Effects of fermentation products of pro- and prebiotics on trans-epithelial electrical resistance in an in vitro model of the colon

Evidence from in vivo and in vitro studies suggests that the consumption of pro- and prebiotics may inhibit colon carcinogenesis; however, the mechanisms involved have, thus far, proved elusive. There are some indications from animal studies that the effects are being exerted during the promotion stage of carcinogenesis. One feature of the promotion stage of colorectal cancer is the disruption of tight junctions, leading to a loss of integrity across the intestinal barrier. We have used the Caco-2 human adenocarcinoma cell line as a model for the intestinal epithelia. Trans-epithelial electrical resistance measurements indicate Caco-2 monolayer integrity, and we recorded changes to this integrity following exposure to the fermentation products of selected probiotics and prebiotics, in the form of nondigestible oligosaccharides (NDOs). Our results indicate that NDOs themselves exert varying, but generally minor, effects upon the strength of the tight junctions, whereas the fermentation products of probiotics and NDOs tend to raise tight junction integrity above that of the controls. This effect was bacterial species and oligosaccharide specific. Bifidobacterium Bb 12 was particularly effective, as were the fermentation products of Raftiline and Raftilose. We further investigated the ability of Raftilose fermentations to protect against the negative effects of deoxycholic acid (DCA) upon tight junction integrity. We found protection to be species dependent and dependent upon the presence of the fermentation products in the media at the same time as or after exposure to the DCA. Results suggest that the Raftilose fermentation products may prevent disruption of the intestinal epithelial barrier function during damage by tumor promoters.

The link between the Barents Sea and ENSO events simulated by NEMO model

An analysis of observational data in the Barents Sea along a meridian at 33°30' E between 70°30' and 72°30' N has reported a negative correlation between El Niño/La Niña Southern Oscillation (ENSO) events and water temperature in the top 200 m: the temperature drops about 0.5 °C during warm ENSO events while during cold ENSO events the top 200 m layer of the Barents Sea is warmer. Results from 1 and 1/4-degree global NEMO models show a similar response for the whole Barents Sea. During the strong warm ENSO event in 1997–1998 an anomalous anticyclonic atmospheric circulation over the Barents Sea enhances heat loses, as well as substantially influencing the Barents Sea inflow from the North Atlantic, via changes in ocean currents. Under normal conditions along the Scandinavian peninsula there is a warm current entering the Barents Sea from the North Atlantic, however after the 1997–1998 event this current is weakened. During 1997–1998 the model annual mean temperature in the Barents Sea is decreased by about 0.8 °C, also resulting in a higher sea ice volume. In contrast during the cold ENSO events in 1999–2000 and 2007–2008, the model shows a lower sea ice volume, and higher annual mean temperatures in the upper layer of the Barents Sea of about 0.7 °C. An analysis of model data shows that the strength of the Atlantic inflow in the Barents Sea is the main cause of heat content variability, and is forced by changing pressure and winds in the North Atlantic. However, surface heat-exchange with the atmosphere provides the means by which the Barents sea heat budget relaxes to normal in the subsequent year after the ENSO events.

The variant rpoS allele of S-enteritidis strain 27655R does not affect virulence in a chick model nor constitutive curliation but does generate a cold-sensitive phenotype

Adherence of pathogenic Escherichia coli and Salmonella spp. to host cells is in part mediated by curli fimbriae which, along with other virulence determinants, are positively regulated by RpoS. Interested in the role and regulation of curli (SEF17) fimbriae of Salmonella enteritidis in poultry infection, we tested the virulence of naturally occurring S. enteritidis PT4 strains 27655R and 27655S which displayed constitutive and null expression of curli (SEF17) fimbriae, respectively, in a chick invasion assay and analysed their rpoS alleles. Both strains were shown to be equally invasive and as invasive as a wild-type phage type 4 strain and an isogenic derivative defective for the elaboration of curli. We showed that the rpoS allele of 27655S was intact even though this strain was non-curliated and we confirmed that a S. enteritidis rpoS::str(r) null mutant was unable to express curli, as anticipated. Strain 27655R, constitutively curliated, possessed a frameshift mutation at position 697 of the rpoS coding sequence which resulted in a truncated product and remained curliated even when transduced to rpoS::str(r). Additionally, rpoS mutants are known to be cold-sensitive, a phenotype confirmed for strain 27655R. Collectively, these data indicated that curliation was not a significant factor for pathogenesis of S. enteritidis in this model and that curliation of strains 27655R and 27655S was independent of RpoS. Significantly, strain 27655R possessed a defective rpoS allele and remained virulent. Here was evidence that supported the concept that different naturally occurring rpoS alleles may generate varying virulence phenotypic traits. (C) 1998 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.

