Introduction » au dossier « Méthodologie complexe et plurielle dans la recherche doctorale en sciences sociales

L’hybridation méthodologique au coeur d’une journée d’étude à destination des doctorant.e.s de l’UMR ES

Solutions to axion electrodynamics in various geometries

Recently there has been a surge of new experimental proposals to search for ultralight axion dark matter with axion mass, m_{a}≲1  μeV. Many of these proposals search for small oscillating magnetic fields induced in or around a large static magnetic field. Lately, there has been interest in alternate detection schemes which search for oscillating electric fields in a similar setup. In this paper, we explicitly solve Maxwell’s equations in a simplified geometry and demonstrate that in this mass range, the axion-induced electric fields are heavily suppressed by boundary conditions. Unfortunately, experimentally measuring axion-induced electric fields is not feasible in this mass regime using the currently proposed setups with static primary fields. We show that at larger axion masses, induced electric fields are not suppressed, but boundary effects may still be relevant for an experiment’s sensitivity. We then make a general argument about a generic detector configuration with a static magnetic field to show that the electric fields are always suppressed in the limit of large wavelength.National Science Foundation (U.S.) (Award No. 1806440

Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?

Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs) is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i) what constitutes an iN cell, ii) which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii) whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications.This research has received funding from the New York Stem Cell Foundation, the European Research Council under the European Union's Seventh Framework Programme: FP/2007-2013 Neuro Stem Cell Repair (no. 602278), ERC Grant Agreement no. 30971, the Swedish Research Council treatment of the future grant agreement K2012-99X-22324-01-5, the Swedish Research Council 70862601/Bagadilico, Swedish Parkinson Foundation (Parkinsonfonden), the Strategic Research Area at Lund University Multipark and StemTherapy. JJ is supported by the Swedish Foundation for Strategic Research (#FFL12-0074). JD is supported by a Canadian Institutes of Health Research (CIHR) fellowship (#358492), and RB is supported by an NIHR Biomedical Research Centre grant to the University of Cambridge/Addenbrooke's Hospital. MP is a New York Stem Cell Foundation—Robertson Investigator

Pharmacodynamic differentiation of lorazepam sleepiness and dizziness using an ordered categorical measure

Categorical measures of lorazepam sleepiness and dizziness were modeled to identify differences in pharmacodynamic (PD) parameters between these adverse events (AEs). Differences in data-derived PD parameters were compared with relative incidence rates in the drug label (15.7% and 6.9%, respectively). Healthy volunteers ( n  = 20) received single oral doses of 2 mg lorazepam or placebo in a randomized, double-blind, cross-over fashion. A seven-point categorical scale measuring the intensity of AEs was serially administered over 24 h. The maximum score (MaxS), and area under the effect curve (AUEC) were determined by noncompartmental methods and compared using a paired t -test. Individual scores were modeled using a logistic function implemented in NONMEM. AUEC and MaxS for sleepiness were significantly higher than dizziness (20.35 vs. 9.76, p  < 0.01) and (2.35 vs. 1.45, p  < 0.01). Model slope estimates were similar for sleepiness and dizziness (0.21 logits × mL/ng vs. 0.19 logits × mL/ng), but baseline logits were significantly higher for sleepiness (−2.81 vs. −4.34 logits). Data-derived PD parameters were in concordance with label incidence rates. The higher intensity of sleepiness may be directly related to baseline (no drug present) while the increase in intensity as a result of drug was relatively similar for both AEs. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3628–3641, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77428/1/22093_ftp.pd

Mechanical prions: Self-assembling microstructures

Prions are misfolded proteins that transmit their structural arrangement to neighboring proteins. In biological systems, prion dynamics can produce a variety of complex functional outcomes. Yet, an understanding of prionic causes has been hampered by the fact that few computational models exist that allow for experimental design, hypothesis testing, and control. Here, we identify essential prionic properties and present a biologically inspired model of prions using simple mechanical structures capable of undergoing complex conformational change. We demonstrate the utility of our approach by designing a prototypical mechanical prion and validating its properties experimentally. Our work provides a design framework for harnessing and manipulating prionic properties in natural and artificial systems.Comment: Added supplements, 25 pages, 11 figure

Reprogramming Human Adult Fibroblasts into GABAergic Interneurons.

