NCube/papyrus huggingface dataset:
Développement de liquides synoviaux synthétiques bio-inspirés

Bioinspiration consists in the design of materials inspired by biological systems which have developed ingenious solutions to suit their environment. This project deals with  bioinspiration for joint lubrication and in particular for the development of treatments for patients suffering from osteoarthritis (OA). To do so, we took our inspiration from joints which are amongst the most efficient aqueous tribological systems. Their unique properties arise from the complex synergistic interactions between cartilage structure and the lubricant macromolecules of the synovial fluid (SF). However, during OA, inflammatory mechanisms as long as mechanical erosion result in the degeneration of cartilage and lubricant macromolecules (aggrecan and lubricin). Polymeric mimes of the SF have been synthesized based on the bottle-brush (BB) architecture of LUB and AGG which is responsible for the joint lubrication. Tribological tests (SFA, tribometer) showed that BB polymers provided mica surfaces with a low friction and a wear protection up to several megapascals, typically in the range of natural joints. This wear protection was essentially due to the incorporation of anchoring groups specific to mica tribopairs on the BB polymers and the intermolecular bridging and entanglements emerging between BB polymers and high molecular weight HA, another main SF component. Cartilage mimes composed of multilayered chitosan hydrogels were designed to mimic the basic features of cartilage. Along with our BB polymers, the hydrogels, which are poroelastic and fragile materials, provided a low friction and a great decrease of wear.

Keyphrases: Tribologie, Friction, Hydrogel, Liquide synovial, Cartilage, Bottle-brush polymers, Tribology, Wear, Joints, Synovial fluid
Impact of the pulvinar on the ventral pathway of the cat visual cortex

Signals from the retina are relayed to the lateral geniculate nucleus from which they are sent to the primary visual cortex. At the cortical level, the information is transferred across several visual areas in which the complexity of the processing increases progressively. Anatomical and functional evidence demonstrate the existence of two main pathways in visual cortex processing distinct features of the visual information: the dorsal and ventral streams. Cortical areas composing the dorsal stream are implicated mostly in motion processing while those comprising the ventral stream are involved in the processing of form and colour. This classic view of the cortical functional organization is challenged by the existence of reciprocal connections of visual cortical areas with the thalamic nucleus named pulvinar. These connections allow the creation of a trans-thalamic pathway that parallels the cortico-cortical communications across the visual hierarchy.  The main goal of the present thesis is twofold: first, to obtain a better comprehension of the processing of light increments and decrements in an area of the cat ventral stream (area 21a); second, to characterize the nature of the thalamo-cortical inputs from the cat lateral posterior nucleus (LP) to area 21a.  In study #1, we investigated the spatiotemporal response profile of neurons from area 21a to light increments (brights) and decrements (darks) using a reverse correlation analysis of a sparse noise stimulus. Our findings showed that 21a neurons exhibited stronger responses to darks with receptive fields exhibiting larger dark subfields. However, no differences were found between the temporal dynamics of brights and darks. In comparison with the primary visual cortex, the dark preference in area 21a was found to be strongly enhanced, supporting the notion that the asymmetries between brights and darks are transmitted and amplified along the ventral stream.  In study #2, we investigated the impact of the reversible pharmacological inactivation of the LP nucleus on the contrast response function (CRF) of neurons from area 21a and the primary visual cortex (area 17). The thalamic inactivation yielded distinct effects on both cortical areas. While in area 17 the LP inactivation caused a slight decrease in the response gain, in area 21a a strong increase was observed. Thus, our findings suggest that the LP exerts a modulatory influence on the cortical processing along the ventral stream with stronger impact on higher order extrastriate areas.  Taken together, our findings allowed a better comprehension of the functional properties of the cat ventral stream and contributed to the current knowledge on the role of the pulvinar on the cortico-thalamo-cortical processing of visual information.

