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Sphingolipids are a family of lipids that regulate the cell cycle, differentiation and cell death. Sphingolipids are known to play a role in the induction of apoptosis, but a role for these lipids in necroptosis is largely unknown. Necroptosis is a programmed form of cell death that, unlike apoptosis, does not require ATP. Necroptosis can be induced under a variety of conditions, including nutrient deprivation and plays a major role in ischaemia/reperfusion injury to organs. Sphingolipids play a role in ischaemia/reperfusion injury in several organs. Thus, we hypothesized that sphingolipids mediate nutrient-deprivation-induced necroptosis. To address this, we utilized mouse embryonic fibroblast (MEFs) treated with 2-deoxyglucose (2DG) and antimycin A (AA) to inhibit glycolysis and mitochondrial electron transport. 2DG/AA treatment of MEFs induced necroptosis as it was receptor- interacting protein (RIP)-1/3 kinase-dependent and caspase-independent. Ceramides, sphingosine (Sph) and sphingosine 1-phosphate (S1P) were increased following 2DG/AA treatment. Cells lacking neutral ceramidase (nCDase−/−) were protected from 2DG/AA. Although nCDase−/− cells generated ceramides following 2DG/AA treatment, they did not generate Sph or S1P. This protection was stimulus-independent as nCDase−/− cells were also protected from endoplasmic reticulum (ER) stressors [tunicamycin (TN) or thapsigargin (TG)]. nCDase−/− MEFs had higher autophagic flux and mitophagy than wild-type (WT) MEFs and inhibition of autophagy sensitized them to necroptosis. These data indicate that loss of nCDase protects cells from nutrient- deprivation-induced necroptosis via autophagy, and clearance of damaged mitochondria. Results suggest that nCDase is a mediator of necroptosis and might be a novel therapeutic target for protection from ischaemic injury.

Nearly one half of patients with lupus develop glomerulonephritis (GN), which often leads to renal failure. Although nephritis is diagnosed by the presence of proteinuria, the pathology of nephritis can fall into one of five classes defined by different forms of tissue injury, and the mechanisms involved in pathogenesis are not completely understood. Glycosphingolipids are abundant in the kidney, have roles in many cellular functions, and were shown to be involved in other renal diseases. Here, we show dysfunctional glycosphingolipid metabolism in patients with lupus nephritis and MRL/lpr lupus mice. Specifically, we found that glucosylceramide (GlcCer) and lactosylceramide (LacCer) levels are significantly higher in the kidneys of nephritic MRL/lpr lupus mice than the kidneys of non-nephritic lupus mice or healthy controls. This elevation may be, in part, caused by altered transcriptional regulation and/or activity of LacCer synthase (GalT5) and neuraminidase 1, enzymes that mediate glycosphingolipid metabolism. We show increased neuraminidase 1 activity early during the progression of nephritis (before significant elevation of GlcCer and LacCer in the kidney). Elevated levels of urinary LacCer were detected before proteinuria in lupus mice. Notably, LacCer levels were higher in the urine and kidneys of patients with lupus and nephritis than patients with lupus without nephritis or healthy controls. Together, these results show early and significant dysfunction of the glycosphingolipid metabolic pathway in the kidneys of lupus mice and patients with lupus nephritis and suggest that molecules in this pathway may serve as early markers in lupus nephritis.

Coastal erosion on the southeast African coastline shows an apparent 18 year cycle which last peaked in 2006. It is in phase with the longshore sediment transport cycle. Both these cycles appear to be in phase with the Lunar Nodal Cycle (LNC). However, the dominant tidal erosion driver on this coast appears to be the 4.4 year Lunar Perigean Subharmonic (LPS). We suggest that the apparent 18 year coastal erosion and longshore sediment budget cycle is a response to the 18 year Mean Annual Precipitation Cycle. This cycle is 180° out of phase with the apparent coastal erosion- and longshore sediment transport- cycles. The summer rainfall areas, of southeastern Africa show an 18 year MAP cyclicity, which drives river runoff and hence controls sediment input to the coast and nearshore environment. The MAP cycle dominates the coastal sediment budget during the LNC trough and suppresses the LPS coastal erosion cycle during this time. This explains why LPS coastal erosion occurs close to the LNC peak. Thus although the LPS cycle dominates the coastline, it is masked during the wet portion of the 18 year MAP cycle. It seems very likely that the LNC drives the MAP cycle in some way but this process is not known. Nevertheless, these relationships can be used to predict, in a general way, both cyclic coastal erosion and the longshore sediment volume fluctuation. This can be translated into a vital coastal planning tool which has the potential to forecast cyclic coastal erosion and hence significantly reduce the sea-defense expenditure bill. Based on this, severe cyclic coastal erosion is anticipated in 2023 and 2024.

