Modeling Effective Dosages in Hormetic Dose-Response Studies

BACKGROUND: Two hormetic modifications of a monotonically decreasing log-logistic dose-response function are most often used to model stimulatory effects of low dosages of a toxicant in plant biology. As just one of these empirical models is yet properly parameterized to allow inference about quantities of interest, this study contributes the parameterized functions for the second hormetic model and compares the estimates of effective dosages between both models based on 23 hormetic data sets. Based on this, the impact on effective dosage estimations was evaluated, especially in case of a substantially inferior fit by one of the two models. METHODOLOGY/PRINCIPAL FINDINGS: The data sets evaluated described the hormetic responses of four different test plant species exposed to 15 different chemical stressors in two different experimental dose-response test designs. Out of the 23 data sets, one could not be described by any of the two models, 14 could be better described by one of the two models, and eight could be equally described by both models. In cases of misspecification by any of the two models, the differences between effective dosages estimates (0-1768%) greatly exceeded the differences observed when both models provided a satisfactory fit (0-26%). This suggests that the conclusions drawn depending on the model used may diverge considerably when using an improper hormetic model especially regarding effective dosages quantifying hormesis. CONCLUSIONS/SIGNIFICANCE: The study showed that hormetic dose responses can take on many shapes and that this diversity can not be captured by a single model without risking considerable misinterpretation. However, the two empirical models considered in this paper together provide a powerful means to model, prove, and now also to quantify a wide range of hormetic responses by reparameterization. Despite this, they should not be applied uncritically, but after statistical and graphical assessment of their adequacy

A Conserved Mechanism for Hormesis in Molecular Systems

Hormesis refers to dose-response phenomena where low dose treatments elicit a response that is opposite the response observed at higher doses. Hormetic dose-response relationships have been observed throughout all of biology, but the underlying determinants of many reported hormetic dose-responses have not been identified. In this report, we describe a conserved mechanism for hormesis on the molecular level where low dose treatments enhance a response that becomes reduced at higher doses. The hormetic mechanism relies on the ability of protein homo-multimers to simultaneously interact with a substrate and a competitor on different subunits at low doses of competitor. In this case, hormesis can be observed if simultaneous binding of substrate and competitor enhances a response of the homo-multimer. We characterized this mechanism of hormesis in binding experiments that analyzed the interaction of homotrimeric proliferating cell nuclear antigen (PCNA) with uracil DNA glycosylase (UNG2) and a fluorescein-labeled peptide. Additionally, the basic features of this molecular mechanism appear to be conserved with at least two enzymes that are stimulated by low doses of inhibitor: dimeric BRAF and octameric glutamine synthetase 2 (GS2). Identifying such molecular mechanisms of hormesis may help explain specific hormetic responses of cells and organisms treated with exogenous compounds

Multiple Dendritic Cell Populations Activate CD4+ T Cells after Viral Stimulation

Dendritic cells (DC) are a heterogeneous cell population that bridge the innate and adaptive immune systems. CD8α DC play a prominent, and sometimes exclusive, role in driving amplification of CD8+ T cells during a viral infection. Whether this reliance on a single subset of DC also applies for CD4+ T cell activation is unknown. We used a direct ex vivo antigen presentation assay to probe the capacity of flow cytometrically purified DC populations to drive amplification of CD4+ and CD8+ T cells following infection with influenza virus by different routes. This study examined the contributions of non-CD8α DC populations in the amplification of CD8+ and CD4+ T cells in cutaneous and systemic influenza viral infections. We confirmed that in vivo, effective immune responses for CD8+ T cells are dominated by presentation of antigen by CD8α DC but can involve non-CD8α DC. In contrast, CD4+ T cell responses relied more heavily on the contributions of dermal DC migrating from peripheral lymphoid tissues following cutaneous infection, and CD4 DC in the spleen after systemic infection. CD4+ T cell priming by DC subsets that is dependent upon the route of administration raises the possibility that vaccination approaches could be tailored to prime helper T cell immunity

