When should clinicians search for GLUT1 deficiency syndrome in childhood generalized epilepsies?

UNLABELLED: GLUT1 deficiency (GLUT1D) has recently been identified as an important cause of generalized epilepsies in childhood. As it is a treatable condition, it is crucial to determine which patients should be investigated. METHODS: We analyzed SLC2A1 for mutations in a group of 93 unrelated children with generalized epilepsies. Fasting lumbar puncture was performed following the identification of a mutation. We compared our results with a systematic review of 7 publications of series of patients with generalized epilepsies screened for SLC2A1 mutations. RESULTS: We found 2/93 (2.1%) patients with a SLC2A1 mutation. One, carrying a novel de novo deletion had epilepsy with myoclonic-atonic seizures (MAE), mild slowing of head growth, choreiform movements and developmental delay. The other, with a paternally inherited missense mutation, had childhood absence epilepsy with atypical EEG features and paroxysmal exercise-induced dyskinesia (PED) initially misdiagnosed as myoclonic seizures. Out of a total of 1110 screened patients with generalized epilepsies from 7 studies, 2.4% (29/1110) had GLUT1D. This rate was higher (5.6%) among 303 patients with early onset absence epilepsy (EOAE) from 4 studies. About 50% of GLUT1D patients had abnormal movements and 41% a family history of seizures, abnormal movements or both. CONCLUSION: GLUT1D is most likely to be found in MAE and in EOAE. The probability of finding GLUT1D in the classical idiopathic generalized epilepsies is very low. Pointers to GLUT1D include an increase in seizures before meals, cognitive impairment, or PED which can easily be overlooked.

Debris flow susceptibility mapping at a regional scale along the National Road N7, Argentina

A first assessment of debris flow susceptibility at a large scale was performed along the National Road N7, Argentina. Numerous catchments are prone to debris flows and likely to endanger the road-users. A 1:50,000 susceptibility map was created. The use of a DEM (grid 30 m) associated to three complementary criteria (slope, contributing area, curvature) allowed the identification of potential source areas. The debris flow spreading was estimated using a process- and GISbased model (Flow-R) based on basic probabilistic and energy calculations. The best-fit values for the coefficient of friction and the mass-to-drag ratio of the PCM model were found to be ? = 0.02 and M/D = 180 and the resulting propagation on one of the calibration site was validated using the Coulomb friction model. The results are realistic and will be useful to determine which areas need to be prioritized for detailed studies.

Generalized food-deceptive orchid species flower earlier and occur at lower altitudes than rewarding ones

Aims Food-deceptive pollination, in which plants do not offer any food reward to their pollinators, is common within the Orchidaceae. As food-deceptive orchids are poorer competitors for pollinator visitation than rewarding orchids, their occurrence in a given habitat may be more constrained than that of rewarding orchids. In particular, the success of deceptive orchids strongly relies on several biotic factors such as interactions with co-flowering rewarding species and pollinators, which may vary with altitude and over time. Our study compares generalized food-deceptive (i.e. excluding sexually deceptive) and rewarding orchids to test whether (i) deceptive orchids flower earlier compared to their rewarding counterparts and whether (ii) the relative occurrence of deceptive orchids decreases with increasing altitude. Methods To compare the flowering phenology of rewarding and deceptive orchids, we analysed data compiled from the literature at the species level over the occidental Palaearctic area. Since flowering phenology can be constrained by the latitudinal distribution of the species and by their phylogenetic relationships, we accounted for these factors in our analysis. To compare the altitudinal distribution of rewarding and deceptive orchids, we used field observations made over the entire Swiss territory and over two Swiss mountain ranges. Important Findings We found that deceptive orchid species start flowering earlier than rewarding orchids do, which is in accordance with the hypotheses of exploitation of naive pollinators and/or avoidance of competition with rewarding co-occurring species. Also, the relative frequency of deceptive orchids decreases with altitude, suggesting that deception may be less profitable at high compared to low altitude.

