Adapting the Dutch 'mobility explorer' program to investigate possible car taxation futures in the UK

This paper reports work being conducted as part of the only transport project in the current ESRC programme on the Environment and Human Behaviour. The concept of generalised road user changes eventually replacing existing Fuel Duties and Vehicle Excise Duty (VED) is in the ascendant, with several studies concentrating upon the eventual adoption of a GPS-based congestion charging system. The Dutch and Swiss have also been exploring such schemes. In particular the Dutch have looked at a more quickly and easily implemented option of distance charging rather than congestion charging that is favoured in the UK. This project seeks to explore a wider range of new taxation options, particularly seeking more pragmatic paths towards early implementation rather than the 10 – 20 year timescale currently envisaged. Indeed, the Dutch studies have suggested that distance charging might yield most of the traffic management and emission reduction benefits of congestion charging, with a modelled reduction in car kilometres travelled of between 18 and 35 per cent compared with a ‘business as usual’ base case. In this project, the Dutch Mobility Explorer program that was used to estimate the effects of a national distance charge, is being adapted using UK data to investigate a series of possible car taxation futures. These range from a low-key introduction of a distance charge to replace VED, through to a distance charging system replacing fuel tax and VED and a GPS congestion charging system. This will permit a comparison of the traffic, congestion and emission reductions between such options and also a cross-country comparison on a comparable basis with the existing Dutch work. The adaptation of the Dutch model to the UK has not been straightforward, and possibly the greatest lessons have been in helping to understand the differences in context in which a seemingly similar transport policy measure is being proposed. The paper concludes with a reflection upon the rapid rise in favour by the UK government for of generalised road user changes to replace Fuel Duties and VED. It is suggested that this is not a way to avoid hard decisions in transport policy that it may at first seem

Taxation Futures for Sustainable Mobility: final report to the ESRC

The existing transport tax and charging regime has stimulated limited behavioural change and has been politically problematic (as demonstrated by the September 2000 fuel duty protests). This project synthesised a range of research that has explored ways in which road user charging could replace the present regime based on taxing fuels and car ownership. In 2002, when this project was proposed, this was a fringe transport policy issue. Throughout 2003 the subject achieved a sudden prominence, with a government working party being established to explore the possibility of long-term area-wide road user charging. A tax regime change towards a car road user charge for cars has occurred, or is being considered, in societies as contrasting as Oregon State in the USA, the Netherlands, Switzerland and the UK, reflecting a range of policy considerations. For the UK, these include: the ongoing failure of transport policy measures to achieve adequate cuts in congestion and emissions; the success of the London Congestion Charge; the rise in the cost of transport policy interventions; the reduction in Treasury income of eco-reforms to the current tax regime; and the difficulties of, and equity issues relating to, taxing fuel in a future multi-fuel transport sector. The project developed tax change scenarios in conjunction with the project's user group (including policymakers, NGOs and researchers). Five scenarios were modelled using an adaptation of the Dutch Mobility Explorer program. An 'opt-in' transitional policy mechanism involved replacing VED with a small flat-rate kilometre charge for cars of 0.77 p/km. The model suggested it would have little policy impact, but could be used to familiarise car drivers with the concept of a distance charge. A fiscally neutral scenario involved the replacement of VED and Fuel Duty with a banded kilometre charge for cars of between 2.3 and 8.5 p/km (varied by the environmental performance of the vehicle type). This induced little behaviour change, reducing car driver mobility by only 4%. A further scenario, restored the tax revenues lost from post-2000 tax changes, generating an additional £3 billion or £6b per annum. These reduced car driver mobility by 9% - 14%, and total CO2 emissions were predicted to drop by 6% - 9% by 2015, compared to the base scenario. The type of change involved in the revenue-raising scenarios is significant. There would be only a small increase in the use of public transport, with the predominant response being the better utilisation of cars with higher occupancy and more linking of trips to cut distances driven. The project results suggest that road user charging may deliver more revenue stability than fuel taxation. However, clarity is needed over the policy goals – congestion reduction, emission reduction, revenue stability – for a national road user charge, because the goals are not necessarily complementary. It should also be emphasised that a change of tax regime would not remove the need the hard political decisions in this area

Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2

TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5′-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail, we designed synthetic routes to novel analogues of ADPR and 2′-deoxy-ADPR that were modified only by removal of a single hydroxyl group from the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2″-based analogues proved to be unstable. The C1″- and C3″-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1″-β-O-methyl-2″,3″-O-isopropylidene derivative was evaluated. Removal of either C1″ or C3″ hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications and blocking all three hydroxyl groups resulted in TRPM2 antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation.</p

Brian Ferneyhough

&nbsp; &nbsp

SHIP2:structure, function and inhibition

SHIP2 is a phosphatase that acts at the 5-position of phosphatidylinositol 3,4,5-trisphosphate. It is one of several enzymes that catalyse dephosphorylation at the 5-position of phosphoinositides or inositol phosphates. SHIP2 has a confirmed role in opsismodysplasia, a disease of bone development, but also interacts with proteins involved in insulin signalling, cytoskeletal function (thus having an impact on endocytosis, adhesion, proliferation and apoptosis) and immune system function. The structure of three domains (constituting about 38% of the protein) is known. Inhibitors of SHIP2 activity have been designed to interact with the catalytic domain with sub-micromolar IC50 values: these come from a range of structural classes and have been shown to have in vivo effects consistent with SHIP2 inhibition. Much remains unknown about the roles of SHIP2 and possible future directions for research are indicated

