The impact of SPARC on age-related cardiac dysfunction and fibrosis in Drosophila

Tissue fibrosis, an accumulation of extracellular matrix proteins such as collagen, accompanies cardiac ageing in humans and this is linked to an increased risk of cardiac failure. The mechanisms driving age-related tissue fibrosis and cardiac dysfunction are unclear, yet clinically important. Drosophila is amenable to the study of cardiac ageing as well as collagen deposition; however it is unclear whether collagen accumulates in the ageing Drosophila heart. This work examined collagen deposition and cardiac function in ageing Drosophila, in the context of reduced expression of collagen-interacting protein SPARC (Secreted Protein Acidic and Rich in Cysteine) an evolutionarily conserved protein linked with fibrosis. Heart function was measured using high frame rate videomicroscopy. Collagen deposition was monitored using a fluorescently-tagged collagen IV reporter (encoded by the Viking gene) and staining of the cardiac collagen, Pericardin. The Drosophila heart accumulated collagen IV and Pericardin as flies aged. Associated with this was a decline in cardiac function. SPARC heterozygous flies lived longer than controls and showed little to no age-related cardiac dysfunction. As flies of both genotypes aged, cardiac levels of collagen IV (Viking) and Pericardin increased similarly. Over-expression of SPARC caused cardiomyopathy and increased Pericardin deposition. The findings demonstrate that, like humans, the Drosophila heart develops a fibrosis-like phenotype as it ages. Although having no gross impact on collagen accumulation, reduced SPARC expression extended Drosophila lifespan and cardiac health span. It is proposed that cardiac fibrosis in humans may develop due to the activation of conserved mechanisms and that SPARC may mediate cardiac ageing by mechanisms more subtle than gross accumulation of collagen

Burden, benefit, gift or duty?: Dutch mayors’ framing of the multilevel governance of asylum in rural localities and cities in Zeeland

This article engages with critiques of multilevel governance (MLG) perspectives on asylum governance andidentifies two additional points of concern. First, it highlights the importance of empirically groundingreflections on the limits of the MLG approach, beyond the activism of city actors, by examining localasylum dynamics from the vantage point of mayors inrural and small urbanmunicipalities. It examineshow Dutch mayors in rural and small urban municipalities in the Dutch province of Zeeland experiencedand framed asylum governance in a multilevel setting between 2015 and 2016. Second, this articlebrings into focus internal dynamics, interactions between mayors and municipal actors within themunicipality, alongside external interactions and pre-existing local and regional challenges, such as ruralcrisis. It argues that even in the context of cooperative modes of governance, mayors navigate variouschallenges. In terms of framing, this article shows how mayors in this multilevel context commonlyframed municipal involvement in asylum governance as a duty rather than as a burden or benefittotheir localities. It argues that this framing reflects a local‘politics of consensus’rather than‘localpragmatism

Introduction: Theorizing local migration law and governance

Serving as an introduction to the volume, this chapter begins by setting out some of the recent dynamics in migration governance, including devolution, recentralization and the increasingly proactive stance taken by local authorities in this domain. This, in turn, brought about a “local turn” in migration scholarship. Although generally transdisciplinary and integrative of various methodologies including quantitative, historical, and ethnographic studies, scholarship on the “local turn” has failed to consider legal perspectives where it rescales analyses of migrant reception and inclusion away from the state. This chapter interrogates the relegation of the law to mere context or epiphenomenon and discusses the analytical implications of this curious demotion of a central dimension of governance. In the second instance, this contribution introduces the three themes of this volume as potential launchpads for the further theorization of migration governance based on analyses of legal debates, processes and principles. For this purpose, it offers a brief account of the already existing relevant literature that can inform empirical, conceptual and normative engagements with law as migration governance. The overview of the three themes is, in each case, complemented by a short description of the contribution that the various chapters make to their discussion

Of Bastions and Bulwarks: A Multi-Scalar Understanding of Local Bordering Practices in Europe

