Analyse et modélisation de la dynamique des chromosomes durant la mitose chez la levure à fission

La mitose est une étape clé du cycle cellulaire, très préservée chez toutes les cellules eucaryotes, durant laquelle le matériel génétique de la cellule (les chromosomes) réparti de manière égale dans les deux cellules filles. Cette équipartition du matériel génétique est cruciale pour le maintien de la stabilité génétique. Durant ce processus, les chromosomes, composés des chromatides soeurs, établissent une plaque métaphasique au centre du fuseau mitotique. Chaque chromatide est attachée à un pôle du fuseau mitotique respectif (on parle d'attachement bipolaire) vers lequel elle se dirigera durant l'anaphase. Les chromatides sont l'unité indivisible du matériel génétique durant la mitose, à l'image des atomes dans une molécule. Initialement, une fois la chromatine condensée en chromosomes, chacun de ces " objets " est détaché et réparti suivant une position précise appellée territoires chromosomiques. Toute la complexité de la mitose est de capturer chacune des chromatides et de les positionner sur la plaque métaphasique avant leur séparation et migration vers leur pôle respectif durant l'anaphase. Cette étape de la division cellulaire requiert donc non seulement un réseau complexe d'interaction et de signalisation biochimique comme dans beaucoup d'autres processus biologiques mais aussi un fin contrôle spatio-temporel du mouvement et du positionnement de ces objets de grande taille à l'échelle de la cellule. Il semblerait que l'origine du mouvement des chromosomes provienne pour une grande part de la dynamique des microtubules. Ce qui est moins certain est la part relative accordée aux différents processus régulant cette dynamique; que ce soit la dynamique intrinsèque (appelée instabilité dynamique des microtubules) ou l'effet de différentes protéines sur les microtubules comme les MAPs (Microtubule Associated Proteins) et les kinésines (protéines motrices). On notera par ailleurs que le mécanisme de transfert d'énergie entre la dynamique des microtubules et le mouvement des chromosomes est encore très largement hypothétique. La dynamique des chromosomes durant la mitose est aussi largement contrôlée par un grand nombre d'acteurs autres que les microtubules. Certains d'entre eux étant responsables de l'attachement MTs-kinétochore comme les complexes NDC80 et DAM1, tandis que d'autres sont impliqués dans la régulation de la dynamique des microtubules comme la kinésine-8 et la kinésine-13. Durant mon travail de thèse, j'ai étudié la dynamique des chromosomes en mitose chez la levure à fission, modèle celulaire dont les mécanismes primordiaux qui contrôlent la mitose sont conservés avec les eucaryotes supérieurs. En effet, j'ai caractérisé deux de ces mécanismes conservés au cours de l'évolution: l'alignement des chromosomes durant la métaphase ainsi qu'un mouvement de va et vient plus ou moins régulier le long du fuseau aussi appelé oscillation des chromosomes. J'ai montré, en analysant les trajectoires des chromosomes que ces deux processus sont pour une large part indépendants [@Mary2015]. De plus, le processus d'alignement des chromosomes, encore mal compris, est en partie contrôlé par la kinésine-8 via une activité dépendante de la longueur des microtubules. Il semblerait donc que cette kinésine soit capable de fournir une information spatiale le long du fuseau mitotique afin de positionner correctement les chromosomes. Enfin, j'ai utilisé un modèle mathématique de la ségrégation des chromosomes précédemment développé dans l'équipe afin de tester de manière quantitative les hypothèses de mécanisme du centrage des chromosomes par la kinésine-8. L'ensemble de mon travail porte donc sur le contrôle du mouvement, de l'attachement et du positionnement des chromosomes durant la mitose afin de mieux comprendre les processus biophysiques associés à la mitose.Mitosis is a highly preserved process in all eukaryotic cells during which the genetic material (chromosomes) is divided in two parts which spread in both daughter cells. This equipartition is crucial for maintaining genetic stability. During this process, chromosomes form a metaphasic plate at the center of the mitotic spindle. Each chromatid is attached to its respective spindle pole (called bipolar attachment) toward which it will move during anaphase. Chromatids are the indivisible units of genetic material during mitosis just like atoms in a molecule. Originally each of these "\ objects\ " are detached and organized in chromosomes territories. All the complexity of mitosis resides in the capture of each chromatid by the spindle pole to exert forces to position them on the metaphase plate before their separation and migration towards their respective poles in anaphase. This step of cell division not only requires complex interaction networks and metabolic signaling pathways just like many other biological processes but also a fine spatio-temporal control of movement and positioning of these big objects relative to cell size. It is usually accepted that the origin of chromosome movement arises from microtubule dynamics. However, what is less clear is the relative importance of each of these processes regulating chromosome movement: the intrinsic dynamic instability of microtubules or the effect of their associated proteins such as MAPs and kinesins. It is also important to note that the mechanism controlling the transfer of energy between microtubule dynamics and chromosome movement is still largely hypothetical. Moreover, chromosome dynamics during mitosis is regulated by a large number of actors apart from microtubules. Some of them being responsible for MT-kinetochore attachment such as NDC80 and DAM1 complex. While others are involved in the regulation of MT dynamics such as Kinesin-8 and Kinesin-13. During my PhD, I studied fission yest chromosome dynamic during mitosis. This cellular model has the advantage of sharing many fundamental mechanisms of symmetrically dividing higher eukaryotic cells. I characterized two of these conserved mechanisms: chromosome alignment during metaphase and back and forth movement along the spindle, called chromosome oscillation. By analyzing chromosome trajectories, I showed that both processes are performed through independent mechanisms [@Mary2015]. Moreover, chromosome alignment process, which is still poorly understood, is regulated by Kinesin-8 via a length dependent activity on microtubules. This suggests that Kinesin-8 is able to provide spatial information along the mitotic spindle to properly position chromosomes. Finally, I used a mathematical model of chromosome segregation in order to test quantitatively different hypotheses of chromosome centering process. This work is thus deciphering the control of movement, attachment and positioning of chromosomes during mitosis and seeks to better understand the biophysical processes controlling mitosis

