Alpha rhythm collapse predicts iso-electric suppressions during anesthesia.

Could an overly deep sedation be anticipated from ElectroEncephaloGram (EEG) patterns? We report here motifs hidden in the EEG signal that predict the appearance of Iso-Electric Suppressions (IES), observed during epileptic encephalopathies, drug intoxications, comatose, brain death or during anesthetic over-dosage that are considered to be detrimental. To show that IES occurrences can be predicted from EEG traces dynamics, we focus on transient suppression of the alpha rhythm (8-14 Hz) recorded for 80 patients, that had a Propofol target controlled infusion of 5 μg/ml during a general anesthesia. We found that the first time of appearance as well as changes in duration of these Alpha-Suppressions (αS) are two parameters that anticipate the appearance of IES. Using machine learning, we predicted IES appearance from the first 10 min of EEG (AUC of 0.93). To conclude, transient motifs in the alpha rhythm predict IES during anesthesia and can be used to identify patients, with higher risks of post-operative complications

The structure and global distribution of the endoplasmic reticulum network is actively regulated by lysosomes

The endoplasmic reticulum (ER) comprises morphologically and functionally distinct domains, sheets and interconnected tubules. These domains undergo dynamic reshaping, in response to changes in the cellular environment. However, the mechanisms behind this rapid remodeling are largely unknown. Here, we report that ER remodeling is actively driven by lysosomes, following lysosome repositioning in response to changes in nutritional status: the anchorage of lysosomes to ER growth tips is critical for ER tubule elongation and connection. We validate this causal link via the chemo- and optogenetically driven re-positioning of lysosomes, which leads to both a redistribution of the ER tubules and its global morphology. Therefore, lysosomes sense metabolic change in the cell and regulate ER tubule distribution accordingly. Dysfunction in this mechanism during axonal extension may lead to axonal growth defects. Our results demonstrate a critical role of lysosome-regulated ER dynamics and reshaping in nutrient responses and neuronal development.This research was funded by Infinitus (China) Company Ltd. (supporting M.L. and C.F.K.); a UKRI Engineering and Physical Sciences Research Council (EPSRC) grant (EP/L015889/1) awarded to the Centre for Doctoral Training in Sensor Technologies and Applications (supporting F.W.v.T.); a Sir Henry Wellcome Postdoctoral Fellowship from the Wellcome Trust (215943/Z/19/Z, to J.Q.L.); the Netherlands Organization for Scientific Research (NWO) (supporting W.N.); the European Research Council (ERC) (supporting L.K.); Wellcome Trust Collaborative Grant (203249/Z/16/Z to C.E.H. and C.F.K.); and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK (supporting E.A. and C.F.K.). D.H.’s research is supported by a PSL-Cambridge grant and an ERC grant, agreement no. 88267

The GoldenBricks assembly: A standardized one-shot cloning technique for complete cassette assembly

BBF RFC 92 proposes a new standard assembly method for the Parts Registry. The method makes one-shot cloning of a complete eukaryotic or prokaryotic cassette possible in one day while keeping compatibility with the BBF RFC 10 BioBrick assembly standard

Single particle trajectories reveal active endoplasmic reticulum luminal flow

The endoplasmic reticulum (ER), a network of membranous sheets and pipes, supports functions encompassing biogenesis of secretory proteins and delivery of functional solutes throughout the cell[1, 2]. Molecular mobility through the ER network enables these functionalities, but diffusion alone is not sufficient to explain luminal transport across supramicrometre distances. Understanding the ER structure–function relationship is critical in light of mutations in ER morphology-regulating proteins that give rise to neurodegenerative disorders[3, 4]. Here, super-resolution microscopy and analysis of single particle trajectories of ER luminal proteins revealed that the topological organization of the ER correlates with distinct trafficking modes of its luminal content: with a dominant diffusive component in tubular junctions and a fast flow component in tubules. Particle trajectory orientations resolved over time revealed an alternating current of the ER contents, while fast ER super-resolution identified energy-dependent tubule contraction events at specific points as a plausible mechanism for generating active ER luminal flow. The discovery of active flow in the ER has implications for timely ER content distribution throughout the cell, particularly important for cells with extensive ER-containing projections such as neurons.Wellcome Trust - 3-3249/Z/16/Z and 089703/Z/09/Z [Kaminski] UK Demential Research Institute [Avezov] Wellcome Trust - 200848/Z/16/Z, WT: UNS18966 [Ron] FRM Team Research Grant [Holcman] Engineering and Physical Sciences Research Council (EPSRC) - EP/L015889/1 and EP/H018301/1 [Kaminski] Medical Research Council (MRC) - MR/K015850/1 and MR/K02292X/1 [Kaminski

Organisation et fonction de nanodomaines subcellulaires révélés par l'analyse statistique de trajectoires de particules uniques

