Intramuscular Immunisation with Chlamydial Proteins Induces Chlamydia trachomatis Specific Ocular Antibodies.

BACKGROUND: Ocular infection with Chlamydia trachomatis can cause trachoma, which is the leading cause of blindness due to infection worldwide. Despite the large-scale implementation of trachoma control programmes in the majority of countries where trachoma is endemic, there remains a need for a vaccine. Since C. trachomatis infects the conjunctival epithelium and stimulates an immune response in the associated lymphoid tissue, vaccine regimens that enhance local antibody responses could be advantageous. In experimental infections of non-human primates (NHPs), antibody specificity to C. trachomatis antigens was found to change over the course of ocular infection. The appearance of major outer membrane protein (MOMP) specific antibodies correlated with a reduction in ocular chlamydial burden, while subsequent generation of antibodies specific for PmpD and Pgp3 correlated with C. trachomatis eradication. METHODS: We used a range of heterologous prime-boost vaccinations with DNA, Adenovirus, modified vaccinia Ankara (MVA) and protein vaccines based on the major outer membrane protein (MOMP) as an antigen, and investigated the effect of vaccine route, antigen and regimen on the induction of anti-chlamydial antibodies detectable in the ocular lavage fluid of mice. RESULTS: Three intramuscular vaccinations with recombinant protein adjuvanted with MF59 induced significantly greater levels of anti-MOMP ocular antibodies than the other regimens tested. Intranasal delivery of vaccines induced less IgG antibody in the eye than intramuscular delivery. The inclusion of the antigens PmpD and Pgp3, singly or in combination, induced ocular antigen-specific IgG antibodies, although the anti-PmpD antibody response was consistently lower and attenuated by combination with other antigens. CONCLUSIONS: If translatable to NHPs and/or humans, this investigation of the murine C. trachomatis specific ocular antibody response following vaccination provides a potential mouse model for the rapid and high throughput evaluation of future trachoma vaccines

The crystal structure of superoxide dismutase from Plasmodium falciparum

Background: Superoxide dismutases (SODs) are important enzymes in defence against oxidative stress. In Plasmodium falciparum, they may be expected to have special significance since part of the parasite life cycle is spent in red blood cells where the formation of reactive oxygen species is likely to be promoted by the products of haemoglobin breakdown. Thus, inhibitors of P. falciparum SODs have potential as anti-malarial compounds. As a step towards their development we have determined the crystal structure of the parasite's cytosolic iron superoxide dismutase. Results: The cytosolic iron superoxide dismutase from P. falciparum (PfFeSOD) has been overexpressed in E. coli in a catalytically active form. Its crystal structure has been solved by molecular replacement and refined against data extending to 2.5 angstrom resolution. The structure reveals a two-domain organisation and an iron centre in which the metal is coordinated by three histidines, an aspartate and a solvent molecule. Consistent with ultracentrifugation analysis the enzyme is a dimer in which a hydrogen bonding lattice links the two active centres. Conclusion: The tertiary structure of PfFeSOD is very similar to those of a number of other iron-and manganese-dependent superoxide dismutases, moreover the active site residues are conserved suggesting a common mechanism of action. Comparison of the dimer interfaces of PfFeSOD with the human manganese-dependent superoxide dismutase reveals a number of differences, which may underpin the design of parasite-selective superoxide dismutase inhibitors

Probe spectroscopy in an operating magneto-optical trap: the role of Raman transitions between discrete and continuum atomic states

We report on cw measurements of probe beam absorption and four-wave-mixing spectra in a $^{85}$Rb magneto-optical trap taken while the trap is in operation. The trapping beams are used as pump light. We concentrate on the central feature of the spectra at small pump-probe detuning and attribute its narrow resonant structures to the superposition of Raman transitions between light-shifted sublevels of the ground atomic state and to atomic recoil processes. These two contributions have different dependencies on trap parameters and we show that the former is inhomogeneously broadened. The strong dependence of the spectra on the probe-beam polarization indicates the existence of large optical anisotropy of the cold-atom sample, which is attributed to the recoil effects. We point out that the recoil-induced resonances can be isolated from other contributions, making pump-probe spectroscopy a highly sensitive diagnostic tool for atoms in a working MOT.Comment: 9 pages, 8 figure

Going higher in the First-order Quantifier Alternation Hierarchy on Words

We investigate the quantifier alternation hierarchy in first-order logic on finite words. Levels in this hierarchy are defined by counting the number of quantifier alternations in formulas. We prove that one can decide membership of a regular language to the levels $\mathcal{B}\Sigma_2$ (boolean combination of formulas having only 1 alternation) and $\Sigma_3$ (formulas having only 2 alternations beginning with an existential block). Our proof works by considering a deeper problem, called separation, which, once solved for lower levels, allows us to solve membership for higher levels