With 80 % of world trade carried by sea, seaports provide crucial linkages in global supply-chains and are essential for the ability of all countries to access global markets. Seaports are likely to be affected directly and indirectly by climatic changes, with broader implications for international trade and development. Due to their coastal location, seaports are particularly vulnerable to extreme weather events associated with increasing sea levels and tropical storm activity, as illustrated by hurricane “Sandy”. In view of their strategic role as part of the globalized trading system, adapting ports in different parts of the world to the impacts of climate change is of considerable importance. Reflecting the views of a diverse group of stakeholders with expertise in climate science, engineering, economics, policy, and port management, this essay highlights the climate change challenge for ports and suggests a way forward through the adoption of some initial measures. These include both “soft” and “hard” adaptations that may be spearheaded by individual port entities, but will require collaboration and support from a broad range of public and private sector stakeholders and from society at large. In particular, the essay highlights a need to shift to more holistic planning, investment and operation.

A simple empirical model is proposed for predicting extreme wave run-up on natural beaches during severe wave events (deep water wave heights H0 ≳8 m or return periods of about 50 years). The new model departs from traditional approaches that use the slope of the beach face βf and the Iribarren number ξ0 as parameters for predicting run-up and instead uses the distance offshore xh to water depth h to estimate a near-shore profile slope as S = h/xh, where the depth of closure is the proposed choice for h. Extreme run-up Rx is then expressed in terms of S as Rx/H0 = CS2/3. Observations from recent severe storm events in South Africa are used to estimate the dimensionless coefficient C≃7.5. The data are also compared with those of Holman [1986] and the results verify his regression equations and confirm they are valid for significant wave heights extending to 8.5 m for beach-face slopes around 0.1. The run-up predictions of Holman [1986], Nielsen and Hanslow [1991] and Stockdon et al. [2006] are compared to those of the proposed new model. The results suggest that the new model reduces the uncertainties in predicting wave run-up on natural beaches compared with previous models, and thus enables improved estimates of extreme wave run-up and the upper limit of beach change for coastal planning and management.

During 2006–2007, the KwaZulu-Natal coast of South Africa was exposed to several large swell events (Ho > 3 m), near the peak of the lunar nodal cycle, causing shoreline recession. The largest swell (Hs = 8.5 m) struck the coast on the March equinox (18th–20th) and generated a strong storm-return flow. Observations made before, during and after record dramatic coastal erosion (shoreline recession of up to 40 m and substantial property damage). This swell event removed the semi-continuous nearshore bar system and ‘conditioned’ the coast such that lesser subsequent swell events accomplished much greater amounts of coastal erosion than expected (up to 100 m at certain erosion hotspots) because waves reached the coast without significant energy dissipation. Subsequent bar generation rebuilt the inshore bars within six months. The styles of erosion during the March ’07 event and other 2007 swells were markedly different. Lesser swells are focused by headlands and result in megarip development and activation of erosion hotspots. The March ’07 event still-water level was raised (equinoctial spring high tide and a storm surge of 0.33–0.45 m) to a level that rendered most headlands (and erosion hotspots) ineffective and resulted in laterally extensive erosion of soft shorelines. Results record cumulative effects of successive swell events on coastal behaviour that proved to be critical in enabling erosion to proceed at rapid rates after the coast had been initially destabilized. Unlike hurricanes and tsunamis, surges associated with swell events are relatively minor and therefore extensive erosion is linked with high lunar tides. There is circumstantial evidence that swell-induced erosion follows the broad 18.6 yr lunar nodal tidal cycle when the chances of large swells coinciding with high water levels are increased.