Towards a connectome mapping pipeline for neonates using high-resolution MP2RAGE and DTI

Exploring the anatomical and functional connectivities between different regions of the brain (the "Connectome") is a core challenge in neuroscience. While robust methods are available for the adult brain, mapping the connectome in neonates is highly challenging. The purpose of this pilot study is to present a methodological approach for analyzing structural connectivity of a neonate brain and to exploit the MP2RAGE sequence with its advantageous contrast properties

Mapping of a gene coding for a major late structural polypeptide on the vaccinia virus genome.

Cell-free translation of total RNA isolated from vaccinia virus-infected cells late in infection results in a complex mixture of polypeptides. A monospecific antibody directed against one of the major structural proteins of the virus particle immunoprecipitated a single polypeptide with a molecular weight of 11,000 (11K) from this mixture. Immunoprecipitation was therefore used to identify the structural polypeptide among the in vitro translation products of RNA purified by hybridization selection to restriction fragments of the vaccinia virus genome. This allowed us to map the mRNA coding for the 11K polypeptide to the extreme left-hand end of the HindIII E fragment. Detailed transcriptional mapping of this region of the genome by nuclease S1 analysis revealed the presence of a late RNA transcribed from the rightward-reading strand. Its 5' end mapped at ca. 130 base pairs to the left of the HindIII site at the junction between the HindIII F and E fragments. The map position of this RNA coincided precisely with the map position of the late message coding for the 11K polypeptide.

A generalized mechanistic codon model.

Models of codon evolution have attracted particular interest because of their unique capabilities to detect selection forces and their high fit when applied to sequence evolution. We described here a novel approach for modeling codon evolution, which is based on Kronecker product of matrices. The 61 × 61 codon substitution rate matrix is created using Kronecker product of three 4 × 4 nucleotide substitution matrices, the equilibrium frequency of codons, and the selection rate parameter. The entities of the nucleotide substitution matrices and selection rate are considered as parameters of the model, which are optimized by maximum likelihood. Our fully mechanistic model allows the instantaneous substitution matrix between codons to be fully estimated with only 19 parameters instead of 3,721, by using the biological interdependence existing between positions within codons. We illustrate the properties of our models using computer simulations and assessed its relevance by comparing the AICc measures of our model and other models of codon evolution on simulations and a large range of empirical data sets. We show that our model fits most biological data better compared with the current codon models. Furthermore, the parameters in our model can be interpreted in a similar way as the exchangeability rates found in empirical codon models.

Temporo-Parietal Junction encodes the Embodied Self: Neuro-Robotics, fMRI, and Lesion mapping.

