Molecular investigations into vaginal immunization with HIV gp41 antigenic construct H4A in a quick release solid dosage form

A robust vaginal immune response is considered essential for an effective prophylactic vaccine that prevents transmission of HIV and other sexually acquired diseases. Considerable attention has recently focused on the potential of vaginally administered vaccines as a means to induce such local immunity. However, the potential for vaccination at this site remains in doubt as the vaginal mucosa is generally considered to have low immune inductive potential. In the current study, we explored for the first time the use of a quick release, freeze-dried, solid dosage system for practical vaginal administration of a protein antigen. These solid dosage forms overcome the common problem associated with leakage and poor retention of vaginally administered antigen solutions. Mice were immunized vaginally with H4A, an HIV gp41 envelope based recombinant protein, using quick release, freeze-dried solid rods, and the immune responses compared to a control group immunized via subcutaneous H4A injection. Vaginally immunized mice failed to elicit robust immune responses. Our detailed investigations, involving cytokine analysis, the stability of H4A in mouse cervicovaginal lavage, and elucidation of the state of H4A protein in the immediate-release dosage form, revealed that antigen instability in vaginal fluid, the state of the antigen in the dosage form, and the cytokine profile induced are all likely to have contributed to the observed lack of immunogenicity. These are important factors affecting vaginal immunization and provide a rational basis for explaining the typically poor and variable elicitation of immunity at this site, despite the presence of immune responsive cells within the vaginal mucosae. In future mucosal vaccine studies, a more explicit focus on antigen stability in the dosage form and the immune potential of available antigen-responsive cells is recommended.

Role of the transgenic human thyrotropin receptor A-subunit in thyroiditis induced by A-subunit immunization and regulatory T cell depletion

Transgenic BALB/c mice that express intrathyroidal human thyroid stimulating hormone receptor (TSHR) A-subunit, unlike wild-type (WT) littermates, develop thyroid lymphocytic infiltration and spreading to other thyroid autoantigens after T regulatory cell (Treg) depletion and immunization with human thyrotropin receptor (hTSHR) adenovirus. To determine if this process involves intramolecular epitope spreading, we studied antibody and T cell recognition of TSHR ectodomain peptides (A–Z). In transgenic and WT mice, regardless of Treg depletion, TSHR antibodies bound predominantly to N-terminal peptide A and much less to a few downstream peptides. After Treg depletion, splenocytes from WT mice responded to peptides C, D and J (all in the A-subunit), but transgenic splenocytes recognized only peptide D. Because CD4+ T cells are critical for thyroid lymphocytic infiltration, amino acid sequences of these peptides were examined for in silico binding to BALB/c major histocompatibility complex class II (IA–d). High affinity subsequences (inhibitory concentration of 50% < 50 nm) are present in peptides C and D (not J) of the hTSHR and mouse TSHR equivalents. These data probably explain why transgenic splenocytes do not recognize peptide J. Mouse TSHR mRNA levels are comparable in transgenic and WT thyroids, but only transgenics have human A-subunit mRNA. Transgenic mice can present mouse TSHR and human A-subunit-derived peptides. However, WT mice can present only mouse TSHR, and two to four amino acid species differences may preclude recognition by CD4+ T cells activated by hTSHR-adenovirus. Overall, thyroid lymphocytic infiltration in the transgenic mice is unrelated to epitopic spreading but involves human A-subunit peptides for recognition by T cells activated using the hTSHR.

Control of second-life hybrid battery energy storage system based on modular boost-multilevel buck converter

To fully utilize second-life batteries on the grid system, a hybrid battery scheme needs to be considered for several reasons: the uncertainty over using a single source supply chain for second-life batteries, the differences in evolving battery chemistry and battery configuration by different suppliers to strive for greater power levels, and the uncertainty of degradation within a second-life battery. Therefore, these hybrid battery systems could have widely different module voltage, capacity, and initial state of charge and state of health. In order to suitably integrate and control these widely different batteries, a suitable multimodular converter topology and an associated control structure are required. This paper addresses these issues proposing a modular boost-multilevel buck converter based topology to integrate these hybrid second-life batteries to a grid-tie inverter. Thereafter, a suitable module-based distributed control architecture is introduced to independently utilize each converter module according to its characteristics. The proposed converter and control architecture are found to be flexible enough to integrate widely different batteries to an inverter dc link. Modeling, analysis, and experimental validation are performed on a single-phase modular hybrid battery energy storage system prototype to understand the operation of the control strategy with different hybrid battery configurations.

PDVSA-Bitor revamps Orimulsion formula to boost environmental cost benefits

Orimulsion400 is a new generation of the Orimulsion formula. This new generation is a more environmentally friendly, cost-effective energy source. This article describes the product's evolution as well as test results from diverse power plants.

Astrocytes target presynaptic NMDA receptors to give synapses a boost

Astrocytes modulate synaptic strength. This effect occurs, reports a new paper, because ATP-dependent vesicular release of astrocytic glutamate acts on presynaptic neuronal NMDA receptors to increase synaptic efficacy. © 2007 Nature Publishing Group.

Does rapport-building boost the eyewitness eyeclosure effect in closed questioning?

Purpose: Several studies have documented that people's ability to correctly report details of witnessed events is enhanced when they merely close their eyes. Yet closing one's eyes in front of a stranger could sometimes create social discomfort, which other studies suggest can impair memory reports. This paper reports two experiments exploring the extent to which the memory benefits of eyeclosure are enhanced when efforts are taken to build interviewer/witness rapport, thus potentially reducing discomfort. Methods: In both studies participants observed filmed events and, afterwards, half underwent a basic rapport-building exercise with an interviewer. All participants then answered closed questions about specific details of the event, and half were instructed to close their eyes throughout this questioning. We recorded the proportion of questions answered correctly, incorrectly, or with 'don't know' responses. Results: Both eyeclosure and rapport-building separately enhanced correct responding. The data offer no evidence, though, that rapport-building moderated this eyeclosure benefit. This is despite the fact that rapport-building did appear to moderate the effect of eyeclosure on participants' self-reported comfort during the interviews. Conclusions: These studies give us initial cause for doubt over a hypothesized - but heretofore untested - social psychological constraint on the benefits of eyeclosure.