HAL Portal ESPCI (Ecole Supérieure de Physique et de Chimie Industrielles)
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Conventional chemotherapy: millions of cures, unresolved therapeutic index
No full textInternational audienceIn recent decades, millions of patients with cancer have been cured by chemotherapy alone. By ‘cure’, we mean that patients with cancers that would be fatal if left untreated receive a time-limited course of chemotherapy and their cancer disappears, never to return. In an era when hundreds of thousands of cancer genomes have been sequenced, a remarkable fact persists: in most patients who have been cured, we still do not fully understand the mechanisms underlying the therapeutic index by which the tumour cells are killed, but normal cells are somehow spared. In contrast, in more recent years, patients with cancer have benefited from targeted therapies that usually do not cure but whose mechanisms of therapeutic index are, at least superficially, understood. In this Perspective, we will explore the various and sometimes contradictory models that have attempted to explain why chemotherapy can cure some patients with cancer, and what gaps in our understanding of the therapeutic index of chemotherapy remain to be filled. We will summarize principles which have benefited curative conventional chemotherapy regimens in the past, principles which might be deployed in constructing combinations that include modern targeted therapies
Unraveling motion in proteins by combining NMR relaxometry and molecular dynamics simulations: A case study on ubiquitin
No full textInternational audienceNuclear magnetic resonance (NMR) relaxation experiments shine light onto the dynamics of molecular systems in the picosecond to millisecond timescales. As these methods cannot provide an atomically resolved view of the motion of atoms, functional groups, or domains giving rise to such signals, relaxation techniques have been combined with molecular dynamics (MD) simulations to obtain mechanistic descriptions and gain insights into the functional role of side chain or domain motion. In this work, we present a comparison of five computational methods that permit the joint analysis of MD simulations and NMR relaxation experiments. We discuss their relative strengths and areas of applicability and demonstrate how they may be utilized to interpret the dynamics in MD simulations with the small protein ubiquitin as a test system. We focus on the aliphatic side chains given the rigidity of the backbone of this protein. We find encouraging agreement between experiment, Markov state models built in the χ1/χ2 rotamer space of isoleucine residues, explicit rotamer jump models, and a decomposition of the motion using ROMANCE. These methods allow us to ascribe the dynamics to specific rotamer jumps. Simulations with eight different combinations of force field and water model highlight how the different metrics may be employed to pinpoint force field deficiencies. Furthermore, the presented comparison offers a perspective on the utility of NMR relaxation to serve as validation data for the prediction of kinetics by state-of-the-art biomolecular force fields
Dew and Rain Evolution from Climate Change in Semi-Arid South-Western Madagascar between 1991 and 2033 (Extrapolated)
No full textInternational audienceIn the context of global warming and the increasing scarcity of fresh water resources, it becomes significant to evaluate the contribution and evolution of non-rainfall waters such as dew. This study therefore aims to evaluate the relative dew and rain contributions in three sites of south-western of Madagascar (Ifaty, Toliara, and Andremba), a semi-arid region which suffers from a strong water deficit. The studied period is 1/1991–7/2023, with extrapolation to 7/2033. Dew is calculated from meteo data by using a well-established energy model. The extrapolation of dew and rain follows an artificial neural network approach. It is found that dew forms regularly (2–3 days on average between events), in contrast to rain (10–15 days). The evolutions of dew and rain are similar, with an increase from 1991 to 2000, a decrease up to 2020 and a further increase until 2033. These oscillations follow the Indian Ocean dipole variations and should be influenced by climate change. Dew contributions to the water balance remain modest on a yearly basis (3–4%) but is important during the dry season (Apr.