Dysregulated circulating dendritic cell function in ulcerative colitis is partially restored by probiotic strain Lactobacillus casei Shirota

BACKGROUND: Dendritic cells regulate immune responses to microbial products and play a key role in ulcerative colitis (UC) pathology. We determined the immunomodulatory effects of probiotic strain Lactobacillus casei Shirota (LcS) on human DC from healthy controls and active UC patients. METHODS: Human blood DC from healthy controls (control-DC) and UC patients (UC-DC) were conditioned with heat-killed LcS and used to stimulate allogeneic T cells in a 5-day mixed leucocyte reaction. RESULTS: UC-DC displayed a reduced stimulatory capacity for T cells (P < 0.05) and enhanced expression of skin-homing markers CLA and CCR4 on stimulated T cells (P < 0.05) that were negative for gut-homing marker β7. LcS treatment restored the stimulatory capacity of UC-DC, reflecting that of control-DC. LcS treatment conditioned control-DC to induce CLA on T cells in conjunction with β7, generating a multihoming profile, but had no effects on UC-DC. Finally, LcS treatment enhanced DC ability to induce TGFβ production by T cells in controls but not UC patients. CONCLUSIONS: We demonstrate a systemic, dysregulated DC function in UC that may account for the propensity of UC patients to develop cutaneous manifestations. LcS has multifunctional immunoregulatory activities depending on the inflammatory state; therapeutic effects reported in UC may be due to promotion of homeostasis.

An anatomy of the cooling of the North Atlantic Ocean in the 1960s and 1970s

In the 1960s and early 1970s sea surface temperatures in the North Atlantic Ocean cooled rapidly. There is still considerable uncertainty about the causes of this event, although various mechanisms have been proposed. In this observational study it is demonstrated that the cooling proceeded in several distinct stages. Cool anomalies initially appeared in the mid-1960s in the Nordic Seas and Gulf Stream Extension, before spreading to cover most of the Subpolar Gyre. Subsequently, cool anomalies spread into the tropical North Atlantic before retreating, in the late 1970s, back to the Subpolar Gyre. There is strong evidence that changes in atmospheric circulation, linked to a southward shift of the Atlantic ITCZ, played an important role in the event, particularly in the period 1972-76. Theories for the cooling event must account for its distinctive space-time evolution. Our analysis suggests that the most likely drivers were: 1) The “Great Salinity Anomaly” of the late 1960s; 2) An earlier warming of the subpolar North Atlantic, which may have led to a slow-down in the Atlantic Meridional Overturning Circulation; 3) An increase in anthropogenic sulphur dioxide emissions. Determining the relative importance of these factors is a key area for future work.

The importance of wind and buoyancy forcing for the boundary density variations and the geostrophic component of the AMOC at 26°N

It is widely thought that changes in both the surface buoyancy fluxes and wind stress drive variability in the Atlantic meridional overturning circulation (AMOC), but that they drive variability on different time scales. For example, wind forcing dominates short-term variability through its effects on Ekman currents and coastal upwelling, whereas buoyancy forcing is important for longer time scales (multiannual and decadal). However, the role of the wind forcing on multiannual to decadal time scales is less clear. Here the authors present an analysis of simulations with the Nucleus for European Modelling of the Ocean (NEMO) ocean model with the aim of explaining the important drivers of the zonal density gradient at 26°N, which is directly related to the AMOC. In the experiments, only one of either the wind stress or the buoyancy forcing is allowed to vary in time, whereas the other remains at its seasonally varying climatology. On subannual time scales, variations in the density gradient, and in the AMOC minus Ekman, are driven largely by local wind-forced coastal upwelling at both the western and eastern boundaries. On decadal time scales, buoyancy forcing related to the North Atlantic Oscillation dominates variability in the AMOC. Interestingly, however, it is found that wind forcing also plays a role at longer time scales, primarily impacting the interannual variability through the excitation of Rossby waves in the central Atlantic, which propagate westward to interact with the western boundary, but also by modulating the decadal time-scale response to buoyancy forcing.

