Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells.

Resilience is an increasingly more important concept to understand the response urban systems are able to deliver to endogenous and exogenous shocks in the current context of climate change and socioeconomic uncertainty. Urban mobility, a fundamental component of urban systems, is naturally sensitive to shocks with significant impacts on daily life of individuals and businesses. The concept of resilience in urban mobility is under intensive research with increasingly more sophisticated approaches and methods being developed to assess resilience in transport modes due to different shocks. The literature is, however, absent on applications aimed at using simpler mobility indicators that are used and validated in urban mobility planning processes in the context of lack of 2 data or expertise. We propose a resilience evaluation method that uses commonly available origin-destination (OD) datasets to evaluate an overall indicator of resilience.We consider the possibility of trips made in motorised modes to be transferred to active modes in the event of a disruption of the mobility system. Results of the application of the method to two urban areas in Brazil show that each one has a specific pattern of mode change that is related to the OD patterns. The spatial distribution of trips shows the relative importance of resilient trips in the urban area. Finally, different levels of income have different sensitivity to the variation of resilience.

Accessibility is a key factor in defining the quality of life and potential for development of both cities and regions. This article presents a new accessibilitymaximization approach to inter-urban road network long-term planning. The approach is based on a nonlinear combinatorial optimization model. Two heuristics have been developed for solving the model, based on local search and simulated annealing principles, respectively. The efficiency of the heuristics was evaluated on a sample of test problems involving 10-, 20-, and 40-node networks. In the analysis both solution quality and computing effort were taken into account. The approach was used to analyze the ongoing transformation of the Portuguese main road network. The results obtained so far indicate that the model is a valuable decision-aid tool for inter-urban road network long-term planning.

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Cellular automata (CA) models of spatial change have been developed and applied in the context of large regional or metropolitan areas and usually use regular cells, with spatial interactions and transition rules operating within fixed-size neighbourhoods. Model calibration has also been an area of intensive research with many models still using expertbased input to ensure visual calibration of modelled land use maps. In this paper, we present an innovative CA model where irregular cells and variable neighbourhoods are used to better represent space and spatial interaction. Calibration is based on an optimisation procedure that uses particle swarm (PS) to determine the optimal set of parameters of the CA model. Hypothetical test instances are used to assess the CA model and its calibration to small urban areas. Our conclusion was that the use of PS ensures calibration results for the CA model that compare very well with results obtained through other approaches reported in the literature.