Global Properties of Locally Spatially Homogeneous Cosmological Models with Matter

The existence and nature of singularities in locally spatially homogeneous solutions of the Einstein equations coupled to various phenomenological matter models is investigated. It is shown that, under certain reasonable assumptions on the matter, there are no singularities in an expanding phase of the evolution and that unless the spacetime is empty a contracting phase always ends in a singularity where at least one scalar invariant of the curvature diverges uniformly. The class of matter models treated includes perfect fluids, mixtures of non-interacting perfect fluids and collisionless matter.Comment: 18 pages, MPA-AR-94-

Ablative Treatment With Autologous Bone Marrow Transplantation for Acute Myeloid Leukaemia

Improvements have taken place in recent years, in the treatment of acute myeloid leukaemia(AML) with a steady increase in the proportion of patients entering complete remission. There has been less progress in devising appropriate post-remission therapy, with the result that there is a continuous risk of disease recurrence with most patients dying from their disease within five years. For a minority of patients a combination of chemotherapy and total body irradiation, designed to be ablative to the bone marrow, supported by bone marrow transplantation from an HLA matched sibling donor has proved effective, being capable of curing half the patients, but having the probability of eradicating leukaemia in approximately 80% of patients

The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias

Tefinostat (CHR-2845) is a novel monocyte/macrophage-targeted histone deacetylase (HDAC) inhibitor which is cleaved into its active acid by the intracellular esterase human carboxylesterase-1 (hCE-1). The in vitro efficacy of tefinostat was characterised in cell lines and in a cohort of 73 primary AML and CMML samples. Dose-dependent induction of apoptosis and significant growth inhibitory effects were seen in myelomonocytic (M4), monocytic/monoblastic (M5) and CMML samples in comparison to non-monocytoid AML sub-types (p = 0.007). Importantly, no growth inhibitory effects were seen in normal bone marrow CD34+ cells exposed to AML-toxic doses of tefinostat in clonogenic assays. Expression of hCE-1 was measured by intracellular flow cytometry and immunoblotting across the cohort, with highest levels seen in M5 AML patients. hCE-1 levels correlated with significantly increased tefinostat sensitivity (low EC50) as measured by growth inhibition assays (p = 0.001)and concomitant elevation of the mature monocytoid marker CD14+. Strong induction of intracellular histone protein acetylation was observed in tefinostat-responsive samples, as were high levels of the DNA damage sensor γ-H2A.X, highlighting potential biomarkers of patient responsiveness. Synergistic interaction between tefinostat and the current standard treatment cytarabine was demonstrated in dose response and clonogenic assays using simultaneous drug addition in primary samples (median Combination Index value = 0.51). These data provide a strong rationale for the further clinical evaluation of tefinostat in monocytoid-lineage haematological neoplasms including CMML and monocyte-lineage AMLs

Assessment of the occlusion technique as a means for evaluating the distraction potential of driver support systems

Driver distraction is a safety-critical issue that has been bought to greater public attention with the recent developments of more advanced driver support systems (DSS), such as navigation and collision warning. Tasks performed with such systems have the potential to distract drivers significantly from the primary task of controlling their vehicle, and this may result in an accident. Designers of DSS need to be able to assess this distraction potential in the early stages of design. In this respect, the occlusion technique and its associated measures are claimed to be reliable indicators of potential visual distraction. In particular, it has been argued that the technique provides more information concerning the likely visual demand of a system than other economical methods based on static task time, such as the 15-second rule. To investigate these assertions, a study compared results from an occlusion assessment and a road-based assessment. Sixteen experienced drivers carried out a range of tasks using two alternative user-interfaces under three conditions: statically, with full vision, statically, with restricted vision (occlusion), and whilst driving on a dual carriageway road within the UK. It was found that occlusion measures provided more information regarding the prospective visual demand of a DSS than did static task times. In particular, the resumability ratio assessed how far a task can be progressed whilst in periods with vision and without vision. It is concluded that the technique offers advantages over other methods, but requires a robust prototype for use as part of a driver-centred design process

SO_2-rock interaction on Io 2. Interaction with pure SO_2

A Na-S mineral on the surface of Io is required to be the source of the famous atomic cloud. SO_2 is a confirmed atmospheric and surface constituent, and because of the rapid volcanic resurfacing rate, the SO_2 is buried within the crust, where at least occasionally, over many cycles of burial and eruption, it must contact silicate materials at midlevel crustal temperatures. Surface interaction experiments were performed for a wide variety of silicate compositions showing that interaction products of these with SO_2 could be observed at 1123 K on laboratory timescales, even in the absence of external redox agents. Not all experiments produced deposits that could be studied by scanning electron microscopy; some required the greater sensitivity of photoelectron spectroscopy (XPS). Characterization of the alteration products by XPS showed that both oxidized and reduced sulfur species were formed, indicating that a disproportionation mechanism producing a sulfate and a reduced S species although smaller amounts of interaction leading to Na_2SO_3 formation cannot be ruled out. The reduced sulfur species is best explained as elemental S which was independently documented for two compositions. Scanning electron microscopy studies for those compositions where reaction was extensive enough to be observed showed (1) Na_2SO_4 for a soda-lime composition, (2) a mixed Na-Ca-sulfate liquid and CaSO_4 for AbAnDi and a chondrule glass composition, and (3) Fe-sulfate for a natural obsidian. Infrared spectroscopy for the soda-lime glass composition showed peaks best explained by Na_2SO_4. We conclude that SO_2 disproportionation as well as direct formation from SO_3 under oxidizing conditions can produce Na_2SO_4 by interaction of SO_2 with silicates on Io, but Ca and Fe sulfates may form preferentially in more basaltic compositions. As highly oxidizing conditions may be unlikely for Io, the disproportionation mechanism may be more competitive on Io than it is in laboratory experiments. Very low rates of Na_2SO_4 production are required to supply the Io atomic cloud, so the interaction processes can be very inefficient

