Dense Deformation Field Estimation for Atlas Registration using the Active Contour Framework

In this paper, we propose a new paradigm to carry outthe registration task with a dense deformation fieldderived from the optical flow model and the activecontour method. The proposed framework merges differenttasks such as segmentation, regularization, incorporationof prior knowledge and registration into a singleframework. The active contour model is at the core of ourframework even if it is used in a different way than thestandard approaches. Indeed, active contours are awell-known technique for image segmentation. Thistechnique consists in finding the curve which minimizesan energy functional designed to be minimal when thecurve has reached the object contours. That way, we getaccurate and smooth segmentation results. So far, theactive contour model has been used to segment objectslying in images from boundary-based, region-based orshape-based information. Our registration technique willprofit of all these families of active contours todetermine a dense deformation field defined on the wholeimage. A well-suited application of our model is theatlas registration in medical imaging which consists inautomatically delineating anatomical structures. Wepresent results on 2D synthetic images to show theperformances of our non rigid deformation field based ona natural registration term. We also present registrationresults on real 3D medical data with a large spaceoccupying tumor substantially deforming surroundingstructures, which constitutes a high challenging problem.

Genetic redox dysregulation induces behavioural deficits in the adult mouse: an animal model for schizophrenia

Background: Glutathione (GSH), a major cellular redox regulator and antioxidant, is decreased in cerebrospinal fluid and prefrontal cortex of schizophrenia patients. The gene of the key GSH-synthesizing enzyme, glutamate-cysteine ligase, modifier (GCLM) subunit, is associated with schizophrenia, suggesting that the deficit in the GSH system is of genetic origin. Using the GCLM knock-out (KO) mouse as model system with 60% decreased brain GSH levels and, thus, strong vulnerability to oxidative stress, we have shown that GSH dysregulation results in abnormal mouse brain morphology (e.g., reduced parvalbumin, PV, immuno-reactivity in frontal areas) and function. Additional oxidative stress, induced by GBR12909 (a dopamine re-uptake inhibitor), enhances morphological changes even further. Aim: In the present study we use the GCLM KO mouse model system, asking now, whether GSH dysregulation also compromises mouse behaviour and cognition. Methods: Male and female wildtype (WT) and GCLM-KO mice are treated with GBR12909 or phosphate buffered saline (PBS) from postnatal day (P) 5 to 10, and are behaviourally tested at P 60 and older. Results: In comparison to WT, KO animals of both sexes are hyperactive in the open field, display more frequent open arm entries on the elevated plus maze, longer float latencies in the Porsolt swim test, and more frequent contacts of novel and familiar objects. Contrary to other reports of animal models with reduced PV immuno-reactivity, GCLM-KO mice display normal rule learning capacity and perform normally on a spatial recognition task. GCLM-KO mice do, however, show a strong deficit in object-recognition after a 15 minutes retention delay. GBR12909 treatment exerts no additional effect. Conclusions: The results suggest that animals with impaired regulation of brain oxidative stress are impulsive and have reduced behavioural control in novel, unpredictable contexts. Moreover, GSH dysregulation seems to induce a selective attentional or stimulus-encoding deficit: despite intensive object exploration, GCLM-KO mice cannot discriminate between novel and familiar objects. In conclusion, the present data indicate that GSH dysregulation may contribute to the manifestation of behavioural and cognitive anomalies that are associated with schizophrenia.

Weighted Shape-based Averaging with Neighborhood Prior Model for Multiple Atlas Fusion-based Medical Image Segmentation

In medical imaging, merging automated segmentations obtained from multiple atlases has become a standard practice for improving the accuracy. In this letter, we propose two new fusion methods: "Global Weighted Shape-Based Averaging" (GWSBA) and "Local Weighted Shape-Based Averaging" (LWSBA). These methods extend the well known Shape-Based Averaging (SBA) by additionally incorporating the similarity information between the reference (i.e., atlas) images and the target image to be segmented. We also propose a new spatially-varying similarity-weighted neighborhood prior model, and an edge-preserving smoothness term that can be used with many of the existing fusion methods. We first present our new Markov Random Field (MRF) based fusion framework that models the above mentioned information. The proposed methods are evaluated in the context of segmentation of lymph nodes in the head and neck 3D CT images, and they resulted in more accurate segmentations compared to the existing SBA.

