Target mimicry provides a new mechanism for regulation of microRNA activity

MicroRNAs (miRNA) regulate key aspects of development and physiology in animals and plants. These regulatory RNAs act as guides of effector complexes to recognize specific mRNA sequences based on sequence complementarity, resulting in translational repression or site-specific cleavage. In plants, most miRNA targets are cleaved and show almost perfect complementarity with the miRNAs around the cleavage site. Here, we examined the non-protein coding gene IPS1 (INDUCED BY PHOSPHATE STARVATION 1) from Arabidopsis thaliana. IPS1 contains a motif with sequence complementarity to the phosphate (Pi) starvation-induced miRNA miR-399, but the pairing is interrupted by a mismatched loop at the expected miRNA cleavage site. We show that IPS1 RNA is not cleaved but instead sequesters miR-399. Thus, IPS1 overexpression results in increased accumulation of the miR-399 target PHO2 mRNA and, concomitantly, in reduced shoot Pi content. Engineering of IPS1 to be cleavable abolishes its inhibitory activity on miR-399. We coin the term 'target mimicry' to define this mechanism of inhibition of miRNA activity. Target mimicry can be generalized beyond the control of Pi homeostasis, as demonstrated using artificial target mimics.     

Complement factor H in host defense and immune evasion

Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.     

Predicting Recessions with Factor Linear Dynamic Harmonic Regressions

We propose a new framework for building composite leading indicators for the Spanish economy using monthly targeted predictors and small‐scale dynamic factor models. Our leading indicator index, based on the low‐frequency components of four monthly economic variables, is able to predict the onset of the Spanish recessions as well as the gross domestic product (GDP) growth cycles and classical industrial production cycles, both historically and in real time. Also, our leading indicator provides substantial aid in forecasting annual and quarterly GDP growth rates. Using only real data available at the beginning of each forecast period, our indicator one‐step‐ahead forecasts shows substantial improvements over other alternatives. Copyright © 2013 John Wiley & Sons, Ltd.     

Forecasting European GNP data through common factor models and other procedures

In this paper we present an extensive study of annual GNP data for five European countries. We look for intercountry dependence and analyse how the different economies interact, using several univariate ARIMA and unobserved components models and a multivariate model for the GNP incorporating all the common information among the variables. We use a dynamic factor model to take account of the common dynamic structure of the variables. This common dynamic structure can be non‐stationary (i.e. common trends) or stationary (i.e. common cycles). Comparisons of the models are made in terms of the root mean square error (RMSE) for one‐step‐ahead forecasts. For this particular group of European countries, the factor model outperforms the remaining ones. Copyright © 2002 John Wiley & Sons, Ltd.     

A MULTI-AGENT SYSTEM FOR MANAGING THE QUALITY OF SERVICE IN TELECOMMUNICATIONS NETWORKS

1. Introduction In this paper we propose X-MAQoS, a novel XML-based multi-agent system for the QoS management in telecommunications networks. The motivations underlying our system and its general characteristics are illustrated in this section. Specifically, the motivations are presented in Section 1.1, whereas the general characteristics are described in Section 1.2. 1.1 Motivations The last few years are witnessing a fast evolution of the telecommunications systems towards the full dep…     

Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.