Integrin-linked kinase regulates the rate of platelet activation and is essential for the formation of stable thrombi

BACKGROUND: Integrin-linked kinase (ILK) and its associated complex of proteins are involved in many cellular activation processes, including cell adhesion and integrin signaling. We have previously demonstrated that mice with induced platelet ILK deficiency show reduced platelet activation and aggregation, but only a minor bleeding defect. Here, we explore this apparent disparity between the cellular and hemostatic phenotypes. METHODS: The impact of ILK inhibition on integrin αII b β3 activation and degranulation was assessed with the ILK-specific inhibitor QLT0267, and a conditional ILK-deficient mouse model was used to assess the impact of ILK deficiency on in vivo platelet aggregation and thrombus formation. RESULTS: Inhibition of ILK reduced the rate of both fibrinogen binding and α-granule secretion, but was accompanied by only a moderate reduction in the maximum extent of platelet activation or aggregation in vitro. The reduction in the rate of fibrinogen binding occurred prior to degranulation or translocation of αII b β3 to the platelet surface. The change in the rate of platelet activation in the absence of functional ILK led to a reduction in platelet aggregation in vivo, but did not change the size of thrombi formed following laser injury of the cremaster arteriole wall in ILK-deficient mice. It did, however, result in a marked decrease in the stability of thrombi formed in ILK-deficient mice. CONCLUSION: Taken together, the findings of this study indicate that, although ILK is not essential for platelet activation, it plays a critical role in facilitating rapid platelet activation, which is essential for stable thrombus formation.

A novel transport assimilation method for the Atlantic meridional overturning circulation at 26°N

One of the prerequisites for achieving skill in decadal climate prediction is to initialize and predict the circulation in the Atlantic Ocean successfully. The RAPID array measures the Atlantic Meridional Overturning Circulation (MOC) at 26°N. Here we develop a method to include these observations in the Met Office Decadal Prediction System (DePreSys). The proposed method uses covariances of overturning transport anomalies at 26°N with ocean temperature and salinity anomalies throughout the ocean to create the density structure necessary to reproduce the observed transport anomaly. Assimilating transport alone in this way effectively reproduces the observed transport anomalies at 26°N and is better than using basin-wide temperature and salinity observations alone. However, when the transport observations are combined with in situ temperature and salinity observations in the analysis, the transport is not currently reproduced so well. The reasons for this are investigated using pseudo-observations in a twin experiment framework. Sensitivity experiments show that the MOC on monthly time-scales, at least in the HadCM3 model, is modulated by a mechanism where non-local density anomalies appear to be more important for transport variability at 26°N than local density gradients.

Vertical structure and physical processes of the Madden-Julian oscillation: Linking hindcast fidelity to simulated diabatic heating and moistening

Many theories for the Madden-Julian oscillation (MJO) focus on diabatic processes, particularly the evolution of vertical heating and moistening. Poor MJO performance in weather and climate models is often blamed on biases in these processes and their interactions with the large-scale circulation. We introduce one of three components of a model-evaluation project, which aims to connect MJO fidelity in models to their representations of several physical processes, focusing on diabatic heating and moistening. This component consists of 20-day hindcasts, initialised daily during two MJO events in winter 2009-10. The 13 models exhibit a range of skill: several have accurate forecasts to 20 days' lead, while others perform similarly to statistical models (8-11 days). Models that maintain the observed MJO amplitude accurately predict propagation, but not vice versa. We find no link between hindcast fidelity and the precipitation-moisture relationship, in contrast to other recent studies. There is also no relationship between models' performance and the evolution of their diabatic-heating profiles with rain rate. A more robust association emerges between models' fidelity and net moistening: the highest-skill models show a clear transition from low-level moistening for light rainfall to mid-level moistening at moderate rainfall and upper-level moistening for heavy rainfall. The mid-level moistening, arising from both dynamics and physics, may be most important. Accurately representing many processes may be necessary, but not sufficient for capturing the MJO, which suggests that models fail to predict the MJO for a broad range of reasons and limits the possibility of finding a panacea.

