Identification of genes involved in leukaemia and differentiation induced by activated mutants of the GM-CSF receptor β subunit.

Interleukin (IL)-3, IL-5 and granulocyte-macrophage-colony-stimulating factor (GM-CSF) are cytokines that affect the growth, survival and differentiation of many cells within the haematopoietic system. The functions of these factors are mediated by membrane bound receptor complexes that are composed of specific ligand binding subunits (α)and a common signal transducing subunit(hβc). Constitutively activated mutants of hβc have been previously identified that are able to confer factor-independent signalling in a number of haematopoietic cell lines (including FDC-P1 and FDB-1). These activated mutants fall into two classes defined by the location of the mutation and their biochemical and leukaemogenic properties. In particular, the transmembrane mutant, V449E, causes an acute myeloid leukaemia in vivo, whereas the extracellular mutants (FI∆ or I374N) cause chronic myeloproliferative disorders. The work described in this thesis used the activated hβc mutants to uncover novel transcriptional events induced by the GM-CSF/IL-3/IL-5 receptor complex and to define pathways associated with proliferation and differentiation. Large-scale gene expression profiling techniques were used to investigate the genes involved in these biological processes in the murine myelomonocytic cell line FDC-P1, and the bi-potent FDB-1 myeloid cell line, which are responsive to IL-3 and GM-CSF. Membrane arrays were used to identify differences in gene expression between I374N and V449E expressing FDC-P1 cells. This technique revealed that the gene Ptpmt1 was differentially expressed between V449E and I374N, which was subsequently confirmed by Northern blotting. This finding suggested that the phosphatase encoded by Ptpmt1 may be involved in the different outcomes induced by these two hβc mutants. Northern analysis also revealed Ptpmt1, Nab1 and Ddx26b to be regulated in response to human GM-CSF in FDC-P1 cells expressing human GM CSFα and hβc. A large-scale cDNA microarray experiment was also performed to identify genes that are selectively expressed during differentiation of FI∆ expressing FDB-1 cells, compared to proliferating V449E expressing FDB-1 cells over 24 hours. A comprehensive analysis approach was adopted to examine the microarray data and identify differentially expressed genes. Among the genes displaying differential expression were Btg1, S100a9, Cd24, and Ltf found to be differentiation-associated and Bnip3, Cd34, Myc, Nucleophosmin, and Nucleostemin found to be proliferation-associated. Hipk1, Klf6, Sp100, and Sfrs3 were also identified as potential transcriptional regulators during growth and differentiation. Northern analysis was used to confirm differences in expression for these 13 genes between FI∆ and V449E expressing FDB-1 cells. Eleven of the 13 genes examined were confirmed to be differentially expressed between FI∆ and V449E expressing FDB-1 cells over 24 hours. Furthermore, six genes (Btg1, Hipk1, Cd24, Cd34, Klf6 and Nucleostemin) examined over 72 hours revealed differences in gene expression at early (6-12 hours) and late (48-72 hours) time points. Cell surface expression of CD24 protein was also shown to be induced upon FI∆ expression or GM-CSF induced differentiation of FDB-1 cells, consistent with elevated levels of Cd24 mRNA in FI∆ cells over time. Based on their confirmed gene expression differences seen on the microarrays and Northern analysis, four genes (Btg1, Cd24, Klf6 and Nucleostemin) were selected for over-expression analysis in FDC-P1 or FDB-1 cells, in order to gain insights into the function of these genes. Optimisation of the retroviral infection process was performed so that the role of these genes in proliferation and differentiation could be investigated in the FDB-1 model. Such preliminary functional experiments in FDB-1 cells will enable prioritisation of the genes for further analysis of their function in primary cells. Thus, the work in this thesis describes the first use of microarrays to identify gene expression differences between hβc mutants with differential activities affecting myeloid growth and differentiation.Thesis (PhD)-- School of Medicine, 200

Task-level robot programming: Integral part of evolution from teleoperation to autonomy

An explanation is presented of task-level robot programming and of how it differs from the usual interpretation of task planning for robotics. Most importantly, it is argued that the physical and mathematical basis of task-level robot programming provides inherently greater reliability than efforts to apply better known concepts from artificial intelligence (AI) to autonomous robotics. Finally, an architecture is presented that allows the integration of task-level robot programming within an evolutionary, redundant, and multi-modal framework that spans teleoperation to autonomy

MCE 2018: The 1st Multi-target Speaker Detection and Identification Challenge Evaluation

The Multi-target Challenge aims to assess how well current speech technology is able to determine whether or not a recorded utterance was spoken by one of a large number of blacklisted speakers. It is a form of multi-target speaker detection based on real-world telephone conversations. Data recordings are generated from call center customer-agent conversations. The task is to measure how accurately one can detect 1) whether a test recording is spoken by a blacklisted speaker, and 2) which specific blacklisted speaker was talking. This paper outlines the challenge and provides its baselines, results, and discussions.Comment: http://mce.csail.mit.edu . arXiv admin note: text overlap with arXiv:1807.0666

Graphical programming and the use of simulation for space-based manipulators

Robotic manipulators are difficult to program even without the special requirements of a zero-gravity environment. While attention should be paid to investigating the usefulness of industrial application programming methods to space manipulators, new methods with potential application to both environments need to be invented. These methods should allow various levels of autonomy and human-in-the-loop interaction and simple, rapid switching among them. For all methods simulation must be integrated to provide reliability and safety. Graphical programming of manipulators is a candidate for an effective robot programming method despite current limitations in input devices and displays. A research project in task-level robot programming has built an innovative interface to a state-of-the-art commercial simulation and robot programming platform. The prototype demonstrates simple augmented methods for graphical programming and simulation which may be of particular interest to those concerned with Space Station applications; its development has also raised important issues for the development of more sophisticated robot programming tools. Both aspects of the project are discussed

Magnetohydrodynamic simulations of black hole accretion

We discuss the results of three-dimensional magnetohydrodynamic simulations, using a pseudo-Newtonian potential, of thin disk (h/r ~ 0.1) accretion onto black holes. We find (i) that magnetic stresses persist within the marginally stable orbit, and (ii) that the importance of those stresses for the dynamics of the flow depends upon the strength of magnetic fields in the disk outside the last stable orbit. Strong disk magnetic fields (alpha > 0.1) lead to a gross violation of the zero-torque boundary condition at the last stable orbit, while weaker fields (alpha ~ 0.01) produce results more akin to traditional models for thin disk accretion onto black holes. Fluctuations in the magnetic field strength in the disk could lead to changes in the radiative efficiency of the flow on short timescales.Comment: 6 pages, to appear in proceedings, 20th Texas Symposium on Relativistic Astrophysics, eds J.C. Wheeler and H. Marte

Transformative souls and transformed selves : 'Buffy', 'Angel' and the daimonic tale

This essay explores one of the most significant factors in the continuing appeal of Buffy and Angel — the features of the sacred they employ in narrative arcs of character development, and the ritualistic interaction this creates with fans of the television shows. I argue that Buffy and Angel’s deployment of the idea of the soul produces a distinctive approach to identity, and I here use the concept of the daimonic as a framework for textual analysis. Their distinctive approach to identity begins with the idea of the soul as an essential self that can be separated from the body and relocated. These transportable identities support particular types of narrative, and thus help in recognising why these shows continue to appeal. These divisible and changeable selves also help us to understand the Buffy-verse’s style of horror. In combination, these features help us appreciate not only the ritual of watching and re-watching, but also the ways in which Buffy and Angel bring the religious themes of ancient, spiritual traditions into popular culture and fandom—with vital contemporaneity