Steroid sulfatase:a pivotal player in estrogen synthesis and metabolism

International audienceSteroid sulfatase plays a pivotal role in regulating the formation of biologically active steroids from inactive steroid sulfates. It is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be subsequently reduced to steroids with estrogenic properties (i.e. estradiol and androstenediol) that can stimulate the growth of tumors in hormone-responsive tissues of the breast, endometrium and prostate. Hence, the action of steroid sulfatase is implicated in physiological processes and pathological conditions. It has been five years since our group last reviewed the important role of this enzyme in steroid synthesis and the progress made in the development of potent inhibitors of this important enzyme target. This timely review therefore concentrates on recent advances in steroid sulfatase research, and summarises the findings of clinical trials with Irosustat (BN83495), the only steroid sulfatase inhibitor that is being trialed in postmenopausal women with breast or endometrial cancer

Second messenger analogues highlight unexpected substrate sensitivity of CD38: total synthesis of the hybrid “L-cyclic inosine 5'-diphosphate ribose”

The multifunctional, transmembrane glycoprotein human CD38 catalyses the synthesis of three key Ca2+-mobilising messengers, including cyclic adenosine 5′-diphosphate ribose (cADPR), and CD38 knockout studies have revealed the relevance of the related signalling pathways to disease. To generate inhibitors of CD38 by total synthesis, analogues based on the cyclic inosine 5′-diphosphate ribose (cIDPR) template were synthesised. In the first example of a sugar hybrid cIDPR analogue, “L-cIDPR”, the natural “northern” N1-linked D-ribose of cADPR was replaced by L-ribose. L-cIDPR is surprisingly still hydrolysed by CD38, whereas 8-Br-L-cIDPR is not cleaved, even at high enzyme concentrations. Thus, the inhibitory activity of L-cIDPR analogues appears to depend upon substitution of the base at C-8; 8-Br-L-cIDPR and 8-NH2-L-cIDPR inhibit CD38-mediated cADPR hydrolysis (IC50 7 μM and 21 µM respectively) with 8-Br-L-cIDPR over 20-fold more potent than 8-Br-cIDPR. In contrast, L-cIDPR displays a comparative 75-fold reduction in activity, but is only ca 2-fold less potent than cIDPR itself. Molecular modelling was used to explore the interaction of the CD38 catalytic residue Glu-226 with the “northern” ribose. We propose that Glu226 still acts as the catalytic residue even for an L-sugar substrate. 8-Br-L-cIDPR potentially binds non-productively in an upside-down fashion. Results highlight the key role of the “northern” ribose in the interaction of cADPR with CD38

A Fluorescent Probe Identifies Active Site Ligands of Inositol Pentakisphosphate 2-Kinase

Inositol pentakisphosphate 2-kinase catalyzes the phosphorylation of the axial 2-OH of myo-inositol 1,3,4,5,6-pentakisphosphate for de novo synthesis of myo-inositol hexakisphosphate. Disruption of inositol pentakisphosphate 2-kinase profoundly influences cellular processes; from nuclear mRNA export and phosphate homeostasis in yeast and plants, to establishment of left-right asymmetry in zebra fish. We elaborate an active site fluorescent probe that allows high throughput screening of Arabidopsis inositol pentakisphosphate 2-kinase. We show that the probe has a binding constant comparable to the Km values of inositol phosphate substrates of this enzyme, and can be used to prospect for novel substrates and inhibitors of inositol phosphate kinases. Weidentify several micromolar Ki inhibitors and validate this approach by solving the crystal structure of protein in complex with purpurogallin. We additionally solve structures of protein in complexes with epimeric higher inositol phosphates. This probe may find utility in characterization of a wide family of inositol phosphate kinases

Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury

We previously found that myocardial ischemia/ reperfusion (I/R) initiates expression of tumor necrosis factor-α (TNF) leading to coronary endothelial dysfunction. However, it is not clear whether there is a direct relationship between levels of TNF expression and endothelial dysfunction in reperfusion injury. We studied levels of TNF expression by using different transgenic animals expressing varying amounts of TNF in I/R. We crossed TNF overexpression (TNF++/++) with TNF knockout (TNF-/-) mice; thus we have a heterozygote population of mice with the expression of TNF "in between" the TNF-/- and TNF++/++ mice. Mouse hearts were subjected to 30 min of global ischemia followed by 90 min of reperfusion and their vasoactivity before and after I/R was examined in wild type (WT), TNF-/-, TNF++/++ and TNF heterozygote (TNF -/++, cross between TNF-/- and TNF++/++) mice. In heterozygote TNF-/++ mice with intermediate cardiac-specific expression of TNF, acetyl-choline-induced or flow-induced endothelial-dependent vasodilation following I/R was between TNF++/++ and TNF-/- following I/R. Neutralizing antibodies to TNF administered immediately before the onset of reperfusion-preserved endothelial-dependent dilation following I/R in WT, TNF-/++ and TNF++/++ mice. In WT, TNF -/++ and TNF++/++ mice, I/R-induced endothelial dysfunction was progressively lessened by administration of free-radical scavenger TEMPOL immediately before initiating reperfusion. During I/R, production of superoxide (O2-) was greatest in TNF ++/++ mice as compared to WT, TNF-/++ and TNF -/- mice. Following I/R, arginase mRNA expression was elevated in the WT, substantially elevated in the TNF-/++ and TNF ++/++mice and not affected in the TNF-/- mice. These results suggest that the level of TNF expression determines arginase expression in endothelial cells during myocardial I/R, which is one of the mechanisms by which TNF compromises coronary endothelial function in reperfusion injury