On the predictability of extremes: Does the butterfly effect ever decrease?

This is the peer reviewed version of the following article: Sterk, A. E., Stephenson, D. B., Holland, M. P. and Mylne, K. R. (2015), On the predictability of extremes: Does the butterfly effect ever decrease?. Quarterly Journal of the Royal Meteorological Society, which has been published in final form at http://dx.doi.org/10.1002/qj.2627. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving: http://olabout.wiley.com/WileyCDA/Section/id-820227.html#termsThis study investigates whether or not predictability always decreases for more extreme events. Predictability is measured by the Mean Squared Error (MSE), estimated here from the difference of pairs of ensemble forecasts, conditioned on one of the forecast variables (the 'pseudo-observation') exceeding a threshold. Using an exchangeable linear regression model for pairs of forecast variables, we show that the MSE can be decomposed into the sum of three terms: a threshold-independent constant, a mean term that always increases with threshold, and a variance term that can either increase, decrease, or stay constant with threshold. Using the generalised Pareto distribution to model wind speed excesses over a threshold, we show that MSE always increases with threshold at sufficiently high threshold. However, MSE can be a decreasing function of threshold at lower thresholds but only if the forecasts have finite upper bounds. The methods are illustrated by application to daily wind speed forecasts for London made using the 24 member Met Office Global and Regional Ensemble Prediction System from 1 January 2009 to 31 May 2011. For this example, the mean term increases faster than the variance term decreases with increasing threshold, and so predictability decreases for more extreme events.Engineering and Physical Sciences Research Council (EPSRC)Netherlands Organisation for Scientific Research (NWO

Time to Lead on Climate

Timed just prior to the kick-off of this year\u27s UN Climate Conference in Paris and next year\u27s US Presidential and Congressional elections -- and energized by California\u27s growing climate leadership and the Pope\u27s call for global action -- the event poses the increasingly urgent question, How do we fire up the political will to solve Climate Change, and what can each of us do to help

Plasma endotoxin core antibody concentration and linear growth are unrelated in rural Malawian children aged 2–5 years

BACKGROUND: Environmental enteropathy is subclinical inflammation of the upper gastrointestinal tract associated with reduced linear growth in developing countries. Usually investigators have used biopsy or a dual sugar absorption test to assess environmental enteropathy. Such tests are time and resource intensive, restricting their utility as screening methods. Serum endotoxin core antibody (EndoCab) concentration is a potential indicator of intestinal inflammation and integrity, and thus may be useful to predict environmental enteropathy. We analyzed the association of serum EndoCab levels versus linear growth and lactulose-mannitol assay results in 2–5 year old rural Malawian children. METHODS: This was an observational study of 388 rural, asymptomatic Malawian children who had anthropometric measurements taken at least every 3 months since birth. In June and July 2011, dual sugar permeability tests were performed and serum samples were drawn for EndoCab assays. Pearson correlation, Student’s t test and multivariable linear regression were used to compare ln EndoCab concentrations with height-for-age z scores (HAZ) at time of sampling and 3 months later. Identical analysis was also performed for ln EndoCab versus measurements from dual sugar permeability testing performed in conjunction with serum sampling. In a subgroup of children with anthropometric data in the months prior to serum sampling, Pearson correlation was used to estimate the relationship between ln EndoCab and recent linear growth. RESULTS: Ln EndoCab concentrations were not correlated with HAZ at time of measurement (B = −0.078, P = 0.14) nor change in HAZ over the subsequent 3 months HAZ (B = −0.018, P = 0.27). EndoCab concentration was not associated with %lactulose excretion (B < 0.001, P = 0.98) nor the lactulose:mannitol ratio (B = 0.021, P = 0.62). Subgroup analysis also did not reveal any significant association between EndoCab and recent growth. CONCLUSION: EndoCab titers were not correlated with measurements of growth or intestinal permeability in rural pre-school aged Malawian children

Environmental enteric dysfunction and the fecal microbiota in malawian children

Environmental enteric dysfunction (EED) is often measured with a dual sugar absorption test and implicated as a causative factor in childhood stunting. Disturbances in the gut microbiota are hypothesized to be a mechanism by which EED is exacerbated, although this supposition lacks support. We performed 16S ribosomal RNA gene sequencing of fecal samples from 81 rural Malawian children with varying degrees of EED to determine which bacterial taxa were associated with EED. At the phyla level, Proteobacteria abundance is reduced with severe EED. Among bacterial genera, Megasphaera, Mitsuokella, and Sutterella were higher in EED and Succinivibrio, Klebsiella, and Clostridium_XI were lower in EED. Bacterial diversity did not vary with the extent of EED. Though EED is a condition that is typically believed to affect the proximal small bowel, and our focus was on stool, our data do suggest that there are intraluminal microbial differences that reflect, or plausibly lead to, EED

The Hippo Signaling Pathway Components Lats and Yap Pattern Tead4 Activity to Distinguish Mouse Trophectoderm from Inner Cell Mass

Outside cells of the preimplantation mouse embryo form the trophectoderm (TE), a process requiring the transcription factor Tead4. Here, we show that transcriptionally active Tead4 can induce Cdx2 and other trophoblast genes in parallel in embryonic stem cells. In embryos, the Tead4 coactivator protein Yap localizes to nuclei of outside cells, and modulation of Tead4 or Yap activity leads to changes in Cdx2 expression. In inside cells, Yap is phosphorylated and cytoplasmic, and this involves the Hippo signaling pathway component Lats. We propose that active Tead4 promotes TE development in outside cells, whereas Tead4 activity is suppressed in inside cells by cell contact- and Lats-mediated inhibition of nuclear Yap localization. Thus, differential signaling between inside and outside cell populations leads to changes in cell fate specification during TE formation

Precompetitive data sharing as a catalyst to address unmet needs in Parkinson's disease

Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease

Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T lymphocytes

Autophagy is implicated in many functions of mammalian cells such as organelle recycling, survival and differentiation, and is essential for the maintenance of T and B lymphocytes. Here, we demonstrate that autophagy is a constitutive process during T cell development. Deletion of the essential autophagy genes Atg5 or Atg7 in T cells resulted in decreased thymocyte and peripheral T cell numbers, and Atg5-deficient T cells had a decrease in cell survival. We employed functional-genetic and integrative computational analyses to elucidate specific functions of the autophagic process in developing T-lineage lymphocytes. Our whole-genome transcriptional profiling identified a set of 699 genes differentially expressed in Atg5-deficient and Atg5-sufficient thymocytes (Atg5-dependent gene set). Strikingly, the Atg5-dependent gene set was dramatically enriched in genes encoding proteins associated with the mitochondrion. In support of a role for autophagy in mitochondrial maintenance in T lineage cells, the deletion of Atg5 led to increased mitochondrial mass in peripheral T cells. We also observed a correlation between mitochondrial mass and Annexin-V staining in peripheral T cells. We propose that autophagy is critical for mitochondrial maintenance and T cell survival. We speculate that, similar to its role in yeast or mammalian liver cells, autophagy is required in T cells for the removal of damaged or aging mitochondria and that this contributes to the cell death of autophagy-deficient T cells