Protein structure prediction servers at University College London

A number of state-of-the-art protein structure prediction servers have been developed by researchers working in the Bioinformatics Unit at University College London. The popular PSIPRED server allows users to perform secondary structure prediction, transmembrane topology prediction and protein fold recognition. More recent servers include DISOPRED for the prediction of protein dynamic disorder and DomPred for domain boundary prediction.

Predicting metal-binding site residues in low-resolution structural models

The accurate prediction of the biochemical function of a protein is becoming increasingly important, given the unprecedented growth of both structural and sequence databanks. Consequently, computational methods are required to analyse such data in an automated manner to ensure genomes are annotated accurately. Protein structure prediction methods, for example, are capable of generating approximate structural models on a genome-wide scale. However, the detection of functionally important regions in such crude models, as well as structural genomics targets, remains an extremely important problem. The method described in the current study, MetSite, represents a fully automatic approach for the detection of metal-binding residue clusters applicable to protein models of moderate quality. The method involves using sequence profile information in combination with approximate structural data. Several neural network classifiers are shown to be able to distinguish metal sites from non-sites with a mean accuracy of 94.5%. The method was demonstrated to identify metal-binding sites correctly in LiveBench targets where no obvious metal-binding sequence motifs were detectable using InterPro. Accurate detection of metal sites was shown to be feasible for low-resolution predicted structures generated using mGenTHREADER where no side-chain information was available. High-scoring predictions were observed for a recently solved hypothetical protein from Haemophilus influenzae, indicating a putative metal-binding site.

Precise calculations of the existence of multiple AMOC equilibria in coupled climate models Part I: equilibrium states

This study examines criteria for the existence of two stable states of the Atlantic Meridional Overturning Circulation (AMOC) using a combination of theory and simulations from a numerical coupled atmosphere–ocean climate model. By formulating a simple collection of state parameters and their relationships, the authors reconstruct the North Atlantic Deep Water (NADW) OFF state behavior under a varying external salt-flux forcing. This part (Part I) of the paper examines the steady-state solution, which gives insight into the mechanisms that sustain the NADW OFF state in this coupled model; Part II deals with the transient behavior predicted by the evolution equation. The nonlinear behavior of the Antarctic Intermediate Water (AAIW) reverse cell is critical to the OFF state. Higher Atlantic salinity leads both to a reduced AAIW reverse cell and to a greater vertical salinity gradient in the South Atlantic. The former tends to reduce Atlantic salt export to the Southern Ocean, while the latter tends to increases it. These competing effects produce a nonlinear response of Atlantic salinity and salt export to salt forcing, and the existence of maxima in these quantities. Thus the authors obtain a natural and accurate analytical saddle-node condition for the maximal surface salt flux for which a NADW OFF state exists. By contrast, the bistability indicator proposed by De Vries and Weber does not generally work in this model. It is applicable only when the effect of the AAIW reverse cell on the Atlantic salt budget is weak.

Non-D9-tetrahydrocannabinol phytocannabinoids stimulate feeding in rats

Cannabinoid type 1 receptor-mediated appetite stimulation by D9tetrahydrocannabinol (D9THC) is well understood. Recently, it has become apparent that non-D9THC phytocannabinoids could also alter feeding patterns. Here, we show definitively that non-D9THC phytocannabinoids stimulate feeding. Twelve male, Lister-Hooded rats were prefed to satiety prior to administration of a standardized cannabis extract or to either of two mixtures of pure phytocannabinoids (extract analogues) comprising the phytocannabinoids present in the same proportions as the standardized extract (one with and one without D9THC). Hourly intake and meal pattern data were recorded and analysed using two-way analysis of variance followed by one-way analysis of variance and Bonferroni post-hoc tests. Administration of both extract analogues significantly increased feeding behaviours over the period of the test. All three agents increased hour-one intake and meal-one size and decreased the latency to feed, although the zero-D9THC extract analogue did so to a lesser degree than the high-D9THC analogue. Furthermore, only the analogue containing D9THC significantly increased meal duration. The data confirm that at least one non-D9THC phytocannabinoid induces feeding pattern changes in rats, although further trials using individual phytocannabinoids are required to fully understand the observed effects.