Meeting Programme Prof David O'Hagan [University of St Andrews, UK]—Enzymatic C–18F Bond Synthesis: A New Strategy for PET Synthesis. Dr Michael Carroll [University of Newcastle, UK]—Studies Towards 6-[18F]Fluoro-m-tyramine using Iodonium Salts. Dr John Gardiner [University of Manchester, UK]—Methods Towards Isotopomer-Versatile Synthesis of 13C-Labelled Carbohydrates. Prof William Lockley [University of Surrey, UK]—Some New Catalytic Systems for Isotope-Exchange Labelling. Dr David Rustidge [Scynexis Europe, UK]—14C-Synthesis—Not Always as Easy as it Looks. Dr Richard Hartley [University of Glasgow, UK]—The Potential for using Titanium Alkylidene Chemistry in Solid-Phase Radiochemical Synthesis. Dr Ian Wilson [Turku Imanet, Finland]—Transition of PET Tracers from Clinical Research Tools to Commercial Diagnostics. Dr Simon Harwood [GlaxoSmithKline, UK]—The Synthesis of Stable Labelled Ketamine. Dr John Herbert [Sanofi-Aventis, UK]—Towards Robust Conditions for Iridium-mediated Exchange. Dr Conor Barry [University of Bristol, UK]—Total Synthesis of Clavosolide A.

Studies on the chromoprotein antibiotic neocarzinostatin The ‘special effects’ of microwaving in radiochemistry. Stable isotopes and membrane transport proteins: chemical synthesis and biochemical analysis by solid state NMR Synthetic aspects of c-deuteriation of enolates Opportunities for isotope labelling via solid phase synthesis with organogermanium linkers Labelled methyllycaconitine (MLA)—a key nicotinic acetylcholine receptor ligand Challenges in the preparation of radiolabelled drugs for nuclear medicine The synthesis of carbon-14 labelled PEGs Development of palladium catalysed carbonylations for asymmetric synthesis The versatility of labelled cyanide Poster abstracts on the stability and storage of 14C-labelled compounds The preparation of the P2 receptor agonist 2-[methyl-3H]methylthioadenosine-5′-diphosphate Tritium labelling of aromatic and aliphatic aldehydes using Crabtree's catalyst, [Ir(cod)py(PCy3)]PF6 The specific activity determination and confirmation of identity of a radiolabelled peptide using tandem mass spectrometry Design and applicatoin of stable or radiolabelled carbamates Synthesis of the various isotopomers of the MHC II antagonist AZD2315 Synthesis of isotopomers of gefitinib Mercuration/iododemercuration/deiodination: A practical first-line strategy for the rapid preparation of iodinated labelling precursors Deuterium labelling with cycloocta-1,5-dienyliridium(i)1,1,1,5,5,5-hexafluoropentan-2,4-dionate: a comparison of D2o and d2 isotope donors Martin D. Kamen (1913-2002): The co-discoverer of carbon-14 An efficient synthesis of [2-14c] ethyl nipecotate Radiosynthesis conducted under cGMP compliance Computer-simulations for the reactor-synthesis of high-activity, high specific activity, teletherapy sources of europium-152 Parallel optimisation of hydrogen isotope exchange mediated by homogeneous catalysts: A collaboration between the isotope groups at molndal and charnwood R&D New opportunities for isotope labelling using solid phase organic synthesis Rapid synthesis of 11C-flumazenil in a micro-reactor placed in the hplc loop: A fast captive solvent method Spatiotemporal imaging of receptor systems using pet

Recent coastal storms in southern Africa have highlighted the need for more proactive management of the coastline. Within the southern and eastern African region the availability of coastal information is poor. The greatest gap in information is the likely effects of a combination of severe sea storms and future sea level rise (SLR) on the shoreline. This lack of information creates a barrier to informed decision making. This research outlines a practical localized approach to this problem, which can be applied as a first order assessment within the region. In so doing it provides a cost effective and simple decision support tool for the built environment and disaster professionals in development and disaster assessments. In a South African context the newly promulgated Integrated Coastal Management Act requires that all proposed coastal developments take into consideration future SLR, however such information currently does not exist, despite it being vital for informed planning in the coastal zone. This practical approach has been applied to the coastline of Durban, South Africa as a case study. The outputs are presented in a Geographic Information System (GIS) based freeware viewer tool enabling ease of access to both professionals and laypersons. This demonstrates that a simple approach can provide valuable information about the current and future risk of flooding and coastal erosion under climate change to buildings, infrastructure as well as natural features along the coast.

