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No description available.

This work provides a comparative and genetic analysis of the responses to water stress in desiccation-tolerant and desiccation-sensitive nematodes. Caenorhabditis elegans, a model organism for the study of development, aging, and cell biology was shown to be a desiccation-sensitive organism that survives relative humidities above 40\% for periods of up to seven days. Transcripts from the desiccation-tolerant species Panagrolaimus rigidus AF36 and sp. PS1579, which were expressed uniquely during separate desiccation and osmotic stresses, as well as during recovery from exposure to the dual stresses, were cloned. These sequences were used to search for similarities in the genome sequence data of C. elegans. Putative anhydrobiotic-related transcripts were identified that potentially encode heat shock protein 70, late embryogenic abundant protein, and trehalose-phosphate synthase. Other putative genes that were identified within eight separate libraries encode proteins involved in transcription (histones), protein biosynthesis (ribosomal proteins, elongation factors), protein degradation (ubiquitin, proteases), and transport and cell structure (actin, collagen). Gene ontology analysis of the cloned transcripts revealed that developmental processes are activated during exposure to the stresses as well as during recovery, which may suggest a "rejuvenation" process as a key to survival in Panagrolaimus nematodes. Genes that were up-regulated during desiccation stress in C. elegans were classified as belonging either to an early response (until 12 hours of stress), or to a late response (after 12 hours of stress). The early response was characterized by the up-regulation of a large number of genes encoding mono-oxygenases, which may suggest onset of oxidation stress during desiccation of C. elegans. The late response was characterized by the appearance of transcripts encoding proteins of the immune system, heat shock proteins (protein denaturation), and superoxide dismutases (oxidation damage). Genes in C. elegans that were down-regulated in response to desiccation stress include those encoding proteases and lysozymes (metabolic shutdown). Genes that encode channel proteins (water homeostasis) were found among the transcripts up-regulated during recovery of C. elegans. The up-regulation of gpdh-1 and hmit-1.1, two transcripts linked to hyperosmotic stress, suggest that osmotic stress is experienced by C. elegans. Comparison of these data with those obtained from exposure of C. elegans to a range of other stresses showing that the nematode C. elegans uses specific transcripts for the desiccation response; transcripts that are not induced in other stresses such as heat, anoxia or starvation. In addition, transcripts regulated during desiccation stress of C. elegans were also regulated during dauer formation, which may indicate common stress tolerant mechanisms. Recent studies in mammalian cells and C. elegans have shown that microRNAs are able to degrade and to sequester mRNA especially during stress in so called stress bodies. In this study, C. elegans microRNA knock-outs showed a significant decrease in desiccation stress survival compared to wild type C. elegans which may suggest the importance of microRNAs for stress survival in C. elegans and other organisms. / Ph. D.

Yes / Nottingham Trent University, United Kingdom, UoA03 QR and Capital Funds (MIA), as well as by the grant from Amway, USA to VAB and NVB.

<p dir="ltr">Angiosarcoma (AS) is a rare, understudied cancer that arises from endothelial cells with an extremely poor prognosis. More research is necessary to understand AS pathogenesis, which will lead to the development of novel therapies to improve patient survival. Evidence from our lab highlights the importance of miRNAs in disease progression by demonstrating that endothelial cell-specific loss of mature miRNAs drives AS in mice. Furthermore, individual miRNAs have been characterized as tumor suppressors in AS. Taken together, this underscores the role of miRNAs in AS pathogenesis and suggests that they are an underexplored therapeutic strategy that could be efficacious in treating this cancer. Due to the evidence that miRNA loss is a driver of AS, we hypothesized that global miRNA enhancement would reduce cancer phenotypes. We interrogated this question through the use of a small molecule enhancer of RNAi, enoxacin. We found that enoxacin robustly reduced cancer phenotypes, particularly in AS models driven by miRNA loss, and that enoxacin increased the expression of mature tumor-suppressing miRNAs. We then thoroughly characterized miR-497 in angiosarcoma, demonstrating that miR-497 overexpression ablated tumor formation in mice through the regulation of a network of target genes. Furthermore, we identified <i>Vat1</i> as a novel target gene of miR-497, and found that genetic and pharmacologic inhibition of <i>Vat1</i> reduced cell migration in AS. Overall, this work further highlights the important roles miRNAs play in AS pathogenesis, and points toward miRNAs as an exciting therapy that should be explored further.</p>