Vertical structure and physical processes of the Madden-Julian oscillation: synthesis and summary

The "Vertical structure and physical processes of the Madden-Julian oscillation (MJO)" project comprises three experiments, designed to evaluate comprehensively the heating, moistening and momentum associated with tropical convection in general circulation models (GCMs). We consider here only those GCMs that performed all experiments. Some models display relatively higher or lower MJO fidelity in both initialized hindcasts and climate simulations, while others show considerable variations in fidelity between experiments. Fidelity in hindcasts and climate simulations are not meaningfully correlated. The analysis of each experiment led to the development of process-oriented diagnostics, some of which distinguished between GCMs with higher or lower fidelity in that experiment. We select the most discriminating diagnostics and apply them to data from all experiments, where possible, to determine if correlations with MJO fidelity hold across scales and GCM states. While normalized gross moist stability had a small but statistically significant correlation with MJO fidelity in climate simulations, we find no link with fidelity in medium-range hindcasts. Similarly, there is no association between timestep-to-timestep rainfall variability, identified from short hindcasts, and fidelity in medium-range hindcasts or climate simulations. Two metrics that relate precipitation to free-tropospheric moisture--the relative humidity for extreme daily precipitation, and variations in the height and amplitude of moistening with rain rate--successfully distinguish between higher- and lower-fidelity GCMs in hindcasts and climate simulations. To improve the MJO, developers should focus on relationships between convection and both total moisture and its rate of change. We conclude by offering recommendations for further experiments.

Vertical structure and physical processes of the Madden-Julian oscillation: exploring key model physics in climate simulations

Aimed at reducing deficiencies in representing the Madden-Julian oscillation (MJO) in general circulation models (GCMs), a global model evaluation project on vertical structure and physical processes of the MJO was coordinated. In this paper, results from the climate simulation component of this project are reported. It is shown that the MJO remains a great challenge in these latest generation GCMs. The systematic eastward propagation of the MJO is only well simulated in about one-fourth of the total participating models. The observed vertical westward tilt with altitude of the MJO is well simulated in good MJO models, but not in the poor ones. Damped Kelvin wave responses to the east of convection in the lower troposphere could be responsible for the missing MJO preconditioning process in these poor MJO models. Several process-oriented diagnostics were conducted to discriminate key processes for realistic MJO simulations. While large-scale rainfall partition and low-level mean zonal winds over the Indo-Pacific in a model are not found to be closely associated with its MJO skill, two metrics, including the low-level relative humidity difference between high and low rain events and seasonal mean gross moist stability, exhibit statistically significant correlations with the MJO performance. It is further indicated that increased cloud-radiative feedback tends to be associated with reduced amplitude of intraseasonal variability, which is incompatible with the radiative instability theory previously proposed for the MJO. Results in this study confirm that inclusion of air-sea interaction can lead to significant improvement in simulating the MJO.

Vertical structure and physical processes of the Madden-Julian oscillation: Biases and uncertainties at short range

An analysis of diabatic heating and moistening processes from 12-36 hour lead time forecasts from 12 Global Circulation Models are presented as part of the "Vertical structure and physical processes of the Madden-Julian Oscillation (MJO)" project. A lead time of 12-36 hours is chosen to constrain the large scale dynamics and thermodynamics to be close to observations while avoiding being too close to the initial spin-up for the models as they adjust to being driven from the YOTC analysis. A comparison of the vertical velocity and rainfall with the observations and YOTC analysis suggests that the phases of convection associated with the MJO are constrained in most models at this lead time although the rainfall in the suppressed phase is typically overestimated. Although the large scale dynamics is reasonably constrained, moistening and heating profiles have large inter-model spread. In particular, there are large spreads in convective heating and moistening at mid-levels during the transition to active convection. Radiative heating and cloud parameters have the largest relative spread across models at upper levels during the active phase. A detailed analysis of time step behaviour shows that some models show strong intermittency in rainfall and differences in the precipitation and dynamics relationship between models. The wealth of model outputs archived during this project is a very valuable resource for model developers beyond the study of the MJO. In addition, the findings of this study can inform the design of process model experiments, and inform the priorities for field experiments and future observing systems.

