Developmental expression of myostatin in cardiomyocytes and its effect on foetal and neonatal rat cardiomyocyte proliferation

Objectives: Myostatin, a member of the transforming growth factor-beta (TGF-beta) family, plays a key role in skeletal muscle myogenesis by limiting hyperplastic and hypertrophic muscle growth. In cardiac muscle, myostatin has been shown to limit agonist-induced cardiac hypertrophic growth. However, its role in cardiac hyperplastic growth remains undetermined. The aim of this study was to characterise the expression of myostatin in developing myocardium, determine its effect on cardiomyocyte proliferation, and explore the signalling mechanisms affected by myostatin in dividing cardiomyocytes. Methods: We used quantitative PCR and Western blotting to study the expression of myostatin in cardiomyocytes isolated from rat myocardium at different developmental ages. We. determined the effect of recombinant myostatin on proliferation and cell viability in dividing cardiomyocytes in culture. We analysed myostatin's effect on cardiomyocyte cell cycle progression by flow cytometry and used Western blotting to explore the signalling mechanisms involved. Results: Myostatin is expressed differentially in cardiomyocytes during cardiac development such that increasing expression correlated with a low cardiomyocyte proliferation index. Proliferating foetal cardiomyocytes, from embryos at 18 days of gestation, expressed low levels of myostatin mRNA and protein, whereas isolated cardiomyocytes from postnatal day 10 hearts, wherein the majority of cardiomyocytes have lost their ability to proliferate, displayed a 6-fold increase in myostatin expression. Our in vitro studies demonstrated that myostatin inhibited proliferation of dividing foetal and neonatal cardiomyocytes. Flow cytometric analysis showed that this inhibition occurs mainly via a block in the G1-S phase transition of the cardiomyocyte cell cycle. Western blot analysis showed that part of the mechanism underpinning the inhibition of cardiomyocyte proliferation by myostatin involves phosphorylation of SMAD2 and altered expressions of the cell cycle proteins p21 and CDK2. Conclusions: We conclude that myostatin is an inhibitor of cardiomyocyte proliferation with the potential to limit cardiomyocyte hyperplastic growth by altering cardiac cell cycle progression. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All fights reserved.

Sensitivity of large-scale atmospheric analyses to humidity observations and its impact on the global water cycle and tropical and extratropical weather systems in ERA40

Reanalysis data obtained from data assimilation are increasingly used for diagnostic studies of the general circulation of the atmosphere, for the validation of modelling experiments and for estimating energy and water fluxes between the Earth surface and the atmosphere. Because fluxes are not specifically observed, but determined by the data assimilation system, they are not only influenced by the utilized observations but also by model physics and dynamics and by the assimilation method. In order to better understand the relative importance of humidity observations for the determination of the hydrological cycle, in this paper we describe an assimilation experiment using the ERA40 reanalysis system where all humidity data have been excluded from the observational data base. The surprising result is that the model, driven by the time evolution of wind, temperature and surface pressure, is able to almost completely reconstitute the large-scale hydrological cycle of the control assimilation without the use of any humidity data. In addition, analysis of the individual weather systems in the extratropics and tropics using an objective feature tracking analysis indicates that the humidity data have very little impact on these systems. We include a discussion of these results and possible consequences for the way moisture information is assimilated, as well as the potential consequences for the design of observing systems for climate monitoring. It is further suggested, with support from a simple assimilation study with another model, that model physics and dynamics play a decisive role for the hydrological cycle, stressing the need to better understand these aspects of model parametrization. .

Simulation of the diurnal cycle in a climate model and its evaluation using data from Meteosat 7

The representation of the diurnal cycle in the Hadley Centre climate model is evaluated using simulations of the infrared radiances observed by Meteosat 7. In both the window and water vapour channels, the standard version of the model with 19 levels produces a good simulation of the geographical distributions of the mean radiances and of the amplitude of the diurnal cycle. Increasing the vertical resolution to 30 levels leads to further improvements in the mean fields. The timing of the maximum and minimum radiances reveals significant model errors, however, which are sensitive to the frequency with which the radiation scheme is called. In most regions, these errors are consistent with well documented errors in the timing of convective precipitation, which peaks before noon in the model, in contrast to the observed peak in the late afternoon or evening. When the radiation scheme is called every model time step (half an hour), as opposed to every three hours in the standard version, the timing of the minimum radiance is improved for convective regions over central Africa, due to the creation of upper-level layer-cloud by detrainment from the convection scheme, which persists well after the convection itself has dissipated. However, this produces a decoupling between the timing of the diurnal cycles of precipitation and window channel radiance. The possibility is raised that a similar decoupling may occur in reality and the implications of this for the retrieval of the diurnal cycle of precipitation from infrared radiances are discussed.

