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Pharmacological Manipulation of Skeletal Stem/Progenitor Cell Fate Decisions
No full textThe mature bone houses a population of multipotent stem/progenitor cells named the skeletal stem/progenitor cells (SSPCs). Studies carried out in our lab proved the existence, in the growth plate of postnatal mice, of self-renewing putative skeletal stem cells (SSCs) thought to be involved with progenitor cells in the growth, homeostatic maintenance and repair of skeletal tissue following trauma.
As the organism ages, bone mass is lost and the prevalence of age-related conditions of the skeletal system increases. Unlike in young individuals, SSPCs are less likely to ensure perfect bone maintenance in the elderly, despite their presence in the aged bone. In the setting of this work, I hypothesized that: the decrease in their proliferative capacity as they enter senescence is responsible for the phenotypic and pathological changes observed in the bones with age; and, the pharmacological targeting of signaling pathways activated during bone development and growth can change SSPCs fate decisions, alleviate age-related bone loss and modify the pathological outcome in the aging organisms. I pursued the following aims: 1) to study SSPCs proliferation and senescence in aged mice; 2) to pharmacologically manipulate SSPCs fate decisions.
With methods involving lineage tracing and imaging cytometry, the conducted experiments showed that the SSPC population shrinks in aged mice growth plate and their proliferation and senescence levels decrease. Of the compounds tested, 20(S)-hydroxycholesterol, a Hedgehog pathway agonist, keeps SSPCs quiescent/non-proliferative in vitro; and tamoxifen exerts a sex-dependent effect on growth plate chondrocytes (including SSPCs) in vivo. Tamoxifen stimulates chondrocytes proliferation and senescence entry in male mice, while protecting them from senescence in female mice.
This is the first report of its kind on the Sox9+ SSPC population. More in-depth investigations into the specific mechanisms of action of these compounds are necessary.
This work brings us closer to our goal of addressing acute and chronic age-related conditions of the skeletal system with novel stem-cell based therapies
Transformation of the Ukrainian Institutional Apparatus Between 2017 and 2022
No full textThis thesis examines the transformation of Ukraine’s institutional apparatus between 2017 and 2022, a period marked by significant political, legal, and economic reforms. Focusing on the transition from Petro Poroshenko’s presidency to Volodymyr Zelensky’s administration, the study analyzes how internal and external pressures, including civil society mobilization and conditionality from Western organizations such as the European Union, NATO, the World Bank, and the International Monetary Fund, shaped the restructuring of Ukraine’s governance framework. Key reforms, including the 2021 Anti-Oligarch Act, judicial and land market reforms, and the creation of specialized anti-corruption institutions, are assessed for their impact on dismantling entrenched patronal networks and advancing transparency and accountability. Employing a qualitative methodology grounded in comparative politics and international relations, the thesis integrates empirical and theoretical perspectives to explain the dynamics of institutional change in a hybrid regime. The findings highlight the resilience of informal power structures, the ambivalent role of the presidency, and the critical influence of civil society and external actors in driving reform. Ultimately, the study contributes to understanding the complexities of institutional transformation in post-Soviet states and offers insights into Ukraine’s ongoing pursuit of democratic consolidation and European integration
Clean Combustion Flue Gas Polishing Through Catalytic Combustion in an Integrated Heat Exchanger Reactor System
No full textCombustion flue gas from various sources contains contaminants requiring removal prior to pipeline transport for carbon, capture, utilization and storage. Depending on the combustion method, the main contaminants are often residual fuel such as CH₄, partial combustion product CO, and oxidizer such as O₂. Process intensified heat exchange reactors known as integrated heat exchange reactors (IHXR) can be designed to facilitate contaminant removal while recovering the heat of combustion generated during the removal process. This work describes the formulation and use of a 1-dimensional reduced order reactor model in facilitating the IHXR design for oxy-fuel combustion flue gas where the contaminant of concern is O₂.
The heat exchanger sections of the IHXR can be described by a 2-dimensional reduced order heat exchanger model (2-D ROM), accounting for the cross-flow pattern of the proposed design. A micro-channel cross-flow heat exchanger plate was manufactured as part of a bench-scale experimental set-up, the gas and solid phase temperatures of the experimental set-up were collected and used as the basis for a Nusselt number correlation. The 2-D ROM fitted with the Nusselt number correlation was then used to aid in generating a 3-D OpenFOAM model, in which the heat fluxes between the curved flow channels were calculated to confirm the that the conduction shape factor was near (0.8 to 0.9) unity.