–Oct.), up to 30%. Dew therefore appears to be a reliable and sustainable resource for plants, small animals, and the population, especially during droughts.Dans le contexte du réchauffement climatique et de la raréfaction des ressources en eau douce, il devient important d'évaluer la contribution et l'évolution des eaux non pluviales telles que la rosée. Cette étude vise donc à évaluer les contributions relatives de la rosée et de la pluie dans trois sites du sud-ouest de Madagascar (Ifaty, Toliara et Andremba), une région semi-aride qui souffre d'un fort déficit hydrique. La période étudiée est 1/1991–7/2023, avec extrapolation à 7/2033. La rosée est calculée à partir des données météorologiques en utilisant un modèle énergétique bien établi. L'extrapolation de la rosée et de la pluie suit une approche de réseau de neurones artificiels. On constate que la rosée se forme régulièrement (2 à 3 jours en moyenne entre les événements), contrairement à la pluie (10 à 15 jours). Les évolutions de la rosée et des pluies sont similaires, avec une augmentation de 1991 à 2000, une diminution jusqu'en 2020 et une nouvelle augmentation jusqu'en 2033. Ces oscillations suivent les variations dipolaires de l'océan Indien et devraient être influencées par le changement climatique. Les contributions de la rosée au bilan hydrique restent modestes sur une base annuelle (3-4%) mais sont importantes pendant la saison sèche (avril-octobre), jusqu'à 30%. La rosée apparaît donc comme une ressource fiable et durable pour les plantes, la petite faune et la population, notamment en période de sécheresse
PKCδ is an activator of neuronal mitochondrial metabolism that mediates the spacing effect on memory consolidation
No full textInternational audienceRelevance-based selectivity and high energy cost are two distinct features of long-term memory (LTM) formation that warrant its default inhibition. Spaced repetition of learning is a highly conserved cognitive mechanism that can lift this inhibition. Here, we questioned how the spacing effect integrates experience selection and energy efficiency at the cellular and molecular levels. We showed in Drosophila that spaced training triggers LTM formation by extending over several hours an increased mitochondrial metabolic activity in neurons of the associative memory center, the mushroom bodies (MBs). We found that this effect is mediated by PKCδ, a member of the so-called ‘novel PKC’ family of enzymes, which uncovers the critical function of PKCδ in neurons as a regulator of mitochondrial metabolism for LTM. Additionally, PKCδ activation and translocation to mitochondria result from LTM-specific dopamine signaling on MB neurons. By bridging experience-dependent neuronal circuit activity with metabolic modulation of memory-encoding neurons, PKCδ signaling binds the cognitive and metabolic constraints underlying LTM formation into a unified gating mechanism
Freezing receding contact lines
No full textWe investigate experimentally the receding of a contact line when a Peltier module is pulled out of a water bath at constant speed, while a ice layer is also growing at constant speed on the Peltier module. A steady regime is therefore reached for all the parameters used in this studied, corresponding to a dynamical stationnary meniscus. We show that the height of the meniscus provides most of the properties of the flow. For high pulling rate, it is related to the amount of liquid of the equivalent Landau-Levich (LL) film that would be extracted from the bath, which is eventually freezing as the plate is lifted upward. For smaller velocity, so that no LL film would be formed without freezing, the meniscus height is directly linked to the contact angle of water on ice in these conditions. Solving numerically the meniscus equation taking into account the solidifcation of water, our results suggest that the contact angle of water on ice should be around
A molecularly defined subpopulation of oligodendrocyte precursor cells controls the generation of myelinating oligodendrocytes during postnatal development
No full textInternational audienceOligodendrocyte precursor cells (OPCs) are a class of glial cells that uniformly tiles the entire central nervous system (CNS). They play several key functions across the brain including the generation of oligodendrocytes and the control of myelination. Whether the functional diversity of OPCs is the result of genetically defined subpopulations or of their regulation by external factors has not been definitely established. We discovered that a subpopulation of OPCs found across the brain is defined by the expression of C1ql1 , a gene previously described for its synaptic function in neurons. This subpopulation starts to appear during the first postnatal week in the mouse cortex. Ablation of C1ql1 -expressing OPCs in the mouse leads to a massive lack of oligodendrocytes and myelination in many brain regions. This deficit cannot be rescued, even though some OPCs escape Sox10 -driven ablation and end up partially compensating the OPC loss in the adult. Therefore, C1ql1 is a molecular marker of a functionally non-redundant subpopulation of OPCs, which controls the generation of myelinating oligodendrocytes
Viral and immune dynamics of HPV genital infections in young women