A new feedback on climate change from the hydrological cycle

An intensification of the hydrological cycle is a likely consequence of global warming. But changes in the hydrological cycle could affect sea-surface temperature by modifying diffusive ocean heat transports. We investigate this mechanism by studying a coupled general circulation model sensitivity experiment in which the hydrological cycle is artificially amplified. We find that the amplified hydrological cycle depresses sea-surface temperature by enhancing ocean heat uptake in low latitudes. We estimate that a 10% increase in the hydrological cycle will contribute a basin-scale sea-surface temperature decrease of around 0.1°C away from high latitudes, with larger decreases locally. We conclude that an intensified hydrological cycle is likely to contribute a weak negative feedback to anthropogenic climate change.

Observations of the diurnal cycle of outgoing longwave radiation from the Geostationary Earth Radiation Budget instrument

The Geostationary Earth Radiation Budget instrument on Meteosat-8, located over Africa, provides unprecedented temporal sampling (~17 minutes) of the broadband emitted thermal and reflected solar radiances. We analyse the diurnal cycle of the outgoing longwave radiation (OLR) fluxes derived from the thermal radiances for July 2006. Principal component (PC) analysis separates the signals of the surface temperature response to solar heating and of the development of convective clouds. The first two PCs explain most of the OLR variations: PC1 (surface heating) explains 82.3% of the total variance and PC2 (cloud development) explains 12.8% of the variance. Convection is initiated preferentially over mountainous regions and the cloud then advects downstream in the ambient flow. Diurnal variations are much weaker over the oceans, but a coherent signal over the Gulf of Guinea suggests that the cloudiness is modulated by the diurnally varying contrast between the Gulf and the adjacent land mass.

Life-cycle simulations of shallow frontal waves and the impact of deformation strain

The life-cycle of shallow frontal waves and the impact of deformation strain on their development is investigated using the idealised version of the Met Office non-hydrostatic Unified Model which includes the same physics and dynamics as the operational forecast model. Frontal wave development occurs in two stages; first, a deformation strain is applied to a front and a positive potential vorticity (PV) strip forms, generated by latent heat release in the frontal updraft; second, as the deformation strain is reduced the PV strip breaks up into individual anomalies. The circulations associated with the PV anomalies cause shallow frontal waves to form. The structure of the simulated frontal waves is consistent with the conceptual model of a frontal cyclone. Deeper frontal waves are simulated if the stability of the atmosphere is reduced. Deformation strain rates of different strengths are applied to the PV strip to determine whether a deformation strain threshold exists above which frontal wave development is suppressed. An objective method of frontal wave activity is defined and frontal wave development was found to be suppressed by deformation strain rates $\ge 0.4\times10^{-5}\mbox{s}^{-1}$. This value compares well with observed deformation strain rate thresholds and the analytical solution for the minimum deformation strain rate needed to suppress barotropic frontal wave development. The deformation strain rate threshold is dependent on the strength of the PV strip with strong PV strips able to overcome stronger deformation strain rates (leading to frontal wave development) than weaker PV strips.

Examination of Relationships between Clear-Sky Longwave Radiation and Aspects of the Atmospheric Hydrological Cycle in Climate Models, Reanalyses, and Observations

Relationships between clear-sky longwave radiation and aspects of the atmospheric hydrological cycle are quantified in models, reanalyses, and observations over the period 1980-2000. The robust sensitivity of clear-sky surface net longwave radiation (SNLc) to column-integrated water vapor (CWV) of 1-1.5 Wm(-2) mm(-1) combined with the positive relationship between CWV and surface temperature (T-s) explains substantial increases in clear-sky longwave radiative cooling of the atmosphere (Q(LWc)) to the surface over the period. Clear-sky outgoing longwave radiation (OLRc) is highly sensitive to changes in aerosol and greenhouse gas concentrations in addition to temperature and humidity. Over tropical ocean regions of mean descent, Q(LWc) increases with T-s at similar to 3.5-5.5 W m(-2) K-1 for reanalyses, estimates derived from satellite data, and models without volcanic forcing included. Increased Q(LWc) with warming across the tropical oceans helps to explain model ensemble mean increases in precipitation of 0.1-0.15 mm day(-1) K-1, which are primarily determined by ascent regions where precipitation increases at the rate expected from the Clausius-Clapeyron equation. The implications for future projections in the atmospheric hydrological cycle are discussed

Developmental changes in presynaptic muscarinic modulation of excitatory and inhibitory neurotransmission in rat piriform cortex in vitro: relevance to epileptiform bursting susceptibility

