No abstract

Directed cell migration is essential for cells to efficiently migrate in physiological and pathological processes. While migrating in their native environment, cells interact with multiple types of cues, such as mechanical and chemical signals. The role of chemical guidance via chemotaxis has been studied in the past, the understanding of mechanical guidance of cell migration via durotaxis remained unclear until very recently. Nonetheless, durotaxis has become a topic of intensive research and several advances have been made in the study of mechanically guided cell migration across multiple fields. Thus, in this article we provide a state of the art about durotaxis by discussing in silico, in vitro and in vivo data. We also present insights on the general mechanisms by which cells sense, transduce and respond to environmental mechanics, to then contextualize these mechanisms in the process of durotaxis and explain how cells bias their migration in anisotropic substrates. Furthermore, we discuss what is known about durotaxis in vivo and we comment on how haptotaxis could arise from integrating durotaxis and chemotaxis in native environments.

The application of high-field 1 H NMR spectroscopy to the analysis of biological fluids has proved to be a valuable approach to toxicological screening. Coupled with data reduction and chemometric analyses, this technology has a high capacity for elucidating relevant metabolic information pertaining to the nature and mechanism of toxic processes in an organism. This approach is encapsulated in the concept of metabonomics, which is defined as 'the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification', and can be regarded as complementary to studies of the genome (genomics) and the proteins in an organism (proteomics). Here the metabonomics approach to drug toxicity evaluation is exemplified using 1 H NMR spectroscopy to investigate the biochemical perturbations in urine after dosing Fischer rats with the cationic, amphiphilic drugs chloroquine, amiodarone and DMP 777, a neutrophil elastase inhibitor. These drugs are known to induce phospholipidosis, characterized by lysosomal lamellar body and drug accumulation. Using a metabonomic approach, combinations of specific urinary biomarkers were identified for each compound, together with a putative general marker of phospholipidosis, phenylacetylglycine. Furthermore, in the case of chloroquine, clear evidence of hepatotoxicity was determined.

The CSRNP (cystein-serine-rich nuclear protein) transcription factors are conserved from Drosophila to human. Functional studies in mice, through knockout for each of their paralogs, have resulted insufficient to elucidate the function of this family of proteins in vertebrate development. Previously, we described the function of the zebrafish ortholog, Csnrp1/Axud1, showing its essential role in the survival and proliferation of cephalic progenitors. To extend our understanding of this family, we have studied the function of its paralog csrnp1a. Our results show that csrnp1a is expressed from 0 hpf, until larval stages, particularly in cephalic territories and in the intermediate cell mass (ICM). Using morpholinos in wild type and transgenic lines we observed that Csrnp1a knockdown generates a mild reduction in head size and a depletion of blood cells in circulation. This was combined with in situ hybridizations to analyze the expression of different mesodermal and primitive hematopoiesis markers. Morphant embryos have impaired blood formation without disruption of mesoderm specification, angiogenesis or heart development. The reduction of circulating blood cells occurs at the hematopoietic progenitor level, affecting both the erythroid and myeloid lineages. In addition, cell proliferation was also altered in hematopoietic anterior sites, specifically in spi1 expression domain. These and previous observations suggest an important role of Csnrps transcription factors in progenitor biology, both in the neural and hematopoietic linages.