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Drosophilasessile hemocyte clusters are true hematopoietic tissues that regulate larval blood cell differentiation
Get PDFVirtually all species of coelomate animals contain blood cells that display a division of labor necessary for homeostasis. This functional partition depends upon the balance between proliferation and differentiation mostly accomplished in the hematopoietic organs. In Drosophila melanogaster, the lymph gland produces plasmatocytes and crystal cells that are not released until pupariation. Yet, throughout larval development, both hemocyte types increase in numbers. Mature plasmatocytes can proliferate but it is not known if crystal cell numbers increase by self-renewal or by de novo differentiation. We show that new crystal cells in third instar larvae originate through a Notch-dependent process of plasmatocyte transdifferentiation. This process occurs in the sessile clusters and is contingent upon the integrity of these structures. The existence of this hematopoietic tissue, relying on structure-dependent signaling events to promote blood homeostasis, creates a new paradigm for addressing outstanding questions in Drosophila hematopoiesis and establishing further parallels with vertebrate systems.Fundação Calouste Gulbenkian/Instituto Gulbenkian de Ciência, FCT grant: (SFRH/BD/51175/2010)
Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis
Get PDFThe proneural transcription factor Ascl1 coordinates gene expression in both proliferating and differentiating progenitors along the neuronal lineage. Here, we used a cellular model of neurogenesis to investigate how Ascl1 interacts with the chromatin landscape to regulate gene expression when promoting neuronal differentiation. We find that Ascl1 binding occurs mostly at distal enhancers and is associated with activation of gene transcription. Surprisingly, the accessibility of Ascl1 to its binding sites in neural stem/progenitor cells remains largely unchanged throughout their differentiation, as Ascl1 targets regions of both readily accessible and closed chromatin in proliferating cells. Moreover, binding of Ascl1 often precedes an increase in chromatin accessibility and the appearance of new regions of open chromatin, associated with de novo gene expression during differentiation. Our results reveal a function of Ascl1 in promoting chromatin accessibility during neurogenesis, linking the chromatin landscape at Ascl1 target regions with the temporal progression of its transcriptional program.FCT doctoral fellowship, FCT investigator program, Marie Curie CIG: (303644), Welcome Trust grants: (WT095908, WT098051)
Genomics and the challenging translation into conservation practice
Get PDFThe global loss of biodiversity continues at an alarming rate. Genomic approaches have been suggested as a promising tool for conservation practice as scaling up to genome-wide data can improve traditional conservation genetic inferences and provide qualitatively novel insights. However, the generation of genomic data and subsequent analyses and interpretations remain challenging and largely confined to academic research in ecology and evolution. This generates a gap between basic research and applicable solutions for conservation managers faced with multifaceted problems. Before the real-world conservation potential of genomic research can be realized, we suggest that current infrastructures need to be modified, methods must mature, analytical pipelines need to be developed, and successful case studies must be disseminated to practitioners.ConGenOmics Initiative of the European Science Foundation (Refnr. 5005); Swedish Research Council (ID: 70720201); Uppsala University
Manipulation of the Quorum Sensing Signal AI-2 Affects the Antibiotic-Treated Gut Microbiota
Get PDFThe mammalian gut microbiota harbors a diverse ecosystem where hundreds of bacterial species interact with each other and their host. Given that bacteria use signals to communicate and regulate group behaviors (quorum sensing), we asked whether such communication between different commensal species can influence the interactions occurring in this environment. We engineered the enteric bacterium, Escherichia coli, to manipulate the levels of the interspecies quorum sensing signal, autoinducer-2 (AI-2), in the mouse intestine and investigated the effect upon antibiotic-induced gut microbiota dysbiosis. E. coli that increased intestinal AI-2 levels altered the composition of the antibiotic-treated gut microbiota, favoring the expansion of the Firmicutes phylum. This significantly increased the Firmicutes/Bacteroidetes ratio, to oppose the strong effect of the antibiotic, which had almost cleared the Firmicutes. This demonstrates that AI-2 levels influence the abundance of the major phyla of the gut microbiota, the balance of which is known to influence human health.Howard Hughes Medical Institute grants: (International Early Career Scientist, HHMI 55007436); Fundação para a Ciência e Tecnologia grants: (PTDC/BIA-EVF/118075/2010, RECI/IMI-IMU/0038/2012); Ministerio de Ciencia e Innovacion grants: (MICINN, SAF2011-29458)