Towards Foundational Models for Molecular Learning on Large-Scale Multi-Task Datasets

Recently, pre-trained foundation models have enabled significant advancements in multiple fields. In molecular machine learning, however, where datasets are often hand-curated, and hence typically small, the lack of datasets with labeled features, and codebases to manage those datasets, has hindered the development of foundation models. In this work, we present seven novel datasets categorized by size into three distinct categories: ToyMix, LargeMix and UltraLarge. These datasets push the boundaries in both the scale and the diversity of supervised labels for molecular learning. They cover nearly 100 million molecules and over 3000 sparsely defined tasks, totaling more than 13 billion individual labels of both quantum and biological nature. In comparison, our datasets contain 300 times more data points than the widely used OGB-LSC PCQM4Mv2 dataset, and 13 times more than the quantum-only QM1B dataset. In addition, to support the development of foundational models based on our proposed datasets, we present the Graphium graph machine learning library which simplifies the process of building and training molecular machine learning models for multi-task and multi-level molecular datasets. Finally, we present a range of baseline results as a starting point of multi-task and multi-level training on these datasets. Empirically, we observe that performance on low-resource biological datasets show improvement by also training on large amounts of quantum data. This indicates that there may be potential in multi-task and multi-level training of a foundation model and fine-tuning it to resource-constrained downstream tasks