UK: racial violence and the night-time economy

This article examines fifty-five racist attacks over a six-month period in the UK’s night-time economy, showing the risks faced by members of the public and workers at taxi firms, takeaways, convenience stores and service stations. It argues that flexible and highly casualised labour conditions exacerbate the risk of racial violence

The PDK1 master kinase is over-expressed in acute myeloid leukemia and promotes PKC-mediated survival of leukemic blasts

PDK1 is a master kinase that activates at least six protein kinase groups including AKT, PKC and S6K and is a potential target in the treatment of a range of malignancies. Here we show overexpression of PDK1 in over 40% of myelomonocytic acute leukemia patients. Overexpression of PDK1 occurred uniformly throughout the leukemic population, including putative leukemia-initiating cells. Clinical outcome analysis revealed PDK1 overexpression was associated with poorer treatment outcome. Primary acute myeloid leukemia blasts over-expressing PDK1 showed improved in vitro survival and ectopic expression of PDK1 promoted the survival of myeloid cell lines. Analysis of PDK1 target kinases revealed that PDK1 overexpression was most closely associated with increased phosphorylation of PKC isoenzymes and inhibition of PKC strongly inhibited the survival advantage of PDK1 over-expressing cells. Membrane localization studies implicated PKCα as a major target for PDK1 in this disease. PDK1 over-expressing blasts showed differential sensitivity to PDK1 inhibition (in the low micromolar range) suggesting oncogene addiction, whilst normal bone marrow progenitors were refractory to PDK1 inhibition at effective inhibitor concentrations. PDK1 inhibition also targeted subpopulations of leukemic blasts with a putative leukemia-initiating cell phenotype. Together these data show that overexpression of PDK1 is common in acute myelomonocytic leukemia and is associated with poorer treatment outcome, probably arising from the cytoprotective function of PDK1. We also show that therapeutic targeting of PDK1 has the potential to be both an effective and selective treatment for these patients, and is also compatible with current treatment regimes

Explaining Reinforcement Learning to Mere Mortals: An Empirical Study

We present a user study to investigate the impact of explanations on non-experts' understanding of reinforcement learning (RL) agents. We investigate both a common RL visualization, saliency maps (the focus of attention), and a more recent explanation type, reward-decomposition bars (predictions of future types of rewards). We designed a 124 participant, four-treatment experiment to compare participants' mental models of an RL agent in a simple Real-Time Strategy (RTS) game. Our results show that the combination of both saliency and reward bars were needed to achieve a statistically significant improvement in mental model score over the control. In addition, our qualitative analysis of the data reveals a number of effects for further study.Comment: 7 page

Ral is both necessary and sufficient for the inhibition of myeloid differentiation mediated by Ras

Hyperactivation of Ras is one of the most common abnormalities in acute myeloid leukemia. In experimental models, Ras inhibits myeloid differentiation, which is characteristic of leukemia; however, the mechanism through which it disrupts hematopoiesis is poorly understood. In multipotent FDCP-mix cells, Ras inhibits terminal neutrophil differentiation, thereby indefinitely extending their proliferative potential. Ras also strongly promotes the sensitivity of these cells to granulocyte-macrophage colony-stimulating factor (GM-CSF). Using this model, we have dissected the signaling elements downstream of Ras to determine their relative contribution to the dysregulation of hematopoiesis. Cells expressing Ras mutants selectively activating Raf (Ras*T35S) or phosphatidylinositol 3-kinase (Ras*Y40C) did not significantly affect differentiation or proliferative capacity, whereas Ras*E37G (which selectively activates RalGEFs) perpetuated proliferation and blocked neutrophil development in a manner similar to that of Ras. Correspondingly, expression of constitutively active versions of these effectors confirmed the overriding importance of Ral guanine nucleotide exchange factors. Cells expressing Ras demonstrated hyperactivation of Ral, which itself was able to exactly mimic the phenotype of Ras, including hypersensitivity to GM-CSF. Conversely, dominant negative Ral promoted spontaneous neutrophil development. Ral, in turn, appears to influence differentiation through multiple effectors. These data show, for the first time, the importance of Ral in regulating differentiation and self-renewal in hematopoietic cells