Quantitative trait locus analysis of parasite density reveals that HbS gene carriage protects severe malaria patients against Plasmodium falciparum hyperparasitaemia
Get PDFThis deposit is composed by the main article, and it hasn't any supplementary materials associated.Haemoglobin S (HbS) is the gene known to confer the strongest advantage against malaria morbidity and mortality. Multiple HbS effects have been described resulting in protection against parasitaemia and reduction of severe malaria risk. This study aimed to explore HbS protection against severe malaria and Plasmodium falciparum parasitaemia in Angolan children exhibiting different severe malaria syndromes.Instituto Gulbenkian de Ciência
Control of complex networks requires both structure and dynamics
Get PDFThe study of network structure has uncovered signatures of the organization
of complex systems. However, there is also a need to understand how to control
them; for example, identifying strategies to revert a diseased cell to a
healthy state, or a mature cell to a pluripotent state. Two recent
methodologies suggest that the controllability of complex systems can be
predicted solely from the graph of interactions between variables, without
considering their dynamics: structural controllability and minimum dominating
sets. We demonstrate that such structure-only methods fail to characterize
controllability when dynamics are introduced. We study Boolean network
ensembles of network motifs as well as three models of biochemical regulation:
the segment polarity network in Drosophila melanogaster, the cell cycle of
budding yeast Saccharomyces cerevisiae, and the floral organ arrangement in
Arabidopsis thaliana. We demonstrate that structure-only methods both
undershoot and overshoot the number and which sets of critical variables best
control the dynamics of these models, highlighting the importance of the actual
system dynamics in determining control. Our analysis further shows that the
logic of automata transition functions, namely how canalizing they are, plays
an important role in the extent to which structure predicts dynamics.National Institutes of Health; National Library of Medicine Program grant: (01LM011945-01 “BLR: Evidence-based Drug-Interaction Discovery: In-Vivo, In-Vitro and Clinical”); NSF IGERT fellowship; FCT grant: (The Dynamics of Brain-Body-Environment Systems in Behavior and Cognition); Fundação Luso-Americana para o Desenvolvimento (Portugal) and National Science Foundation (USA) grant from the joint program: (“Network Mining For Gene Regulation And Biochemical Signaling.”)
Dissection of miRNA Pathways Using Arabidopsis Mesophyll Protoplasts
Get PDFMicroRNAs (miRNAs) control gene expression mostly post-transcriptionally by guiding transcript cleavage and/or translational repression of complementary mRNA targets, thereby regulating developmental processes and stress responses. Despite the remarkable expansion of the field, the mechanisms underlying miRNA activity are not fully understood. In this article, we describe a transient expression system in Arabidopsis mesophyll protoplasts, which is highly amenable for the dissection of miRNA pathways. We show that by transiently overexpressing primary miRNAs and target mimics, we can manipulate miRNA levels and consequently impact on their targets. Furthermore, we developed a set of luciferase-based sensors for quantifying miRNA activity that respond specifically to both endogenous and overexpressed miRNAs and target mimics. We demonstrate that these miRNA sensors can be used to test the impact of putative components of the miRNA pathway on miRNA activity, as well as the impact of specific mutations, by either overexpression or the use of protoplasts from the corresponding mutants. We further show that our miRNA sensors can be used for investigating the effect of chemicals on miRNA activity. Our cell-based transient expression system is fast and easy to set up, and generates quantitative results, being a powerful tool for assaying miRNA activity in vivo.Fundação para a Ciência e Tecnologia fellowships: (SFRH/BD/33563/2008, SFRH/BPD/47280/2008, SFRH/BPD/79255/2011) and grant: (PTCD/BIA-BCM/107924/2008); EMBO fellowship & EMBO Installation program; Deutsche Forschungsgemeinschaft grant: (SPP1530); Max Planck Society grant
Multifaceted Role of Heme during Severe Plasmodium falciparum Infections in India