Chromosome dynamics during mitosis in fission yeast

La mitose est une étape clé du cycle cellulaire, très préservée chez toutes les cellules eucaryotes, durant laquelle le matériel génétique de la cellule (les chromosomes) réparti de manière égale dans les deux cellules filles. Cette équipartition du matériel génétique est cruciale pour le maintien de la stabilité génétique. Durant ce processus, les chromosomes, composés des chromatides soeurs, établissent une plaque métaphasique au centre du fuseau mitotique. Chaque chromatide est attachée à un pôle du fuseau mitotique respectif (on parle d'attachement bipolaire) vers lequel elle se dirigera durant l'anaphase. Les chromatides sont l'unité indivisible du matériel génétique durant la mitose, à l'image des atomes dans une molécule. Initialement, une fois la chromatine condensée en chromosomes, chacun de ces " objets " est détaché et réparti suivant une position précise appellée territoires chromosomiques. Toute la complexité de la mitose est de capturer chacune des chromatides et de les positionner sur la plaque métaphasique avant leur séparation et migration vers leur pôle respectif durant l'anaphase. Cette étape de la division cellulaire requiert donc non seulement un réseau complexe d'interaction et de signalisation biochimique comme dans beaucoup d'autres processus biologiques mais aussi un fin contrôle spatio-temporel du mouvement et du positionnement de ces objets de grande taille à l'échelle de la cellule. Il semblerait que l'origine du mouvement des chromosomes provienne pour une grande part de la dynamique des microtubules. Ce qui est moins certain est la part relative accordée aux différents processus régulant cette dynamique; que ce soit la dynamique intrinsèque (appelée instabilité dynamique des microtubules) ou l'effet de différentes protéines sur les microtubules comme les MAPs (Microtubule Associated Proteins) et les kinésines (protéines motrices). On notera par ailleurs que le mécanisme de transfert d'énergie entre la dynamique des microtubules et le mouvement des chromosomes est encore très largement hypothétique. La dynamique des chromosomes durant la mitose est aussi largement contrôlée par un grand nombre d'acteurs autres que les microtubules. Certains d'entre eux étant responsables de l'attachement MTs-kinétochore comme les complexes NDC80 et DAM1, tandis que d'autres sont impliqués dans la régulation de la dynamique des microtubules comme la kinésine-8 et la kinésine-13. Durant mon travail de thèse, j'ai étudié la dynamique des chromosomes en mitose chez la levure à fission, modèle celulaire dont les mécanismes primordiaux qui contrôlent la mitose sont conservés avec les eucaryotes supérieurs. En effet, j'ai caractérisé deux de ces mécanismes conservés au cours de l'évolution: l'alignement des chromosomes durant la métaphase ainsi qu'un mouvement de va et vient plus ou moins régulier le long du fuseau aussi appelé oscillation des chromosomes. J'ai montré, en analysant les trajectoires des chromosomes que ces deux processus sont pour une large part indépendants [@Mary2015]. De plus, le processus d'alignement des chromosomes, encore mal compris, est en partie contrôlé par la kinésine-8 via une activité dépendante de la longueur des microtubules. Il semblerait donc que cette kinésine soit capable de fournir une information spatiale le long du fuseau mitotique afin de positionner correctement les chromosomes. Enfin, j'ai utilisé un modèle mathématique de la ségrégation des chromosomes précédemment développé dans l'équipe afin de tester de manière quantitative les hypothèses de mécanisme du centrage des chromosomes par la kinésine-8. L'ensemble de mon travail porte donc sur le contrôle du mouvement, de l'attachement et du positionnement des chromosomes durant la mitose afin de mieux comprendre les processus biophysiques associés à la mitose.Mitosis is a highly preserved process in all eukaryotic cells during which the genetic material (chromosomes) is divided in two parts which spread in both daughter cells. This equipartition is crucial for maintaining genetic stability. During this process, chromosomes form a metaphasic plate at the center of the mitotic spindle. Each chromatid is attached to its respective spindle pole (called bipolar attachment) toward which it will move during anaphase. Chromatids are the indivisible units of genetic material during mitosis just like atoms in a molecule. Originally each of these "\ objects\ " are detached and organized in chromosomes territories. All the complexity of mitosis resides in the capture of each chromatid by the spindle pole to exert forces to position them on the metaphase plate before their separation and migration towards their respective poles in anaphase. This step of cell division not only requires complex interaction networks and metabolic signaling pathways just like many other biological processes but also a fine spatio-temporal control of movement and positioning of these big objects relative to cell size. It is usually accepted that the origin of chromosome movement arises from microtubule dynamics. However, what is less clear is the relative importance of each of these processes regulating chromosome movement: the intrinsic dynamic instability of microtubules or the effect of their associated proteins such as MAPs and kinesins. It is also important to note that the mechanism controlling the transfer of energy between microtubule dynamics and chromosome movement is still largely hypothetical. Moreover, chromosome dynamics during mitosis is regulated by a large number of actors apart from microtubules. Some of them being responsible for MT-kinetochore attachment such as NDC80 and DAM1 complex. While others are involved in the regulation of MT dynamics such as Kinesin-8 and Kinesin-13. During my PhD, I studied fission yest chromosome dynamic during mitosis. This cellular model has the advantage of sharing many fundamental mechanisms of symmetrically dividing higher eukaryotic cells. I characterized two of these conserved mechanisms: chromosome alignment during metaphase and back and forth movement along the spindle, called chromosome oscillation. By analyzing chromosome trajectories, I showed that both processes are performed through independent mechanisms [@Mary2015]. Moreover, chromosome alignment process, which is still poorly understood, is regulated by Kinesin-8 via a length dependent activity on microtubules. This suggests that Kinesin-8 is able to provide spatial information along the mitotic spindle to properly position chromosomes. Finally, I used a mathematical model of chromosome segregation in order to test quantitatively different hypotheses of chromosome centering process. This work is thus deciphering the control of movement, attachment and positioning of chromosomes during mitosis and seeks to better understand the biophysical processes controlling mitosis

