Gene expression patterns following unilateral traumatic brain injury reveals a local pro-inflammatory and remote anti-inflammatory response.

BackgroundTraumatic brain injury (TBI) results in irreversible damage at the site of impact and initiates cellular and molecular processes that lead to secondary neural injury in the surrounding tissue. We used microarray analysis to determine which genes, pathways and networks were significantly altered using a rat model of TBI. Adult rats received a unilateral controlled cortical impact (CCI) and were sacrificed 24 h post-injury. The ipsilateral hemi-brain tissue at the site of the injury, the corresponding contralateral hemi-brain tissue, and naïve (control) brain tissue were used for microarray analysis. Ingenuity Pathway Analysis (IPA) software was used to identify molecular pathways and networks that were associated with the altered gene expression in brain tissues following TBI.ResultsInspection of the top fifteen biological functions in IPA associated with TBI in the ipsilateral tissues revealed that all had an inflammatory component. IPA analysis also indicated that inflammatory genes were altered on the contralateral side, but many of the genes were inversely expressed compared to the ipsilateral side. The contralateral gene expression pattern suggests a remote anti-inflammatory molecular response. We created a network of the inversely expressed common (i.e., same gene changed on both sides of the brain) inflammatory response (IR) genes and those IR genes included in pathways and networks identified by IPA that changed on only one side. We ranked the genes by the number of direct connections each had in the network, creating a gene interaction hierarchy (GIH). Two well characterized signaling pathways, toll-like receptor/NF-kappaB signaling and JAK/STAT signaling, were prominent in our GIH.ConclusionsBioinformatic analysis of microarray data following TBI identified key molecular pathways and networks associated with neural injury following TBI. The GIH created here provides a starting point for investigating therapeutic targets in a ranked order that is somewhat different than what has been presented previously. In addition to being a vehicle for identifying potential targets for post-TBI therapeutic strategies, our findings can also provide a context for evaluating the potential of therapeutic agents currently in development

Neuregulin 1-Beta cytoprotective role in AML 12 mouse hepatocytes exposed to pentachlorophenol.

Neuregulins are a family of growth factor domain proteins that are structurally related to the epidermal growth factor. Accumulating evidence has shown that neuregulins have cyto- and neuroprotective properties in various cell types. In particular, the neuregulin-1 Beta (NRG1-Beta) isoform is well documented for its antiinflammatory properties in rat brain after acute stroke episodes. Pentachlorophenol (PCP) is an organochlorine compound that has been widely used as a biocide in several industrial, agricultural, and domestic applications. Previous investigations from our laboratory have demonstrated that PCP exerts both cytotoxic and mitogenic effects in human liver carcinoma (HepG2) cells, primary catfish hepatocytes and AML 12 mouse hepatocytes. We have also shown that in HepG2 cells, PCP has the ability to induce stress genes that may play a role in the molecular events leading to toxicity and tumorigenesis. In the present study, we hypothesize that NRG1-Beta will exert its cytoprotective effects in PCP-treated AML 12 mouse hepatocytes by its ability to suppress the toxic effects of PCP. To test this hypothesis, we performed the MTT-cell respiration assay to assess cell viability, and Western-blot analysis to assess stress-related proteins as a consequence of PCP exposure. Data obtained from 48 h-viability studies demonstrated a biphasic response; showing a dose-dependent increase in cell viability within the range of 0 to 3.87 microg/mL, and a gradual decrease within the concentration range of 7.75 to 31.0 microg/mL in concomitant treatments of NRG1-Beta+PCP and PCP. Cell viability percentages indicated that NRG1-Beta+PCPtreated cells were not significantly impaired, while PCP-treated cells were appreciably affected; suggesting that NRG1-Beta has the ability to suppress the toxic effects of PCP. Western Blot analysis demonstrated the potential of PCP to induce oxidative stress and inflammatory response (c-fos), growth arrest and DNA damage (GADD153), proteotoxic effects (HSP70), cell cycle arrest as consequence of DNA damage (p53), mitogenic response (cyclin- D1), and apoptosis (caspase-3). NRG1-Beta exposure attenuated stress-related protein expression in PCP-treated AML 12 mouse hepatocytes. Here we provide clear evidence that NRG1-Beta exerts cytoprotective effects in AML 12 mouse hepatocytes exposed to PCP