Neuroplasticity of inhibitory control

Executive control refers to a set of abilities enabling us to plan, control and implement our behavior to rapidly and flexibly adapt to environmental requirements. These adaptations notably involve the suppression of intended or ongoing cognitive or motor processes, a skill referred to as "inhibitory control". To implement efficient executive control of behavior, one must monitor our performance following errors to adjust our behavior accordingly. Deficits in inhibitory control have been associated with the emergènce of a wide range of psychiatric disorders, ranging from drug addiction to attention deficit/hyperactivity disorders. Inhibitory control deficits could, however, be remediated- The brain has indeed the amazing possibility to reorganize following training to allow for behavioral improvements. This mechanism is referred to as neural and behavioral plasticity. Here, our aim is to investigate training-induced plasticity in inhibitory control and propose a model of inhibitory control explaining the spatio- temporal brain mechanisms supporting inhibitory control processes and their plasticity. In the two studies entitled "Brain dynamics underlying training-induced improvement in suppressing inappropriate action" (Manuel et al., 2010) and "Training-induced neuroplastic reinforcement óf top-down inhibitory control" (Manuel et al., 2012c), we investigated the neurophysiological and behavioral changes induced by inhibitory control training with two different tasks and populations of healthy participants. We report that different inhibitory control training developed either automatic/bottom-up inhibition in parietal areas or reinforced controlled/top-down inhibitory control in frontal brain regions. We discuss the results of both studies in the light of a model of fronto-basal inhibition processes. In "Spatio-temporal brain dynamics mediating post-error behavioral adjustments" (Manuel et al., 2012a), we investigated how error detection modulates the processing of following stimuli and in turn impact behavior. We showed that during early integration of stimuli, the activity of prefrontal and parietal areas is modulated according to previous performance and impacts the post-error behavioral adjustments. We discuss these results in terms of a shift from an automatic to a controlled form of inhibition induced by the detection of errors, which in turn influenced response speed. In "Inter- and intra-hemispheric dissociations in ideomotor apraxia: a large-scale lesion- symptom mapping study in subacute brain-damaged patients" (Manuel et al., 2012b), we investigated ideomotor apraxia, a deficit in performing pantomime gestures of object use, and identified the anatomical correlates of distinct ideomotor apraxia error types in 150 subacute brain-damaged patients. Our results reveal a left intra-hemispheric dissociation for different pantomime error types, but with an unspecific role for inferior frontal areas. Les fonctions exécutives désignent un ensemble de processus nous permettant de planifier et contrôler notre comportement afin de nous adapter de manière rapide et flexible à l'environnement. L'une des manières de s'adapter consiste à arrêter un processus cognitif ou moteur en cours ; le contrôle de l'inhibition. Afin que le contrôle exécutif soit optimal il est nécessaire d'ajuster notre comportement après avoir fait des erreurs. Les déficits du contrôle de l'inhibition sont à l'origine de divers troubles psychiatriques tels que l'addiction à la drogue ou les déficits d'attention et d'hyperactivité. De tels déficits pourraient être réhabilités. En effet, le cerveau a l'incroyable capacité de se réorganiser après un entraînement et ainsi engendrer des améliorations comportementales. Ce mécanisme s'appelle la plasticité neuronale et comportementale. Ici, notre but èst d'étudier la plasticité du contrôle de l'inhibition après un bref entraînement et de proposer un modèle du contrôle de l'inhibition qui permette d'expliquer les mécanismes cérébraux spatiaux-temporels sous-tendant l'amélioration du contrôle de l'inhibition et de leur plasticité. Dans les deux études intitulées "Brain dynamics underlying training-induced improvement in suppressing inappropriate action" (Manuel et al., 2010) et "Training-induced neuroplastic reinforcement of top-down inhibitory control" (Manuel et al., 2012c), nous nous sommes intéressés aux changements neurophysiologiques et comportementaux liés à un entraînement du contrôle de l'inhibition. Pour ce faire, nous avons étudié l'inhibition à l'aide de deux différentes tâches et deux populations de sujets sains. Nous avons démontré que différents entraînements pouvaient soit développer une inhibition automatique/bottom-up dans les aires pariétales soit renforcer une inhibition contrôlée/top-down dans les aires frontales. Nous discutons ces résultats dans le contexte du modèle fronto-basal du contrôle de l'inhibition. Dans "Spatio-temporal brain dynamics mediating post-error behavioral adjustments" (Manuel et al., 2012a), nous avons investigué comment la détection d'erreurs influençait le traitement du prochain stimulus et comment elle agissait sur le comportement post-erreur. Nous avons montré que pendant l'intégration précoce des stimuli, l'activité des aires préfrontales et pariétales était modulée en fonction de la performance précédente et avait un impact sur les ajustements post-erreur. Nous proposons que la détection d'erreur ait induit un « shift » d'un mode d'inhibition automatique à un mode contrôlé qui a à son tour influencé le temps de réponse. Dans "Inter- and intra-hemispheric dissociations in ideomotor apraxia: a large-scale lesion-symptom mapping study in subacute brain-damaged patients" (Manuel et al., 2012b), nous avons examiné l'apraxie idémotrice, une incapacité à exécuter des gestes d'utilisation d'objets, chez 150 patients cérébro-lésés. Nous avons mis en avant une dissociation intra-hémisphérique pour différents types d'erreurs avec un rôle non spécifique pour les aires frontales inférieures.

