, a single subcutaneous vaccination of GMCSF-MOG in saline elicited a major population of FOXP3+ Tregs that appeared within 3 days, was sustained over several weeks, expressed canonical Treg markers, and was present systemically at high frequencies in the blood, spleen, and lymph nodes. Subcutaneous and intravenous injections of GMCSF-MOG were equally effective for induction of FOXP3+ Tregs. Repeated booster vaccinations with GMCSF-MOG elicited FOXP3 expression in over 40% of all circulating T cells. Covalent linkage of GM-CSF with MOG35-55 was required for Treg induction whereas vaccination with GM-CSF and MOG35-55 as separate molecules lacked Treg-inductive activity. GMCSF-MOG elicited high levels of Tregs even when administered in immunogenic adjuvants such as CFA or Alum. Conversely, incorporation of GM-CSF and MOG35-55 as separate molecules in CFA did not support Treg induction. The ability of the vaccine to induce Tregs was dependent upon the efficiency of T cell antigen recognition, because vaccination of 2D2-FIG or OTII-FIG mice with the high-affinity ligands GMCSF-NFM or GMCSF-OVA (Ovalbumin323-339), respectively, did not elicit Tregs. Comparison of 2D2-FIG and 2D2-FIG-Rag1−/− strains revealed that GMCSF-MOG may predominantly drive Treg expansion because the kinetics of vaccine-induced Treg emergence was a function of pre-existing Treg levels. In conclusion, these findings indicate that the antigenic domain of the GMCSF-NAg tolerogenic vaccine is critical in setting the balance between regulatory and conventional T cell responses in both quiescent and inflammatory environments
Neuroantigen-specific, tolerogenic vaccines: GM-CSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE)
<p>Abstract</p> <p>Background</p> <p>Vaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease. This study focused on whether cytokine-neuroantigen (NAg) fusion proteins could inhibit disease in chronic murine models of experimental autoimmune encephalomyelitis (EAE) and thus serve as potential therapeutic modalities for multiple sclerosis.</p> <p>Results</p> <p>A fusion protein comprised of murine GM-CSF as the N-terminal domain and the encephalitogenic MOG35-55 peptide as the C-terminal domain was tested as a tolerogenic, therapeutic vaccine (TTV) in the C57BL/6 model of EAE. Administration of GMCSF-MOG before active induction of EAE, or alternatively, at the onset of EAE blocked the development and progression of EAE. Covalent linkage of the GM-CSF and MOG35-55 domains was required for tolerogenic activity. Likewise, a TTV comprised of GM-CSF and PLP139-151 was a tolerogen in the SJL model of EAE.</p> <p>Conclusion</p> <p>These data indicated that fusion proteins containing GM-CSF coupled to myelin auto-antigens elicit tolerance rather than immunity.</p
An Approach Using PSA Levels of 1.5 ng/mL as the Cutoff for Prostate Cancer Screening in Primary Care.
Identification of folate receptor α (FRα) binding oligopeptides and their evaluation for targeted virotherapy applications
Oncolytic virotherapies (OV) based on human adenoviral (HAdV) vectors hold significant promise for the treatment of advanced ovarian cancers where local, intraperitoneal delivery to tumour metastases is feasible, bypassing many complexities associated with intravascular delivery. The efficacy of HAdV-C5-based OV is hampered by a lack of tumour selectivity, where the primary receptor, hCAR, is commonly downregulated during malignant transformation. Conversely, folate receptor alpha (FRα) is highly expressed on ovarian cancer cells, providing a compelling target for tumour selective delivery of virotherapies. Here, we identify high-affinity FRα-binding oligopeptides for genetic incorporation into HAdV-C5 vectors. Biopanning identified a 12-mer linear peptide, DWSSWVYRDPQT, and two 7-mer cysteine-constrained peptides, CIGNSNTLC and CTVRTSAEC that bound FRα in the context of the phage particle. Synthesised lead peptide, CTVRTSAEC, bound specifically to FRα and could be competitively inhibited with folic acid. To assess the capacity of the elucidated FRα-binding oligopeptides to target OV to FRα, we genetically incorporated the peptides into the HAdV-C5 fiber-knob HI loop including in vectors genetically ablated for hCAR interactions. Unfortunately, the recombinant vectors failed to efficiently target transduction via FRα due to defective intracellular trafficking following entry via FRα, indicating that whilst the peptides identified may have potential for applications for targeted drug delivery, they require additional refinement for targeted virotherapy applications
Histone deacetylase inhibitor trichostatin A sensitises cisplatin-resistant ovarian cancer cells to oncolytic adenovirus
Ovarian cancer is often termed a silent killer due to the late onset of symptoms. Whilst patients initially respond to chemotherapy, they rapidly develop chemo-resistance. Oncolytic adenoviruses (OAds) are promising anti-cancer agents engineered to “hijack” the unique molecular machinery of cancer cells enabling tumour-selective viral replication. This allows spread to adjacent cells and amplification of oncolysis within the tumour. OAds represent an excellent opportunity for ovarian cancer therapy via intra-peritoneal delivery, however the efficacy of OAds thus far is limited. Here, we evaluate chromatin (histone) modification in chemo-resistant cells and its relationship to Ad efficacy (wild-type or oncolytic Ad). In contrast to cisplatin-sensitive A2780 cells that show an efficient reduction of cell viability by Ad in the presence of cisplatin, cisplatin-resistant A2780/cp70 cells show diminishing Ad-mediated reduction of cell viability with escalating doses of cisplatin. Histone deacetylase (HDAC)-2 and to a lesser extent HDAC1 were up-regulated in cisplatin-resistant but not cisplatin-sensitive cells. Cisplatin-resistant cells treated with a pan-HDAC inhibitor trichostatin A (TsA) significantly enhanced Ad-mediated reduction of cell viability in the presence of cisplatin. Cells treated with TsA alone did not reduce cell viability suggesting these findings are Ad-dependent. Thus, we identify HDAC inhibition as a potential means to sensitise cisplatin-resistant ovarian cancer cells to virotherapies, an observation that may offer improved outcomes for patients with late stage, chemotherapy-resistant ovarian cancer
Constraints on the Progenitor System of the Type Ia Supernova SN 2011fe/PTF11kly
Type Ia supernovae (SNe) serve as a fundamental pillar of modern cosmology,
owing to their large luminosity and a well-defined relationship between
light-curve shape and peak brightness. The precision distance measurements
enabled by SNe Ia first revealed the accelerating expansion of the universe,
now widely believed (though hardly understood) to require the presence of a
mysterious "dark" energy. General consensus holds that Type Ia SNe result from
thermonuclear explosions of a white dwarf (WD) in a binary system; however,
little is known of the precise nature of the companion star and the physical
properties of the progenitor system. Here we make use of extensive historical
imaging obtained at the location of SN 2011fe/PTF11kly, the closest SN Ia
discovered in the digital imaging era, to constrain the visible-light
luminosity of the progenitor to be 10-100 times fainter than previous limits on
other SN Ia progenitors. This directly rules out luminous red giants and the
vast majority of helium stars as the mass-donating companion to the exploding
white dwarf. Any evolved red companion must have been born with mass less than
3.5 times the mass of the Sun. These observations favour a scenario where the
exploding WD of SN 2011fe/PTF11kly, accreted matter either from another WD, or
by Roche-lobe overflow from a subgiant or main-sequence companion star.Comment: 22 pages, 6 figures, submitte
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