Yes / MicroRNAs are short, non-coding RNAs that target messenger RNAs for degradation. miR-145 is a vascular-enriched microRNA that is important for smooth muscle cell (SMC) differentiation. Under healthy circumstances, SMC exist in a contractile, differentiated phenotype promoted by miR-145. In cases of disease or injury, SMC can undergo reversible dedifferentiation into a synthetic phenotype, accompanied by inhibition of miR-145 expression. Vascular disorders such as atherosclerosis and neointimal hyperplasia are characterised by aberrant phenotypic switching in SMC. This review will summarise the physiological roles of miR-145 in vascular SMC, including the molecular regulation of differentiation, proliferation and migration. Furthermore, it will discuss the different ways in which miR-145 can be dysregulated and the downstream impact this has on the progression of vascular pathologies. Finally, it will discuss whether miR-145 may be suitable for use as a biomarker of vascular disease.

Les virus sont des parasites intracellulaires obligatoires, qui détournent la quasi-totalité des voies cellulaires. La voie des miRNA et du RNAi ne font pas exception. D'abord, les miRNA peuvent reconnaître les ARN viraux, permettant le recrutement de la machinerie du RNAi, en particulier AGO2, sur les messagers viraux, ce qui peut moduler la réplication du virus. Pendant ma thèse, nous avons identifié un nouveau moyen de recruter AGO2, sur les messagers viraux, qui n'impliquent pas les miRNA, ni sa capacité à induire l'extinction des gènes. Nous avons montré qu'AGO2 interagit avec GAG et se fixe aux ARN viraux par les séquences d'encapsidation. Ensuite, les virus peuvent moduler le répertoire de miRNA cellulaires, de sorte à créer un contexte favorable à sa propre réplication. Ainsi, nous avions pour objectif, d'identifier de nouveaux partenaires cellulaires de VIH. Nous avons alors analysé des données transcriptomiques, obtenues à partir de cellules infectées par VIH-1 ou VIH-2, et reconstitué des réseaux de régulations impliquant les facteurs de transcription et les miRNA. Nous avons montré que les modulations de miRNA dépendent du mode d'entrée du virus, en particulier de l'utilisation des co-récepteurs. De plus, l'approche de Biologie Intégrative que nous avons suivie, nous a permis de caractériser une nouvelle protéine cellulaire, capable de réguler l'expression du VIH et de restreindre sa réplication. / Viruses are obligatory intracellular parasites that hijack many, if not all, cellular pathways. The RNA interference (RNAi) and the micro(mi)RNA pathways are no exceptions. First, cellular micro(mi)RNAs are able to recognize viral RNAs through imperfect micro-homologies. Similar to the miRNA-mediated repression of cellular translation, this recognition is thought to tether the RNAi machinery, in particular Argonaute(AGO)2, on viral messengers and eventually to modulate virus replication. During my PhD, we have unveiled another pathway by which AGO2 can interact with retroviral mRNAs without involving host miRNAs and translation repression. We have shown that AGO2 interacts with the retroviral GAG core proteins and preferentially binds unspliced retroviral RNAs through the RNA packaging sequences. The interaction between AGO2 and GAG, observed with both the Human Immunodeficiency Virus 1 (HIV-1) and the Primate Foamy Virus 1 (PFV-1), facilitates GAG multimerization and retroviral particle formation. Second, viruses modulate the miRNA repertoire presumably to create favorable conditions for viral replication. Hence, in order to identify novel cellular partners of HIV, we have analyzed transcriptomics data obtained from HIV1 and HIV-2-infected cells and reconstituted Transcription Factor- and miRNA-based regulation networks. Strikingly, we have noticed that the modulations of the transcriptome (coding and non-coding RNAs) depend on the mode of entry of the virus (i.e. co-receptor usage). Our in silico approach also helped us characterize a novel cellular protein able to regulate virus gene expression and

A unique computational approach was undertaken to identify targets of miR-17-3p that impart an oncogenic potential to the cells of the prostate. Utilizing this approach, we identified insulin growth factor receptor 1 (IGF1R) as a potential target of miR-17-3p. IGF1R imparts an oncogenic approach to the cells by helping cells escape apoptosis, become hypertrophic and increase the production of extracellular proteases that allow cells to detach from neighbors. The regulation of insulin growth factor receptor 1 by human microRNA-17-3p was evaluated using a western blot analysis of prostate cancer cell lines. Protein levels were compared in a cell line that expressed a non-targeting control RNA and a cell line that expressed microRNA-17-3p. The cell line that expressed the non-targeting control had significantly higher levels of IGF1R protein than the cell line expressing more of the active microRNA. Based on this experiment, it appears that microRNA-17-3p might regulate the insulin growth factor receptor 1.

