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The therapeutic concept of antibody drug conjugates (ADCs) is to selectively target tumour cells with small molecule cytotoxic drugs to maximise cell kill benefit and minimise healthy tissue toxicity. An ADC generally consists of an antibody that targets a protein on the surface of tumour cells chemically linked to a warhead small molecule cytotoxic drug. To deliver the warhead to the tumour cell, the antibody must bind to the target protein and in general be internalised into the cell. Following internalisation, the cytotoxic agent can be released in the endosomal or lysosomal compartment (via different mechanisms). Diffusion or transport out of the endosome or lysosome allows the cytotoxic drug to express its cell-killing pharmacology. Alternatively, some ADCs (e.g. EDB-ADCs) rely on extracellular cleavage releasing membrane permeable warheads. One potentially important aspect of the ADC mechanism is the 'bystander effect' whereby the cytotoxic drug released in the targeted cell can diffuse out of that cell and into other (non-target expressing) tumour cells to exert its cytotoxic effect. This is important as solid tumours tend to be heterogeneous and not all cells in a tumour will express the targeted protein. The combination of large and small molecule aspects in an ADC poses significant challenges to the disposition scientist in describing the ADME properties of the entire molecule. This article will review the ADC landscape and the ADME properties of successful ADCs, with the aim of outlining best practice and providing a perspective of how the field can further facilitate the discovery and development of these important therapeutic modalities. [ABSTRACT FROM AUTHOR]

Accurate determination of fraction unbound in plasma is required for the interpretation of pharmacology and toxicology data, in addition to predicting human pharmacokinetics, dose, and drug-drug interaction potential. A trend, largely driven by changing target space and new chemical modalities, has increased the occurrence of compounds beyond the traditional rule of 5 physicochemical property space, meaning many drugs under development have high lipophilicity. This can present challenges for ADME assays, including non-specific binding to labware, low dynamic range and solubility. When determining unbound fraction, low recovery, due to non-specific binding, makes bioanalytical sensitivity limiting and prevents determination of free fraction for highly bound compounds. Here, mitigation of non-specific binding through the addition of 0.01% v/v of the excipient Solutol® to an equilibrium dialysis assay has been explored. Solutol® prevented non-specific binding to the dialysis membrane and showed no significant binding to plasma proteins. A test set of compounds demonstrates that this method gives comparable values of fraction unbound. In conclusion, the use of Solutol® as an additive in equilibrium dialysis formats could provide a method of mitigating non-specific binding, enabling the determination of fraction unbound values for highly lipophilic compounds. [ABSTRACT FROM AUTHOR]

• PROTACs have become an established modality with examples reaching the clinic. • PROTACs often breach "rule-of-5" limits, but oral bioavailability is achievable. • The wide range of physicochemical properties can challenge ADME assays. • The complex metabolism of PROTACs can potentially impact pharmacodynamics. • Lessons learned supporting PROTAC oral drug discovery will be highlighted. Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality with the potential to open target space not accessible to conventional small molecules via a degradation-based mechanism; however, their bifunctional nature can result in physicochemical properties that breach commonly accepted limits for small-molecule oral drugs. We offer a drug metabolism and pharmacokinetics (DMPK) perspective on the optimisation of oral PROTACs across a diverse set of projects within Oncology R&D at AstraZeneca, highlighting some of the challenges that they have presented to our established screening cascade. Furthermore, we challenge some of the perceptions and dogma surrounding the feasibility of oral PROTACS and demonstrate that acceptable oral PK properties for this modality can be regularly achievable despite the physicochemical property challenges they present. [ABSTRACT FROM AUTHOR]

'Levelling up' is the new UK government mantra to describe its ambitions for addressing longstanding local and regional inequalities and, especially, for tackling the problems of 'left‐behind' places. This article examines the thinking behind this slogan and the associated policy agenda. We identify a danger of misdiagnosis leading to policies that do little to ameliorate conditions in the places that most need help. The government's agenda appears, so far, to be driven by electoral calculation rather than a real engagement with tackling deep inequalities. [ABSTRACT FROM AUTHOR]

Abstract: PF‐06456384 is an extremely potent and selective blocker of the Nav1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Nav1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion‐transporting polypeptide mediated hepatic uptake and subsequent biliary excretion. However, the physicochemical properties of the i.v. lead matter were substantially different, moving from acidic, amphiphilic chemical space to zwitterions as well as substantially increasing molecular weight. This report describes the continued relevance of organic anion‐transporting polypeptide driven hepatic uptake in this physicochemical space and highlights an apparent impact of the formulation excipient Solutol on the clearance and distribution of PF‐06456384. [ABSTRACT FROM AUTHOR]

