Generation of anti-complement "prodrugs": cleavable reagents for specific delivery of complement regulators to disease sites

Expression of biologically active molecules as fusion proteins with antibody Fc can substantially extend the plasma half-life of the active agent but may also influence function. We have previously generated a number of fusion proteins comprising a complement regulator coupled to Fc and shown that the hybrid molecule has a long plasma half-life and retains biological activity. However, several of the fusion proteins generated had substantially reduced biological activity when compared with the native regulator or regulator released from the Fc following papain cleavage. We have taken advantage of this finding to engineer a prodrug with low complement regulatory activity that is cleaved at sites of inflammation to release active regulator. Two model prodrugs, comprising, respectively, the four short consensus repeats of human decay accelerating factor (CD55) linked to IgG4 Fc and the three NH2-terminal short consensus repeats of human decay accelerating factor linked to IgG2 Fc have been developed. In each, specific cleavage sites for matrix metalloproteinases and/or aggrecanases have been incorporated between the complement regulator and the Fc. These prodrugs have markedly decreased complement inhibitory activity when compared with the parent regulator in vitro. Exposure of the prodrugs to the relevant enzymes, either purified, or in supernatants of cytokine-stimulated chondrocytes or in synovial fluid, efficiently cleaved the prodrug, releasing active regulator. Such agents, having negligible systemic effects but active at sites of inflammation, represent a paradigm for the next generation of anti-C therapeutics.

Plant conservation: old problems, new perspectives

A review is given of the major conceptual changes that have taken place during the last 50 years in our understanding of the nature of plant conservation and of the principal methodological advances in undertaking conservation assessments and actions, largely through the incorporation of tools and techniques from other disciplines. The interrelationships between conservation and sustainable use are considered as well as the impact of the development of the discipline of conservation biology, the effects of the general acceptance of the concept of biodiversity and the practical implications of the implementation of the Convention on Biological diversity. The effect on conservation policy and management of the accelerating loss or conversion of habitats throughout the world and approaches for combating this are discussed.

Mapping CD55 function: the structure of two pathogen-binding domains at 1.7 A

Decay-accelerating factor (CD55), a regulator of the alternative and classical pathways of complement activation, is expressed on all serum-exposed cells. It is used by pathogens, including many enteroviruses and uropathogenic Escherichia coli, as a receptor prior to infection. We describe the x-ray structure of a pathogen-binding fragment of human CD55 at 1.7 A resolution containing two of the three domains required for regulation of human complement. We have used mutagenesis to map biological functions onto the molecule; decay-accelerating activity maps to a single face of the molecule, whereas bacterial and viral pathogens recognize a variety of different sites on CD55.

The kinetics of the 2π+2π photodimerisation reactions of single-crystalline derivatives of trans-cinnamic acid: a study by infrared microspectroscopy

The kinetics of the photodimerisation reactions of the 2- and 4-β-halogeno-derivatives of trans-cinnamic acid (where the halogen is fluorine, chlorine or bromine) have been investigated by infrared microspectroscopy. It is found that none of the reactions proceed to 100% yield. This is in line with a reaction mechanism developed by Wernick and his co-workers that postulates the formation of isolated monomers within the solid, which cannot react. β-4-Bromo and β-4-chloro-trans-cinnamic acids show approximately first order kinetics, although in both cases the reaction accelerates somewhat as it proceeds. First order kinetics is explained in terms of a reaction between one excited- and one ground-state monomer molecule, while the acceleration of the reaction implies that it is promoted as defects are formed within the crystal. By contrast β-2-chloro-trans-cinnamic acid shows a strongly accelerating reaction which models closely to the contracting cube equation. β-2-Fluoro- and β-4-fluoro-trans-cinnamic acids show a close match to first order kinetics. The 4-fluoro-derivative, however, shows a reaction that proceeds via a structural intermediate. The difference in behaviour between the 2-fluoro- and 4-fluoro-derivative may be due to different C–HF hydrogen bonds observed within these single-crystalline starting materials.