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.

Ultramarathon is an outstanding model for the study of adaptive responses to extreme load and stress.

ABSTRACT: Ultramarathons comprise any sporting event involving running longer than the traditional marathon length of 42.195 km (26.2 miles). Studies on ultramarathon participants can investigate the acute consequences of ultra-endurance exercise on inflammation and cardiovascular or renal consequences, as well as endocrine/energetic aspects, and examine the tissue recovery process over several days of extreme physical load. In a study published in BMC Medicine, Schütz et al. followed 44 ultramarathon runners over 4,487 km from South Italy to North Cape, Norway (the Trans Europe Foot Race 2009) and recorded daily sets of data from magnetic resonance imaging, psychometric, body composition and biological measurements. The findings will allow us to better understand the timecourse of degeneration/regeneration of some lower leg tissues such as knee joint cartilage, to differentiate running-induced from age-induced pathologies (for example, retropatelar arthritis) and finally to assess the interindividual susceptibility to injuries. Moreover, it will also provide new information about the complex interplay between cerebral adaptations/alterations and hormonal influences resulting from endurance exercise and provide data on the dose-response relationship between exercise and brain structure/function. Overall, this study represents a unique attempt to investigate the limits of the adaptive response of human bodies.Please see related article: http://www.biomedcentral.com/1741-7015/10/78.

Determining the best population-level alcohol consumption model and its impact on estimates of alcohol-attributable harms.

BACKGROUND: The goals of our study are to determine the most appropriate model for alcohol consumption as an exposure for burden of disease, to analyze the effect of the chosen alcohol consumption distribution on the estimation of the alcohol Population- Attributable Fractions (PAFs), and to characterize the chosen alcohol consumption distribution by exploring if there is a global relationship within the distribution. METHODS: To identify the best model, the Log-Normal, Gamma, and Weibull prevalence distributions were examined using data from 41 surveys from Gender, Alcohol and Culture: An International Study (GENACIS) and from the European Comparative Alcohol Study. To assess the effect of these distributions on the estimated alcohol PAFs, we calculated the alcohol PAF for diabetes, breast cancer, and pancreatitis using the three above-named distributions and using the more traditional approach based on categories. The relationship between the mean and the standard deviation from the Gamma distribution was estimated using data from 851 datasets for 66 countries from GENACIS and from the STEPwise approach to Surveillance from the World Health Organization. RESULTS: The Log-Normal distribution provided a poor fit for the survey data, with Gamma and Weibull distributions providing better fits. Additionally, our analyses showed that there were no marked differences for the alcohol PAF estimates based on the Gamma or Weibull distributions compared to PAFs based on categorical alcohol consumption estimates. The standard deviation of the alcohol distribution was highly dependent on the mean, with a unit increase in alcohol consumption associated with a unit increase in the mean of 1.258 (95% CI: 1.223 to 1.293) (R2 = 0.9207) for women and 1.171 (95% CI: 1.144 to 1.197) (R2 = 0. 9474) for men. CONCLUSIONS: Although the Gamma distribution and the Weibull distribution provided similar results, the Gamma distribution is recommended to model alcohol consumption from population surveys due to its fit, flexibility, and the ease with which it can be modified. The results showed that a large degree of variance of the standard deviation of the alcohol consumption Gamma distribution was explained by the mean alcohol consumption, allowing for alcohol consumption to be modeled through a Gamma distribution using only average consumption.