The discovery and selection of a highly potent and selective Na V 1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein–ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation. [ABSTRACT FROM AUTHOR]

Evolutionary approaches in economic geography face questions about the relationships between their concepts, theories, methods, politics, and policy implications. Amidst the growing but unsettled consensus that evolutionary approaches should employ plural methodologies, the aims here are, first, to identify some of the difficult issues confronting those working with different frameworks. The concerns comprise specifying and connecting research objects, subjects, and levels; handling agency and context; engaging and integrating the quantitative and the qualitative; comparing cases; and, considering politics, policy, and praxis. Second, the purpose is to articulate a distinctive geographical political economy approach, methods, and illustrative examples in addressing these issues. Bringing different views of evolution in economic geography into dialogue and disagreement renders methodological pluralism a means toward improved understanding and explanation rather than an end in itself. Confronting such thorny matters needs to be embedded in our research practices and supported by greater openness; more and better substantiation of our conceptual, theoretical, and empirical claims; enhanced critical reflection; and deeper engagement with politics, policy, and praxis. [ABSTRACT FROM AUTHOR]

Local and regional development has characteristically focused upon localities and regions in the historically industrialized and urbanized countries of the Global North. Development Studies has been concerned with more recently industrializing and urbanizing nations in the Global South. Each strand has continued to have only limited interaction but such disconnection constrains explanation and policy formulation in addressing global development challenges. This article argues for stronger connection and deeper interaction concerning local and regional development between and within the Global North and South. The basis for stimulating dialogue is situated in the critique of developmentalism, defining development regionally and locally, common issues and context sensitivity and place. [ABSTRACT FROM AUTHOR]

Brands and branding are an underinvestigated area in economic geography. Despite their pervasive growth as sources and carriers of meaning and value, the economic geographic dimensions of brands and branding lack conceptual clarity and remain undertheorized. This article introduces the idea of geographical associations to provide stronger conceptual and theoretical foundations to explain the importance and role of brands and branding in economic geographies. It then builds on and critically examines the worth of this understanding in an empirical exploration of the Burberry brand and its branding in the luxury fashion business. The argument is that conceiving of the geographical associations constituting the economic geographies of brands and branding explains their role as means of cohering and stabilizing meaning and value in spatial circuits. Concerted attention to brands and branding can broaden the reach of economic geography in its intersections between cultural and political economy. [ABSTRACT FROM AUTHOR]

After a decade of devolution and amid uncertainties about its effects, it is timely to assess and reflect upon the evidence and enduring meaning of any 'economic dividend' of devolution in the UK. Taking an institutionalist and quantitative approach, we seek to discern the nature and extent of any economic dividend through a conceptual and empirical analysis of the relationships between spatial disparities, spatial economic policy, and decentralisation. Situating the UK experience within its evolving historical context, we find: (i) a varied and uneven nature of the relationships between regional disparities, spatial economic policy, and decentralisation that change direction during specific time periods; (ii) the role of national economic growth is pivotal in explaining spatial disparities and the nature and extent of their relationship with the particular forms of spatial economic policy and decentralisation deployed; and, (iii) there is limited evidence that any economic dividend of devolution has emerged, but this remains difficult to discern because its likely effects are overridden by the role of national economic growth in decisively shaping the pattern of spatial disparities and in determining the scope and effects of spatial economic policy and decentralisation. [ABSTRACT FROM AUTHOR]

Despite their apparently pervasive reach and relevance, the geographies of branded commodities and their branding have been unevenly recognised and under-researched. This paper presents a way of conceptualising and analysing brand and branding geographies. Focusing upon goods and services, the notion of geographical entanglements is developed to understand the spatial associations and connotations that unavoidably ensnare brands and branding. Second, it examines how such attachments shape and are shaped by brand and branding agents, including producers, circulators, consumers and regulators. Last, the placing of the geographical entanglements of brands and branding is developed as a means of lifting their 'mystical veils' and prompting reflections upon their politics and relationships to uneven development. Situating branding genealogies in geographical context, the empirical analysis comprises a socio-spatial biography of Newcastle Brown Ale (NBA). It explains how NBA's geographical entanglements have been (re)constructed in its contrasting survival in the UK and growth in the US. As a way of thinking about brand and branding geographies, the paper seeks to broaden the reach of economic geographies at their intersections with cultural economy approaches and to stimulate debate about their politics and alternatives to uneven development. [ABSTRACT FROM AUTHOR]

In this article, the author reflects on the impact of neoliberalism on local and regional development during economic crisis. The author notes that neoliberalism has contributed of relatively rapid, but geographically uneven economic development in the 2008-2009 global financial crisis (GFC). According to the author, local and regional development is where strategy making should start.