Gap junctions and connexin hemichannels underpin hemostasis and thrombosis

BACKGROUND: Connexins are a widespread family of membrane proteins that assemble into hexameric hemichannels, also known as connexons. Connexons regulate membrane permeability in individual cells or couple between adjacent cells to form gap junctions and thereby provide a pathway for regulated intercellular communication. We have now examined the role of connexins in platelets, blood cells that circulate in isolation, but upon tissue injury adhere to each other and the vessel wall to prevent blood loss and facilitate wound repair. METHODS AND RESULTS: We report the presence of connexins in platelets, notably connexin37, and that the formation of gap junctions within platelet thrombi is required for the control of clot retraction. Inhibition of connexin function modulated a range of platelet functional responses prior to platelet-platelet contact, and reduced laser induced thrombosis in vivo in mice. Deletion of the Cx37 gene (Gja4) in transgenic mice reduced platelet aggregation, fibrinogen binding, granule secretion and clot retraction indicating an important role for Cx37 hemichannels and gap junctions in platelet thrombus function. CONCLUSIONS: Together, these data demonstrate that platelet gap junctions and hemichannels underpin the control of haemostasis and thrombosis and represent potential therapeutic targets.

Staphylococcal extracellular adherence protein induces platelet activation by stimulation of thiol isomerases

OBJECTIVE: Staphylococcus aureus can induce platelet aggregation. The rapidity and degree of this correlates with the severity of disseminated intravascular coagulation, and depends on platelet peptidoglycans. Surface-located thiol isomerases play an important role in platelet activation. The staphylococcal extracellular adherence protein (Eap) functions as an adhesin for host plasma proteins. Therefore we tested the effect of Eap on platelets. METHODS AND RESULTS: We found a strong stimulation of the platelet-surface thiol isomerases protein disulfide isomerase, endoplasmic reticulum stress proteins 57 and 72 by Eap. Eap induced thiol isomerase-dependent glycoprotein IIb/IIIa activation, granule secretion, and platelet aggregation. Treatment of platelets with thiol blockers, bacitracin, and anti-protein disulfide isomerase antibody inhibited Eap-induced platelet activation. The effect of Eap on platelets and protein disulfide isomerase activity was completely blocked by glycosaminoglycans. Inhibition by the hydrophobic probe bis(1-anilinonaphthalene 8-sulfonate) suggested the involvement of hydrophobic sites in protein disulfide isomerase and platelet activation by Eap. CONCLUSIONS: In the present study, we found an additional and yet unknown mechanism of platelet activation by a bacterial adhesin, involving stimulation of thiol isomerases. The thiol isomerase stimulatory and prothrombotic features of a microbial secreted protein are probably not restricted to S aureus and Eap. Because many microorganisms are coated with amyloidogenic proteins, it is likely that the observed mechanism is a more general one.

The Climate-G testbed: towards large scale distributed data management for climate change

Climate-G is a large scale distributed testbed devoted to climate change research. It is an unfunded effort started in 2008 and involving a wide community both in Europe and US. The testbed is an interdisciplinary effort involving partners from several institutions and joining expertise in the field of climate change and computational science. Its main goal is to allow scientists carrying out geographical and cross-institutional data discovery, access, analysis, visualization and sharing of climate data. It represents an attempt to address, in a real environment, challenging data and metadata management issues. This paper presents a complete overview about the Climate-G testbed highlighting the most important results that have been achieved since the beginning of this project.

The influence of eddy parameterizations on the transport of the Antarctic Circumpolar Current in coupled climate models

The transport of the Antarctic Circumpolar Current (ACC) varies strongly across the coupled GCMs (general circulation models) used for the IPCC AR4. This note shows that a large fraction of this across-model variance can be explained by relating it to the parameterization of eddy-induced transports. In the majority of models this parameterization is based on the study by Gent and McWilliams (1990). The main parameter is the quasi-Stokes diffusivity kappa (often referred to less accurately as ’’thickness diffusion’’). The ACC transport and the meridional density gradient both correlate strongly with kappa across those models where kappa is a prescribed constant. In contrast, there is no correlation with the isopycnal diffusivity jiso across the models. The sensitivity of the ACC transport to kappa is larger than to the zonal wind stress maximum. Experiments with the fast GCM FAMOUS show that changing kappa directly affects the ACC transport by changing the density structure throughout the water column. Our results suggest that this limits the role of the wind stress magnitude in setting the ACC transport in FAMOUS. The sensitivities of the ACC and the meridional density gradient are very similar across the AR4 GCMs (for those models where kappa is a prescribed constant) and among the FAMOUS experiments. The strong sensitivity of the ACC transport to kappa needs careful assessment in climate models.

