Abstract
Cochleates represent a powerful subunit vaccine delivery system, uniquely suited to meeting the challenges of modern vaccine development. The intrinsic properties of cochleates lead to ...advantages in the important areas of safety, stability, efficacy, immune response targeting, combining vaccines to multiple infectious agents, alternate routes of administration (including oral and intranasal), and the generation of mucosal immunity. Cochleates are alternating layers of cations and negatively charged lipids, in stacked sheets or rolled scrolls, with little or no internal aqueous space. Bacterial membrane proteins or the surface glycoproteins of enveloped viruses can be efficiently integrated into the lipid bilayers of the cochleates. The current study investigated the relative amounts of the different classes and subtypes of antibodies generated in mice in response to the oral administration of influenza glycoprotein cochleates. Analysis of circulating antibody revealed significant levels of flu glycoprotein-specific IgG, IgM, and IgA class, and IgGI and IgG2a subtype, antibodies. Oral administration of influenza glycoprotein cochleates also induced antigen-specific salivary IgA levels. The immune responses induced were protective against infection in the respiratory tract following intranasal challenge with live influenza virus. DNA plasmids and oligonucleotides can also be formulated into cochleates. Cochleates containing a plasmid that expresses the human immunodeficiency virus, (HIV-1), proteins env (gp160), rev, and tat, in mammalian cells, was given to mice orally or by intramuscular injection. Two oral administrations yielded strong splenocyte cytolytic and proliferative responses. These cellular responses were essentially the same as those obtained by analogous intramuscular injection of DNA cochleates. Very small quantities of encochleated DNA were required to induce these responses, whereas a higher dose of naked DNA given orally induced no cytotoxic or proliferative responses. Cochleates containing pathogen proteins or DNA, formulated, adjuvanted, and delivered in a variety of ways, represent powerful tools for dissecting and directing the immune response to complex pathogens. The ability of cochleates to induce antibody and cell mediated responses, systemically and on mucosal surfaces, makes them desirable candidates for development of preventive and therapeutic vaccines.
Worldwide, influenza virus remains a serious disease which has successfully eluded numerous attempts to design a consistently effective vaccine. In part, these attempts have been thwarted because of ...a lack of basic understanding of the mechanisms which mediate protection and recovery from influenza infection. A better understanding of the roles of secretory antibody, serum antibody and cell mediated immunity vis-à-vis protection and recovery from influenza infection has allowed us more rationally to approach the design and administration of a vaccine for influenza. We have constructed a vaccine composed of glycoproteins from the envelopes of either influenza of Sendai virus embedded in a lipid bilayer (immunosomes) mimicking the presentation of the virus to the cells during natural infection. Intranasal immunization with these immunosomes induces an adequate systemic Ir compared with intramuscular immunization and a superior local IgA response. These animals were specifically protected from virus challenge.
The LUX prototype detector: Heat exchanger development Akerib, D.S.; Bai, X.; Bedikian, S. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
05/2013, Letnik:
709, Številka:
C
Journal Article
Recenzirano
Odprti dostop
The LUX (large underground xenon) detector is a two-phase xenon time projection chamber (TPC) designed to search for WIMP–nucleon dark matter interactions. As with all noble element detectors, ...continuous purification of the detector medium is essential to produce a large (>1ms) electron lifetime; this is necessary for efficient measurement of the electron signal which in turn is essential for achieving robust discrimination of signal from background events. In this paper, we describe the development of a novel purification system deployed in a prototype detector. The results from the operation of this prototype indicated heat exchange with an efficiency above 94% up to a flow rate of 42 slpm, allowing for an electron drift length greater than 1m to be achieved in approximately 2 days and sustained for the duration of the testing period.
Results from the LUX dark matter experiment Horn, Markus; Akerib, D. S.; Araújo, H. M. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
11/2014, Letnik:
784
Journal Article
Recenzirano
Odprti dostop
The LUX (Large Underground Xenon) experiment aims at the direct detection of dark matter particles via their collisions with xenon nuclei. The 370 kg two-phase liquid xenon time projection chamber ...measures simultaneously the scintillation and ionization from interactions in the target. The ratio of these two signals provides very good discrimination between potential nuclear recoil and electronic recoil signals to search for WIMP-nucleon scattering. The LUX detector operates at the Sanford Underground Research Facility (Lead, South Dakota, USA) since February 2013. Of note, first results were presented in late 2013 setting the world's most stringent limits on WIMP-nucleon scattering cross-sections over a wide range of WIMP masses. A 300 day run beginning in 2014 will further improve the sensitivity and new calibration techniques will reduce systematics for the WIMP signal search.