The bench-scale heat transfer experiments were also used to validate the transient modelling capabilities of the 2-D ROM, which was then used along with a reduced order reactor model to create process models of several proposed IHXR designs. The process models were then used to investigate the ability of the IHXR to reject inlet temperature disturbances through Bode diagrams. The results show that the IHXR designs are generally stable, with their stability increasing as the number of flow channels increases.
Another source of combustion flue gases, pressurized chemical looping combustion (PCLC), was used for IHXR design via process simulation. The contaminants of concern are CH₄ and CO, where the IHXR design features the equilibrium reactor from Aspen HYSYS to determine the effluent species concentration, and plug flow reactor for reactor sizing. A sensitivity analysis was performed on the potential scenario where fuel conversion within the PCLC unit was reduced to 97% from 98.5% to simulate variable combustion efficiency
Acute AMPK Activation Does Not Adequately Stimulate Insulin Signaling in Skeletal Muscle Models of Myotonic Dystrophy Type 1
No full textMyotonic Dystrophy Type 1 (DM1) is a multisystemic neuromuscular disease characterized by skeletal muscle weakness, muscle atrophy, and myotonia. However, patients often also experience cognitive impairments, gastrointestinal complications, and insulin resistance. Insulin resistance exacerbates muscle weakness and atrophy in DM1, but its pathomechanism has not been adequately described in the context of DM1. The aim of this study is to characterize the molecular mechanisms of insulin resistance in DM1 and how AMPK stimulation can impact insulin signaling. My first aim analyzes proteomic data from sedentary wildtype, sedentary HSA-LR, and exercised HSA-LR mice to detect and predict dysregulated proteins in insulin and exercise molecular pathways. My second aim examines molecular interactions impacting GLUT4 translocation in the HSA-LR mouse model after acute AMPK stimulation. My final aim examines molecular interactions impacting GLUT4 translocation in a DM1 myotube model after insulin and AMPK stimulation. Proteomic analysis predicted that exercise significantly upregulates PGC-1α, a transcription coactivator integral to metabolic regulation. When AMPK, an upstream regulator to PGC-1α, is targeted in HSA-LR mice and DM1 myotubes with AICAR, there is no improvement in the AKT-AS160 insulin signaling axis. Our findings confirm insulin resistance in DM1 and demonstrates an impaired response to acute AMPK stimulation
Prolonged impact of the COVID-19 pandemic on the well-being and roles of family/friend caregivers of older adults living at home in Canadian official language minority or majority communities—Supplementary data file
No full textRésumé: Ce fichier de données supplémentaires a été créé pour compléter un article qui présente les résultats d'une étude qui examinait les impacts à long terme de la pandémie de COVID-19 chez 83 proches aidants de personnes âgées provenant de 4 provinces canadiennes.
L'article principal sera publié dans la Revue canadienne du vieillissement. https://doi.org/10.1017/S0714980825100494
Abstract: This supplementary data file was produced to complement an article presenting the result of a study examining the longer-term impacts of the COVID-19 pandemic among 83 unpaid caregivers of older adults from 4 Canadian provinces. The main article will be published in the Canadian Journal on Aging. https://doi.org/10.1017/S071498082510049
The Glucocorticoid Receptor Regulates Myonuclear Positioning During Skeletal Muscle Differentiation
No full textProper myonuclear positioning is essential for skeletal muscle function and relies on the coordination of the nucleoskeleton, cytoskeleton, and the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. Although glucocorticoids are widely used therapeutically to treat muscular dystrophies, the muscle-intrinsic mechanisms underlying their effects on improving muscle strength remain unclear. Here, we investigate the role of the glucocorticoid receptor in regulating myonuclear positioning during myogenic differentiation and skeletal muscle regeneration. Pharmacological inhibition of the glucocorticoid receptor (GR) with RU-486 in C2C12 myotubes or knockdown of GR expression in vivo resulted in disrupted nuclear alignment. Mechanistically, GR inhibition decreased the levels of Lamin A and SUN1 proteins within the soluble fraction. This, in turn, disrupted the alignment of pericentrin and the Golgi apparatus to the nuclear envelope, ultimately disorganizing the microtubule network. Together, these data identify GR as a critical regulator of myonuclear positioning and of nuclear-cytoskeletal integrity during muscle differentiation, providing mechanistic insight into how glucocorticoid therapies may improve muscle function in patients with muscular dystrophies
Exploring markers of feasibility for a pragmatic study of biomarkers in adolescents with eating disorders: steps towards a precision psychiatry approach