No full textHuman papillomavirus (HPV) infections drive one in twenty new cancer cases. Despite the potential for improving treatment, screening, and vaccination strategies, little is known as to why most HPV infections clear spontaneously within two years. To untangle the dynamics of these non-persisting infections, we performed a combined quantitative analysis of virological, immunological, and clinical data from an original longitudinal cohort of 189 women with high temporal resolution. We find that HPV viral load reaches a plateau within two months, and clears within a median time of 14 months. Furthermore, we identify immune correlates associated with infection clearance, especially TCR-gamma-delta cells. Our results open new perspectives for understanding the frontier between acute and chronic infections and for controlling HPVassociated diseases
Functionalization of microbubbles in a microfluidic chip for biosensing application
No full textInternational audienceMicrobubbles are widely used for biomedical applications, ranging from imagery to therapy. In these applications, microbub- bles can be functionalized to allow targeted drug delivery or imaging of the human body. However, functionalization of the microbubbles is quite difficult, due to the unstable nature of the gas/liquid interface. In this paper, we describe a simple protocol for rapid functionalization of microbubbles and show how to use them inside a microfluidic chip to develop a novel type of biosensor. The microbubbles are functionalized with biochemical ligand directly at their generation inside the microfluidic chip using a DSPE-PEG-Biotin phospholipid. The microbubbles are then organized inside a chamber before injecting the fluid with the bioanalyte of interest through the static bubbles network. In this proof-of-concept demonstration, we use streptavidin as the bioanalyte of interest. Both functionalization and capture are assessed using fluorescent microscopy thanks to fluorescent labeled chemicals. The main advantages of the proposed technique compared to classical ligand based biosensor using solid surface is its ability to rapidly regenerate the functionalized surface, with the complete functionalization/capture/measurement cycle taking less than 10 min
Convective Drying of Films of Polymer Solutions: Front Propagation Revealed by Thermal Measurements
No full textInternational audienceWe report on the drying of films of polymer solutions under a controlled laminar air flow. Temperature measurements reveal that a drying front propagates in the film at constant velocity. Using thermal calibration, we are able to quantitatively determine the local drying rate of the film, and we find it agrees with conservation arguments. We further show that a simple mass balance allows us to relate the front velocity to the drying rate. IntroductionEvaporation of water is a slow process because, in usual conditions, it is limited by diffusion of vapor in the atmosphere. Techniques to accelerate drying have been developed in industrial lines. Submitting the sample from which water or solvent must be extracted to a gas flow is particularly efficient and convective drying is widely used, for instance in the food [13] and coating [8] industries. When a thin liquid film is dried in a gas flow, as in a coating process, a front forms at the upstream edge, which propagates and separates a dry region from a liquid one. During the so-called directional drying, the microscopic structure of the sample may be modified by the passage of the front ; for instance, ordering [6] or aggregation [12] have been reported in colloidal suspensions.The kinetics of the front in unidirectional drying has been the object of less attention, although it could provide crucial information on the local drying rate. Measurements of global drying kinetics by techniques such as gravimetry [2], were conducted but they do not provide information on the front propagation. Recently, the volume fraction distribution of drying colloidal suspensions obtained from transmitted light intensity in presence of and added dye [9] was reported but the authors did not discuss the front kinetics. Other systems dried in air flows were studied with spatially resolved techniques, such as Fourier Transform Infrared Microscopy [19] or thickness measurements based on laser reflectometry [20, 21], but the front velocity was not inferred from those measurements, although the effect of the front passage on local shrinking was emphasised.In contrast, the kinetics of spontaneously forming drying fronts in evaporating films has been considered in several studies. Without air convection, lateral fronts form because drying is faster at the edges of the film. In the literature, the mechanism of faster drying is under debate and is attributed either to a larger evaporation flux at the edges [3] or to the film being thinner at the edges in the case of a small contact</div
Modulation nicotinique de l'activité dopaminergique et des comportements motivés
