Implementation of a land use and spatial interaction model based on random utility choices and social accounting matrices

Random utility modelling has been established as one of the main paradigms for the implementation of land use and transport interaction (LUTI) models. Despite widespread application of such models, the respective literature provides relatively little detail on the theoretical consistency of the overall formal framework of the random utility based LUTI models. To address this gap, we present a detailed formal description of a generic land use and spatial interaction model that adheres to the random utility paradigm through the explicit distinction between utility and cost across all processes that imply behaviour of agents. The model is rooted in an extended input-output table, with the workforce and households accounts being disaggregated by socio-economic type. Similarly, the land account is broken down by domestic and non-domestic land use types. The model is developed around two processes. Firstly, the generation of demand for inputs required by established production; the estimation of the level of demand between sectors, households and land use types is supported by social accounting techniques. When appropriate the implicit production functions are assumed depended on costs of inputs, which gives rise to price-elastic demands. Secondly, the spatial assignment of demanded inputs (industrial activity, workforce, land) to locations of production; here sequences of decisions are used to distribute demand (both spatially and, when necessary, a-spatially) and to propagate costs and utilities of production and consumption that emerge from imbalances between supply and demand. The implementation of this generic model is discussed in relation to the case of the Greater South East region of the UK, including London, the South East and the East of England. We present the calibration process, data requirements, necessary assumptions and resulting implications. We discuss outputs under various land use strategies and economic scenarios, such as regulated versus competing land uses, constrained versus unconstrained densities, and high versus low economic and population growth rates. By adjusting the design constraints of the spatial planning and infrastructure supply strategies we aim to improve their sustainability.

MutS/MutL crystal structure reveals that the MutS sliding clamp loads MutL onto DNA

To avoid mutations in the genome, DNA replication is generally followed by DNA mismatch repair (MMR). MMR starts when a MutS homolog recognizes a mismatch and undergoes an ATP-dependent transformation to an elusive sliding clamp state. How this transient state promotes MutL homolog recruitment and activation of repair is unclear. Here we present a crystal structure of the MutS/MutL complex using a site-specifically crosslinked complex and examine how large conformational changes lead to activation of MutL. The structure captures MutS in the sliding clamp conformation, where tilting of the MutS subunits across each other pushes DNA into a new channel, and reorientation of the connector domain creates an interface for MutL with both MutS subunits. Our work explains how the sliding clamp promotes loading of MutL onto DNA, to activate downstream effectors. We thus elucidate a crucial mechanism that ensures that MMR is initiated only after detection of a DNA mismatch

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms

Progress towards the measurement of absolute elastic electron-molecular radical scattering cross sections

We report on our progress in developing a dedicated crossed beam apparatus, for the measurement of absolute cross sections for elastic scattering of electrons from molecular radicals. Features which are original to this apparatus will be highlighted, and a discussion of its current status and future developments provided

Magnesium coordination controls the molecular switch function of DNA mismatch repair protein MutS

The DNA mismatch repair protein MutS acts as a molecular switch. It toggles between ADP and ATP states and is regulated by mismatched DNA. This is analogous to G-protein switches and the regulation of their "on" and "off" states by guanine exchange factors. Although GDP release in monomeric GTPases is accelerated by guanine exchange factorinduced removal of magnesium from the catalytic site, we found that release of ADP from MutS is not influenced by the metal ion in this manner. Rather, ADP release is induced by the binding of mismatched DNA at the opposite end of the protein, a long-range allosteric response resembling the mechanism of activation of heterotrimeric GTPases. Magnesium influences switching in MutS by inducing faster and tighter ATP binding, allowing rapid downstream responses. MutS mutants with decreased affinity for the metal ion are impaired in fast switching and in vivo mismatch repair. Thus, the G-proteins and MutS conceptually employ the same efficient use of the high energy cofactor: slow hydrolysis in the absence of a signal and fast conversion to the active state when required