KymographBuilder: Version 1.2.0

KymographBuilder is Yet Another Kymograph Fiji plugin

KymographBuilder: Release 1.2.3

KymographBuilder is Yet Another Kymograph Fiji plugin

Real-World Molecular Out-Of-Distribution: Specification and Investigation

This study presents a rigorous framework for investigating Molecular Out-Of-Distribution (MOOD) generalization in drug discovery. The concept of MOOD is first clarified through a problem specification that demonstrates how the covariate shifts encountered during real-world deployment can be characterized by the distribution of sample distances to the training set. We find that these shifts can cause performance to drop by up to 60% and uncertainty calibration by up to 40%. This leads us to propose a splitting protocol that aims to close the gap between deployment and testing. Then, using this protocol, a thorough investigation is conducted to assess the impact of model design, model selection and dataset characteristics on MOOD performance and uncertainty calibration. We find that appropriate representations and algorithms with built-in uncertainty estimation are crucial to improve performance and uncertainty calibration. This study sets itself apart by its exhaustiveness and opens an exciting avenue to benchmark meaningful, algorithmic progress in molecular scoring. All related code can be found on Github at https://github.com/valence-labs/mood-experiments

A Rosetta stone linking melt trajectories in the mantle to the stress field and lithological heterogeneities (Trinity ophiolite, California)

Infiltration triggered by selective dissolution of pyroxenes is a major mode of melt migration in the mantle. A common view, supported by experiments and numerical models, is that the geometry of the melt plumbing system is governed by the stress field induced by solid-state flow of the host peridotite. Yet, salient melt migration structures frozen at an early stage of development in the mantle section of the Trinity ophiolite reveal that lithological heterogeneities drastically impact melt trajectories. Where melts reach a pyroxenite layer, dissolution-induced permeability abruptly increases, initiating a feedback loop confining melt migration to that layer regardless of its orientation relative to the stress field. This process results in the development of a network of interweaved dunitic channels evolving to thick tabular dunites where the melt reacts with closely spaced pyroxenite layers. This reacting melt was rich in alkali elements and water, as evidenced by the minerals (mostly amphibole and micas) encapsulated in the Cr-spinel grains that crystallized during the reaction. This “pioneer melt” differs from the volumetrically dominant depleted andesite that fed the crustal section. In fact, the migration of andesite benefited from the enhanced permeability provided by the dunites formed by the pioneer melt. As a result, dunites are palimpsests, the compositions of which record successive percolation events. The geometry of the melt pathways is extremely challenging to model because the abundance, spacing, and orientation of lithological heterogeneities cannot be predicted, being inherited from a long geological history

Fission yeast Kinesin-8 controls chromosome congression independently of oscillations

International audienceIn higher eukaryotes, efficient chromosome congression relies, among other players, on the activity of chromokinesins. Here, we provide a quantitative analysis of kinetochore oscillations and positioning in Schizosaccharomyces pombe, a model organism lacking chromokinesins. In wild-type cells, chromosomes align during prophase and, while oscillating, maintain this alignment throughout metaphase. Chromosome oscillations are dispensable both for kinetochore congression and stable kinetochore alignment during metaphase. In higher eukaryotes, kinesin-8 family members control chromosome congression by regulating their oscillations. By contrast, here, we demonstrate that fission yeast kinesin-8 controls chromosome congression by an alternative mechanism. We propose that kinesin-8 aligns chromosomes by controlling pulling forces in a length-dependent manner. A coarse-grained model of chromosome segregation implemented with a length-dependent process that controls the force at kinetochores is necessary and sufficient to mimic kinetochore alignment, and prevents the appearance of lagging chromosomes. Taken together, these data illustrate how the local action of a motor protein at kinetochores provides spatial cues within the spindle to align chromosomes and to prevent aneuploidy

Deformation of mantle pyroxenites provides clues to geodynamic processes in subduction zones: Case study of the Cabo Ortegal Complex, Spain

