A Modification of the Social Force Model by Foresight

The motion of pedestrian crowds (e.g. for simulation of an evacuation situation) can be modeled as a multi-body system of self driven particles with repulsive interaction. We use a few simple situations to determine the simplest allowed functional form of the force function. More complexity may be necessary to model more complex situations. There are many unknown parameters to such models, which have to be adjusted correctly. The parameters can be related to quantities that can be measured independently, like step length and frequency. The microscopic behavior is, however, only poorly reproduced in many situations, a person approaching a standing or slow obstacle will e.g. show oscillations in position, and the trajectories of two persons meeting in a corridor in opposite direction will be far from realistic and somewhat erratic. This is inpart due to the assumption of instantaneous reaction on the momentary situation. Obviously, persons react with a small time lag, while on the other hand they will anticipate changing situations for at least a short time. Thus basing the repulsive interaction on a (linear) extrapolation over a short time (e.g. 1 s) eliminates the oscillations at slowing down and smoothes the patterns of giving way to others to a more realistic behavior. A second problem is the additive combination of binary interactions. It is shown that combining only a few relevant interactions gives better model performance.Comment: 6 pages, 5 figures, Preprint from PED 2008 (Wuppertal

Press-pulse: a novel therapeutic strategy for the metabolic management of cancer

Background A shift from respiration to fermentation is a common metabolic hallmark of cancer cells. As a result, glucose and glutamine become the prime fuels for driving the dysregulated growth of tumors. The simultaneous occurrence of “Press-Pulse” disturbances was considered the mechanism responsible for reduction of organic populations during prior evolutionary epochs. Press disturbances produce chronic stress, while pulse disturbances produce acute stress on populations. It was only when both disturbances coincide that population reduction occurred. Methods This general concept can be applied to the management of cancer by creating chronic metabolic stresses on tumor cell energy metabolism (press disturbance) that are coupled to a series of acute metabolic stressors that restrict glucose and glutamine availability while also stimulating cancer-specific oxidative stress (pulse disturbances). The elevation of non-fermentable ketone bodies protect normal cells from energy stress while further enhancing energy stress in tumor cells that lack the metabolic flexibility to use ketones as an efficient energy source. Mitochondrial abnormalities and genetic mutations make tumor cells vulnerable metabolic stress. Results The press-pulse therapeutic strategy for cancer management is illustrated with calorie restricted ketogenic diets (KD-R) used together with drugs and procedures that create both chronic and intermittent acute stress on tumor cell energy metabolism, while protecting and enhancing the energy metabolism of normal cells. Conclusions Optimization of dosing, timing, and scheduling of the press-pulse therapeutic strategy will facilitate the eradication of tumor cells with minimal patient toxicity. This therapeutic strategy can be used as a framework for the design of clinical trials for the non-toxic management of most cancers

Geophysical Imaging of Watershed Subsurface Patterns and Prediction of Soil Texture and Water Holding Capacity

The spatial distribution of subsurface soil textural properties across the landscape is an important control on the hydrological and ecological function of a watershed. Traditional methods of mapping soils involving subjective assignment of soil boundaries are inadequate for studies requiring a quantitative assessment of the landscape and its subsurface connectivity and storage capacity. Geophysical methods such as electromagnetic induction (EMI) provide the possibility of obtaining high-resolution images across a landscape to identify subtle changes in subsurface soil patterns. In this work we show how EMI can be used to image the subsurface of a ∼38 ha watershed. We present an imaging approach using kriging to interpolate and sequential Gaussian simulation to estimate the uncertainty in the maps. We also explore the idea of difference ECa mapping to try to exploit changes in soil moisture to identify more hydrologically active locations. In addition, we use a digital elevation model to identify flow paths and compare these with the ECa measurement as a function of distance. Finally, we perform a more traditional calibration of ECa with clay percentage across the watershed and determine soil water holding capacity (SWHC). The values of SWHC range from 0.07 to 0.22 m3 m−3 across the watershed, which contrast with the uniform value of 0.13 derived from the traditional soil survey maps. Additional work is needed to appropriately interpret and incorporate EMI data into hydrological studies; however, we argue that there is considerable merit in identifying subsurface soil patterns from these geophysical images

Electrophysiological evidence for rapid 5-HT1A autoreceptor inhibition by vilazodone, a 5-HT1A receptor partial agonist and 5-HT reuptake inhibitor

Abstract This study examined the effect of vilazodone, a combined serotonin (5-HT) reuptake inhibitor and 5-HT 1A receptor partial agonist, paroxetine and fluoxetine on the sensitivity of 5-HT 1A autoreceptors of serotonergic dorsal raphe nucleus neurons in rats. These effects were assessed by determining the intravenous dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) required to suppress the basal firing rate of these neurons by 50% (ID 50 ) in anesthetized rats using in vivo electrophysiology. 5-HT uptake inhibition was determined by the ability of the compounds to reverse (±)- p -chloroamphetamine (PCA)-induced rat hypothalamic 5-HT depletion ex vivo . Acute vilazodone administration (0.63 and 2.1 µmol/kg, s.c.), compared with vehicle, significantly increased (2–3-fold) the ID 50 of 8-OH-DPAT at 4 h, but not 24 h after administration. Subchronic administration (3 days) significantly increased the ID 50 value at 4 h (3–4-fold) and at 24 h (~2-fold). In contrast, paroxetine and fluoxetine at doses that were supramaximal for 5-HT uptake inhibition did not significantly alter the ID 50 value of 8-OH-DPAT after acute or subchronic administration. Vilazodone antagonized the action of PCA 3.5 h and 5 h after a single dose (ID 50 1.49 and 0.46 µmol/kg, s.c., respectively), but was inactive 18 h post-administration, corroborating the electrophysiological results at 24 h following acute administration. The results are consistent with the concept of rapid and, following repeated treatment, prolonged inhibition of 5-HT 1A autoreceptors by vilazodone. This effect could occur by either direct interaction with, or desensitization of, these receptors, an effect which cannot be ascribed to vilazodone's 5-HT reuptake inhibiting properties

