Biomedical Science Research Center Al Fleming

Vári, Greece

Biomedical Science Research Center Al Fleming

Vári, Greece

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Brelsfoard C.,St. Catharine College | Tsiamis G.,University of Patras | Falchetto M.,University of Pavia | Gomulski L.M.,University of Pavia | And 9 more authors.
PLoS Neglected Tropical Diseases | Year: 2014

Tsetse flies (Glossina spp.) are the cyclical vectors of Trypanosoma spp., which are unicellular parasites responsible for multiple diseases, including nagana in livestock and sleeping sickness in humans in Africa. Glossina species, including Glossina morsitans morsitans (Gmm), for which the Whole Genome Sequence (WGS) is now available, have established symbiotic associations with three endosymbionts: Wigglesworthia glossinidia, Sodalis glossinidius and Wolbachia pipientis (Wolbachia). The presence of Wolbachia in both natural and laboratory populations of Glossina species, including the presence of horizontal gene transfer (HGT) events in a laboratory colony of Gmm, has already been shown. We herein report on the draft genome sequence of the cytoplasmic Wolbachia endosymbiont (cytWol) associated with Gmm. By in silico and molecular and cytogenetic analysis, we discovered and validated the presence of multiple insertions of Wolbachia (chrWol) in the host Gmm genome. We identified at least two large insertions of chrWol, 527,507 and 484,123 bp in size, from Gmm WGS data. Southern hybridizations confirmed the presence of Wolbachia insertions in Gmm genome, and FISH revealed multiple insertions located on the two sex chromosomes (X and Y), as well as on the supernumerary B-chromosomes. We compare the chrWol insertions to the cytWol draft genome in an attempt to clarify the evolutionary history of the HGT events. We discuss our findings in light of the evolution of Wolbachia infections in the tsetse fly and their potential impacts on the control of tsetse populations and trypanosomiasis. © 2014 Brelsfoard et al.


Abd-Alla A.M.M.,International Atomic Energy Agency | Bergoin M.,Montpellier University | Parker A.G.,International Atomic Energy Agency | Vlak J.M.,Wageningen University | And 4 more authors.
Journal of Invertebrate Pathology | Year: 2013

Tsetse flies (Diptera: Glossinidae) are the cyclical vectors of the trypanosomes, which cause human African trypanosomosis (HAT) or sleeping sickness in humans and African animal trypanosomosis (AAT) or nagana in animals. Due to the lack of effective vaccines and inexpensive drugs for HAT, and the development of resistance of the trypanosomes against the available trypanocidal drugs, vector control remains the most efficient strategy for sustainable management of these diseases. Among the control methods used for tsetse flies, Sterile Insect Technique (SIT), in the frame of area-wide integrated pest management (AW-IPM), represents an effective tactic to suppress and/or eradicate tsetse flies. One constraint in implementing SIT is the mass production of target species. Tsetse flies harbor obligate bacterial symbionts and salivary gland hypertrophy virus which modulate the fecundity of the infected flies. In support of the future expansion of the SIT for tsetse fly control, the Joint FAO/IAEA Programme of Nuclear Techniques in Food and Agriculture implemented a six year Coordinated Research Project (CRP) entitled " Improving SIT for Tsetse Flies through Research on their Symbionts and Pathogens" . The consortium focused on the prevalence and the interaction between the bacterial symbionts and the virus, the development of strategies to manage virus infections in tsetse colonies, the use of entomopathogenic fungi to control tsetse flies in combination with SIT, and the development of symbiont-based strategies to control tsetse flies and trypanosomosis. The results of the CRP and the solutions envisaged to alleviate the constraints of the mass rearing of tsetse flies for SIT are presented in this special issue. © 2013 International Atomic Energy Agency.


