Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

Conditional mean functions of non-linear models of US output

We compare a number of models of post War US output growth in terms of the degree and pattern of non-linearity they impart to the conditional mean, where we condition on either the previous period's growth rate, or the previous two periods' growth rates. The conditional means are estimated non-parametrically using a nearest-neighbour technique on data simulated from the models. In this way, we condense the complex, dynamic, responses that may be present in to graphical displays of the implied conditional mean.

Models of human behaviour in social-ecological systems

Environmental change research often relies on simplistic, static models of human behaviour in social-ecological systems. This limits understanding of how social-ecological change occurs. Integrative, process-based behavioural models, which include feedbacks between action, and social and ecological system structures and dynamics, can inform dynamic policy assessment in which decision making is internalised in the model. These models focus on dynamics rather than states. They stimulate new questions and foster interdisciplinarity between and within the natural and social sciences.

Influence of mass diffusion in sea ice dynamical models

The mixing of floes of different thickness caused by repeated deformation of the ice cover is modeled as diffusion, and the mass balance equation for sea ice accounting for mass diffusion is developed. The effect of deformational diffusion on the ice thickness balance is shown to reach 1% of the divergence effect, which describes ridging and lead formation. This means that with the same accuracy the mass balance equation can be written in terms of mean velocity rather than mean mass-weighted velocity, which one should correctly use for a multicomponent fluid such as sea ice with components identified by floe thickness. Mixing (diffusion) of sea ice also occurs because of turbulent variations in wind and ocean drags that are unresolved in models. Estimates of the importance of turbulent mass diffusion on the dynamic redistribution of ice thickness are determined using empirical data for the turbulent diffusivity. For long-time-scale prediction (≫5 days), where unresolved atmospheric motion may have a length scale on the order of the Arctic basin and the time scale is larger than the synoptic time scale of atmospheric events, turbulent mass diffusion can exceed 10% of the divergence effect. However, for short-time-scale prediction, for example, 5 days, the unresolved scales are on the order of 100 km, and turbulent diffusion is about 0.1% of the divergence effect. Because inertial effects are small in the dynamics of the sea ice pack, diffusive momentum transfer can be disregarded.

A comprehensive benchmarking system for evaluating global vegetation models

We present a benchmark system for global vegetation models. This system provides a quantitative evaluation of multiple simulated vegetation properties, including primary production; seasonal net ecosystem production; vegetation cover; composition and height; fire regime; and runoff. The benchmarks are derived from remotely sensed gridded datasets and site-based observations. The datasets allow comparisons of annual average conditions and seasonal and inter-annual variability, and they allow the impact of spatial and temporal biases in means and variability to be assessed separately. Specifically designed metrics quantify model performance for each process, and are compared to scores based on the temporal or spatial mean value of the observations and a "random" model produced by bootstrap resampling of the observations. The benchmark system is applied to three models: a simple light-use efficiency and water-balance model (the Simple Diagnostic Biosphere Model: SDBM), the Lund-Potsdam-Jena (LPJ) and Land Processes and eXchanges (LPX) dynamic global vegetation models (DGVMs). In general, the SDBM performs better than either of the DGVMs. It reproduces independent measurements of net primary production (NPP) but underestimates the amplitude of the observed CO2 seasonal cycle. The two DGVMs show little difference for most benchmarks (including the inter-annual variability in the growth rate and seasonal cycle of atmospheric CO2), but LPX represents burnt fraction demonstrably more accurately. Benchmarking also identified several weaknesses common to both DGVMs. The benchmarking system provides a quantitative approach for evaluating how adequately processes are represented in a model, identifying errors and biases, tracking improvements in performance through model development, and discriminating among models. Adoption of such a system would do much to improve confidence in terrestrial model predictions of climate change impacts and feedbacks.

How well can we simulate past climates? Evaluating the models using global palaeoenvironmental datasets.

