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Comment on Rohrscheib et al. 2016 "Intensity of mutualism breakdown is determined by temperature not amplification of Wolbachia genes"
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publication.Rohrscheib et al. (PLOS Pathogens, 2016) discuss the interaction between the pathogenicity of the wMel variant wMelPop, temperature and Octomom copy number. The effect of temperature on wMelPop pathogenicity was already reported in the original work on wMelPop. The absence of pathogenicity at low temperatures was also shown before. We have recently demonstrated, in Chrostek and Teixeira 2015, that Octomom copy number determines wMelPop pathogenicity.Fundação para a Ciência e Tecnologia grants: (PTDC/BEXGMG/3128/2014); EMBO Long Term Fellowship: (EMBO ALTF 1497-2015); Marie Curie Actions; European Commission grants: (LTFCOFUND2013, GA-2013-609409).info:eu-repo/semantics/publishedVersio
Effect of celastrol on bone structure and mechanics in arthritic rats
Full text linkRheumatoid arthritis (RA) is characterised by chronic inflammation leading to articular bone and cartilage damage. Despite recent progress in RA management, adverse effects, lack of efficacy and economic barriers to treatment access still limit therapeutic success. Therefore, safer and less expensive treatments that control inflammation and bone resorption are needed. We have previously shown that celastrol is a candidate for RA treatment. We have observed that it inhibits both interleukin (IL)-1β and tumor necrosis factor (TNF) in vitro, and that it has anti-inflammatory properties and ability to decrease synovial CD68+ macrophages in vivo. Herein our goal was to evaluate the effect of celastrol in local and systemic bone loss.There are no funders and sponsors indicated explicitly in the document. There is no public supplementary material available.info:eu-repo/semantics/publishedVersio
iRAGu: A Novel Inducible and Reversible Mouse Model for Ubiquitous Recombinase Activity
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publication.Developing lymphocytes express the recombination activating genes (RAGs) 1 and 2 products that form a site specific recombinase complex (RAG), introducing double strand DNA breaks (DSBs) at recombination signal sequences (RSSs) flanking the V, D, and J gene segments in the antigen receptor loci. The subsequent steps in the reaction consist in the ligation of DSBs by ubiquitous enzymes of the non-homologous end joining DNA repair pathway. This mutagenesis process is responsible for the generation of the very large clonal diversity of T and B lymphocytes, itself allowing the recognition of a virtually open-ended antigenic universe. Sequences resembling RSS are found at high frequency all over the genome, and involved in RAG mediated illegitimate recombination and translocations. Hence, natural and induced ectopic activity of RAG is a threat to the genome only recently underscored. Here, we report and characterize a novel mouse transgenic system for which ubiquitous expression of the recombinase is inducible. In this system, the RAG1 protein is constitutively expressed and functional, while the RAG2 protein, coupled to the estrogen receptor, becomes functionally active upon 4-hydroxytamoxifen (TAM) administration. We describe two transgenic lines. The first one, when introgressed into an endogenous Rag2−/− genetic background is faithfully recapitulating lymphocyte development, repertoire dynamics and cryptic rearrangements, in a TAM-dependent manner. In this model, deprivation of TAM is followed by lymphocyte development arrest, evidencing the reversibility of the system. The second transgenic line is leaky, as the transgenes promote lymphocyte differentiation in absence of TAM treatment. Upon TAM-induction defects in lymphocytes composition and global health reveals the deleterious effect of uncontrolled RAG activity. Overall, this novel transgenic model provides a tool where RAG activity can be specifically manipulated to assess the dynamics of lymphocyte differentiation and the challenges imposed by the recombinase on the vertebrate genome.Fundação para a Ciência e a Tecnologia grants: (PTDC/BIA-GEN/116830/2010, fellowships); Portuguese League Against Cancer; Terry Fox Foundation.info:eu-repo/semantics/publishedVersio
Signaling with Ions: The Keystone for Apical Cell Growth and Morphogenesis in Pollen Tubes
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Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior
Full text linkoai:arca.igc.gulbenkian.pt:10400.7/742No supplementary materials.Proper response to stress and social stimuli depends on orchestrated development of hypothalamic neuronal circuits. Here we address the effects of the developmental transcription factor orthopedia (Otp) on hypothalamic development and function. We show that developmental mutations in the zebrafish paralogous gene otpa but not otpb affect both stress response and social preference. These behavioral phenotypes were associated with developmental alterations in oxytocinergic (OXT) neurons. Thus, otpa and otpb differentially regulate neuropeptide switching in a newly identified subset of OXT neurons that co-express the corticotropin-releasing hormone (CRH). Single-cell analysis revealed that these neurons project mostly to the hindbrain and spinal cord. Ablation of this neuronal subset specifically reduced adult social preference without affecting stress behavior, thereby uncoupling the contribution of a specific OXT cluster to social behavior from the general otpa(-/-) deficits. Our findings reveal a new role for Otp in controlling developmental neuropeptide balance in a discrete OXT circuit whose disrupted development affects social behavior.Israel Science Foundation grants: (1511/16, 957/12, 2137/16).info:eu-repo/semantics/publishedVersio
Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases
Full text linkThis deposit is composed by the main article, and it hasn't any supplementary materials associated.The identification of new bioactive compounds derived from medicinal plants with significant therapeutic properties has attracted considerable interest in recent years. Such is the case of the Tripterygium wilfordii (TW), an herb used in Chinese medicine. Clinical trials performed so far using its root extracts have shown impressive therapeutic properties but also revealed substantial gastrointestinal side effects. The most promising bioactive compound obtained from TW is celastrol. During the last decade, an increasing number of studies were published highlighting the medicinal usefulness of celastrol in diverse clinical areas. Here we systematically review the mechanism of action and the therapeutic properties of celastrol in inflammatory diseases, namely, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, osteoarthritis and allergy, as well as in cancer, neurodegenerative disorders and other diseases, such as diabetes, obesity, atherosclerosis, and hearing loss. We will also focus in the toxicological profile and limitations of celastrol formulation, namely, solubility, bioavailability, and dosage issues that still limit its further clinical application and usefulness.Fundação para a Ciência e a Tecnologia grants: (SFRH/BPD/92860/2013, PTDC/BIM-MEC/4665/2014); European Research Council grants: (ERC-2014-CoG 647888-iPROTECTION).info:eu-repo/semantics/publishedVersio
Commensal-to-pathogen transition: One-single transposon insertion results in two pathoadaptive traits in Escherichia coli -macrophage interaction
Full text linkThere are no funders and sponsors indicated explicitly in the document. This deposit is composed by the main article plus the supplementary materials of the publication.Escherichia coli is both a harmless commensal in the intestines of many mammals, as well as a dangerous pathogen. The evolutionary paths taken by strains of this species in the commensal-to-pathogen transition are complex and can involve changes both in the core genome, as well in the pan-genome. One way to understand the likely paths that a commensal strain of E. coli takes when evolving pathogenicity is through experimentally evolving the strain under the selective pressures that it will have to withstand as a pathogen. Here, we report that a commensal strain, under continuous pressure from macrophages, recurrently acquired a transposable element insertion, which resulted in two key phenotypic changes: increased intracellular survival, through the delay of phagosome maturation and increased ability to escape macrophages. We further show that the acquisition of the pathoadaptive traits was accompanied by small but significant changes in the transcriptome of macrophages upon infection. These results show that under constant pressures from a key component of the host immune system, namely macrophage phagocytosis, commensal E. coli rapidly acquires pathoadaptive mutations that cause transcriptome changes associated to the host-microbe duet.There are no funders and sponsors indicated explicitly in the document.info:eu-repo/semantics/publishedVersio
Glutamate receptor-like channels are essential for chemotaxis and reproduction in mosses