Does T Helper Differentiation Correlate with Resistance or Susceptibility to Infection with L. major? Some Insights From the Murine Model.

The murine model of Leishmania major infection has been an invaluable tool in understanding T helper differentiation in vivo. The initial evidence for a role of distinct CD4(+) T helper subsets in the outcome of infection was first obtained with this experimental model. The development of CD4(+) Th1 cells was associated with resolution of the lesion, control of parasite replication, and resistance to re-infection in most of the mouse strains investigated (i.e., C57BL/6). In contrast, differentiation of CD4(+) Th2 cells correlated with the development of unhealing lesions, and failure to control parasite load in a few strains (i.e., BALB/c). Since these first reports, an incredible amount of effort has been devoted to understanding the various parameters involved in the differentiation of these, and more recently discovered T helper subsets such as Th17 and T regulatory cells. The discovery of cross-talk between T helper subsets, as well as their plasticity force us to reevaluate the events driving a protective/deleterious T helper immune response following infection with L. major in mice. In this review, we describe the individual contributions of each of these CD4(+) T helper subsets following L. major inoculation, emphasizing recent advances in the field, such as the impact of different substrains of L. major on the pathogenesis of disease.

SlimCodeML: An Optimized Version of CodeML for the Branch-Site Model

CodeML (part of the PAML package) im- plements a maximum likelihood-based approach to de- tect positive selection on a specific branch of a given phylogenetic tree. While CodeML is widely used, it is very compute-intensive. We present SlimCodeML, an optimized version of CodeML for the branch-site model. Our performance analysis shows that SlimCodeML substantially outperforms CodeML (up to 9.38 times faster), especially for large-scale genomic analyses.

Model structure of human APOBEC3G.

BACKGROUND: APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) has antiretroviral activity associated with the hypermutation of viral DNA through cytosine deamination. APOBEC3G has two cytosine deaminase (CDA) domains; the catalytically inactive amino-terminal domain of APOBEC3G (N-CDA) carries the Vif interaction domain. There is no 3-D structure of APOBEC3G solved by X-ray or nuclear magnetic resonance. METHODOLOGY/PRINCIPAL FINDINGS: We predicted the structure of human APOBEC3G based on the crystal structure of APOBEC2. To assess the model structure, we evaluated 48 mutants of APOBEC3G N-CDA that identify novel variants altering DeltaVif HIV-1 infectivity and packaging of APOBEC3G. Results indicated that the key residue D128 is exposed at the surface of the model, with a negative local electrostatic potential. Mutation D128K changes the sign of that local potential. In addition, two novel functionally relevant residues that result in defective APOBEC3G encapsidation, R122 and W127, cluster at the surface. CONCLUSIONS/SIGNIFICANCE: The structure model identifies a cluster of residues important for packaging of APOBEC3G into virions, and may serve to guide functional analysis of APOBEC3G.

