Optimizing peri-operative care to prevent acute kidney injury

Post-operative acute kidney injury (AKI) is a common complication of surgery. Rates vary according to type of surgery, ranging from 13% following gastrointestinal surgery and 10% after orthopaedic surgery to 26% following cardiac surgery [1–3].Understanding the aetiology of post-operative AKI is vital to peri-operative optimization. However, the pathogenesis is complex and usually multifactorial (Figure 1). Renal hypoperfusion plays an important role in post-operative AKI. This can occur as a result of a number of different factors including hypovolaemia, loss of autoregulation during anaesthesia, cardiogenic shock, sepsis and high-risk medicines such as non-steroid anti-inflammatory drugs (NSAIDs) and inhibitors of the renin–angiotensin system

The use of scenarios in legal education to develop future thinking and sustainability competencies

Achieving sustainability requires a populace equipped to deal with complex, interacting and ever-changing realities as well as uncertain futures. There is however a significant lack of focus on developing sustainability competencies within legal and governance education. Legal education plays a key role in shaping sustainable futures. Long-term sustainability relies on lawyers, judges and policy-makers being able to make optimal decisions in the present when faced with significant uncertainty about the future. This paper discusses how the combination of problem-based learning (PBL) and scenario-based pedagogical approaches can provide an authentic contextualised learning environment to empower law students to deal with the challenges of global change. The paper highlights the potential of the approach to equip students with the skills to work through plausible future challenges; to consider a range of options; and to manage interacting environmental, social and economic issues in an adaptive fashion. The paper describes how the approach was applied in the context of the Water Law Master’s (LLM) course at the University of Dundee. The paper concludes with recommendations of how scenario-based approaches could be used in other contexts and further highlights the importance of such approaches in developing sustainability competencies through the legal curriculum.Michelle Lim and Andrew Alla

Modeling the dynamics of bivalent histone modifications

Epigenetic modifications to histones may promote either activation or repression of the transcription of nearby genes. Recent experimental studies show that the promoters of many lineage-control genes in stem cells have "bivalent domains" in which the nucleosomes contain both active (H3K4me3) and repressive (H3K27me3) marks. It is generally agreed that bivalent domains play an important role in stem cell differentiation, but the underlying mechanisms remain unclear. Here we formulate a mathematical model to investigate the dynamic properties of histone modification patterns. We then illustrate that our modeling framework can be used to capture key features of experimentally observed combinatorial chromatin states.Comment: 23 pages, 10 figure

Coastal road asset management: Dealing with uncertainty using quantitative erosion monitoring and modelling

The A183 is an essential transportation link in the northeast UK that joins coastal areas from South Shields to Sunderland. The route runs through the hinterland of Marsden Bay and concerns have been raised about the proximity of the road to the eroding cliff line. The Shoreline Management Plan (Lane and Guthrie, 2007) sets out the overarching management policy in the area and, based on the analyses of historic map data, uses projected coastal cliff retreat rates of 0.1 – 0.2 m a-1, although more recent investigations have suggested the rates may be nearer 0.04 – 0.1 m a-1. Quantitative data on the true rates and nature of cliff erosion are scarce and asset management decisions typically use the higher rate of 0.2 m a-1 when considering the potential impact on road operations and lifespan in order to account for uncertainty and future sea-level rise; which is additionally used to accelerate the predicted rates of retreat. Consequently, an enhanced high order estimate of cliff erosion rates has restricted the serviceability of the A183 to within 20 – 50 years, and there are three areas (pinch points) of particular concern where the close proximity of the cliff line threatens the safe operation of the road. This approach and the data it uses suggest that significant and potentially costly decisions may soon be required to ensure the viability of this vital transport corridor. Set against the context of assumed high cliff erosion rates, and further predicted increases to this metric, this work presents the results of a re-evaluation of existing map and aerial imagery data that highlights the typically high uncertainty associated with historic map data. The errors often exceed the changes being detected in rock cliffs, producing contradictory results and variability in processing and interpretation that restricts the reliability of the data used in current policy decisions. Using a significance-based analysis, questions are raised about how appropriate it is to reduce a three-dimensional recession process down to a single linear retreat. To provide a more appropriate and accurate assessment of the erosion occurring here we present the results of a monitoring approach of the Marsden Bay site using three-dimensional survey analyses to improve understanding of cliff failures at the site and ultimately to aid policy decisions

Building Bridges Across Jurisdictional and Disciplinary Boundries: The Need for New Environmental Law Research Methods