The stable phases of the Cs2CuCl4-xBrx mixed systems

Starting from Cs2CuCl4 and Cs2CuBr4 our project focuses on the growth of the Cs2CuCl4-xBrx mixed crystals from aqueous solution and the investigation of the occurring structural variations. The well known orthorhombic structure (space group Pnma) of the end members of this system is interrupted within the intermediate composition range Cs2CuCl3Br1 - Cs2CuCl2Br2, if the growth takes place at room temperature. Within this range a new tetragonal phase is found (space group I4/mmm). However, in case the growth temperature will be increased to 50 {\deg}C, the existence of the orthorhombic structure can be extended over the whole Cs2CuCl4-xBrx mixed system. A detailed analysis of the composition dependence of the lattice parameters is used to draw conclusions on the incorporation of Cl- and Br-ions at different sites which is important for the magnetic interactions between the Cu-ions.Comment: 16 pages,8 figure

Air fluorescence measurements in the spectral range 300-420 nm using a 28.5 GeV electron beam

Measurements are reported of the yield and spectrum of fluorescence, excited by a 28.5 GeV electron beam, in air at a range of pressures of interest to ultra-high energy cosmic ray detectors. The wavelength range was 300 - 420 nm. System calibration has been performed using Rayleigh scattering of a nitrogen laser beam. In atmospheric pressure dry air at 304 K the yield is 20.8 +/- 1.6 photons per MeV.Comment: 29 pages, 10 figures. Submitted to Astroparticle Physic

Neutron Star Constraints on the H Dibaryon

We study the influence of a possible H dibaryon condensate on the equation of state and the overall properties of neutron stars whose population otherwise contains nucleons and hyperons. In particular, we are interested in the question of whether neutron stars and their masses can be used to say anything about the existence and properties of the H dibaryon. We find that the equation of state is softened by the appearance of a dibaryon condensate and can result in a mass plateau for neutron stars. If the limiting neutron star mass is about that of the Hulse-Taylor pulsar a condensate of H dibaryons of vacuum mass 2.2 GeV and a moderately attractive potential in the medium could not be ruled out. On the other hand, if the medium potential were even moderately repulsive, the H, would not likely exist in neutron stars. If neutron stars of about 1.6 solar mass were known to exist, attractive medium effects for the H could be ruled out. Certain ranges of dibaryon mass and potential can be excluded by the mass of the Hulse-Taylor pulsar which we illustrate graphically.Comment: Revised by the addition of a figure showing the region of dibaryon mass and potential excluded by the Hulse-Taylor pulsar. 18 pages, 11 figures, latex (submitted to Phys. Rev. C

Search for the Weak Decay of an H Dibaryon

We have searched for a neutral $H$ dibaryon decaying via $H\to\Lambda n$ and $H\to\Sigma^0 n$. Our search has yielded two candidate events from which we set an upper limit on the $H$ production cross section. Normalizing to the inclusive $\Lambda$ production cross section, we find $(d\sigma_H/d\Omega) / (d\sigma_\Lambda/d\Omega) < 6.3\times 10^{-6}$ at 90% C.L., for an $H$ of mass $\approx$ 2.15 GeV/$c^2$.Comment: 11 pages, 6 postscript figures, epsfig, aps, preprint, revte

Cosmic Rays: The Second Knee and Beyond

We conduct a review of experimental results on Ultra-High Energy Cosmic Rays (UHECR's) including measurements of the features of the spectrum, the composition of the primary particle flux and the search for anisotropy in event arrival direction. We find that while there is a general consensus on the features in the spectrum -- the Second Knee, the Ankle, and (to a lesser extent) the GZK Cutoff -- there is little consensus on the composition of the primaries that accompany these features. This lack of consensus on the composition makes interpretation of the agreed upon features problematic. There is also little direct evidence about potential sources of UHECRs, as early reports of arrival direction anisotropies have not been confirmed in independent measurements.Comment: 46 pages, 30 figures. Topical Review to appear in J. Physics

QCD Rescattering and High Energy Two-Body Photodisintegration of the Deuteron

Photon absorption by a quark in one nucleon followed by its high momentum transfer interaction with a quark in the other may produce two final-state nucleons with high relative momentum. We sum the relevant quark rescattering diagrams, to show that the scattering amplitude depends on a convolution between the large angle $pn$ scattering amplitude, the hard photon-quark interaction vertex and the low-momentum deuteron wave function. The computed absolute values of the cross section are in reasonable agreement with the data.Comment: 4 pages, revised version to be published in Phys. Rev. Let