Self-nucleation and crystallization kinetics of double crystalline poly(p-dioxanone)-b-poly(epsilon-caprolactone) diblock copolymers

The crystallization kinetics of each constituent of poly(p-dioxanone)-b-poly(epsilon-caprolactone) diblock copolymers (PPDX-b-PCL) has been determined in a wide composition range by differential scanning calorimetry and compared to that of the equivalent homopolymers. Spherulitic growth rates were also measured by polarized optical microscopy while atomic force microscopy was employed to reveal the morphology of one selected diblock copolymer. It was found that crystallization drives structure formation and both components form lamellae within mixed spherulitic superstructures. The overall isothermal crystallization kinetics of the PPDX block at high temperatures, where the PCL is molten, was determined by accelerating the kinetics through a previous self-nucleation procedure. The application of the Lauritzen and Ho. man theory to overall growth rate data yielded successful results for PPDX and the diblock copolymers. The theory was applied to isothermal overall crystallization of previously self-nucleated PPDX ( where growth should be the dominant factor if self-nucleation was effective) and the energetic parameters obtained were perfectly matched with those obtained from spherulitic growth rate data of neat PPDX. A quantitative estimate of the increase in the energy barrier for crystallization of the PPDX block, caused by the covalently bonded molten PCL as compared to homo-PPDX, was thus determined. This energy increase can dramatically reduce the crystallization rate of the PPDX block as compared to homo-PPDX. In the case of the PCL block, both the crystallization kinetics and the self-nucleation results indicate that the PPDX is able to nucleate the PCL within the copolymers and heterogeneous nucleation is always present regardless of composition. Finally, preliminary results on hydrolytic degradation showed that the presence of relatively small amounts of PCL within PPDX-bPCL copolymers substantially retards hydrolytic degradation of the material in comparison to homo-PPDX. This increased resistance to hydrolysis is a complex function of composition and its knowledge may allow future prediction of the lifetime of the material for biomedical applications.

Distributed acceleration of mobile radio network optimisation algorithms

The past decade has witnessed explosive growth of mobile subscribers and services. With the purpose of providing better-swifter-cheaper services, radio network optimisation plays a crucial role but faces enormous challenges. The concept of Dynamic Network Optimisation (DNO), therefore, has been introduced to optimally and continuously adjust network configurations, in response to changes in network conditions and traffic. However, the realization of DNO has been seriously hindered by the bottleneck of optimisation speed performance. An advanced distributed parallel solution is presented in this paper, as to bridge the gap by accelerating the sophisticated proprietary network optimisation algorithm, while maintaining the optimisation quality and numerical consistency. The ariesoACP product from Arieso Ltd serves as the main platform for acceleration. This solution has been prototyped, implemented and tested. Real-project based results exhibit a high scalability and substantial acceleration at an average speed-up of 2.5, 4.9 and 6.1 on a distributed 5-core, 9-core and 16-core system, respectively. This significantly outperforms other parallel solutions such as multi-threading. Furthermore, augmented optimisation outcome, alongside high correctness and self-consistency, have also been fulfilled. Overall, this is a breakthrough towards the realization of DNO.

Using learning networks to understand complex systems: a case study of biological, geophysical and social research in the Amazon

