The properties of Msh2-Msh6 ATP binding mutants suggest a signal amplification mechanism in DNA mismatch repair.

DNA mismatch repair (MMR) corrects mispaired DNA bases and small insertion/deletion loops generated by DNA replication errors. After binding a mispair, the eukaryotic mispair recognition complex Msh2-Msh6 binds ATP in both of its nucleotide-binding sites, which induces a conformational change resulting in the formation of an Msh2-Msh6 sliding clamp that releases from the mispair and slides freely along the DNA. However, the roles that Msh2-Msh6 sliding clamps play in MMR remain poorly understood. Here, using Saccharomyces cerevisiae, we created Msh2 and Msh6 Walker A nucleotide-binding site mutants that have defects in ATP binding in one or both nucleotide-binding sites of the Msh2-Msh6 heterodimer. We found that these mutations cause a complete MMR defect in vivo The mutant Msh2-Msh6 complexes exhibited normal mispair recognition and were proficient at recruiting the MMR endonuclease Mlh1-Pms1 to mispaired DNA. At physiological (2.5 mm) ATP concentration, the mutant complexes displayed modest partial defects in supporting MMR in reconstituted Mlh1-Pms1-independent and Mlh1-Pms1-dependent MMR reactions in vitro and in activation of the Mlh1-Pms1 endonuclease and showed a more severe defect at low (0.1 mm) ATP concentration. In contrast, five of the mutants were completely defective and one was mostly defective for sliding clamp formation at high and low ATP concentrations. These findings suggest that mispair-dependent sliding clamp formation triggers binding of additional Msh2-Msh6 complexes and that further recruitment of additional downstream MMR proteins is required for signal amplification of mispair binding during MMR

Networks, Urban

For much of the twentieth century, urban networks was a term used by sociologists and others to describe social networks, their importance for bonding within communities and bridging between communities, and their relationship to the geographical mobility implied by late-nineteenth- and early-twentieth-century urbanization, mid-twentieth-century suburbanization, and late-twentieth-century globalization. This relationship is often assumed to be one in which social networks are threatened by geographical mobility. From sometime in the 1980s, in a context of globalization, network became a metaphor used across the social sciences to describe how people, ideas, and objects flow between nodes in a globalizing world, and urban networks became a term used by geographers and others to describe at least four more or less connected things: (1) archipelagos of world or global cities, in which centrality depends on networks of producer services and information and communications technology infrastructure; (2) this information and communications technology infrastructure, among other networked infrastructure, which has become unbundled in recent years, leading to fragmented or splintered cities; (3) other smaller networks of humans and nonhumans – actor networks – that help to maintain urban life; and (4) twenty-first-century social networks, characterized by their transnational geographies and relatively high levels of institutionalization and self-consciousnes

Epidemiology and management of major salivary gland cancers

The incidence of major salivary gland cancer has increased in England but the reasons for this are unclear. This report aims to examine the epidemiology of incidence trends by age, sex, histological type, deprivation and ethnicity of major salivary gland cancers in England. This report also provides a descriptive overview of the current management and survival of patients with these rare types of head and neck cancer

The multi-layered nature of the internet-based democratization of brand management

The evolution of the internet, including developments such as Web 2.0, has led to new relationship realities between organizations and their stakeholders. One manifestation of these complex new realities has been the emergence of an internet-based democratization of brand management. Research about this phenomenon has so far mainly focused on investigating just one or more individual themes and thereby disregarded the inherent multi-layered nature of the internet-based democratization of brand management as a holistic, socio-technological phenomenon. The aim of this paper is to address this limitation through an investigation of the various socio-technological democratization developments of the phenomenon. To achieve this aim, a balanced and stakeholder-oriented perspective on brand management has been adopted to conduct an integrative literature review. The review reveals three key developments, which together form the essential parts of the phenomenon: (I) the democratization of internet technology, (II) the democratization of information, and (III) the democratization of social capital. The insights gained help to clarify the basic structures of the multi-layered phenomenon. The findings contribute also to the substantiation of a call for a new brand management paradigm: one that takes not only company-initiated but also stakeholder-initiated brand management activities into accoun

