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Michael Steed predicts that devolution will create new career paths for politicians, ending three centuries of centralised ‘court’ politics.

TNF is a pleiotropic cytokine required for normal development and function of the immune system; however, TNF overexpression also induces inflammation and is associated with autoimmune diseases. TNF exists as both a soluble and a transmembrane protein. Genetic studies in mice have suggested that inflammation in disease models involves soluble TNF (solTNF) and that maintenance of innate immune function involves transmembrane TNF (tmTNF). These findings imply that selective pharmacologic inhibition of solTNF may be anti-inflammatory and yet preserve innate immunity to infection. To address this hypothesis, we now describe dominant-negative inhibitors of TNF (DN-TNFs) as a new class of biologics that selectively inhibits solTNF. DN-TNFs blocked solTNF activity in human and mouse cells, a human blood cytokine release assay, and two mouse arthritis models. In contrast, DN-TNFs neither inhibited the activity of human or mouse tmTNF nor suppressed innate immunity to Listeria infection in mice. These results establish DN-TNFs as the first selective inhibitors of solTNF, demonstrate that inflammation in mouse arthritis models is primarily driven by solTNF, and suggest that the maintenance of tmTNF activity may improve the therapeutic index of future anti-inflammatory agents.

A dominant hypomorphic allele of Tnf, PanR1, was identified in a population of G1 mice born to N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes produced no detectable TNF bioactivity, although normal quantities of immunoreactive TNF were secreted. The phenotype was confined to a critical region on mouse chromosome 17, and then ascribed to a C→A transversion at position 3480 of the Tnf gene, corresponding to the amino acid substitution P138T. As a result of subunit exchange, the protein exerts a dominant-negative effect on normal TNF trimers, interfering with the trimer/receptor interaction. Homozygotes are highly susceptible to infection by Listeria monocytogenes, confirming the essential role of TNF in innate immune defense. However, PanR1 mutant mice show normal architecture of the spleen and Peyer’s patches, suggesting that TNF is not essential for the formation of these lymphoid structures.

Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.

The debate about electoral reform in Britain has taken a new turn with the latest upsurge in mid-term support for the Liberals, the launch of the SDP, and the immediate electoral success of the Alliance between the two parties. We do not deal here with the durability or consequences of these developments. We are concerned with the electoral system that they put under challenge. This concern is the more important because, as we shall show here, the working of that system altered fundamentally between 1955 and 1979. Before considering how fragile ‘the mould of British polities’ is or whether it should be broken, it is appropriate to reconsider and remeasure the precise shape and texture of that mould, and establish what are the chemical bonds which have determined those characteristics.

The impact of the direct election of the European Parliament is assessed with reference to the hopes of the proponents of European integration—increased weight for the Parliament, legitimacy for the institutions and achievements of European integration, and the development of trans-national political forces. Particular examination is made of the low level of turnout in the elections, of the absence of any Community-wide focus on personalities or on issues in the campaign and of the problems of the Socialist, Christian Democratic and Liberal party federations. One effect offering an integrative prospect is the emerging elite of full-time trans-national politicians.

Study of the territorial dimension of British politics has focused on the division of Great Britain into England, Scotland and Wales. Yet this fits badly with the geography of voting behaviour and of attitudes to devolution. It is suggested that the three-country arrangement rests on the assumption of an English history and identity similar to that of the Scottish and Welsh. The meanings assigned to England or English are explored and shown to be several and confused. Other approaches used by political scientists to study territorial variation within Britain are considered, especially Miller's distinction between national, cultural and peripheral differences and the centre—periphery concept. The core—periphery concept is preferred, and a definition proposed which includes both a dichotomy between lowland and upland Britain and a gradient based on locational advantage. The Roman conquest of Britain, the political arrangements among the Anglo-Saxon kingdoms, the initial territorial structure of the Church and the creation of a unified English monarchy are examined in these terms. The core-based character of the English/British state, and its permanent claim to the whole periphery, are demonstrated. This pattern continues into more recent British history, and it is concluded that its persistence into modern politics requires more attention from social scientists.

The British electoral system has traditionally been defended on the grounds that its systematic exaggeration of the lead of the Conservatives over Labour or vice versa secured for the largest party an overall majority of seats on a minority of the votes and thereby enabled the electorate directly to determine which party holds office. Recent changes in the electoral geography of Britain have eroded that systematic exaggeration at Westminster elections and may soon remove it entirely. Meanwhile the electoral system is discouraging the pursuit of geographically aggregative policies. Consequently, the single member plurality system is no longer a suitable instrument to achieve the ends of its defenders but, despite their availability, alternative systems which could meet those aims have not been seriously considered.

THE POSSIBILITY THAT THE PARLIAMENT OF THE ENLARGED EUROPEAN Community may, wholly or in part, be elected directly within the next few years must excite both advocates of European unification and students of that curious political phenomenon, the European Community. The event is still exceedingly problematical; no attempt is made here to assess just how much so. But the demand for direct election, and specific proposals to that end, have been actual for just over a decade and are worth analysing both as they relate to the possible future event and as they relate to other known factors – the existing state of organized political forces in Western Europe and the role of elections in the political life of member-states.

The four elections analysed in this article all took place in the autumn of 1965. In formal terms, there is an important distinction between the election of legislatures (or at most of parliamentary governments) in Norway, Turkey and West Germany and that of a President in France; in terms of results, between the replacement of the Labour government in Norway by a four-party coalition and of the four party coalition government in Turkey by the Justice Party and the confirmation in office of the CDU-FDP coalition and of General de Gaulle.

The Liberal Party provides at once the confirmation and the denial of the view that Britain naturally has a two-party system. In its period of growth and greatness from the mid-nineteenth century to the outbreak of the First World War, the Liberal Party functioned as the left wing of a two-party system. Breakaway parties, such as the Peelites or the Liberal Unionists, were duly absorbed into one wing or the other. Then, when the Labour Party emerged on the scene, the demise of the Liberal Party seemed to confirm the essentially dualistic character of British politics. During the 1930s, 1940s or early 1950s the persistence of the Liberal Party at a minor level was seen as the obstinate refusal of a dying party to accept that fate. The only outcome other than death allowed by the inexorable system was absorption into one of its two wings.

I respond to the chapters by David Marquand and William Wallace as a student of politics and particularly of the phenomenon of supranational integration. I will also be making one remark as a participant in the political process later on.