Keyphrases: corrélation reverse, area 21a, primary visual cortex, reverse correlation, lateral posterior nucleus, contrast response, electrophysiology, thalamic inactivation
Vers une forme répétitive instable : recherche de nouveaux moyens d’expression par la répétition de gestes et de textures complexes

This thesis aims to explore, through a compositional approach, a phenomenon that is omnipresent both in nature and in art: repetition. The relationship between the process of writing a piece and the end result perceived by the listener is not always obvious. At times, perceiving the composer's concept can be challenging. Repetition even helps in memorizing and perceiving complexity better. In my music, repetition as I see it is purposely unidentical: changes occur in each iteration, are found in the musical material itself, or are created simply by a variation in the listener’s perception. This research explores theoretically and conceptually the term unstable repetition - the term which I coined to denote the phenomenon - and its application to a cycle of instrumental and live electronic compositions. The main research questions discussed are (1) the definition of a repetitive form and its use in the music of the XXth-XXIth centuries, (2) the definition of a musical gesture and a complex texture, (3) the effect of repetition on the perception of these textures, and (4) the compositional strategies to produce an unstable repetitive effect. Inspired by the electroacoustic expression, my instrumental music uses noisy textures, and by using amplification like a microscope, subtle textures are revealed.

Keyphrases: variations, geste musical, perception, amplification, textures complexes, instrumental music, live electronics, repetition, repetitive music, musical gesture, computer assisted composition, complex textures
Understanding the underlying biomechanical mechanisms and strategies in dysvascular lower-limb amputees during Gait Initiation : implications for Gait analysis

A large number of biomechanical parameters are readily available with which to quantify gait but no consensus on the most relevant parameters for gait analysis in healthy adults exists with which to compare these results. The first objective of this thesis was therefore to complete a systematic review in order to establish those parameters most relevant for gait analysis in healthy adults. Results showed spatio-temporal parameters, specifically walking velocity, to be the most often measured biomechanical parameters and reported by the greatest number of articles for gait analysis in the healthy adult population. Further research should aim to compare these results to those of other populations and determine their clinical relevance.    In gait initiation, anticipatory postural adjustments (APA) allow for body weight to be transferred and propulsion while maintaining balance. As well, the first step accounts for 75% to 90% of the steady-state walking velocity (SSWV). Though the dysvascular transtibial amputee (DTTA) is the most sizeable and growing amputee population, no studies have yet investigated the APA’s and first step gait initiation pattern in this specific population. Thus, the second and third objectives of this thesis were aimed at comparing the APA’s pattern and underlying first step kinetics in 10 DTTA with 10 healthy controls prior during gait initiation. Participants were asked to initiate gait with their right then left limb leading until they reached SSWV.  In the second study, the increased APA time observed in the DTTA support the strategy to improve impulse by increasing time in the presence of diminished force production. The most important result is with regards to A/P total APA, as a total anterior displacement was observed in the prosthetic limb and would appear to be related to further reductions in propulsion specifically associated with dysvascular amputation.   Lastly, the results of the third study showed that propulsive impulse was significantly reduced in the prosthetic limb when compared to intact and control limbs. The reduction in propulsive impulse testifies of the missing plantarflexor muscles of the prosthetic limb. Interestingly, with regards to maximum vertical force at weight acceptance and loading rate there was no difference between the intact limb and the control limb. Though the DTTA are able to produce less intact limb vertical force, this may also place them at a reduced osteoarthritis risk in the intact limb.  Rehabilitation specialists should focus on both prosthetic and intact leading limb for gait initiation to aid the DTTA with everyday perturbations. As well, increasing SSWV should perhaps not be a goal of rehabilitation. Future research should focus on comparing gait initiation in the DTTA when compared to the traumatic TTA counterpart as well as understanding gait termination in the DTTA.

