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Gaspar P.,Cancer Research UK Research Institute | Gaspar P.,Instituto Gulbenkian Of Ciencia | Tapon N.,Cancer Research UK Research Institute
Current Opinion in Cell Biology | Year: 2014

The Hippo network is a major conserved growth suppressor pathway that participates in organ size control during development and prevents tumour formation during adult homeostasis. Recent evidence has implicated the actin cytoskeleton as a link between tissue architecture and Hippo signalling. In this review, we will consider the evidence and models proposed for the regulation of Hippo signalling by actin dynamics and structure. We cover aspects of signalling regulation by mechanotransduction, cytoskeletal tethering and the spatial reorganization of signalling components. We also examine the physiological and pathological contexts in which these mechanisms are relevant. © 2014 Elsevier Ltd.


Teixeira L.,Instituto Gulbenkian Of Ciencia
Briefings in Functional Genomics | Year: 2012

Drosophila melanogaster is an established model organism for the study of host-pathogen interactions. The sequencing of its genome allowed the prediction of all the genes encoded in it and, consequently, enabled a more comprehensive view of its immune responses. Whole-genome transcription analyses of Drosophila response to bacteria, fungi, parasitoids and viruses allow a comparison of the response between different classes of microorganisms and between pathogens of the same class. Overall, there is great diversity in the immune responses but there are a few pathways that are frequently activated. These studies provide a better understanding of how the host resists the infection and responds to the associated damage. Moreover, the data give insights into how microorganisms can manipulate their host and successfully establish an infection. © The Author 2012. Published by Oxford University Press. All rights reserved.


Soares M.P.,Instituto Gulbenkian Of Ciencia
Cell | Year: 2015

Schieber et al. demonstrate that a specific gut microbiota bacterial strain induces a host-mediated protection mechanism against inflammation-driven wasting syndrome. This salutary effect confers a net survival advantage against bacterial infection, without interfering with the host's pathogen load, revealing that host-microbiota interactions regulate disease tolerance to infection. Schieber et al. demonstrate that a specific gut microbiota bacterial strain protects against inflammation-driven wasting syndrome, conferring a net survival advantage against bacterial infection, revealing that host-microbiota interactions regulate disease tolerance to infection. © 2015 Elsevier Inc.


Athanasiadis A.,Instituto Gulbenkian Of Ciencia
Seminars in Cell and Developmental Biology | Year: 2012

The involvement of A to I RNA editing in antiviral responses was first indicated by the observation of genomic hyper-mutation for several RNA viruses in the course of persistent infections. However, in only a few cases an antiviral role was ever demonstrated and surprisingly, it turns out that ADARs - the RNA editing enzymes - may have a prominent pro-viral role through the modulation/down-regulation of the interferon response. A key role in this regulatory function of RNA editing is played by ADAR1, an interferon inducible RNA editing enzyme. A distinguishing feature of ADAR1, when compared with other ADARs, is the presence of a Z-DNA binding domain, Zalpha. Since the initial discovery of the specific and high affinity binding of Zalpha to CpG repeats in a left-handed helical conformation, other proteins, all related to the interferon response pathway, were shown to have similar domains throughout the vertebrate lineage. What is the biological function of this domain family remains unclear but a significant body of work provides pieces of a puzzle that points to an important role of Zalpha domains in the recognition of foreign nucleic acids in the cytoplasm by the innate immune system. Here we will provide an overview of our knowledge on ADAR1 function in interferon response with emphasis on Zalpha domains. © 2011 Elsevier Ltd.


Brito D.A.,Instituto Gulbenkian Of Ciencia | Gouveia S.M.,Instituto Gulbenkian Of Ciencia | Bettencourt-Dias M.,Instituto Gulbenkian Of Ciencia
Current Opinion in Cell Biology | Year: 2012

Centrioles are very small microtubule-based organelles essential for centrosome, cilia and flagella assembly, which are involved in a variety of cellular and developmental processes. Although the centriole was first described almost a century ago, the knowledge on its assembly mechanism remains poor. In the past decade, forefront functional studies have provided important data on the different players involved in centriole biogenesis. Centriole research has now started to profit from highly sensitive structural, imaging, and biochemical techniques that are unveiling how those players contribute to assemble such a small and complex structure. We will review those studies and discuss how this field will increasingly benefit from the newborn and exciting era of super resolution analyses. © 2012 Elsevier Ltd.


Chrostek E.,Instituto Gulbenkian Of Ciencia | Teixeira L.,Instituto Gulbenkian Of Ciencia
PLoS Biology | Year: 2015

Most insect species are associated with vertically transmitted endosymbionts. Because of the mode of transmission, the fitness of these symbionts is dependent on the fitness of the hosts. Therefore, these endosymbionts need to control their proliferation in order to minimize their cost for the host. The genetic bases and mechanisms of this regulation remain largely undetermined. The maternally inherited bacteria of the genus Wolbachia are the most common endosymbionts of insects, providing some of them with fitness benefits. In Drosophila melanogaster, Wolbachia wMelPop is a unique virulent variant that proliferates massively in the hosts and shortens their lifespan. The genetic bases of wMelPop virulence are unknown, and their identification would allow a better understanding of how Wolbachia levels are regulated. Here we show that amplification of a region containing eight Wolbachia genes, called Octomom, is responsible for wMelPop virulence. Using Drosophila lines selected for carrying Wolbachia with different Octomom copy numbers, we demonstrate that the number of Octomom copies determines Wolbachia titers and the strength of the lethal phenotype. Octomom amplification is unstable, and reversion of copy number to one reverts all the phenotypes. Our results provide a link between genotype and phenotype in Wolbachia and identify a genomic region regulating Wolbachia proliferation. We also prove that these bacteria can evolve rapidly. Rapid evolution by changes in gene copy number may be common in endosymbionts with a high number of mobile elements and other repeated regions. Understanding wMelPop pathogenicity and variability also allows researchers to better control and predict the outcome of releasing mosquitoes transinfected with this variant to block human vector-borne diseases. Our results show that transition from a mutualist to a pathogen may occur because of a single genomic change in the endosymbiont. This implies that there must be constant selection on endosymbionts to control their densities. © 2015 Chrostek, Teixeira.