Temperature and oxygen dependent metabolite utilization by Salmonella enterica Serovars Derby and Mbandaka

Salmonella enterica is a zoonotic pathogen of clinical and veterinary significance, with over 2500 serovars. In previous work we compared two serovars displaying host associations inferred from isolation statistics. Here, to validate genome sequence data and to expand on the role of environmental metabolite constitution in host range determination we use a phenotypic microarray approach to assess the ability of these serovars to metabolise ~500 substrates at 25°C with oxygen (aerobic conditions) to represent the ex vivo environment and at 37°C with and without oxygen (aerobic/anaerobic conditions) to represent the in vivo environment. A total of 26 substrates elicited a significant difference in the rate of metabolism of which only one, D-galactonic acid-g-lactone, could be explained by the presence (S. Mbandaka) or the absence (S. Derby) of metabolic genes. We find that S. Mbandaka respires more efficiently at ambient temperatures and under aerobic conditions on 18 substrates including: glucosominic acid, saccharic acid, trehalose, fumaric acid, maltotriose, N-acetyl-D-glucosamine, N-acetyl-beta-D-mannosamine, fucose, L-serine and dihydroxy-acetone; whereas S. Derby is more metabolically competent anaerobically at 37°C for dipeptides, glutamine-glutamine, alanine-lysine, asparagine-glutamine and nitrogen sources glycine and nitrite. We conclude that the specific phenotype cannot be reliably predicted from the presence of metabolic genes directly relating to the metabolic pathways under study.

Parametrizing the horizontal inhomogeneity of ice water content using CloudSat data products

In order to calculate unbiased microphysical and radiative quantities in the presence of a cloud, it is necessary to know not only the mean water content but also the distribution of this water content. This article describes a study of the in-cloud horizontal inhomogeneity of ice water content, based on CloudSat data. In particular, by focusing on the relations with variables that are already available in general circulation models (GCMs), a parametrization of inhomogeneity that is suitable for inclusion in GCM simulations is developed. Inhomogeneity is defined in terms of the fractional standard deviation (FSD), which is given by the standard deviation divided by the mean. The FSD of ice water content is found to increase with the horizontal scale over which it is calculated and also with the thickness of the layer. The connection to cloud fraction is more complicated; for small cloud fractions FSD increases as cloud fraction increases while FSD decreases sharply for overcast scenes. The relations to horizontal scale, layer thickness and cloud fraction are parametrized in a relatively simple equation. The performance of this parametrization is tested on an independent set of CloudSat data. The parametrization is shown to be a significant improvement on the assumption of a single-valued global FSD

Pharmacological actions of nobiletin in the modulation of platelet function

Background and Purpose The discovery that flavonoids are capable of inhibiting platelet function has led to their investigation as potential antithrombotic agents. However, despite the range of studies on the antiplatelet properties of flavonoids, little is known about the mechanisms by which flavonoids inhibit platelet function. In this study, we aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin in the modulation of platelet function. Experimental Approach The ability of nobiletin to modulate platelet function was explored by using a range of in vitro and in vivo experimental approaches. Aggregation, dense granule secretion and spreading assays were performed using washed platelets. The fibrinogen binding, α-granule secretion and calcium mobilisation assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice. Key Results Nobiletin was shown to supress a range of well-established activatory mechanisms, including platelet aggregation, granule secretion, integrin modulation, calcium mobilisation and thrombus formation. Nobiletin was shown to extend bleeding time in mice and reduce the phosphorylation of Akt and PLCγ2 within the collagen receptor (GPVI) - stimulated pathway, in addition to increasing the levels of cGMP and phosphorylation of VASP, a protein whose activity is associated with inhibitory cyclic nucleotide signalling. Conclusions and Implications This study provides insight into the underlying molecular mechanisms through which nobiletin modulates haemostasis and thrombus formation. Therefore nobiletin may represent a potential antithrombotic agent of dietary origins.