No full textAbstract Objective To examine markers of feasibility for a pragmatic interdisciplinary multi-axial study of biomarkers in adolescents with eating disorders (EDs). Method The study included the collection of medical and clinical variables, psychometric measures, dietary logs, sensory and sleep assessments, and biological samples (i.e., blood and stool collection) for biomarker analyses. Adolescents between the ages of 11 to 17 diagnosed with a restrictive ED, along with control participants were enrolled between November 2021 to July 2024. Participants with EDs underwent concurrent treatment while enrolled in the study. Time points for low-weight patients included baseline, 4, 12, and 26 weeks, depending on the biological marker. Control subjects and patients over 90% treatment goal weight were assessed once. Feasibility was evaluated using clinical participant recruitment efficiency and uptake, adherence to the study protocol, rates of study completion, and self-reported ratings of acceptability. Results In total, 100 participants with an ED, and 52 controls participated. We observed high rates of clinical participant enrolment, high adherence with most protocol collection procedures, modest dropout for longitudinal clinical participants (17% at 12 weeks), and positive feedback returned on surveys. We observed higher dropout at the 26-week timepoint (33%). Food log and sleep assessments were hindered by several contributing factors, resulting in completion rates of 31–70% and 40–87%. Discussion Overall, results suggest acceptable feasibility for most variables assessed. Protocols requiring participation beyond 12 weeks, and utilizing dietary logs and sleep assessments, should be powered accordingly to account for lower completion rates. Further studies are needed to determine methods to optimize dietary and sleep assessments. This study provides valuable insights that can inform future precision psychiatry ED research strategies.Plain English Summary In this study, we report on the feasibility of collecting biomarker samples in adolescents with eating disorders (ED) to help inform a platform of precision psychiatry research. We included standardized questionnaires, dietary logs, sleep, sensory, and pharmacogenetic assessments, and collected blood and stool samples. Depending on the biomarker and grouping of participants, we collected data at 1, 3 or 4 timepoints. We evaluated feasibility using rates of recruitment, adherence to the protocol, timepoints and study completion, and overall acceptability. We recruited 100 participants with an ED and 52 controls. We observed high rates of clinical enrolment and adherence to most collection procedures, low rates of drop out over the first 12 weeks, and positive feedback returned on surveys. Dietary log completion and sleep assessments were the most challenging research tasks, with the highest rates of non-completion. Our results suggest that most participants followed longitudinally completed testing up to twelve weeks. Protocols requiring participation beyond this timeframe should account for substantial dropout. Further studies are required to investigate the optimal method to track nutritional intake and assess sleep characteristics for research purposes in adolescents with EDs
Wittgenstein's Reception of Gödel's Incompleteness Theorems
No full textWittgenstein’s remarks on Gödel’s (first) incompleteness theorem were initially dismissed by scholars who thought Wittgenstein misunderstood the syntactic nature of Gödel’s proof. Following the release of the 1998 Bergen Electronic Edition of Wittgenstein’s Nachlass, remarks on Gödel that were excluded in the two editions of the Remarks on the Foundations of Mathematics were brought to light, reviving an interest in the topic. As part of the same efforts of reinterpretation, this thesis delineates an alternative approach to Wittgenstein’s reception of Gödel. Rather than simply comparing Wittgenstein’s comments on Gödel to Gödel’s seminal paper on Undecidability, the present work does not assume that “Gödel’s theorem,” as an object of philosophical investigation, is identical to “Gödel’s theorem” as conceived within the discipline of mathematics. Hence, the object of Wittgenstein’s discussions must be determined first. To do this, I give an account of late Wittgenstein’s philosophical methods in general, and interpret his remarks on the aims of his discussions of the foundations of mathematics. Wittgenstein’s philosophy is a dialectical exposition of our tendencies in thinking which avoids issuing any apodictic claims. He proposes a kind of philosophical investigation which describes rather than explains. Thus, his intention is not to advance competing theories or interpretations of mathematical theories, but to describe the use of words which appear in mathematics but originate in ordinary language. Given these strictures, a more charitable reading of Wittgenstein’s reception of Gödel is available. For Wittgenstein, Gödel’s theorem is a case study of our tendencies to imagine metaphysical theories, being misled by pictures associated with words that occur in the prose which accompanies the proof. Wittgenstein shows us how we are tempted to interpret words like “truth” and “proof” and thus to impose unwarranted expectations on Gödel’s proof. This is further demonstrated by appealing to passages from the Nachlass (MS 163, 43r-47v) that are for the first time shown to concern Gödel’s paper, passages in which Wittgenstein problematizes the notion of “interpreting content.” As a result, this thesis shows that by a close study of Wittgenstein’s method and stated intentions, the common conclusion that Wittgenstein misunderstood Gödel can be avoided
Les marques humaines : exploration d'une co-construction de la marque des athlètes paralympiques avec les parties prenantes du mouvement paralympique en France et au Canada
No full textComme le témoignait Howe (2008), « à mesure que l'IPC devient de plus en plus commercialisé, il est impératif pour les athlètes, les entraîneurs et les officiels de devenir plus professionnels dans la manière dont ils s'engagent dans la pratique du sport paralympique » (p.84). S'il existe des preuves empiriques de la capacité de commercialisation des athlètes vedettes, les recherches portant sur les stratégies de commercialisation des para-athlètes restent à ce jour limitées (Hu et al., 2023). En s'intéressant à la construction de la marque personnelle des athlètes paralympiques entre deux territoires, la France et le Canada, la présente thèse introduit le concept de co-construction de marque pour identifier le niveau d'implication des parties prenantes dans ce processus. Elle s'articule autour d'une méthodologie qualitative construite sur la base de 60 entretiens semi-directifs avec les para-athlètes (30) et les parties prenantes (30).
