KCNK5 is Functionally Down-Regulated Upon Long-Term Hypotonicity in Ehrlich Ascites Tumor Cells

Background/Aims: Regulatory volume decrease (RVD) in response to acute cell swelling is well described and KCNK5 (also known as TASK-2 or K2P5.1) has been shown to be the volume sensitive K+ channel in Ehrlich cells. Very little is, on the other hand, known about the effects of long-term hypotonicity on expression and function of KCNK5, thus we have investigated the effect of long-term hypotonicity (24h - 48h) on KCNK5 in Ehrlich cells on the mRNA, protein and physiological levels. Methods: Physiological effects of long-term hypotonicity were measured using patch-clamp and Coulter counter techniques. Expression patterns of KCNK5 on mRNA and protein levels were established using real-time qPCR and western blotting respectively. Results: The maximum swelling-activated current through KCNK5 was significantly decreased upon 48h of hypotonicity and likewise the RVD response was significantly impaired after both 24 and 48h of hypotonic stimulation. No significant differences in the KCNK5 mRNA expression patterns between control and stimulated cells were observed, but a significant decrease in the KCNK5 protein level 48h after stimulation was found. Conclusion: The data suggest that the strong physiological impairment of KCNK5 in Ehrlich cells after long-term hypotonic stimulation is predominantly due to down-regulation of the KCNK5 protein synthesis

In vitro efficacy of artemisinin-based treatments against SARS-CoV-2

Effective and affordable treatments for patients suffering from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are needed. We report in vitro efficacy of Artemisia annua extracts as well as artemisinin, artesunate, and artemether against SARS-CoV-2. The latter two are approved active pharmaceutical ingredients of anti-malarial drugs. Concentration–response antiviral treatment assays, based on immunostaining of SARS-CoV-2 spike glycoprotein, revealed that treatment with all studied extracts and compounds inhibited SARS-CoV-2 infection of VeroE6 cells, human hepatoma Huh7.5 cells and human lung cancer A549-hACE2 cells, without obvious influence of the cell type on antiviral efficacy. In treatment assays, artesunate proved most potent (range of 50% effective concentrations (EC50) in different cell types: 7–12 µg/mL), followed by artemether (53–98 µg/mL), A. annua extracts (83–260 µg/mL) and artemisinin (151 to at least 208 µg/mL). The selectivity indices (SI), calculated based on treatment and cell viability assays, were mostly below 10 (range 2 to 54), suggesting a small therapeutic window. Time-of-addition experiments in A549-hACE2 cells revealed that artesunate targeted SARS-CoV-2 at the post-entry level. Peak plasma concentrations of artesunate exceeding EC50 values can be achieved. Clinical studies are required to further evaluate the utility of these compounds as COVID-19 treatment

[Introduction] The making and unmaking of precarious, ideal subjects – migration brokerage in the Global South

The migration literature is often underpinned by the idea that migrants are either completely ‘free’ agents, individually choosing how best to achieve returns on their human capital and resources (Sjaastad 1962) or ‘agents of development’ for their home countries and regions (Turner and Kleist 2013). Conversely they are viewed as exploited slaves, being pushed into low-paid occupations and controlled by middlemen and employers. Unsurprisingly, in many close-knit societies a process as expensive and life-defining as migration is rarely undertaken as an individual act and is shaped by complex social interactions within kinship networks and beyond (Lindquist 2012). Brokerage is ever-present in migrant labour markets around the world, variously interpreted as occupying the ‘middle space’ between migrants and the state, helping migrants navigate complex immigration regimes (Lindquist, Xiang, and Yeoh 2012; McKeown 2012; Schapendonk 2017), acting as an extension of the state seeking to outsource border controls (Goh, Wee, and Yeoh 2017) and colluding with employers to cheapen and commoditise migrant labour (Guérin 2013; McCollum and Findlay 2018). It is increasingly recognised that an understanding of contemporary migration is not complete without an understanding of the mediating practices that facilitate and constrain it (Coe and Jordhus-Lier 2011; Cranston, Schapendonk, and Spaan 2018). This special issue investigates the role that migration brokers play in the subjectivation and precarisation of migrant men and women from marginalised classes and ethnicities in the Global South. It shows how these processes are critical for them to become a part of contemporary economic and political systems of international and internal labour circulation. It responds to the call of labour geographers for a deeper understanding of the ways in which diverse economic and social contexts result in complex forms of precarity (McDowell 2015) and adds to the evidence on the role of actors beyond the workplace in co-creating precarity (Buckley, McPhee, and Rogaly 2017)

