Exploring the impact of CMIP5 model biases on the simulation of North Atlantic decadal variability

Instrumental observations, palaeo-proxies, and climate models suggest significant decadal variability within the North Atlantic subpolar gyre (NASPG). However, a poorly sampled observational record and a diversity of model behaviours mean that the precise nature and mechanisms of this variability are unclear. Here, we analyse an exceptionally large multi-model ensemble of 42 present-generation climate models to test whether NASPG mean state biases systematically affect the representation of decadal variability. Temperature and salinity biases in the Labrador Sea co-vary and influence whether density variability is controlled by temperature or salinity variations. Ocean horizontal resolution is a good predictor of the biases and the location of the dominant dynamical feedbacks within the NASPG. However, we find no link to the spectral characteristics of the variability. Our results suggest that the mean state and mechanisms of variability within the NASPG are not independent. This represents an important caveat for decadal predictions using anomaly-assimilation methods.

Detecting regular sound changes in linguistics as events of concerted evolution

Background: Concerted evolution is normally used to describe parallel changes at different sites in a genome, but it is also observed in languages where a specific phoneme changes to the same other phoneme in many words in the lexicon—a phenomenon known as regular sound change. We develop a general statistical model that can detect concerted changes in aligned sequence data and apply it to study regular sound changes in the Turkic language family. Results: Linguistic evolution, unlike the genetic substitutional process, is dominated by events of concerted evolutionary change. Our model identified more than 70 historical events of regular sound change that occurred throughout the evolution of the Turkic language family, while simultaneously inferring a dated phylogenetic tree. Including regular sound changes yielded an approximately 4-fold improvement in the characterization of linguistic change over a simpler model of sporadic change, improved phylogenetic inference, and returned more reliable and plausible dates for events on the phylogenies. The historical timings of the concerted changes closely follow a Poisson process model, and the sound transition networks derived from our model mirror linguistic expectations. Conclusions: We demonstrate that a model with no prior knowledge of complex concerted or regular changes can nevertheless infer the historical timings and genealogical placements of events of concerted change from the signals left in contemporary data. Our model can be applied wherever discrete elements—such as genes, words, cultural trends, technologies, or morphological traits—can change in parallel within an organism or other evolving group.

A mechanism of internal decadal atlantic ocean variability in a high-resolution coupled climate model

The North Atlantic Ocean subpolar gyre (NA SPG) is an important region for initialising decadal climate forecasts. Climate model simulations and palaeo climate reconstructions have indicated that this region could also exhibit large, internally generated variability on decadal timescales. Understanding these modes of variability, their consistency across models, and the conditions in which they exist, is clearly important for improving the skill of decadal predictions — particularly when these predictions are made with the same underlying climate models. Here we describe and analyse a mode of internal variability in the NA SPG in a state-of-the-art, high resolution, coupled climate model. This mode has a period of 17 years and explains 15–30% of the annual variance in related ocean indices. It arises due to the advection of heat content anomalies around the NA SPG. Anomalous circulation drives the variability in the southern half of the NA SPG, whilst mean circulation and anomalous temperatures are important in the northern half. A negative feedback between Labrador Sea temperatures/densities and those in the North Atlantic Current is identified, which allows for the phase reversal. The atmosphere is found to act as a positive feedback on to this mode via the North Atlantic Oscillation which itself exhibits a spectral peak at 17 years. Decadal ocean density changes associated with this mode are driven by variations in temperature, rather than salinity — a point which models often disagree on and which we suggest may affect the veracity of the underlying assumptions of anomaly-assimilating decadal prediction methodologies.