Sensitivity of an Earth system climate model to idealized radiative forcing

We diagnose forcing and climate feedbacks in benchmark sensitivity experiments with the new Met Office Hadley Centre Earth system climate model HadGEM2-ES. To identify the impact of newly-included biogeophysical and chemical processes, results are compared to a parallel set of experiments performed with these processes switched off, and different couplings with the biogeochemistry. In abrupt carbon dioxide quadrupling experiments we find that the inclusion of these processes does not alter the global climate sensitivity of the model. However, when the change in carbon dioxide is uncoupled from the vegetation, or when the model is forced with a non-carbon dioxide forcing – an increase in solar constant – new feedbacks emerge that make the climate system less sensitive to external perturbations. We identify a strong negative dust-vegetation feedback on climate change that is small in standard carbon dioxide sensitivity experiments due to the physiological/fertilization effects of carbon dioxide on plants in this model.

The structure of the optimal income tax in the quasi-linear model

Existing numerical characterizations of the optimal income tax have been based on a limited number of model specifications. As a result, they do not reveal which properties are general. We determine the optimal tax in the quasi-linear model under weaker assumptions than have previously been used; in particular, we remove the assumption of a lower bound on the utility of zero consumption and the need to permit negative labor incomes. A Monte Carlo analysis is then conducted in which economies are selected at random and the optimal tax function constructed. The results show that in a significant proportion of economies the marginal tax rate rises at low skills and falls at high. The average tax rate is equally likely to rise or fall with skill at low skill levels, rises in the majority of cases in the centre of the skill range, and falls at high skills. These results are consistent across all the specifications we test. We then extend the analysis to show that these results also hold for Cobb-Douglas utility.

Updated estimate of aerosol direct radiative forcing from satellite observations and comparison against the Hadley Centre climate model

The fourth assessment report of the Intergovernmental Panel on Climate Change (IPCC) includes a comparison of observation-based and modeling-based estimates of the aerosol direct radiative forcing. In this comparison, satellite-based studies suggest a more negative aerosol direct radiative forcing than modeling studies. A previous satellite-based study, part of the IPCC comparison, uses aerosol optical depths and accumulation-mode fractions retrieved by the Moderate Resolution Imaging Spectroradiometer (MODIS) at collection 4. The latest version of MODIS products, named collection 5, improves aerosol retrievals. Using these products, the direct forcing in the shortwave spectrum defined with respect to present-day natural aerosols is now estimated at −1.30 and −0.65 Wm−2 on a global clear-sky and all-sky average, respectively, for 2002. These values are still significantly more negative than the numbers reported by modeling studies. By accounting for differences between present-day natural and preindustrial aerosol concentrations, sampling biases, and investigating the impact of differences in the zonal distribution of anthropogenic aerosols, good agreement is reached between the direct forcing derived from MODIS and the Hadley Centre climate model HadGEM2-A over clear-sky oceans. Results also suggest that satellite estimates of anthropogenic aerosol optical depth over land should be coupled with a robust validation strategy in order to refine the observation-based estimate of aerosol direct radiative forcing. In addition, the complex problem of deriving the aerosol direct radiative forcing when aerosols are located above cloud still needs to be addressed.

Large-scale surface mass balance of ice sheets from a comprehensive atmospheric model

The surface mass balance for Greenland and Antarctica has been calculated using model data from an AMIP-type experiment for the period 1979–2001 using the ECHAM5 spectral transform model at different triangular truncations. There is a significant reduction in the calculated ablation for the highest model resolution, T319 with an equivalent grid distance of ca 40 km. As a consequence the T319 model has a positive surface mass balance for both ice sheets during the period. For Greenland, the models at lower resolution, T106 and T63, on the other hand, have a much stronger ablation leading to a negative surface mass balance. Calculations have also been undertaken for a climate change experiment using the IPCC scenario A1B, with a T213 resolution (corresponding to a grid distance of some 60 km) and comparing two 30-year periods from the end of the twentieth century and the end of the twenty-first century, respectively. For Greenland there is change of 495 km3/year, going from a positive to a negative surface mass balance corresponding to a sea level rise of 1.4 mm/year. For Antarctica there is an increase in the positive surface mass balance of 285 km3/year corresponding to a sea level fall by 0.8 mm/year. The surface mass balance changes of the two ice sheets lead to a sea level rise of 7 cm at the end of this century compared to end of the twentieth century. Other possible mass losses such as due to changes in the calving of icebergs are not considered. It appears that such changes must increase significantly, and several times more than the surface mass balance changes, if the ice sheets are to make a major contribution to sea level rise this century. The model calculations indicate large inter-annual variations in all relevant parameters making it impossible to identify robust trends from the examined periods at the end of the twentieth century. The calculated inter-annual variations are similar in magnitude to observations. The 30-year trend in SMB at the end of the twenty-first century is significant. The increase in precipitation on the ice sheets follows closely the Clausius-Clapeyron relation and is the main reason for the increase in the surface mass balance of Antarctica. On Greenland precipitation in the form of snow is gradually starting to decrease and cannot compensate for the increase in ablation. Another factor is the proportionally higher temperature increase on Greenland leading to a larger ablation. It follows that a modest increase in temperature will not be sufficient to compensate for the increase in accumulation, but this will change when temperature increases go beyond any critical limit. Calculations show that such a limit for Greenland might well be passed during this century. For Antarctica this will take much longer and probably well into following centuries.