Developing high-quality scientific research will be most effective if research communities with diverse skills and interests are able to share information and knowledge, are aware of the major challenges across disciplines, and can exploit economies of scale to provide robust answers and better inform policy. We evaluate opportunities and challenges facing the development of a more interactive research environment by developing an interdisciplinary synthesis of research on a single geographic region. We focus on the Amazon as it is of enormous regional and global environmental importance and faces a highly uncertain future. To take stock of existing knowledge and provide a framework for analysis we present a set of mini-reviews from fourteen different areas of research, encompassing taxonomy, biodiversity, biogeography, vegetation dynamics, landscape ecology, earth-atmosphere interactions, ecosystem processes, fire, deforestation dynamics, hydrology, hunting, conservation planning, livelihoods, and payments for ecosystem services. Each review highlights the current state of knowledge and identifies research priorities, including major challenges and opportunities. We show that while substantial progress is being made across many areas of scientific research, our understanding of specific issues is often dependent on knowledge from other disciplines. Accelerating the acquisition of reliable and contextualized knowledge about the fate of complex pristine and modified ecosystems is partly dependent on our ability to exploit economies of scale in shared resources and technical expertise, recognise and make explicit interconnections and feedbacks among sub-disciplines, increase the temporal and spatial scale of existing studies, and improve the dissemination of scientific findings to policy makers and society at large. Enhancing interaction among research efforts is vital if we are to make the most of limited funds and overcome the challenges posed by addressing large-scale interdisciplinary questions. Bringing together a diverse scientific community with a single geographic focus can help increase awareness of research questions both within and among disciplines, and reveal the opportunities that may exist for advancing acquisition of reliable knowledge. This approach could be useful for a variety of globally important scientific questions.

Slideshow by POLLYFIBRE

A live work where digital and analogue media collide. This work uses the Internet as a central point of departure in that the script is taken from the Wikipedia entry for the word 'slideshow'. Words are randomly extracted and transferred onto photographic 35mm slide to be projected with analogue carousel slide projectors taking the audience into a visual wordplay, from Google to PowerPoint presentation. The sound of projectors is manipulated gradually into a clashing, confrontational, digital/analogue crescendo. 'Slideshow' investigates how information is sourced, navigated and considered in a culture of accelerating mediation. It posits the notion of a post-digital era in which we are increasingly faced with challenging questions of authenticity and authority.

Acidity controls on dissolved organic carbon mobility in organic soils

Dissolved organic carbon (DOC) concentrations in surface waters have increased across much of Europe and North America, with implications for the terrestrial carbon balance, aquatic ecosystem functioning, water treatment costs and human health. Over the past decade, many hypotheses have been put forward to explain this phenomenon, from changing climate and land-management to eutrophication and acid deposition. Resolution of this debate has been hindered by a reliance on correlative analyses of time-series data, and a lack of robust experimental testing of proposed mechanisms. In a four-year, four-site replicated field experiment involving both acidifying and de-acidifying treatments, we tested the hypothesis that DOC leaching was previously suppressed by high levels of soil acidity in peat and organo-mineral soils, and therefore that observed DOC increases a consequence of decreasing soil acidity. We observed a consistent, positive relationship between DOC and acidity change at all sites. Responses were described by similar hyperbolic relationships between standardised changes in DOC and hydrogen ion concentrations at all sites, suggesting potentially general applicability. These relationships explained a substantial proportion of observed changes in peak DOC concentrations in nearby monitoring streams, and application to a UK-wide upland soil pH dataset suggests that recovery from acidification alone could have led to soil solution DOC increases in the range 46-126% by habitat type since 1978. Our findings raise the possibility that changing soil acidity may have wider impacts on ecosystem carbon balances. Decreasing sulphur deposition may be accelerating terrestrial carbon loss, and returning surface waters to a natural, high-DOC condition.

Oxygen isotope ratios in the shell of Mytilus edulis: archives of glacier meltwater in Greenland?