Immunization is today the most effective defense mechanism against microbial infections. Although highly effective vaccines are currently available for a number of infectious diseases, vaccine ...formulations can still be improved in a number of important areas. The ability to induce antigen-specific humoral and cell-mediated immunity is crucial to the development of effective prophylactic and therapeutic vaccines for HIV and other pathogens. The approach of our laboratory has been to design and test simple, highly defined antigen-lipid complexes that would stimulate antibody and cell-mediated immune responses in the absence of any nonspecific immunological activators such as Freund's adjuvant, lipopolysaccharide (LPS), or alum. These studies have provided insight into the relationships between the properties of an immunogen and the induction of the desired immune responses. We have previously utilized this approach to define the minimal structures required for the induction of antibody responses. Our more recent studies have focused on defining the parameters involved in the induction of cell-mediated and mucosal immune responses. Toward this end we have developed a new type of subunit vaccine that is effective when given orally or intramuscularly, and elucidated structure-function relationships in peptide vaccines that affect induction of CD8+ cell responses.
The Large Underground Xenon (LUX) dark matter experiment aims to detect rare low-energy interactions from Weakly Interacting Massive Particles (WIMPs). The radiogenic backgrounds in the LUX detector ...have been measured and compared with Monte Carlo simulation. Measurements of LUX high-energy data have provided direct constraints on all background sources contributing to the background model. The expected background rate from the background model for the 85.3 day WIMP search run is (2.6±0.2stat±0.4sys) ×10-3 events keV$ ee\atop{-1}$ kg-1 day-1 in a 118 kg fiducial volume. The observed background rate is (3.6±0.4stat)×10-3 events keV$ ee\atop{-1}$ kg-1 day-1, consistent with model projections. The expectation for the radiogenic background in a subsequent one-year run is presented.
The Large Underground Xenon (LUX) dark matter experiment aims to detect rare low-energy interactions from Weakly Interacting Massive Particles (WIMPs). The radiogenic backgrounds in the LUX detector ...have been measured and compared with Monte Carlo simulation. Measurements of LUX high-energy data have provided direct constraints on all background sources contributing to the background model. The expected background rate from the background model for the 85.3 day WIMP search run is (2.6±0.2stat±0.4sys) ×10-3 events keV$ ee\atop{-1}$ kg-1 day-1 in a 118 kg fiducial volume. The observed background rate is (3.6±0.4stat)×10-3 events keV$ ee\atop{-1}$ kg-1 day-1, consistent with model projections. The expectation for the radiogenic background in a subsequent one-year run is presented.
We have previously demonstrated that the compound 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole exerts immunosuppressive effects in several experimental models of autoimmunity. These ...results were achieved by subcutaneously administering ST1959 after dissolution in an oily vehicle, because of its poor water solubility. To circumvent this problem, we sought to determine whether nanocochleate technology could be successfully exploited to deliver ST1959 and protect mice undergoing lethal acute graft-versus-host disease (GVHD). Orally-administered encochleated ST1959 significantly protected animals from lethality, resulting in survival rates of 57% and 100% at doses of 2 and 10 mg/kg, respectively, whereas oral administration of 2 mg/kg ST1959, mixed with empty nanocochleates, was completely inactive. Increased survival was associated with diminished serum chemokine levels and donor CD8+ T cells in the spleen of ST1959-treated mice. Moreover, ST1959 treatment significantly counteracted GVHD-induced normocitic anemia by increasing hemoglobin, hematocrit, platelet, and red and white blood cell counts. Overall, these data show that orally-administered encochleated ST1959 significantly protects mice from GVHD.
An ultra-low background PMT for liquid xenon detectors Akerib, D. S.; Bai, X.; Bernard, E. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
11/2012, Letnik:
703, Številka:
C
Journal Article
Recenzirano
Odprti dostop
Results are presented from radioactivity screening of two models of photomultiplier tubes designed for use in current and future liquid xenon experiments. The Hamamatsu 5.6 cm diameter R8778 PMT, ...used in the LUX dark matter experiment, has yielded a positive detection of four common radioactive isotopes: 238U, 232Th, 40K, and 60Co. Screening of LUX materials has rendered backgrounds from other detector materials subdominant to the R8778 contribution. A prototype Hamamatsu 7.6 cm diameter R11410 MOD PMT has also been screened, with benchmark isotope counts measured at <0.4 238U / <0.3 232Th / < 8.340K / 2.0+-0.2 60Co mBq/PMT. This represents a large reduction, equal to a change of x $\frac{1}{24}$ 238U / x $\frac{1}{9}$ 232Th / x $\frac{1}{8}$ 40K per PMT, between R8778 and R11410 MOD, concurrent with a doubling of the photocathode surface area (4.5 cm to 6.4 cm diameter). 60Co measurements are comparable between the PMTs, but can be significantly reduced in future R11410 MOD units through further material selection. Assuming PMT activity equal to the measured 90% upper limits, Monte Carlo estimates indicate that replacement of R8778 PMTs with R11410 MOD PMTs will change LUX PMT electron recoil background contributions by a factor of x $\frac{1}{25}$ after further material selection for 60Co reduction, and nuclear recoil backgrounds by a factor of \times $\frac{1}{36}$. The strong reduction in backgrounds below the measured R8778 levels makes the R11410 MOD a very competitive technology for use in large-scale liquid xenon detectors.
PDF