This article argues that financialization—shorthand for the growing influence of capital markets, their intermediaries, and processes in contemporary economic and political life—generates an analytical opportunity and political economic imperative to move finance into the heart of economic geographic analysis. Drawing upon long-standing concerns about the relatively marginal location of finance in economic geography, we emphasize the integral role of finance in connecting the entangled geographies of the economic to the social, the cultural, and the political. In the wake of various "turns" in the discipline, we develop this integrationist approach to finance in ways that retain political economies of states, markets, and social power in our interpretations of geographically uneven development. In this article, we discuss the plural nature of emergent work on financialization and develop three analytical themes to shape our discussion of financialization. Next, we elaborate our analytical approach by warning against functional, political, and spatial disconnections traced in the literature on the geographies of money. We then explore how financialization is broadening and deepening the array of agents, relations, and sites that require consideration in economic geography and is generating tensions between territorial and relational spatialities of geographic differentiation. Finally, we address the relative dearth of empirical work by examining the financialization of brands that have shaped the evolution of the brewing business and the development of new derivative instruments to hedge against weather risks. We conclude by arguing that our analysis of financialization demonstrates how finance occupies an integral position within economic geographies and reveals some of the sociospatial relations, constructions, and reach of existing and new actors, relations, and sites in shaping the uneven development of financialized contemporary capitalism. [ABSTRACT FROM AUTHOR]

This paper seeks to elucidate the geographies of brands and branding through interpreting their geographical entanglements. Focusing upon goods and services, it argues, first, that the object of the brand and the process of branding are geographical because they are entangled in inescapable spatial associations. Second, these spatial associations matter because they are geographically differentiated and uneven. Third, geographically entangled brands and branding are closely related to spatially uneven development through the articulation and reinforcement of economic and social inequalities and unequal and competitive sociospatial relations and divisions of labour. Despite their apparent pervasiveness and significance for geographical inquiry, the geographical entanglements of brands and branding have been under-investigated in Geography and hardly recognized and poorly specified in other social science research. A critical account is provided that demonstrates the entangled geographies of brands and branding in their: (1) geographical origins, provenance and sociospatial histories; (2) spatial circuits of value and meaning and uneven development; and (3) territorial and relational spaces and places. Reading the changing forms, extent and nature of the geographical entanglements of brands and branding provides a novel but relatively overlooked window to consider and illustrate the vital spaces at the intersections of economic, social, cultural and political geographies, the tensions between relational and territorial notions of space and place and the politics and limits of brands and branding. Learning from wider social science, the paper demonstrates the importance of geography by projecting more clearly specified and sophisticated treatments of space and place into accounts of brands and branding. [ABSTRACT FROM AUTHOR]

Key themes for evolution in economic geography are identified that clarify and further refine and reinforce our argument for broader conceptions of institutions, social agency, and power and for the situation of the plural and emerging field of evolutionary approaches more fully within geographical political economy. We address the following issues: conceptual and terminological clarity; evolution and institutions within and beyond the firm; agency, bounded determinacy, and power; and research method and design. Our central contention is that geographical political economy provides a coherent and well-structured conceptual and theoretical framework with which to broaden and deepen our understanding, exploration, and practice of evolutionary thinking in economic geography. [ABSTRACT FROM AUTHOR]

Abstract: The cyclopyrrolone pagoclone binds with roughly equivalent high affinity (0.7–9.1nM) to the benzodiazepine binding site of human recombinant GABAA receptors containing either an α1, α2, α3 or α5 subunit. However, whereas it was a partial agonist at α1-, α2- and α5-containing GABAA receptors, pagoclone was a full agonist at receptors containing an α3 subunit. In the rat elevated plus maze assay pagoclone (3mg/kg) had significant anxiolytic-like activity but at all three doses tested (0.3, 1 and 3mg/kg p.o.) it produced a significant reduction in the total distance travelled. This sedative-like effect was confirmed in rat chain-pulling and spontaneous locomotor assays. Surprisingly, in the plasma and brain samples derived from the elevated plus maze assay, the major metabolite of pagoclone, 5′-hydroxy pagoclone, was present at 10–20-fold higher concentrations relative to the parent compound. In order to establish whether this metabolite might have pharmacological activity, we measured its affinity and efficacy profile and found that both were comparable to those of pagoclone with the exception that efficacy at the α1 subtype was considerably greater for 5′-hydroxy pagoclone compared with the parent. This metabolite had significant anxiolytic-like activity in the elevated plus maze but at these same doses (0.3–3mg/kg p.o.) also produced sedation. It is therefore likely that in rats 5′-hydroxy pagoclone mediates the majority of the pharmacological actions following pagoclone administration. [Copyright &y& Elsevier]

