67 research outputs found

    An interactive stated adaptation survey of activity scheduling decisions

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    The paper reports on current research in a project exploring new approaches for analyzing travel demand induced by changes in generalized costs of travel and activity participation. A sample of respondents were administered a five-day travel diary, from which one day was selected for further analysis. The conditions of that day were changed using predefined heuristics based on the household characteristics, to attain significant changes in the generalized costs of the reported trips. The households were then faced with these hypothetical scenarios in face-to-face interviews. All household members are asked to state how the implied changes would have affected their activity scheduling on the specified day, that is to adapt their reported schedule to the new conditions. The data will allow the computation of discrete choice models of activity scheduling. The results are expected to reflect the effects of the changes in generalized costs on activity generation. The results will be applied in MATSim, an agent-based micro-simulation. The application will allow the validation of the model results and the evaluation of aggregated effects of measures changing generalized costs, as well as their repercussions on the transport system and the resulting feedback effects, thus allowing the assessment of total induced demand and a comparison to the results from earlier aggregate models. The paper focuses on the description of the survey approach, which to our best knowledge is novel in its application, and reports preliminary analyses of the respondents’ reactions to the changes implied in the household interviews

    Within-Day Replanning

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    Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development

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    De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs

    Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development

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    De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages

    A Tentative Gamma-Ray Line from Dark Matter Annihilation at the Fermi Large Area Telescope

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    The observation of a gamma-ray line in the cosmic-ray fluxes would be a smoking-gun signature for dark matter annihilation or decay in the Universe. We present an improved search for such signatures in the data of the Fermi Large Area Telescope (LAT), concentrating on energies between 20 and 300 GeV. Besides updating to 43 months of data, we use a new data-driven technique to select optimized target regions depending on the profile of the Galactic dark matter halo. In regions close to the Galactic center, we find a 4.6 sigma indication for a gamma-ray line at 130 GeV. When taking into account the look-elsewhere effect the significance of the observed excess is 3.2 sigma. If interpreted in terms of dark matter particles annihilating into a photon pair, the observations imply a dark matter mass of 129.8\pm2.4^{+7}_{-13} GeV and a partial annihilation cross-section of = 1.27\pm0.32^{+0.18}_{-0.28} x 10^-27 cm^3 s^-1 when using the Einasto dark matter profile. The evidence for the signal is based on about 50 photons; it will take a few years of additional data to clarify its existence.Comment: 23 pages, 9 figures, 3 tables; extended discussion; matches published versio

    Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma

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    The impact of proton pump inhibitors (PPIs) on clinical outcomes with first-line immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma was previously analyzed in the phase II study, CheckMate 069. This retrospective analysis utilized data from three phase II/III studies of first-line ICI therapy in untreated advanced melanoma: CheckMate 066, 067, and 069. All randomized patients with PPI use ≤ 30 days before initiating study treatment were included in the PPI-use subgroup. Possible associations between baseline PPI use and efficacy were evaluated within each treatment arm of each study using multivariable modeling. Approximately 20% of 1505 randomized patients across the studies reported baseline PPI use. The median follow-up was 52.6–58.5 months. Objective response rate (ORR), progression-free survival (PFS), and overall survival analyses provided insufficient evidence of a meaningful association between PPI use and efficacy outcomes with nivolumab-plus-ipilimumab, nivolumab, or ipilimumab therapy. In five of the six ICI treatment arms, 95% confidence intervals for odds ratios or hazard ratios traversed 1. Significant associations were observed in the CheckMate 069 combination arm between PPI use and poorer ORR and PFS. This multivariable analysis found insufficient evidence to support meaningful associations between PPI use and ICI efficacy in patients with advanced melanoma

    Disaggregating physiological components of cortisol output: A novel approach to cortisol analysis in a clinical sample - A proof-of-principle study.

