Ibrutinib inhibits platelet integrin αIIbβ3 outside-in signaling and thrombus stability but not adhesion to collagen

OBJECTIVE: Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. APPROACH AND RESULTS: By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin αIIbβ3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively. CONCLUSIONS: These findings suggest that (1) ibrutinib causes GPVI and integrin αIIbβ3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis.

Climate response to basin-scale warming and cooling of the North Atlantic Ocean

Using experiments with an atmospheric general circulation model, the climate impacts of a basin-scale warming or cooling of the North Atlantic Ocean are investigated. Multidecadal fluctuations with this pattern were observed during the twentieth century, and similar variations--but with larger amplitude--are believed to have occurred in the more distant past. It is found that in all seasons the response to warming the North Atlantic is strongest, in the sense of highest signal-to-noise ratio, in the Tropics. However there is a large seasonal cycle in the climate impacts. The strongest response is found in boreal summer and is associated with suppressed precipitation and elevated temperatures over the lower-latitude parts of North and South America. In August­-September-­October there is a significant reduction in the vertical shear in the main development region for Atlantic hurricanes. In winter and spring, temperature anomalies over land in the extratropics are governed by dynamical changes in circulation rather than simply reflecting a thermodynamic response to the warming or cooling of the ocean. The tropical climate response is primarily forced by the tropical SST anomalies, and the major features are in line with simple models of the tropical circulation response to diabatic heating anomalies. The extratropical climate response is influenced both by tropical and higher-latitude SST anomalies and exhibits nonlinear sensitivity to the sign of the SST forcing. Comparisons with multidecadal changes in sea level pressure observed in the twentieth century support the conclusion that the impact of North Atlantic SST change is most important in summer, but also suggest a significant influence in lower latitudes in autumn and winter. Significant climate impacts are not restricted to the Atlantic basin, implying that the Atlantic Ocean could be an important driver of global decadal variability. The strongest remote impacts are found to occur in the tropical Pacific region in June­-August and September­-November. Surface anomalies in this region have the potential to excite coupled ocean­atmosphere feedbacks, which are likely to play an important role in shaping the ultimate climate response.

Can the dynamical impact of the stratosphere on the troposphere be described by large-scale adjustment to the stratospheric PV distribution?

Recent numerical experiments have demonstrated that the state of the stratosphere has a dynamical impact on the state of the troposphere. To account for such an effect, a number of mechanisms have been proposed in the literature, all of which amount to a large-scale adjustment of the troposphere to potential vorticity (PV) anomalies in the stratosphere. This paper analyses whether a simple PV adjustment suffices to explain the actual dynamical response of the troposphere to the state of the stratosphere, the actual response being determined by ensembles of numerical experiments run with an atmospheric general-circulation model. For this purpose, a new PV inverter is developed. It is shown that the simple PV adjustment hypothesis is inadequate. PV anomalies in the stratosphere induce, by inversion, flow anomalies in the troposphere that do not coincide spatially with the tropospheric changes determined by the numerical experiments. Moreover, the tropospheric anomalies induced by PV inversion are on a larger scale than the changes found in the numerical experiments, which are linked to the Atlantic and Pacific storm-tracks. These findings imply that the impact of the stratospheric state on the troposphere is manifested through the impact on individual synoptic-scale systems and their self-organization in the storm-tracks. Changes in these weather systems in the troposphere are not merely synoptic-scale noise on a larger scale tropospheric response, but an integral part of the mechanism by which the state of the stratosphere impacts that of the troposphere.