Melting of the Greenland Ice Sheet (GrIS) is accelerating and will contribute significantly to global sea level rise during the 21st century. Instrumental data on GrIS melting only cover the last few decades, and proxy data extending our knowledge into the past are vital for validating models predicting the influence of ongoing climate change. We investigated a potential meltwater proxy in Godthåbsfjord (West Greenland), where glacier meltwater causes seasonal excursions with lower oxygen isotope water (δ18Ow) values and salinity. The blue mussel (Mytilus edulis) potentially records these variations, because it precipitates its shell calcite in oxygen isotopic equilibrium with ambient seawater. As M. edulis shells are known to occur in raised shorelines and archaeological shell middens from previous Holocene warm periods, this species may be ideal in reconstructing past meltwater dynamics. We investigate its potential as a palaeo-meltwater proxy. First, we confirmed that M. edulis shell calcite oxygen isotope (δ18Oc) values are in equilibrium with ambient water and generally reflect meltwater conditions. Subsequently we investigated if this species recorded the full range of δ18Ow values occurring during the years 2007 to 2010. Results show that δ18Ow values were not recorded at very low salinities (< ~ 19), because the mussels appear to cease growing. This implies that Mytilus edulis δ18Oc values are suitable in reconstructing past meltwater amounts in most cases, but care has to be taken that shells are collected not too close to a glacier, but rather in the mid-region or mouth of the fjord. The focus of future research will expand on the geographical and temporal range of the shell measurements by sampling mussels in other fjords in Greenland along a south–north gradient, and by sampling shells from raised shorelines and archaeological shell middens from prehistoric settlements in Greenland.

Temporal evolution and electric potential structure of the auroral acceleration region from multispacecraft measurements

Bright aurorae can be excited by the acceleration of electrons into the atmosphere in violation of ideal magnetohydrodynamics. Modelling studies predict that the accelerating electric potential consists of electric double layers at the boundaries of an acceleration region but observations suggest that particle acceleration occurs throughout this region. Using multi-spacecraft observations from Cluster we have examined two upward current regions on 14 December 2009. Our observations show that the potential difference below C4 and C3 changed by up to 1.7 kV between their respective crossings, which were separated by 150 s. The field-aligned current density observed by C3 was also larger than that observed by C4. The potential drop above C3 and C4 was approximately the same in both crossings. Using a novel technique of quantitatively comparing the electron spectra measured by Cluster 1 and 3, which were separated in altitude, we determine when these spacecraft made effectively magnetically conjugate observations and use these conjugate observations to determine the instantaneous distribution of the potential drop in the AAR. Our observations show that an average of 15% of the potential drop in the AAR was located between C1 at 6235 km and C3 at 4685 km altitude, with a maximum potential drop between the spacecraft of 500~V and that the majority of the potential drop was below C3. By assuming a spatial invariance along the length of the upward current region, we discuss these observations in terms of temporal changes and the vertical structure of the electrostatic potential drop and in the context of existing models and previous observations single- and multi-spacecraft observations.

The ocean's role in polar climate change: asymmetric Arctic and Antarctic responses to greenhouse gas and ozone forcing

In recent decades, the Arctic has been warming and sea ice disappearing. By contrast, the Southern Ocean around Antarctica has been (mainly) cooling and sea-ice extent growing. We argue here that interhemispheric asymmetries in the mean ocean circulation, with sinking in the northern North Atlantic and upwelling around Antarctica, strongly influence the sea-surface temperature (SST) response to anthropogenic greenhouse gas (GHG) forcing, accelerating warming in the Arctic while delaying it in the Antarctic. Furthermore, while the amplitude of GHG forcing has been similar at the poles, significant ozone depletion only occurs over Antarctica. We suggest that the initial response of SST around Antarctica to ozone depletion is one of cooling and only later adds to the GHG-induced warming trend as upwelling of sub-surface warm water associated with stronger surface westerlies impacts surface properties. We organize our discussion around ‘climate response functions’ (CRFs), i.e. the response of the climate to ‘step’ changes in anthropogenic forcing in which GHG and/or ozone-hole forcing is abruptly turned on and the transient response of the climate revealed and studied. Convolutions of known or postulated GHG and ozone-hole forcing functions with their respective CRFs then yield the transient forced SST response (implied by linear response theory), providing a context for discussion of the differing warming/cooling trends in the Arctic and Antarctic. We speculate that the period through which we are now passing may be one in which the delayed warming of SST associated with GHG forcing around Antarctica is largely cancelled by the cooling effects associated with the ozone hole. By mid-century, however, ozone-hole effects may instead be adding to GHG warming around Antarctica but with diminished amplitude as the ozone hole heals. The Arctic, meanwhile, responding to GHG forcing but in a manner amplified by ocean heat transport, may continue to warm at an accelerating rate.

