Effect of ethanol and of noise on reaction time in the monkey: Variation with stimulus level

To determine whether the latency-increasing effects of ethanol were differential with respect to the intensity of the stimulus that initiated the response, three rhesus monkeys were trained on a behavioral task in which the latency of a simple motor response was measured following the onset of a pure tone stimulus. Following training, the animals were tested at a number of different tone intensities and functions relating latency to tone intensity were constructed. When these were stable, the animals were given ethanol in doses of 1.0–2.5 g/kg and the effects on response latencies to different tone intensities were determined. It was found that, for all except the lowest stimulus levels, the effect of ethanol was dose-related, while for a given dose the effect was equal across intensity. These results indicate that the effects of ethanol in this situation are on response execution rather than stimulus detection. The effects of ethanol were compared to those of exposure to high intensity noise. This treatment, which affects primarily the inner ear, resulted in substantial increases in latency to low intensity tones, but little, if any, shift at high intensities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46413/1/213_2004_Article_BF00426520.pd

Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer.

Genomic alterations in cancer cells result in vulnerabilities that clinicians can exploit using molecularly targeted drugs, guided by knowledge of the tumour genotype. However, the selective activity of these drugs exerts an evolutionary pressure on cancers that can result in the outgrowth of resistant clones. Use of rational drug combinations can overcome resistance to targeted drugs, but resistance may eventually develop to combinatorial therapies. We selected MAPK- and PI3K-pathway inhibition in colorectal cancer as a model system to dissect out mechanisms of resistance. We focused on these signalling pathways because they are frequently activated in colorectal tumours, have well-characterised mutations and are clinically relevant. By treating a panel of 47 human colorectal cancer cell lines with a combination of MEK- and PI3K-inhibitors, we observe a synergistic inhibition of growth in almost all cell lines. Cells with KRAS mutations are less sensitive to PI3K inhibition, but are particularly sensitive to the combined treatment. Colorectal cancer cell lines with inherent or acquired resistance to monotherapy do not show a synergistic response to the combination treatment. Cells that acquire resistance to an MEK-PI3K inhibitor combination treatment still respond to an ERK-PI3K inhibitor regimen, but subsequently also acquire resistance to this combination treatment. Importantly, the mechanisms of resistance to MEK and PI3K inhibitors observed, MEK1/2 mutation or loss of PTEN, are similar to those detected in the clinic. ERK inhibitors may have clinical utility in overcoming resistance to MEK inhibitor regimes; however, we find a recurrent active site mutation of ERK2 that drives resistance to ERK inhibitors in mono- or combined regimens, suggesting that resistance will remain a hurdle. Importantly, we find that the addition of low concentrations of the BCL2-family inhibitor navitoclax to the MEK-PI3K inhibitor regimen improves the synergistic interaction and blocks the acquisition of resistance

Increase urban freight efficiency with delivery and servicing plan

Delivery and Servicing Plan (DSP) is an innovative logistics concept for more efficient organisation of deliveries from the point of view of the receiver of the goods. DSP actions tested in this study include reducing the number of suppliers, grouping deliveries, selecting less distant suppliers and others. It is shown that DSP can help reduce externalities and lead to a substantial reduction of costs. A new tool was developed to calculate the benefits of different DSP options for businesses and the public sector. Reductions in costs and externalities exceeding 50% have been demonstrated in a few cases. Remaining difficulties with the concept are organisational issues, lack of knowledge, need to give external advisory support for shop owners and the limited number of successful applications to date

Sustainable procurement for greener logistics in the Higher Education sector

Purpose: Using the University of Southampton as a case study example, this paper reviews how procurement practices (i.e. purchasing of goods and services) of large organisations impact upon goods and service vehicle activity, with a view to investigating what approaches may be taken to reduce carbon footprint and improve environmental sustainability. The approaches considered included consolidation of suppliers, buyers (individuals and departments), orders and consignments. Research Approach: Existing procurement operating frameworks or models were initially reviewed with a view to understanding the key structures, principles, constraints and drivers that determine or influence purchasing practice. The review also considered measures that have been taken to address environmental sustainability concerns, particularly associated with goods and service vehicle activity (e.g. development of delivery and service plans). By considering both the procurement processes and the resulting generation of freight transport in tandem an improved framework can be developed to reduce freight traffic on site. Following the review, purchasing records over a period of one year from the Faculty of Engineering and the Environment at the University of Southampton were analysed to determine purchasing behaviour and to assess the volumes and frequencies of purchases made. Findings and Originality: Our preliminary analyses have illustrated the widely distributed nature of purchasing with around 250 requisitioners in a single faculty placing orders with nearly 1000 suppliers and with multiple delivery points on campus. Originality lies in the consideration of both procurement and resulting logistics activity and in the detailed analyses that are seldom undertaken by large organisations let alone published. The research builds on similar types of study undertaken at the universities of Newcastle and Westminster.Research Impact: The main research impact lies in establishing the links between procurement practices and goods and servicing activity at a large organisation, with the aim of improving environmental sustainability. Practical Impact: The study illustrates how large municipal organisations can reduce the carbon footprint associated with their purchasing activities. There is a strong practical focus to the research using purchasing records to raise awareness of purchasing behaviour and identifying practical ways to operate more sustainably. The concepts, results and conclusions are likely to be transferable to any large municipal organisation where a wide range of purchases are made by many buyers, using many different suppliers