Consistant en une analyse thématique, au travers des discours des para-athlètes, des sponsors, des médias, des institutions et des agents, cette recherche dresse un état des lieux des stratégies de construction des marques humaines dans un contexte politique, économique, social et culturel différent. En considérant la manière dont ces derniers perçoivent le développement de leur propre marque, comme des antagonistes, supporters ou gestionnaires de marque, les résultats démontrent que la performance n'est pas le seul attribut dans la construction d'une marque forte, et dont d'autres attributs personnels comme l'âge, la discipline pratiquée ou le niveau de notoriété ainsi que la motivation et les intérêts des athlètes paralympiques sont à prendre en compte.
Cette étude dédiée à la représentation des para-athlètes dans le marketing sportif et leur commercialisation soulève d'importantes considérations sociales et commerciales. Elle apporte une contribution au processus du personal branding par l'intermédiaire d'une modélisation cartographique de l'implication des parties prenantes sur la marque personnelle des athlètes paralympiques dans une perspective de co-construction de marque. Elle met en lumière le transfert de ressources entre ces acteurs ayant un impact direct ou indirect sur la construction de la marque personnelle des athlètes paralympiques
Temporal trends of no moderate to vigorous physical activity in adolescents: a 16-year trend analysis of 115,926 participants
No full textAbstract Background Engaging in no moderate-to-vigorous physical activity (MVPA) has been recognized as an important indicator in physical activity (PA) surveillance, as any engagement in MVPA confers health benefits compared to none. Studying the prevalence of no MVPA can provide valuable insights into physical inactivity patterns and inform public health intervention efforts. While some cross-sectional studies have examined this issue, no research has analysed year-to-year trends. Therefore, the aim of this study was to assess trends of no MVPA among adolescents and key subgroups using a nationally representative US sample. Methods Data from 2005 to 2021 cycles of the Youth Risk Behavior Surveillance System were used, with 115,926 US adolescents aged 14–17 years included (female: unweighted sample size = 58,582, 50.5%; weighted%=49.4%). Participants self-reported their demographic (sex, age, race/ethnicity, body mass index) and behavioural information (days of ≥ 60 min of MVPA over the past week, and recreational screen time). No MVPA was operationalized as reporting 0 days of ≥ 60 min of MVPA. Trend analysis was performed to assess temporal variations from 2005 to 2021 using a series of binary logistic regression models after controlling for demographic and screen time related variables. Results Declining trends in no MVPA were observed among adolescents from 2005 (weighted: 24.3%) to 2021 (weighted: 15.5%). After stratifying by sex, age, race/ethnicity, body mass index and recreational screen time, similar downward trends were shown across all adolescent subgroups consistently (p for trend < 0.001). Girls, older adolescents, those who identified as non-White, adolescents with excess weight, and those engaging in more than 2 h of recreational screen time per day tended to report no MVPA at higher rates (all p < 0.001) compared to their counterparts. Conclusions No MVPA has declined among the US adolescents, especially after 2009. Notably, sociodemographic disparities were observed in no MVPA among different population subgroups. PA promotion strategies targeting girls and older adolescents should be prioritized to further reduce the prevalence of no MVPA