No full textSmoking affects one billion people worldwide, and is responsible for over 8 million preventable deaths a year, making it a major health concern. Nicotine, the main active compound in tobacco, acts on the nervous system by binding to nicotinic acetylcholine receptors (nAChRs). There is a wide diversity of nAChR subunits (α2 to 10 and β2 to 4) which assemble in different combinations to form pentameric receptors with different biophysical properties and localizations. Nicotine concomitantly produces rewarding and aversive effects, promoting and limiting nicotine consumption, respectively. While nAChRs are expressed in the reward system, notably the ventral tegmental area (VTA), they are also present in many other brain regions susceptible to nicotine-induced disruptions. The aim of my thesis work was to investigate the involvement of two non-canonical VTA-connected brain pathways in nicotine addiction: the pathways linking the interpeduncular nucleus (IPN) and the VTA, and the one connecting the VTA to the claustrum (CLA). I first studied the involvement of the IPN in nicotine reinforcement. We showed that IPN neurons respond heterogeneously to nicotine, and discovered that they are sensitive to low doses of nicotine that do not activate the VTA. Using new chemogenetic tools that I have developed, we have shown that β4-containing nAChRs of the IPN act as a brake on the response to nicotine in the VTA, thereby reducing the rewarding effects of the drug. The IPN would therefore contribute not only to aversion but also to nicotine reinforcement. Secondly, I studied how prolonged exposure to nicotine alters social interactions, and the potential involvement of the VTA-CLA pathway in these behavioral perturbations. We showed that chronic nicotine exposure increased the saliency of a novel social stimulus in a three-chamber task, resulting in an increased interaction time with novel conspecifics. Moreover, optogenetic activation of the VTA-CLA pathway induced a loss of preference for the novel social stimulus, while non-contingent optogenetic stimulation replicated the behavioral effects of prolonged nicotine exposure. Therefore, the VTA-CLA pathway seems to be involved in the saliency for new social stimuli, and this function may be disrupted by chronic nicotine exposure. Taken together, these studies highlight the importance of these two non-canonical pathways in nicotine addictionLe tabagisme, qui concerne un milliard de personnes à travers le monde, est à l’origine de plus de 8 millions de décès évitables par an, et constitue ainsi un enjeu sanitaire majeur. La nicotine, principal composé actif du tabac, agit au niveau du système nerveux en se liant aux récepteurs nicotiniques de l’acétylcholine (nAChR). Cette liaison produit de manière concomitante des effets récompensants et aversifs, permettant respectivement de promouvoir et limiter la consommation de tabac. Les nAChR sont exprimés au niveau du système de la récompense, notamment l’aire tegmentale ventrale (VTA), mais également dans de nombreuses autres régions cérébrales perturbées par la nicotine. L’objectif de mes travaux de thèse a été d’étudier l’effet de la nicotine sur deux voies cérébrales centrées sur la VTA et non canoniques : la voie reliant noyau interpédonculaire (IPN) et la VTA d’une part, et la voie projetant de la VTA vers le claustrum (CLA) d’autre part. J’ai dans un premier temps étudié l’implication de l’IPN dans le renforcement à la nicotine. Nous avons montré que les neurones de l’IPN répondent de manière hétérogène à la nicotine, et découvert qu’ils sont sensibles à de faibles doses de nicotine qui n’activent pas la VTA. A l’aide de nouveaux outils chémogénétiques que j’ai développés, nous avons mis en évidence que les nAChR contenant β4 de l’IPN jouent un rôle de frein sur la réponse à la nicotine dans la VTA, et diminuent ainsi l’effet récompensant de la drogue. L’IPN ne jouerait donc pas uniquement un rôle dans l’aversion mais également dans le renforcement à la nicotine. Dans un second temps, j’ai étudié comment une exposition prolongée à la nicotine modifie les interactions sociales, et comment la voie VTA-CLA pourrait participer à ces perturbations comportementales. Nous avons observé qu’une exposition chronique à la nicotine produit une augmentation de la saillance d’un stimulus social nouveau dans une tâche trois-chambres, se traduisant par une augmentation du temps passé avec le nouveau congénère. De plus, l’activation optogénétique de la voie VTA-CLA induit une perte de la préférence pour le stimulus social nouveau dans la tâche trois-chambre, tandis que la stimulation optogénétique non contingente reproduit les effets comportementaux d’une exposition prolongée à la nicotine. La voie VTA-CLA semble donc impliquée dans la saillance pour de nouveaux stimuli sociaux, et cette fonction serait perturbée par la nicotine chronique. L’ensemble de ces travaux permet de mettre en évidence l’importance de ces deux nouvelles voies non canoniques dans l’addiction à la nicotine