657 research outputs found
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Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cells
Full text linkThis deposit is composed by the main article and supplementary files of the publication.Studies of the role of actin in tumour progression have highlighted its key contribution in cell softening associated with cell invasion. Here, using a human breast cell line with conditional Src induction, we demonstrate that cells undergo a stiffening state prior to acquiring malignant features. This state is characterized by the transient accumulation of stress fibres and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibres leading to transient cell stiffening, ERK-dependent cell proliferation, as well as enhancement of Src activation and progression towards a fully transformed state. Accordingly, EVL accumulates predominantly in premalignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. While cell softening allows for cancer cell invasion, our work reveals that stress fibre-mediated cell stiffening could drive tumour growth during premalignant stages. A careful consideration of the mechanical properties of tumour cells could therefore offer new avenues of exploration when designing cancer-targeting therapies.Bloomington Drosophila Stock Centre; Vienna Drosophila Research Center (VDRC); Developmental Studies Hybridoma Bank (DSHB); Fundação para a Ciência e Tecnologia (FCT) grant: (IF/01031/2012); Laço Grant in breast cancer 2015; Alexander von Humboldt Foundation grant: (Alexander von Humboldt Professorship); Liga Portuguesa contra o Cancro/Pfizer.info:eu-repo/semantics/publishedVersio
Disease tolerance and immunity in host protection against infection
Full text linkThe deposited article is a pre-print version.This publication hasn't any creative commons license associated.This deposit is composed by the main article which contains attached the supplementary materials.The immune system probably evolved to limit the negative effects exerted by pathogens on host homeostasis. This defence strategy relies on the concerted action of innate and adaptive components of the immune system, which sense and target pathogens for containment, destruction or expulsion. Resistance to infection refers to these immune functions, which reduce the pathogen load of an infected host as the means to preserve homeostasis. Immune-driven resistance to infection is coupled to an additional, and arguably as important, defence strategy that limits the extent of dysfunction imposed on host parenchymal tissues during infection, without exerting a direct negative effect on pathogens. This defence strategy, known as disease tolerance, relies on tissue damage control mechanisms that prevent the deleterious effects of pathogens and that uncouples immune-driven resistance mechanisms from immunopathology and disease. In this Review, we provide a unifying view of resistance and disease tolerance in the framework of immunity to infection.Instituto Gulbenkian de Ciência; Fundação Calouste Gulbenkian; Fundação para a Ciência e Tecnologia grants: (PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, PTDC/BEX-GMG/3128/2014); ERC grants: (ERC-2011-AdG 294709-DAMAGECONTROL, ERC-2014-CoG 647888-iPROTECTION).info:eu-repo/semantics/publishedVersio
Maintenance of Microbial Cooperation Mediated by Public Goods in Single- and Multiple-Trait Scenarios
Full text linkMicrobes often form densely populated communities, which favor competitive and cooperative interactions. Cooperation among bacteria often occurs through the production of metabolically costly molecules produced by certain individuals that become available to other neighboring individuals; such molecules are called public goods. This type of cooperation is susceptible to exploitation, since nonproducers of a public good can benefit from it while saving the cost of its production (cheating), gaining a fitness advantage over producers (cooperators). Thus, in mixed cultures, cheaters can increase in frequency in the population, relative to cooperators. Sometimes, and as predicted by simple game-theoretic arguments, such increases in the frequency of cheaters cause loss of the cooperative traits by exhaustion of the public goods, eventually leading to a collapse of the entire population. In other cases, however, both cooperators and cheaters remain in coexistence. This raises the question of how cooperation is maintained in microbial populations. Several strategies to prevent cheating have been studied in the context of a single trait and a unique environmental constraint. In this review, we describe current knowledge on the evolutionary stability of microbial cooperation and discuss recent discoveries describing the mechanisms operating in multiple-trait and multiple-constraint settings. We conclude with a consideration of the consequences of these complex interactions, and we briefly discuss the potential role of social interactions involving multiple traits and multiple environmental constraints in the evolution of specialization and division of labor in microbes.info:eu-repo/semantics/publishedVersio
Quantitative Microscopy Reveals Centromeric Chromatin Stability, Size, and Cell Cycle Mechanisms to Maintain Centromere Homeostasis
Full text linkThe deposited item is a book chapter and is part of the series "Centromeres and Kinetochores" published by the publisher Springer Verlag. The deposited book chapter is a post-print version and has been submitted to peer reviewing. There is no public supplementary material available for this publication. This publication hasn't any creative commons license associated.Centromeres are chromatin domains specified by nucleosomes containing the histone H3 variant, CENP-A. This unique centromeric structure is at the heart of a strong self-templating epigenetic mechanism that renders centromeres heritable. We review how specific quantitative microscopy approaches have contributed to the determination of the copy number, architecture, size, and dynamics of centromeric chromatin and its associated centromere complex and kinetochore. These efforts revealed that the key to long-term centromere maintenance is the slow turnover of CENP-A nucleosomes, a critical size of the chromatin domain and its cell cycle-coupled replication. These features come together to maintain homeostasis of a chromatin locus that directs its own epigenetic inheritance and facilitates the assembly of the mitotic kinetochore.There are no funders and sponsors indicated explicitly in the document.info:eu-repo/semantics/publishedVersio
Evolution of commensal bacteria in the intestinal tract of mice
