The impact of transposable element activity on therapeutically relevant human stem cells

Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016- 21395 and SAF2015–71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015–71589- P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the Federal Republic of Germany (FKZ2518FSB403)

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is the most common acute hyperglycaemic emergency in people with diabetes mellitus. A diagnosis of DKA is confirmed when all of the three criteria are present — ‘D’, either elevated blood glucose levels or a family history of diabetes mellitus; ‘K’, the presence of high urinary or blood ketoacids; and ‘A’, a high anion gap metabolic acidosis. Early diagnosis and management are paramount to improve patient outcomes. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement and treatment of any underlying precipitating event. Without optimal treatment, DKA remains a condition with appreciable, although largely preventable, morbidity and mortality. In this Primer, we discuss the epidemiology, pathogenesis, risk factors and diagnosis of DKA and provide practical recommendations for the management of DKA in adults and children

Mo TiO2 110 Mixed Oxide Layer Structure and Reactivity

We present a STM/XPS/TPD/LEED study of the structural and electronic properties of Mo+Ti mixed oxide layers on TiO₂(110), and of their interaction with water, methanol and ethanol. Several different preparation procedures were tested and layers with different degrees of Mo/Ti mixing were prepared. Ordered mixed oxide surface phases with distinct LEED patterns could not be found; for all investigated Mo concentrations a TiO₂(110) like pattern was observed. Mo tends to agglomerate on the surface where it is found predominantly as Mo⁶⁺ at low coverages and as Mo⁴⁺ at high coverages. Mo⁴⁺ was also identified in the bulk of the mixed oxide layer. The Mo3d binding energies categorize the Mo⁴⁺ species as being dimeric. A third Mo3d doublet is attributed to a Mo species (Moⁿ⁺) with an oxidation state between those reported for Mo in MoO₂ and metallic Mo. Two types of Mo-induced features could be identified in the STM images for low Mo concentrations (in the range of 1 %). At higher Mo concentrations (~50 %) the surface is characterized by stripes with limited lengths in [001] direction. The concentration of bridging oxygen vacancies, which are common defects on TiO₂(110), is reduced significantly even at low Mo concentrations. Methanol and ethanol TPD spectra reflect this effect by a decrease of the intensity of the features related to these surface defects. At elevated MoO_x coverages, the yield of reaction products in methanol and ethanol TPD spectra are somewhat smaller than those found for clean TiO₂(110) and the reactions occur at lower temperature

The expressions of genes causing histone modifications in colorectal carcinomas with signet ring cells

WOS: 000431649800068