Implications of MicroRNAs in the Vascular Homeostasis and Remodeling

Vascular remodeling or arterial remodeling is a process of adaptive alteration of vascular wall architecture and leads to the endothelial cell (EC) dysfunction and synthetic or contractile phenotypic change of VSMCs, and the infiltration of monocytes and Macrophages that promotes vascular diseases including atherosclerosis. Recent findings have demonstrated that microRNAs (miRNAs) are involved in regulating gene expression at posttranscriptional level and disease pathogenesis. A change of miRNA expression profiles plays key roles in the gene expressions and the regulation of cellular functions. In this chapter, we summarize the vascular remodeling-related miRNAs and their functions in vascular biology

Looking for Pyroptosis-Modulating miRNAs as a Therapeutic Target for Improving Myocardium Survival

Pyroptosis is the most recently identified type of regulated cell death with inflammatory response and has characteristics distinct from those of apoptosis or necrosis. Recently, independent studies have reported that small noncoding RNAs termed microRNAs (miRNAs) are involved in the regulation of pyroptosis. Nevertheless, only a handful of empirical data regarding miRNA-dependent regulation of pyroptosis is currently available. This review is aimed to provide a current update on the role of miRNAs in pyroptosis and to offer suggestions for future studies probing miRNAs as a linker connecting pyroptosis to various cardiovascular diseases (CVDs) and their potential as a therapeutic target for preventing excessive cell death of myocardium during CVDs

Human Long Noncoding RNA Regulation of Stem Cell Potency and Differentiation

Because of their capability of differentiation into lineage-specific cells, stem cells are an attractive therapeutic modality in regenerative medicine. To develop an effective stem cell-based therapeutic strategy with predictable results, deeper understanding of the underlying molecular mechanisms of stem cell differentiation and/or pluripotency maintenance is required. Thus, reviewing the key factors involved in the transcriptional and epigenetic regulation of stem cell differentiation and maintenance is important. Accumulating data indicate that long noncoding RNAs (lncRNAs) mediate numerous biological processes, including stem cell differentiation and maintenance. Here, we review recent findings on the human lncRNA regulation of stem cell potency and differentiation. Although the clinical implication of these lncRNAs is only beginning to be elucidated, it is anticipated that lncRNAs will become important therapeutic targets in the near future

Les déterminants des performances scolaires des élèves marocains

Le Maroc fait partie des pays en développement dont le niveau des acquis des élèves reste relativement faible. En dépit des efforts engagés en vue d’améliorer en partie la qualité des apprentissages, les résultats des enquêtes internationales et nationales révèlent de faibles niveaux des acquis. Dès lors, l’objectif de cet article est de revenir sur les facteurs qui influencent les performances scolaires des élèves. Nous nous intéressons plus spécifiquement aux déterminants microéconomiques de la qualité de l’éducation à travers les performances des élèves. Les études sur les déterminants des performances scolaires sont riches d’enseignement. Les premières contributions se sont focalisées sur le rôle de l’environnement familial dans l’explication de la réussite des élèves (Coleman, 1966, par exemple). D’autres, plus récemment, ont abordé les facteurs liés à l’établissement scolaire. Pour autant, les contributions récentes mettent en avant l’importance à la fois de l’environnement familial et de l’école (Hanushek, 2003). Des travaux plus récents oulignent également l’influence des pairs sur les performances scolaires. Le présent travail s’inscrit dans cette logique. Son originalité se situe à un double niveau. La première réside dans la mise en évidence de l’ensemble des facteurs explicatifs des performances des élèves et des inégalités scolaires. Malgré l’existence d’une littérature abondante sur le sujet, cette question n’a pas été abordée, à notre connaissance, dans le cas marocain. La seconde cherche à corriger les problèmes d’endogénéité dans les modèles multiniveaux. Enfin, La technique d’imputation adoptée permet de traiter de façon pertinente les valeurs manquantes dans les bases de données. Cet article est structuré en trois parties. La première aborde la littérature empirique sur les déterminants de la réussite scolaire des élèves. La deuxième partie examine le modèle utilisé et décrit la base de données du Programme national d’évaluation des acquis (PNEA). Elle examine l’approche et la méthodologie utilisée. Enfin, la troisième partie traite des résultats obtenus et nous permet de formuler les principaux enseignements pouvant être tirés de nos résultats en matière de politiques publiques