Introduction: Neuroimaging of the self focused on high-level mechanisms such as language, memory or imagery of the self. Recent evidence suggests that low-level mechanisms of multisensory and sensorimotor integration may play a fundamental role in encoding self-location and the first-person perspective (Blanke and Metzinger, 2009). Neurological patients with out-of body experiences (OBE) suffer from abnormal self-location and the first-person perspective due to a damage in the temporo-parietal junction (Blanke et al., 2004). Although self-location and the first-person perspective can be studied experimentally (Lenggenhager et al., 2009), the neural underpinnings of self-location have yet to be investigated. To investigate the brain network involved in self-location and first-person perspective we used visuo-tactile multisensory conflict, magnetic resonance (MR)-compatible robotics, and fMRI in study 1, and lesion analysis in a sample of 9 patients with OBE due to focal brain damage in study 2. Methods: Twenty-two participants saw a video showing either a person's back or an empty room being stroked (visual stimuli) while the MR-compatible robotic device stroked their back (tactile stimulation). Direction and speed of the seen stroking could either correspond (synchronous) or not (asynchronous) to those of the seen stroking. Each run comprised the four conditions according to a 2x2 factorial design with Object (Body, No-Body) and Synchrony (Synchronous, Asynchronous) as main factors. Self-location was estimated using the mental ball dropping (MBD; Lenggenhager et al., 2009). After the fMRI session participants completed a 6-item adapted from the original questionnaire created by Botvinick and Cohen (1998) and based on questions and data obtained by Lenggenhager et al. (2007, 2009). They were also asked to complete a questionnaire to disclose the perspective they adopted during the illusion. Response times (RTs) for the MBD and fMRI data were analyzed with a 3-way mixed model ANOVA with the in-between factor Perspective (up, down) and the two with-in factors Object (body, no-body) and Stroking (synchronous, asynchronous). Quantitative lesion analysis was performed using MRIcron (Rorden et al., 2007). We compared the distributions of brain lesions confirmed by multimodality imaging (Knowlton, 2004) in patients with OBE with those showing complex visual hallucinations involving people or faces, but without any disturbance of self-location and first person perspective. Nine patients with OBE were investigated. The control group comprised 8 patients. Structural imaging data were available for normalization and co-registration in all the patients. Normalization of each patient's lesion into the common MNI (Montreal Neurological Institute) reference space permitted simple, voxel-wise, algebraic comparisons to be made. Results: Even if in the scanner all participants were lying on their back and were facing upwards, analysis of perspective showed that half of the participants had the impression to be looking down at the virtual human body below them, despite any cues about their body position (Down-group). The other participants had the impression to be looking up at the virtual body above them (Up-group). Analysis of Q3 ("How strong was the feeling that the body you saw was you?") indicated stronger self-identification with the virtual body during the synchronous stroking. RTs in the MBD task confirmed these subjective data (significant 3-way interaction between perspective, object and stroking). fMRI results showed eight cortical regions where the BOLD signal was significantly different during at least one of the conditions resulting from the combination of Object and Stroking, relative to baseline: right and left temporo-parietal junction, right EBA, left middle occipito-temporal gyrus, left postcentral gyrus, right medial parietal lobe, bilateral medial occipital lobe (Fig 1). The activation patterns in right and left temporo-parietal junction and right EBA reflected changes in self-location and perspective as revealed by statistical analysis that was performed on the percentage of BOLD change with respect to the baseline. Statistical lesion overlap comparison (using nonparametric voxel based lesion symptom mapping) with respect to the control group revealed the right temporo-parietal junction, centered at the angular gyrus (Talairach coordinates x = 54, y =-52, z = 26; p>0.05, FDR corrected). Conclusions: The present questionnaire and behavioural results show that - despite the noisy and constraining MR environment) our participants had predictable changes in self-location, self-identification, and first-person perspective when robotic tactile stroking was applied synchronously with the robotic visual stroking. fMRI data in healthy participants and lesion data in patients with abnormal self-location and first-person perspective jointly revealed that the temporo-parietal cortex especially in the right hemisphere encodes these conscious experiences. We argue that temporo-parietal activity reflects the experience of the conscious "I" as embodied and localized within bodily space.

Flow-R, a model for susceptibility mapping of debris flows and other gravitational hazards at a regional scale

The development of susceptibility maps for debris flows is of primary importance due to population pressure in hazardous zones. However, hazard assessment by processbased modelling at a regional scale is difficult due to the complex nature of the phenomenon, the variability of local controlling factors, and the uncertainty in modelling parameters. A regional assessment must consider a simplified approach that is not highly parameter dependant and that can provide zonation with minimum data requirements. A distributed empirical model has thus been developed for regional susceptibility assessments using essentially a digital elevation model (DEM). The model is called Flow-R for Flow path assessment of gravitational hazards at a Regional scale (available free of charge under www.flow-r.org) and has been successfully applied to different case studies in various countries with variable data quality. It provides a substantial basis for a preliminary susceptibility assessment at a regional scale. The model was also found relevant to assess other natural hazards such as rockfall, snow avalanches and floods. The model allows for automatic source area delineation, given user criteria, and for the assessment of the propagation extent based on various spreading algorithms and simple frictional laws.We developed a new spreading algorithm, an improved version of Holmgren's direction algorithm, that is less sensitive to small variations of the DEM and that is avoiding over-channelization, and so produces more realistic extents. The choices of the datasets and the algorithms are open to the user, which makes it compliant for various applications and dataset availability. Amongst the possible datasets, the DEM is the only one that is really needed for both the source area delineation and the propagation assessment; its quality is of major importance for the results accuracy. We consider a 10m DEM resolution as a good compromise between processing time and quality of results. However, valuable results have still been obtained on the basis of lower quality DEMs with 25m resolution.