Planar cell polarity signalling coordinates heart tube remodelling through tissue-scale polarisation of actomyosin activity

Development of a multiple-chambered heart from the linear heart tube is inherently linked to cardiac looping. Although many molecular factors regulating the process of cardiac chamber ballooning have been identified, the cellular mechanisms underlying the chamber formation remain unclear. Here, we demonstrate that cardiac chambers remodel by cell neighbour exchange of cardiomyocytes guided by the planar cell polarity (PCP) pathway triggered by two non-canonical Wnt ligands, Wnt5b and Wnt11. We find that PCP signalling coordinates the localisation of actomyosin activity, and thus the efficiency of cell neighbour exchange. On a tissue-scale, PCP signalling planar-polarises tissue tension by restricting the actomyosin contractility to the apical membranes of outflow tract cells. The tissue-scale polarisation of actomyosin contractility is required for cardiac looping that occurs concurrently with chamber ballooning. Taken together, our data reveal that instructive PCP signals couple cardiac chamber expansion with cardiac looping through the organ-scale polarisation of actomyosin-based tissue tension

The Fundamental Diagram of Pedestrian Movement Revisited

The empirical relation between density and velocity of pedestrian movement is not completely analyzed, particularly with regard to the `microscopic' causes which determine the relation at medium and high densities. The simplest system for the investigation of this dependency is the normal movement of pedestrians along a line (single-file movement). This article presents experimental results for this system under laboratory conditions and discusses the following observations: The data show a linear relation between the velocity and the inverse of the density, which can be regarded as the required length of one pedestrian to move. Furthermore we compare the results for the single-file movement with literature data for the movement in a plane. This comparison shows an unexpected conformance between the fundamental diagrams, indicating that lateral interference has negligible influence on the velocity-density relation at the density domain $1 m^{-2}<\rho<5 m^{-2}$. In addition we test a procedure for automatic recording of pedestrian flow characteristics. We present preliminary results on measurement range and accuracy of this method.Comment: 13 pages, 9 figure

Pedestrian, Crowd, and Evacuation Dynamics

This contribution describes efforts to model the behavior of individual pedestrians and their interactions in crowds, which generate certain kinds of self-organized patterns of motion. Moreover, this article focusses on the dynamics of crowds in panic or evacuation situations, methods to optimize building designs for egress, and factors potentially causing the breakdown of orderly motion.Comment: This is a review paper. For related work see http://www.soms.ethz.c

Genetic background influences the 5XFAD Alzheimer\u27s disease mouse model brain proteome.

There is an urgent need to improve the translational validity of Alzheimer’s disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable the discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. In this study, we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in the hippocampus and cortex (n = 3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across the hippocampus and cortex in 5XFAD and non- transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress responses and neuronal synapse/signaling. The modules with the strongest relationship to human disease—neuronal synapse/signaling and lysosome/stress response—were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated with AD genotype in the hippocampus compared with the cortex. Our findings suggest that the genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD

AAV-Mediated Gene Delivery in Adult GM1-Gangliosidosis Mice Corrects Lysosomal Storage in CNS and Improves Survival

Background: GM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid β-galactosidase (βgal), which results in the accumulation of GM1-ganglioside and its asialo-form (GA1) primarily in the CNS. Age of onset ranges from infancy to adulthood, and excessive ganglioside accumulation produces progressive neurodegeneration and psychomotor retardation in humans. Currently, there are no effective therapies for the treatment of GM1-gangliosidosis. Methodology/Principal Findings: In this study we examined the effect of thalamic infusion of AAV2/1-βgal vector in adult GM1 mice on enzyme distribution, activity, and GSL content in the CNS, motor behavior, and survival. Six to eight week-old GM1 mice received bilateral injections of AAV vector in the thalamus, or thalamus and deep cerebellar nuclei (DCN) with pre-determined endpoints at 1 and 4 months post-injection, and the humane endpoint, or 52 weeks of age. Enzyme activity was elevated throughout the CNS of AAV-treated GM1 mice and GSL storage nearly normalized in most structures analyzed, except in the spinal cord which showed ∼50% reduction compared to age-matched untreated GM1 mice spinal cord. Survival was significantly longer in AAV-treated GM1 mice (52 wks) than in untreated mice. However the motor performance of AAV-treated GM1 mice declined over time at a rate similar to that observed in untreated GM1 mice. Conclusions/Significance: Our studies show that the AAV-modified thalamus can be used as a ‘built-in’ central node network for widespread distribution of lysosomal enzymes in the mouse cerebrum. In addition, this study indicates that thalamic delivery of AAV vectors should be combined with additional targets to supply the cerebellum and spinal cord with therapeutic levels of enzyme necessary to achieve complete correction of the neurological phenotype in GM1 mice