Interpretation of ambiguity: differences between children and adolescents with and without an anxiety disorder

Background: Theory and treatment of anxiety disorders in young people are commonly based on the premise that interpretation biases found in anxious adults are also found in children and adolescents. Although there is some evidence that this may be the case, studies have not typically taken age into account, which is surprising given the normative changes in cognition that occur throughout childhood. The aim of the current study was to identify whether associations between anxiety disorder status and interpretation biases differed in children and adolescents. Methods: The responses of children (7-10 years) and adolescents (13-16 years) with and without anxiety disorders (n = 120) were compared on an ambiguous scenarios task. Results: Children and adolescents with an anxiety disorder showed significantly higher levels of threat interpretation and avoidant strategies than non-anxious children and adolescents. However, age significantly moderated the effect of anxiety disorder status on interpretation of ambiguity, in that adolescents with anxiety disorders showed significantly higher levels of threat interpretation and associated negative emotion than non-anxious adolescents, but a similar relationship was not observed among children. Conclusions: The findings suggest that theoretical accounts of interpretation biases in anxiety disorders in children and adolescents should distinguish between different developmental periods. For both ages, treatment that targets behavioral avoidance appears warranted. However, while adolescents are likely to benefit from treatment that addresses interpretation biases, there may be limited benefit for children under the age of ten.

A framework for designing multi-functional cover crops

Cover crops are sown to provide a number of ecosystem services including nutrient management, mitigation of diffuse pollution, improving soil structure and organic matter content, weed suppression, nitrogen fixation and provision of resources for biodiversity. Although the decision to sow a cover crop may be driven by a desire to achieve just one of these objectives, the diversity of cover crops species and mixtures available means that there is potential to combine a number of ecosystem services within the same crop and growing season. Designing multi-functional cover crops would potentially help to reconcile the often conflicting agronomic and environmental agendas and contribute to the optimal use of land. We present a framework for integrating multiple ecosystem services delivered by cover crops that aims to design a mixture of species with complementary growth habit and functionality. The optimal number and identity of species will depend on the services included in the analysis, the functional space represented by the available species pool and the community dynamics of the crop in terms of dominance and co-existence. Experience from a project that applied the framework to fertility building leys in organic systems demonstrated its potential and emphasised the importance of the initial choice of species to include in the analysis

Fibrin activates GPVI in human and mouse platelets

The glycoprotein VI (GPVI)-Fc receptor γ (FcRγ) chain is the major platelet signaling receptor for collagen. Paradoxically, in a FeCl3 injury model, occlusion, but not initiation of thrombus formation, is delayed in GPVI-deficient and GPVI-depleted mice. In this study, we demonstrate that GPVI is a receptor for fibrin and speculate that this contributes to development of an occlusive thrombus. We observed a marked increase in tyrosine phosphorylation, including the FcRγ chain and Syk, in human and mouse platelets induced by thrombin in the presence of fibrinogen and the αIIbβ3 blocker eptifibatide. This was not seen in platelets stimulated by a protease activated receptor (PAR)-4 peptide, which is unable to generate fibrin from fibrinogen. The pattern of tyrosine phosphorylation was similar to that induced by activation of GPVI. Consistent with this, thrombin did not induce tyrosine phosphorylation of Syk and the FcRγ chain in GPVI-deficient mouse platelets. Mouse platelets underwent full spreading on fibrin but not fibrinogen, which was blocked in the presence of a Src kinase inhibitor or in the absence of GPVI. Spreading on fibrin was associated with phosphatidylserine exposure (procoagulant activity), and this too was blocked in GPVI-deficient platelets. The ectodomain of GPVI was shown to bind to immobilized monomeric and polymerized fibrin. A marked increase in embolization was seen following FeCl3 injury in GPVI-deficient mice, likely contributing to the delay in occlusion in this model. These results demonstrate that GPVI is a receptor for fibrin and provide evidence that this interaction contributes to thrombus growth and stability.

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.

Regulation of early steps of GPVI signal transduction by phosphatases: a systems biology approach

We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation.

A high-density immunoblotting methodology for quantification of total protein levels and phosphorylation modifications

The components of many signaling pathways have been identified and there is now a need to conduct quantitative data-rich temporal experiments for systems biology and modeling approaches to better understand pathway dynamics and regulation. Here we present a modified Western blotting method that allows the rapid and reproducible quantification and analysis of hundreds of data points per day on proteins and their phosphorylation state at individual sites. The approach is of particular use where samples show a high degree of sample-to-sample variability such as primary cells from multiple donors. We present a case study on the analysis of >800 phosphorylation data points from three phosphorylation sites in three signaling proteins over multiple time points from platelets isolated from ten donors, demonstrating the technique's potential to determine kinetic and regulatory information from limited cell numbers and to investigate signaling variation within a population. We envisage the approach being of use in the analysis of many cellular processes such as signaling pathway dynamics to identify regulatory feedback loops and the investigation of potential drug/inhibitor responses, using primary cells and tissues, to generate information about how a cell's physiological state changes over time.