ParentCompany's decision to closeR&DCoin North East England caused the loss of highly skilled scientific and technical jobs.R&DCowas a“white-collar” R&D operation and supplier of services toParentCompany's lead factories in the East Midlands and South West regions. The economic and social costs of closure were acute for the North East with its relatively weak growth, high unemployment and limited R&D activity. This paper argues that a clearer understanding and progressive response to such closures may benefit from a conceptualisation founded upon spatialised social relations and characterised by a social process of production that unfolds over time, across space and in place. Periodised in episodic socio-spatial“moments”, a historically evolving social process of closure reveals differential potential—contingent upon specific conjunctures of structural forces, social agency and the particularities of places—to enable and/or inhibit intervention through public policy and institutional action and political mobilisation and resistance. [ABSTRACT FROM AUTHOR]

An emergent heterodox approach is challenging the prevailing orthodoxy of thinking, doing, and governing economic development, particularly at the subnational, regional, and local levels. Looking at underlying debates concerning institutionalism and a ‘new centrism’, the author draws together the theoretical and conceptual threads of the heterodox agenda. Several critical issues are outlined: the historical evolution of economic development approaches; the lack of coherency and consensus in conceptual, theoretical, and policy terms; the underdeveloped empirical base and; the translation into policy and institutional practice. This discussion informs an analytical framework based upon the central dimensions of heterodoxy, experimentation, context specificity, and governance. Empirical analysis of the substance of the new heterodoxy is undertaken by focusing upon a new institutional experiment for organising economic development—the task force—and drawing upon evidence from the national (UK), regional (North East of England), and local (South Tyneside) levels. The argument is that there is a mixed picture with patchy evidence of the emergence of the heterodox agenda, comprising genuine experimentation and innovation, coexisting and interrelating with substantial continuities and the extension and reinforcement of established practices. It is concluded that the currently dominant narrative and technocratic mode of ‘quasi-governance’ of economic development requires a renewed and democratised politics to open up discussion of alter- native responses to the fundamental questions of what kind of economic development is desired and for whom. Strengthened democratic structures as part of the devolution process in the UK nations and regions may offer the potential to begin this debate. [ABSTRACT FROM AUTHOR]

Comments on the issues challenging the subnational governance and economic and social development in the developed and developing world. Impact of the devolution of subnational governance among territories; Insights on the relation between subnational governance and economic and social development; Factors that contributes in the emergence of governance system.

The task force has emerged as a mechanism for coordinating economic development activity in the context of the current New Labour government's emphasis upon including 'stakeholders' in 'joined-up' approaches to 'crosscutting' issues. In this paper I examine the use of task forces to organise economic development at employer, sectoral, and territorial levels at the local and regional scales in the North East region of England. It is argued that New Labour's experimental use of task forces reflects a particular mediation of more general tendencies in the historical evolution of state modernisation, which varies in particular and contingent ways at the local and regional levels. The research reveals the continued importance of the existing public-sector and public-private-sector institutions, the less significant and contingent role of the private sector, and the contribution of the task force to the 'quasi-governance' of the United Kingdom, with its problems of coordination, transparency, and accountability. A renewed politics of economic development governance is required to establish the accountability and legitimacy of such bodies in the context of the emergent multilayered governance system of the UK political economy. [ABSTRACT FROM AUTHOR]

This paper explores the neglected issue in the 'globalisation' debate concerning the contraction and withdrawal of capital from the territories. The analysis is built upon consideration of the institutional architecture, state inter-relations and territoriality and nationality of capital. The paper concludes that historical evolution and contingency are critical to left analysis of the 'globalisation' of capital and may help to resist and contest regressive changes and lay the foundations of collaboration and alliance building for more progressive economic and social strategies. [ABSTRACT FROM AUTHOR]

