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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 08 September 2015, Vol.112(36), pp.11276-81
    Description: Viral vectors based on the adeno-associated virus (AAV) hold great promise for in vivo gene transfer; several unknowns, however, still limit the vectors' broader and more efficient application. Here, we report the results of a high-throughput, whole-genome siRNA screening aimed at identifying cellular factors regulating AAV transduction. We identified 1,483 genes affecting vector efficiency more than 4-fold and up to 50-fold, either negatively or positively. Most of these factors have not previously been associated to AAV infection. The most effective siRNAs were independent from the virus serotype or analyzed cell type and were equally evident for single-stranded and self-complementary AAV vectors. A common characteristic of the most effective siRNAs was the induction of cellular DNA damage and activation of a cell cycle checkpoint. This information can be exploited for the development of more efficient AAV-based gene delivery procedures. Administration of the most effective siRNAs identified by the screening to the liver significantly improved in vivo AAV transduction efficiency.
    Keywords: DNA-Damage Response ; RNA Interference ; Adeno-Associated Virus ; High-Throughput Screening ; Self-Complementary Vectors ; RNA Interference ; Transduction, Genetic ; Dependovirus -- Genetics ; Genome, Human -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2012, Vol.492(7429), p.376
    Description: In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high-content microscopy, high-throughput functional screening for human miRNAs that promoted neonatal cardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs (hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shownto promote cell cycle re-entry of adult cardiomyocytes ex vivo and to promote cardiomyocyte proliferation in both neonatal and adult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regeneration and almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss. [PUBLICATION ]
    Keywords: Animals–Biosynthesis ; Cell Proliferation–Growth & Development ; Cytokinesis–Analysis ; DNA–Genetics ; Down-Regulation–Therapeutic Use ; Gene Library–Genetics ; Genetic Therapy–Pathology ; Heart–Prevention & Control ; Humans–Therapy ; Mice–Cytology ; Micrornas–Metabolism ; Micrornas–Cytology ; Micrornas–Metabolism ; Myocardial Infarction–Genetics ; Myocardial Infarction–Genetics ; Myocardial Infarction–Genetics ; Myocardial Infarction–Genetics ; Myocardium–Genetics ; Myocardium–Genetics ; Myocytes, Cardiac–Genetics ; Myocytes, Cardiac–Genetics ; Rats–Genetics ; Rats, Wistar–Genetics ; Regeneration–Genetics ; Heart Attacks ; Kinases ; Rodents ; Cell Division ; Cell Cycle ; Gene Expression ; Mirn590 Microrna, Human ; Micrornas ; Mirn199 Microrna, Human ; DNA;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: PLoS ONE, 2011, Vol.6(3), p.e17296
    Description: P-bodies are dynamic aggregates of RNA and proteins involved in several post-transcriptional regulation processes. P-bodies have been shown to play important roles in regulating viral infection, whereas their interplay with bacterial pathogens, specifically intracellular bacteria that extensively manipulate host cell pathways, remains unknown. Here, we report that Salmonella infection induces P-body disassembly in a cell type-specific manner, and independently of previously characterized pathways such as inhibition of host cell RNA synthesis or microRNA-mediated gene silencing. We show that the Salmonella -induced P-body disassembly depends on the activation of the SPI-2 encoded type 3 secretion system, and that the secreted effector protein SpvB plays a major role in this process. P-body disruption is also induced by the related pathogen, Shigella flexneri , arguing that this might be a new mechanism by which intracellular bacterial pathogens subvert host cell function.