Gomes M.G.,Instituto Gulbenkian Of Ciencia
Proceedings. Biological sciences / The Royal Society | Year: 2012

Recurrent episodes of tuberculosis (TB) can be due to relapse of latent infection or exogenous reinfection, and discrimination is crucial for control planning. Molecular genotyping of Mycobacterium tuberculosis isolates offers concrete opportunities to measure the relative contribution of reinfection in recurrent disease. Here, a mathematical model of TB transmission is fitted to data from 14 molecular epidemiology studies, enabling the estimation of relevant epidemiological parameters. Meta-analysis reveals that rates of reinfection after successful treatment are higher than rates of new TB, raising an important question about the underlying mechanism. We formulate two alternative mechanisms within our model framework: (i) infection increases susceptibility to reinfection or (ii) infection affects individuals differentially, thereby recruiting high-risk individuals to the group at risk for reinfection. The second mechanism is better supported by the fittings to the data, suggesting that reinfection rates are inflated through a population phenomenon that occurs in the presence of heterogeneity in individual risk of infection. As a result, rates of reinfection are higher when measured at the population level even though they might be lower at the individual level. Finally, differential host recruitment is modulated by transmission intensity, being less pronounced when incidence is high.


Baena-Gonzalez E.,Instituto Gulbenkian Of Ciencia
Molecular Plant | Year: 2010

Maintenance of homeostasis is pivotal to all forms of life. In the case of plants, homeostasis is constantly threatened by the inability to escape environmental fluctuations, and therefore sensitive mechanisms must have evolved to allow rapid perception of environmental cues and concomitant modification of growth and developmental patterns for adaptation and survival. Re-establishment of homeostasis in response to environmental perturbations requires reprogramming of metabolism and gene expression to shunt energy sources from growth-related biosynthetic processes to defense, acclimation, and, ultimately, adaptation. Failure to mount an initial 'emergency' response may result in nutrient deprivation and irreversible senescence and cell death. Early signaling events largely determine the capacity of plants to orchestrate a successful adaptive response. Early events, on the other hand, are likely to be shared by different conditions through the generation of similar signals and before more specific responses are elaborated. Recent studies lend credence to this hypothesis, underpinning the importance of a shared energy signal in the transcriptional response to various types of stress. Energy deficiency is associated with most environmental perturbations due to their direct or indirect deleterious impact on photosynthesis and/or respiration. Several systems are known to have evolved for monitoring the available resources and triggering metabolic, growth, and developmental decisions accordingly. In doing so, energy-sensing systems regulate gene expression at multiple levels to allow flexibility in the diversity and the kinetics of the stress response.


Chelo I.M.,Instituto Gulbenkian Of Ciencia
Nature Protocols | Year: 2014

Estimation of fitness is a key step in experimental evolution studies. However, no established methods currently exist to specifically estimate how successful new alleles are in invading populations. The main reason is that most assays do not accurately reflect the randomness associated with the first stages of the invasion, when invaders are rare and extinctions are frequent. In this protocol, I describe how such experiments can be done in an effective way. By using the nematode model, Caenorhabditis elegans, a large number of invasion experiments are set up, whereby invading individuals carrying a visual marker are introduced into populations in very low numbers. The number of invaders counted in consecutive generations, together with the number of extinctions, is then used in the context of individual-based computer simulations to provide likelihood (Lk) estimates for fitness. This protocol can take up to five generations of experimental invasions and a few hours of computer processing time. © 2014 Nature America, Inc.


Gozzelino R.,Instituto Gulbenkian Of Ciencia | Soares M.P.,Instituto Gulbenkian Of Ciencia
Antioxidants and Redox Signaling | Year: 2014

Significance: Inflammation and immunity can be associated with varying degrees of heme release from hemoproteins, eventually leading to cellular and tissue iron (Fe) overload, oxidative stress, and tissue damage. Presumably, these deleterious effects contribute to the pathogenesis of systemic infections. Recent Advances: Heme release from hemoglobin sensitizes parenchyma cells to undergo programmed cell death in response to proinflammatory cytokines, such as tumor necrosis factor. This cytotoxic effect is driven by a mechanism involving intracellular accumulation of free radicals, which sustain the activation of the c-Jun N-terminal kinase (JNK) signaling transduction pathway. While heme catabolism by heme oxygenase-1 (HO-1) prevents programmed cell death, this cytoprotective effect requires the co-expression of ferritin H (heart/heavy) chain (FTH), which controls the pro-oxidant effect of labile Fe released from the protoporphyrin IX ring of heme. This antioxidant effect of FTH restrains JNK activation, whereas JNK activation inhibits FTH expression, a cross talk that controls metabolic adaptation to cellular Fe overload associated with systemic infections. Critical Issues and Future Directions: Identification and characterization of the mechanisms via which FTH provides metabolic adaptation to tissue Fe overload should provide valuable information to our current understanding of the pathogenesis of systemic infections as well as other immune-mediated inflammatory diseases. © Copyright 2014, Mary Ann Liebert, Inc. 2014.

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