1,173 research outputs found
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
A multi-component prime-boost vaccination regimen with a consensus MOMP antigen enhances Chlamydia trachomatis clearance
An adaptive prefix-assignment technique for symmetry reduction
This paper presents a technique for symmetry reduction that adaptively
assigns a prefix of variables in a system of constraints so that the generated
prefix-assignments are pairwise nonisomorphic under the action of the symmetry
group of the system. The technique is based on McKay's canonical extension
framework [J.~Algorithms 26 (1998), no.~2, 306--324]. Among key features of the
technique are (i) adaptability---the prefix sequence can be user-prescribed and
truncated for compatibility with the group of symmetries; (ii)
parallelizability---prefix-assignments can be processed in parallel
independently of each other; (iii) versatility---the method is applicable
whenever the group of symmetries can be concisely represented as the
automorphism group of a vertex-colored graph; and (iv) implementability---the
method can be implemented relying on a canonical labeling map for
vertex-colored graphs as the only nontrivial subroutine. To demonstrate the
practical applicability of our technique, we have prepared an experimental
open-source implementation of the technique and carry out a set of experiments
that demonstrate ability to reduce symmetry on hard instances. Furthermore, we
demonstrate that the implementation effectively parallelizes to compute
clusters with multiple nodes via a message-passing interface.Comment: Updated manuscript submitted for revie
AZD9773, a novel anti-TNFα immune Fab in development for severe sepsis and septic shock: demonstration of safety and efficacy in a murine CLP sepsis model
Observation of contemporaneous optical radiation from a gamma-ray burst
The origin of gamma-ray bursts (GRBs) has been enigmatic since their
discovery. The situation improved dramatically in 1997, when the rapid
availability of precise coordinates for the bursts allowed the detection of
faint optical and radio afterglows - optical spectra thus obtained have
demonstrated conclusively that the bursts occur at cosmological distances. But,
despite efforts by several groups, optical detection has not hitherto been
achieved during the brief duration of a burst. Here we report the detection of
bright optical emission from GRB990123 while the burst was still in progress.
Our observations begin 22 seconds after the onset of the burst and show an
increase in brightness by a factor of 14 during the first 25 seconds; the
brightness then declines by a factor of 100, at which point (700 seconds after
the burst onset) it falls below our detection threshold. The redshift of this
burst, approximately 1.6, implies a peak optical luminosity of 5 times 10^{49}
erg per second. Optical emission from gamma-ray bursts has been generally
thought to take place at the shock fronts generated by interaction of the
primary energy source with the surrounding medium, where the gamma-rays might
also be produced. The lack of a significant change in the gamma-ray light curve
when the optical emission develops suggests that the gamma-rays are not
produced at the shock front, but closer to the site of the original explosion.Comment: 10 pages, 2 figures. Accepted for publication in Nature. For
additional information see http://www.umich.edu/~rotse
Unwinding of a cholesteric liquid crystal and bidirectional surface anchoring
We examine the influence of bidirectional anchoring on the unwinding of a planar cholesteric liquid crystal induced by the application of a magnetic field. We consider a liquid crystal layer confined between two plates with the helical axis perpendicular to the substrates. We fixed the director twist on one boundary and allow for bidirectional anchoring on the other by introducing a high-order surface potential. By minimizing the total free energy for the system, we investigate the untwisting of the cholesteric helix as the liquid crystal attempts to align with the magnetic field. The transitions between metastable states occur as a series of pitchjumps as the helix expels quarter or half-turn twists, depending on the relative sizes of the strength of the surface potential and the bidirectional anchoring. We show that secondary easy axis directions can play a significant role in the unwinding of the cholesteric in its transition towards a nematic, especially when the surface anchoring strength is large
Blocking T-cell egress with FTY720 extends DNA vaccine expression but reduces immunogenicity
Optimal immunogenicity from nucleic acid vaccines requires a balance of antigen expression that effectively engages the host immune system without generating a cellular response that rapidly destroys cells producing the antigen and thereby limiting vaccine antigen expression. We investigated the role of the cellular response on the expression and antigenicity of DNA vaccines using a plasmid DNA construct expressing luciferase. Repeated intramuscular administration led to diminished luciferase expression, suggesting a role for immune-mediated clearance of expression. To investigate the role of cell trafficking, we used the sphingosine 1-phosphate receptor (S1PR) modulator, FTY720 (Fingolimod), which traps lymphocytes within the lymphoid tissues. When lymphocyte trafficking was blocked with FTY720, DNA transgene expression was maintained at a constant level for a significantly extended time period. Both continuous and staggered administration of FTY720 prolonged transgene expression. However, blocking lymphocyte egress during primary transgene administration did not result in an increase of transgene expression during secondary administration. Interestingly, there was a disconnect between transgene expression and immunogenicity, as increasing expression by this approach did not enhance the overall immune response. Furthermore, when FTY720 was administered alongside a DNA vaccine expressing the HIV gp140 envelope antigen, there was a significant reduction in both antigen-specific antibody and T-cell responses. This indicates that the developing antigen-specific cellular response clears DNA vaccine expression but requires access to the site of expression in order to develop an effective immune response
