Acute Downregulation of ENaC by EGF Involves the PY Motif and Putative ERK Phosphorylation Site

The epithelial sodium channel (ENaC) is expressed in a variety of tissues, including the renal collecting duct, where it constitutes the rate-limiting step for sodium reabsorption. Liddle's syndrome is caused by gain-of-function mutations in the β and γ subunits of ENaC, resulting in enhanced Na reabsorption and hypertension. Epidermal growth factor (EGF) causes acute inhibition of Na absorption in collecting duct principal cells via an extracellular signal–regulated kinase (ERK)–dependent mechanism. In experiments with primary cultures of collecting duct cells derived from a mouse model of Liddle's disease (β-ENaC truncation), it was found that EGF inhibited short-circuit current (Isc) by 24 ± 5% in wild-type cells but only by 6 ± 3% in homozygous mutant cells. In order to elucidate the role of specific regions of the β-ENaC C terminus, Madin-Darby canine kidney (MDCK) cell lines that express β-ENaC with mutation of the PY motif (P616L), the ERK phosphorylation site (T613A), and C terminus truncation (R564stop) were created using the Phoenix retroviral system. All three mutants exhibited significant attenuation of the EGF-induced inhibition of sodium current. In MDCK cells with wild-type β-ENaC, EGF-induced inhibition of Isc (<30 min) was fully reversed by exposure to an ERK kinase inhibitor and occurred with no change in ENaC surface expression, indicative of an effect on channel open probability (Po). At later times (>30 min), EGF-induced inhibition of Isc was not reversed by an ERK kinase inhibitor and was accompanied by a decrease in ENaC surface expression. Our results are consistent with an ERK-mediated decrease in ENaC open probability and enhanced retrieval of sodium channels from the apical membrane

Achieving sustainable sanitation chains through better informed and more systematic improvements: lessons from multi-city research in Sub-Saharan Africa

This paper presents the synthesised findings of the SPLASH Urban Sanitation research programme through the framework of the sanitation service chain. Urban sanitation service chains are complex and fragmented, involving a multiplicity of service providers and typically resulting in unsustainable or inadequate services. The aggregate data set covers a wide range of research methods including; household surveys, a randomised control trial, a willingness to pay survey prototype testing of technologies, focus group discussions and deliberative forums. Thorough the research, it has been possible to identify situations where incremental improvements are being made with varying degrees of success. Most importantly, it has identified weaknesses to the sanitation service chains where progress is either slow or extremely limited. It is through these weaknesses that key questions affecting the long term sustainability of sanitation service chains need to be answered

Modelling biological form in evolution

How are processes working at the individual level, the species level and the macro-ecological level connected? This thesis explores the theoretical and structural constraints on biological evolution. It does this by developing an evolutionary program to model biological form. This development was necessary as the existing models of evolution are poorly suited to modelling morphological constraint. The model of biological form developed in this thesis uses graphs to abstractly represent organisms and the relationships of their internal structure. We show that by increasing the number of degrees of freedom, or by increasing the ruggedness of the fitness landscape, higher levels of diversity are supported - particularly when there is strong directional selection. We explore whether meta-regulation is bounded in the model by using an analytical framework. We show that there is no analytical steady state, but that one can be induced in the model by selection effects. We find that a mixed strategy between increasing object complexity and increasing hierarchical complexity maximises the average degree of a vertex. This agrees with the evolutionary history of meta-regulation. We claim that the macro-ecological response to environmental perturbation is determined by both the characteristic time scale of mutation and the time scale of the environmental change. We show that for high amplitude changes the system can adapt provide the mutation time scale is smaller than the environmental change. We also show that low amplitude environmental changes cause rapid turnovers in species' diversity. Finally, we show that mass extinctions can be the result of species' interactions and background rates of extinction, and do not need large external perturbations to occur. This, combined with the results above, suggests that many of the trends seen over geologically long time periods can be explained as a result of the interacting processes at the individual and species level

Urban sanitation: where to next?

This paper sets the current research-related innovations in urban sanitation of low to middle income countries within a broader historic context. It highlights the key threads of urban sanitation discourse over the past four decades; from putting the last first, to a more nuanced understanding of household demand and uptake, and a focus on faecal sludge management (FSM). Particularly since 2008 the International Year of Sanitation, there has been increasing specialisation around the sanitation value chain and FSM, producing deeper knowledge and several diagnostic / decision support tools. Whist the sector has, in no doubt, made great progress, the paper suggests that there is a risk of (over)simplification. Now is the time, armed with a better understanding and decision support tools, to embrace urban complexity; to place sanitation back into the wider human-technology-environment systems of the city; and to plan for integrated basic services in the domestic and peri-domestic domains

Towards improved labour standards for construction of minor works in low income countries

Purpose of the paper: The construction industry is one of the largest employment providers in the developing world. It is also one of the least safe industries, with a high frequency of accidents resulting in financial losses, injuries, disabilities and deaths. Decent working conditions and resulting improved worker satisfaction are key to sustainable productivity in the industry. International standards safeguarding construction workers are abundant and ratified by most low-income countries. Are these standards adequately reflected in contracts for construction works? If not, how can contract clauses be improved and operationalised? Design/methodology/approach: Based on research undertaken in Ghana, India and Zambia from 2000 to 2003, this paper explores the aforementioned questions. The paper comprises of analysis of contract clauses from the International Federation of Consulting Engineers (FIDIC) and developing country contracts, along with cases study findings. Findings: This paper finds that more legislation is not the urgent issue; incorporating existing legislation into construction contracts and making clauses operational is a priority. This paper identifies practical and cost-effective procedures for bringing stakeholders together to implement and monitor labour standards, with the aim of contributing to the overall goal of providing “decent work” for all workers in the construction industry. Original/value of the paper: This paper explores issues around implementing labour standards in construction of minor infrastructure works in low income countries and concludes with suggestions on how best to operationalise contract clauses through a process approach