Full text linkThe deposited article version is a "Accelerated Article Preview" provided by Nature Publishing Group, and it contains attached the supplementary materials within the pdf.». This publication hasn't any creative commons license associated.Glutamate receptors are well characterized channels that mediate cell-to-cell communication during neurotransmission in animals. Nevertheless, information regarding their functional role in organisms without nervous systems is still limited. In plants, Glutamate Receptor-like (GLR) genes have been implicated in defence against pathogens, reproduction, control of stomata aperture and light signal transduction(1-5). However, the numerous GLR genes present in angiosperm genomes (20 to 70)(6) has prevented the observation of strong phenotypes in loss-of-function mutants. Here, we show that in the moss Physcomitrella patens, a basal land plant, mutation of GLR genes cause sperm failure in targeting the female reproductive organs. In addition, we show that GLR genes encode non-selective Ca(2+) permeable channels that can regulate cytoplasmic Ca(2+) and are needed to induce the expression of a BELL1-like transcription factor essential for zygote development. Our work reveals novel functions for GLRs in sperm chemotaxis and transcriptional regulation. Sperm chemotaxis is essential for fertilization in both animals and early land plants like bryophytes and pteridophytes. Therefore, our results are suggestive that ionotropic glutamate receptors may have been conserved throughout plant evolution to mediate cell-to-cell communication during sexual reproduction.Phillips University; Oxford University; University of Marburg; University of Muenster; MarieCurie ITN-Plant
Origins grant: (FP7-PEOPLE-ITN-2008); FCT grants: (BEX-BCM/0376/2012; PTDC/BIA-PLA/4018/2012); NSF-US grant: (MCB 1616437/2016).info:eu-repo/semantics/acceptedVersio
Diverse Cis-Regulatory Mechanisms Contribute to Expression Evolution of Tandem Gene Duplicates
Full text linkThe deposited article is a post-print version and has peer review. The deposited article version contains attached the supplementary materials within the pdf.Pairs of duplicated genes generally display a combination of conserved expression patterns inherited from their unduplicated ancestor and newly acquired domains. However, how the cis-regulatory architecture of duplicated loci evolves to produce these expression patterns is poorly understood. We have directly examined the gene-regulatory evolution of two tandem duplicates, the Drosophila Ly6 genes CG9336 and CG9338, which arose at the base of the drosophilids between 40 and 60 million years ago. Comparing the expression patterns of the two paralogs in four Drosophila species with that of the unduplicated ortholog in the tephritid Ceratitis capitata, we show that they diverged from each other as well as from the unduplicated ortholog. Moreover, the expression divergence appears to have occurred close to the duplication event and also more recently in a lineage-specific manner. The comparison of the tissue-specific cis-regulatory modules (CRMs) controlling the paralog expression in the four Drosophila species indicates that diverse cis-regulatory mechanisms, including the novel tissue-specific enhancers, differential inactivation, and enhancer sharing, contributed to the expression evolution. Our analysis also reveals a surprisingly variable cis-regulatory architecture, in which the CRMs driving conserved expression domains change in number, location, and specificity. Altogether, this study provides a detailed historical account that uncovers a highly dynamic picture of how the paralog expression patterns and their underlying cis-regulatory landscape evolve. We argue that our findings will encourage studying cis-regulatory evolution at the whole-locus level in order to understand how interactions between enhancers and other regulatory levels shape the evolution of gene expression.Fundação Calouste Gulbenkian/Instituto Gulbenkian de Ciência; Toulouse RIO Imaging platform; Bloomington Drosophila Stock Center (Indiana, USA); Developmental Studies Hybridoma Bank (Iowa, USA); Drosophila Genomics Resource Center (Indiana, USA); NIH grant: (2P0OD010949); Agence Nationale de la Recherche grant: (ANR-13-ISV7-0001-01); Fundação para a Ciência e a Tecnologia grants: (SFRH/BPD/75139/2010, FCT-ANR/BIA-ANM/0003/2013, FCT-EXPL/BEX-GMG/2197/2013).info:eu-repo/semantics/acceptedVersio
Fatal CTLA-4 heterozygosity with autoimmunity and recurrent infections: a de novo mutation
Full text linkFurther funders are not indicated in the document. There is no public supplementary material available for this publication. This deposit is composed by the main article, and it hasn't any supplementary materials associated.Primary immunodeficiency disorders are rarely diagnosed in adults but must be considered in the differential diagnosis of combined recurrent infections and autoimmune disease. We describe a patient with CTLA-4 haploinsufficiency and an abnormal regulatory T-cell phenotype. Unusually, infections were more severe than autoimmunity, illustrating therapeutic challenges in disease course.This work supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, USA.info:eu-repo/semantics/publishedVersio