Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer

Duchenne muscular dystrophy is a fatal muscle-wasting disorder. Lack of dystrophin compromises the integrity of the sarcolemma and results in myofibers that are highly prone to contraction-induced injury. Recombinant adenoassociated virus (rAAV)-mediated dystrophin gene transfer strategies to muscle for the treatment of Duchenne muscular dystrophy (DMD) have been limited by the small cloning capacity of rAAV vectors and high titers necessary to achieve efficient systemic gene transfer. In this study, we assess the impact of codon optimization on microdystrophin (ΔAB/R3-R18/ΔCT) expression and function in the mdx mouse and compare the function of two different configurations of codon-optimized microdystrophin genes (ΔAB/R3-R18/ΔCT and ΔR4-R23/ΔCT) under the control of a muscle-restrictive promoter (Spc5-12). Codon optimization of microdystrophin significantly increases levels of microdystrophin mRNA and protein after intramuscular and systemic administration of plasmid DNA or rAAV2/8. Physiological assessment demonstrates that codon optimization of ΔAB/R3-R18/ΔCT results in significant improvement in specific force, but does not improve resistance to eccentric contractions compared with noncodon-optimized ΔAB/ R3-R18/ΔCT. However, codon-optimized microdystrophin ΔR4-R23/ΔCT completely restored specific force generation and provided substantial protection from contraction-induced injury. These results demonstrate that codon optimization of microdystrophin under the control of a muscle-specific promoter can significantly improve expression levels such that reduced titers of rAAV vectors will be required for efficient systemic administration.

Influences of increasing temperature on Indian wheat: quantifying limits to predictability

As climate changes, temperatures will play an increasing role in determining crop yield. Both climate model error and lack of constrained physiological thresholds limit the predictability of yield. We used a perturbed-parameter climate model ensemble with two methods of bias-correction as input to a regional-scale wheat simulation model over India to examine future yields. This model configuration accounted for uncertainty in climate, planting date, optimization, temperature-induced changes in development rate and reproduction. It also accounts for lethal temperatures, which have been somewhat neglected to date. Using uncertainty decomposition, we found that fractional uncertainty due to temperature-driven processes in the crop model was on average larger than climate model uncertainty (0.56 versus 0.44), and that the crop model uncertainty is dominated by crop development. Simulations with the raw compared to the bias-corrected climate data did not agree on the impact on future wheat yield, nor its geographical distribution. However the method of bias-correction was not an important source of uncertainty. We conclude that bias-correction of climate model data and improved constraints on especially crop development are critical for robust impact predictions.

Trade-offs and responsiveness of the single-layer urban canopy parametrization in WRF: an offline evaluation using the MOSCEM optimization algorithm and field observations

For an increasing number of applications, mesoscale modelling systems now aim to better represent urban areas. The complexity of processes resolved by urban parametrization schemes varies with the application. The concept of fitness-for-purpose is therefore critical for both the choice of parametrizations and the way in which the scheme should be evaluated. A systematic and objective model response analysis procedure (Multiobjective Shuffled Complex Evolution Metropolis (MOSCEM) algorithm) is used to assess the fitness of the single-layer urban canopy parametrization implemented in the Weather Research and Forecasting (WRF) model. The scheme is evaluated regarding its ability to simulate observed surface energy fluxes and the sensitivity to input parameters. Recent amendments are described, focussing on features which improve its applicability to numerical weather prediction, such as a reduced and physically more meaningful list of input parameters. The study shows a high sensitivity of the scheme to parameters characterizing roof properties in contrast to a low response to road-related ones. Problems in partitioning of energy between turbulent sensible and latent heat fluxes are also emphasized. Some initial guidelines to prioritize efforts to obtain urban land-cover class characteristics in WRF are provided. Copyright © 2010 Royal Meteorological Society and Crown Copyright.

Sparse model construction using coordinate descent optimization

We propose a new sparse model construction method aimed at maximizing a model’s generalisation capability for a large class of linear-in-the-parameters models. The coordinate descent optimization algorithm is employed with a modified l1- penalized least squares cost function in order to estimate a single parameter and its regularization parameter simultaneously based on the leave one out mean square error (LOOMSE). Our original contribution is to derive a closed form of optimal LOOMSE regularization parameter for a single term model, for which we show that the LOOMSE can be analytically computed without actually splitting the data set leading to a very simple parameter estimation method. We then integrate the new results within the coordinate descent optimization algorithm to update model parameters one at the time for linear-in-the-parameters models. Consequently a fully automated procedure is achieved without resort to any other validation data set for iterative model evaluation. Illustrative examples are included to demonstrate the effectiveness of the new approaches.