Generalized linear and generalized additive models in studies of species distributions: setting the scene

An important statistical development of the last 30 years has been the advance in regression analysis provided by generalized linear models (GLMs) and generalized additive models (GAMs). Here we introduce a series of papers prepared within the framework of an international workshop entitled: Advances in GLMs/GAMs modeling: from species distribution to environmental management, held in Riederalp, Switzerland, 6-11 August 2001.We first discuss some general uses of statistical models in ecology, as well as provide a short review of several key examples of the use of GLMs and GAMs in ecological modeling efforts. We next present an overview of GLMs and GAMs, and discuss some of their related statistics used for predictor selection, model diagnostics, and evaluation. Included is a discussion of several new approaches applicable to GLMs and GAMs, such as ridge regression, an alternative to stepwise selection of predictors, and methods for the identification of interactions by a combined use of regression trees and several other approaches. We close with an overview of the papers and how we feel they advance our understanding of their application to ecological modeling.

Mapping the structural core of human cerebral cortex.

Structurally segregated and functionally specialized regions of the human cerebral cortex are interconnected by a dense network of cortico-cortical axonal pathways. By using diffusion spectrum imaging, we noninvasively mapped these pathways within and across cortical hemispheres in individual human participants. An analysis of the resulting large-scale structural brain networks reveals a structural core within posterior medial and parietal cerebral cortex, as well as several distinct temporal and frontal modules. Brain regions within the structural core share high degree, strength, and betweenness centrality, and they constitute connector hubs that link all major structural modules. The structural core contains brain regions that form the posterior components of the human default network. Looking both within and outside of core regions, we observed a substantial correspondence between structural connectivity and resting-state functional connectivity measured in the same participants. The spatial and topological centrality of the core within cortex suggests an important role in functional integration.

MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field.

The large spatial inhomogeneity in transmit B(1) field (B(1)(+)) observable in human MR images at high static magnetic fields (B(0)) severely impairs image quality. To overcome this effect in brain T(1)-weighted images, the MPRAGE sequence was modified to generate two different images at different inversion times, MP2RAGE. By combining the two images in a novel fashion, it was possible to create T(1)-weighted images where the result image was free of proton density contrast, T(2) contrast, reception bias field, and, to first order, transmit field inhomogeneity. MP2RAGE sequence parameters were optimized using Bloch equations to maximize contrast-to-noise ratio per unit of time between brain tissues and minimize the effect of B(1)(+) variations through space. Images of high anatomical quality and excellent brain tissue differentiation suitable for applications such as segmentation and voxel-based morphometry were obtained at 3 and 7 T. From such T(1)-weighted images, acquired within 12 min, high-resolution 3D T(1) maps were routinely calculated at 7 T with sub-millimeter voxel resolution (0.65-0.85 mm isotropic). T(1) maps were validated in phantom experiments. In humans, the T(1) values obtained at 7 T were 1.15+/-0.06 s for white matter (WM) and 1.92+/-0.16 s for grey matter (GM), in good agreement with literature values obtained at lower spatial resolution. At 3 T, where whole-brain acquisitions with 1 mm isotropic voxels were acquired in 8 min, the T(1) values obtained (0.81+/-0.03 s for WM and 1.35+/-0.05 for GM) were once again found to be in very good agreement with values in the literature.