Viazis N.,Evangelismos Hospital | Keyoglou A.,Evangelismos Hospital | Kanellopoulos A.K.,Biomedical Science Research Center Al Fleming | Karamanolis G.,National and Kapodistrian University of Athens | And 4 more authors.
American Journal of Gastroenterology | Year: 2012

Objectives:Ambulatory 24-h pHimpedance monitoring can be used to assess the relationship of persistent symptoms and reflux episodes, despite proton pump inhibitor (PPI) therapy. Using this technique, we aimed to identify patients with hypersensitive esophagus and evaluate the effect of selective serotonin reuptake inhibitors (SSRIs) on their symptoms. Methods: Patients with normal endoscopy and typical reflux symptoms (heartburn, chest pain, and regurgitation), despite PPI therapy twice daily, underwent 24-h pHimpedance monitoring. Distal esophageal acid exposure (% time pH 4) was measured and reflux episodes were classified into acid or non-acid. A positive symptom index (SI) was declared if at least half of the symptom events were preceded by reflux episodes. Patients with a normal distal esophageal acid exposure time, but with a positive SI were classified as having hypersensitive esophagus and were randomized to receive citalopram 20 mg or placebo once daily for 6 months. Results: A total of 252 patients (150 females (59.5%); mean age 55 (range 1875) years) underwent 24-h pHimpedance monitoring. Two hundred and nineteen patients (86.9%) recorded symptoms during the study day, while 105 (47.9%) of those had a positive SI (22 (20.95%) with acid, 5 (4.76%) with both acid and non-acid, and 78 (74.29%) with non-acid reflux). Among those 105 patients, 75 (71.4%) had normal distal esophageal acid exposure time and were randomized to receive citalopram 20 mg (group A, n39) or placebo (group B, n36). At the end of the follow-up period, 15 out of the 39 patients of group A (38.5%) and 24 out of the 36 patients of group B (66.7%) continue to report reflux symptoms (P0.021). Conclusions: Treatment with SSRIs is effective in a select group of patients with hypersensitive esophagus. © 2012 by the American College of Gastroenterology.


Ellegaard K.M.,Uppsala University | Klasson L.,Uppsala University | Naslund K.,Uppsala University | Bourtzis K.,University of Western Greece | And 3 more authors.
PLoS Genetics | Year: 2013

The importance of host-specialization to speciation processes in obligate host-associated bacteria is well known, as is also the ability of recombination to generate cohesion in bacterial populations. However, whether divergent strains of highly recombining intracellular bacteria, such as Wolbachia, can maintain their genetic distinctness when infecting the same host is not known. We first developed a protocol for the genome sequencing of uncultivable endosymbionts. Using this method, we have sequenced the complete genomes of the Wolbachia strains wHa and wNo, which occur as natural double infections in Drosophila simulans populations on the Seychelles and in New Caledonia. Taxonomically, wHa belong to supergroup A and wNo to supergroup B. A comparative genomics study including additional strains supported the supergroup classification scheme and revealed 24 and 33 group-specific genes, putatively involved in host-adaptation processes. Recombination frequencies were high for strains of the same supergroup despite different host-preference patterns, leading to genomic cohesion. The inferred recombination fragments for strains of different supergroups were of short sizes, and the genomes of the co-infecting Wolbachia strains wHa and wNo were not more similar to each other and did not share more genes than other A- and B-group strains that infect different hosts. We conclude that Wolbachia strains of supergroup A and B represent genetically distinct clades, and that strains of different supergroups can co-exist in the same arthropod host without converging into the same species. This suggests that the supergroups are irreversibly separated and that barriers other than host-specialization are able to maintain distinct clades in recombining endosymbiont populations. Acquiring a good knowledge of the barriers to genetic exchange in Wolbachia will advance our understanding of how endosymbiont communities are constructed from vertically and horizontally transmitted genes. © 2013 Ellegaard et al.


Dimas A.S.,University of Geneva | Dimas A.S.,University of Oxford | Dimas A.S.,Biomedical Science Research Center Al Fleming | Nica A.C.,University of Geneva | And 14 more authors.
Genome Research | Year: 2012

Human regulatory variation, reported as expression quantitative trait loci (eQTLs), contributes to differences between populations and tissues. The contribution of eQTLs to differences between sexes, however, has not been investigated to date. Here we explore regulatory variation in females and males and demonstrate that 12%-15% of autosomal eQTLs function in a sex-biased manner. We show that genes possessing sex-biased eQTLs are expressed at similar levels across the sexes and highlight cases of genes controlling sexually dimorphic and shared traits that are under the control of distinct regulatory elements in females and males. This study illustrates that sex provides important context that can modify the effects of functional genetic variants. © 2012, Published by Cold Spring Harbor Laboratory Press.