Lightcone fluctuations in flat spacetimes with nontrivial topology

The quantum lightcone fluctuations in flat spacetimes with compactified spatial dimensions or with boundaries are examined. The discussion is based upon a model in which the source of the underlying metric fluctuations is taken to be quantized linear perturbations of the gravitational field. General expressions are derived, in the transverse trace-free gauge, for the summation of graviton polarization tensors, and for vacuum graviton two-point functions. Because of the fluctuating light cone, the flight time of photons between a source and a detector may be either longer or shorter than the light propagation time in the background classical spacetime. We calculate the mean deviations from the classical propagation time of photons due to the changes in the topology of the flat spacetime. These deviations are in general larger in the directions in which topology changes occur and are typically of the order of the Planck time, but they can get larger as the travel distance increases.Comment: 25 pages, 5 figures, some discussions added and a few typos corrected, final version to appear in Phys. Rev.

An integral test of inelastic scattering cross sections using measured neutron spectra from thick shells of Ta, W, Mo, and Be

Integral test of inelastic scattering cross sections using measured neutron spectra from thick shells of Ta, W, Mo, and B

Gravitons and Lightcone Fluctuations II: Correlation Functions

A model of a fluctuating lightcone due to a bath of gravitons is further investigated. The flight times of photons between a source and a detector may be either longer or shorter than the light propagation time in the background classical spacetime, and will form a Gaussian distribution centered around the classical flight time. However, a pair of photons emitted in rapid succession will tend to have correlated flight times. We derive and discuss a correlation function which describes this effect. This enables us to understand more fully the operational significance of a fluctuating lightcone. Our results may be combined with observational data on pulsar timing to place some constraints on the quantum state of cosmological gravitons.Comment: 16 pages and two figures, uses eps

Maximum st-flow in directed planar graphs via shortest paths

Minimum cuts have been closely related to shortest paths in planar graphs via planar duality - so long as the graphs are undirected. Even maximum flows are closely related to shortest paths for the same reason - so long as the source and the sink are on a common face. In this paper, we give a correspondence between maximum flows and shortest paths via duality in directed planar graphs with no constraints on the source and sink. We believe this a promising avenue for developing algorithms that are more practical than the current asymptotically best algorithms for maximum st-flow.Comment: 20 pages, 4 figures. Short version to be published in proceedings of IWOCA'1

Semiclassical Gravity Theory and Quantum Fluctuations

We discuss the limits of validity of the semiclassical theory of gravity in which a classical metric is coupled to the expectation value of the stress tensor. It is argued that this theory is a good approximation only when the fluctuations in the stress tensor are small. We calculate a dimensionless measure of these fluctuations for a scalar field on a flat background in particular cases, including squeezed states and the Casimir vacuum state. It is found that the fluctuations are small for states which are close to a coherent state, which describes classical behavior, but tend to be large otherwise. We find in all cases studied that the energy density fluctuations are large whenever the local energy density is negative. This is taken to mean that the gravitational field of a system with negative energy density, such as the Casimir vacuum, is not described by a fixed classical metric but is undergoing large metric fluctuations. We propose an operational scheme by which one can describe a fluctuating gravitational field in terms of the statistical behavior of test particles. For this purpose we obtain an equation of the form of the Langevin equation used to describe Brownian motion.Comment: In REVTEX. 20pp + 4 figures(not included, available upon request) TUTP-93-

Quantum Inequalities on the Energy Density in Static Robertson-Walker Spacetimes

Quantum inequality restrictions on the stress-energy tensor for negative energy are developed for three and four-dimensional static spacetimes. We derive a general inequality in terms of a sum of mode functions which constrains the magnitude and duration of negative energy seen by an observer at rest in a static spacetime. This inequality is evaluated explicitly for a minimally coupled scalar field in three and four-dimensional static Robertson-Walker universes. In the limit of vanishing curvature, the flat spacetime inequalities are recovered. More generally, these inequalities contain the effects of spacetime curvature. In the limit of short sampling times, they take the flat space form plus subdominant curvature-dependent corrections.Comment: 18 pages, plain LATEX, with 3 figures, uses eps

A quantum weak energy inequality for the Dirac field in two-dimensional flat spacetime

Fewster and Mistry have given an explicit, non-optimal quantum weak energy inequality that constrains the smeared energy density of Dirac fields in Minkowski spacetime. Here, their argument is adapted to the case of flat, two-dimensional spacetime. The non-optimal bound thereby obtained has the same order of magnitude, in the limit of zero mass, as the optimal bound of Vollick. In contrast with Vollick's bound, the bound presented here holds for all (non-negative) values of the field mass.Comment: Version published in Classical and Quantum Gravity. 7 pages, 1 figur