Global syntheses of palaeoenvironmental data are required to test climate models under conditions different from the present. Data sets for this purpose contain data from spatially extensive networks of sites. The data are either directly comparable to model output or readily interpretable in terms of modelled climate variables. Data sets must contain sufficient documentation to distinguish between raw (primary) and interpreted (secondary, tertiary) data, to evaluate the assumptions involved in interpretation of the data, to exercise quality control, and to select data appropriate for specific goals. Four data bases for the Late Quaternary, documenting changes in lake levels since 30 kyr BP (the Global Lake Status Data Base), vegetation distribution at 18 kyr and 6 kyr BP (BIOME 6000), aeolian accumulation rates during the last glacial-interglacial cycle (DIRTMAP), and tropical terrestrial climates at the Last Glacial Maximum (the LGM Tropical Terrestrial Data Synthesis) are summarised. Each has been used to evaluate simulations of Last Glacial Maximum (LGM: 21 calendar kyr BP) and/or mid-Holocene (6 cal. kyr BP) environments. Comparisons have demonstrated that changes in radiative forcing and orography due to orbital and ice-sheet variations explain the first-order, broad-scale (in space and time) features of global climate change since the LGM. However, atmospheric models forced by 6 cal. kyr BP orbital changes with unchanged surface conditions fail to capture quantitative aspects of the observed climate, including the greatly increased magnitude and northward shift of the African monsoon during the early to mid-Holocene. Similarly, comparisons with palaeoenvironmental datasets show that atmospheric models have underestimated the magnitude of cooling and drying of much of the land surface at the LGM. The inclusion of feedbacks due to changes in ocean- and land-surface conditions at both times, and atmospheric dust loading at the LGM, appears to be required in order to produce a better simulation of these past climates. The development of Earth system models incorporating the dynamic interactions among ocean, atmosphere, and vegetation is therefore mandated by Quaternary science results as well as climatological principles. For greatest scientific benefit, this development must be paralleled by continued advances in palaeodata analysis and synthesis, which in turn will help to define questions that call for new focused data collection efforts.

Calibration of structure in a distributed forecasting model for a semiarid flash flood: dynamic surface storage and channel roughness

Flash floods pose a significant danger for life and property. Unfortunately, in arid and semiarid environment the runoff generation shows a complex non-linear behavior with a strong spatial and temporal non-uniformity. As a result, the predictions made by physically-based simulations in semiarid areas are subject to great uncertainty, and a failure in the predictive behavior of existing models is common. Thus better descriptions of physical processes at the watershed scale need to be incorporated into the hydrological model structures. For example, terrain relief has been systematically considered static in flood modelling at the watershed scale. Here, we show that the integrated effect of small distributed relief variations originated through concurrent hydrological processes within a storm event was significant on the watershed scale hydrograph. We model these observations by introducing dynamic formulations of two relief-related parameters at diverse scales: maximum depression storage, and roughness coefficient in channels. In the final (a posteriori) model structure these parameters are allowed to be both time-constant or time-varying. The case under study is a convective storm in a semiarid Mediterranean watershed with ephemeral channels and high agricultural pressures (the Rambla del Albujón watershed; 556 km 2 ), which showed a complex multi-peak response. First, to obtain quasi-sensible simulations in the (a priori) model with time-constant relief-related parameters, a spatially distributed parameterization was strictly required. Second, a generalized likelihood uncertainty estimation (GLUE) inference applied to the improved model structure, and conditioned to observed nested hydrographs, showed that accounting for dynamic relief-related parameters led to improved simulations. The discussion is finally broadened by considering the use of the calibrated model both to analyze the sensitivity of the watershed to storm motion and to attempt the flood forecasting of a stratiform event with highly different behavior.

Comparing projections of future changes in runoff from hydrological and biome models in ISI-MIP

Future changes in runoff can have important implications for water resources and flooding. In this study, runoff projections from ISI-MIP (Inter-sectoral Impact Model Inter-comparison Project) simulations forced with HadGEM2-ES bias-corrected climate data under the Representative Concentration Pathway 8.5 have been analysed for differences between impact models. Projections of change from a baseline period (1981-2010) to the future (2070-2099) from 12 impacts models which contributed to the hydrological and biomes sectors of ISI-MIP were studied. The biome models differed from the hydrological models by the inclusion of CO2 impacts and most also included a dynamic vegetation distribution. The biome and hydrological models agreed on the sign of runoff change for most regions of the world. However, in West Africa, the hydrological models projected drying, and the biome models a moistening. The biome models tended to produce larger increases and smaller decreases in regionally averaged runoff than the hydrological models, although there is large inter-model spread. The timing of runoff change was similar, but there were differences in magnitude, particularly at peak runoff. The impact of vegetation distribution change was much smaller than the projected change over time, while elevated CO2 had an effect as large as the magnitude of change over time projected by some models in some regions. The effect of CO2 on runoff was not consistent across the models, with two models showing increases and two decreases. There was also more spread in projections from the runs with elevated CO2 than with constant CO2. The biome models which gave increased runoff from elevated CO2 were also those which differed most from the hydrological models. Spatially, regions with most difference between model types tended to be projected to have most effect from elevated CO2, and seasonal differences were also similar, so elevated CO2 can partly explain the differences between hydrological and biome model runoff change projections. Therefore, this shows that a range of impact models should be considered to give the full range of uncertainty in impacts studies.