In the past forty years the global population has doubled and global CO2 emissions have increased by 70%. Human induced change to ecosystems is more rapid and extensive than any comparable period in history. Current biodiversity loss exceeds that of the historical past by several orders of magnitude and shows no indication of slowing. Anthropogenic changes to ecosystems have contributed to improvements to human well-being and economic development. This has been achieved at growing costs in the form of the degradation of many ecosystem services. Population growth and economic development have intensified competition over natural resources worldwide. Rapid increases in globalization since the first Rio Conference in 1992 has exceeded the ability of global governance systems to respond to the resulting sustainability challenges. The need for integrated interdisciplinary approaches to address these challenges is widely accepted. There are however a lack of methods to address such approaches. In this context, traditional doctrinal approaches to legal scholarship are clearly inadequate. There is growing recognition that the design of effective legal instruments requires research methods that go beyond traditional approaches and include social and institutional considerations. This recognition has led to socio-legal approaches to legal research and the use of empirical research methods. The design of environmental law instruments faces challenges in addition to those found in other areas of law. These challenges include the meaningful incorporation of ecological knowledge into decision-making and addressing issues that span jurisdictional boundaries from the global to the local. In this presentation, I discuss the methods used in a research project aimed at developing strategies for the effective management of transboundary natural resources. I use this research to explore the particular methodological challenges that face environmental law research and provide directions for the further development of environmental law scholarship. The research used an iterative process which combined desk-based legal-doctrinal research, case-studies and comparative legal research. Two transboundary projects were used as case studies. The first case-study was located in the Pamir-Alai Mountains of Central Asia and involved the adjacent former Soviet nations of Tajikistan and the Kyrgyz Republic. The second case study was based in the highlands of Borneo and included the island’s three countries: Brunei, Indonesia and Malaysia. A comparative study of the legal and institutional requirements for transboundary biodiversity conservation and transboundary water management was conducted to identify core principles for the governance of transboundary resources. This research highlights the transferability of legal methods for the management of natural resources. It also highlights that the creation of effective environmental law instruments requires additional methods to incorporate essential science-policy linkages

Composite Dissolving Microneedles for Coordinated Control of Antigen and Adjuvant Delivery Kinetics in Transcutaneous Vaccination

Transcutaneous administration has the potential to improve therapeutics delivery, providing an approach that is safer and more convenient than traditional alternatives, while offering the opportunity for improved therapeutic efficacy through sustained/controlled drug release. To this end, a microneedle materials platform is demonstrated for rapid implantation of controlled-release polymer depots into the cutaneous tissue. Arrays of microneedles composed of drug-loaded poly(lactide-co-glycolide) (PLGA) microparticles or solid PLGA tips are prepared with a supporting and rapidly water-soluble poly(acrylic acid) (PAA) matrix. Upon application of microneedle patches to the skin of mice, the microneedles perforate the stratum corneum and epidermis. Penetration of the outer skin layers is followed by rapid dissolution of the PAA binder on contact with the interstitial fluid of the epidermis, implanting the microparticles or solid polymer microneedles in the tissue, which are retained following patch removal. These polymer depots remain in the skin for weeks following application and sustain the release of encapsulated cargos for systemic delivery. To show the utility of this approach the ability of these composite microneedle arrays to deliver a subunit vaccine formulation is demonstrated. In comparison to traditional needle-based vaccination, microneedle delivery gives improved cellular immunity and equivalent generation of serum antibodies, suggesting the potential of this approach for vaccine delivery. However, the flexibility of this system should allow for improved therapeutic delivery in a variety of diverse contexts.Massachusetts Institute of Technology. Ragon Institute of MGH, MIT and HarvardNational Institutes of Health (U.S.) (Award AI095109)United States. Army Research Office (Contract W911NF-07-D-0004

Identification of caspase 3 motifs and critical aspartate residues in human Phospholipase D1b and Phopsholipase D2a

Stimulation of mammalian cells frequently initiates phospholipase D-catalysed hydrolysis of phosphatidylcholine in the plasma membrane to yield phosphatidic acid (PA) a novel lipid messenger. PA plays a regulatory role in important cellular processes such as secretion, cellular shape change and movement. A number of studies have highlighted that PLD-based signalling also plays a pro-mitogenic and pro-survival role in cells and therefore anti-apoptotic. We show that human PLD1b and PLD2a contain functional caspase-3 cleavage sites and identify the critical aspartate residues within PLD1b that affect its activation by phorbol esters and attenuate phosphatidylcholine hydrolysis during apoptosis

Function of A20 in the regulation of Helicobacter pylori-induced alternative NK-[kappa]B and caspase-8-dependent apoptotic cell death

