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

Using Swift observations of prompt and afterglow emission to classify GRBs

We present an analysis of early BAT and XRT data for 107 gamma--ray bursts (GRBs) observed by the Swift satellite. We use these data to examine the behaviour of the X-ray light curve and propose a classification scheme for GRBs based on this behaviour. As found for previous smaller samples, the earliest X-ray light curve can be well described by an exponential which relaxes into a power law, often with flares superimposed. The later emission is well fit using a similar functional form and we find that these two functions provide a good description of the entire X-ray light curve. For the prompt emission, the transition time between the exponential and the power law gives a well-defined timescale, T_p, for the burst duration. We use T_p, the spectral index of the prompt emission, beta_p, and the prompt power law decay index, alpha_p to define four classes of burst: short, slow, fast and soft. Bursts with slowly declining emission have spectral and temporal properties similar to the short bursts despite having longer durations. Some of these GRBs may therefore arise from similar progenitors including several types of binary system. Short bursts tend to decline more gradually than longer duration bursts and hence emit a significant fraction of their total energy at times greater than T_p. This may be due to differences in the environment or the progenitor for long, fast bursts.Comment: 10 pages. 8 figures. Proceedings of the Royal Society Discussion meeting on Gamma-ray Bursts, September 18-20, 2006. To appear in Phil. Trans. Roy. Soc.

The coastal-inland income gap in China from 1991 to 1999: the role of geography and policy

We investigate the enlarging coastal-inland income gap in China during the 1990s, using GMM estimation of a Solow growth model. Disaggregating capital investment by source: public, foreign and private: helps to disentangle the effect of policy from those of geography. The impact of public investment on growth is insignificant in our panel data for 29 provinces; that of foreign investment is significant; private investment is most influential. We also use the distance by railway of each province’s capital city to its nearest port city as a proxy for transportation costs, and find significant differences across regions. Distance has negative effects on economic development but its marginal impact effects become less as distance increases. The coastal-inland gap will grow in the foreseeable future, if inland areas are not able to benefit from an increase in private investment and infrastructure improvements (to reduce transport costs).

View-dependent adaptive cloth simulation

This paper describes a method for view-dependent cloth simulation using dynamically adaptive mesh refinement and coarsening. Given a prescribed camera motion, the method adjusts the criteria controlling refinement to account for visibility and apparent size in the camera's view. Objectionable dynamic artifacts are avoided by anticipative refinement and smoothed coarsening. This approach preserves the appearance of detailed cloth throughout the animation while avoiding the wasted effort of simulating details that would not be discernible to the viewer. The computational savings realized by this method increase as scene complexity grows, producing a 2× speed-up for a single character and more than 4× for a small group

The Effectiveness of Britain's Financial Service Authority: An Economic Analysis

Sweeping regulatory reforms in Britain resulted in the formation of the Financial Services Authority (FSA). Because greater transparency of information is a major objective for this Act, shifting from one information system to another has re-distributive effects. We identify these effects at a sector level and their drivers at the firm level. At a sector level, FSA has generally increased the precision of investors’ priors reducing the information risk component of the cost of capital. At a firm level, large firms act as “Stackelberg leaders” in voluntary disclosure games. FSA regulation shifts power from leaders to “followers”.Disclosure, Regulation, Game Theory, Stackelberg Leader, Cost of Capital: information asymmetry

Measuring the Impact of Regulationon Market Stability: Evidence from the US Markets

In this paper, we introduce a new methodology designed to test the effect of new regulatory disclosure requirements on the disclosure threshold as predicted by the extant literature (Verrecchia (1983), Dye (1985)). We apply our methodology to test the consistency between observed effects from major US regulation past and present (1933/1934 Securities Acts, Regulation Fair Disclosure 2000, and the Sarbanes-Oxley Act 2002) with regulatory objectives.

The Financial Services Reform Act 2001: Impact on Systemic risk in Australia

The rise of conglomerate banks and their interrelated balance sheets, pose new challenges to theories of financial regulation. We measure the impact of recent legislative changes in Australia upon systemic risk, for banking and near banking sectors, and demonstrate a significant reduction post the legislation. This is consistent with a major legislative goal, to promote global competitiveness, because it implies a reduction in the cost of equity capital. In addition, we find no evidence in support of the HIH collapse increasing systemic risk in the overall financial sector but a relatively small effect was detected in the banking sector.Ris, Banks, Disclosure, Regulation, Entropy

Probabilistic analysis of cost-effectiveness models: choosing between treatment strategies for gastroesophageal reflux disease

When choosing between mutually exclusive treatment options, it is common to construct a cost-effectiveness frontier on the cost-effectiveness plane that represents efficient points from among the treatment choices. Treatment options internal to the frontier are considered inefficient and are excluded either by strict dominance or by appealing to the principle of extended dominance. However, when uncertainty is considered, options excluded under the baseline analysis may form part of the cost-effectiveness frontier. By adopting a Bayesian approach, where distributions for model parameters are specified, uncertainty in the decision concerning which treatment option should be implemented is addressed directly. The approach is illustrated using an example from a recently published cost-effectiveness analysis of different possible treatment strategies for gastroesophageal reflux disease.It is argued that probabilistic analyses should be encouraged because they have potential to quantify the strength of evidence in favor of particular treatment choices