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.
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.
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.
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.
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.