Get PDFSeveral immunomodulatory factors are involved in malaria pathogenesis. Among them, heme has been shown to play a role in the pathophysiology of severe malaria in rodents, but its role in human severe malaria remains unclear. Circulating levels of total heme and its main scavenger, hemopexin, along with cytokine/chemokine levels and biological parameters, including hemoglobin and creatinine levels, as well as transaminase activities, were measured in the plasma of 237 Plasmodium falciparum-infected patients living in the state of Odisha, India, where malaria is endemic. All patients were categorized into well-defined groups of mild malaria, cerebral malaria (CM), or severe noncerebral malaria, which included acute renal failure (ARF) and hepatopathy. Our results show a significant increase in total plasma heme levels with malaria severity, especially for CM and malarial ARF. Spearman rank correlation and canonical correlation analyses have shown a correlation between total heme, hemopexin, interleukin-10, tumor necrosis factor alpha, gamma interferon-induced protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels. In addition, canonical correlations revealed that heme, along with IP-10, was associated with the CM pathophysiology, whereas both IP-10 and MCP-1 together with heme discriminated ARF. Altogether, our data indicate that heme, in association with cytokines and chemokines, is involved in the pathophysiology of both CM and ARF but through different mechanisms.Indo-French Centre for the Promotion of Advanced Research, Associated International Laboratory Systems (LIA; CNRS), Immunology and Genetics of Infectious Diseases (SIGID), Department of Biotechnology from the Ministry of Science and Technology of India (DBT), Tata Institute of Fundamental Research (TIFR) (intramural funds), Université Lille (doctoral contract), IFCPAR (Raman-Charpak award), College Doctoral Lille Nord de France (AAP n10 award), Fondation des Treille, Conseil Régional du Nord-Pas de Calais
Linking appraisal to behavioral flexibility in animals: implications for stress research
Get PDFIn fluctuating environments, organisms require mechanisms enabling the rapid expression of context-dependent behaviors. Here, we approach behavioral flexibility from a perspective rooted in appraisal theory, aiming to provide a better understanding on how animals adjust their internal state to environmental context. Appraisal has been defined as a multi-component and interactive process between the individual and the environment, in which the individual must evaluate the significance of a stimulus to generate an adaptive response. Within this framework, we review and reframe the existing evidence for the appraisal components in animal literature, in an attempt to reveal the common ground of appraisal mechanisms between species. Furthermore, cognitive biases may occur in the appraisal of ambiguous stimuli. These biases may be interpreted either as states open to environmental modulation or as long-lasting phenotypic traits. Finally, we discuss the implications of cognitive bias for stress research.FCT Ph.D. fellowships: (SFRH/BD/79087/2011, SFRH/BD/68528/2010), FCT strategic grant: (PEst-OE/MAR/UI0331/2011)
Extraction of Pharmacokinetic Evidence of Drug-drug Interactions from the Literature
Get PDFDrug-drug interaction (DDI) is a major cause of morbidity and mortality and a
subject of intense scientific interest. Biomedical literature mining can aid
DDI research by extracting evidence for large numbers of potential interactions
from published literature and clinical databases. Though DDI is investigated in
domains ranging in scale from intracellular biochemistry to human populations,
literature mining has not been used to extract specific types of experimental
evidence, which are reported differently for distinct experimental goals. We
focus on pharmacokinetic evidence for DDI, essential for identifying causal
mechanisms of putative interactions and as input for further pharmacological
and pharmaco-epidemiology investigations. We used manually curated corpora of
PubMed abstracts and annotated sentences to evaluate the efficacy of literature
mining on two tasks: first, identifying PubMed abstracts containing
pharmacokinetic evidence of DDIs; second, extracting sentences containing such
evidence from abstracts. We implemented a text mining pipeline and evaluated it
using several linear classifiers and a variety of feature transforms. The most
important textual features in the abstract and sentence classification tasks
were analyzed. We also investigated the performance benefits of using features
derived from PubMed metadata fields, various publicly available named entity
recognizers, and pharmacokinetic dictionaries. Several classifiers performed
very well in distinguishing relevant and irrelevant abstracts (reaching
F1~=0.93, MCC~=0.74, iAUC~=0.99) and sentences (F1~=0.76, MCC~=0.65,
iAUC~=0.83). We found that word bigram features were important for achieving
optimal classifier performance and that features derived from Medical Subject
Headings (MeSH) terms significantly improved abstract classification. ...National Institutes of Health, National Library of Medicine Program grant: (01LM011945-01 "BLR:
Evidence-based Drug-Interaction Discovery: In-Vivo, In-Vitro and Clinical), Indiana University Collaborative Research Program 2013 grant, Fundação Luso-Americana para o Desenvolvimento (Portugal) and National Science Foundation (USA) 2012-2014 grant