PU.1 opposes IL-7-dependent proliferation of developing b cells with involvement of the direct target gene bruton tyrosine kinase

Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro-B cells from CD19-CreDPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells

PU.1 opposes IL-7-dependent proliferation of developing b cells with involvement of the direct target gene bruton tyrosine kinase

Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro-B cells from CD19-CreDPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells

Workflow Modelling of Construction Projects

This report details the work carried out by the Study Group on workflow modelling of con- struction projects. Data on the progress of about a hundred projects over a single five-year planning period were provided by Heathrow Airport (the client) and their four Tier 1 construction contrac- tors. These data are mapped and analysed. Several unusual features are discovered. For example, most projects undergo several tens of adjustments in their scope and price such that while most projects are technically completed under budget, the price and duration is significantly higher than originally planned. The main question addressed was whether an optimised scheduling of the project would lead to decreased costs and more rapid completion. First, a machine learning approach is used to gain insight onto which factors are most significant in predicting the final cost and duration of each project. If more data were available, these methods could be further exploited to allow for predictions to be made on which projects are likely to over-run or go over budget and to examine connections between projects at the subcontractor level. In addition to the data-centric approach, a complementary mathematical model was de- veloped to gain a better understanding of the effect of resource constraints on cost and price extension due to resource competition of concurrent projects, ignoring the confound- ing effect of scope creep seen in the data. The model takes the form of a discrete time stochastic simulation, whose parameters are fit to the existing data. Tentative conclusions from the model indicate that better outcomes can be achieved by spreading out project start dates, and by prioritising completion of smaller projects. While more data is needed to validate the model, the results suggested that gains can be made if more thoughtful scheduling of projects is implemented, and also if the prioritisation of projects is monitored and adjusted intelligently. Our major recommendation to Heathrow Airport is to collect or retrieve more data, as outlined in the report, so that both models can be made more realistic and useful. This would allow Heathrow Airport and their contractors to develop and test strategies to make the system more efficient, ultimately saving time and money

Mobile device remote tracking and lock-down

As mobile phone becomes a common device in our daily life-style and getting features rich, its protection and tracking becomes an essential functionality. This project requires the development of an agent-based application that track the location of the mobile device via GPS and also enable remote 'lock-down' (all functionalities blocked) of the device if lost. The application will be built on an Android powered mobile phone with GPS capability. The GPS details should enable the locating of the position on the map. Commands to capture the device's location, remote lock-down, etc are triggered via SMS. An interactive SMS process is required.Bachelor of Engineering (Computer Engineering

Personal non-commercial use only

ABSTRACT. Objective. To determine the efficacy of methotrexate (MTX) with infliximab (IFX) compared with MTX alone in the prevention of atherosclerosis and arterial stiffness in patients with early rheumatoid arthritis (RA). Methods. A randomized, open-label study in which early RA patients with active disease were treated with MTX alone (n = 20) and MTX plus IFX (n = 20) for 6 months. Patients were assessed every 3 months. Patients from the MTX-alone group who failed to achieve 28-joint Disease Activity Score remission (DAS28 ≤ 2.6) at 6 months were permitted to escape to open-label IFX. Intima-media thickness (IMT), pulse wave velocity (PWV), and augmentation index (AIx) were measured at baseline, 6 months, and 12 months. Results. At 6 months, there was a significantly greater reduction in PWV in the MTX-alone group (0.18 ± 1.59 m/s) compared with the MTX plus IFX group (−0.78 ± 1.13 m/s; p = 0.044), accompanied by significantly greater reduction in patient's global assessment, number of swollen joints, C-reactive protein, and DAS28 in the MTX plus IFX group compared to the MTX-alone group. The changes in IMT and AIx were similar between the 2 groups. At 12 months, there was a trend favoring early combination treatment with regard to the reduction in PWV (p = 0.06). Conclusion. MTX plus IFX causes a more significant reduction in PWV than MTX alone in patients with early RA after 6-month treatment, and further improvement may be achieved in patients who continued on longterm tumor necrosis factor-α blockers, suggesting that early, effective suppression of inflammation may prevent progression of atherosclerosis by improving vascular function

Personal non-commercial use only

ABSTRACT. Objective. To determine the efficacy of methotrexate (MTX) with infliximab (IFX) compared with MTX alone in the prevention of atherosclerosis and arterial stiffness in patients with early rheumatoid arthritis (RA). Methods. A randomized, open-label study in which early RA patients with active disease were treated with MTX alone (n = 20) and MTX plus IFX (n = 20) for 6 months. Patients were assessed every 3 months. Patients from the MTX-alone group who failed to achieve 28-joint Disease Activity Score remission (DAS28 ≤ 2.6) at 6 months were permitted to escape to open-label IFX. Intima-media thickness (IMT), pulse wave velocity (PWV), and augmentation index (AIx) were measured at baseline, 6 months, and 12 months. Results. At 6 months, there was a significantly greater reduction in PWV in the MTX-alone group (0.18 ± 1.59 m/s) compared with the MTX plus IFX group (−0.78 ± 1.13 m/s; p = 0.044), accompanied by significantly greater reduction in patient's global assessment, number of swollen joints, C-reactive protein, and DAS28 in the MTX plus IFX group compared to the MTX-alone group. The changes in IMT and AIx were similar between the 2 groups. At 12 months, there was a trend favoring early combination treatment with regard to the reduction in PWV (p = 0.06). Conclusion. MTX plus IFX causes a more significant reduction in PWV than MTX alone in patients with early RA after 6-month treatment, and further improvement may be achieved in patients who continued on longterm tumor necrosis factor-α blockers, suggesting that early, effective suppression of inflammation may prevent progression of atherosclerosis by improving vascular function