Evaluation of the immunomodulatory effects of 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate in C57BL/6 mice.

2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate was designed to replace perfluorooctanoic acid (PFOA), which has been mostly phased out of U.S. production due to environmental persistence, detectable human and wildlife serum concentrations, and reports of systemic toxicity. In rodent models, PFOA exposure suppresses T cell-dependent antibody responses (TDAR) and vaccine responses in exposed humans. To determine replacement compound effects on TDAR and related parameters, male and female C57BL/6 mice were gavaged with 0, 1, 10, or 100 mg/kg/day for 28 days. Mice immunized with antigen on day 24 were evaluated for TDAR and splenic lymphocyte subpopulations five days later. Serum and urine were collected for test compound concentrations and liver peroxisome proliferation was measured. Relative liver weight at 10 and 100 mg/kg and peroxisome proliferation at 100 mg/kg were increased in both sexes. TDAR was suppressed in females at 100 mg/kg. T lymphocyte numbers were increased in males at 100 mg/kg; B lymphocyte numbers were unchanged in both sexes. Females had less serum accumulation and higher clearance than males, and males had higher urine concentrations than females at all times and doses. While this PFOA-replacement compound appears less potent at suppressing TDAR relative to PFOA, it produces detectable changes in parameters affected by PFOA; further studies are necessary to determine its full immunomodulatory profile and potential synergism with other per- and polyfluoroalkyl substances of environmental concern

Perfluorooctanoic Acid–Induced Immunomodulation in Adult C57BL/6J or C57BL/6N Female Mice

BackgroundPerfluorooctanoic acid (PFOA), an environmentally persistent compound of regulatory concern, has been reported to reduce antibody responses in mice at a single dose.ObjectiveThe aim of this study was to evaluate PFOA effects on humoral and cellular immunity using standard assays for assessing immune function, and to derive dose–response data.MethodsC57BL/6J mice received 0 or 30 mg PFOA/kg/day for 10 days; half of the exposed groups were switched to vehicle and half continued on PFOA for five days. C57BL/6N mice received 0–30 mg/kg/day of PFOA in drinking water for 15 days. Mice were immunized with sheep red blood cells or sensitized to bovine serum albumin in Freund’s complete adjuvant on day 10 of exposure; immune responses were determined 1 day post-exposure.ResultsWe found that 30 mg PFOA/kg/day given for 10 or 15 days reduced IgM synthesis; serum collected 1 day postexposure contained 8.4 × 104 or 2.7 × 105 ng PFOA/mL, respectively. IgM synthesis was suppressed at exposures ≥ 3.75 mg PFOA/kg/day in a dose-dependent manner, and IgG titers were elevated at 3.75 and 7.5 mg PFOA/kg/day. Serum PFOA at 3.75 mg/kg/day was 7.4 × 104 ng/mL 1 day postexposure, or 150-fold greater than the levels reported in individuals living near a PFOA production site. Using a second-degree polynomial model, we calculated a benchmark dose of 3 mg/kg/day, with a lower bound (95% confidence limit) of 1.75 mg/kg/day. Cell-mediated function was not affected.ConclusionsIgM antibodies were suppressed after PFOA exposure. The margin of exposure for reduced IgM antibody synthesis was approximately 150 for highly exposed human populations

Breaking Patterns of Environmentally Influenced Disease for Health Risk Reduction: Immune Perspectives

Diseases rarely, if ever, occur in isolation. Instead, most represent part of a more complex web or “pattern� of conditions that are connected via underlying biological mechanisms and processes, emerge across a lifetime, and have been identified with the aid of large medical databases. Objective We have described how an understanding of patterns of disease may be used to develop new strategies for reducing the prevalence and risk of major immune-based illnesses and diseases influenced by environmental stimuli. Findings Examples of recently defined patterns of diseases that begin in childhood include not only metabolic syndrome, with its characteristics of inflammatory dysregulation, but also allergic, autoimmune, recurrent infection, and other inflammatory patterns of disease. The recent identification of major immune-based disease patterns beginning in childhood suggests that the immune system may play an even more important role in determining health status and health care needs across a lifetime than was previously understood. Conclusions Focusing on patterns of disease, as opposed to individual conditions, offers two important venues for environmental health risk reduction. First, prevention of developmental immunotoxicity and pediatric immune dysfunction can be used to act against multiple diseases. Second, pattern-based treatment of entryway diseases can be tailored with the aim of disrupting the entire disease pattern and reducing the risk of later-life illnesses connected to underlying immune dysfunction. Disease-pattern–based evaluation, prevention, and treatment will require a change from the current approach for both immune safety testing and pediatric disease management

Heterokairy: a significant form of developmental plasticity?

