Targeting BCL-2 regulated apoptosis in cancer

The ability of a cell to undergo mitochondrial apoptosis is governed by pro- and anti-apoptotic members of the BCL-2 protein family. The equilibrium of pro- versus anti-apoptotic BCL-2 proteins ensures appropriate regulation of programmed cell death during development and maintains organismal health. When unbalanced, the BCL-2 family can act as a barrier to apoptosis and facilitate tumour development and resistance to cancer therapy. Here we discuss the BCL-2 family, their deregulation in cancer and recent pharmaceutical developments to target specific members of this family as cancer therapy

An Analysis of the Stabilizing and Welfare Effects of Intervention in Spot and Futures Markets

This paper analyzes the effects of three alternative rules on the long-run distributions of both the spot and futures prices ina single commodity market, in which the key behavioral relationships are derived from the optimizing behavior of producers and speculators.The rules considered include: (i) leaning against the wind in the spot market; (ii) utility maximizing speculative behavior by the stabilization authority in the futures market; (iii) leaning against the wind in the futures market. Since the underlying model is sufficiently complex to preclude analytical solutions, the analysis makes extensive use of simulation methods. As a general proposition we find that intervention in the futures market is not as effective in stabilizing either the spot price of the futures price as is intervention in the spot market. Indeed, Rule (iii), while stabilizing the futures price may actually destabilize the spot price. Furthermore, the analogous type of rule undertaken in the spot market will always stabilize the futures price to a greater degree than it does the spot price. The welfare implications of these rules are also discussed. Our analysis shows how these can generate rather different distributions of welfare gains, including the overall benefits.

Self-tuning diagnosis of routine alarms in rotating plant items

Condition monitoring of rotating plant items in the energy generation industry is often achieved through examination of vibration signals. Engineers use this data to monitor the operation of turbine generators, gas circulators and other key plant assets. A common approach in such monitoring is to trigger an alarm when a vibration deviates from a predefined envelope of normal operation. This limit-based approach, however, generates a large volume of alarms not indicative of system damage or concern, such as operational transients that result in temporary increases in vibration. In the nuclear generation context, all alarms on rotating plant assets must be analysed and subjected to auditable review. The analysis of these alarms is often undertaken manually, on a case- by-case basis, but recent developments in monitoring research have brought forward the use of intelligent systems techniques to automate parts of this process. A knowledge- based system (KBS) has been developed to automatically analyse routine alarms, where the underlying cause can be attributed to observable operational changes. The initialisation and ongoing calibration of such systems, however, is a problem, as normal machine state is not uniform throughout asset life due to maintenance procedures and the wear of components. In addition, different machines will exhibit differing vibro- acoustic dynamics. This paper proposes a self-tuning knowledge-driven analysis system for routine alarm diagnosis across the key rotating plant items within the nuclear context common to the UK. Such a system has the ability to automatically infer the causes of routine alarms, and provide auditable reports to the engineering staff

Estimating and explaining differences in income related inequality in health across general practices.

We use data on individual patients in general practices to examine whether income related inequality in self reported health differs across general practices and whether such differences are explained by characteristics of the practices. We allow for the simultaneous determination of health and income by instrumenting income. We also allow for item non response for the income question by a two stage selection model. We find that item non response has little effect on the estimated relationship between income and health but that allowing for simultaneity doubles the estimated effect of income on health. We show that there are significant differences in the effect of income on health across practices and that these differences are related to the number of patients per GP, a measure of practice prescribing quality, and the provision of out of hours services.Health; Income; Inequality; Primary care.

Self-tuning routine alarm analysis of vibration signals in steam turbine generators

This paper presents a self-tuning framework for knowledge-based diagnosis of routine alarms in steam turbine generators. The techniques provide a novel basis for initialising and updating time series feature extraction parameters used in the automated decision support of vibration events due to operational transients. The data-driven nature of the algorithms allows for machine specific characteristics of individual turbines to be learned and reasoned about. The paper provides a case study illustrating the routine alarm paradigm and the applicability of systems using such techniques

Investigation of gas circulator response to load transients in nuclear power plant operation

Gas circulator units are a critical component of the Advanced Gas-cooled Reactor (AGR), one of the nuclear power plant (NPP) designs in current use within the UK. The condition monitoring of these assets is central to the safe and economic operation of the AGRs and is achieved through analysis of vibration data. Due to the dynamic nature of reactor operation, each plant item is subject to a variety of system transients of which engineers are required to identify and reason about with regards to asset health. The AGR design enables low power refueling (LPR) which results in a change in operational state for the gas circulators, with the vibration profile of each unit reacting accordingly. The changing conditions subject to these items during LPR and other such events may impact on the assets. From these assumptions, it is proposed that useful information on gas circulator condition can be determined from the analysis of vibration response to the LPR event. This paper presents an investigation into asset vibration during an LPR. A machine learning classification approach is used in order to define each transient instance and its behavioral features statistically. Classification and reasoning about the regular transients such as the LPR represents the primary stage in modeling higher complexity events for advanced event driven diagnostics, which may provide an enhancement to the current methodology, which uses alarm boundary limits

Distinctive cellular response to aluminum based adjuvants.

Aluminum-based adjuvants (ABAs) are used in human vaccines to enhance the magnitude of protective immune responses elicited against specific pathogens. One hypothesis is that stress signals released by aluminum-exposed necrotic cells play a role in modulating an immune response that contributes to the adjuvant's effectiveness. We hypothesized that aluminum adjuvant-induced necrosis would be similar irrespective of cellular origin or composition of the adjuvant. To test this hypothesis, human macrophages derived from peripheral monocytic cell line (THP-1) and cells derived from the human brain (primary astrocytes) were evaluated. Three commercially available formulations of ABAs (Alhydrogel, Imject alum, and Adju-Phos) were examined. Alum was also used as a reference. Cell viability, reactive oxygen species formation, and production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were quantified. Cells were exposed to different concentrations (10-100 μg/mL) of the adjuvants for 24 h or 72 h. The two FDA approved adjuvants (Alhydrogel and Adju-Phos) decreased cell viability in both cell types. At the 72 h time point, the decrease in viability was accompanied with increased ROS formation. The size of the aluminum agglomerates was not relatable to the changes observed. After exposure to ABAs, astrocytes and macrophages presented a distinct profile of cytokine secretion which may relate to the function and unique characteristics of each cell type. These variations indicate that aluminum adjuvants may have differing capability of activating cells of different origin and thus their utility in specific vaccine design should be carefully assessed for optimum efficacy