Optimization of a sea ice model using basinwide observations of Arctic sea ice thickness, extent, and velocity

A stand-alone sea ice model is tuned and validated using satellite-derived, basinwide observations of sea ice thickness, extent, and velocity from the years 1993 to 2001. This is the first time that basin-scale measurements of sea ice thickness have been used for this purpose. The model is based on the CICE sea ice model code developed at the Los Alamos National Laboratory, with some minor modifications, and forcing consists of 40-yr ECMWF Re-Analysis (ERA-40) and Polar Exchange at the Sea Surface (POLES) data. Three parameters are varied in the tuning process: Ca, the air–ice drag coefficient; P*, the ice strength parameter; and α, the broadband albedo of cold bare ice, with the aim being to determine the subset of this three-dimensional parameter space that gives the best simultaneous agreement with observations with this forcing set. It is found that observations of sea ice extent and velocity alone are not sufficient to unambiguously tune the model, and that sea ice thickness measurements are necessary to locate a unique subset of parameter space in which simultaneous agreement is achieved with all three observational datasets.

Urban and agricultural soils: conflicts and trade-offs in the optimization of ecosystem services

On-going human population growth and changing patterns of resource consumption are increasing global demand for ecosystem services, many of which are provided by soils. Some of these ecosystem services are linearly related to the surface area of pervious soil, whereas others show non-linear relationships, making ecosystem service optimization a complex task. As limited land availability creates conflicting demands among various types of land use, a central challenge is how to weigh these conflicting interests and how to achieve the best solutions possible from a perspective of sustainable societal development. These conflicting interests become most apparent in soils that are the most heavily used by humans for specific purposes: urban soils used for green spaces, housing, and other infrastructure and agricultural soils for producing food, fibres and biofuels. We argue that, despite their seemingly divergent uses of land, agricultural and urban soils share common features with regards to interactions between ecosystem services, and that the trade-offs associated with decision-making, while scale- and context-dependent, can be surprisingly similar between the two systems. We propose that the trade-offs within land use types and their soil-related ecosystems services are often disproportional, and quantifying these will enable ecologists and soil scientists to help policy makers optimizing management decisions when confronted with demands for multiple services under limited land availability.

Broad range of 2050 warming from an observationally constrained large climate model ensemble

Incomplete understanding of three aspects of the climate system—equilibrium climate sensitivity, rate of ocean heat uptake and historical aerosol forcing—and the physical processes underlying them lead to uncertainties in our assessment of the global-mean temperature evolution in the twenty-first century1,2. Explorations of these uncertainties have so far relied on scaling approaches3,4, large ensembles of simplified climate models1,2, or small ensembles of complex coupled atmosphere–ocean general circulation models5,6 which under-represent uncertainties in key climate system properties derived from independent sources7–9. Here we present results from a multi-thousand-member perturbed-physics ensemble of transient coupled atmosphere–ocean general circulation model simulations. We find that model versions that reproduce observed surface temperature changes over the past 50 years show global-mean temperature increases of 1.4–3 K by 2050, relative to 1961–1990, under a mid-range forcing scenario. This range of warming is broadly consistent with the expert assessment provided by the Intergovernmental Panel on Climate Change Fourth Assessment Report10, but extends towards larger warming than observed in ensemblesof-opportunity5 typically used for climate impact assessments. From our simulations, we conclude that warming by the middle of the twenty-first century that is stronger than earlier estimates is consistent with recent observed temperature changes and a mid-range ‘no mitigation’ scenario for greenhouse-gas emissions.