An Automated System for Hydroxide Catalysis Bonding of Precision-Aligned Optical Systems

Precision-aligned, robust, ultra-stable optical assemblies are required in an increasing number of space-based applications such as fundamental science, metrology and geodesy. Hydroxide catalysis bonding is a proven, glue-free, technology for building such optical systems from materials such as ULE, Zerodur and fused silica. Hydroxide catalysis bonded optical systems have flown in missions such as GP-B and LISA Pathfinder achieving picometer path-length stability and microradian component stability over full mission lifetime. Component alignment and bonding was previously a largely manual process that required skilled operators and significant time. We have recently automated most of the alignment and bonding steps with the goals of improving overall precision, speed and reliability. Positioning and bonding of an optical component to within 4 microns and 10 microradians of a target position and alignment can now be reliably completed within half an hour, compared to the many hours typically taken previously. The key new features of this system are an interferometer that monitors the parallelism and separation of the surfaces to be bonded and a precision multi-axis manipulator that can optimise component alignment as it brings it down to the point of bonding. We present a description of the system and a summary of the alignment results obtained in a series of 9 test bonds. We also show how this system is being developed for integration into a precision optical manufacturing facility for assembly of large optical systems

Lightweighting design optimisation for additively manufactured mirrors

Design for additive manufacture (AM; 3D printing) is significantly different than design for subtractive machining. Although there are some limitations on the designs that can be printed, the increase in the AM design-space removes some of the existing challenges faced by the traditional lightweight mirror designs; for example, sandwich mirrors are just as easy to fabricate as open-back mirrors via AM, and they provide an improvement in structural rigidity. However, the ability to print a sandwich mirror as a single component does come with extra considerations; such as orientation upon the build plate and access to remove any temporary support material. This paper describes the iterations in optimisation applied to the lightweighting of a small, 84 mm diameter by 20 mm height, spherical concave mirror intended for CubeSat applications. The initial design, which was fabricated, is discussed in terms of the internal lightweighting design and the design constraints that were imposed by printing and post-processing. Iterations on the initial design are presented; these include the use of topology optimisation to minimise the total internal strain energy during mirror polishing and the use of lattices combined with thickness variation i.e. having a thicker lattice in strategic support locations. To assess the suitability of each design, finite element analysis is presented to quantify the print-through of the lightweighting upon the optical surface for a given mass reduction

Delineation of a unique protein-protein interaction site on the surface of the estrogen receptor

Recent studies have identified a series of estrogen receptor (ER)interacting peptides that recognize sites that are distinct from the classic coregulator recruitment (AF2) region. Here, we report the structural and functional characterization of an ER alpha-specific peptide that binds to the liganded receptor in an AF2-independent manner. The 2-angstrom crystal structure of the ER/peptide complex reveals a binding site that is centered on a shallow depression on the beta-hairpin face of the ligand-binding domain. The peptide binds in an unusual extended conformation and makes multiple contacts with the ligand-binding domain. The location and architecture of the binding site provides an insight into the peptide's ER subtype specificity and ligand interaction preferences. In vivo, an engineered coactivator containing the peptide motif is able to strongly enhance the transcriptional activity of liganded ER alpha, particularly in the presence of 4-hydroxytamoxifen. Furthermore, disruption of this binding surface alters ER's response to the coregulator TIF2. Together, these results indicate that this previously unknown interaction site represents a bona fide control surface involved in regulating receptor activity

Experimental study of the impact of ion orbit losses on the edge radial electric field at the ASDEX Upgrade tokamak

Spanish Ministry of Science, Innovation and Universities (grant FPU17/06273)EUROfusion Consortium 63305

Size dependence of carrier dynamics and carrier multiplication in PbS quantum dots

The time dynamics of the photoexcited carriers and carrier-multiplication efficiencies in PbS quantum dots (QDs) are investigated. In particular, we report on the carrier dynamics, including carrier multiplication, as a function of QD size and compare them to the bulk value. We show that the intraband 1P - \u3e 1S decay becomes faster for smaller QDs, in agreement with the absence of a phonon bottleneck. Furthermore, as the size of the QDs decreases, the energy threshold for carrier multiplication shifts from the bulk value to higher energies. However, the energy threshold shift is smaller than the band-gap shift and, therefore, for the smallest QDs, the threshold approaches 2.35 E(g), which is close to the theoretical energy conservation limit of twice the band gap. We also show that the carrier-multiplication energy efficiency increases with decreasing QD size. By comparing to theoretical models, our results suggest that impact ionization is sufficient to explain carrier multiplication in QDs