An evaluation of decadal probability forecasts from state-of-the-art climate models

While state-of-the-art models of Earth's climate system have improved tremendously over the last 20 years, nontrivial structural flaws still hinder their ability to forecast the decadal dynamics of the Earth system realistically. Contrasting the skill of these models not only with each other but also with empirical models can reveal the space and time scales on which simulation models exploit their physical basis effectively and quantify their ability to add information to operational forecasts. The skill of decadal probabilistic hindcasts for annual global-mean and regional-mean temperatures from the EU Ensemble-Based Predictions of Climate Changes and Their Impacts (ENSEMBLES) project is contrasted with several empirical models. Both the ENSEMBLES models and a “dynamic climatology” empirical model show probabilistic skill above that of a static climatology for global-mean temperature. The dynamic climatology model, however, often outperforms the ENSEMBLES models. The fact that empirical models display skill similar to that of today's state-of-the-art simulation models suggests that empirical forecasts can improve decadal forecasts for climate services, just as in weather, medium-range, and seasonal forecasting. It is suggested that the direct comparison of simulation models with empirical models becomes a regular component of large model forecast evaluations. Doing so would clarify the extent to which state-of-the-art simulation models provide information beyond that available from simpler empirical models and clarify current limitations in using simulation forecasting for decision support. Ultimately, the skill of simulation models based on physical principles is expected to surpass that of empirical models in a changing climate; their direct comparison provides information on progress toward that goal, which is not available in model–model intercomparisons.

Modeling plant transpiration under limited soil water: comparison of different plant and soil hydraulic parameterizations and preliminary implications for their use in land surface models

Accurate estimates of how soil water stress affects plant transpiration are crucial for reliable land surface model (LSM) predictions. Current LSMs generally use a water stress factor, β, dependent on soil moisture content, θ, that ranges linearly between β = 1 for unstressed vegetation and β = 0 when wilting point is reached. This paper explores the feasibility of replacing the current approach with equations that use soil water potential as their independent variable, or with a set of equations that involve hydraulic and chemical signaling, thereby ensuring feedbacks between the entire soil–root–xylem–leaf system. A comparison with the original linear θ-based water stress parameterization, and with its improved curvi-linear version, was conducted. Assessment of model suitability was focused on their ability to simulate the correct (as derived from experimental data) curve shape of relative transpiration versus fraction of transpirable soil water. We used model sensitivity analyses under progressive soil drying conditions, employing two commonly used approaches to calculate water retention and hydraulic conductivity curves. Furthermore, for each of these hydraulic parameterizations we used two different parameter sets, for 3 soil texture types; a total of 12 soil hydraulic permutations. Results showed that the resulting transpiration reduction functions (TRFs) varied considerably among the models. The fact that soil hydraulic conductivity played a major role in the model that involved hydraulic and chemical signaling led to unrealistic values of β, and hence TRF, for many soil hydraulic parameter sets. However, this model is much better equipped to simulate the behavior of different plant species. Based on these findings, we only recommend implementation of this approach into LSMs if great care with choice of soil hydraulic parameters is taken

Nuclear Factor-kappaB controls the reaggregation of 3D neurosphere cultures in vitro