Is optical imaging spectroscopy a viable measurement technique for the investigation of the negative BOLD phenomenon? A concurrent optical imaging spectroscopy and fMRI study at high field (7T)

Traditionally functional magnetic resonance imaging (fMRI) has been used to map activity in the human brain by measuring increases in the Blood Oxygenation Level Dependent (BOLD) signal. Often accompanying positive BOLD fMRI signal changes are sustained negative signal changes. Previous studies investigating the neurovascular coupling mechanisms of the negative BOLD phenomenon have used concurrent 2D-optical imaging spectroscopy (2D-OIS) and electrophysiology (Boorman et al., 2010). These experiments suggested that the negative BOLD signal in response to whisker stimulation was a result of an increase in deoxy-haemoglobin and reduced multi-unit activity in the deep cortical layers. However, Boorman et al. (2010) did not measure the BOLD and haemodynamic response concurrently and so could not quantitatively compare either the spatial maps or the 2D-OIS and fMRI time series directly. Furthermore their study utilised a homogeneous tissue model in which is predominantly sensitive to haemodynamic changes in more superficial layers. Here we test whether the 2D-OIS technique is appropriate for studies of negative BOLD. We used concurrent fMRI with 2D-OIS techniques for the investigation of the haemodynamics underlying the negative BOLD at 7 Tesla. We investigated whether optical methods could be used to accurately map and measure the negative BOLD phenomenon by using 2D-OIS haemodynamic data to derive predictions from a biophysical model of BOLD signal changes. We showed that despite the deep cortical origin of the negative BOLD response, if an appropriate heterogeneous tissue model is used in the spectroscopic analysis then 2D-OIS can be used to investigate the negative BOLD phenomenon.

Proactive R&D management and firm growth: a punctuated equilibrium model

The external environment is characterized by periods of relative stability interspersed with periods of extreme change, implying that high performing firms must practice exploration and exploitation in order to survive and thrive. In this paper, we posit that R&D expenditure volatility indicates the presence of proactive R&D management, and is evidence of a firm moving from exploitation to exploration over time. This is consistent with a punctuated equilibrium model of R&D investment where shocks are induced by reactions to external turbulence. Using an unbalanced panel of almost 11,000 firm-years from 1997 to 2006, we show that greater fluctuations in the firm's R&D expenditure over time are associated with higher firm growth. Developing a contextual view of the relationship between R&D expenditure volatility and firm growth, we find that this relationship is weaker among firms with higher levels of corporate diversification and negative among smaller firms and those in slow clockspeed industries.

Analysis of the seasonal cycle within the first international urban land-surface model comparison

A number of urban land-surface models have been developed in recent years to satisfy the growing requirements for urban weather and climate interactions and prediction. These models vary considerably in their complexity and the processes that they represent. Although the models have been evaluated, the observational datasets have typically been of short duration and so are not suitable to assess the performance over the seasonal cycle. The First International Urban Land-Surface Model comparison used an observational dataset that spanned a period greater than a year, which enables an analysis over the seasonal cycle, whilst the variety of models that took part in the comparison allows the analysis to include a full range of model complexity. The results show that, in general, urban models do capture the seasonal cycle for each of the surface fluxes, but have larger errors in the summer months than in the winter. The net all-wave radiation has the smallest errors at all times of the year but with a negative bias. The latent heat flux and the net storage heat flux are also underestimated, whereas the sensible heat flux generally has a positive bias throughout the seasonal cycle. A representation of vegetation is a necessary, but not sufficient, condition for modelling the latent heat flux and associated sensible heat flux at all times of the year. Models that include a temporal variation in anthropogenic heat flux show some increased skill in the sensible heat flux at night during the winter, although their daytime values are consistently overestimated at all times of the year. Models that use the net all-wave radiation to determine the net storage heat flux have the best agreement with observed values of this flux during the daytime in summer, but perform worse during the winter months. The latter could result from a bias of summer periods in the observational datasets used to derive the relations with net all-wave radiation. Apart from these models, all of the other model categories considered in the analysis result in a mean net storage heat flux that is close to zero throughout the seasonal cycle, which is not seen in the observations. Models with a simple treatment of the physical processes generally perform at least as well as models with greater complexity.