International audienceIn the Herbeira massif, Cabo Ortegal Complex, Spain, a well exposed assemblage of deformed dunites and pyroxenites offers a unique opportunity to investigate key upper mantle tectonic processes. Four types of pyroxenites are recognized: clinopyroxenites with enclosed dunitic lenses (type-1), massive websterites (type-2), foliated and commonly highly amphibolitized clinopyroxenites (type-3) and orthopyroxenites (type-4). Field and petrological observations together with EBSD analysis provide new insights on the physical behavior of the pyroxenes and their conditions of deformation and reveal the unexpected journey of the Cabo Ortegal pyroxenites. We show that, during deformation, type-1 pyroxenites, due to their enclosed dunitic lenses, are more likely to localize the deformation than types-2 and -4 pyroxenites and may latter act as preferred pathway for fluid/melt percolation, eventually resulting in type-3 pyroxenites. All pyroxenite types display a similar response to deformation. Orthopyroxene deformed mostly by dislocation creep; it shows kink bands and undulose extinction and its fabric is dominated by [001](100). Clinopyroxene displays subgrain rotation, dynamic recrystallization and fabric with [010] axes clustering next to the foliation pole and [001] axes clustering next to the lineation suggesting activation of [001]{110} and [001](100) in some samples. These observations are in good agreement with deformation at temperatures greater than 1000 °C. Olivine in type-1 and type-4 pyroxenites shows [100](010) or [001](010) fabrics that are consistent with deformation at temperatures >1000 °C and may indicate deformation in a hydrous environment. The amphibole [001](100) fabric gives insights on a lower-temperature deformation episode (∼800 to 500 °C). Our results, interpreted in the light of published experimental data, together with the regional geological and geochemical studies are consistent with the following tectonic evolution of the Cabo Ortegal pyroxenites: (1) delamination from an arc root in a mantle-wedge setting at temperatures above 1000 °C and (2) introduction into a relatively softer subduction channel where deformation was accommodated by localized shear zones, thus preserving the high-temperature fabrics of pyroxenites. The Cabo Ortegal pyroxenites may therefore be seen as a rare exposure of deformed mantle-wedge material

The microstructure of layered ultramafic cumulates: Case study of the Bear Creek intrusion, Trinity ophiolite, California, USA

International audienceIn the Trinity ophiolite, California, USA, several mafic-ultramafic plutons intruded a peridotitic host 435 to 405 m.y. ago in a tectonic setting interpreted as an arc-related spreading centre. One of these intrusions, in the Bear Creek area, exposes basal ultramafic cumulates with igneous layering comprising an alternation of uncommonly thin (down to a few mm) layers of dunite, peridotite and pyroxenite that might be specific to this tectonic setting. These layers offer an excellent opportunity to characterise the microstructure of uncommon cumulates from the lower crust using EBSD (Electron Backscatter Diffraction). This "high-frequency" layering rests on underlying lherzolites and grades upward to more massive pyroxenites (i.e. clinopyroxenites with minor olivine-rich layers). Our field observations and data from the Bear Creek cumulates together with the preservation of magmatic features suggest the environment was tectonically stable after the emplacement of the cumulates. A detailed microstructural investigation of all minerals from the Bear Creek cumulates allows us to decipher their magmatic and plastic deformation history. In a structural reference frame defined by the compositional layering and the elongation direction of the surrounding host peridotites, olivine in the cumulates presents a [010]-fibre fabric and rarely a [001](010) fabric. Clinopyroxene shows a concentration of [010] axes normal to the layering plane with [100] and [001] defining girdles. Orthopyroxene mostly has a fabric with [100] and/or [010] subnormal to the layering plane and [001] scattered along a girdle in the plane of layering. All minerals show a strong fabric. We interpret the formation of the developed planar microstructures as a result of magmatic processes, with high contribution of crystal settling. To a lesser extent, compaction could have been operating and may be linked to the rare evidence of plastic deformation. Clusters of axes within the girdles of olivine and pyroxene CPOs preferentially appear close to the direction of elongation of the surrounding peridotites (i.e. N115°). EBSD analysis of the shape-preferred orientation of Bear Creek's minerals revealed a preferential alignment of the olivine and cpx long axis with the N°115 direction. This magmatic lineation and the preferred direction in the CPOs girdles are both consistent with the stretching lineation acquired during solid-state deformation by the mantle peridotite of the Trinity ophiolite. We suggest that a weak magma flux early on and/or an ongoing but limited regional stress could be responsible for these clusters. Although a direct coupling between asthenospheric flow and magmatic flow cannot be invoked in this context of melt intrusion in the lithosphere, this result highlights that the stress field applied on the mantle could have been still active and similar during the formation of Bear Creek intrusion. Our new field and microstructural data, together with previously presented petrological data, fit a scenario for the evolution of the Trinity ophiolite in which a mantle segment was intruded by a single large batch of primitive boninitic-andesitic melt. Our results emphasise the importance of considering the initial magmatic microstructures and the original shape anisotropy when investigating later deformation in ultramafic rocks