Towards a typology for constrained climate model forecasts

In recent years several methodologies have been developed to combine and interpret ensembles of climate models with the aim of quantifying uncertainties in climate projections. Constrained climate model forecasts have been generated by combining various choices of metrics used to weight individual ensemble members, with diverse approaches to sampling the ensemble. The forecasts obtained are often significantly different, even when based on the same model output. Therefore, a climate model forecast classification system can serve two roles: to provide a way for forecast producers to self-classify their forecasts; and to provide information on the methodological assumptions underlying the forecast generation and its uncertainty when forecasts are used for impacts studies. In this review we propose a possible classification system based on choices of metrics and sampling strategies. We illustrate the impact of some of the possible choices in the uncertainty quantification of large scale projections of temperature and precipitation changes, and briefly discuss possible connections between climate forecast uncertainty quantification and decision making approaches in the climate change context.

Network optimization for enhanced resilience of urban heat island measurements

The urban heat island is a well-known phenomenon that impacts a wide variety of city operations. With greater availability of cheap meteorological sensors, it is possible to measure the spatial patterns of urban atmospheric characteristics with greater resolution. To develop robust and resilient networks, recognizing sensors may malfunction, it is important to know when measurement points are providing additional information and also the minimum number of sensors needed to provide spatial information for particular applications. Here we consider the example of temperature data, and the urban heat island, through analysis of a network of sensors in the Tokyo metropolitan area (Extended METROS). The effect of reducing observation points from an existing meteorological measurement network is considered, using random sampling and sampling with clustering. The results indicated the sampling with hierarchical clustering can yield similar temperature patterns with up to a 30% reduction in measurement sites in Tokyo. The methods presented have broader utility in evaluating the robustness and resilience of existing urban temperature networks and in how networks can be enhanced by new mobile and open data sources.

Gaussian processes autoencoder for dimensionality reduction

Learning low dimensional manifold from highly nonlinear data of high dimensionality has become increasingly important for discovering intrinsic representation that can be utilized for data visualization and preprocessing. The autoencoder is a powerful dimensionality reduction technique based on minimizing reconstruction error, and it has regained popularity because it has been efficiently used for greedy pretraining of deep neural networks. Compared to Neural Network (NN), the superiority of Gaussian Process (GP) has been shown in model inference, optimization and performance. GP has been successfully applied in nonlinear Dimensionality Reduction (DR) algorithms, such as Gaussian Process Latent Variable Model (GPLVM). In this paper we propose the Gaussian Processes Autoencoder Model (GPAM) for dimensionality reduction by extending the classic NN based autoencoder to GP based autoencoder. More interestingly, the novel model can also be viewed as back constrained GPLVM (BC-GPLVM) where the back constraint smooth function is represented by a GP. Experiments verify the performance of the newly proposed model.

Acceleration and visualization of Dynamic Network Optimization

With the emerging prevalence of smart phones and 4G LTE networks, the demand for faster-better-cheaper mobile services anytime and anywhere is ever growing. The Dynamic Network Optimization (DNO) concept emerged as a solution that optimally and continuously tunes the network settings, in response to varying network conditions and subscriber needs. Yet, the DNO realization is still at infancy, largely hindered by the bottleneck of the lengthy optimization runtime. This paper presents the design and prototype of a novel cloud based parallel solution that further enhances the scalability of our prior work on various parallel solutions that accelerate network optimization algorithms. The solution aims to satisfy the high performance required by DNO, preliminarily on a sub-hourly basis. The paper subsequently visualizes a design and a full cycle of a DNO system. A set of potential solutions to large network and real-time DNO are also proposed. Overall, this work creates a breakthrough towards the realization of DNO.

Distributed parallelization of greedy Mobile Network Optimization algorithms

The Mobile Network Optimization (MNO) technologies have advanced at a tremendous pace in recent years. And the Dynamic Network Optimization (DNO) concept emerged years ago, aimed to continuously optimize the network in response to variations in network traffic and conditions. Yet, DNO development is still at its infancy, mainly hindered by a significant bottleneck of the lengthy optimization runtime. This paper identifies parallelism in greedy MNO algorithms and presents an advanced distributed parallel solution. The solution is designed, implemented and applied to real-life projects whose results yield a significant, highly scalable and nearly linear speedup up to 6.9 and 14.5 on distributed 8-core and 16-core systems respectively. Meanwhile, optimization outputs exhibit self-consistency and high precision compared to their sequential counterpart. This is a milestone in realizing the DNO. Further, the techniques may be applied to similar greedy optimization algorithm based applications.