Keyphrases: anticipatory postural adjustments, gait, gait initiation, biomechanics, transtibial amputee
Étude du rôle de la signalisation canonique des Bmp lors de la régénération de la patte d'axolotl

Salamanders possess the rare ability to perfectly regenerate its limbs following amputation. This makes it a great model to understand how to bring the phenomenon closer to human use. However, the inner workings of regeneration remain largely unknown. A limited number of genes have been studied in this context and even fewer have been analyzed functionally. This work focuses on the roles of the canonical Bmp signaling pathway. We find that Bmps act distinctly from Tgf-β during limb regeneration. We also find that Bmps, and many of their potential targets are expressed throughout the redevelopment blastema phase of regeneration. By using the chemical inhibitor LDN193189, we explore the consequences of loss of canonical Bmp signaling in regeneration. This results in severe hypoplasia or complete absence of the regenerated limbs. By limiting treatments to specific timeframes, we try to separate the possible roles of Bmp temporally. We find that Bmp signaling is indeed required for the expression of selected target genes, but that requirement varies from one stages of regeneration to another. Bmp signaling maintains expression of Msx genes and is required for proliferation during the growth stage of the blastema. It is required for the induction of Fgf8 and Shh during the early pattern formation events. Chondrogenic genes are also dependent on Bmp signaling, but only at later stages. By administering LDN193189 treatments at different time points during regeneration, we clearly show that limb regeneration progresses in a proximal to distal fashion, going against an intercalary interpretation of regeneration that has lasted for 50 years. Our results also suggest that antero-posterior patterning is determined during a narrow period. This demonstrates that Bmps play a major role in patterning of regenerated limbs and that regeneration is a progressive process like development.

Keyphrases: Bmp, Msx, Fgf, Development, Signaling, Pharmacological inhibitor
Méthodes et algorithmes pour l’amélioration de l’inférence de l’histoire évolutive des génomes

Gene trees offer a proper framework for comparative genomics. Not only do they provide information about species evolution through speciation events, but they also capture gene family expansion and contraction by gene gains and losses. They are thus used to infer the evolutionary history of gene families and accurately predict the orthologous relationship between genes, on which several biological analyses rely. Methods for inferring gene family evolution explicitly assume that gene trees are known without errors. However, standard phylogenetic methods for tree construction based on se- quence data are well documented as error-prone. Gene trees constructed using these methods will usually introduce biases during the inference of gene family histories. In this thesis, we present new methods aiming to improve the quality of phylogenetic gene trees and thereby the accuracy of underlying evolutionary histories of their corresponding gene families. We start by providing a framework to study genetic code deviations, one possible reason of annotation errors that could then spread to the phylogeny reconstruction. Our framework is based on analysing coding sequences and tRNAs to predict codon reassignments. We first show its efficiency, then apply it to green plant mitochondrial genomes. The second part of this thesis focuses on the development of efficient species tree aware methods for gene tree construction. We present ProfileNJ , a fast and deterministic correction method that targets weakly supported branches of a gene tree. When applied to the gene families of the Ensembl Compara database, ProfileNJ produces an arguably better set of gene trees compared to the ones available in Ensembl Compara. We later use a different strategy, based on a genetic algorithm, allowing both construction and correction of gene trees. This second method called GATC, treats the problem as a multi-objective optimisation problem in which we are looking for the set of gene trees optimal for both sequence data and information of gene family evolution through gene gain and loss. We show that this approach yields accurate trees and is suitable for the construction of reference datasets to benchmark other methods.

