Designing a therapeutic hepatitis B vaccine to circumvent immune tolerance

An effective prophylactic hepatitis B virus (HBV) vaccine has long been available but is ineffective for chronic infection. The primary cause of chronic hepatitis B (CHB) and greatest impediment for a therapeutic vaccine is the direct and indirect effects of immune tolerance to HBV antigens. The resulting defective CD4+/CD8+ T cell response, poor cytokine production, insufficient neutralizing anti-body (nAb) and poor response to HBsAg vaccination characterize CHB infection. The objective of this study was to develop virus-like-particles (VLPs) that elicit nAb to prevent viral spread and prime CD4+/CD8+ T cells to eradicate intracellular HBV. Eight neutralizing B cell epitopes from the envelope PreS1 region were consolidated onto a species-variant of the HBV core protein, the woodchuck hepatitis core antigen (WHcAg). PreS1-specific B cell epitopes were chosen because of preferential expression on HBV virions. Because WHcAg and HBcAg are not crossreactive at the B cell level and only partially cross-reactive at the CD4+/CD8+ T cell level, CD4+ T cells specific for WHcAg-unique T cell sites can provide cognate T-B cell help for anti-PreS1 Ab production that is not curtailed by immune tolerance. Immunization of immune tolerant HBV transgenic (Tg) mice with PreS1-WHc VLPs elicited levels of high titer anti-PreS1 nAbs equivalent to wildtype mice. Passive transfer of PreS1 nAbs into human-liver chimeric mice prevented acute infection and cleared serum HBV from mice previously infected with HBV in a model of CHB. At the T cell level, PreS1-WHc VLPs and hybrid WHcAg/HBcAg DNA immunogens elicited HBcAg-specific CD4+ Th and CD8+ CTL responses

Finite element simulation of three-dimensional free-surface flow problems

An adaptive finite element algorithm is described for the stable solution of three-dimensional free-surface-flow problems based primarily on the use of node movement. The algorithm also includes a discrete remeshing procedure which enhances its accuracy and robustness. The spatial discretisation allows an isoparametric piecewise-quadratic approximation of the domain geometry for accurate resolution of the curved free surface. The technique is illustrated through an implementation for surface-tension-dominated viscous flows modelled in terms of the Stokes equations with suitable boundary conditions on the deforming free surface. Two three-dimensional test problems are used to demonstrate the performance of the method: a liquid bridge problem and the formation of a fluid droplet

Can forest management based on natural disturbances maintain ecological resilience?

Given the increasingly global stresses on forests, many ecologists argue that managers must maintain ecological resilience: the capacity of ecosystems to absorb disturbances without undergoing fundamental change. In this review we ask: Can the emerging paradigm of natural-disturbance-based management (NDBM) maintain ecological resilience in managed forests? Applying resilience theory requires careful articulation of the ecosystem state under consideration, the disturbances and stresses that affect the persistence of possible alternative states, and the spatial and temporal scales of management relevance. Implementing NDBM while maintaining resilience means recognizing that (i) biodiversity is important for long-term ecosystem persistence, (ii) natural disturbances play a critical role as a generator of structural and compositional heterogeneity at multiple scales, and (iii) traditional management tends to produce forests more homogeneous than those disturbed naturally and increases the likelihood of unexpected catastrophic change by constraining variation of key environmental processes. NDBM may maintain resilience if silvicultural strategies retain the structures and processes that perpetuate desired states while reducing those that enhance resilience of undesirable states. Such strategies require an understanding of harvesting impacts on slow ecosystem processes, such as seed-bank or nutrient dynamics, which in the long term can lead to ecological surprises by altering the forest's capacity to reorganize after disturbance

Partial Dynamical Symmetry in the Symplectic Shell Model

We present an example of a partial dynamical symmetry (PDS) in an interacting fermion system and demonstrate the close relationship of the associated Hamiltonians with a realistic quadrupole-quadrupole interaction, thus shedding new light on this important interaction. Specifically, in the framework of the symplectic shell model of nuclei, we prove the existence of a family of fermionic Hamiltonians with partial SU(3) symmetry. We outline the construction process for the PDS eigenstates with good symmetry and give analytic expressions for the energies of these states and E2 transition strengths between them. Characteristics of both pure and mixed-symmetry PDS eigenstates are discussed and the resulting spectra and transition strengths are compared to those of real nuclei. The PDS concept is shown to be relevant to the description of prolate, oblate, as well as triaxially deformed nuclei. Similarities and differences between the fermion case and the previously established partial SU(3) symmetry in the Interacting Boson Model are considered.Comment: 9 figure