Local and average structure in zinc cyanide: towards an understanding of the atomistic origin of negative thermal expansion

Neutron diffraction at 11.4 and 295 K and solid-state 67Zn NMR are used to determine both the local and average structures in the disordered, negative thermal expansion (NTE) material, Zn(CN)2. Solid-state NMR not only confirms that there is head-to-tail disorder of the C≡N groups present in the solid, but yields information about the relative abundances of the different Zn(CN)4-n(NC)n tetrahedral species, which do not follow a simple binomial distribution. The Zn(CN)4 and Zn(NC)4 species occur with much lower probabilities than are predicted by binomial theory, supporting the conclusion that they are of higher energy than the other local arrangements. The lowest energy arrangement is Zn(CN)2(NC)2. The use of total neutron diffraction at 11.4 K, with analysis of both the Bragg diffraction and the derived total correlation function, yields the first experimental determination of the individual Zn−N and Zn−C bond lengths as 1.969(2) and 2.030(2) Å, respectively. The very small difference in bond lengths, of ~0.06 Å, means that it is impossible to obtain these bond lengths using Bragg diffraction in isolation. Total neutron diffraction also provides information on both the average and local atomic displacements responsible for NTE in Zn(CN)2. The principal motions giving rise to NTE are shown to be those in which the carbon and nitrogen atoms within individual Zn−C≡N−Zn linkages are displaced to the same side of the Zn···Zn axis. Displacements of the carbon and nitrogen atoms to opposite sides of the Zn···Zn axis, suggested previously in X-ray studies as being responsible for NTE behavior, in fact make negligible contribution at temperatures up to 295 K.

Aerosol indirect effects – general circulation model intercomparison and evaluation with satellite data

Aerosol indirect effects continue to constitute one of the most important uncertainties for anthropogenic climate perturbations. Within the international AEROCOM initiative, the representation of aerosol-cloud-radiation interactions in ten different general circulation models (GCMs) is evaluated using three satellite datasets. The focus is on stratiform liquid water clouds since most GCMs do not include ice nucleation effects, and none of the model explicitly parameterises aerosol effects on convective clouds. We compute statistical relationships between aerosol optical depth (τa) and various cloud and radiation quantities in a manner that is consistent between the models and the satellite data. It is found that the model-simulated influence of aerosols on cloud droplet number concentration (Nd ) compares relatively well to the satellite data at least over the ocean. The relationship between �a and liquid water path is simulated much too strongly by the models. This suggests that the implementation of the second aerosol indirect effect mainly in terms of an autoconversion parameterisation has to be revisited in the GCMs. A positive relationship between total cloud fraction (fcld) and �a as found in the satellite data is simulated by the majority of the models, albeit less strongly than that in the satellite data in most of them. In a discussion of the hypotheses proposed in the literature to explain the satellite-derived strong fcld–�a relationship, our results indicate that none can be identified as a unique explanation. Relationships similar to the ones found in satellite data between �a and cloud top temperature or outgoing long-wave radiation (OLR) are simulated by only a few GCMs. The GCMs that simulate a negative OLR - �a relationship show a strong positive correlation between �a and fcld. The short-wave total aerosol radiative forcing as simulated by the GCMs is strongly influenced by the simulated anthropogenic fraction of �a, and parameterisation assumptions such as a lower bound on Nd . Nevertheless, the strengths of the statistical relationships are good predictors for the aerosol forcings in the models. An estimate of the total short-wave aerosol forcing inferred from the combination of these predictors for the modelled forcings with the satellite-derived statistical relationships yields a global annual mean value of −1.5±0.5Wm−2. In an alternative approach, the radiative flux perturbation due to anthropogenic aerosols can be broken down into a component over the cloud-free portion of the globe (approximately the aerosol direct effect) and a component over the cloudy portion of the globe (approximately the aerosol indirect effect). An estimate obtained by scaling these simulated clearand cloudy-sky forcings with estimates of anthropogenic �a and satellite-retrieved Nd–�a regression slopes, respectively, yields a global, annual-mean aerosol direct effect estimate of −0.4±0.2Wm−2 and a cloudy-sky (aerosol indirect effect) estimate of −0.7±0.5Wm−2, with a total estimate of −1.2±0.4Wm−2.

