Current Care and Investigational Therapies in Achondroplasia.

The goal of this review is to evaluate the management options for achondroplasia, the most common non-lethal skeletal dysplasia. This disease is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications. Achondroplasia is the most common non-lethal skeletal dysplasia. It is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications

ECCC TEST PROGRAMME AND DATA ASSESSMENT ON GTD111 CREEP RUPTURE, STRAIN AND DUCTILITY

GTD111, a creep resistant Ni-based superalloy developed by GE, is widely used in land-based gas turbine first stage blades. However, there is little published information on its creep properties and microstructure. The European Creep Collaborative Committee (ECCC) Working Group 3C consequently selected GTD111 as a model material for testing and complementary data assessment. The aim of this paper is to present the results from the ECCC test program and data assessment, and to compare equiaxed (EA) and directionally solidified (DS) material performance. Testing and metallographic laboratories from six European nations collaborated to produce strain monitored creep rupture data on four EA and DS materials out to beyond 10,000 hours within a wide range of temperatures, 850-950°C, and stresses, 293-99 MPa. Available (generally short term) results from other sources were also included in the compiled, small but viable, 51-test data set. Assessment was carried out by three different assessors using different tools and adopting different prediction models. Conventional ECCC post-assessment techniques and novel “back-fitting” methods were used to identify a preferred model. It was shown that assessing all the EA and DS data together can lead to non-conservative predictions for EA materials, but separating the two classes creates small data subsets which cannot be modelled effectively. As a pragmatic compromise, the DS data and those EA data which also showed good ductility were included in a final "ductile GTD111" assessment. The resulting creep rupture material models and rupture strength predictions are presented up to 3 times the longest test duration. It was then shown that the performance of lower ductility EA materials can also be predicted effectively with the "ductile" model by truncating the rupture time at the measured fracture strain. For this exercise, a creep strain model based on rupture and time to strain data was fitted. In parallel, microstructural examination was performed to characterize the damage modes involved in the low ductility failures. It was thereby shown that the creep rupture strength shortfall of an EA material compared to its DS equivalent is not a constant factor, but is primarily governed by the reduced creep ductility. Hence, the shortfall varies between different EA casts, and tends to become greater in the longer term.JRC.F.4-Innovative Technologies for Nuclear Reactor Safet

SARMENTI: Smart multisensor embedded and secure system for soil nutrient and gaseous emission monitoring

Demand for sustainably produced food is driving current strategies for intensification of the agricultural sector worldwide. To meet these challenges farmers will need to adopt a whole-farm approach to resource efficiency. They will increase their productivity with a better application of knowledge per hectare. Optimising soil fertility will enable farmers to maximise their productivity and profitability with higher grass and crop yield and quality

Spatial Analysis of Expression Patterns Predicts Genetic Interactions at the Mid-Hindbrain Boundary

The isthmic organizer mediating differentiation of mid- and hindbrain during vertebrate development is characterized by a well-defined pattern of locally restricted gene expression domains around the mid-hindbrain boundary (MHB). This pattern is established and maintained by a regulatory network between several transcription and secreted factors that is not yet understood in full detail. In this contribution we show that a Boolean analysis of the characteristic spatial gene expression patterns at the murine MHB reveals key regulatory interactions in this network. Our analysis employs techniques from computational logic for the minimization of Boolean functions. This approach allows us to predict also the interplay of the various regulatory interactions. In particular, we predict a maintaining, rather than inducing, effect of Fgf8 on Wnt1 expression, an issue that remained unclear from published data. Using mouse anterior neural plate/tube explant cultures, we provide experimental evidence that Fgf8 in fact only maintains but does not induce ectopic Wnt1 expression in these explants. In combination with previously validated interactions, this finding allows for the construction of a regulatory network between key transcription and secreted factors at the MHB. Analyses of Boolean, differential equation and reaction-diffusion models of this network confirm that it is indeed able to explain the stable maintenance of the MHB as well as time-courses of expression patterns both under wild-type and various knock-out conditions. In conclusion, we demonstrate that similar to temporal also spatial expression patterns can be used to gain information about the structure of regulatory networks. We show, in particular, that the spatial gene expression patterns around the MHB help us to understand the maintenance of this boundary on a systems level

Mathematical analysis of the Escherichia coli chemotaxis signalling pathway

We undertake a detailed mathematical analysis of a recent nonlinear ordinary differential equation (ODE) model describing the chemotactic signalling cascade within an {\it Escherichia coli} cell. The model includes a detailed description of the cell signalling cascade and an average approximation of the receptor activity. A steady-state stability analysis reveals the system exhibits one positive real steady-state which is shown to be asymptotically stable. Given the occurrence of a negative feedback between phosphorylated CheB (CheB-P) and the receptor state, we ask under what conditions, the system may exhibit oscillatory type behaviour. A detailed analysis of parameter space reveals that whilst variation in kinetic rate parameters within known biological limits is unlikely to lead to such behaviour, changes in the total concentration of the signalling proteins does. We postulate that experimentally observed overshoot behaviour can actually be described by damped oscillatory dynamics and consider the relationship between overshoot amplitude, total cell protein concentration and the magnitude of the external ligand stimulus. Model reductions of the full ODE model allow us to understand the link between phosphorylation events and the negative feedback between CheB-P and receptor methylation, as well as elucidate why some mathematical models exhibit overshoot and others do not. Our manuscript closes by discussing intercell variability of total protein concentration as means of ensuring the overall survival of a population as cells are subjected to different environments

Upscaling Flow and Transport Processes

Peer reviewe

Monotone and near-monotone biochemical networks

Monotone subsystems have appealing properties as components of larger networks, since they exhibit robust dynamical stability and predictability of responses to perturbations. This suggests that natural biological systems may have evolved to be, if not monotone, at least close to monotone in the sense of being decomposable into a “small” number of monotone components, In addition, recent research has shown that much insight can be attained from decomposing networks into monotone subsystems and the analysis of the resulting interconnections using tools from control theory. This paper provides an expository introduction to monotone systems and their interconnections, describing the basic concepts and some of the main mathematical results in a largely informal fashion