The Phosphorus Indicators Tool: a simple model of diffuse P loss from agricultural land to water

The Phosphorus Indicators Tool provides a catchment-scale estimation of diffuse phosphorus (P) loss from agricultural land to surface waters using the most appropriate indicators of P loss. The Tool provides a framework that may be applied across the UK to estimate P loss, which is sensitive not only to land use and management but also to environmental factors such as climate, soil type and topography. The model complexity incorporated in the P Indicators Tool has been adapted to the level of detail in the available data and the need to reflect the impact of changes in agriculture. Currently, the Tool runs on an annual timestep and at a 1 km(2) grid scale. We demonstrate that the P Indicators Tool works in principle and that its modular structure provides a means of accounting for P loss from one layer to the next, and ultimately to receiving waters. Trial runs of the Tool suggest that modelled P delivery to water approximates measured water quality records. The transparency of the structure of the P Indicators Tool means that identification of poorly performing coefficients is possible, and further refinements of the Tool can be made to ensure it is better calibrated and subsequently validated against empirical data, as it becomes available.

Problems with determining the particle size distribution of chalk soil and some of their implications

Particle size distribution (psd) is one of the most important features of the soil because it affects many of its other properties, and it determines how soil should be managed. To understand the properties of chalk soil, psd analyses should be based on the original material (including carbonates), and not just the acid-resistant fraction. Laser-based methods rather than traditional sedimentation methods are being used increasingly to determine particle size to reduce the cost of analysis. We give an overview of both approaches and the problems associated with them for analyzing the psd of chalk soil. In particular, we show that it is not appropriate to use the widely adopted 8 pm boundary between the clay and silt size fractions for samples determined by laser to estimate proportions of these size fractions that are equivalent to those based on sedimentation. We present data from field and national-scale surveys of soil derived from chalk in England. Results from both types of survey showed that laser methods tend to over-estimate the clay-size fraction compared to sedimentation for the 8 mu m clay/silt boundary, and we suggest reasons for this. For soil derived from chalk, either the sedimentation methods need to be modified or it would be more appropriate to use a 4 pm threshold as an interim solution for laser methods. Correlations between the proportions of sand- and clay-sized fractions, and other properties such as organic matter and volumetric water content, were the opposite of what one would expect for soil dominated by silicate minerals. For water content, this appeared to be due to the predominance of porous, chalk fragments in the sand-sized fraction rather than quartz grains, and the abundance of fine (<2 mu m) calcite crystals rather than phyllosilicates in the clay-sized fraction. This was confirmed by scanning electron microscope (SEM) analyses. "Of all the rocks with which 1 am acquainted, there is none whose formation seems to tax the ingenuity of theorists so severely, as the chalk, in whatever respect we may think fit to consider it". Thomas Allan, FRS Edinburgh 1823, Transactions of the Royal Society of Edinburgh. (C) 2009 Natural Environment Research Council (NERC) Published by Elsevier B.V. All rights reserved.

Analysis of the calving pattern of herds in small-scale dairy systems in central Mexico

This study sets out to find the best calving pattern for small-scale dairy systems in Michoacan State, central Mexico. Two models were built. First, a linear programming model was constructed to optimize calving pattern and herd structure according to metabolizable energy availability. Second, a Markov chain model was built to investigate three reproductive scenarios (good, average and poor) in order to suggest factors that maintain the calving pattern given by the linear programming model. Though it was not possible to maintain the optimal linear programming pattern, the Markov chain model suggested adopting different reproduction strategies according to period of the year that the cow is expected to calve. Comparing different scenarios, the Markov model indicated the effect of calving interval on calving pattern and herd structure.

Application of Gaussian multi-scale representation to feature tracking in meteorological satellite imagery

Gaussian multi-scale representation is a mathematical framework that allows to analyse images at different scales in a consistent manner, and to handle derivatives in a way deeply connected to scale. This paper uses Gaussian multi-scale representation to investigate several aspects of the derivation of atmospheric motion vectors (AMVs) from water vapour imagery. The contribution of different spatial frequencies to the tracking is studied, for a range of tracer sizes, and a number of tracer selection methods are presented and compared, using WV 6.2 images from the geostationary satellite MSG-2.

