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Protective immunity elicited by recombinant bacille Calmette-Guerin (BCG) expressing outer surface protein A (OspA) lipoprotein: a candidate Lyme disease vaccine.
The current vaccine against tuberculosis, Mycobacterium bovis strain bacille Calmette-Guerin (BCG), offers potential advantages as a live, innately immunogenic vaccine vehicle for the expression and delivery of protective recombinant antigens (Stover, C.K., V.F. de la Cruz, T.R. Fuerst, J.E. Burlein, L.A. Benson, L.T. Bennett, G.P. Bansal, J.F. Young, M.H. Lee, G.F. Hatfull et al. 1991. Nature [Lond]. 351:456; Jacobs, W.R., Jr., S.B. Snapper, L. Lugosi and B.R. Bloom. 1990. Curr. Top. Microbiol. Immunol. 155:153; Jacobs, W.R., M. Tuckman, and B.R. Bloom. 1987. Nature [Lond.]. 327:532); but as an attenuated intracellular bacterium residing in macrophages, BCG would seem to be best suited for eliciting cellular responses and not humoral responses. Since bacterial lipoproteins are often among the most immunogenic of bacterial antigens, we tested whether BCG expression of a target antigen as a membrane-associated lipoprotein could enhance the potential for a recombinant BCG vaccine to elicit high-titered protective antibody responses to target antigens. Immunization of mice with recombinant BCG vaccines expressing the outer surface protein A (OspA) antigen of Borrelia burgdorferi as a membrane-associated lipoprotein resulted in protective antibody responses that were 100-1,000-fold higher than responses elicited by immunization with recombinant BCG expressing OspA cytoplasmically or as a secreted fusion protein. Furthermore, these improved antibody responses were observed in heterogeneous mouse strains that vary in their immune responsiveness to OspA and sensitivity to BCG growth. Thus, expression of protective antigens as chimeric membrane-associated lipoproteins on recombinant BCG may result in the generation of new candidate vaccines against Lyme borreliosis and other human or veterinary diseases where humoral immunity is the protective response
The developmentally regulated expression of twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development
The evolutionarily conserved, secreted protein Twisted gastrulation (Tsg) modulates morphogenetic effects of decapentaplegic (dpp) and its orthologs, the bone morphogenetic proteins 2 and 4 (BMP2/4), in early Drosophila and vertebrate embryos. We have uncovered a role for Tsg at a much later stage of mammalian development, during T cell differentiation in the thymus. BMP4 is expressed by thymic stroma and inhibits the proliferation of CD4(-)CD8(-) double-negative (DN) thymocytes and their differentiation to the CD4(+)CD8(+) double-positive (DP) stage in vitro. Tsg is expressed by thymocytes and up-regulated after T cell receptor signaling at two developmental checkpoints, the transition from the DN to the DP and from the DP to the CD4(+) or CD8(+) single-positive stage. Tsg can synergize with the BMP inhibitor chordin to block the BMP4-mediated inhibition of thymocyte proliferation and differentiation. These data suggest that the developmentally regulated expression of Tsg may allow thymocytes to temporarily withdraw from inhibitory BMP signals
Effect of SC on frequency content of geomagnetic data using DWT application: SC automatic detection
Primary prevention of beta-cell autoimmunity and type 1 diabetes - The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) perspectives.
OBJECTIVE: Type 1 diabetes can be identified by the presence of beta-cell autoantibodies that often arise in the first few years of life. The purpose of this perspective is to present the case for primary prevention of beta-cell autoimmunity and to provide a study design for its implementation in Europe. METHODS: We examined and summarized recruitment strategies, enrollment rates, and outcomes in published TRIGR, FINDIA and BABYDIET primary prevention trials, and the TEDDY intensive observational study. A proposal for a recruitment and implementation strategy to perform a phase II/III primary prevention randomized controlled trial in infants with genetic risk for developing beta-cell autoimmunity is outlined. RESULTS: Infants with a family history of type 1 diabetes (TRIGR, BABYDIET, TEDDY) and infants younger than age 3 months from the general population (FINDIA, TEDDY) were enrolled into these studies. All studies used HLA genotyping as part of their eligibility criteria. Predicted beta-cell autoimmunity risk in the eligible infants ranged from 3% (FINDIA, TEDDY general population) up to 12% (TRIGR, BABYDIET). Amongst eligible infants, participation was between 38% (TEDDY general population) and 97% (FINDIA). Outcomes, defined as multiple beta-cell autoantibodies, were consistent with predicted risks. We subsequently modeled recruitment into a randomized controlled trial (RCT) that could assess the efficacy of oral insulin treatment as adapted from the Pre-POINT pilot trial. The RCT would recruit infants with and without a first-degree family history of type 1 diabetes and be based on general population genetic risk testing. HLA genotyping and, for the general population, genotyping at additional type 1 diabetes susceptibility SNPs would be used to identify children with around 10% risk of beta-cell autoimmunity. The proposed RCT would have 80% power to detect a 50% reduction in multiple beta-cell autoantibodies by age 4 years at a two-tailed alpha of 0.05, and would randomize around 1160 infants to oral insulin or placebo arms in order to fulfill this. It is estimated that recruitment would require testing of between 400,000 and 500,000 newborns or infants. CONCLUSION: It is timely and feasible to establish a platform for primary prevention trials for type 1 diabetes in Europe. This multi-site European infrastructure would perform RCTs, supply data coordination and biorepository, provide cohorts for mechanistic and observational studies, and increase awareness for autoimmune diabetes.This work was supported by The Leona M. & Harry B. Helmsley Charitable Trust Grants #2015PG-T1D072 and #2015PG-T1D071.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.molmet.2016.02.00