Coastal stabilization, mostly involving coastal dune cordon destruction, has been practised on the KwaZulu-Natal coast for the last two decades. During this time no major swells occurred. The last Lunar Nodal Cycle (LNC) tidal peak was associated with a series of unusually high swells. The temporal coincidence of exceptionally high tide and large swell led to catastrophic coastal erosion and underlined the folly of coastal stabilization, especially at reversing erosion hotspots, many of which are urbanized and defended. These locations remain at risk and will experience future erosion.

Glycosphingolipids, derived from the addition of sugar-moieties to the sphingolipid ceramide, are highly abundant in the kidney. Glycosphingolipids are known to play an important role in organ function at least in part from inherited lipid storage diseases such as Anderson-Fabry disease (Fabry's disease; FD) that results from a mutation in alpha-galactosidase a (α-GLA or α-Gal A), the enzyme responsible for catalyzing the removal of terminal galactose residues from glycosphingolipids. The inactivation in α-GLA in FD results in the accumulation of glycosphingolipids, including globosides and lactosylceramides, which manifests as several common pathologies including end-stage kidney disease. More recently, glycosphingolipids and other sphingolipids have become increasingly recognized for their roles in a variety of other kidney diseases including polycystic kidney disease, acute kidney injury, glomerulonephritis, diabetic nephropathy and kidney cancer. This chapter reviews evidence supporting a mechanistic role for glycosphingolipids in kidney disease and discusses data implicating a role for these lipids in kidney disease resulting from metabolic syndrome. Importantly, inhibitors of glycosphingolipid synthesis are well tolerated in animal models as well as in humans. Thus, an increased understanding of the mechanisms by which altered renal glycosphingolipid metabolism leads to kidney disease has great therapeutic potential.

Glycosphingolipids, derived from the addition of sugar-moieties to the sphingolipid ceramide, are highly abundant in the kidney. Glycosphingolipids are known to play an important role in organ function at least in part from inherited lipid storage diseases such as Anderson-Fabry disease (Fabry's disease; FD) that results from a mutation in alpha-galactosidase a (α-GLA or α-Gal A), the enzyme responsible for catalyzing the removal of terminal galactose residues from glycosphingolipids. The inactivation in α-GLA in FD results in the accumulation of glycosphingolipids, including globosides and lactosylceramides, which manifests as several common pathologies including end-stage kidney disease. More recently, glycosphingolipids and other sphingolipids have become increasingly recognized for their roles in a variety of other kidney diseases including polycystic kidney disease, acute kidney injury, glomerulonephritis, diabetic nephropathy and kidney cancer. This chapter reviews evidence supporting a mechanistic role for glycosphingolipids in kidney disease and discusses data implicating a role for these lipids in kidney disease resulting from metabolic syndrome. Importantly, inhibitors of glycosphingolipid synthesis are well tolerated in animal models as well as in humans. Thus, an increased understanding of the mechanisms by which altered renal glycosphingolipid metabolism leads to kidney disease has great therapeutic potential.

This paper outlines the development of the first municipal adaptation plans for climate change in Durban, South Africa. Particular attention is paid to the storm water and coastal plans developed for the water sector. Key adaptation activities in the main operational departments are highlighted as well as the key challenges and lessons learned during the development of the plans. Three factors were significant in determining the success of the project: (1) the emergence of political and technical champions, (2) the existence of high level technical expertise within the municipality and (3) broad based and appropriate communication with stakeholders.

The tidal records of existing South African and Namibian tide gauges are examined and corrected. Regional sea level trends vary, with the West Coast rising by +1.87 mm y–1 (1959–2006), the southern coast by +1.48 mm y–1 (1957–2006) and the East Coast by +2.74 mm y–1 (1967–2006). The effects of barometric pressure and vertical crustal movement changes on these trends are examined. The derived relationship between sea levels and barometric pressure changes varied between 5.71 and 7.67 mm hPa–1, significantly less than the theoretical inverse barometric correction. Barometric pressure has been dropping along the west coast at 1.63 hPa per decade (1987–2006), has remained fairly static along the southern coast and is rising at 0.30 hPa per decade (1970–2007) along the east coast of southern Africa. The West Coast barometrically corrected sea level trends show that most of the change can be attributed to falling barometric pressure, whereas along the East Coast, the barometric pressure increase is suppressing sea level by 0.2 mm y–1. Vertical crust movements vary, with the largest recorded movements of +1.11 ± 0.25 mm y–1 found along the East Coast. Movement rate reduces southwards. Eustatic sea level trends vary from +3.55 mm y–1 along the East Coast and +1.57 mm y–1 along the southern coast to +0.42 mm y–1 along the West Coast. Keywords: barometric pressure; sea level rise; tide levelsAfrican Journal of Marine Science 2009, 31(2): 145–156

Cervicofacial subcutaneous emphysema is an infrequently reported sequela of dental surgery. It may be caused by the inadvertent introduction of air into the soft tissues during procedures using high-speed, air-driven handpieces or air-water syringes. In this paper, we present a case in which subcutaneous emphysema developed in a middle-aged woman following routine restorative treatment. We review the features of the condition and its treatment and discuss means of prevention.