Assessment of a climate model to reproduce rainfall variability and extremes over Southern Africa

It is increasingly accepted that any possible climate change will not only have an influence on mean climate but may also significantly alter climatic variability. A change in the distribution and magnitude of extreme rainfall events (associated with changing variability), such as droughts or flooding, may have a far greater impact on human and natural systems than a changing mean. This issue is of particular importance for environmentally vulnerable regions such as southern Africa. The sub-continent is considered especially vulnerable to and ill-equipped (in terms of adaptation) for extreme events, due to a number of factors including extensive poverty, famine, disease and political instability. Rainfall variability and the identification of rainfall extremes is a function of scale, so high spatial and temporal resolution data are preferred to identify extreme events and accurately predict future variability. The majority of previous climate model verification studies have compared model output with observational data at monthly timescales. In this research, the assessment of ability of a state of the art climate model to simulate climate at daily timescales is carried out using satellite-derived rainfall data from the Microwave Infrared Rainfall Algorithm (MIRA). This dataset covers the period from 1993 to 2002 and the whole of southern Africa at a spatial resolution of 0.1° longitude/latitude. This paper concentrates primarily on the ability of the model to simulate the spatial and temporal patterns of present-day rainfall variability over southern Africa and is not intended to discuss possible future changes in climate as these have been documented elsewhere. Simulations of current climate from the UKMeteorological Office Hadley Centre’s climate model, in both regional and global mode, are firstly compared to the MIRA dataset at daily timescales. Secondly, the ability of the model to reproduce daily rainfall extremes is assessed, again by a comparison with extremes from the MIRA dataset. The results suggest that the model reproduces the number and spatial distribution of rainfall extremes with some accuracy, but that mean rainfall and rainfall variability is underestimated (over-estimated) over wet (dry) regions of southern Africa.

