The FEBS journal
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Mesenchymal stem cells (MSCs) are multipotent cells that have been widely used in cell based transplantation therapy. The use of MSCs requires in vitro expansion in order to fulfill their regenerative capacity. Therefore the proliferative ability of MSCs is one of the key factors which determine MSC therapeutic efficacy. ⋯ Utilizing a specific GSK-3β inhibitor SB216763 or siRNA-mediated inhibition of GSK-3β produced effects similar to those induced by lithium. In contrast, either quercetin, an inhibitor of the β-catenin/TCF pathway, or siRNA-mediated knockdown of β-catenin abolished the proliferative effect of lithium, suggesting that lithium stimulates MSC proliferation via the GSK-3β-dependent β-catenin/Wnt pathway. Collectively, these studies elucidate a novel role of lithium, which may not only provide a simple and effective way to strengthen MSC transplantation therapy efficacy but also shed light on lithium's clinical application for the treatment of certain disorders resulting from β-catenin/Wnt pathway suppression.
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The bacterial clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system is a versatile RNA-guided mammalian genome modification system. One-step generation of mouse genome targeting has been achieved by co-microinjection of one-cell stage embryos with Cas9 mRNA and small/single guide (sg)RNA. ⋯ We further observed that the target gene modifications were characterized by efficient germline transmission and site-dependent off-target effects, and also that the apolipoprotein E gene knockout-mediated defects in blood biochemical parameters were recapitulated by CRISPR/Cas9-mediated heritable gene modification. Our results provide a dual sgRNAs strategy to facilitate CRISPR/Cas9-mediated mouse genome targeting.
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The RNA world has gained increasing importance in the recent past as its role beyond coding for proteins and components of translational machinery is becoming more and more prominent. Recent studies have shown pervasive transcription throughout the genome generating a large number of non-coding RNAs (ncRNAs) but few of these RNAs have been shown to perform regulatory functions. ⋯ While lncRNAs are well known for their role in repressing gene expression, their role in gene activation is only emerging from recent studies. Here we review how the lncRNAs can mediate gene activation by a variety of mechanisms and explore their importance in biological processes.
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Conformational selection between pre-existing structural states of an oligomeric protein was the conceptual step behind the formulation of Monod-Wyman-Changeux (MWC) allosteric theory. Variations on the basic theme of allosteric control are briefly illustrated in this paper by reference to some hemoglobins from different species whose functional properties were found to respond to specific physiological requirements. In my opinion the enormous success of the allosteric theory may be attributed not only to its efficiency in accounting for data and its formal mathematical elegance, but also because the selective mechanism conforms to the founding concept of Darwinian evolution.
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Histopathology, the examination of an architecturally artefactual, two-dimensional and static image remains a potent tool allowing diagnosis and empirical expectation of prognosis. Considerable optimism exists that the advent of molecular genetic testing and other biomarker strategies will improve or even replace this ancient technology. A number of biomarkers already add considerable value for prediction of whether a treatment will work. ⋯ Systems approaches need to incorporate quantitative morphological, protein, mRNA and DNA data. A significant challenge for clinical implementation of systems pathology is how to optimize information available from tissue, which is frequently sub-optimal in quality and amount, and yet generate useful predictive models that work. The transition of histopathology to systems pathophysiology and the use of multiscale data sets usher in a new era in diagnosis, prognosis and prediction based on the analysis of human tissue.