Exploring academic perspectives on immersive scheduling in a UK university

This study examined how academic staff responded to a cross-institutional change initiative to integrate immersive scheduling into the first-year undergraduate curriculum. Immersive scheduling, also referred to as block or compressed delivery, sought to create a supportive first-year experience, to ease students’ transition to university. Adopting an immersive approach is associated with considerable change as academic staff adapt their practice to accommodate the compressed time frame of modules and embrace learning and assessment methods associated with this delivery format. In this study, we undertook semi-structured interviews with 17 academics who were leading the development and delivery of immersive modules or supporting the teaching and learning initiative. Our data indicated that academics played a significant role in the acceptance or rejection of the vision for immersive scheduling. Acceptance was reliant on academics recognising value in the vision, and this varied depending on the extent to which it resonated with local practice. In some cases, the move to immersive scheduling represented a valued opportunity to update pedagogic and assessment practices. However, in other contexts, academic resistance led to dilution of key elements of the vision, with compliance rather than innovation being the outcome. This study also highlights the value of using a combination of module delivery formats to mitigate recognised drawbacks associated with immersive delivery. We conclude this paper by proposing recommendations to support the future development of immersive scheduling in higher education institutions

Mapping EU support for sanitation in Africa

This study addresses a number of key concerns of AMCOW, the European Union (EU) and other donors around the need to increase support to sanitation in order to accelerate the progress of national plans, Africawide goals, and the attainment of the MDG target on sanitation. The purpose of the study is to obtain an overview of the status of the involvement of EU Member States and the European Commission in sanitation-related activities in Africa. It is anticipated that the findings of this work will have the potential to be used for both arguing for greater priority for sanitation within the international architecture and also for individual donors to use in discussing their own Official Development Assistance (ODA). The work is complementary to the report from 2008 on mapping EU development assistance to the water sector in Africa. This earlier report had a much wider remit and as such, the Sanitation Mapping report can be considered as being supplementary to it

European Union support for sanitation in sub-Saharan Africa: aid flows and effectiveness

Within sub-Saharan Africa, 569 million people, amounting to 69% of the population, do not use improved sanitation. This study presents an overview of European Union (EU) donor support to sanitation in sub-Saharan Africa and proposes a method for investigating the effectiveness of national sanitation programmes through linking aid flows to sanitation outcomes in terms of trends in open defecation; this can be used to locate the relative performance of different countries. The work addresses key concerns of the African Ministers' Council on Water and the European donors around the need to increase support to sanitation. Results show that EU donors are the major source of external finance for sanitation in sub-Saharan Africa. Case studies from Mozambique, Uganda and Burkina Faso show that the majority of national planned expenditure on sanitation comes from donor sources, with EU donors being the substantive contributors. National policies on subsidy for sanitation and expenditure allocations vary extremely widely and do not necessarily align with sanitation outcomes. EU member states' donor policies on sanitation are consistent and well-aligned with those of the African Union; this is a major achievement for Europe and Africa. Inadequate national monitoring of sanitation expenditure remains a constraint to determining programme effectiveness

Technological innovations in mental healthcare: harnessing the digital revolution

Digital technology has the potential to transform mental healthcare by connecting patients, services and health data in new ways. Digital online and mobile applications can offer patients greater access to information and services and enhance clinical management and early intervention through access to real-time patient data. However, substantial gaps exist in the evidence base underlying these technologies. Greater patient and clinician involvement is needed to evaluate digital technologies and ensure they target unmet needs, maintain public trust and improve clinical outcomes

Multi‐century stasis in C3 and C4 grass distributions across the contiguous United States since the industrial revolution

AimsUnderstanding the functional response of ecosystems to past global change is crucial to predicting performance in future environments. One sensitive and functionally significant attribute of grassland ecosystems is the percentage of species that use the C4 versus C3 photosynthetic pathway. Grasses using C3 and C4 pathways are expected to have different responses to many aspects of anthropogenic environmental change that have followed the industrial revolution, including increases in temperature and atmospheric CO2, changes to land management and fire regimes, precipitation seasonality, and nitrogen deposition. In spite of dramatic environmental changes over the past 300 years, it is unknown if the C4 grass percentage in grasslands has shifted.LocationContiguous United States of America.MethodsHere, we used stable carbon isotope data (i.e. δ13C) from 30 years of soil samples, as well as herbivore tissues that date to 1739 CE, to reconstruct coarse‐grain C3 and C4 grass composition in North American grassland sites to compare with modern vegetation. We spatially resampled these three datasets to a shared 100‐km grid, allowing comparison of δ13C values at a resolution and extent common for climate model outputs and biogeographical studies.ResultsAt this spatial grain, the bison tissue proxy was superior to the soil proxy because the soils reflect integration of local carbon inputs, whereas bison sample vegetation across landscapes. Bison isotope values indicate that historical grassland photosynthetic‐type composition was similar to modern vegetation.Main conclusionsDespite major environmental change, comparing modern plot vegetation data to three centuries of bison δ13C data revealed that the biogeographical distribution of C3 and C4 grasses has not changed significantly since the 1700s. This is particularly surprising given the expected CO2 fertilization of C3 grasses. Our findings highlight the critical importance of capturing the full range of physiological, ecological and demographical processes in biosphere models predicting future climates and ecosystems.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139065/1/jbi13061.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139065/2/jbi13061_am.pd