Technologies for biological containment of GM and Non-GM crops

International Perspective The development of GM technology continues to expand into increasing numbers of crops and conferred traits. Inevitably, the focus remains on the major field crops of soybean, maize, cotton, oilseed rape and potato with introduced genes conferring herbicide tolerance and/or pest resistance. Although there are comparatively few GM crops that have been commercialised to date, GM versions of 172 plant species have been grown in field trials in 31 countries. European Crops with Containment Issues Of the 20 main crops in the EU there are four for which GM varieties are commercially available (cotton, maize for animal feed and forage, and oilseed rape). Fourteen have GM varieties in field trials (bread wheat, barley, durum wheat, sunflower, oats, potatoes, sugar beet, grapes, alfalfa, olives, field peas, clover, apples, rice) and two have GM varieties still in development (rye, triticale). Many of these crops have hybridisation potential with wild and weedy relatives in the European flora (bread wheat, barley, oilseed rape, durum wheat, oats, sugar beet and grapes), with escapes (sunflower); and all have potential to cross-pollinate fields non-GM crops. Several fodder crops, forestry trees, grasses and ornamentals have varieties in field trials and these too may hybridise with wild relatives in the European flora (alfalfa, clover, lupin, silver birch, sweet chestnut, Norway spruce, Scots pine, poplar, elm, Agrostis canina, A. stolonifera, Festuca arundinacea, Lolium perenne, L. multiflorum, statice and rose). All these crops will require containment strategies to be in place if it is deemed necessary to prevent transgene movement to wild relatives and non-GM crops. Current Containment Strategies A wide variety of GM containment strategies are currently under development, with a particular focus on crops expressing pharmaceutical products. Physical containment in greenhouses and growth rooms is suitable for some crops (tomatoes, lettuce) and for research purposes. Aquatic bioreactors of some non-crop species (algae, moss, and duckweed) expressing pharmaceutical products have been adopted by some biotechnology companies. There are obvious limitations of the scale of physical containment strategies, addressed in part by the development of large underground facilities in the US and Canada. The additional resources required to grow plants underground incurs high costs that in the long term may negate any advantage of GM for commercial productioNatural genetic containment has been adopted by some companies through the selection of either non-food/feed crops (algae, moss, duckweed) as bio-pharming platforms or organisms with no wild relatives present in the local flora (safflower in the Americas). The expression of pharmaceutical products in leafy crops (tobacco, alfalfa, lettuce, spinach) enables growth and harvesting prior to and in the absence of flowering. Transgenically controlled containment strategies range in their approach and degree of development. Plastid transformation is relatively well developed but is not suited to all traits or crops and does not offer complete containment. Male sterility is well developed across a range of plants but has limitations in its application for fruit/seed bearing crops. It has been adopted in some commercial lines of oilseed rape despite not preventing escape via seed. Conditional lethality can be used to prevent flowering or seed development following the application of a chemical inducer, but requires 100% induction of the trait and sufficient application of the inducer to all plants. Equally, inducible expression of the GM trait requires equally stringent application conditions. Such a method will contain the trait but will allow the escape of a non-functioning transgene. Seed lethality (‘terminator’ technology) is the only strategy at present that prevents transgene movement via seed, but due to public opinion against the concept it has never been trialled in the field and is no longer under commercial development. Methods to control flowering and fruit development such as apomixis and cleistogamy will prevent crop-to-wild and wild-to-crop pollination, but in nature both of these strategies are complex and leaky. None of the genes controlling these traits have as yet been identified or characterised and therefore have not been transgenically introduced into crop species. Neither of these strategies will prevent transgene escape via seed and any feral apomicts that form are arguably more likely to become invasives. Transgene mitigation reduces the fitness of initial hybrids and so prevents stable introgression of transgenes into wild populations. However, it does not prevent initial formation of hybrids or spread to non-GM crops. Such strategies could be detrimental to wild populations and have not yet been demonstrated in the field. Similarly, auxotrophy prevents persistence of escapes and hybrids containing the transgene in an uncontrolled environment, but does not prevent transgene movement from the crop. Recoverable block of function, intein trans-splicing and transgene excision all use recombinases to modify the transgene in planta either to induce expression or to prevent it. All require optimal conditions and 100% accuracy to function and none have been tested under field conditions as yet. All will contain the GM trait but all will allow some non-native DNA to escape to wild populations or to non-GM crops. There are particular issues with GM trees and grasses as both are largely undomesticated, wind pollinated and perennial, thus providing many opportunities for hybridisation. Some species of both trees and grass are also capable of vegetative propagation without sexual reproduction. There are additional concerns regarding the weedy nature of many grass species and the long-term stability of GM traits across the life span of trees. Transgene stability and conferred sterility are difficult to trial in trees as most field trials are only conducted during the juvenile phase of tree growth. Bio-pharming of pharmaceutical and industrial compounds in plants Bio-pharming of pharmaceutical and industrial compounds in plants offers an attractive alternative to mammalian-based pharmaceutical and vaccine production. Several plantbased products are already on the market (Prodigene’s avidin, β-glucuronidase, trypsin generated in GM maize; Ventria’s lactoferrin generated in GM rice). Numerous products are in clinical trials (collagen, antibodies against tooth decay and non-Hodgkin’s lymphoma from tobacco; human gastric lipase, therapeutic enzymes, dietary supplements from maize; Hepatitis B and Norwalk virus vaccines from potato; rabies vaccines from spinach; dietary supplements from Arabidopsis). The initial production platforms for plant-based pharmaceuticals were selected from conventional crops, largely because an established knowledge base already existed. Tobacco and other leafy crops such as alfalfa, lettuce and spinach are widely used as leaves can be harvested and no flowering is required. Many of these crops can be grown in contained greenhouses. Potato is also widely used and can also be grown in contained conditions. The introduction of morphological markers may aid in the recognition and traceability of crops expressing pharmaceutical products. Plant cells or plant parts may be transformed and maintained in culture to produce recombinant products in a contained environment. Plant cells in suspension or in vitro, roots, root cells and guttation fluid from leaves may be engineered to secrete proteins that may be harvested in a continuous, non-destructive manner. Most strategies in this category remain developmental and have not been commercially adopted at present. Transient expression produces GM compounds from non-GM plants via the utilisation of bacterial or viral vectors. These vectors introduce the trait into specific tissues of whole plants or plant parts, but do not insert them into the heritable genome. There are some limitations of scale and the field release of such crops will require the regulation of the vector. However, several companies have several transiently expressed products in clinical and pre-clinical trials from crops raised in physical containment.