Estimates of global multicomponent aerosol optical depth and direct radiative perturbation in the Laboratoire de Météorologie Dynamique general circulation model

The global cycle of multicomponent aerosols including sulfate, black carbon (BC),organic matter (OM), mineral dust, and sea salt is simulated in the Laboratoire de Me´te´orologie Dynamique general circulation model (LMDZT GCM). The seasonal open biomass burning emissions for simulation years 2000–2001 are scaled from climatological emissions in proportion to satellite detected fire counts. The emissions of dust and sea salt are parameterized online in the model. The comparison of model-predicted monthly mean aerosol optical depth (AOD) at 500 nm with Aerosol Robotic Network (AERONET) shows good agreement with a correlation coefficient of 0.57(N = 1324) and 76% of data points falling within a factor of 2 deviation. The correlation coefficient for daily mean values drops to 0.49 (N = 23,680). The absorption AOD (ta at 670 nm) estimated in the model is poorly correlated with measurements (r = 0.27, N = 349). It is biased low by 24% as compared to AERONET. The model reproduces the prominent features in the monthly mean AOD retrievals from Moderate Resolution Imaging Spectroradiometer (MODIS). The agreement between the model and MODIS is better over source and outflow regions (i.e., within a factor of 2).There is an underestimation of the model by up to a factor of 3 to 5 over some remote oceans. The largest contribution to global annual average AOD (0.12 at 550 nm) is from sulfate (0.043 or 35%), followed by sea salt (0.027 or 23%), dust (0.026 or 22%),OM (0.021 or 17%), and BC (0.004 or 3%). The atmospheric aerosol absorption is predominantly contributed by BC and is about 3% of the total AOD. The globally and annually averaged shortwave (SW) direct aerosol radiative perturbation (DARP) in clear-sky conditions is �2.17 Wm�2 and is about a factor of 2 larger than in all-sky conditions (�1.04 Wm�2). The net DARP (SW + LW) by all aerosols is �1.46 and �0.59 Wm�2 in clear- and all-sky conditions, respectively. Use of realistic, less absorbing in SW, optical properties for dust results in negative forcing over the dust-dominated regions.

A mathematical model of the sterol regulatory element binding protein 2 cholesterol biosynthesis pathway

Cholesterol is one of the key constituents for maintaining the cellular membrane and thus the integrity of the cell itself. In contrast high levels of cholesterol in the blood are known to be a major risk factor in the development of cardiovascular disease. We formulate a deterministic nonlinear ordinary differential equation model of the sterol regulatory element binding protein 2 (SREBP-2) cholesterol genetic regulatory pathway in an hepatocyte. The mathematical model includes a description of genetic transcription by SREBP-2 which is subsequently translated to mRNA leading to the formation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a main precursor of cholesterol synthesis. Cholesterol synthesis subsequently leads to the regulation of SREBP-2 via a negative feedback formulation. Parameterised with data from the literature, the model is used to understand how SREBP-2 transcription and regulation affects cellular cholesterol concentration. Model stability analysis shows that the only positive steady-state of the system exhibits purely oscillatory, damped oscillatory or monotic behaviour under certain parameter conditions. In light of our findings we postulate how cholesterol homestasis is maintained within the cell and the advantages of our model formulation are discussed with respect to other models of genetic regulation within the literature.

Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for miRNAs in immediate early gene regulation

Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation. Introduction of an autorepressive loop for Atf3 tuned down its expression and inhibition of Egr1 was lost, demonstrating that negative feedback regulation of Atf3 by Atf3 itself is implausible in this context. Experimentally, signals downstream from ERK1/2 suppress Atf3 expression. Mathematical modelling indicated that this cannot occur by phosphorylation of pre-existing inhibitory transcriptional regulators because the time delay is too short. De novo synthesis of an inhibitory transcription factor (ITF) with a high affinity for the Atf3 promoter could suppress Atf3 expression, but (as with the Atf3 autorepression loop) inhibition of Egr1 was lost. Developing the model to include newly-synthesised miRNAs very efficiently terminated Atf3 protein expression and, with a 4-fold increase in the rate of degradation of mRNA from the mRNA/miRNA complex, profiles for Atf3 mRNA, Atf3 protein and Egr1 mRNA approximated to the experimental data. Combining the ITF model with that of the miRNA did not improve the profiles suggesting that miRNAs are likely to play a dominant role in switching off Atf3 expression post-induction.