Androgen receptor phosphorylation status at serine 578 predicts poor outcome in prostate cancer patients

Purpose: Prostate cancer growth is dependent upon androgen receptor (AR) activation, regulated via phosphorylation. Protein kinase C (PKC) is one kinase that can mediate AR phosphorylation. This study aimed to establish if AR phosphorylation by PKC is of prognostic significance. Methods: Immunohistochemistry for AR, AR phosphorylated at Ser-81 (pARS81), AR phosphorylated at Ser-578 (pARS578), PKC and phosphorylated PKC (pPKC) was performed on 90 hormone-naïve prostate cancer specimens. Protein expression was quantified using the weighted histoscore method and examined with regard to clinico-pathological factors and outcome measures; time to biochemical relapse, survival from biochemical relapse and disease-specific survival. Results: Nuclear PKC expression strongly correlated with nuclear pARS578 (c.c. 0.469, p=0.001) and cytoplasmic pARS578 (c.c. 0.426 p=0.002). High cytoplasmic and nuclear pARS578 were associated with disease-specific survival (p<0.001 and p=0.036 respectively). High nuclear PKC was associated with lower disease-specific survival when combined with high pARS578 in the cytoplasm (p=0.001) and nucleus (p=0.038). Combined high total pARS81 and total pARS578 was associated with decreased disease-specific survival (p=0.005) Conclusions: pARS578 expression is associated with poor outcome and is a potential independent prognostic marker in hormone-naïve prostate cancer. Furthermore, PKC driven AR phosphorylation may promote prostate cancer progression and provide a novel therapeutic target

Microbial oxidation of arsenite in a subarctic environment: diversity of arsenite oxidase genes and identification of a psychrotolerant arsenite oxidiser

Background: Arsenic is toxic to most living cells. The two soluble inorganic forms of arsenic are arsenite (+3) and arsenate (+5), with arsenite the more toxic. Prokaryotic metabolism of arsenic has been reported in both thermal and moderate environments and has been shown to be involved in the redox cycling of arsenic. No arsenic metabolism (either dissimilatory arsenate reduction or arsenite oxidation) has ever been reported in cold environments (i.e. < 10°C). Results: Our study site is located 512 kilometres south of the Arctic Circle in the Northwest Territories, Canada in an inactive gold mine which contains mine waste water in excess of 50 mM arsenic. Several thousand tonnes of arsenic trioxide dust are stored in underground chambers and microbial biofilms grow on the chamber walls below seepage points rich in arsenite-containing solutions. We compared the arsenite oxidisers in two subsamples (which differed in arsenite concentration) collected from one biofilm. 'Species' (sequence) richness did not differ between subsamples, but the relative importance of the three identifiable clades did. An arsenite-oxidising bacterium (designated GM1) was isolated, and was shown to oxidise arsenite in the early exponential growth phase and to grow at a broad range of temperatures (4-25°C). Its arsenite oxidase was constitutively expressed and functioned over a broad temperature range. Conclusions: The diversity of arsenite oxidisers does not significantly differ from two subsamples of a microbial biofilm that vary in arsenite concentrations. GM1 is the first psychrotolerant arsenite oxidiser to be isolated with the ability to grow below 10°C. This ability to grow at low temperatures could be harnessed for arsenic bioremediation in moderate to cold climates

Public health economics: a systematic review of guidance for the economic evaluation of public health interventions and discussion of key methodological issues

BACKGROUND: If Public Health is the science and art of how society collectively aims to improve health, and reduce inequalities in health, then Public Health Economics is the science and art of supporting decision making as to how society can use its available resources to best meet these objectives and minimise opportunity cost. A systematic review of published guidance for the economic evaluation of public health interventions within this broad public policy paradigm was conducted. METHODS: Electronic databases and organisation websites were searched using a 22 year time horizon (1990–2012). References of papers were hand searched for additional papers for inclusion. Government reports or peer-reviewed published papers were included if they; referred to the methods of economic evaluation of public health interventions, identified key challenges of conducting economic evaluations of public health interventions or made recommendations for conducting economic evaluations of public health interventions. Guidance was divided into three categories UK guidance, international guidance and observations or guidance provided by individual commentators in the field of public health economics. An assessment of the theoretical frameworks underpinning the guidance was made and served as a rationale for categorising the papers. RESULTS: We identified 5 international guidance documents, 7 UK guidance documents and 4 documents by individual commentators. The papers reviewed identify the main methodological challenges that face analysts when conducting such evaluations. There is a consensus within the guidance that wider social and environmental costs and benefits should be looked at due to the complex nature of public health. This was reflected in the theoretical underpinning as the majority of guidance was categorised as extra-welfarist. CONCLUSIONS: In this novel review we argue that health economics may have come full circle from its roots in broad public policy economics. We may find it useful to think in this broader paradigm with respect to public health economics. We offer a 12 point checklist to support government, NHS commissioners and individual health economists in their consideration of economic evaluation methodology with respect to the additional challenges of applying health economics to public health