A New, Better BET: Rescuing and Revising Basic Emotion Theory

Basic Emotion Theory, or BET, has dominated the affective sciences for decades (Ekman, 1972, 1992, 1999; Ekman and Davidson, 1994; Griffiths, 2013; Scarantino and Griffiths, 2011). It has been highly influential, driving a number of empirical lines of research (e.g., in the context of facial expression detection, neuroimaging studies and evolutionary psychology). Nevertheless, BET has been criticized by philosophers, leading to calls for it to be jettisoned entirely (Colombetti, 2014; Hufendiek, 2016). This paper defuses those criticisms. In addition, it shows that we have good reason to retain BET. Finally, it reviews and puts to rest worries that BET’s commitment to affect programs renders it outmoded. We propose that, with minor adjustments, BET can avoid such criticisms when conceived under a radically enactive account of emotions. Thus, rather than leaving BET behind, we show how its basic ideas can be revised, refashioned and preserved. Hence, we conclude, our new BET is still a good bet

Constitutivism

A brief explanation and overview of constitutivism

International Coercion, Emulation and Policy Diffusion: Market-Oriented Infrastructure Reforms, 1977-1999

Why do some countries adopt market-oriented reforms such as deregulation, privatization and liberalization of competition in their infrastructure industries while others do not? Why did the pace of adoption accelerate in the 1990s? Building on neo-institutional theory in sociology, we argue that the domestic adoption of market-oriented reforms is strongly influenced by international pressures of coercion and emulation. We find robust support for these arguments with an event-history analysis of the determinants of reform in the telecommunications and electricity sectors of as many as 205 countries and territories between 1977 and 1999. Our results also suggest that the coercive effect of multilateral lending from the IMF, the World Bank or Regional Development Banks is increasing over time, a finding that is consistent with anecdotal evidence that multilateral organizations have broadened the scope of the “conditionality” terms specifying market-oriented reforms imposed on borrowing countries. We discuss the possibility that, by pressuring countries into policy reform, cross-national coercion and emulation may not produce ideal outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/40099/3/wp713.pd

Essentialist Beliefs About Bodily Transplants in the United States and India

Psychological essentialism is the belief that some internal, unseen essence or force determines the common outward appearances and behaviors of category members. We investigated whether reasoning about transplants of bodily elements showed evidence of essentialist thinking. Both A mericans and I ndians endorsed the possibility of transplants conferring donors' personality, behavior, and luck on recipients, consistent with essentialism. Respondents also endorsed essentialist effects even when denying that transplants would change a recipient's category membership (e.g., predicting that a recipient of a pig's heart would act more pig‐like but denying that the recipient would become a pig). This finding runs counter to predictions from the strongest version of the “minimalist” position (Strevens,2000), an alternative to essentialism. Finally, studies asking about a broader range of donor‐to‐recipient transfers indicated that I ndians essentialized more types of transfers than A mericans, but neither sample essentialized monetary transfer. This suggests that results from bodily transplant conditions reflect genuine essentialism rather than broader magical thinking.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98212/1/cogs12023.pd

Life satisfaction and confidence in national institutions: evidence from South America

A number of South American countries experienced turbulent democratic, political and economic upheaval over the last 40 years in the form of coup d’états in the 1970s, tumultuous elections, and repeated severe economic crises, some of which happened fairly recently. Starting in 2010, a number of court proceedings across the region have made past military coup d’états the focus of national conversations. South American citizens may, therefore, have lost confidence in national institutions that have repeatedly disappointed their trust and expectations; a situation with potentially detrimental effects on their well-being. Using eight waves of the Gallup World Poll collected between 2009 and 2016 across ten South American countries, we investigate to what extent people’s confidence in financial institutions, the honesty of elections, the military, the judicial system, the national government and the police is associated with people’s current and expectation of future life satisfaction. We find that people who report confidence in these six institutions rate their current and expected life satisfaction, on average, to be higher than those who lack these types of institutional confidence, even after controlling for demographic factors and macroeconomic indicators. In addition, we investigate changes over time for all six measures of confidence in institutions as well as for current and expectation of future life satisfaction. Our results suggest that governments’ investments in well-functioning institutions may contribute positively to subjective well-being in a society. However, our analysis is correlational and we thus cannot rule out reverse causality

The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states