Signalling cell cycle arrest and cell death through the MMR System

Loss of DNA mismatch repair (MMR) in mammalian cells, as well as having a causative role in cancer, has been linked to resistance to certain DNA damaging agents including clinically important cytotoxic chemotherapeutics. MMR-deficient cells exhibit defects in G<sub>2</sub>/M cell cycle arrest and cell killing when treated with these agents. MMR-dependent cell cycle arrest occurs, at least for low doses of alkylating agents, only after the second S-phase following DNA alkylation, suggesting that two rounds of DNA replication are required to generate a checkpoint signal. These results point to an indirect role for MMR proteins in damage signalling where aberrant processing of mismatches leads to the generation of DNA structures (single-strand gaps and/or double-strand breaks) that provoke checkpoint activation and cell killing. Significantly, recent studies have revealed that the role of MMR proteins in mismatch repair can be uncoupled from the MMR-dependent damage responses. Thus, there is a threshold of expression of MSH2 or MLH1 required for proper checkpoint and cell-death signalling, even though sub-threshold levels are sufficient for fully functional MMR repair activity. Segregation is also revealed through the identification of mutations in MLH1 or MSH2 that provide alleles functional in MMR but not in DNA damage responses and mutations in MSH6 that compromise MMR but not in apoptotic responses to DNA damaging agents. These studies suggest a direct role for MMR proteins in recognizing and signalling DNA damage responses that is independent of the MMR catalytic repair process. How MMR-dependent G<sub>2</sub> arrest may link to cell death remains elusive and we speculate that it is perhaps the resolution of the MMR-dependent G<sub>2</sub> cell cycle arrest following DNA damage that is important in terms of cell survival

Measurement of collagen synthesis by cells grown under different mechanical stimuli

INTRODUCTION: The use of scaffolds in tissue engineering is essential to provide cells with a matrix for cell proliferation and differentiation resulting in tissue regeneration. Normally this process involves seeding cells onto an artificial biodegradable scaffold providing mechanical support for cells until there is sufficient extracellular matrix deposition (ECM) to replace the artificial scaffold. Collagen is the bulk protein found in the ECM and measurement of its synthesis is the most direct, absolute indicator of ECM production

Cellular responses to external mechanical stimuli when seeded to 3D collagen

INTRODUCTION: Collagen is a naturally occurring visco-elastic protein and widely used biomaterial in Tissue engineering. Mechanical stimulation of cell seeded collagen constructs and its effects on cell orientation, intracellular signalling and molecular responses have been reported in literature2. Monitoring of cellular responses to mechanical stimulation include synthesis of active regulatory molecules such as growth factors or hormones, changes in matrix synthesis, cell alignment and enzyme release. The aim of this study was to investigate cellular responses to pre strained, stiffer and more organised collagen bio-artificial matrices

Giant Leaps and Minimal Branes in Multi-Dimensional Flux Landscapes

There is a standard story about decay in multi-dimensional flux landscapes: that from any state, the fastest decay is to take a small step, discharging one flux unit at a time; that fluxes with the same coupling constant are interchangeable; and that states with N units of a given flux have the same decay rate as those with -N. We show that this standard story is false. The fastest decay is a giant leap that discharges many different fluxes in unison; this decay is mediated by a 'minimal' brane that wraps the internal manifold and exhibits behavior not visible in the effective theory. We discuss the implications for the cosmological constant.Comment: Minor updates to agree with published version. 9 pages, 4 figure

External loading determines specific ECM genes regulation

Bio artificial matrices embedded with cells are simulated in bioreactors to facilitate ECM production. As cells attach, they develop forces, which are dependent on cell type and matrix stiffness. External forces (i.e strain), however, are critical for tissue homeostasis and elicit specific cellular responses, such as gene expression and protein production. Collagen Type I is a widely used scaffold in Tissue engineering. The aim of this study was to study the mechanical and molecular responses, of different cell types to increasing collagen substrate stiffness

Higher Descent Data as a Homotopy Limit

We define the 2-groupoid of descent data assigned to a cosimplicial 2-groupoid and present it as the homotopy limit of the cosimplicial space gotten after applying the 2-nerve in each cosimplicial degree. This can be applied also to the case of $n$-groupoids thus providing an analogous presentation of "descent data" in higher dimensions.Comment: Appeared in JHR

Extension and application of a sequential estimator

Improved sequential estimation technique for nonlinear time varying system

Quantum atom optics with fermions from molecular dissociation

We study a fermionic atom optics counterpart of parametric down-conversion with photons. This can be realized through dissociation of a Bose-Einstein condensate of molecular dimers consisting of fermionic atoms. We present a theoretical model describing the quantum dynamics of dissociation and find analytic solutions for mode occupancies and atomic pair correlations, valid in the short time limit. The solutions are used to identify upper bounds for the correlation functions, which are applicable to any fermionic system and correspond to ideal particle number-difference squeezingComment: Changes in response to referees' comments, updated reference

Temporal and Spatial Turbulent Spectra of MHD Plasma and an Observation of Variance Anisotropy

The nature of MHD turbulence is analyzed through both temporal and spatial magnetic fluctuation spectra. A magnetically turbulent plasma is produced in the MHD wind-tunnel configuration of the Swarthmore Spheromak Experiment (SSX). The power of magnetic fluctuations is projected into directions perpendicular and parallel to a local mean field; the ratio of these quantities shows the presence of variance anisotropy which varies as a function of frequency. Comparison amongst magnetic, velocity, and density spectra are also made, demonstrating that the energy of the turbulence observed is primarily seeded by magnetic fields created during plasma production. Direct spatial spectra are constructed using multi-channel diagnostics and are used to compare to frequency spectra converted to spatial scales using the Taylor Hypothesis. Evidence for the observation of dissipation due to ion inertial length scale physics is also discussed as well as the role laboratory experiment can play in understanding turbulence typically studied in space settings such as the solar wind. Finally, all turbulence results are shown to compare fairly well to a Hall-MHD simulation of the experiment.Comment: 17 pages, 17 figures, Submitted to Astrophysical Journa

Revised Results for Non-thermal Recombination Flare Hard X-Ray Emission

Brown and Mallik (BM) recently showed that, for hot sources, recombination of non-thermal electrons (NTR) onto highly ionised heavy ions is not negligible compared to non-thermal bremsstrahlung (NTB) as a source of flare hard X-rays (HXRs) and so should be included in modelling non-thermal HXR flare emission. In view of major discrepancies between BM results for the THERMAL continua and those of the Chianti code and of RHESSI solar data, we critically re-examine and correct the BM analysis and modify the conclusions concerning the importance of NTR. Although the analytic Kramers expression used by BM is correct for the purely hydrogenic recombination cross section, the heuristic expressions used by BM to extend the Kramers expression beyond the `bare nucleus' case to which it applies had serious errors. BM results have therefore been recalculated using corrected expressions, which have been validated against the results of detailed calculations. At T ~ 10-30 MK the dominant ions are Fe 22+, 23+, 24+ for which BM erroneously overestimated NTR emission by around an order of magnitude. Contrary to the BM claim, NTR in hot flare plasmas does NOT dominate over NTB, although in some cases it can be comparable and so still very important in inversions of photon spectra to derive electron spectra, especially as NTR includes sharp edge features. The BM claim of dominance of NTR over NTB in deka-keV emission is incorrect due to a serious error in their analysis. However, the NTR contribution can still be large enough to demand inclusion in spectral fitting, the spectral edges having potentially serious effects on inversion of HXR spectra to infer fast electron spectra.Comment: 6 pages, 8 figures, 1 tabl