INTRODUÇÃO: Cardiotoxicidade é frequentemente associada ao uso crônico de doxorubicina (DOX) podendo levar a cardiomiopatia e insuficiência cardíaca. A identificação de miRNAs cardiotoxicidade-específicos e seu potencial como biomarcadores poderia fornecer uma ferramenta prognostica valiosa e uma potencial área de intervenção. METODOLOGIA: Este é um sub-estudo do ensaio clínico prospectivo \"Efeito do Carvedilol na Prevenção da Cardiotoxicidade Induzida por Quimioterapia\" (ensaio CECCY) no qual incluiu 56 pacientes do sexo feminino (idade 49.9±3.3) provenientes do braço placebo. Os pacientes incluídos foram submetidos à quimioterapia com DOX seguido por taxanos. Troponina cardiaca I (cTnI), fração de ejeção do ventrículo esquerdo (FEVE) e microRNAs foram mensurados periodicamente. RESULTADOS: Os níveis circulantes de miR-1, -133b, -146a e -423-5p aumentaram significativamente durante o tratamento (18.6, 11.5, 10.6 e 12.1-vezes respectivamente; p < 0.001) enquanto miR-208a e -208b foram indetectáveis. cTnI aumentou de 6.6 ± 0.3 para 46.7 ± 5.5 pg/ml (p < 0.001) enquanto FEVE tendeu a diminuir de 65.3±0.5 para 63.8±0.9 (p=0.053) após 12 meses; deis pacientes (17.9%) desenvolveram cardiotoxicidade. miR-1 foi associado a mudanças na FEVE (r2=0.363, p < 0.001) enquanto miR-1 e -133b foram associados a cTnI (r2 = 0.675 e 0.758; p < 0.001). Além disso, miR-1 antecipou a cardiotoxicidade e mostrou uma area sobre a curva maior que cTnI para discriminar pacientes que desenvolveram cardiotoxicidade daqueles que não desenvolveram (AUC = 0.849 e 456, p<0.001 e 0.663, respectivamente). CONCLUSÃO: Nossos dados sugerem miR-1 como um potencial novo biomarcador de cardiotoxicidade induzida por DOX em pacientes com câncer de mama. Estes resultados podem levar a novas estratégias de detecção precoce do risco de lesão cardíaca induzida por DOX bem como a introdução de uma nova área para intervenção / INTRODUCTION: Cardiotoxicity is frequently associated with the chronic use of doxorubicin (DOX) and may lead to cardiomyopathy and heart failure. Identification of cardiotoxicity-specific miRNA biomarkers could provide clinicians with a valuable prognosis tool and a potential area for intervention. METHODS: This is an ancillary study from the prospective trial \"Carvedilol Effect in Preventing Chemotherapy-Induced Cardiotoxicity.\" (CECCY trial) which included 56 female patients (49.9±3.3 age) from placebo arm. Enrolled patients were treated with DOX followed by taxanes. Cardiac troponin I (cTnI), left ventricle ejection fraction (LVEF) and miRNAs were measured periodically. RESULTS: Circulating levels of miR-1, -133b, -146a and -423-5p increased along the treatment (18.6, 11.5, 10.6 and 12.1-fold respectively; p < 0.001); miR-208a and -208b were undetectable. cTnI increased from 6.6±0.3 to 46.7 ± 5.5 pg/ml (p < 0.001) while LVEF tended to decrease from 65.3±0.5 to 63.8±0.9 (p=0.053) over 12 months; ten patients (17.9%) developed cardiotoxicity. miR-1 was associated to changes in LVEF (r2=0.363, p < 0.001) while miR-1 and -133b were associated to cTnI (r2 = 0.675 and 0.758; p < 0.001). Furthermore, miR-1 anticipated cardiotoxicity and showed greater area under the curve than cTnI to discriminate between patients who did and did not developed cardiotoxicity (AUC = 0.849 and 456, p < 0.001 and 0.663, respectively). CONCLUSION: Our data suggest circulating miR-1 as a potential new biomarker of DOX-induced cardiotoxicity in breast cancer patients. These results may lead to new earlier strategies to detect drug-induced cardiac injury risk before it develops to an irreversible stage or introduce new area for intervention