Direct reprogramming is an appealing strategy to generate neurons from a somatic cell by forced expression of transcription factors. The generated neurons can be used for both cell replacement strategies and disease modelling. Using this technique, previous studies have shown that γ-aminobutyric acid (GABA) expressing interneurons can be generated from different cell sources, such as glia cells or fetal fibroblasts. Nevertheless, the generation of neurons from adult human fibroblasts, an easily accessible cell source to obtain patient-derived neurons, has proved to be challenging due to the intrinsic blockade of neuronal commitment. In this paper, we used an optimized protocol for adult skin fibroblast reprogramming based on RE1 Silencing Transcription Factor (REST) inhibition together with a combination of GABAergic fate determinants to convert human adult skin fibroblasts into GABAergic neurons. Our results show a successful conversion in 25 days with upregulation of neuronal gene and protein expression levels. Moreover, we identified specific gene combinations that converted fibroblasts into neurons of a GABAergic interneuronal fate. Despite the well-known difficulty in converting adult fibroblasts into functional neurons in vitro, we could detect functional maturation in the induced neurons. GABAergic interneurons have relevance for cognitive impairments and brain disorders, such as Alzheimer's and Parkinson's diseases, epilepsy, schizophrenia and autism spectrum disorders

Intrinsically motivated graph exploration using network theories of human curiosity

Intrinsically motivated exploration has proven useful for reinforcement learning, even without additional extrinsic rewards. When the environment is naturally represented as a graph, how to guide exploration best remains an open question. In this work, we propose a novel approach for exploring graph-structured data motivated by two theories of human curiosity: the information gap theory and the compression progress theory. The theories view curiosity as an intrinsic motivation to optimize for topological features of subgraphs induced by the visited nodes in the environment. We use these proposed features as rewards for graph neural-network-based reinforcement learning. On multiple classes of synthetically generated graphs, we find that trained agents generalize to larger environments and to longer exploratory walks than are seen during training. Our method computes more efficiently than the greedy evaluation of the relevant topological properties. The proposed intrinsic motivations bear particular relevance for recommender systems. We demonstrate that curiosity-based recommendations are more predictive of human behavior than PageRank centrality for several real-world graph datasets, including MovieLens, Amazon Books, and Wikispeedia.Comment: 14 pages, 5 figures in main text, and 15 pages, 8 figures in supplemen

Early careers on ecohydraulics:Challenges, opportunities and future directions

Early career researchers (ECRs) play a critical role in our knowledge-based society, yet they are the most vulnerable group in the scientific community. As a young, interdisciplinary science, ecohydraulics is particularly reliant on ECRs for future progress. In 2014, the Early Careers on Ecohydraulics Network (ECoENet) was created to help the development of young researchers in this field. In this paper, we synthesize the outcomes of a workshop for ECRs organized by ECoENet in February 2016. We aim to show how the potential of ECRs can be maximized to drive progress in ecohydraulics. According to the most recent entrants to the field, major challenges lie in becoming more integrated as a discipline, developing a common vocabulary and a collective vision, engaging effectively with policy-makers, and encouraging public participation. ECRs need to develop their careers on an international scale in a way that crosses traditional disciplinary boundaries, including the social sciences, and allows them time to work at fundamental levels rather than focusing solely on individual applications. We propose a strategy to facilitate this by providing: a platform for disseminating research; an international support network; and a set of services for enhancing ECR training and experience. Early career researchers; interdisciplinary science; ecohydraulics; society; ecology; hydraulicsacceptedVersio