Modelling the regulation of telomere length: the effects of telomerase and G-quadruplex stabilising drugs

Telomeres are guanine-rich sequences at the end of chromosomes which shorten during each replication event and trigger cell cycle arrest and/or controlled death (apoptosis) when reaching a threshold length. The enzyme telomerase replenishes the ends of telomeres and thus prolongs the life span of cells, but also causes cellular immortalisation in human cancer. G-quadruplex (G4) stabilising drugs are a potential anticancer treatment which work by changing the molecular structure of telomeres to inhibit the activity of telomerase. We investigate the dynamics of telomere length in different conformational states, namely t-loops, G-quadruplex structures and those being elongated by telomerase. By formulating deterministic differential equation models we study the effects of various levels of both telomerase and concentrations of a G4-stabilising drug on the distribution of telomere lengths, and analyse how these effects evolve over large numbers of cell generations. As well as calculating numerical solutions, we use quasicontinuum methods to approximate the behaviour of the system over time, and predict the shape of the telomere length distribution. We find those telomerase and G4-concentrations where telomere length maintenance is successfully regulated. Excessively high levels of telomerase lead to continuous telomere lengthening, whereas large concentrations of the drug lead to progressive telomere erosion. Furthermore, our models predict a positively skewed distribution of telomere lengths, that is, telomeres accumulate over lengths shorter than the mean telomere length at equilibrium. Our model results for telomere length distributions of telomerase-positive cells in drug-free assays are in good agreement with the limited amount of experimental data available

Single point incremental forming: state-of-the-art and prospects

peer reviewedIncremental sheet metal forming in general and Single Point Incremental Forming (SPIF) specifically have gone through a period of intensive development with growing attention from research institutes worldwide. The result of these efforts is significant progress in the understanding of the underlying forming mechanisms and opportunities as well as limitations associated with this category of flexible forming processes. Furthermore, creative process design efforts have enhanced the process capabilities and process planning methods. Also, simulation capabilities have evolved substantially. This review paper aims to provide an overview of the body of knowledge with respect to Single Point Incremental Forming. Without claiming to be exhaustive, each section aims for an up-to-date state-of-the-art review with corresponding conclusions on scientific progress and outlook on expected further developments.PAI P7-21 Intemat