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    Although childhood adversity (CA) increases risk for subsequent mental illnesses, developmental mechanisms underpinning this association remain unclear. The hypothalamic-pituitary-adrenal axis (HPAA) is one candidate system potentially linking CA with psychopathology. However, determining developmental effects of CA on HPAA output and differentiating these from effects of current illness has proven difficult. Different aspects of HPAA output are governed by differentiable physiological mechanisms. Disaggregating HPAA output according to its biological components (baseline tonic cortisol, background diurnal variation, phasic stress response) may improve precision of associations with CA and/or psychopathology. In a novel proof-of-principle investigation we test whether different predictors, CA (distal risk factor) and current depressive symptoms, show distinct associations with dissociable HPAA components. A clinical group (aged 16-25) at high-risk for developing severe psychopathology (n = 20) were compared to age and sex matched healthy controls (n = 21). Cortisol was measured at waking (x4), following stress induction (x8), and during a time-environment-matched non-stress condition. Using piecewise multilevel modeling, stress responses were disaggregated into increase and decrease, while controlling for waking cortisol, background diurnal output and confounding variables. Elevated waking cortisol was specifically associated with higher CA scores. Higher non-stress cortisol was specifically associated with higher depressive scores. Following stress induction, depressive symptoms attenuated cortisol increase, whilst CA attenuated cortisol decrease. The results support a differential HPAA dysregulation hypothesis where physiologically dissociable components of HPAA output are differentially associated with distal (CA) or proximal (depressive symptoms) predictors. This proof-of-principle study demonstrates that future cortisol analyses need to disaggregate biologically independent mechanisms of HPAA output.Wellcome Trus

    Shift toward prior knowledge confers a perceptual advantage in early psychosis and psychosis-prone healthy individuals

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    Many neuropsychiatric illnesses are associated with psychosis, i.e., hallucinations (perceptions in the absence of causative stimuli) and delusions (irrational, often bizarre beliefs). Current models of brain function view perception as a combination of two distinct sources of information: bottom-up sensory input and top-down influences from prior knowledge. This framework may explain hallucinations and delusions. Here, we characterized the balance between visual bottom-up and top-down processing in people with early psychosis (study 1) and in psychosis-prone, healthy individuals (study 2) to elucidate the mechanisms that might contribute to the emergence of psychotic experiences. Through a specialized mental-health service, we identified unmedicated individuals who experience early psychotic symptoms but fall below the threshold for a categorical diagnosis. We observed that, in early psychosis, there was a shift in information processing favoring prior knowledge over incoming sensory evidence. In the complementary study, we capitalized on subtle variations in perception and belief in the general population that exhibit graded similarity with psychotic experiences (schizotypy). We observed that the degree of psychosis proneness in healthy individuals, and, specifically, the presence of subtle perceptual alterations, is also associated with stronger reliance on prior knowledge. Although, in the current experimental studies, this shift conferred a performance benefit, under most natural viewing situations, it may provoke anomalous perceptual experiences. Overall, we show that early psychosis and psychosis proneness both entail a basic shift in visual information processing, favoring prior knowledge over incoming sensory evidence. The studies provide complementary insights to a mechanism by which psychotic symptoms may emerge

    Background model systematics for the Fermi GeV excess

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    The possible gamma-ray excess in the inner Galaxy and the Galactic center (GC) suggested by Fermi-LAT observations has triggered a large number of studies. It has been interpreted as a variety of different phenomena such as a signal from WIMP dark matter annihilation, gamma-ray emission from a population of millisecond pulsars, or emission from cosmic rays injected in a sequence of burst-like events or continuously at the GC. We present the first comprehensive study of model systematics coming from the Galactic diffuse emission in the inner part of our Galaxy and their impact on the inferred properties of the excess emission at Galactic latitudes 2∘<∣b∣<20∘2^\circ<|b|<20^\circ and 300 MeV to 500 GeV. We study both theoretical and empirical model systematics, which we deduce from a large range of Galactic diffuse emission models and a principal component analysis of residuals in numerous test regions along the Galactic plane. We show that the hypothesis of an extended spherical excess emission with a uniform energy spectrum is compatible with the Fermi-LAT data in our region of interest at 95%95\% CL. Assuming that this excess is the extended counterpart of the one seen in the inner few degrees of the Galaxy, we derive a lower limit of 10.0∘10.0^\circ (95%95\% CL) on its extension away from the GC. We show that, in light of the large correlated uncertainties that affect the subtraction of the Galactic diffuse emission in the relevant regions, the energy spectrum of the excess is equally compatible with both a simple broken power-law of break energy 2.1±0.22.1\pm0.2 GeV, and with spectra predicted by the self-annihilation of dark matter, implying in the case of bˉb\bar{b}b final states a dark matter mass of 49−5.4+6.449^{+6.4}_{-5.4} GeV.Comment: 65 pages, 28 figures, 7 table
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