Full text linkThe deposited article is a post-print version and has been submitted to peer review.This deposit is composed by the main article, and it hasn't any supplementary materials associated.This publication hasn't any creative commons license associated.Hundreds of different bacterial species inhabit our intestines and contribute to our health status, with significant loss of species diversity typically observed in disease conditions. Within each microbial species a great deal of diversity is hidden and such intra-specific variation is also key to the proper homeostasis between the host and its microbial inhabitants. Indeed, it is at this level that new mechanisms of antibiotic resistance emerge and pathogenic characteristics evolve. Yet, our knowledge on intra-species variation in the gut is still limited and an understanding of the evolutionary mechanisms acting on it is extremely reduced. Here we review recent work that has begun to reveal that adaptation of commensal bacteria to the mammalian intestine may be fast and highly repeatable, and that the time scales of evolutionary and ecological change can be very similar in these ecosystems.Deutsche Forschungsgemeinschaft Grant SFB 680 and the Portuguese Science and Technology Foundation FCT (SFRH/BPD/111725/2015 and UID/BIM/04501/2013 support to AS, SFRH/BPD/110750/2015 support to NF).info:eu-repo/semantics/publishedVersio
Open Science, Open Data, Open Source
No full textMaking research findings available free of charge for all readers has been a major challenge identified by the European Commission. Several initiatives have been made to facilitate scientific data to the community. But has science progresses, the volume of data and platforms where information can be found also increases. The task of searching for data can be overwhelming. Pedro Fernandes, IGC member and Coordinator of the GTPB - the Gulbenkian Training Programme in Bioinformatics, and Rutger Vos, from Naturalis Biodiversity Center, set to tackle this problem by creating useful information to help producing, storing, managing and finding scientific information in open resources. Their efforts resulted in 'Open Science, Open Data, Open Source - 21st century research skills for the life sciences', an e-book that can be freely used by the scientific community, policy-makers, funding agencies, among others.info:eu-repo/semantics/publishedVersio
Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publication.Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents. Here, we report a role for iRhom2 in TACE stimulation on the cell surface. TACE shedding stimuli trigger MAP kinase-dependent phosphorylation of iRhom2 N-terminal cytoplasmic tail. This recruits 14-3-3 proteins, enforcing the dissociation of TACE from complexes with iRhom2, promoting the cleavage of TACE substrates. Our data reveal that iRhom2 controls multiple aspects of TACE biology, including stimulated shedding on the cell surface.Fundação Calouste Gulbenkian; Worldwide Cancer Research grant: (14-1289); Marie Curie Career Integration Grant: (project no. 618769); Fundação para a Ciência e Tecnologia grants:( SFRH/BCC/52507/2014, PTDC/BEX-BCM/3015/2014, LISBOA-01-0145-FEDER-007660, FCT-ANR/NEU-NMC/0006/2013, PTDC/NEU-NMC/2459/2014, IF/00697/2014, SFRH/BPD/117216/2016); European Crohn’s and Colitis Organization, and COST grant: (BM1406).info:eu-repo/semantics/publishedVersio
Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publication.Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis.Fundação para a Ciência e a Tecnologia grants: (HMSP-ICT/0024/2010, UID/Multi/04462/2013, SFRH/BD/62197/2009, SFRH/BD/90258/2012, SFRH /BD/51877/2012, SFRH/BD/52293/2013, PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010 ); European Union FEDER support: (COMPETE, QREN, PT2020 Partnership Agreement), ERC grant: (ERC-2011-AdG 294709-DAMAGECONTROL).info:eu-repo/semantics/publishedVersio
Mechanisms of social buffering of fear in zebrafish
Full text linkThe supplementary materials such the videos, are not present in the deposit due to incompatibilty of the extension of the files with the repository.Some humans thrive whereas others resign when exposed to threatening situations throughout life. Social support has been identified as an important modulator of these discrepancies in human behaviour, and other social animals also exhibit phenomena in which individuals recover better from aversive events when conspecifics are present - aka social buffering. Here we studied social buffering in zebrafish, by exposing focal fish to an aversive stimulus (alarm substance - AS) either in the absence or presence of conspecific cues. When exposed to AS in the presence of both olfactory (shoal water) and visual (sight of shoal) conspecific cues, focal fish exhibited a lower fear response than when tested alone, demonstrating social buffering in zebrafish. When separately testing each cue's effectiveness, we verified that the visual cue was more effective than the olfactory in reducing freezing in a persistent threat scenario. Finally, we verified that social buffering was independent of shoal size and coincided with a distinct pattern of co-activation of brain regions known to be involved in mammalian social buffering. Thus, this study suggests a shared evolutionary origin for social buffering in vertebrates, bringing new evidence on the behavioural, sensory and neural mechanisms underlying this phenomenon.info:eu-repo/semantics/publishedVersio
A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publication.Connection of the heart to the systemic circulation is a critical developmental event that requires selective preservation of embryonic vessels (aortic arches). However, why some aortic arches regress while others are incorporated into the mature aortic tree remains unclear. By microdissection and deep sequencing in mouse, we find that neural crest (NC) only differentiates into vascular smooth muscle cells (SMCs) around those aortic arches destined for survival and reorganization, and identify the transcription factor Gata6 as a crucial regulator of this process. Gata6 is expressed in SMCs and its target genes activation control SMC differentiation. Furthermore, Gata6 is sufficient to promote SMCs differentiation in vivo, and drive preservation of aortic arches that ought to regress. These findings identify Gata6-directed differentiation of NC to SMCs as an essential mechanism that specifies the aortic tree, and provide a new framework for how mutations in GATA6 lead to congenital heart disorders in humans.Medical Research Council grant: (MR/L009986/1); Biotechnology and Biological Sciences Research Council grant: (BB/N00907X/1); National Institute of Neurological Disorders and Stroke grant: (NS038183).info:eu-repo/semantics/publishedVersio