Constrained set-up of the tGAP structure for progressive vector data transfer

A promising approach to submit a vector map from a server to a mobile client is to send a coarse representation first, which then is incrementally refined. We consider the problem of defining a sequence of such increments for areas of different land-cover classes in a planar partition. In order to submit well-generalised datasets, we propose a method of two stages: First, we create a generalised representation from a detailed dataset, using an optimisation approach that satisfies certain cartographic constraints. Second, we define a sequence of basic merge and simplification operations that transforms the most detailed dataset gradually into the generalised dataset. The obtained sequence of gradual transformations is stored without geometrical redundancy in a structure that builds up on the previously developed tGAP (topological Generalised Area Partitioning) structure. This structure and the algorithm for intermediate levels of detail (LoD) have been implemented in an object-relational database and tested for land-cover data from the official German topographic dataset ATKIS at scale 1:50 000 to the target scale 1:250 000. Results of these tests allow us to conclude that the data at lowest LoD and at intermediate LoDs is well generalised. Applying specialised heuristics the applied optimisation method copes with large datasets; the tGAP structure allows users to efficiently query and retrieve a dataset at a specified LoD. Data are sent progressively from the server to the client: First a coarse representation is sent, which is refined until the requested LoD is reached

Constrained tGAP for generalisation between scales: the case of Dutch topographic data

This article presents the results of integrating large- and medium-scale data into a unified data structure. This structure can be used as a single non-redundant representation for the input data, which can be queried at any arbitrary scale between the source scales. The solution is based on the constrained topological Generalized Area Partition (tGAP), which stores the results of a generalization process applied to the large-scale dataset, and is controlled by the objects of the medium-scale dataset, which act as constraints on the large-scale objects. The result contains the accurate geometry of the large-scale objects enriched with the generalization knowledge of the medium-scale data, stored as references in the constraint tGAP structure. The advantage of this constrained approach over the original tGAP is the higher quality of the aggregated maps. The idea was implemented with real topographic datasets from The Netherlands for the large- (1:1000) and medium-scale (1:10,000) data. The approach is expected to be equally valid for any categorical map and for other scales as well

Neural connectivity predicts spreading of alpha-synuclein pathology in fibril-injected mouse models: Involvement of retrograde and anterograde axonal propagation.

In Parkinson's disease, some of the first alpha-synuclein aggregates appear in the olfactory system and the dorsal motor nucleus of the vagus nerve before spreading to connected brain regions. We previously demonstrated that injection of alpha-synuclein fibrils unilaterally into the olfactory bulb of wild type mice leads to widespread synucleinopathy in brain regions directly and indirectly connected to the injection site, consistently, over the course of periods longer than 6 months. Our previously reported observations support the idea that alpha-synuclein inclusions propagates between brain region through neuronal networks. In the present study, we further defined the pattern of propagation of alpha-synuclein inclusions and developed a mathematical model based on known mouse brain connectivity. Using this model, we first predicted the pattern of alpha-synuclein inclusions propagation following an injection of fibrils into the olfactory bulb. We then analyzed the fitting of these predictions to our published histological data. Our results demonstrate that the pattern of propagation we observed in vivo is consistent with axonal transport of alpha-synuclein aggregate seeds, followed by transsynaptic transmission. By contrast, simple diffusion of alpha-synuclein fits very poorly our in vivo data. We also found that the spread of alpha-synuclein inclusions appeared to primarily follow neural connections retrogradely until 9 months after injection into the olfactory bulb. Thereafter, the pattern of spreading was consistent with anterograde propagation mathematical models. Finally, we applied our mathematical model to a different, previously published, dataset involving alpha-synuclein fibril injections into the striatum, instead of the olfactory bulb. We found that the mathematical model accurately predicts the reported progressive increase in alpha-synuclein neuropathology also in that paradigm. In conclusion, our findings support that the progressive spread of alpha-synuclein inclusions after injection of protein fibrils follows neural networks in the mouse connectome

Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.

BackgroundThe trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown.MethodWe investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation.ResultsIncreased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo.ConclusionsWe report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy

Increased bradykinesia in Parkinson’s disease with increased movement complexity: elbow flexion-extension movements

The present research investigates factors contributing to bradykinesia in the control of simple and complex voluntary limb movement in Parkinson’s disease (PD) patients. The functional scheme of the basal ganglia (BG)–thalamocortical circuit was described by a mathematical model based on the mean firing rates of BG nuclei. PD was simulated as a reduction in dopamine levels, and a loss of functional segregation between two competing motor modules. In order to compare model simulations with performed movements, flexion and extension at the elbow joint is taken as a test case. Results indicated that loss of segregation contributed to bradykinesia due to interference between competing modules and a reduced ability to suppress unwanted movements. Additionally, excessive neurotransmitter depletion is predicted as a possible mechanism for the increased difficulty in performing complex movements. The simulation results showed that the model is in qualitative agreement with the results from movement experiments on PD patients and healthy subjects. Furthermore, based on changes in the firing rate of BG nuclei, the model demonstrated that the effective mechanism of Deep Brain Stimulation (DBS) in STN may result from stimulation induced inhibition of STN, partial synaptic failure of efferent projections, or excitation of inhibitory afferent axons even though the underlying methods of action may be quite different for the different mechanisms

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Peer reviewedPostprin

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

The impact of Social Security and other factors on the distribution of wealth

Auerbach et al. (1995), document the dramatic postwar increase in the annuitization of the resources of America’s elderly. Gokhale et al. (1996) suggest that greater annuitization may explain the significant postwar rise in the consumption propensity of the elderly out of remaining lifetime resources. Gokhale et al. (2000) consider the related point that increased annuitization will reduce bequests, especially for lower and middle-income households, whose entire earnings are taxed under Social Security. By differentially disenfranchising the children of the poor from receipt of inheritances, Social Security may materially alter the distribution of wealth. This paper uses data from the PSID to further analyze how Social Security and other factors affect wealth inequality.Social security ; Wealth