    Keywords: Research Article ; Biology ; Medicine ; Infectious Diseases ; Microbiology ; Molecular Biology ; Cell Biology
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: The Journal of biological chemistry, 04 December 2015, Vol.290(49), pp.29652-62
    Description: MageB2 belongs to the melanoma antigen gene (MAGE-I) family of tumor-specific antigens. Expression of this gene has been detected in human tumors of different origins. However, little is known about the protein function and how its expression affects tumor cell phenotypes. In this work, we found that human MageB2 protein promotes tumor cell proliferation in a p53-independent fashion, as observed both in cultured cells and growing tumors in mice. Gene expression analysis showed that MageB2 enhances the activity of E2F transcription factors. Mechanistically, the activation of E2Fs is related to the ability of MageB2 to interact with the E2F inhibitor HDAC1. Cellular distribution of MageB2 protein includes the nucleoli. Nevertheless, ribotoxic drugs rapidly promote its nucleolar exit. We show that MageB2 counteracts E2F inhibition by ribosomal proteins independently of Mdm2 expression. Importantly, MageB2 plays a critical role in impairing cell cycle arrest in response to Actinomycin D. The data presented here support a relevant function for human MageB2 in cancer cells both under cycling and stressed conditions, presenting a distinct functional feature with respect to other characterized MAGE-I proteins.
    Keywords: E2f Transcription Factor ; Cancer Biology ; Cell Proliferation ; Histone Deacetylase 1 (Hdac1) ; Molecular Cell Biology ; Antigens, Neoplasm -- Metabolism ; E2f Transcription Factors -- Metabolism ; Neoplasm Proteins -- Metabolism ; Proto-Oncogene Proteins C-Mdm2 -- Metabolism
    E-ISSN: 1083-351X
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  • 5
    In: PLoS ONE, 2014, Vol.9(4)
    Description: Replication of many RNA viruses benefits from subversion of the autophagic pathway through many different mechanisms. Rotavirus, the main etiologic agent of pediatric gastroenteritis worldwide, has been recently described to induce accumulation of autophagosomes as a mean for targeting viral proteins to the sites of viral replication. Here we show that the viral-induced increase of the lipidated form of LC3 does not correlate with an augmented formation of autophagosomes, as detected by immunofluorescence and electron microscopy. The LC3-II accumulation was found to be dependent on active rotavirus replication through the use of antigenically intact inactivated viral particles and of siRNAs targeting viral genes that are essential for viral replication. Silencing expression of LC3 or of Atg7, a protein involved in LC3 lipidation, resulted in a significant impairment of viral titers, indicating that these elements of the autophagic pathway are required at late stages of the viral cycle.
    Keywords: Research Article ; Biology And Life Sciences ; Medicine And Health Sciences
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: The Journal of Physical Chemistry Part B, 2010, Vol.114(10), pp.3518-3525
    Description: Here, monoolein-based nanoparticles (NPs), obtained through fragmentation of bulk liquid crystalline phases, and stabilized by two different emulsifiers, namely, Pluronic F127 (PF127) and lauroylcholine chloride (LCh), are investigated for structural features and for short-term in vitro cytotoxicity. Depending on the emulsifiers, different morphologies of the lipid NPs (cubosomes and liposomes) are obtained, as demonstrated by cryo-TEM images. Although NPs offer many advantages in medical applications and various chemicals used for their preparation are under investigation, so far there are no standardized procedures to evaluate cell biocompatibility. Two different protocols to evaluate the impact of these lipid NPs on biological systems are presented. Results show that nanoparticles stabilized by PF127 (cubosomes) display a relevant toxicity toward different cell lines, whereas those stabilized by LCh (liposomes) affect cell viability at a much lesser extent.