Neutrino Interferometry In Curved Spacetime

Gravitational lensing introduces the possibility of multiple (macroscopic) paths from an astrophysical neutrino source to a detector. Such a multiplicity of paths can allow for quantum mechanical interference to take place that is qualitatively different to neutrino oscillations in flat space. After an illustrative example clarifying some under-appreciated subtleties of the phase calculation, we derive the form of the quantum mechanical phase for a neutrino mass eigenstate propagating non-radially through a Schwarzschild metric. We subsequently determine the form of the interference pattern seen at a detector. We show that the neutrino signal from a supernova could exhibit the interference effects we discuss were it lensed by an object in a suitable mass range. We finally conclude, however, that -- given current neutrino detector technology -- the probability of such lensing occurring for a (neutrino-detectable) supernova is tiny in the immediate future.Comment: 25 pages, 1 .eps figure. Updated version -- with simplified notation -- accepted for publication in Phys.Rev.D. Extra author adde

The Refederalization of American Health Care

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69090/2/10.1177_107755878704400103.pd

Effects of watershed land use on nitrogen concentrations and δ15 Nitrogen in groundwater

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Biogeochemistry 77 (2006): 199-215, doi:10.1007/s10533-005-1036-2.Eutrophication is a major agent of change affecting freshwater, estuarine, and marine systems. It is largely driven by transportation of nitrogen from natural and anthropogenic sources. Research is needed to quantify this nitrogen delivery and to link the delivery to specific land-derived sources. In this study we measured nitrogen concentrations and δ15N values in seepage water entering three freshwater ponds and six estuaries on Cape Cod, Massachusetts and assessed how they varied with different types of land use. Nitrate concentrations and δ15N values in groundwater reflected land use in developed and pristine watersheds. In particular, watersheds with larger populations delivered larger nitrate loads with higher δ15N values to receiving waters. The enriched δ15N values confirmed nitrogen loading model results identifying wastewater contributions from septic tanks as the major N source. Furthermore, it was apparent that N coastal sources had a relatively larger impact on the N loads and isotopic signatures than did inland N sources further upstream in the watersheds. This finding suggests that management priorities could focus on coastal sources as a first course of action. This would require management constraints on a much smaller population.This work was supported by funds from the Woods Hole Oceanographic Institution Sea Grant Program, from the Cooperative Institute for Coastal and Estuarine Environmental Technology, from Massachusetts Department of Environmental Protection to Applied Science Associates, Narragansett, RI, as well as from Palmer/McLeod and NOAA National Estuarine Research Reserve Fellowships to Kevin Kroeger. This work is the result of research sponsored by NOAA National Sea Grant College Program Office, Department of Commerce, under Grant No. NA86RG0075, Woods Hole Oceanographic Institution Sea Grant Project No. R/M-40

Active Galactic Nuclei at the Crossroads of Astrophysics

Over the last five decades, AGN studies have produced a number of spectacular examples of synergies and multifaceted approaches in astrophysics. The field of AGN research now spans the entire spectral range and covers more than twelve orders of magnitude in the spatial and temporal domains. The next generation of astrophysical facilities will open up new possibilities for AGN studies, especially in the areas of high-resolution and high-fidelity imaging and spectroscopy of nuclear regions in the X-ray, optical, and radio bands. These studies will address in detail a number of critical issues in AGN research such as processes in the immediate vicinity of supermassive black holes, physical conditions of broad-line and narrow-line regions, formation and evolution of accretion disks and relativistic outflows, and the connection between nuclear activity and galaxy evolution.Comment: 16 pages, 5 figures; review contribution; "Exploring the Cosmic Frontier: Astrophysical Instruments for the 21st Century", ESO Astrophysical Symposia Serie