Syncytiotrophoblast extracellular vesicles from pre-eclampsia placentas differentially affect platelet function

Pre-eclampsia (PE) complicates around 3% of all pregnancies and is one of the most common causes of maternal mortality worldwide. The pathophysiology of PE remains unclear however its underlying cause originates from the placenta and manifests as raised blood pressure, proteinuria, vascular or systemic inflammation and hypercoagulation in the mother. Women who develop PE are also at significantly higher risk of subsequently developing cardiovascular (CV) disease. In PE, the failing endoplasmic reticulum, oxidative and inflammatory stressed syncytiotrophoblast layer of the placenta sheds increased numbers of syncytiotrophoblast extracellular vesicles (STBEV) into the maternal circulation. Platelet reactivity, size and concentration are also known to be altered in some women who develop PE, although the underlying reasons for this have not been determined. In this study we show that STBEV from disease free placenta isolated ex vivo by dual placental perfusion associate rapidly with platelets. We provide evidence that STBEV isolated from normal placentas cause platelet activation and that this is increased with STBEV from PE pregnancies. Furthermore, treatment of platelets with aspirin, currently prescribed for women at high risk of PE to reduce platelet aggregation, also inhibits STBEV-induced reversible aggregation of washed platelets. Increased platelet reactivity as a result of exposure to PE placenta derived STBEVs correlates with increased thrombotic risk associated with PE. These observations establish a possible direct link between the clotting disturbances of PE and dysfunction of the placenta, as well as the known increased risk of thromboembolism associated with this condition.

Interactions between cocoa flavanols and inorganic nitrate: additive effects on endothelial function at achievable dietary amounts

Dietary intervention studies have shown that flavanols and inorganic nitrate can improve vascular function, suggesting that these two bioactives may be responsible for beneficial health effects of diets rich in fruits and vegetables. We aimed to study interactions between cocoa flavanols (CF) and nitrate, focusing on absorption, bioavailability, excretion, and efficacy to increase endothelial function. In a double-blind randomized, dose-response crossover study, flow-mediated dilation (FMD) was measured in 15 healthy subjects before and at 1, 2, 3, and 4 h after consumption of CF (1.4-10.9 mg/kg bw) or nitrate (0.1-10 mg/kg bw). To study flavanol-nitrate interactions, an additional intervention trial was performed with nitrate and CF taken in sequence at low and high amounts. FMD was measured before (0 h) and at 1h after ingestion of nitrate (3 or 8.5 mg/kg bw) or water. Then subjects received a CF drink (2.7 or 10.9 mg/kg bw) or a micro- and macronutrient-matched CF-free drink. FMD was measured at 1, 2, and 4 h thereafter. Blood and urine samples were collected and assessed for CF and nitric oxide (NO) metabolites with HPLC and gas-phase reductive chemiluminescence. Finally, intragastric formation of NO after CF and nitrate consumption was investigated. Both CF and nitrate induced similar intake-dependent increases in FMD. Maximal values were achieved at 1 h postingestion and gradually decreased to reach baseline values at 4 h. These effects were additive at low intake levels, whereas CF did not further increase FMD after high nitrate intake. Nitrate did not affect flavanol absorption, bioavailability, or excretion, but CF enhanced nitrate-related gastric NO formation and attenuated the increase in plasma nitrite after nitrate intake. Both flavanols and inorganic nitrate can improve endothelial function in healthy subjects at intake amounts that are achievable with a normal diet. Even low dietary intake of these bioactives may exert relevant effects on endothelial function when ingested together.