Phase-slip induced dissipation in an atomic Bose-Hubbard system
Phase slips play a primary role in dissipation across a wide spectrum of
bosonic systems, from determining the critical velocity of superfluid helium to
generating resistance in thin superconducting wires. This subject has also
inspired much technological interest, largely motivated by applications
involving nanoscale superconducting circuit elements, e.g., standards based on
quantum phase-slip junctions. While phase slips caused by thermal fluctuations
at high temperatures are well understood, controversy remains over the role of
phase slips in small-scale superconductors. In solids, problems such as
uncontrolled noise sources and disorder complicate the study and application of
phase slips. Here we show that phase slips can lead to dissipation for a clean
and well-characterized Bose-Hubbard (BH) system by experimentally studying
transport using ultra-cold atoms trapped in an optical lattice. In contrast to
previous work, we explore a low velocity regime described by the 3D BH model
which is not affected by instabilities, and we measure the effect of
temperature on the dissipation strength. We show that the damping rate of
atomic motion-the analogue of electrical resistance in a solid-in the confining
parabolic potential fits well to a model that includes finite damping at zero
temperature. The low-temperature behaviour is consistent with the theory of
quantum tunnelling of phase slips, while at higher temperatures a cross-over
consistent with the transition to thermal activation of phase slips is evident.
Motion-induced features reminiscent of vortices and vortex rings associated
with phase slips are also observed in time-of-flight imaging.Comment: published in Nature 453, 76 (2008
Formulation, inflammation, and RNA sensing impact the immunogenicity of self-amplifying RNA vaccines
To be effective, RNA vaccines require both in situ translation and the induction of an immune response to recruit cells to the site of immunization. These factors can pull in opposite directions with the inflammation reducing expression of the vaccine antigen. We investigated how formulation affects the acute systemic cytokine response to a self-amplifying RNA (saRNA) vaccine. We compared a cationic polymer (pABOL), a lipid emulsion (nanostructured lipid carrier, NLC), and three lipid nanoparticles (LNP). After immunization, we measured serum cytokines and compared the response to induced antibodies against influenza virus. Formulations that induced a greater cytokine response induced a greater antibody response, with a significant correlation between IP-10, MCP-1, KC, and antigen-specific antibody titers. We then investigated how innate immune sensing and signaling impacted the adaptive immune response to vaccination with LNP-formulated saRNA. Mice that lacked MAVS and are unable to signal through RIG-I-like receptors had an altered cytokine response to saRNA vaccination and had significantly greater antibody responses than wild-type mice. This indicates that the inflammation induced by formulated saRNA vaccines is not solely deleterious in the induction of antibody responses and that targeting specific aspects of RNA vaccine sensing might improve the quality of the response
Developing an intervention to facilitate family communication about inherited genetic conditions, and training genetic counsellors in its delivery.
Many families experience difficulty in talking about an inherited genetic condition that affects one or more of them. There have now been a number of studies identifying the issues in detail, however few have developed interventions to assist families. The SPRinG collaborative have used the UK Medical Research Council's guidance on Developing and Evaluating Complex Interventions, to work with families and genetic counsellors (GCs) to co-design a psycho-educational intervention to facilitate family communication and promote better coping and adaptation to living with an inherited genetic condition for parents and their children (<18 years). The intervention is modelled on multi-family discussion groups (MFDGs) used in psychiatric settings. The MFDG was developed and tested over three phases. First focus groups with parents, young people, children and health professionals discussed whether MFDG was acceptable and proposed a suitable design. Using evidence and focus group data, the intervention and a training manual were developed and three GCs were trained in its delivery. Finally, a prototype MFDG was led by a family therapist and co-facilitated by the three GCs. Data analysis showed that families attending the focus groups and intervention thought MFDG highly beneficial, and the pilot sessions had a significant impact on their family' functioning. We also demonstrated that it is possible to train GCs to deliver the MFDG intervention. Further studies are now required to test the feasibility of undertaking a definitive randomised controlled trial to evaluate its effectiveness in improving family outcomes before implementing into genetic counselling practice.The National Institute of Health Research funded the study but any views expressed do not necessarily reflect those of the Authority. Funded by NIHR reference number: RP-DG-1211-10015
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