Fast die Hälfte der Weltbevölkerung ist mit dem humanpathogenen Bakterium Helicobacter pylori, einem Paradigma für eine hartnäckige jedoch asymptomatische Infektion, infiziert. Eine Infektion mit H. pylori erhöht das Risiko der Entstehung von Magenerkrankungen einschließlich des Magenkrebses. Ein Kennzeichen der Infektion mit H. pylori, welches das Magenepithel besiedelt, ist die gleichzeitige Aktivierung des klassischen und des alternativen ‘nuclear factor kappa-light-chain-enhancer of activated B cells’ (NF-kappaB) Signalweges. Der klassische Signalweg reguliert Gene, die bei Entzündungsprozessen und dem Überleben der Zelle eine Rolle spielen, wohingegen die Funktion des alternativen Signalweges in Bezug auf die H. pylori Infektion ungeklärt ist. Des Weiteren aktiviert die Infektion mit H. pylori apoptotische Signalwege, welche zum Zelltod führen. Das Studium der obengenannten Signalwege ist bedeutend, da in vivo das Gleichgewicht zwischen Überleben und Tod der Zelle einen direkten Einfluss auf die Homödynamik der Magenmukosa hat. Die Homöodynamik ist eindeutig mit Art und Schwere der Erkrankung, die durch die H. pylori Infektion hervorgerufen wird, verknüpft. Wir berichteten, dass A20 als Zielgen des klassischen NF-kappaB Signalweges zur Negativregulation des alternativen NF-kappaB Signalweges, während der H. pylori Infektion von Magenepithelzellen, beiträgt. Mechanistisch bindet das de novo synthetisierte A20 Protein an das ‘tumour necrosis factor receptor-associated factor-interacting protein with forkhead-associated domain’ (TIFA) Protein und interferiert so mit der Bindung von TIFA an den ‘NF-kappaB-inducing kinase’ (NIK)-regulierenden Komplex. Dies führt zur Stabilisierung der ‘cellular inhibitor of apoptosis protein 1’ (cIAP1) im NIK-regulierenden Komplex und zur Beendigung der Aktivierung des alternativen NF-kappaB Signalweges. Wir zeigten ebenfalls, dass die Aktivität des alternativen NF-kappaB Signalweges in Magenepithelzellen zur vermehrten Expression von antiapoptotischen Genen wie ‘baculoviral IAP repeat-containing 2’ (BIRC2), BIRC3 und ‘B-cell lymphoma 2-related protein A1’ (BCL2A1) führte. Dies und die beobachtete RelB abhängige Unterdrückung des apoptotischen Zelltods während der H. pylori Infektion weisen auf eine Mitwirkung des alternativen NF-kappaB Signalweges an der Regulation des apoptotischen Zelltods hin. Andererseits ist A20 auch an der Negativregulation des Caspase-8 abhängigen apoptotischen Zelltod beteiligt. In diesem Fall wirkt die Deubiquitinylierungsaktivität des A20 Proteins der Cullin3 vermittelten Ubiquitinylierung (Lysin 63) der Caspase-8 entgegen, um deren Aktivität einzudämmen. Interessanterweise ist ein anderes NF-kappaB Zielgen, nämlich das p62 Protein, für die Wechselwirkung zwischen A20 und Caspase-8 essenziell. Zusammenfassend geben diese Untersuchungen einen neuen Einblick in die Funktion des A20 Proteins hinsichtlich der Modulation des alternativen NF-kappaB Signalweges, als auch des Caspase-8 abhängigen apoptotischen Zelltods während der H. pylori Infektion.The human pathogen Helicobacter pylori infects almost half of the world’s population and is a paradigm for persistent yet asymptomatic infection. Infection by H. pylori increases the risk for developing gastric diseases including gastric adenocarcinoma. A hallmark of infection by H. pylori, which colonises the human gastric epithelium, is the simultaneous activation of the classical and alternative nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) pathways. In H. pylori infection, classical NF-kappaB signalling regulates genes involved in inflammation and cell survival, while the function of the alternative NF-kappaB signalling remains unclarified. Infection of gastric epithelial cells by H. pylori also triggers apoptotic signalling cascades leading to cell death. Studying the regulation of all the above-mentioned signalling cascades is important given that in vivo, the balance between cell survival and cell death has a direct impact on mucosal homeodynamics, which in turn is explicitly linked to the type and severity of disease(s) associated with H. pylori infection. We reported that the classical NF-kappaB target gene product A20 contributes to the negative regulation of alternative NF-kappaB activation in gastric epithelial cells infected by H. pylori. Mechanistically, the de novo synthesised A20 interacts with tumour necrosis factor receptor-associated factor-interacting protein with forkhead-associated domain (TIFA), and thereby interferes with the association of TIFA with the cellular inhibitor of apoptosis protein 1 (cIAP1) of the NF-kappaB-inducing kinase (NIK) regulatory complex. This leads to stabilisation of the NIK regulatory complex and the termination of alternative NF-kappaB activation. We also showed that alternative NF-kappaB activity contributes to the up-regulation of anti-apoptotic genes such as baculoviral IAP repeat-containing 2 (BIRC2), BIRC3 and B-cell lymphoma 2-related protein A1 (BCL2A1) in gastric epithelial cells. This and the observed RelB-dependent suppression of apoptotic cell death highlight a contributory role of the alternative NF-kappaB pathway towards cell survival in H. pylori infection. On the other hand, A20 also participates in the negative regulation of caspase-8-dependent apoptotic cell death. Herein, the deubiquitinylase activity of A20 counteracts the cullin3-mediated K63-linked ubiquitinylation of caspase-8 to curtail its activity. Interestingly, another inducible NF-kappaB target gene product, the scaffold protein p62, was found to ameliorate the interaction of A20 with caspase-8. In conclusion, these studies provide novel insight into the function of A20 in modulating the alternative NF-kappaB pathway as well as caspase-8-dependent apoptotic cell death in H. pylori infection