In recent years, local authorities in Europe have increasingly developed bordering practices that hinder or further migrant rights, such as the freedom of movement. They bypass national borders by facilitating refugee resettlement, they claim local space to welcome or shun certain migrants, and they develop or break down local impediments to migrant mobility. These local practices, we argue, can best be understood from a multiscalar perspective, which considers processes of placemaking as reproductive of power dynamics. Applying such a perspective to local bordering practices in Greece, Turkey, the Netherlands, Italy, and Germany, we point out the importance of the multitude of the actors involved; legal pluralism; and the contextual role of social, economic, and spatial factors. This offers a theoretical foothold for understanding the power dynamics at play when local authorities become bastions or bulwarks, in which some migrants are welcomed, and others are not

General introduction: Urban politics of human rights

Human rights and the urban – two concepts that both seem to quiver with hope, promise and potential. Songs, selfies and cinematography praising city life conjure images of growth, freedom and emancipation. The slums behind the shiny facades, the people begging next to high rise banks, the divergent life-worlds and opportunities of children in a single city. The different contributions highlight the involvement of a myriad of actors who use human rights, for instance, to respond to urbanisation processes. At the same time, this volume is mindful of critics who argue, for instance, that human rights city initiatives may preserve the state-centric human rights framework, by emphasising local ‘state actors’ and by only indirectly recognising the role of other local actors, such as community-based groups and social movements. The urban condition is often argued to define future life on the planet

The ‘safe harbor’ of Berlin: Socio-legal constellations and complex strategies of divergence

This chapter analyzes the ‘strategies of divergence’ adopted by the City of Berlin following the widespread mobilization in Germany calling for high sea rescues. With its legal status as a city-state, Berlin is generally seen as having played a supportive role when proclaiming itself a ‘safe harbor’. By contrast, this chapter makes three observations to draw attention to the more complex reality shaping strategies of divergence from restrictive national policies. First, local authorities may pursue multiple strategies simultaneously, with the example of Berlin highlighting their interconnection and the extent to which competencies determine a given course of action. Second, the approach taken by municipal actors is shaped fundamentally by its interaction with civil society. Rather than only narrowing discretionary spaces, such movements may widen them by offering local authorities the ability to position themselves strategically. Finally, the coexistence of distinct socio-legal constellations confronting a city necessarily complicates normative assessments of the ‘local turn’ in migration policy. Particularly in the case of legally resourceful localities like Berlin, municipal approaches may seem ambiguous and contradictory, while being pragmatic and strategic from the perspective of the local authorities. This raises questions regarding the reasons behind, and viability of local strategies of divergence

Insect nephrocyte function is regulated by a store operated calcium entry mechanism controlling endocytosis and Amnionless turnover

Insect nephrocytes are ultrafiltration cells that remove circulating proteins and exogenous toxins from the haemolymph. Experimental disruption of nephrocyte development or function leads to systemic impairment of insect physiology as evidenced by cardiomyopathy, chronic activation of immune signalling and shortening of lifespan. The genetic and structural basis of the nephrocyte’s ultrafiltration mechanism is conserved between arthropods and mammals, making them an attractive model for studying human renal function and systemic clearance mechanisms in general. Although dynamic changes to intracellular calcium are fundamental to the function of many cell types, there are currently no studies of intracellular calcium signalling in nephrocytes. In this work we aimed to characterise calcium signalling in the pericardial nephrocytes of Drosophila melanogaster. To achieve this, a genetically encoded calcium reporter (GCaMP6) was expressed in nephrocytes to monitor intracellular calcium both in vivo within larvae and in vitro within dissected adults. Larval nephrocytes exhibited stochastically timed calcium waves. A calcium signal could be initiated in preparations of adult nephrocytes and abolished by EGTA, or the store operated calcium entry (SOCE) blocker 2-APB, as well as RNAi mediated knockdown of the SOCE genes Stim and Orai. Neither the presence of calcium-free buffer nor EGTA affected the binding of the endocytic cargo albumin to nephrocytes but they did impair the subsequent accumulation of albumin within nephrocytes. Pre-treatment with EGTA, calcium-free buffer or 2-APB led to significantly reduced albumin binding. Knock-down of Stim and Orai was non-lethal, caused an increase to nephrocyte size and reduced albumin binding, reduced the abundance of the endocytic cargo receptor Amnionless and disrupted the localisation of Dumbfounded at the filtration slit diaphragm. These data indicate that pericardial nephrocytes exhibit stochastically timed calcium waves in vivo and that SOCE mediates the localisation of the endocytic co-receptor Amnionless. Identifying the signals both up and downstream of SOCE may highlight mechanisms relevant to the renal and excretory functions of a broad range of species, including humans