Drug uptake in a rodent sarcoma model after intravenous injection or isolated lung perfusion of free liposomal doxorubicin /

Rapport de synthèseDrug uptake in a rodent sarcoma model after intravenous injection or isolated lungperfusion of free/liposomal doxorubicinIntroductionLa distribution de doxorubicine libre et doxorubicin liposomale pegylée (Liporubicin?) a été comparée après administration intraveineuse ou application via perfusion isolée du poumon (ILP) dans le parenchyme pulmonaire et dans la tumeur des poumons de rongeurs, porteurs d'une tumeur sarcomateuse.Matériel et méthodeUne tumeur sarcomateuse unique a été générée dans le poumon gauche de 36 rongeurs (Fisher rats) suivie, 10 jours plus tard, par application de doxorubicine ou Liporubicin? soit par perfusion isolée du poumon (n = 20) ou administration intraveineuse (n = 12). Deux différentes concentrations ont été utilisées (100 μg et 400 pg) à doses équimolaires pour les deux formulations de doxorubicine. La concentration des agents cytostatiques ont été mesurées dans la tumeur et le parenchyme pulmonaire à l'aide de chromatographic (HPLC).RésultatsLes résultats indiquent que pour doxorubicine libre, le taux de concentration dans la tumeur et le parenchyme pulmonaire est 3 fois (dosage de 100 μ§) et 10 fois (dosage de 400 plus élevé après ILP par rapport à l'administration intraveineuse. En revanche, pour Liporubicin , le taux de concentration est similaire dans la tumeur et le parenchyme pulmonaire entre ILP et administration intraveineuse, pour les deux doses appliquées.ConclusionPour ILP et administration intraveineuse, le ratio entre accumulation de l'agent cytostatique dans la tumeur versus dans le parenchyme pulmonaire a été comparé pour les deux formulations de doxorubicine ainsi que pour les deux dosages. Pour les deux formulations et dosages de doxorubicine, ILP aboutit à un ratio plus élevé par rapport à l'administration intraveineuse. Cependant, pour les deux formulations et dosages de doxorubicine, ILP résulte également en une distribution de l'agent cytostatique plus hétérogène dans le parenchyme pulmonaire comparé à l'administration intraveineuse.En résumé, l'application de doxorubicine par ILP aboutit donc à une accumulation tumorale élevée et à une augmentation du ratio tumeur-parenchyme pulmonaire, mais en même temps également à une distribution plus hétérogène dans le parenchyme pulmonaire par rapport à l'application intraveineuse. Ceci a été observé pour les deux formulations de doxorubicine et pour les deux dosages appliqué.

Towards Integrated Governance of Landscape Development : The Swiss Model of Regional Nature Parks

Coherent regulation of landscape as a resource is a major challenge. How can the development interests of some actors (eg cable car operators and property developers) be reconciled with those of others (agriculture, forestry) and with conservation of biodiversity and scenic value? To help understand how the newly introduced Regional Nature Parks (RNPs) can improve the coherence of the regulation regime in Switzerland, we highlight current direct mechanisms for regulation of landscape as a resource (bans, inventories, subsidies) as well as indirect mechanisms (taking place through the regulation of the physical basis of landscapes, eg forest, land, and water planning policies). We show that RNPs are fundamentally innovative because they make it possible to manage and coordinate indirect strategies for appropriate regulation of resources at a landscape scale. In other words, RNPs enable organization of governance of landscape as a resource in a perimeter that is not necessarily restricted to administrative boundaries.

Not one odour but two: A new model for nestmate recognition.

Recognition systems play a key role in a range of biological processes, including mate choice, immune defence and altruistic behaviour. Social insects provide an excellent model for studying recognition systems because workers need to discriminate between nestmates and non-nestmates, enabling them to direct altruistic behaviour towards closer kin and to repel potential invaders. However, the level of aggression directed towards conspecific intruders can vary enormously, even among workers within the same colony. This is usually attributed to differences in the aggression thresholds of individuals or to workers having different roles within the colony. Recent evidence from the weaver ant Oecophylla smaragdina suggests that this does not tell the whole story. Here I propose a new model for nestmate recognition based on a vector template derived from both the individual's innate odour and the shared colony odour. This model accounts for the recent findings concerning weaver ants, and also provides an alternative explanation for why the level of aggression expressed by a colony decreases as the diversity within the colony increases, even when odour is well-mixed. The model makes additional predictions that are easily tested, and represents a significant advance in our conceptualisation of recognition systems.