Crises spur reflection and re-evaluation of what matters and what is valued. The impacts of the 2008 global financial crisis, COVID-19 pandemic and climate emergency are reigniting debates about the nature of economic development approaches and what they aim to achieve in urban settings. Addressing a substantive gap in contemporary debates by helping to navigate a burgeoning and diverse field, this paper provides a critical and comparative assessment of five leading agendas that have been positioned as alternative and progressive policy responses to urban economic change: inclusive growth; the wellbeing economy; community wealth building; doughnut economics; and the foundational economy. Taking an international perspective, the paper provides a comparative review of their stated visions, mechanisms for change, and the spatial scales through which they are led and implemented. Our argument is that these alternative approaches to urban economic development are shaping creative, innovative and progressive responses to longstanding urban problems within policy and practice communities but require on-going scrutiny and evaluation to realise their potential to meaningfully achieve transformative change. [ABSTRACT FROM AUTHOR]

The term ‘left behind’ has come to connote political disaffection, alongside social and spatial inequalities in wealth and opportunity. Yet the term is also widely contested, often prioritising a regional and economic perspective at the expense of a more local and nuanced approach. In response, we argue that neighbourhood context is integral to understanding and identifying ‘left behind’ places. Building a neighbourhood classification of ‘left behindness’ for England, we evaluate the extent to which the neighbourhood trajectory contributes to our understanding of a range of multidimensional individual‐level outcomes. Our findings reveal a geography of neighbourhoods that are systematically disadvantaged over time, concentrated in major urban conurbations, and post‐industrial and coastal towns. The magnitude and impact is highlighted through poorer economic, health, social and political outcomes for those living in ‘left behind’ areas. [ABSTRACT FROM AUTHOR]

Presents a study which explored the extent and nature of the concept of localization in relation to economic renewal of declining industrial regions. Review of literature discussing localization; Analysis of localization at Sedgefield Borough in north-east England; Findings of the study; Conclusions.

This article explores a tension between financialisation of electricity infrastructures and efforts to bring critical urban systems into common ownership. Focusing on the emerging landscape of electricity regulation and e-mobility in the United Kingdom (UK), it examines how electricity grid ownership has become financialised, and why the economic assumptions that enabled this financialisation are being called into question. New technologies, such as smart electricity meters and electric vehicles, provide cities with new tools to tackle poor air quality and greenhouse gas emissions. Electricity grids are key enabling infrastructures but the companies that run them do not get rewarded for improving air quality or tackling climate change. UK government regulation of electricity grids both enables financialisation and forecloses opportunities to manage the infrastructure for wider environmental and public benefit. Nonetheless, the addition of smart devices to this network – the 'smart grid' – opens up an opportunity for common ownership of the infrastructure. Transforming the smart grid into commons necessitates deep structural reform to the entire architecture of infrastructure regulation in the UK. [ABSTRACT FROM AUTHOR]

This Special Issue attempts to clarify how urban infrastructure is being funded, financed and governed. In this commentary, I seek to engage the topic of the Special Issue as a whole – infrastructure financialisation and its governance – albeit through examples provided by individual article contributions. It is a collection emphasising the tangled interaction between public and private, urging a view of financialisation beyond the binary states vs. markets, and highlighting the multiple actors with multiple agendas at play. The articles provide richly detailed accounts of how the local state remains active, participatory and deeply – if not daily – involved in infrastructure financialisation, even/especially when finance is at its most influential. Not without its limitations, three occlusions in this Special Issue present opportunities for future research, namely the need to: i) extend critical analyses of financialisation; ii) enhance related research on social infrastructure, operational phase processes and treatment of the global South; and iii) advance academic analysis of alternatives to infrastructure financialisation. [ABSTRACT FROM AUTHOR]

This Special Issue aims to further understanding and explanation of the funding, financing and governing of urban infrastructure amidst its engagements with contemporary financialisation. Drawing upon empirical material from international cases from Europe, North America, Africa and Asia, it identifies critical issues to advance work in this area. These themes concern: the impacts of financialisation upon shifting the definitions and conceptualisations of urban infrastructure; the worth of adopting more actor-oriented and grounded approaches to financialisation; the importance of affording greater recognition to national and local states as the objects and agents of financialising relations, processes and practices; the substance and ramifications of the emergent informalisation of infrastructure policy-making and governance; and, the implications of financialisation for the evolving and uneven landscapes of urban infrastructure provision. The arguments are, first, that how infrastructure is funded, financed and governed is integral to explaining socially and spatially uneven infrastructural provision and its urban development ramifications; and second, the engagements of urban infrastructure with contemporary financialisation have become central in such accounts. Future research avenues are identified. These comprise: identifying exactly how revenues are generated from infrastructure assets; specifying the relations of financialisation with other processes such as 'assetisation', 'marketisation' and privatisation; extending the geographical and comparative reach of current studies; elaborating the spaces of regulation in negotiating and accommodating infrastructure financialisation; and, scrutinising the roles of decentralised powers and resources in financialising urban infrastructure and exploring its alternatives. [ABSTRACT FROM AUTHOR]