Keyphrases: gene tree, evolutionary history, phylogeny, reconciliation, orthology, genetic code, codon reassignment, evolution
Implication de l'expression et localisation de TDP-43 dans le mécanisme des granules de stress dans la sclérose latérale amyotrophique

Stress granules (SGs) are cytoplasmic foci that form in response to various external stimuli and are essential to cell survival following stress. SGs are studied in several diseases, including amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD), which involve the degeneration of motor and cortical neurons, respectively, and are now realized to be linked pathogenically by TDP-43, originally discovered as a component of ubiquitin-positive aggregates within patients’ neurons and some glial cells. So far, studies to undercover the role of TDP-43 in SGs have used primarily transformed cell lines, and thus rely on the extrapolation of the mechanisms to cell types affected in ALS/FTD, potentially masking cell specific effects. Here, we investigate SG dynamics in primary motor and cortical neurons as well as astrocytes. Our data suggest a cell and stress specificity and demonstrate a requirement for TDP-43 for efficient SG dynamics. In addition, based on our in vitro approach, our data suggest that aging may be an important modifier of SG dynamics which could have relevance to the initiation and/or progression of age-related neurodegenerative diseases. In our in vivo mouse model, we can observe formation of mRNA granules in different regions of the brain and in the spinal cord following hyperthermic choc. This formation is inhibited with age. Finally, nuclear depletion of TDP-43 induce a decrease of G3BP1, important scaffolding protein for SG assembly, in motor neurons following sciatic injury, in mice. This result show a loss of nuclear function of TDP-43 in vivo with a possible repercussion on the stress response. Together my thesis work has advanced SGs studies in the field of neurodegenerative diseases as well as shown for the first time in vivo proof of loss of TDP-43 nuclear function through G3BP1 misregulation.

Keyphrases: TDP-43, Astrocytes, G3BP1, Amyotrophic Lateral Sclerosis, Fronto Temporal Dementia, Stress response, Stress granules, Spinal cord, Motor and cortical neurons, Astrocytes, mRNA, Aging
Étude de la relation entre structure, dynamique et fonction de l’ARN par l’ingénierie du ribozyme VS de Neurospora

The activity and function of catalytic RNAs are closely related to their three-dimensional structure and dynamics. Better understanding the precise nature of this link would potentially allow to adapt these RNAs to cleave new substrates and modify their kinetic characteristics in a rational way. Neurospora Varkud Satellite (VS) ribozyme is a small nucleolytic ribozyme that has been very well characterized biochemically. Its activity depends on a kissing-loop interaction between loop V of the ribozyme and loop I of its substrate folded into a stem-loop. These features make it an excellent model for studying the link between structure, dynamics, and activity of catalytic RNAs for engineering purposes. Although our understanding of the structure of the VS ribozyme has greatly improved since the beginning of my PhD., it remains essentially a static depiction. It is therefore important to know more about the engineering potential of the VS ribozyme and to draw a dynamic portrait of its cleavage function, in order to proceed to its rational engineering. From this perspective, efforts were made to demonstrate that the VS ribozyme could recognize and cleave substrates of different lengths and furthermore that it was possible to modify the length of helix V to cleave substrates that were too short or too long to be cleaved by the natural ribozyme. The possibility of substituting the I/V kissing-loop interaction, a subdomain crucial for the recognition of its substrate, for structurally similar interactions of the same type was then confirmed. Finally, the kinetic data collected on ribozymes containing either these variants or the natural interaction were compared to the intrinsic dynamics of the kissing-loop interactions, evaluated in molecular dynamics, in order to link their structure, dynamics and activity. This work helped us better understand to what extent and how the VS ribozyme could be modified to be adapted to new substrates. More generally, it gave us an increased understanding of the important structural and dynamic parameters to take into account in order to rationally engineer a functional RNA.

Keyphrases: Neurospora VS ribozyme, molecular dynamics, rational engineering, RNA dynamics
L’usage des codons régule la présentation des peptides associés aux molécules du CMH-I

