A Meta-Analysis of Microarray Gene Expression in Mouse Stem Cells: Redefining Stemness

While much progress has been made in understanding stem cell (SC) function, a complete description of the molecular mechanisms regulating SCs is not yet established. This lack of knowledge is a major barrier holding back the discovery of therapeutic uses of SCs. We investigated the value of a novel meta-analysis of microarray gene expression in mouse SCs to aid the elucidation of regulatory mechanisms common to SCs and particular SC types.We added value to previously published microarray gene expression data by characterizing the promoter type likely to regulate transcription. Promoters of up-regulated genes in SCs were characterized in terms of alternative promoter (AP) usage and CpG-richness, with the aim of correlating features known to affect transcriptional control with SC function. We found that SCs have a higher proportion of up-regulated genes using CpG-rich promoters compared with the negative controls. Comparing subsets of SC type with the controls a slightly different story unfolds. The differences between the proliferating adult SCs and the embryonic SCs versus the negative controls are statistically significant. Whilst the difference between the quiescent adult SCs compared with the negative controls is not. On examination of AP usage, no difference was observed between SCs and the controls. However, comparing the subsets of SC type with the controls, the quiescent adult SCs are found to up-regulate a larger proportion of genes that have APs compared to the controls and the converse is true for the proliferating adult SCs and the embryonic SCs.These findings suggest that looking at features associated with control of transcription is a promising future approach for characterizing “stemness” and that further investigations of stemness could benefit from separate considerations of different SC states. For example, “proliferating-stemness” is shown here, in terms of promoter usage, to be distinct from “quiescent-stemness”

Tales of future weather

Society is vulnerable to extreme weather events and, by extension, to human impacts on future events. As climate changes weather patterns will change. The search is on for more effective methodologies to aid decision-makers both in mitigation to avoid climate change and in adaptation to changes. The traditional approach uses ensembles of climate model simulations, statistical bias correction, downscaling to the spatial and temporal scales relevant to decision-makers, and then translation into quantities of interest. The veracity of this approach cannot be tested, and it faces in-principle challenges. Alternatively, numerical weather prediction models in a hypothetical climate setting can provide tailored narratives for high-resolution simulations of high-impact weather in a future climate. This 'tales of future weather' approach will aid in the interpretation of lower-resolution simulations. Arguably, it potentially provides complementary, more realistic and more physically consistent pictures of what future weather might look like

Adenoviral gene transfer of angiostatic ATF-BPTI inhibits tumour growth

BACKGROUND: The outgrowth of new vessels – angiogenesis – in the tumour mass is considered to be a limiting factor of tumour growth. To inhibit the matrix lysis that is part of the tumour angiogenesis, we employed the chimeric protein mhATF-BPTI, composed of the receptor binding part of the urokinase (ATF) linked to an inhibitor of plasmin (BPTI). METHODS: For delivery, recombinant adenovirus encoding the transgene of interest was injected intravenously or locally into the tumour. The anti tumour effect of this compound was compared to that of human endostatin and of mhATF alone in two different rat bronchial carcinomas growing either as subcutaneous implants or as metastases. RESULTS: Significant inhibition of the tumour growth and decrease of the number of lung metastasis was achieved when the concentration of mhATF-BPTI at the tumour site was above 400 of ng / g tissue. This concentration could be achieved via production by the liver, only if permissive to the recombinant adenovirus. When the tumour cells could be transduced, local delivery of the vector was enough to obtain a response. In the case of metastasis, the capacity of the lung tissue to concentrate the encoded protein was essential to reach the required therapeutic levels. Further, endostatin or mhATF could not reproduce the effects of mhATF-BPTI, at similar concentrations (mhATF) and even at 10-fold higher concentration (endostatin). CONCLUSION: The ATF-BPTI was shown to inhibit tumour growth of different rat lung tumours when critical concentration was reached. In these tumour models, endostatin or ATF induce almost no tumour response