Evaluation of Cirrus Parameterizations for Radiative Flux Computations in Climate Models Using TOVS-ScaRaB Satellite Observations

Combined simultaneous satellite observations are used to evaluate the performance of parameterizations of the microphysical and optical properties of cirrus clouds used for radiative flux computations in climate models. Atmospheric and cirrus properties retrieved from Television and Infrared Observation Satellite (TIROS-N) Operational Vertical Sounder (TOVS) observations are given as input to the radiative transfer model developed for the Met Office climate model to simulate radiative fluxes at the top of the atmosphere (TOA). Simulated cirrus shortwave (SW) albedos are then compared to those retrieved from collocated Scanner for Radiation Budget (ScaRaB) observations. For the retrieval, special care has been given to angular direction models. Three parameterizations of cirrus ice crystal optical properties are represented in the Met Office radiative transfer model. These parameterizations are based on different physical approximations and different hypotheses on crystal habit. One parameterization assumes pristine ice crystals and two ice crystal aggregates. By relating the cirrus ice water path (IWP) retrieved from the effective infrared emissivity to the cirrus SW albedo, differences between the parameterizations are amplified. This study shows that pristine crystals seem to be plausible only for cirrus with IWP less than 30 g m−2. For larger IWP, ice crystal aggregates lead to cirrus SW albedos in better agreement with the observations. The data also indicate that climate models should allow the cirrus effective ice crystal diameter (De) to increase with IWP, especially in the range up to 30 g m−2. For cirrus with IWP less than 20 g m−2, this would lead to SW albedos that are about 0.02 higher than the ones of a constant De of 55 μm

The Impact of Selective-Logging and Forest Clearance for Oil Palm on Fungal Communities in Borneo

Tropical forests are being rapidly altered by logging, and cleared for agriculture. Understanding the effects of these land use changes on soil fungi, which play vital roles in the soil ecosystem functioning and services, is a major conservation frontier. Using 454-pyrosequencing of the ITS1 region of extracted soil DNA, we compared communities of soil fungi between unlogged, once-logged, and twice-logged rainforest, and areas cleared for oil palm, in Sabah, Malaysia. Overall fungal community composition differed significantly between forest and oil palm plantation. The OTU richness and Chao 1 were higher in forest, compared to oil palm plantation. As a proportion of total reads, Basidiomycota were more abundant in forest soil, compared to oil palm plantation soil. The turnover of fungal OTUs across space, true β-diversity, was also higher in forest than oil palm plantation. Ectomycorrhizal (EcM) fungal abundance was significantly different between land uses, with highest relative abundance (out of total fungal reads) observed in unlogged forest soil, lower abundance in logged forest, and lowest in oil palm. In their entirety, these results indicate a pervasive effect of conversion to oil palm on fungal community structure. Such wholesale changes in fungal communities might impact the long-term sustainability of oil palm agriculture. Logging also has more subtle long term effects, on relative abundance of EcM fungi, which might affect tree recruitment and nutrient cycling. However, in general the logged forest retains most of the diversity and community composition of unlogged forest

Stability of Systems with Multiple Time Delays

Systems whose dynamical representations involve multiple transportation lags are generally difficult to analyse. Such systems give rise to infinite strings of poles in the complex plane and subsequently, transfer functions of a transcendental nature. A Nyquist stability analysis of a system with two delay terms reveals a central region of stability even though the system has an infinite number of poles with positive real parts. An input-output stability criterion due to Zadeh is used to confirm the Nyquist analysis and show that systems with an infinite number of poles are not necessarily subject to the same pole location restrictions as systems with a finite number of poles

Ensemble decision tree models using RUSBoost for estimating risk of iron failure in drinking water distribution systems