The coastal area of KwaZuluNatal is subject to regular flooding, ranging from severe regional flood events such as the 1987 floods when 300 people lost their l…

Severe coastal erosion occurred along the KwaZulu-Natal coastline between mid-May and November 2011. Analysis of this erosion event and comparison with previous coastal erosion events in 2006/2007 offered the opportunity to extend the understanding of the time and place of coastal erosion strikes. The swells that drove the erosion hotspots of the 2011 erosion season were relatively low (significant wave heights were between 2 m and 4.5 m) but of long duration. Although swell height was important, swell-propagation direction and particularly swell duration played a dominant role in driving the 2011 erosion event. Two erosion hotspot types were noted: sandy beaches underlain by shallow bedrock and thick sandy beaches. The former are triggered by high swells (as in March 2007) and austral winter erosion events (such as in 2006, 2007 and 2011). The latter become evident later in the austral winter erosion cycle. Both types were associated with subtidal shore-normal channels seaward of megacusps, themselves linked to megarip current heads. This 2011 coastal erosion event occurred during a year in which the lunar perigee sub-harmonic cycle (a ±4.4-year cycle) peaked, a pattern which appears to have recurred on the KwaZulu-Natal coast. If this pattern proves true, severe coastal erosion may be expected in 2015. Evidence indicates that coastal erosion is driven by the lunar nodal cycle peak but that adjacent lunar perigee sub-harmonic peaks can also cause severe coastal erosion. Knowing where and when coastal erosion may occur is vital for coastal managers and planners.

Wave run up is important for quantifying risks to infrastructure in the coastal zone. The performance of global wave run up models are assessed by applying them to two significant storms along the South African coastline in 2007 and 2008. The models produced mixed results and therefore the development of a new wave run up model was undertaken. This model uses the distance offshore to a point on the bathymetric profile, located approximately at the cut off depth, as a proxy for the underwater beach profile. This new wave run up model has been calibrated for open coastlines as well as large and small embayments. The new model outperforms most of the current wave run up models and gives a good first order approximation of wave run up on natural beaches.

Stereoselective reactions involving functionalised β,γ epoxysilanes and epoxide-allylsilanes provide a range of synthetically useful transformations.

The area mapped includes two ultramafites of the alpine type, emplaced in, and with inclusions of, rocks of the Cache Creek Group. Northwest lies the Mitchell Patholith, a Late Jurassic (?) intrusion of diorite to granite. The argillite, chert, greenstone, and limestone of the Cache Creek Group are strongly to isoclinally folded about north-northeasterly trending axes. They have mineral assemblages characteristic of the middle to upper green-schist facies. The ultramafic rocks are fractured and sheared in a north-northeasterly direction, and may be folded. The overall shape of the Mitchell Mountains Ultramafite is not known. The Mitchell Mountains Ultramafite has three metamorphic zones, parallel to the edge of the Mitchell Patholith. They consist of serpentinite, talc-olivine rock, and olivine-enstatite-anthophyllite rock. The Goat Mountain Ultramafite consists mostly of serpentinate, The observed mineral assemblages may be explained in terms of the system CaO-MgO-SiO₂-H₂O-CO₂. At an assumed pressure of 2000 bars, the temperature during metamorphism ranged from 380°C at the eastern edge of the Mitchell Mountains Ultramafite, to almost 700° at the western edge. This contact metamorphism was caused by the Mitchell Patholith.

Stereoselective reactions involving functionalised β,γ epoxysilanes and epoxide-allylsilanes provide a range of synthetically useful transformations.

The epoxy-allylsilane (1) was prepared by two routes and cyclised stereoselectively to give the cis-cyclopentane (9) on treatment with TiCl4; equilibration of the aldehyde corresponding to (9) gave the trans-isomer in high yield.