Mice lacking NF-κB1 exhibit marked DNA damage responses and more severe gastric pathology in response to intraperitoneal tamoxifen administration

Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-κB subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-κB subunits. Groups of five female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150 mg/kg TAM by IP injection. Seventy-two hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of six female WT and Nfkb1-/- mice were exposed to 12 Gy γ-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 h after irradiation. TAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than in WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by γH2AX. To investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to TAM-induced DNA damage or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following γ-irradiation. Six hours after γ-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice. NF-κB1-mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage

Relational agency: Relational sociology, agency and interaction

yesThis article explores how the concept of agency in social theory changes when it is conceptualised as a relational rather than an individual phenomenon. I begin with a critique of the structure/agency debate, particularly of how this emerges in the critical realist approach to agency typified by Margaret Archer. It is argued that this approach, and the critical realist version of relational sociology that has grown from it, reifies social relations as a third entity to which agents have a cognitive, reflexive relation, playing down the importance of interaction. This upholds the Western moral and political view of agents as autonomous, independent, and reflexive individuals. Instead of this I consider agency from a different theoretical tradition in relational sociology in which agents are always located in manifold social relations. From this I create an understanding of agents as interactants, ones who are interdependent, vulnerable, intermittently reflexive, possessors of capacities that can only be practiced in joint actions, and capable of sensitive responses to others and to the situations of interaction. Instead of agency resting on the reflexive monitoring of action or the reflexive deliberation on structurally defined choices, agency emerges from our emotional relatedness to others as social relations unfold across time and space

Intestinal Preparation Techniques for Histological Analysis in the Mouse

The murine intestinal tract represents a difficult organ system to study due to its long convoluted tubular structure, narrow diameter, and delicate mucosa which undergoes rapid changes after sampling prior to fixation. These features do not make for easy histological analysis as rapid fixation in situ, or after simple removal without careful dissection, results in poor postfixation tissue handling and limited options for high quality histological sections. Collecting meaningful quantitative data by analysis of this tissue is further complicated by the anatomical changes in structure along its length. This article describes two methods of intestinal sampling at necropsy that allow systematic histological analysis of the entire intestinal tract, either through examination of cross sections (circumferences) by the gut bundling technique or longitudinal sections by the adapted Swiss roll technique, together with basic methods for data collection

Both Ca2+ and Zn2+ are essential for S100A12 protein oligomerization and function

Background Human S100A12 is a member of the S100 family of EF-hand calcium-modulated proteins that are associated with many diseases including cancer, chronic inflammation and neurological disorders. S100A12 is an important factor in host/parasite defenses and in the inflammatory response. Like several other S100 proteins, it binds zinc and copper in addition to calcium. Mechanisms of zinc regulation have been proposed for a number of S100 proteins e.g. S100B, S100A2, S100A7, S100A8/9. The interaction of S100 proteins with their targets is strongly dependent on cellular microenvironment. Results The aim of the study was to explore the factors that influence S100A12 oligomerization and target interaction. A comprehensive series of biochemical and biophysical experiments indicated that changes in the concentration of calcium and zinc led to changes in the oligomeric state of S100A12. Surface plasmon resonance confirmed that the presence of both calcium and zinc is essential for the interaction of S100A12 with one of its extracellular targets, RAGE – the Receptor for Advanced Glycation End products. By using a single-molecule approach we have shown that the presence of zinc in tissue culture medium favors both the oligomerization of exogenous S100A12 protein and its interaction with targets on the cell surface. Conclusion We have shown that oligomerization and target recognition by S100A12 is regulated by both zinc and calcium. Our present work highlighted the potential role of calcium-binding S100 proteins in zinc metabolism and, in particular, the role of S100A12 in the cross talk between zinc and calcium in cell signaling

Extracting non-linear integrate-and-fire models from experimental data using dynamic I–V curves

The dynamic I–V curve method was recently introduced for the efficient experimental generation of reduced neuron models. The method extracts the response properties of a neuron while it is subject to a naturalistic stimulus that mimics in vivo-like fluctuating synaptic drive. The resulting history-dependent, transmembrane current is then projected onto a one-dimensional current–voltage relation that provides the basis for a tractable non-linear integrate-and-fire model. An attractive feature of the method is that it can be used in spike-triggered mode to quantify the distinct patterns of post-spike refractoriness seen in different classes of cortical neuron. The method is first illustrated using a conductance-based model and is then applied experimentally to generate reduced models of cortical layer-5 pyramidal cells and interneurons, in injected-current and injected- conductance protocols. The resulting low-dimensional neuron models—of the refractory exponential integrate-and-fire type—provide highly accurate predictions for spike-times. The method therefore provides a useful tool for the construction of tractable models and rapid experimental classification of cortical neurons

Unravelling social constructionism

Social constructionist research is an area of rapidly expanding influence that has brought together theorists from a range of different disciplines. At the same time, however, it has fuelled the development of a new set of divisions. There would appear to be an increasing uneasiness about the implications of a thoroughgoing constructionism, with some regarding it as both theoretically parasitic and politically paralysing. In this paper I review these debates and clarify some of the issues involved. My main argument is that social constructionism is not best understood as a unitary paradigm and that one very important difference is between what Edwards (1997) calls its ontological and epistemic forms. I argue that an appreciation of this distinction not only exhausts many of the disputes that currently divide the constructionist community, but also takes away from the apparent radicalism of much of this work

High-statistics finite size scaling analysis of U(1) lattice gauge theory with Wilson action

We describe the results of a systematic high-statistics Monte-Carlo study of finite-size effects at the phase transition of compact U(1) lattice gauge theory with Wilson action on a hypercubic lattice with periodic boundary conditions. We find unambiguously that the critical exponent nu is lattice-size dependent for volumes ranging from 4^4 to 12^4. Asymptotic scaling formulas yield values decreasing from nu(L >= 4) = 0.33 to nu(L >= 9) = 0.29. Our statistics are sufficient to allow the study of different phenomenological scenarios for the corrections to asymptotic scaling. We find evidence that corrections to a first-order transition with nu=0.25 provide the most accurate description of the data. However the corrections do not follow always the expected first-order pattern of a series expansion in the inverse lattice volume V^{-1}. Reaching the asymptotic regime will require lattice sizes greater than L=12. Our conclusions are supported by the study of many cumulants which all yield consistent results after proper interpretation.Comment: revtex, 12 pages, 9 figure