Are property agents to blame for upward only rent reviews?

In negotiating commercial leases, many landlords and tenants employ property agents (brokers) to act on their behalf; typically these people are chartered surveyors. The aim of this paper is to explore the role that these brokers play in the shaping of commercial leases in the context of the current debate in the UK on upward only rent reviews. This role can be described using agency theory and the theories of professionalism. These provide expectations of behaviour which show inherent tensions between the role of agent and professional, particularly regarding the use of knowledge, autonomy and the obligation to the public interest. The parties to eleven recent lease transactions were interviewed to see if the brokers conformed to the expectations of agency theory or professionalism. Brokers that acted for industrial and office tenants behaved as professionals in using their expertise to determine lease structures. However, those acting for landlords and retail tenants simply followed instructions and behaved as conduits for their clients, a role more usually associated with that of an agent within the principal-agent relationship. None of the landlords’ brokers saw themselves as having responsibilities beyond their clients and so they were not promoting the discussion of alternatives to the UORR. The evidence from these case studies suggests that agents are not professionals; to behave entirely as an agent is to contradict the essential characteristics of a professional. While brokers cannot be held entirely responsible for the lack of movement on the UORR, by adopting predominantly agent roles then they must take some of the blame. However, behind this may be a much larger issue that needs to be explored; the institutional pressures that lead to professionals behaving in this way.

Steering across scales: applying Strategic-Relational Approach to a study of land mobilisation for road widening in Kochi

This paper argues for the relevance of paying attention to structuring participation processes across scales as one of the ways in which participation of multi-organisational partnerships that involve conflicting interests might be managed. Issue wise the paper deals with problems in connection with land mobilisation for road widening in complex and concentrated high value urban settings. It discusses a case study of plan implementation involving individual landowners, the land development market, the local government, other governmental and non-governmental organisations and the state government, which together achieved objectives that seemed impossible at first sight. In theoretical terms, the paper engages with Jessop's (2001) Strategic-Relational Approach (SRA), arguing for its potential for informing action in a way that is capable of achieving steering outputs. The claim for SRA is demonstrated by re-examining the case study. The factors that come through as SRA is applied are drawn out and it is suggested that the theory though non-deterministic, helps guide action by highlighting certain dynamics of systems that can be used for institutional intervention. These dynamics point to the importance of paying attention to scale and the way in which participation and negotiation processes are structured so as to favour certain outcomes rather than others

Multiple routes to mammalian diversity

The radiation of the mammals provides a 165-million-year test case for evolutionary theories of how species occupy and then fill ecological niches. It is widely assumed that species often diverge rapidly early in their evolution, and that this is followed by a longer, drawn-out period of slower evolutionary fine-tuning as natural selection fits organisms into an increasingly occupied niche space1,2. But recent studies have hinted that the process may not be so simple3–5. Here we apply statistical methods that automatically detect temporal shifts in the rate of evolution through time to a comprehensive mammalian phylogeny6 and data set7 of body sizes of 3,185 extant species. Unexpectedly, the majority of mammal species, including two of the most speciose orders (Rodentia and Chiroptera), have no history of substantial and sustained increases in the rates of evolution. Instead, a subset of the mammals has experienced an explosive increase (between 10- and 52-fold) in the rate of evolution along the single branch leading to the common ancestor of their monophyletic group (for example Chiroptera), followed by a quick return to lower or background levels. The remaining species are a taxonomically diverse assemblage showing a significant, sustained increase or decrease in their rates of evolution. These results necessarily decouple morphological diversification from speciation and suggest that the processes that give rise to the morphological diversity of a class of animals are far more free to vary than previously considered. Niches do not seem to fill up, and diversity seems to arise whenever, wherever and at whatever rate it is advantageous.