Inhibitor of Kappa B Epsilon (IκBε) Is a Non-Redundant Regulator of c-Rel-Dependent Gene Expression in Murine T and B Cells

Inhibitors of kappa B (IκBs) -α, -β and -ε effect selective regulation of specific nuclear factor of kappa B (NF-κB) dimers according to cell lineage, differentiation state or stimulus, in a manner that is not yet precisely defined. Lymphocyte antigen receptor ligation leads to degradation of all three IκBs but activation only of subsets of NF-κB-dependent genes, including those regulated by c-Rel, such as anti-apoptotic CD40 and BAFF-R on B cells, and interleukin-2 (IL-2) in T cells. We report that pre-culture of a mouse T cell line with tumour necrosis factor-α (TNF) inhibits IL-2 gene expression at the level of transcription through suppressive effects on NF-κB, AP-1 and NFAT transcription factor expression and function. Selective upregulation of IκBε and suppressed nuclear translocation of c-Rel were very marked in TNF-treated, compared to control cells, whether activated via T cell receptor (TCR) pathway or TNF receptor. IκBε associated with newly synthesised c-Rel in activated cells and, in contrast to IκBα and -β, showed enhanced association with p65/c-Rel in TNF-treated cells relative to controls. Studies in IκBε-deficient mice revealed that basal nuclear expression and nuclear translocation of c-Rel at early time-points of receptor ligation were higher in IκBε−/− T and B cells, compared to wild-type. IκBε−/− mice exhibited increased lymph node cellularity and enhanced basal thymidine incorporation by lymphoid cells ex vivo. IκBε−/− T cell blasts were primed for IL-2 expression, relative to wild-type. IκBε−/− splenic B cells showed enhanced survival ex vivo, compared to wild-type, and survival correlated with basal expression of CD40 and induced expression of CD40 and BAFF-R. Enhanced basal nuclear translocation of c-Rel, and upregulation of BAFF-R and CD40 occurred despite increased IκBα expression in IκBε−/− B cells. The data imply that regulation of these c-Rel-dependent lymphoid responses is a non-redundant function of IκBε

Measuring Health Utility in Economics

Quality-adjusted life years (QALYs) are one of the main health outcomes measures used to make health policy decisions. It is assumed that the objective of policymakers is to maximize QALYs. Since the QALY weighs life years according to their health-related quality of life, it is necessary to calculate those weights (also called utilities) in order to estimate the number of QALYs produced by a medical treatment. The methodology most commonly used to estimate utilities is to present standard gamble (SG) or time trade-off (TTO) questions to a representative sample of the general population. It is assumed that, in this way, utilities reflect public preferences. Two different assumptions should hold for utilities to be a valid representation of public preferences. One is that the standard (linear) QALY model has to be a good model of how subjects value health. The second is that subjects should have consistent preferences over health states. Based on the main assumptions of the popular linear QALY model, most of those assumptions do not hold. A modification of the linear model can be a tractable improvement. This suggests that utilities elicited under the assumption that the linear QALY model holds may be biased. In addition, the second assumption, namely that subjects have consistent preferences that are estimated by asking SG or TTO questions, does not seem to hold. Subjects are sensitive to features of the elicitation process (like the order of questions or the type of task) that should not matter in order to estimate utilities. The evidence suggests that questions (TTO, SG) that researchers ask members of the general population produce response patterns that do not agree with the assumption that subjects have well-defined preferences when researchers ask them to estimate the value of health states. Two approaches can deal with this problem. One is based on the assumption that subjects have true but biased preferences. True preferences can be recovered from biased ones. This approach is valid as long as the theory used to debias is correct. The second approach is based on the idea that preferences are imprecise. In practice, national bodies use utilities elicited using TTO or SG under the assumptions that the linear QALY model is a good enough representation of public preferences and that subjects’ responses to preference elicitation methods are coherent