Drawing upon a case study of regional transit in Denver, Colorado, this article describes and accounts for the emergence of the global infrastructure public-private partnership (GIP3) as a novel extra-territorial mechanism for financing and delivering transportation infrastructure projects across large metropolitan regions in the United States (US). Unlike traditional locally-funded public-private partnerships, a GIP3 involves a global (i.e. extra-territorial) consortium of private sector construction firms and investors which enters into a long-term contract with a regional public agency to finance, operate, maintain and deliver strategic investments in transportation infrastructure. In 2004, Denver region voters approved a sales tax increase to fund the Denver Regional Transportation District (RTD)'s US$4.7 billion FasTracks programme, a 122-mile extension of light and commuter rail along six corridors. Faced with a shortfall in regional funding, the Denver RTD subsequently entered into a contract with a GIP3 consortium to finance and deliver the Eagle P3 project, a major component of the FasTracks system to Denver International Airport. The article argues that future research on GIP3 contractual agreements needs to consider the local control of infrastructure assets and the integrity of supporting regional collaborative governance arrangements. [ABSTRACT FROM AUTHOR]

This article explores the financialisation of Brussels Airport following the acquisition in 2004 of a majority stake by the Australian Macquarie Bank. Adopting a variegated capitalism perspective, we argue for a greater sensitivity to the mutually constitutive relation between durable institutional governance structures and financialised practices injected by global investors. The case of Brussels Airport presents an informative case to examine this relation, as Macquarie has had to continuously interact with the Belgian federal state in its different guises of contractor, co-owner and regulator to implement financialisation. While Macquarie indeed brought in risks that are structurally associated with profit making through financial means, the governance of these practices is shaped by the Belgian state's distinctive and pragmatic approach to infrastructure privatisation: the state enables these practices, but also contests them in case of a direct clash with its interests. Meanwhile, the regulatory environment marks the contradictory meeting point of two varieties of capitalism: while the light-handed regulatory framework is inspired by the UK's airport industry, the Belgian regulator does not possess similar abilities as a UK regulator, and resultantly, informal negotiations between the stakeholders are more influential in the airport's governance. The case of Brussels Airport shows that the state plays an active role in constituting global capitalism, yet also shapes how financialisation works out on the ground. To understand the tensions that mark the governance of financialised infrastructure, it is therefore imperative to be sensitive to the local, historical and political trajectories that underwrite the variegated outcomes of financialisation. [ABSTRACT FROM AUTHOR]

In this article, we explore how global infrastructure investment funds and actors are financialising the local growth machine in Chicago, and how Chicago's transforming growth machine uses its influence to financialise urban governance policy goals and institutional arrangements. We view global infrastructure investors through the lens of place entrepreneurs seeking to extract monopoly rents from urban infrastructure. As place entrepreneurs, global infrastructure investors have an interest in forming alliances with other place entrepreneurs to generate political and institutional capacity for infrastructure financialisation. Our case study examines the concrete and specific ways in which global financial firms and actors work in partnership with Chicago's business civic organisation, World Business Chicago, to shape the City of Chicago's planning processes and orchestrate a more mature institutional-regulatory infrastructure investment environment through the formation of the Chicago Infrastructure Trust, the city's public–private partnership infrastructure bank. [ABSTRACT FROM AUTHOR]

Debates around infrastructure tend to focus on the global North, yet in the global South demand for infrastructure is huge and we see new and emergent actors engaged in finance and construction; China being pre-eminent among them. China's interests in the global South have grown apace over the past decade, especially in terms of accessing resources and securing infrastructure deals. The role of Chinese banks and State-Owned Enterprises (SOEs) in financing and building the projects reveals a blurring between geopolitical and commercial interests and processes. The article situates China's entry into the global South as part of a geopolitics that is simultaneously geoeconomic and interrogates these issues through case studies of Chinese-backed projects in Ghana and Cambodia. These projects are spatially and politically complex, with China adopting a range of financing models – often including an element of resource swaps – in which bank finance is critical and marks the Chinese as different from Western financiers. These international deals are secured at the political elite level and so bypass established forms of national governance and accountability in the recipient countries, while the turnkey construction projects remain locally enclaved. The cases also show that wider developmental benefits are limited, with 'ordinary' citizens – especially those in the rural areas – gaining relatively little from these major energy projects and the benefits accruing to urban-based elites. [ABSTRACT FROM AUTHOR]