Safe, trusted drinking water is fundamental to society. Discolouration is a key aesthetic indicator visible to customers. Investigations to understand discolouration and iron failures in water supply systems require assessment of large quantities of disparate, inconsistent, multidimensional data from multiple corporate systems. A comprehensive data matrix was assembled for a seven year period across the whole of a UK water company (serving three million people). From this a novel data driven tool for assessment of iron risk was developed based on a yearly update and ranking procedure, for a subset of the best quality data. To avoid a ‘black box’ output, and provide an element of explanatory (human readable) interpretation, classification decision trees were utilised. Due to the very limited number of iron failures, results from many weak learners were melded into one high-quality ensemble predictor using the RUSBoost algorithm which is designed for class imbalance. Results, exploring simplicity vs predictive power, indicate enough discrimination between variable relationships in the matrix to produce ensemble decision tree classification models with good accuracy for iron failure estimation at District Management Area (DMA) scale. Two model variants were explored: ‘Nowcast’ (situation at end of calendar year) and ‘Futurecast’ (predict end of next year situation from this year’s data). The Nowcast 2014 model achieved 100% True Positive Rate (TPR) and 95.3% True Negative Rate (TNR), with 3.3% of DMAs classified High Risk for un-sampled instances. The Futurecast 2014 achieved 60.5% TPR and 75.9% TNR, with 25.7% of DMAs classified High Risk for un-sampled instances. The output can be used to focus preventive measures to improve iron compliance

Ensemble decision tree models using RUSBoost for estimating risk of iron failure in drinking water distribution systems

Safe, trusted drinking water is fundamental to society. Discolouration is a key aesthetic indicator visible to customers. Investigations to understand discolouration and iron failures in water supply systems require assessment of large quantities of disparate, inconsistent, multidimensional data from multiple corporate systems. A comprehensive data matrix was assembled for a seven year period across the whole of a UK water company (serving three million people). From this a novel data driven tool for assessment of iron risk was developed based on a yearly update and ranking procedure, for a subset of the best quality data. To avoid a ‘black box’ output, and provide an element of explanatory (human readable) interpretation, classification decision trees were utilised. Due to the very limited number of iron failures, results from many weak learners were melded into one high-quality ensemble predictor using the RUSBoost algorithm which is designed for class imbalance. Results, exploring simplicity vs predictive power, indicate enough discrimination between variable relationships in the matrix to produce ensemble decision tree classification models with good accuracy for iron failure estimation at District Management Area (DMA) scale. Two model variants were explored: ‘Nowcast’ (situation at end of calendar year) and ‘Futurecast’ (predict end of next year situation from this year’s data). The Nowcast 2014 model achieved 100% True Positive Rate (TPR) and 95.3% True Negative Rate (TNR), with 3.3% of DMAs classified High Risk for un-sampled instances. The Futurecast 2014 achieved 60.5% TPR and 75.9% TNR, with 25.7% of DMAs classified High Risk for un-sampled instances. The output can be used to focus preventive measures to improve iron compliance

On topological charge carried by nexuses and center vortices

In this paper we further explore the question of topological charge in the center vortex-nexus picture of gauge theories. Generally, this charge is locally fractionalized in units of 1/N for gauge group SU(N), but globally quantized in integral units. We show explicitly that in d=4 global topological charge is a linkage number of the closed two-surface of a center vortex with a nexus world line, and relate this linkage to the Hopf fibration, with homotopy $\Pi_3(S^3)\simeq Z$; this homotopy insures integrality of the global topological charge. We show that a standard nexus form used earlier, when linked to a center vortex, gives rise naturally to a homotopy $\Pi_2(S^2)\simeq Z$, a homotopy usually associated with 't Hooft-Polyakov monopoles and similar objects which exist by virtue of the presence of an adjoint scalar field which gives rise to spontaneous symmetry breaking. We show that certain integrals related to monopole or topological charge in gauge theories with adjoint scalars also appear in the center vortex-nexus picture, but with a different physical interpretation. We find a new type of nexus which can carry topological charge by linking to vortices or carry d=3 Chern-Simons number without center vortices present; the Chern-Simons number is connected with twisting and writhing of field lines, as the author had suggested earlier. In general, no topological charge in d=4 arises from these specific static configurations, since the charge is the difference of two (equal) Chern-Simons number, but it can arise through dynamic reconnection processes. We complete earlier vortex-nexus work to show explicitly how to express globally-integral topological charge as composed of essentially independent units of charge 1/N.Comment: Revtex4; 3 .eps figures; 18 page

Multiple GF-1 binding sites flank the erythroid specific transcription unit of the human carbonic anhydrase I gene

AbstractSix potential GF-1 sites which bind an erythroid factor are present in the 5' and 3' regions flanking the erythroid-speciflc transcription unit of the human carbonic anhydrase 1 (HCAI) gene. When two of these sites are placed upstream of a minimal eukaryotic promoter they confer upregulated expression in erythroid over non-erythroid cells. The presence of the erythroid factor in TPA-treated HEL cells in which the level of HCAI transcript has greatly decreased and in non-HCAI-expressing K562 cells suggests that in these cases the presence of the factor is not sufficient for HCAI expression