Cusp ion steps, field-aligned currents and poleward moving auroral forms

We predict the field-aligned currents around cusp ion steps produced by pulsed reconnection between the geomagnetic field and an interplanetary magnetic field (IMF) with a B-Y component that is large in magnitude. For B-Y > 0, patches of newly opened flux move westward and eastward in the Northern and Southern Hemispheres, respectively, under the influence of the magnetic curvature force. These flow directions are reversed for B-Y < 0. The speed of this longitudinal motion initially grows with elapsed time since reconnection, but then decays as the newly opened field lines straighten. We predict sheets of field-aligned current on the boundaries between the patches produced by successive reconnection pulses, associated with the difference in the speeds of their longitudinal motion. For low elapsed times since reconnection, near the equatorward edge of the cusp region where the field lines are accelerating, the field-aligned current sheets will be downward or upward in both hemispheres for positive or negative IMF B-Y, respectively. At larger elapsed times since reconnection, as events slow and evolve from the cusp into the mantle region, these field-aligned current directions will be reversed. Observations by the Polar spacecraft on August 26,1998, show the predicted upward current sheets at steps seen in the mantle region for IMF B-Y > 0. Mapped into the ionosphere, the steps coincide with poleward moving events seen by the CUTLASS HF radar. The mapped location of the largest step also coincides with a poleward moving arc seen by the UVI imager on Polar. We show that the arc is consistent with a region of upward field-aligned current that has become unstable, such that a potential drop of about 1 kV formed below the spacecraft. The importance of these observations is that they confirm that the poleward moving events, as seen by the HF radar and the UV imager, are due to pulsed magnetopause reconnection. Milan et al. [2000] noted that the great longitudinal extent of these events means that the required reconnection pulses would have contributed almost all the voltage placed across the magnetosphere at this time. The observations also show that auroral arcs can form on open field lines in response to the pulsed application of voltage at the magnetopause.

Climate change: against despair

In the face of accelerating climate change and the parlous state of its politics, despair is tempting. This paper analyses two manifestations of despair about climate change related to (1) the inefficacy of personal emissions reductions, and (2) the inability to make a difference to climate change through personal emissions reductions. On the back of an analysis of despair as a loss of hope, the paper argues that the judgements grounding each form of despair are unsound. The paper concludes with consideration of the instrumental value of hope in effective agency to tackle climate change. Overall, the paper’s assessment of personal despair about climate change as philosophically unjustified provides a fresh perspective on aspects of the debate about how to frame climate change in public debate.

Origin and impact of initialisation shocks in coupled atmosphere-ocean forecasts

Current methods for initialising coupled atmosphere-ocean forecasts often rely on the use of separate atmosphere and ocean analyses, the combination of which can leave the coupled system imbalanced at the beginning of the forecast, potentially accelerating the development of errors. Using a series of experiments with the European Centre for Medium-range Weather Forecasts coupled system, the magnitude and extent of these so-called initialisation shocks is quantified, and their impact on forecast skill measured. It is found that forecasts initialised by separate ocean and atmospheric analyses do exhibit initialisation shocks in lower atmospheric temperature, when compared to forecasts initialised using a coupled data assimilation method. These shocks result in as much as a doubling of root-mean-square error on the first day of the forecast in some regions, and in increases that are sustained for the duration of the 10-day forecasts performed here. However, the impacts of this choice of initialisation on forecast skill, assessed using independent datasets, were found to be negligible, at least over the limited period studied. Larger initialisation shocks are found to follow a change in either the atmospheric or ocean model component between the analysis and forecast phases: changes in the ocean component can lead to sea surface temperature shocks of more than 0.5K in some equatorial regions during the first day of the forecast. Implications for the development of coupled forecast systems, particularly with respect to coupled data assimilation methods, are discussed.