Suppression of depolarizing postsynaptic potentials and isolated GABA-A receptor-mediated fast inhibitory postsynaptic potentials by the muscarinic acetylcholine receptor agonist, oxotremorine-M (10 microM), was investigated in adult and immature (P14-P30) rat piriform cortical (PC) slices using intracellular recording. Depolarizing postsynaptic potentials evoked by layers II-III stimulation underwent concentration-dependent inhibition in oxotremorine-M that was most likely presynaptic and M2 muscarinic acetylcholine receptor-mediated in immature, but M1-mediated in adult (P40-P80) slices; percentage inhibition was smaller in immature than in adult piriform cortex. In contrast, compared with adults, layer Ia-evoked depolarizing postsynaptic potentials in immature piriform cortex slices in oxotremorine-M, showed a prolonged multiphasic depolarization with superimposed fast transients and spikes, and an increased 'all-or-nothing' character. Isolated N-methyl-d-aspartate receptor-mediated layer Ia depolarizing postsynaptic potentials (although significantly larger in immature slices) were however, unaffected by oxotremorine-M, but blocked by dl-2-amino-5-phosphonovaleric acid. Fast inhibitory postsynaptic potentials evoked by layer Ib or layers II-III-fiber stimulation in immature slices were significantly smaller than in adults, despite similar estimated mean reversal potentials ( approximately -69 and -70 mV respectively). In oxotremorine-M, only layer Ib-fast inhibitory postsynaptic potentials were suppressed; suppression was again most likely presynaptic M2-mediated in immature slices, but M1-mediated in adults. The degree of fast inhibitory postsynaptic potential suppression was however, greater in immature than in adult piriform cortex. Our results demonstrate some important physiological and pharmacological differences between excitatory and inhibitory synaptic systems in adult and immature piriform cortex that could contribute toward the increased susceptibility of this region to muscarinic agonist-induced epileptiform activity in immature brain slices.

On the climate response of the low-latitude Pacific Ocean to changes in the global freshwater cycle

Under global warming, the predicted intensification of the global freshwater cycle will modify the net freshwater flux at the ocean surface. Since the freshwater flux maintains ocean salinity structures, changes to the density-driven ocean circulation are likely. A modified ocean circulation could further alter the climate, potentially allowing rapid changes, as seen in the past. The relevant feedback mechanisms and timescales are poorly understood in detail, however, especially at low latitudes where the effects of salinity are relatively subtle. In an attempt to resolve some of these outstanding issues, we present an investigation of the climate response of the low-latitude Pacific region to changes in freshwater forcing. Initiated from the present-day thermohaline structure, a control run of a coupled ocean-atmosphere general circulation model is compared with a perturbation run in which the net freshwater flux is prescribed to be zero over the ocean. Such an extreme experiment helps to elucidate the general adjustment mechanisms and their timescales. The atmospheric greenhouse gas concentrations are held constant, and we restrict our attention to the adjustment of the upper 1,000 m of the Pacific Ocean between 40°N and 40°S, over 100 years. In the perturbation run, changes to the surface buoyancy, near-surface vertical mixing and mixed-layer depth are established within 1 year. Subsequently, relative to the control run, the surface of the low-latitude Pacific Ocean in the perturbation run warms by an average of 0.6°C, and the interior cools by up to 1.1°C, after a few decades. This vertical re-arrangement of the ocean heat content is shown to be achieved by a gradual shutdown of the heat flux due to isopycnal (i.e. along surfaces of constant density) mixing, the vertical component of which is downwards at low latitudes. This heat transfer depends crucially upon the existence of density-compensating temperature and salinity gradients on isopycnal surfaces. The timescale of the thermal changes in the perturbation run is therefore set by the timescale for the decay of isopycnal salinity gradients in response to the eliminated freshwater forcing, which we demonstrate to be around 10-20 years. Such isopycnal heat flux changes may play a role in the response of the low-latitude climate to a future accelerated freshwater cycle. Specifically, the mechanism appears to represent a weak negative sea surface temperature feedback, which we speculate might partially shield from view the anthropogenically-forced global warming signal at low latitudes. Furthermore, since the surface freshwater flux is shown to play a role in determining the ocean's thermal structure, it follows that evaporation and/or precipitation biases in general circulation models are likely to cause sea surface temperature biases.

Variability in the summer season hydrological cycle over the Atlantic-Europe region 1979-2007

Variability in aspects of the hydrological cycle over the Europe-Atlantic region during the summer season is analysed for the period 1979-2007, using observational estimates, reanalyses and climate model simulations. Warming and moistening trends are evident in observations and models although decadal changes in water vapour are not well represented by reanalyses, including the new European Centre for Medium Range Weather Forecasts (ECMWF) Interim reanalysis. Over the north Atlantic and northern Europe, observed water vapour trends are close to that expected from the temperature trends and Clausius-Clapeyron equation (7% K-1), larger than the model simulations. Precipitation over Europe is dominated by large-scale dynamics with positive phases of the North Atlantic Oscillation coinciding with drier conditions over north Europe and wetter conditions over the Mediterranean region. Evaporation trends over Europe are positive in reanalyses and models, especially for the Mediterranean region (1-3% per decade in reanalyses and climate models). Over the north Atlantic, declining precipitation combined with increased moisture contributed to an apparent rise in water vapour residence time. Maximum precipitation minus evaporation over the north Atlantic occurred during summer 1991, declining thereafter.