MHC-I associated peptides (MIPs) are a cornerstone of the adaptive immune system. They are short sequences of amino-acids presented at the surface of cells by the MHC-I molecules. They regulate the development of T lymphocytes and play a major role in the recognition by the immune system of cancerous and virus infected cells. Because the immune system uses MIPs to identify abnormal cells, being able to identify the set of MIPs present at the surface of cells would therefore enable us to design personalized vaccines against cancer and viruses. However, the rules behind the genesis of MIPs are still to be discovered. Current predictors have high false positive rates, and the only reliable, high throughput methods for identifying MIPs heavily depend upon Mass Spectrometry (MS). They require months of cell culture, rendering them inapplicable in a personalized clinical context. In this thesis, we first introduce a new method for identifying MIPs through MS. This method, by integrating subject-specific genomic polymorphisms into MS databases, allowed us to greatly increase identification precision. This increased precision allowed us to discover 34 new Minor Histocompatibility Antigens for cancer immunotherapy. We then introduce the software we wrote for the generation of personalized MS databases: pyGeno, an optimized database for creating and exploring custom personalized genomes. Finally, using a dataset of over 117k RNA sequences, gathered using our proteogenomics pipeline from 18 healthy subjects expressing a total of 33 MHC-I alleles, we demonstrate that codon usage influences MIP presentation. More specifically, we show that synonymous codons have different effects on the presentation, and that this effect depends upon the position of the codon relative to the mRNA encoding the MIPs. Our results strongly suggest that the rules we have extracted using Artificial Neural Networks (ANN) are conserved across species and cell types. This in turn implies that there exists a set of candidate MIPs identifiable through a conserved set of mRNA rules from which MHC-I binders are selected. Finally, they also suggest that building a MIP predictor from mRNA sequences might be possible and illustrate how ANN can be used as effective means for extracting relevant biological information.

Keyphrases: MHC-I associated peptides, Artificial neural networks, Cancer immunotherapy, Neoantigen prediction, Proteogenomics, Mass Spectrometry, Word embeddings, mARN, Codon usage, Software development
Cellules souches, hormones sexuelles et régénération thymique

The thymus undergoes an early deterioration of its function with age, leading to a gradual decrease of the production of naïve T cells. This thymic involution is thought to be responsible for the rising incidence of diseases and cancers with age, as a primary cause of immunosenescence. Despite this, the thymus shows great regenerative capacities following acute involution induced by exposure to different stresses (e.g. infection or radiations). Interestingly, the thymus function is also greatly affected by sex hormones. Ablation or injection of sex hormones leads to thymic hypertrophy and atrophy respectively, and the increase in estrogens and progesterone associated with pregnancy also lead to thymic involution. Therefore, we sought to determine which molecular and cellular mechanisms modulate thymic function in adults, in order to understand which factors are essential for thymic regeneration. As the production of T cells in the thymus is regulated mostly by the stromal cells, we focused our analyses on thymic epithelial cells (TECs), the main cellular component of the thymic stroma.  We first studied the effect of sex hormones on adult TECs phenotype and transcriptome. We found that androgens particularly affected cortical TECs (cTECs), leading to a decreased expression of genes essential for thymopoiesis and reduced proliferation. We next wanted to identify the thymic epithelial progenitor cells, as the cells responsible for the maintenance and regeneration of the thymic epithelium. We found a sub-population of cTECs that were quiescent, radioresistant and that proliferated actively in the first days of regeneration following an acute involution induced by sublethal irradiation. Finally, we studied TECs’ phenotype and gene expression during postpartum thymic regeneration, to identify events driving thymic growth. Surprisingly, despite a 70% reduction in total thymic mass and cellularity, no cellular loss was observed in the thymic epithelium during pregnancy. Furthermore, no TEC expansion is needed to trigger thymic regeneration. Instead, cTECs showed important phenotypic and transcriptomic changes during the first days of regeneration, including upregulation of Foxn1 and its targets. Lastly, our results suggest that Klf4 could be an important regulator of thymic growth and involution, as an effector of hormonal signaling. Globally, our work highlights the importance of cTECs in the regulation of thymic involution and regeneration, as well as identifies Klf4 as a novel potential regulator of thymic function.

Keyphrases: Thymus, Regeneration, Stem cells, Sex steroids, Thymic epithelial cells, Development, Thymic involution