I killed my father, I ate human flesh, I quiver with joy: an obsession with Pier Paolo Pasolini

Group show, curated by Invisible Exports Gallery. Featuring work by Michael Bilsborough, Lizzi Bougatsos, BREYER P-ORRIDGE, Asger Carlsen, Troels Carlsen, Walt Cassidy, Andy Coolquitt, Vaginal Davis, Carlton DeWoody, Joey Frank, Paul Gabrielli, Ludovica Gioscia, Luis Gispert, Terence Hannum, Karen Heagle, Timothy Hull, Doug Ischar, Brian Kenny, Jeremy Kost, Aaron Krach, Yeni Mao, Leigha Mason, Mark McCoy, Robert Melee, Lucas Michael, Jennifer Needleman, Brent Owens, Paul P., Paolo Di Paolo, Franklin Preston, John Russell, Xaviera Simmons, Duston Spear, Scott Treleaven, Ramon Vega, Jordan Wolfson, Dustin Yellin

Platelet signaling: a complex interplay between inhibitory and activatory networks

The role of platelets in hemostasis and thrombosis is dependent on a complex balance of activatory and inhibitory signaling pathways. Inhibitory signals released from the healthy vasculature suppress platelet activation in the absence of platelet receptor agonists. Activatory signals present at a site of injury initiate platelet activation and thrombus formation; subsequently, endogenous negative signaling regulators dampen activatory signals to control thrombus growth. Understanding the complex interplay between activatory and inhibitory signaling networks is an emerging challenge in the study of platelet biology and necessitates a systematic approach to utilize experimental data effectively. In this review, we will explore the key points of platelet regulation and signaling that maintain platelets in a resting state, mediate activation to elicit thrombus formation or provide negative feedback. Platelet signaling will be described in terms of key signaling molecules that are common to the pathways activated by platelet agonists and can be described as regulatory nodes for both positive and negative regulators. This article is protected by copyright. All rights reserved.

Interactional dynamics in on-line and face-to-face peer-tutoring sessions for second language writers

This paper reports the results of a study comparing the interactional dynamics of face-to-face and on-line peer-tutoring in writing by university students in Hong Kong. Transcripts of face-to-face tutoring sessions, as well as logs of on-line sessions conducted by the same peer-tutors, were coded for speech functions using a system based on Halliday's functional-semantic view of dialogue. Results show considerable differences between the interactional dynamics in on-line and face-to-face tutoring sessions. In particular, face-to-face interactions involved more hierarchal encounters in which tutors took control of the discourse, whereas on-line interactions were more egalitarian, with clients controlling the discourse more. Differences were also found in the topics participants chose to focus on in the two modes, with issues of grammar, vocabulary, and style taking precedence in face-to-face sessions and more “global” writing concerns like content and process being discussed more in on-line sessions.

Decadal predictions with the HiGEM high resolution global coupled climate model: description and basic evaluation

This paper describes the development and basic evaluation of decadal predictions produced using the HiGEM coupled climate model. HiGEM is a higher resolution version of the HadGEM1 Met Office Unified Model. The horizontal resolution in HiGEM has been increased to 1.25◦ × 0.83◦ in longitude and latitude for the atmosphere, and 1/3◦ × 1/3◦ globally for the ocean. The HiGEM decadal predictions are initialised using an anomaly assimilation scheme that relaxes anomalies of ocean temperature and salinity to observed anomalies. 10 year hindcasts are produced for 10 start dates (1960, 1965,..., 2000, 2005). To determine the relative contributions to prediction skill from initial conditions and external forcing, the HiGEM decadal predictions are compared to uninitialised HiGEM transient experiments. The HiGEM decadal predictions have substantial skill for predictions of annual mean surface air temperature and 100 m upper ocean temperature. For lead times up to 10 years, anomaly correlations (ACC) over large areas of the North Atlantic Ocean, the Western Pacific Ocean and the Indian Ocean exceed values of 0.6. Initialisation of the HiGEM decadal predictions significantly increases skill over regions of the Atlantic Ocean,the Maritime Continent and regions of the subtropical North and South Pacific Ocean. In particular, HiGEM produces skillful predictions of the North Atlantic subpolar gyre for up to 4 years lead time (with ACC > 0.7), which are significantly larger than the uninitialised HiGEM transient experiments.