Probabilistic simulation for the certification of railway vehicles

The present dynamic certification process that is based on experiments has been essentially built on the basis of experience. The introduction of simulation techniques into this process would be of great interest. However, an accurate simulation of complex, nonlinear systems is a difficult task, in particular when rare events (for example, unstable behaviour) are considered. After analysing the system and the currently utilized procedure, this paper proposes a method to achieve, in some particular cases, a simulation-based certification. It focuses on the need for precise and representative excitations (running conditions) and on their variable nature. A probabilistic approach is therefore proposed and illustrated using an example. First, this paper presents a short description of the vehicle / track system and of the experimental procedure. The proposed simulation process is then described. The requirement to analyse a set of running conditions that is at least as large as the one tested experimentally is explained. In the third section, a sensitivity analysis to determine the most influential parameters of the system is reported. Finally, the proposed method is summarized and an application is presented

Selection of DNA nanoparticles with preferential binding to aggregated protein target.

High affinity and specificity are considered essential for affinity reagents and molecularly-targeted therapeutics, such as monoclonal antibodies. However, life's own molecular and cellular machinery consists of lower affinity, highly multivalent interactions that are metastable, but easily reversible or displaceable. With this inspiration, we have developed a DNA-based reagent platform that uses massive avidity to achieve stable, but reversible specific recognition of polyvalent targets. We have previously selected these DNA reagents, termed DeNAno, against various cells and now we demonstrate that DeNAno specific for protein targets can also be selected. DeNAno were selected against streptavidin-, rituximab- and bevacizumab-coated beads. Binding was stable for weeks and unaffected by the presence of soluble target proteins, yet readily competed by natural or synthetic ligands of the target proteins. Thus DeNAno particles are a novel biomolecular recognition agent whose orthogonal use of avidity over affinity results in uniquely stable yet reversible binding interactions

Associative Memory In Three Aplysiids: Correlation With Heterosynaptic Modulation

Much recent research on mechanisms of learning and memory focuses on the role of heterosynaptic neuromodulatory signaling. Such neuromodulation appears to stabilize Hebbian synaptic changes underlying associative learning, thereby extending memory. Previous comparisons of three related sea-hares ( Mollusca, Opisthobranchia) uncovered interspecific variation in neuromodulatory signaling: strong in Aplysia californica, immeasureable in Dolabrifera dolabrifera, and intermediate in Phyllaplysia taylori. The present study addressed whether this interspecific variation in neuromodulation is correlated with memory of associative ( classical conditioning) learning. We differentially conditioned the tail-mantle withdrawal reflex of each of the three species: Mild touch to one side of the tail was paired with a noxious electrical stimulus to the neck. Mild touch to the other side served as an internal control. Post-training reflex amplitudes were tested 15 -30 min after training and compared with pre-test amplitudes. All three species showed conditioning: training increased the paired reflex more than the unpaired reflex. However, the temporal pattern of conditioning varied between species. Aplysia showed modest conditioning that grew across the post-test period. Dolabrifera showed distinctly short-lived conditioning, present only on the first post-test. The time course of memory in Phyllaplysia was intermediate, although not statistically distinguishable from the other two species. Taken together, these experiments suggest that evolutionary changes in nonassociative heterosynaptic modulation may contribute to evolutionary changes in the stability of the memory of classical conditioning

Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome.

BackgroundThe purpose of this study was to conduct a 20-week controlled trial of lovastatin (10 to 40 mg/day) in youth with fragile X syndrome (FXS) ages 10 to 17 years, combined with an open-label treatment of a parent-implemented language intervention (PILI), delivered via distance video teleconferencing to both treatment groups, lovastatin and placebo.MethodA randomized, double-blind trial was conducted at one site in the Sacramento, California, metropolitan area. Fourteen participants were assigned to the lovastatin group; two participants terminated early from the study. Sixteen participants were assigned to the placebo group. Lovastatin or placebo was administered orally in a capsule form, starting at 10 mg and increasing weekly or as tolerated by 10 mg increments, up to a maximum dose of 40 mg daily. A PILI was delivered to both groups for 12 weeks, with 4 activities per week, through video teleconferencing by an American Speech-Language Association-certified Speech-Language Pathologist, in collaboration with a Board-Certified Behavior Analyst. Parents were taught to use a set of language facilitation strategies while interacting with their children during a shared storytelling activity. The main outcome measures included absolute change from baseline to final visit in the means for youth total number of story-related utterances, youth number of different word roots, and parent total number of story-related utterances.ResultsSignificant increases in all primary outcome measures were observed in both treatment groups. Significant improvements were also observed in parent reports of the severity of spoken language and social impairments in both treatment groups. In all cases, the amount of change observed did not differ across the two treatment groups. Although gains in parental use of the PILI-targeted intervention strategies were observed in both treatment groups, parental use of the PILI strategies was correlated with youth gains in the placebo group and not in the lovastatin group.ConclusionParticipants in both groups demonstrated significant changes in the primary outcome measures. The magnitude of change observed across the two groups was comparable, providing additional support for the efficacy of the use of PILI in youth with FXS.Trial registrationUS National Institutes of Health (ClinicalTrials.gov), NCT02642653. Registered 12/30/2015