Urban Politics of Human Rights

Increasingly, urban actors invoke human rights to address inequalities, combat privatisation, and underline common aspirations, or to protect vested (private) interests. The potential and the pitfalls of these processes are conditioned by the urban, and deeply political. These urban politics of human rights are at the heart of this book. An international line-up of contributors with long-term engagement in this field shed light on these politics in cities on four continents and eight cities, presenting a wealth of empirical detail and disciplinary theoreticalisation perspectives. They analyse the ‘city society’, the urban actors involved, and the mechanisms of human rights mobilisation. In doing so, they show the commonalities in rights engagement in today’s globalised and often deeply unequal cities characterised by urban law, private capital but also communities that rally around concepts as the ‘right to the city’. Most importantly, the chapters highlight the conditions under which this mobilisation truly contributes to social justice, be it concerning the simple right to presence, cultural rights, accessible housing or – in times of COVID – health care. Urban Politics of Human Rights provides indispensable reading for anyone with a practical or theoretical interest in the complex, deeply political, and at times also truly promising interrelationship between human rights and the urban

Multilevel regulation of the glass locus during Drosophila eye development

Development of eye tissue is initiated by a conserved set of transcription factors termed retinal determination network (RDN). In the fruit fly Drosophila melanogaster, the zinc-finger transcription factor Glass acts directly downstream of the RDN to control identity of photoreceptor as well as non-photoreceptor cells. Tight control of spatial and temporal gene expression is a critical feature during development, cell-fate determination as well as maintenance of differentiated tissues. The molecular mechanisms that control expression of glass, however, remain largely unknown. We here identify complex regulatory mechanisms controlling expression of the glass locus. All information to recapitulate glass expression are contained in a compact 5.2 kb cis-acting genomic element by combining different cell-type specific and general enhancers with repressor elements. Moreover, the immature RNA of the locus contains an alternative small open reading frame (smORF) upstream of the actual glass translation start, resulting in a small peptide instead of the three possible Glass protein isoforms. CRISPR/Cas9-based mutagenesis shows that the smORF is not required for the formation of functioning photoreceptors, but is able to attenuate effects of glass misexpression. Furthermore, editing the genome to generate glass loci eliminating either one or two isoforms shows that only one of the three proteins is critical for formation of functioning photoreceptors, while removing the two other isoforms did not cause defects in developmental or photoreceptor function. Our results show that eye development and function is largely unaffected by targeted manipulations of critical features of the glass transcript, suggesting a strong selection pressure to allow the formation of a functioning eye

From Refugee to Resident in the Digital Age: Refugees’ Strategies for Navigating in and Negotiating Beyond Uncertainty During Reception and Settlement in The Netherlands

This article examines digital tactics adopted by refugees and asylum-seekers in the Netherlands to cope with spatial and temporal dimensions of uncertainty during different stages of their arrival. It draws attention to how particular modes of Dutch asylum and refugee reception governance, such as dispersal and housing allocation policies, give rise to spatial and temporal uncertainties. Based on participant observations and 23 qualitative interviews with recognized refugees in the cities of Utrecht and Houten, the article offers insight into how refugees used digital tactics and mobile connectivity to ‘navigate in’ and ‘negotiate beyond uncertainty’. The article seeks to contribute to this conceptual differentiation between ‘navigating in’ and ‘negotiating beyond’ uncertainty, engaging with work on migrant agency that acknowledges their acts of resilience, reworking and resistance. Lastly, I discuss this understanding of digital tactics to cope with uncertainty in light of recent critiques in forced migration studies of essentialist understandings of uncertainty and utilitarian narratives of digitally connected migrants