Newcastle University

About: Newcastle University is a education organization based out in Newcastle upon Tyne, United Kingdom. It is known for research contribution in the topics: Population & Context (language use). The organization has 31772 authors who have published 71187 publications receiving 2539147 citations. The organization is also known as: University of Newcastle upon Tyne.

Feedback between p21 and reactive oxygen production is necessary for cell senescence

Abstract: Cellular senescence—the permanent arrest of cycling in normally proliferating cells such as fibroblasts—contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of ‘deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFβ. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.

Genetic variegation of clonal architecture and propagating cells in leukaemia

Abstract: Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance and propagation Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6–RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or ‘driver’ copy number alterations By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγnull mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo These data have implications for cancer genomics and for the targeted therapy of cancer Genome-wide analysis of cancer cells in individual patients has revealed extensive genetic heterogeneity Two groups have now mapped genetic homogeneity in patients with acute lymphoblastic leukaemia (ALL) Mel Greaves and colleagues obtained mutational profiles of large numbers of single cells from 60 individuals with ETV6–RUNX1-positive ALL, while John Dick and colleagues profile BCR-ABL1-positive ALL Both groups deduce the evolutionary path by which different subclones emerge during disease progression Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insight into the heterogeneity of these functional subpopulations at the genetic level This work has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells Analysing single cells from human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample, the evolutionary path by which different subclones have emerged, and ongoing dynamic changes associated with relapse Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells

Overview of Electric Motor Technologies Used for More Electric Aircraft (MEA)

Abstract: This paper presents an overview of motor drive technologies used for safety-critical aerospace applications, with a particular focus placed on the choice of candidate machines and their drive topologies. Aircraft applications demand high reliability, high availability, and high power density while aiming to reduce weight, complexity, fuel consumption, operational costs, and environmental impact. New electric driven systems can meet these requirements and also provide significant technical and economic improvements over conventional mechanical, hydraulic, or pneumatic systems. Fault-tolerant motor drives can be achieved by partitioning and redundancy through the use of multichannel three-phase systems or multiple single-phase modules. Analytical methods are adopted to compare caged induction, reluctance, and PM motor technologies and their relative merits. The analysis suggests that the dual (or triple) three-phase PMAC motor drive may be a favored choice for general aerospace applications, striking a balance between necessary redundancy and undue complexity, while maintaining a balanced operation following a failure. The modular single-phase approach offers a good compromise between size and complexity but suffers from high total harmonic distortion of the supply and high torque ripple when faulted. For each specific aircraft application, a parametrical optimization of the suitable motor configuration is needed through a coupled electromagnetic and thermal analysis, and should be verified by finite-element analysis.

Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells

Abstract: Langerhans cells (LCs) are a specialized subset of dendritic cells (DCs) that populate the epidermal layer of the skin Langerin is a lectin that serves as a valuable marker for LCs in mice and humans In recent years, new mouse models have led to the identification of other langerin(+) DC subsets that are not present in the epidermis, including a subset of DCs that is found in most non-lymphoid tissues In this Review we describe new developments in the understanding of the biology of LCs and other langerin(+) DCs and discuss the challenges that remain in identifying the role of different DC subsets in tissue immunity

Deciphering death: a commentary on Gompertz (1825) ‘On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies’

Abstract: In 1825, the actuary Benjamin Gompertz read a paper, ‘On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies’, to the Royal Society in which he showed that over much of the adult human lifespan, age-specific mortality rates increased in an exponential manner. Gompertz's work played an important role in shaping the emerging statistical science that underpins the pricing of life insurance and annuities. Latterly, as the subject of ageing itself became the focus of scientific study, the Gompertz model provided a powerful stimulus to examine the patterns of death across the life course not only in humans but also in a wide range of other organisms. The idea that the Gompertz model might constitute a fundamental ‘law of mortality’ has given way to the recognition that other patterns exist, not only across the species range but also in advanced old age. Nevertheless, Gompertz's way of representing the function expressive of the pattern of much of adult mortality retains considerable relevance for studying the factors that influence the intrinsic biology of ageing. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society .