Siozios S.,University of Western Greece | Siozios S.,Research and Innovation Center | Ioannidis P.,University of Western Greece | Ioannidis P.,University of Maryland Baltimore County | And 6 more authors.
PLoS ONE | Year: 2013

Ankyrin repeat domain-encoding genes are common in the eukaryotic and viral domains of life, but they are rare in bacteria, the exception being a few obligate or facultative intracellular Proteobacteria species. Despite having a reduced genome, the arthropod strains of the alphaproteobacterium Wolbachia contain an unusually high number of ankyrin repeat domain-encoding genes ranging from 23 in wMel to 60 in wPip strain. This group of genes has attracted considerable attention for their astonishing large number as well as for the fact that ankyrin proteins are known to participate in protein-protein interactions, suggesting that they play a critical role in the molecular mechanism that determines host-Wolbachia symbiotic interactions. We present a comparative evolutionary analysis of the wMel-related ankyrin repeat domain-encoding genes present in different Drosophila-Wolbachia associations. Our results show that the ankyrin repeat domain-encoding genes change in size by expansion and contraction mediated by short directly repeated sequences. We provide examples of intra-genic recombination events and show that these genes are likely to be horizontally transferred between strains with the aid of bacteriophages. These results confirm previous findings that the Wolbachia genomes are evolutionary mosaics and illustrate the potential that these bacteria have to generate diversity in proteins potentially involved in the symbiotic interactions. © 2013 Siozios et al.


Nikolaou K.C.,Biomedical Science Research Center Al Fleming | Moulos P.,Biomedical Science Research Center Al Fleming | Chalepakis G.,University of Crete | Hatzis P.,Biomedical Science Research Center Al Fleming | And 4 more authors.
EMBO Journal | Year: 2015

PR-SET7-mediated histone 4 lysine 20 methylation has been implicated in mitotic condensation, DNA damage response and replication licensing. Here, we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 phase arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis, accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic regenerative cycles coupled with oncogenic STAT3 activation led to the spontaneous development of hepatic tumors composed of cells with cancer stem cell characteristics. These include a capacity to selfrenew in culture or in xenografts and the ability to differentiate to phenotypically distinct hepatic cells. Hepatocellular carcinoma in PR-SET7-deficient mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes. © 2014 The Authors.


PubMed | Fukuoka University, University of Crete, Biomedical Science Research Center Al Fleming and New York University
Type: Journal Article | Journal: The EMBO journal | Year: 2015

PR-SET7-mediated histone 4 lysine 20 methylation has been implicated in mitotic condensation, DNA damage response and replication licensing. Here, we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 phase arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis, accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic regenerative cycles coupled with oncogenic STAT3 activation led to the spontaneous development of hepatic tumors composed of cells with cancer stem cell characteristics. These include a capacity to self-renew in culture or in xenografts and the ability to differentiate to phenotypically distinct hepatic cells. Hepatocellular carcinoma in PR-SET7-deficient mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes.


Kontaki H.,Biomedical Science Research Center Al Fleming | Talianidis I.,Biomedical Science Research Center Al Fleming
Molecular Cell | Year: 2010

Histone-modifying enzymes can regulate DNA damage-induced apoptosis through modulation of p53 function. Here, we show that, in p53-deficient tumor cells, Set9 and LSD1 regulate DNA damage-induced cell death in a manner opposite to that observed in p53+/+ cells, via modulation of E2F1 stabilization. Set9 methylates E2F1 at lysine-185, which prevents E2F1 accumulation during DNA damage and activation of its proapoptotic target gene p73. This methyl mark is removed by LSD1, which is required for E2F1 stabilization and apoptotic function. The molecular mechanism involves crosstalks between lysine methylation and other covalent modifications that affect E2F1 stability. Methylation at lysine-185 inhibits acetylation and phosphorylation at distant positions and, in parallel, stimulates ubiquitination and degradation of the protein. The findings illustrate that the function of methyltransferases can have opposing biological outcomes depending on the specificity of transcription factor targets. © 2010 Elsevier Inc.


PubMed | Biomedical Science Research Center Al Fleming
Type: Journal Article | Journal: Molecular & cellular oncology | Year: 2016

Cancer stem cells (CSCs) are defined as cells within tumors that can self-renew and differentiate into heterogeneous lineages of cancerous cells. The origin of CSCs is not well understood. Recent evidence suggests that CSCs in hepatocellular carcinoma could be generated via oncogenic transformation and partial differentiation of adult hepatic ductal progenitor cells.

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