How urban infrastructure is funded, financed and governed is a central issue for states at the national, city-regional and city scales. Urban infrastructure is being financialised by financial and state actors and transformed into an asset in the international investment landscape. Local governments are being compelled by national state and financial institutions to be more entrepreneurial in their infrastructure funding and financing and to reorganise their governance arrangements. This article explains the socially and spatially uneven unfolding and implications of urban infrastructure financialisation and local government attempts to implement more entrepreneurial practices and governance forms. The empirical focus is the City Deals in the UK: a new form of urban governance and infrastructure investment based upon negotiated central–local government agreements on decentralised powers, responsibilities and resources. The continued authority of the highly centralised UK national state, its managerialist institutions and conservative/risk-averse administrative culture have constrained urban infrastructure financialisation and entrepreneurial urban governance in the UK City Deals. Situated in their particular spatial, temporal, political-economic and institutional settings, financialisation is understood as a socially and spatially variegated process and urban governance is interpreted as the articulation and mixing of new entrepreneurial and enduring managerialist forms. [ABSTRACT FROM AUTHOR]

The literature on the financialisation of urban infrastructure typically traces how an infrastructure asset's balance sheet is (re)engineered to create a financial asset. What the literature neglects are the processes by which an asset generates urban flows. Attention to these processes, we argue, not only gives better insight into the processes of financialisation of infrastructure but also exposes how the act of financing affects the operations of cities through its influence on the performance of infrastructure assets. The argument presented in the article is informed by case studies of infrastructure investments revealed in interviews conducted in New York, London and Sydney. This material is drawn on to generate a framework for understanding the relationships between infrastructure investing and the infrastructure-enabled flows of a city. This framework has three dimensions through which the financialisation process is seen to be mediated. These are capital structure, organisational structure and regulatory structure. The article argues that these mezzanine-level conceptualisations enable us to explore the to-and-fro between financing and operating cities. A key proposition is that the physical flows of a city are basic not only to the design and enactment of an investment instrument but also to its financial viability. The realisation of this relationship has changed the way investors approach infrastructure assets as investment products. Implications for urban management are drawn. [ABSTRACT FROM AUTHOR]

Since the insertion of urban infrastructure into the risk-taking world of financialisation, techniques for capturing added value from underlying revenue streams, from securitisation and derivatives to the structuring of bond and equity returns, have come to the fore. A value model, based on extraction through interest and dividends paid, as well as multiple fees, in our view, has benefited investors and financial intermediaries alike. Through the example of Carlsbad desalination plant in San Diego, California, the paper sets out to show how a piece of drinking water infrastructure was translated as a value asset to match the needs of institutional investors in the USA and beyond. The geography of value capture and its distribution globally is shown to be not simply financially innovative, but also spatially innovative and perhaps best understood through its topological spaces. [ABSTRACT FROM AUTHOR]

A burgeoning strand of evolutionary economic geography (EEG) research is addressing questions of regional path creation, based on the idea that place-specific legacies and conditions play a critical role in supporting the emergence of new economic activities. Yet there has been little effort thus far to take stock of this emerging body of research. In response, the aims of this article are to offer a fresh synthesis of recent work and to develop a broader theoretical framework to inform future research. First, it presents a critical appraisal of the state of the art in path creation research. In an effort to address identified gaps in EEG research, this incorporates insights from sociological perspectives, the global production networks approach, and transition studies. Second, the article's development of a systematic theoretical framework is based on the identification of key dimensions of path creation and their constitutive interrelations. This contribution is underpinned by a geographical political economy (GPE) approach that provides the ontological basis for the integration of the five key dimensions of path creation within an overarching framework and the positioning of regional processes in relation to the broader dynamics of uneven development. Informed by GPE, the argument is that knowledgeable actors, operating within multiscalar institutional environments, create paths through the strategic coupling of regional and extraregional assets to mechanisms of path creation and associated markets. To inform further research, the article outlines four concrete propositions regarding the operation of path creation processes in different types of regions and explores these through case studies of Berlin and Pittsburgh. [ABSTRACT FROM AUTHOR]

The paper contributes to literature on the geographies of corporate philanthropy through a case study of the origins, growth and decline of the Northern Rock bank's charitable foundation. Analysis reveals the complex, geographically-embedded nature of philanthropic motivations and impacts. It demonstrates that investment in home and community by philanthropists was part of a regionally-inscribed business-model of excessive risk taking that brought them considerable personal financial rewards. It highlights tensions and conflicts between corporate philanthropists and professional grant-makers over the scale and regional focus of giving. The paper concludes that the positive outcomes of corporate philanthropy are difficult to sustain in disadvantaged regions where shifts in corporate strategy and fragilities in the local economy undermine charitable giving. [ABSTRACT FROM AUTHOR]

