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

Demographic history shapes North American gray wolf genomic diversity and informs species' conservation

Effective population size estimates are critical information needed for evolutionary predictions and conservation decisions. This is particularly true for species with social factors that restrict access to breeding or experience repeated fluctuations in population size across generations. We investigated the genomic estimates of effective population size along with diversity, subdivision, and inbreeding from 162,109 minimally filtered and 81,595 statistically neutral and unlinked SNPs genotyped in 437 grey wolf samples from North America collected between 1986 and 2021. We found genetic structure across North America, represented by three distinct demographic histories of western, central, and eastern regions of the continent. Further, grey wolves in the northern Rocky Mountains have lower genomic diversity than wolves of the western Great Lakes and have declined over time. Effective population size estimates revealed the historical signatures of continental efforts of predator extermination, despite a quarter century of recovery efforts. We are the first to provide molecular estimates of effective population size across distinct grey wolf populations in North America, which ranged between N ~ 275 and 3050 since early 1980s. We provide data that inform managers regarding the status and importance of effective population size estimates for grey wolf conservation, which are on average 5.2–9.3% of census estimates for this species. We show that while grey wolves fall above minimum effective population sizes needed to avoid extinction due to inbreeding depression in the short term, they are below sizes predicted to be necessary to avoid long-term risk of extinction

Passive acoustic monitoring complements traditional methods for assessing marine habitat enhancement outcomes

Habitat enhancement, often accomplished through the introduction of artificial structures, is a common strategy used by marine resource managers to provide habitat subsidies, protect sensitive habitat, and create new fishing opportunities. Traditional monitoring methods for assessing habitat enhancement outcomes face numerous limitations, including dependence on environmental conditions and trade-offs between sampling frequency and duration. Passive acoustic monitoring (PAM) is not subject to these same limitations and offers many advantages as a complement to traditional monitoring methods. Our team opportunistically monitored the soundscape and community development of a newly deployed artificial reef and compared it to that of a nearby established artificial reef using PAM and underwater time-lapse videos. Specifically, we compared the sound pressure level (SPL) timeseries, dusk peak in SPL, and dusk power spectrum between the two artificial reefs to evaluate whether and on what timescale the soundscapes converged. Additionally, we tracked temporal patterns in species-specific vocalizations to identify the trajectory of community development on the new reef. Lastly, we compared the qualitative conclusions drawn from PAM to previously published results from video monitoring of the same two artificial reefs. PAM identified minimal difference in mean low-frequency SPL between the two reefs at the onset of monitoring. Though the timeseries correlation, dusk SPL, and dusk power spectra all varied across sampling periods, there were periods of low-frequency soundscape alignment at four and eleven months following artificial reef deployment, associated with the presence of fish chorusing. The high-frequency timeseries on each reef were well correlated during all sampling periods, despite an initial SPL difference of 17 dB. Throughout monitoring, high-frequency sound levels became more similar between the reefs but did not converge. While video monitoring suggested that demersal species did not colonize the reef until five months post-deployment, patterns in species-specific vocalizations suggested that toadfish (Opsanus sp.) a cryptic, demersal species may have colonized the new reef within two weeks. Our findings demonstrate that passive acoustic monitoring is a useful complement to traditional methodologies and can provide a more holistic view of community development than visual monitoring alone

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