    Keywords: Naturvetenskap ; Kemi ; Fysikalisk Kemi ; Natural Sciences ; Chemical Sciences ; Physical Chemistry
    ISSN: 1520-5207
    ISSN: 15206106
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  • 7
    In: EMBO Journal, 03 December 2018, Vol.37(23), pp.n/a-n/a
    Description: While mucosal inflammation is a major source of stress during enteropathogen infection, it remains to be fully elucidated how the host benefits from this environment to clear the pathogen. Here, we show that host stress induced by different stimuli mimicking inflammatory conditions strongly reduces the binding of to epithelial cells. Mechanistically, stress activates acid sphingomyelinase leading to host membrane remodeling. Consequently, knockdown or pharmacological inhibition of the acid sphingomyelinase blunts the stress‐dependent inhibition of binding to host cells. Interestingly, stress caused by intracellular replication also results in remodeling of the host cell membrane, and , which precludes re‐infection by this and other non‐motile pathogens. In contrast, Typhimurium overcomes the shortage of permissive entry sites by gathering effectively at the remaining platforms through its flagellar motility. Overall, our findings reveal host membrane remodeling as a novel stress‐responsive cell‐autonomous defense mechanism that protects epithelial cells from infection by non‐motile bacterial pathogens. Stress‐induced host membrane remodeling constitutes a novel cell‐autonomous defensive mechanism that protects epithelial cells from infection by and other non‐motile bacterial pathogens. Host oxidative stress strongly reduces S. flexneri binding to epithelial cells. Stress leads to host membrane remodeling, via activation of the acid sphingomyelinase by the MAPK p38 pathway, resulting in the formation of ceramide domains. Intracellular Shigella replication induces remodeling of the host cell membrane, in vitro and in vivo. Stress‐induced host membrane remodeling precludes re‐infection by non‐motile pathogens; motile pathogens are able to overcome this barrier through flagellar motility. Host membrane remodeling is a cell‐autonomous defense mechanism that protects epithelial cells from infection by .
    Keywords: Acid Sphingomyelinase ; Host Stress Response ; Membrane Remodeling ; Salmonella ; Shigella
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 8
    Language: English
    In: Review of Industrial Organization, 2010, Vol.37(4), pp.309-333
    Description: This paper discusses a selection of cases and important policy developments in the enforcement activities of the Directorate General for Competition at the European Commission during the past year (2009–2010).
    Keywords: Antitrust ; Merger control ; Best practices
    ISSN: 0889-938X
    E-ISSN: 1573-7160
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  • 9
    In: Circulation, 2010, Vol.122(21_MeetingAbstracts Suppl 1)
    Description: Introduction: To identify novel cardioprotective genes we developed an innovative functional selection approach, based on in vivo gene transfer of cDNA libraries using AAV vectors.Hypothesis: To support the feasibility of in vivo functional screening, we used a pool of AAV expressing 50 different hormones and growth factors and assessed the hypothesis that the clones enriched by selective pressure effectively promoted cardiac function.Methods: After cardiac injection (n=50) of the AAV pool, animals were subjected to myocardial infarction. After 15 days, persisting vector DNA was recovered, recloned into AAV and used for subsequent cycles of functional selection. Individual AAV vectors expressing the selected clones were eventually tested for cardioprotective activity in vitro on primary cardiomyocytes and in mouse models of cardiac fibrosis (isoproterenol i.p. 200 mg/Kg) or myocardial infarction by echocardiography, morphometric and molecular analysis (n=10 per group).Results: In vivo functional selection led to marked enrichment for surviving cardiomyocytes expressing Ghrelin, a neuro-hormone secreted upon starvation. In vitro, transduction with AAV-Ghrelin resulted in improved survival of cardiomyocytes after isoproterenol (〉90% vs 60% vs 〈10%) treatment (p〈0.02). In vivo, AAV-Ghrelin preserved cardiac function upon isoproterenol injection, resulting in decreased heart rate (464±50 and 342±12 bpm in AAV-empty and AAV-Ghrelin, respectively), paralleled by a reduced up-regulation of a few novel markers of heart failure, such as miR-21 and MMP-2.Conclusions: In conclusion, these results support the feasibility of our innovative in vivo selection approach and identify Ghrelin as a novel and powerful molecule protecting from cardiac apoptosis and providing benefit upon cardiac damage.
    ISSN: 0009-7322
    Source: Copyright © 2013 Lippincott Williams & Wilkins. All rights reserved.〈img src=http://exlibris-pub.s3.amazonaws.com/LWW%20logo.png style="vertical-align:middle;margin-left:7px"〉
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  • 10
    Article
    Article
    Language: English
    In: SSRN Electronic Journal, 2018
    ISSN: SSRN Electronic Journal
    E-ISSN: 1556-5068
    Source: CrossRef
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