Enzyme engineering of bovine trypsin

Bovine trypsin is a biocatalyst widely used to cleave recombinant proteins during the downstream processing of therapeutic proteins, and is used particularly for insulin bioprocessing. Evolution has produced a wealth of natural biocatalysts over billions of years, which are generally not optimised for specific industrial applications. Bovine trypsin has a relatively broad specificity towards cleavage at the C-terminal end of arginine or lysine residues. Consequently it has a tendency to cleave alternative sites in the insulin process leading to loss of yield and more complex downstream processing. This project describes efforts to alter the primary specificity of bovine trypsin. Trypsin variants were generated using two traditional random mutagenesis methods tailored to improve the chance of producing a useful mutant. These were focussed error prone PCR (fepPCR) and multiple-site saturation mutagenesis (MSSM). In order to select residues useful for MSSM, a study of the correlation between (1) mutations enhancing specificity or activity and (2) sequence entropy and distance of mutations from the active site was carried out based on past examples of directed and rational evolution. This analysis along with biochemical information for trypsin aided the selection of two specificity "hotspots" for random mutagenesis, each comprising four residues. These hotspots were regions in the trypsin gene close to or directly involved in substrate binding. Depending on the mutagenesis method used, the size of the mutant libraries differed considerably. For example, fepPCR of a 522 bp region of the trypsin gene required approximately 3,000 mutants to encompass all possibilities whereas the library size for MSSM was 160,000 for each of the selected four-residue regions. Two alternative library screening approaches, with different throughput capabilities, were tested to isolate mutants of interest. Automated colony screening was considered suitable for the smaller fepPCR library and consisted of the following steps: (1) transformation of a plasmid library into E. coli BL21-Gold(DE3) cells (2) fermentation of individual colonies in 384 square-well microplates (3) lysis of the cultures and (4) spectrophotometric activity measurement on a variety of substrates. The best mutant had a 2.54-fold improvement in arginine specificity. For the larger MSSM libraries, a nutritional selection method was developed using E. coli arg-auxotrophic strains. An alternative approach to generating trypsin variants was also explored based on the known ability of bovine trypsin to autolyse into "pseudo-trypsins". Since these pseudo-trypsins are variants of the native form of the enzyme, it was anticipated that they would have specificities different to that of the native enzyme. Efforts were made to separate the variants via novel chromatographic techniques and to characterise them with respect to molecular weight and specificity. Finally, the activity profile of bovine trypsin was comprehensively carried out on a range of novel substrates, and a comparison made between commercially available bovine trypsin and Eli Lilly's recombinant trypsin. Similar reaction profiles were returned by both enzymes on all substrates with the previously unreported finding that there was a preference for cleavage at the C-terminal end of two positively charged basic residues (i.e. KR or RR rather than GR)

Cell Adhesion and Long-Term Survival of Transplanted Mesenchymal Stem Cells: A Prerequisite for Cell Therapy

The literature provides abundant evidence that mesenchymal stem cells (MSCs) are an attractive resource for therapeutics and have beneficial effects in regenerating injured tissues due to their self-renewal ability and broad differentiation potential. Although the therapeutic potential of MSCs has been proven in both preclinical and clinical studies, several questions have not yet been addressed. A major limitation to the use of MSCs in clinical applications is their poor viability at the site of injury due to the harsh microenvironment and to anoikis driven by the loss of cell adhesion. To improve the survival of the transplanted MSCs, strategies to regulate apoptotic signaling and enhance cell adhesion have been developed, such as pretreatment with cytokines, growth factors, and antiapoptotic molecules, genetic modifications, and hypoxic preconditioning. More appropriate animal models and a greater understanding of the therapeutic mechanisms of MSCs will be required for their successful clinical application. Nevertheless, the development of stem cell therapies using MSCs has the potential to treat degenerative diseases. This review discusses various approaches to improving MSC survival by inhibiting anoikis

Cell Adhesion and Long-Term Survival of Transplanted Mesenchymal Stem Cells: A Prerequisite for Cell Therapy

The literature provides abundant evidence that mesenchymal stem cells (MSCs) are an attractive resource for therapeutics and have beneficial effects in regenerating injured tissues due to their self-renewal ability and broad differentiation potential. Although the therapeutic potential of MSCs has been proven in both preclinical and clinical studies, several questions have not yet been addressed. A major limitation to the use of MSCs in clinical applications is their poor viability at the site of injury due to the harsh microenvironment and to anoikis driven by the loss of cell adhesion. To improve the survival of the transplanted MSCs, strategies to regulate apoptotic signaling and enhance cell adhesion have been developed, such as pretreatment with cytokines, growth factors, and antiapoptotic molecules, genetic modifications, and hypoxic preconditioning. More appropriate animal models and a greater understanding of the therapeutic mechanisms of MSCs will be required for their successful clinical application. Nevertheless, the development of stem cell therapies using MSCs has the potential to treat degenerative diseases. This review discusses various approaches to improving MSC survival by inhibiting anoikis

Looking for Pyroptosis-Modulating miRNAs as a Therapeutic Target for Improving Myocardium Survival

Pyroptosis is the most recently identified type of regulated cell death with inflammatory response and has characteristics distinct from those of apoptosis or necrosis. Recently, independent studies have reported that small noncoding RNAs termed microRNAs (miRNAs) are involved in the regulation of pyroptosis. Nevertheless, only a handful of empirical data regarding miRNA-dependent regulation of pyroptosis is currently available. This review is aimed to provide a current update on the role of miRNAs in pyroptosis and to offer suggestions for future studies probing miRNAs as a linker connecting pyroptosis to various cardiovascular diseases (CVDs) and their potential as a therapeutic target for preventing excessive cell death of myocardium during CVDs

Looking into a Conceptual Framework of ROS–miRNA–Atrial Fibrillation

Atrial fibrillation (AF) has been recognized as a major cause of cardiovascular-related morbidity and mortality. MicroRNAs (miRNAs) represent recent additions to the collection of biomolecules involved in arrhythmogenesis. Reactive oxygen species (ROS) have been independently linked to both AF and miRNA regulation. However, no attempts have been made to investigate the possibility of a framework composed of ROS–miRNA–AF that is related to arrhythmia development. Therefore, this review was designed as an attempt to offer a new approach to understanding AF pathogenesis. The aim of this review was to find and to summarize possible connections that exist among AF, miRNAs and ROS to understand the interactions among the molecular entities underlying arrhythmia development in the hopes of finding unappreciated mechanisms of AF. These findings may lead us to innovative therapies for AF, which can be a life-threatening heart condition. A systemic literature review indicated that miRNAs associated with AF might be regulated by ROS, suggesting the possibility that miRNAs translate cellular stressors, such as ROS, into AF pathogenesis. Further studies with a more appropriate experimental design to either prove or disprove the existence of an ROS–miRNA–AF framework are strongly encouraged