Single-Particle Trajectories (SPTs) obtained from super-resolution microscopy allow to track proteins with nanometer precision in living cells and are used in neuroscience and cellular biology. In this thesis, I was interested in the high-density nanodomains found in these trajectories that can be modeled as potential wells. To characterize them, I developed a new hybrid method based on the point density and local drift field and compared it to the other state-of-the-art methods. Then, I used it to identify transient potential wells in SPTs of voltage-gated calcium channels (CaV) contributing to a better understanding of the role of the different CaV splice variants in synaptic transmission. In another study, I looked at SPTs from Endoplasmic Reticulum (ER) luminal resident proteins where I developed a method to reconstruct the network from trajectories and used it to characterize the luminal motion as a jump-diffusion process, which allows for a better redistribution of the luminal content than the previously assumed diffusive model. Finally, I discuss other analyses of motions for lysosome-ER interactions, CaV2.1 channels at drosophila’s neuromuscular junctions and the description of the motion of the constituent proteins of the NuRD chromatin remodeling complex.Les trajectoires de molécules individuelles obtenues par microscopie super-résolution permettent de suivre des protéines avec une précision nanométrique dans des cellules vivantes. Dans cette thèse, j’ai étudié les régions de hautes densités présentes dans ces trajectoires, dont un modèle possible est celui des puits de potentiel. Pour les caractériser à partir de trajectoires, j’ai développé une nouvelle méthode hybride basée sur la densité de points et le champ de force local puis je l’ai comparé aux méthodes d’état de l’art. Ensuite, j’ai utilisé celle-ci pour caractériser les puits maintenant les canaux calciques Cav au niveau des zones actives des terminaux présynaptiques ce qui a permis de mieux comprendre le rôle des variantes d’épissage de ces canaux dans la transmission synaptique. Dans une autre étude, j’ai analysé des trajectoires de protéines résidant dans le lumen du Réticulum Endoplasmique (RE). J’ai créé une méthode pour reconstruire le réseau du RE à partir des trajectoires que j’ai utilisé pour caractériser le mouvement de ces molécules par un modèle de saut-diffusion qui a pour conséquence une meilleure redistribution du contenu luminal par rapport à un mouvement diffusif. Enfin, je discute d’autres analyses de trajectoires pour les intéractions lysosome-ER, les canaux Cav à la jonction neuro-musculaire de la drosophile et les protéines composant le complexe NuRD

Single-particle tracking in organelles: bridging the gap between local molecular dynamics and cellular trafficking.

The field of single-molecule tracking has an immense potential as it can theoretically resolve with millisecond and nanometre resolution where and what individual molecules do in live cells. Unleashing this potential has proven very challenging however because of technical, experimental and analytical difficulties that limit the imaging area, time resolution and duration for which a molecule can be reliably followed. I will discuss our progress toward solving these problems in the context of characterising protein motion in the Endoplasmic Reticulum (ER) and mitochondria, two organelles forming extensive networks throughout the cell. I will present our new methodological developments to automatise, improve and assess trajectory reconstruction at very high temporal resolutions to produce longer and more reliable trajectories. These methods consist in improving the accuracy of detected fluorescent spots by merging the results obtained from multiple detectors; Refining the spots linking step by integrating the organelle structure to build an empirical distance measure and performing simulations in reconstructed geometries to evaluate the trajectories certainty. We validated these approaches by resolving the predicted change to the dynamics at the ER membrane upon addition of oleic acid as well as studying protein dynamics in the mitochondrial matrix.</p

Extreme Symmetries in Complex Distributed Systems: the Bag-Oriented Approach

International audienceModel checking is widely used as an automatic exhaustive verification technique to check properties of complex systems. However, it is difficult to operate in the context of today’s emerging systems that combine distribution (and asynchronous communications) together with a large size (and a hierarchical composition of components – and thus, of specifications).This paper combines existing techniques tackling the known combinatorial explosion of model checking. To achieve this, we exploit the structure of such distributed systems (symmetries and hierarchical composition), thus allowing a better compression factor and calculus factorization in favorable cases. We present these techniques and assess their impact on some benchmark examples

Retropath: automated pipeline for embedded metabolic circuits.

Metabolic circuits are a promising alternative to other conventional genetic circuits as modular parts implementing functionalities required for synthetic biology applications. To date, metabolic design has been mainly focused on production circuits. Emergent applications such as smart therapeutics, however, require circuits that enable sensing and regulation. Here, we present RetroPath, an automated pipeline for embedded metabolic circuits that explores the circuit design space from a given set of specifications and selects the best circuits to implement based on desired constraints. Synthetic biology circuits embedded in a chassis organism that are capable of controlling the production, processing, sensing, and the release of specific molecules were enumerated in the metabolic space through a standard procedure. In that way, design and implementation of applications such as therapeutic circuits that autonomously diagnose and treat disease, are enabled, and their optimization is streamlined

Brain fragility among middle-aged and elderly patients from electroencephalogram during induction of anaesthesia

International audienceCognitive decline (CD) is a common condition amongst elderly, affecting memory, language or thinking. Patients experiencing CD have a higher incidence rate of post-operative neurocognitive disorders 1. Moreover, for a fraction of these patients

XTMS: pathway design in an eXTended metabolic space

As metabolic engineering and synthetic biology progress toward reaching the goal of a more sustainable use of biological resources, the need of increasing the number of value-added chemicals that can be produced in industrial organisms becomes more imperative. Exploring, however, the vast possibility of pathways amenable to engineering through heterologous genes expression in a chassis organism is complex and unattainable manually. Here, we present XTMS, a web-based pathway analysis platform available at http://xtms.issb.genopole.fr, which provides full access to the set of pathways that can be imported into a chassis organism such as Escherichia coli through the application of an Extended Metabolic Space modeling framework. The XTMS approach consists on determining the set of biochemical transformations that can potentially be processed in vivo as modeled by molecular signatures, a specific coding system for derivation of reaction rules for metabolic reactions and enumeration of all the corresponding substrates and products. Most promising routes are described in terms of metabolite exchange, maximum allowable pathway yield, toxicity and enzyme efficiency. By answering such critical design points, XTMS not only paves the road toward the rationalization of metabolic engineering, but also opens new processing possibilities for non-natural metabolites and novel enzymatic transformations