Temperature and Metallicity Gradients in the Hot Gas Outflows of M82

We utilize deep Chandra X-ray Observatory imaging and spectra of M82, the prototype of a starbursting galaxy with a multiphase wind, to map the hot plasma properties along the minor axis of the galaxy. We extract spectra from 11 regions up to 2.5 kpc from the starbursting midplane and model the data as a multi-temperature, optically thin thermal plasma with contributions from a non-thermal (power-law) component and from charge exchange (CX). We examine the gradients in best-fit parameters, including the intrinsic column density, plasma temperature, metal abundances, and number density of the hot gas as a function of distance from the M82 nucleus. We find that the temperatures and number densities of the warm-hot and hot plasma peak at the starbursting ridge and decreases along the minor axis. The temperature and density profiles are inconsistent with spherical adiabatic expansion of a super-heated wind and suggest mass loading and mixing of the hot phase with colder material. Non-thermal emission is detected in all of the regions considered, and CX comprises 8-25% of the total absorption-corrected, broad-band (0.5-7 keV) X-ray flux. We show that the abundances of O, Ne, Mg, and Fe are roughly constant across the regions considered, while Si and S peak within 500 pc of the central starburst. These findings support a direct connection between the M82 superwind and the warm-hot, metal-rich circumgalactic medium (CGM).Comment: 15 pages, 8 figures, ApJ in pres

Neural ODEs as a discovery tool to characterize the structure of the hot galactic wind of M82

Dynamic astrophysical phenomena are predominantly described by differential equations, yet our understanding of these systems is constrained by our incomplete grasp of non-linear physics and scarcity of comprehensive datasets. As such, advancing techniques in solving non-linear inverse problems becomes pivotal to addressing numerous outstanding questions in the field. In particular, modeling hot galactic winds is difficult because of unknown structure for various physical terms, and the lack of \textit{any} kinematic observational data. Additionally, the flow equations contain singularities that lead to numerical instability, making parameter sweeps non-trivial. We leverage differentiable programming, which enables neural networks to be embedded as individual terms within the governing coupled ordinary differential equations (ODEs), and show that this method can adeptly learn hidden physics. We robustly discern the structure of a mass-loading function which captures the physical effects of cloud destruction and entrainment into the hot superwind. Within a supervised learning framework, we formulate our loss function anchored on the astrophysical entropy ($K \propto P/\rho^{5/3}$). Our results demonstrate the efficacy of this approach, even in the absence of kinematic data $v$. We then apply these models to real Chandra X-Ray observations of starburst galaxy M82, providing the first systematic description of mass-loading within the superwind. This work further highlights neural ODEs as a useful discovery tool with mechanistic interpretability in non-linear inverse problems. We make our code public at this GitHub repository (https://github.com/dustindnguyen/2023_NeurIPS_NeuralODEs_M82).Comment: 9 Pages, 2 Figures, Accepted at the NeurIPS 2023 workshop on Machine Learning and the Physical Science

Comprehensive Phylogenetic Reconstruction of Amoebozoa Based on Concatenated Analyses of SSU-rDNA and Actin Genes

Evolutionary relationships within Amoebozoa have been the subject of controversy for two reasons: 1) paucity of morphological characters in traditional surveys and 2) haphazard taxonomic sampling in modern molecular reconstructions. These along with other factors have prevented the erection of a definitive system that resolves confidently both higher and lower-level relationships. Additionally, the recent recognition that many protosteloid amoebae are in fact scattered throughout the Amoebozoa suggests that phylogenetic reconstructions have been excluding an extensive and integral group of organisms. Here we provide a comprehensive phylogenetic reconstruction based on 139 taxa using molecular information from both SSU-rDNA and actin genes. We provide molecular data for 13 of those taxa, 12 of which had not been previously characterized. We explored the dataset extensively by generating 18 alternative reconstructions that assess the effect of missing data, long-branched taxa, unstable taxa, fast evolving sites and inclusion of environmental sequences. We compared reconstructions with each other as well as against previously published phylogenies. Our analyses show that many of the morphologically established lower-level relationships (defined here as relationships roughly equivalent to Order level or below) are congruent with molecular data. However, the data are insufficient to corroborate or reject the large majority of proposed higher-level relationships (above the Order-level), with the exception of Tubulinea, Archamoebae and Myxogastrea, which are consistently recovered. Moreover, contrary to previous expectations, the inclusion of available environmental sequences does not significantly improve the Amoebozoa reconstruction. This is probably because key amoebozoan taxa are not easily amplified by environmental sequencing methodology due to high rates of molecular evolution and regular occurrence of large indels and introns. Finally, in an effort to facilitate future sampling of key amoebozoan taxa, we provide a novel methodology for genome amplification and cDNA extraction from single or a few cells, a method that is culture-independent and allows both photodocumentation and extraction of multiple genes from natural samples

A Randomized Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder.

Objective: Selective serotonin reuptake inhibitors like sertraline have been shown in observational studies and anecdotal reports to improve language development in young children with fragile X syndrome (FXS). A previous controlled trial of sertraline in young children with FXS found significant improvement in expressive language development as measured by the Mullen Scales of Early Learning (MSEL) among those with comorbid autism spectrum disorder (ASD) in post hoc analysis, prompting the authors to probe whether sertraline is also indicated in nonsyndromic ASD. Methods: The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 58 children with ASD aged 24 to 72 months. Results: 179 subjects were screened for eligibility, and 58 were randomized to sertraline (32) or placebo (26). Eight subjects from the sertraline arm and five from the placebo arm discontinued. Intent-to-treat analysis showed no significant difference from placebo on the primary outcomes (MSEL expressive language raw score and age equivalent combined score) or secondary outcomes. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events possibly related to study treatment occurred. Conclusion: This randomized controlled trial of sertraline treatment showed no benefit with respect to primary or secondary outcome measures. For the 6-month period, treatment in young children with ASD appears safe, although the long-term side effects of low-dose sertraline in early childhood are unknown. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02385799