There is a current surge of research interest in the potential role of developmental plasticity in adaptation and evolution. Here we make a case that some of this research effort should explore the adaptive significance of heterokairy, a specific type of plasticity that describes environmentally driven, altered timing of development within a species. This emphasis seems warranted given the pervasive occurrence of heterochrony, altered developmental timing between species, in evolution. We briefly review studies investigating heterochrony within an adaptive context across animal taxa, including examples that explore links between heterokairy and heterochrony. We then outline how sequence heterokairy could be included within the research agenda for developmental plasticity. We suggest that the study of heterokairy may be particularly pertinent in (i) determining the importance of non-adaptive plasticity, and (ii) embedding concepts from comparative embryology such as developmental modularity and disassociation within a developmental plasticity framework

Quantum Gravity in Everyday Life: General Relativity as an Effective Field Theory

This article is meant as a summary and introduction to the ideas of effective field theory as applied to gravitational systems. Contents: 1. Introduction 2. Effective Field Theories 3. Low-Energy Quantum Gravity 4. Explicit Quantum Calculations 5. ConclusionsComment: 56 pages, 2 figures, JHEP style, Invited review to appear in Living Reviews of Relativit

Generalized Geometry and M theory

We reformulate the Hamiltonian form of bosonic eleven dimensional supergravity in terms of an object that unifies the three-form and the metric. For the case of four spatial dimensions, the duality group is manifest and the metric and C-field are on an equal footing even though no dimensional reduction is required for our results to hold. One may also describe our results using the generalized geometry that emerges from membrane duality. The relationship between the twisted Courant algebra and the gauge symmetries of eleven dimensional supergravity are described in detail.Comment: 29 pages of Latex, v2 References added, typos fixed, v3 corrected kinetic term and references adde

The motion of point particles in curved spacetime

This review is concerned with the motion of a point scalar charge, a point electric charge, and a point mass in a specified background spacetime. In each of the three cases the particle produces a field that behaves as outgoing radiation in the wave zone, and therefore removes energy from the particle. In the near zone the field acts on the particle and gives rise to a self-force that prevents the particle from moving on a geodesic of the background spacetime. The field's action on the particle is difficult to calculate because of its singular nature: the field diverges at the position of the particle. But it is possible to isolate the field's singular part and show that it exerts no force on the particle -- its only effect is to contribute to the particle's inertia. What remains after subtraction is a smooth field that is fully responsible for the self-force. Because this field satisfies a homogeneous wave equation, it can be thought of as a free (radiative) field that interacts with the particle; it is this interaction that gives rise to the self-force. The mathematical tools required to derive the equations of motion of a point scalar charge, a point electric charge, and a point mass in a specified background spacetime are developed here from scratch. The review begins with a discussion of the basic theory of bitensors (part I). It then applies the theory to the construction of convenient coordinate systems to chart a neighbourhood of the particle's word line (part II). It continues with a thorough discussion of Green's functions in curved spacetime (part III). The review concludes with a detailed derivation of each of the three equations of motion (part IV).Comment: LaTeX2e, 116 pages, 10 figures. This is the final version, as it will appear in Living Reviews in Relativit

Quantization of Midisuperspace Models

We give a comprehensive review of the quantization of midisuperspace models. Though the main focus of the paper is on quantum aspects, we also provide an introduction to several classical points related to the definition of these models. We cover some important issues, in particular, the use of the principle of symmetric criticality as a very useful tool to obtain the required Hamiltonian formulations. Two main types of reductions are discussed: those involving metrics with two Killing vector fields and spherically symmetric models. We also review the more general models obtained by coupling matter fields to these systems. Throughout the paper we give separate discussions for standard quantizations using geometrodynamical variables and those relying on loop quantum gravity inspired methods.Comment: To appear in Living Review in Relativit

Trace anomalies in chiral theories revisited

Motivated by the search for possible CP violating terms in the trace of the energy-momentum tensor in theories coupled to gravity we revisit the problem of trace anomalies in chiral theories. We recalculate the latter and ascertain that in the trace of the energy-momentum tensor of theories with chiral fermions at one-loop the Pontryagin density appears with an imaginary coefficient. We argue that this may break unitarity, in which case the trace anomaly has to be used as a selective criterion for theories, analogous to the chiral anomalies in gauge theories. We analyze some remarkable consequences of this fact, that seem to have been overlooked in the literature

Logarithmic Corrections to Extremal Black Hole Entropy from Quantum Entropy Function

We evaluate the one loop determinant of matter multiplet fields of N=4 supergravity in the near horizon geometry of quarter BPS black holes, and use it to calculate logarithmic corrections to the entropy of these black holes using the quantum entropy function formalism. We show that even though individual fields give non-vanishing logarithmic contribution to the entropy, the net contribution from all the fields in the matter multiplet vanishes. Thus logarithmic corrections to the entropy of quarter BPS black holes, if present, must be independent of the number of matter multiplet fields in the theory. This is consistent with the microscopic results. During our analysis we also determine the complete spectrum of small fluctuations of matter multiplet fields in the near horizon geometry.Comment: LaTeX file, 52 pages; v2: minor corrections, references adde