Response of the North Atlantic storm track to climate change shaped by ocean–atmosphere coupling

A poleward shift of the mid-latitude storm tracks in response to anthropogenic greenhouse-gas forcing has been diagnosed in climate model simulations1, 2. Explanations of this effect have focused on atmospheric dynamics3, 4, 5, 6, 7. However, in contrast to storm tracks in other regions, the North Atlantic storm track responds by strengthening and extending farther east, in particular on its southern flank8. These adjustments are associated with an intensification and extension of the eddy-driven jet towards western Europe9 and are expected to have considerable societal impacts related to a rise in storminess in Europe10, 11, 12. Here, we apply a regression analysis to an ensemble of coupled climate model simulations to show that the coupling between ocean and atmosphere shapes the distinct storm-track response to greenhouse-gas forcing in the North Atlantic region. In the ensemble of simulations we analyse, at least half of the differences between the storm-track responses of different models are associated with uncertainties in ocean circulation changes. We compare the fully coupled simulations with both the associated slab model simulations and an ocean-forced experiment with one climate model to establish causality. We conclude that uncertainties in the response of the North Atlantic storm track to anthropogenic emissions could be reduced through tighter constraints on the future ocean circulation.

Rhinocetin, a venom-derived integrin-specific antagonist inhibits collagen-induced platelet and endothelial cell functions

Snaclecs are small non-enzymatic proteins present in viper venoms reported to modulate haemostasis of victims through effects on platelets, vascular endothelial and smooth muscle cells. In this study, we have isolated and functionally characterised a snaclec which we named rhinocetin from the venom of West African gaboon viper, Bitis gabonica rhinoceros. Rhinocetin was shown to comprise α and β chains with the molecular masses of 13.5 and 13kDa respectively. Sequence and immunoblot analysis of rhinocetin confirmed this to be a novel snaclec. Rhinocetin inhibited collagen-stimulated activation of human platelets in dose dependent manner, but displayed no inhibitory effects on glycoprotein VI (collagen receptor) selective agonist, CRP-XL-, ADP- or thrombin-induced platelet activation. Rhinocetin antagonised the binding of monoclonal antibodies against the α2 subunit of integrin α2β1 to platelets and coimmunoprecipitation analysis confirmed integrin α2β1 as a target for this venom protein. Rhinocetin inhibited a range of collagen induced platelet functions such as fibrinogen binding, calcium mobilisation, granule secretion, aggregation and thrombus formation. It also inhibited integrin α2β1 dependent functions of human endothelial cells. Together, our data suggest rhinocetin to be a modulator of integrin α2β1 function and thus may provide valuable insights into the role of this integrin in physiological and pathophysiological scenarios including haemostasis, thrombosis and envenomation.

Ocean heat uptake and its consequences for the magnitude of sea level rise and climate change

Under increasing greenhouse gas concentrations, ocean heat uptake moderates the rate of climate change, and thermal expansion makes a substantial contribution to sea level rise. In this paper we quantify the differences in projections among atmosphere-ocean general circulation models of the Coupled Model Intercomparison Project in terms of transient climate response, ocean heat uptake efficiency and expansion efficiency of heat. The CMIP3 and CMIP5 ensembles have statistically indistinguishable distributions in these parameters. The ocean heat uptake efficiency varies by a factor of two across the models, explaining about 50% of the spread in ocean heat uptake in CMIP5 models with CO2 increasing at 1%/year. It correlates with the ocean global-mean vertical profiles both of temperature and of temperature change, and comparison with observations suggests the models may overestimate ocean heat uptake and underestimate surface warming, because their stratification is too weak. The models agree on the location of maxima of shallow ocean heat uptake (above 700 m) in the Southern Ocean and the North Atlantic, and on deep ocean heat uptake (below 2000 m) in areas of the Southern Ocean, in some places amounting to 40% of the top-to-bottom integral in the CMIP3 SRES A1B scenario. The Southern Ocean dominates global ocean heat uptake; consequently the eddy-induced thickness diffusivity parameter, which is particularly influential in the Southern Ocean, correlates with the ocean heat uptake efficiency. The thermal expansion produced by ocean heat uptake is 0.12 m YJ−1, with an uncertainty of about 10% (1 YJ = 1024 J).