Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury

The cytosolic protein rubicon (RUBCN) has been implicated in the removal of necrotic debris and autoimmunity. However, the role of RUBCN in models of acute kidney injury (AKI), a condition that typically involves necrotic kidney tubules, was not investigated. Here, we demonstrate that RUBCN-deficient mice are hypersensitive to renal damage induced by ischemia-reperfusion injury (IRI) and cisplatin-induced AKI. Combined deficiency of RUBCN and mixed lineage kinase domain-like (MLKL) partially reversed the sensitivity in the IRI model suggesting that the absence of RUBCN sensitizes to necroptosis in that model. Necroptosis is known to contribute to TNFα-induced severe inflammatory response syndrome (SIRS), but we detected no statistically significant difference in overall survival following injection of TNFα in RUBCN-deficient mice. We additionally generated RUBCN-deficient mice which lack gasdermin D (GSDMD), the terminal mediator of pyroptosis, but no reversal of the AKI phenotype was observed. Finally, and in contrast to the previous understanding of the role of RUBCN, we did not find a significant autoimmune phenotype in RUBCN-deficient mice, but detected chronic kidney injury (CKD) in aged RUBCN-deficient mice of both sexes. In summary, our data indicate that RUBCN-deficient mice are hypersensitive to kidney injury

Everybody’s Hacking:Participation and the Mainstreaming of Hackathons

Hackathons have become a popular tool for bringing people together to imagine new possibilities for technology. Despite originating in technology communities, hackathons have now been widely adopted by a broad range of organisations. This mainstreaming of hackathons means they encompass a very different range of attendees and activities than they once did, to the extent that some events billed as hackathons may involve no coding at all. Given this shift away from production of code, they might instead be seen as an increasingly popular participatory design activity, from which designers and researchers in HCI can learn. Through fieldwork at six hackathons that targeted non-technical communities, we identify the types of activities and contributions that emerge through these events and the barriers and tensions that might exist. In doing so, we contribute a greater understanding of hackathons as a growing phenomenon and as a potential tool for participatory research.Publisher PD

Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion

Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications

Gasdermin D-deficient mice are hypersensitive to acute kidney injury

Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI

The UK Centre for Astrobiology:A Virtual Astrobiology Centre. Accomplishments and Lessons Learned, 2011-2016

Authors thank all those individuals, UK research councils, funding agencies, nonprofit organisations, companies and corporations and UK and non-UK government agencies, who have so generously supported our aspirations and hopes over the last 5 years and supported UKCA projects. They include the STFC, the Engineering and Physical Sciences Research Council (EPSRC), the Natural Environmental Research Council (NERC), the EU, the UK Space Agency, NASA, the European Space Agency (ESA), The Crown Estate, Cleveland Potash and others. The Astrobiology Academy has been supported by the UK Space Agency (UKSA), National Space Centre, the Science and Technology Facilities Council (STFC), Dynamic Earth, The Royal Astronomical Society, The Rotary Club (Shetlands) and the NASA Astrobiology Institute.The UK Centre for Astrobiology (UKCA) was set up in 2011 as a virtual center to contribute to astrobiology research, education, and outreach. After 5 years, we describe this center and its work in each of these areas. Its research has focused on studying life in extreme environments, the limits of life on Earth, and implications for habitability elsewhere. Among its research infrastructure projects, UKCA has assembled an underground astrobiology laboratory that has hosted a deep subsurface planetary analog program, and it has developed new flow-through systems to study extraterrestrial aqueous environments. UKCA has used this research backdrop to develop education programs in astrobiology, including a massive open online course in astrobiology that has attracted over 120,000 students, a teacher training program, and an initiative to take astrobiology into prisons. In this paper, we review these activities and others with a particular focus on providing lessons to others who may consider setting up an astrobiology center, institute, or science facility. We discuss experience in integrating astrobiology research into teaching and education activities.Publisher PDFPeer reviewe

Soil corrosion monitoring near a pipeline under CP

Electrochemical noise (EN), linear polarization resistance (LPR), and harmonic distortion analysis (HDA) were used with three-electrode probes to monitor the corrosion occurring in soil in dry and wet conditions near a gas pipeline under cathodic protection. The test site was a cathodic protection (CP) test station where impressed current CP was applied to a 2 in. (5.1 cm) diameter FBE coated steel pipe using an 84 in. (0.2 m) TA-2 high-silicon cast iron anode. Electrochemical measurements were made at three locations, two inside the CP field and one outside the CP field. Electrochemical measurements were first made with the CP system off to establish the baseline corrosion and then with increasing levels of CP. The degree of protection was based on polarized potential and the adequacy of protection was determined by depolarization measurements. CP of an adjacent pipeline did not affect the measurement of either corrosion rate or pitting factor when using buried soil corrosion probes and the EN, LPR, and HDA techniques

Reflecting on Local Ecological Stewardship, Care, and Action across Two Decades of Research

In this perspective, we draw from 20 years of implementing the Stewardship Mapping and Assessment Project (STEW-MAP) to show how civic actors provide capacity and local knowledge needed for effective decision-making and implementation in the face of multiple interconnected stressors, including climate change and inequality. Urban areas are striving to achieve sustainability and resilience goals while advancing diversity, equity, inclusion, and justice. There is broad recognition that systematic change cannot be achieved via single sector solutions. Rather, just and equitable sustainability and resilience outcomes will be achieved through multi-sector, trans-disciplinary efforts led by diverse and inclusive partnerships. Processes of collaboration between groups and across sectors can foster trust and social cohesion to build adaptive environmental governance capacity. Hindering these outcomes is a lack of approaches for identifying civic groups and their networks, understanding their roles in the larger governance system, and harnessing their capacities systematically and at landscape scales. STEW-MAP was developed to address this gap in a natural resources management context and has been applied in 20 locations across the Americas. Synthesizing key insights for practitioners and researchers, we identify the critical role of civic organizations in collaborative, networked governance, while highlighting inequities that affect this stewardship work. We reflect on how stewardship mapping has been used as a decision-support, networking, and visualization tool and identify future research and practitioner directions that fully acknowledge the persistent role of civic groups in caring for the environment and enlivening democratic practice

Digital girl:Cyberfeminism and the emancipation potential of digital entrepreneurship in emerging economies

Digital entrepreneurship has been described as a “great leveler” in terms of equalizing the entrepreneurial playing field for women. However, little is known of the emancipatory possibilities offered by digital entrepreneurship for women constrained by social and cultural practices such as male guardianship of female relatives and legally enforced gender segregation. In order to address this research gap, this paper examines women’s engagement in digital entrepreneurship in emerging economies with restrictive social and cultural practices. In so doing, we draw upon the analytical frameworks provided by entrepreneurship as emancipation and cyberfeminism. Using empirical data from an exploratory investigation of entrepreneurship in Saudi Arabia, we examine how women use digital technologies in the pursuit of entrepreneurial opportunities. Our findings reveal that women in Saudi Arabia use digital entrepreneurship to transform their embodied selves and lived realities rather than to escape gender embodiment as offered by the online environment