The approach of reaggregation involves the regeneration and self-renewal of histotypical 3D spheres from isolated tissue kept in suspension culture. Reaggregated spheres can be used as tumour, genetic, biohybrid and neurosphere models. In addition the functional superiority of 3D aggregates over conventional 2D cultures developed the use of neurospheres for brain engineering of CNS diseases. Thus 3D aggregate cultures created enormous interest in mechanisms that regulate the formation of multicellular aggregates in vitro. Here we analyzed mechanisms guiding the development of 3D neurosphere cultures. Adult neural stem cells can be cultured as self-adherent clusters, called neurospheres. Neurospheres are characterised as heterogeneous clusters containing unequal stem cell sub-types. Tumour necrosis factor-alpha (TNF-alpha is one of the crucial inflammatory cytokines with multiple actions on several cell types. TNF-alpha strongly activates the canonical Nuclear Factor Kappa-B (NF- kappaB) pathway. In order to investigate further functions of TNF in neural stem cells (NSCs) we tested the hypothesis that TNF is able to modulate the motility and/or migratory behaviour of SVZ derived adult neural stem cells. We observed a significantly faster sphere formation in TNF treated cultures than in untreated controls. The very fast aggregation of isolated NSCs (<2h) is a commonly observed phenomenon, though the mechanisms of 3D neurosphere formation remain largely unclear. Here we demonstrate for the first time, increased aggregation and enhanced motility of isolated NSCs in response to the TNF-stimulus. Moreover, this phenomenon is largely dependent on activated transcription factor NF-kappaB. Both, the pharmacological blockade of NF-kappaB pathway by pyrrolidine dithiocarbamate (PDTC) or Bay11-7082 and genetic blockade by expression of a transdominant-negative super-repressor IkappaB-AA1 led to decreased aggregation.

ENSO representation in climate models: from CMIP3 to CMIP5

We analyse the ability of CMIP3 and CMIP5 coupled ocean–atmosphere general circulation models (CGCMs) to simulate the tropical Pacific mean state and El Niño-Southern Oscillation (ENSO). The CMIP5 multi-model ensemble displays an encouraging 30 % reduction of the pervasive cold bias in the western Pacific, but no quantum leap in ENSO performance compared to CMIP3. CMIP3 and CMIP5 can thus be considered as one large ensemble (CMIP3 + CMIP5) for multi-model ENSO analysis. The too large diversity in CMIP3 ENSO amplitude is however reduced by a factor of two in CMIP5 and the ENSO life cycle (location of surface temperature anomalies, seasonal phase locking) is modestly improved. Other fundamental ENSO characteristics such as central Pacific precipitation anomalies however remain poorly represented. The sea surface temperature (SST)-latent heat flux feedback is slightly improved in the CMIP5 ensemble but the wind-SST feedback is still underestimated by 20–50 % and the shortwave-SST feedbacks remain underestimated by a factor of two. The improvement in ENSO amplitudes might therefore result from error compensations. The ability of CMIP models to simulate the SST-shortwave feedback, a major source of erroneous ENSO in CGCMs, is further detailed. In observations, this feedback is strongly nonlinear because the real atmosphere switches from subsident (positive feedback) to convective (negative feedback) regimes under the effect of seasonal and interannual variations. Only one-third of CMIP3 + CMIP5 models reproduce this regime shift, with the other models remaining locked in one of the two regimes. The modelled shortwave feedback nonlinearity increases with ENSO amplitude and the amplitude of this feedback in the spring strongly relates with the models ability to simulate ENSO phase locking. In a final stage, a subset of metrics is proposed in order to synthesize the ability of each CMIP3 and CMIP5 models to simulate ENSO main characteristics and key atmospheric feedbacks.

A constrained recursive least squares algorithm for adaptive combination of multiple models

In this paper, we develop a novel constrained recursive least squares algorithm for adaptively combining a set of given multiple models. With data available in an online fashion, the linear combination coefficients of submodels are adapted via the proposed algorithm.We propose to minimize the mean square error with a forgetting factor, and apply the sum to one constraint to the combination parameters. Moreover an l1-norm constraint to the combination parameters is also applied with the aim to achieve sparsity of multiple models so that only a subset of models may be selected into the final model. Then a weighted l2-norm is applied as an approximation to the l1-norm term. As such at each time step, a closed solution of the model combination parameters is available. The contribution of this paper is to derive the proposed constrained recursive least squares algorithm that is computational efficient by exploiting matrix theory. The effectiveness of the approach has been demonstrated using both simulated and real time series examples.