An Electronic Mach-Zehnder Interferometer
Double-slit electron interferometers, fabricated in high mobility
two-dimensional electron gas (2DEG), proved to be very powerful tools in
studying coherent wave-like phenomena in mesoscopic systems. However, they
suffer from small fringe visibility due to the many channels in each slit and
poor sensitivity to small currents due to their open geometry. Moreover, the
interferometers do not function in a high magnetic field, namely, in the
quantum Hall effect (QHE) regime, since it destroys the symmetry between left
and right slits. Here, we report on the fabrication and operation of a novel,
single channel, two-path electron interferometer that functions in a high
magnetic field. It is the first electronic analog of the well-known optical
Mach-Zehnder (MZ) interferometer. Based on single edge state and closed
geometry transport in the QHE regime the interferometer is highly sensitive and
exhibits very high visibility (62%). However, the interference pattern decays
precipitously with increasing electron temperature or energy. While we do not
understand the reason for the dephasing we show, via shot noise measurement,
that it is not a decoherence process that results from inelastic scattering
events.Comment: to appear in Natur
Model-Independent Bounds on a Light Higgs
We present up-to-date constraints on a generic Higgs parameter space. An
accurate assessment of these exclusions must take into account statistical, and
potentially signal, fluctuations in the data currently taken at the LHC. For
this, we have constructed a straightforward statistical method for making full
use of the data that is publicly available. We show that, using the expected
and observed exclusions which are quoted for each search channel, we can fully
reconstruct likelihood profiles under very reasonable and simple assumptions.
Even working with this somewhat limited information, we show that our method is
sufficiently accurate to warrant its study and advocate its use over more naive
prescriptions. Using this method, we can begin to narrow in on the remaining
viable parameter space for a Higgs-like scalar state, and to ascertain the
nature of any hints of new physics---Higgs or otherwise---appearing in the
data.Comment: 32 pages, 10 figures; v3: correction made to basis of four-derivative
operators in the effective Lagrangian, references adde
The Algorithmic Origins of Life
Although it has been notoriously difficult to pin down precisely what it is
that makes life so distinctive and remarkable, there is general agreement that
its informational aspect is one key property, perhaps the key property. The
unique informational narrative of living systems suggests that life may be
characterized by context-dependent causal influences, and in particular, that
top-down (or downward) causation -- where higher-levels influence and constrain
the dynamics of lower-levels in organizational hierarchies -- may be a major
contributor to the hierarchal structure of living systems. Here we propose that
the origin of life may correspond to a physical transition associated with a
shift in causal structure, where information gains direct, and
context-dependent causal efficacy over the matter it is instantiated in. Such a
transition may be akin to more traditional physical transitions (e.g.
thermodynamic phase transitions), with the crucial distinction that determining
which phase (non-life or life) a given system is in requires dynamical
information and therefore can only be inferred by identifying causal
architecture. We discuss some potential novel research directions based on this
hypothesis, including potential measures of such a transition that may be
amenable to laboratory study, and how the proposed mechanism corresponds to the
onset of the unique mode of (algorithmic) information processing characteristic
of living systems.Comment: 13 pages, 1 tabl
An anisotropic hybrid non-perturbative formulation for 4D N = 2 supersymmetric Yang-Mills theories
We provide a simple non-perturbative formulation for non-commutative
four-dimensional N = 2 supersymmetric Yang-Mills theories. The formulation is
constructed by a combination of deconstruction (orbifold projection), momentum
cut-off and matrix model techniques. We also propose a moduli fixing term that
preserves lattice supersymmetry on the deconstruction formulation. Although the
analogous formulation for four-dimensional N = 2 supersymmetric Yang-Mills
theories is proposed also in Nucl.Phys.B857(2012), our action is simpler and
better suited for computer simulations. Moreover, not only for the
non-commutative theories, our formulation has a potential to be a
non-perturbative tool also for the commutative four-dimensional N = 2
supersymmetric Yang-Mills theories.Comment: 32 pages, final version accepted in JHE
Network Cosmology
Prediction and control of the dynamics of complex networks is a central
problem in network science. Structural and dynamical similarities of different
real networks suggest that some universal laws might accurately describe the
dynamics of these networks, albeit the nature and common origin of such laws
remain elusive. Here we show that the causal network representing the
large-scale structure of spacetime in our accelerating universe is a power-law
graph with strong clustering, similar to many complex networks such as the
Internet, social, or biological networks. We prove that this structural
similarity is a consequence of the asymptotic equivalence between the
large-scale growth dynamics of complex networks and causal networks. This
equivalence suggests that unexpectedly similar laws govern the dynamics of
complex networks and spacetime in the universe, with implications to network
science and cosmology
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