This paper deals with the relationship between decentralisation, regional economic development, and income inequality within regions. Using multiplicative interaction models and regionally aggregated microeconomic data for more than 100000 individuals in the European Union (EU), it addresses two main questions. First, whether fiscal and political decentralisation in Western Europe has an effect on within-regional interpersonal inequality. Second, whether this potential relationship is mediated by the level of economic development of the region. The results of the analysis show that greater fiscal decentralisation is associated with lower interpersonal income inequality, but, as regional income rises, further decentralisation is connected to a lower decrease in inequality. This finding is robust to the measurement and definition of income inequality, as well as to the weighting of the spatial units by their population size. [ABSTRACT FROM AUTHOR]

Economic geography has, over the past decade or so, drawn upon ideas from evolutionary economics in trying to understand processes of regional growth and change. Recently, some researchers have sought to delimit and develop an "evolutionary economic geography" (EEG), aiming to create a more systematic theoretical framework for research. This article provides a sympathetic critique and elaboration of this emergent EEG but takes issue with some aspects of its characterization in recent programmatic statements. While acknowledging that EEG is an evolving and pluralist project, we are concerned that the reliance on certain theoretical frameworks that are imported from evolutionary economics and complexity science threatens to isolate it from other approaches in economic geography, limiting the opportunities for cross-fertilization. In response, the article seeks to develop a social and pluralist conception of institutions and social agency in EEG, drawing upon the writings of leading institutional economists, and to link evolutionary concepts to political economy approaches, arguing that the evolution of the economic landscape must be related to processes of capital accumulation and uneven development. As such,we favor the use of evolutionary and institutional concepts within a geographical political economy approach, rather than the construction of some kind of theoretically separate EEG-evolution in economic geography, not an evolutionary economic geography. [ABSTRACT FROM AUTHOR]

In recent years, economic geographers have turned their attention to the growing geographical reach and complexity of economic networks to focus on the increasing integration of economies, the geographical organization of economic activity and the social, economic and political relationships within these networks. Within this work, particular attention has been paid to the corporation, allowing for corporate geographies to be rethought using new approaches and new methodologies. Building on these approaches, we seek to develop a holistic economic geography which embeds the globalizing corporation within a broad array of economic, social, political and cultural settings shaped by multiple social agents. We do this in the con- text of the European steel industry. We argue that refocusing attention on the steel industry is important for two reasons. First, the industry itself has radically changed in the last decade. Persistent global overcapacity and cycles of profitability, ongoing consolidation and privatization, the emergence of new steel regions and of more 'globalized' steel producers have all altered the industry's anatomy. Second, the tools of economic geography have changed. New approaches enable us to look again at the steel industry and to rethink its corporate geographies. This article develops these arguments by using an innovative approach, integrating the narratives of two steel corporations and two European steel regions, and focusing on issues of corporate geography, financialization, government and governance, labour and community. In this way, we seek to continue the strong tradition within economic geography of conceptualizing the spatial contexts and consequences of economic change through accounts of the continuous remaking of steel geographies. [ABSTRACT FROM AUTHOR]

Recent research has argued that human capital has become the key driver of city growth and that there is a widening divergence between high- and low-skill cities. This skilled-city view includes several stylised propositions. The first is that more skills and human capital generate stronger economic growth; the second is that already-skilled cities are becoming ever more skilled; and, the third is that larger cities tend to have stronger concentrations of, and faster growth in, high-skilled, cognitive occupations. Using a detailed data set for occupational change in 85 urban Travel to Work Areas in Britain between 1981 and 2015, this paper evaluates whether these propositions apply to British urban evolution, and how they relate to the 'hollowing-out' of medium-skilled jobs. The results confirm the close interactive relationship between growth and high-skilled occupations. However, some of the skilled-city propositions, such as 'smart cities becoming smarter', and a positive relationship between agglomeration and high-skilled employment growth, do not apply in Britain where other factors have been more important. The pattern of high-skill growth has shown a strong regional dimension, and the 'emergence' of newer smaller cities, particularly in southern England, has been more evident than the 'resurgence' of large core and industrial cities. [ABSTRACT FROM AUTHOR]

[Display omitted] Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges. [ABSTRACT FROM AUTHOR]