Transformations in network governance: the case of migration intermediaries

types: Article"This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Ethnic and Migration Studies on 3 February 2015 available online: http://wwww.tandfonline.com/10.1080/1369183X.2014.1003803Market liberalisation has fundamentally changed state interventions in the supply of services and supportive infrastructure across a range of public services. While this trend has been relatively well documented, there has been a dearth of research into the changing nature of state interventions in migration and mobility. Indeed the increasing presence of migration intermediaries to service the many and varied needs of migrant workers, particularly skilled migrants, remains significantly under-researched both theoretically and empirically. In providing an analysis of the location, role and changing nature of migration intermediaries, we highlight the implications of commercially-driven governance structures. In particular we suggest that the shift from government to network governance has important implications for skilled migration including: inequities in access to information regarding the process of migration and labour market integration; and, greater dependence on (largely unregulated) private intermediaries. Accordingly, we present empirical examples of migration intermediaries to illustrate their role and the relationship with and implications of their exchange with migrants

Neonatal mortality: an invisible and marginalised trauma

Neonatal mortality is a major health problem in low and middle income countries and the rate of improvement of newborn survival is slow. This article is a review of the PhD thesis by Mats Målqvist, titled ‘Who can save the unseen – Studies on neonatal mortality in Quang Ninh province, Vietnam,’ from Uppsala University. The thesis aims to investigate structural barriers to newborn health improvements and determinants of neonatal death. The findings reveal a severe under-reporting of neonatal deaths in the official health statistics in Quang Ninh province in northern Vietnam. The neonatal mortality rate (NMR) found was four times higher than what was reported to the Ministry of Health. This underestimation of the problem inhibits adequate interventions and efforts to improve the survival of newborns and highlights the invisibility of this vulnerable group

Retroviral expression of a kinase-defective IGF-I receptor suppresses growth and causes apoptosis of CHO and U87 cells in-vivo

BACKGROUND: Phosphatidylinositol-3,4,5-triphosphate (PtdInsP3) signaling is elevated in many tumors due to loss of the tumor suppressor PTEN, and leads to constitutive activation of Akt, a kinase involved in cell survival. Reintroduction of PTEN in cells suppresses transformation and tumorigenicity. While this approach works in-vitro, it may prove difficult to achieve in-vivo. In this study, we investigated whether inhibition of growth factor signaling would have the same effect as re-expression of PTEN. METHODS: Dominant negative IGF-I receptors were expressed in CHO and U87 cells by retroviral infection. Cell proliferation, transformation and tumor formation in athymic nude mice were assessed. RESULTS: Inhibition of IGF-IR signaling in a CHO cell model system by expression of a kinase-defective IGF-IR impairs proliferation, transformation and tumor growth. Reduction in tumor growth is associated with an increase in apoptosis in-vivo. The dominant-negative IGF-IRs also prevented growth of U87 PTEN-negative glioblastoma cells when injected into nude mice. Injection of an IGF-IR blocking antibody αIR3 into mice harboring parental U87 tumors inhibits tumor growth and increases apoptosis. CONCLUSION: Inhibition of an upstream growth factor signal prevents tumor growth of the U87 PTEN-deficient glioma to the same extent as re-introduction of PTEN. This result suggests that growth factor receptor inhibition may be an effective alternative therapy for PTEN-deficient tumors