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Molecular Mechanism of Necroptosis in Macrophages
No full textRegulated cell death plays a vital role in tissue homeostasis and development. Recent studies have highlighted necroptosis, a programmed cell death mode combining features of necrosis and apoptosis, as having diverse biological impacts. The necroptosis pathway involves activating receptor-interacting protein kinases (RipK-1 and -3), which form a complex with mixed-lineage kinase domain-like protein (MLKL). This complex translocates to the plasma membrane, inducing its rupture. This study reveals that ARF6 targets the RipK1-dependent ripoptosome and necrosome cell death pathways without impacting apoptosis susceptibility. ARF6 regulates the maturation of the endo-lysosomal compartment, promoting cIAP1/2 degradation and facilitating RipK1 phosphorylation towards cell death pathways. This finding unveils a new signaling event preceding RipK1 phosphorylation, which is necessary for activating RipK1-dependent cell death pathways. The research also demonstrates that necroptosis program initiation activates RipK1, leading to MAPK pathway upregulation and increased inflammatory cytokine expression, independent of cell death. This inflammatory response is counterbalanced by type I interferon expression during necrosome activation. The crosstalk between IFNAR1 signalling, the MAPK pathway, and post-transcriptional regulation through ZFP36 plays a crucial role in balancing inflammatory responses and cell death. Furthermore, the study provides compelling evidence for IFNAR1 signalling’s critical role in necroptosis. Ifnar1-deficient macrophages exhibit significant resistance to necroptosis induced by various stimuli. IFNAR1 signaling is crucial for the proper functioning of the ISGF3 complex and the expression and activation of MLKL, a key necroptosis executioner. Surprisingly, restoring MLKL expression in Ifnar1-deficient cells did not fully reverse their necroptosis resistance, suggesting additional mechanisms at play. Further investigation revealed that IFNAR1 signaling is essential for the appropriate translocation of phosphorylated MLKL to the plasma membrane, a critical step in necroptosis execution. These findings significantly advance our understanding of the molecular mechanisms underlying necroptosis and highlight the complex interplay between different pathways that lead to programmed cell death pathways in macrophages. Deregulation of necroptosis is associated with pathological conditions such as cancer, neurodegenerative diseases, inflammatory diseases, and critical response against many viruses, including pox, herpes, and influenza. This research aims to identify potential therapeutic targets that can be exploited in chronic inflammatory conditions and viral infections
Evaluating Microemboli Clearance in a Mouse Model of Microinfarction
No full textCerebral microinfarcts, ranging from 100μm to 3mm in diameter, occur as a result of ischemic microvessel occlusion. Microinfarcts have been found to contribute to cognitive decline and are particularly prevalent in dementia patients and the aging population. Microemboli occlusions are primarily cleared via fibrinolysis and hemodynamic forces to re-establish blood flow. Angiophagy, where vessels engulf and expel microemboli, may also mitigate damage caused by micro-occlusions. Previous rodent studies have proposed conflicting timelines on the extent to which this process occurs and fail to extensively quantify angiophagy in clinically relevant populations, including aging and Alzheimer's disease. To further study this process of angiophagy, we induced micro-occlusions in young, aged and AD mice via injection of 20μm microspheres into the carotid artery. In characterizing this model, we found that most microspheres localized to the cortex, yet when accounting for region size, microspheres were more evenly distributed across regions. When quantifying angiophagy in young non-diseased mice, we found that approximately 43% of microspheres have extravasated from the vessel by day 14. This timeline was delayed in aged mice, with only 10% of microspheres extravasated by day 14. Moreover, in young 3xTg Alzheimer's mice, we find the rate of angiophagy is more efficient at day 14 compared to non-transgenic controls, with 47% and 43% of microspheres extravasated, respectively. A similar trend is observed in aged Alzheimer's mice whereby 38% of microspheres extravasated by day 14 in 3xTg mice, compared to only 30% in non-transgenic controls. Taken together, we show that aging impairs the process of angiophagy, while Alzheimer's mice exhibit an increased ability to extravasate microspheres
Volatile Signatures in the Sudbury Igneous Complex Magmatic Ni-Cu-PGE Deposits: Implications for Sulfide Melt Differentiation and Precious Metal Mineralization
No full textThe offset dykes of the Sudbury Igneous Complex (Ontario, Canada) host significant magmatic Ni-Cu-PGE deposits rich in precious metals (e.g., platinum-group elements, gold), making them superlative sites for understanding metal solubility in fluids and magmatic sulfide differentiation. Despite extensive study, the origin(s) and character of volatile components and their impact on precious metal distribution in the Sudbury sulfide ores remain controversial. Here we aim to evaluate the evidence for volatile activity in differentiated sulfide ores from the distal Podolsky North Zone in the Whistle offset dyke, at the northeast margin of the Sudbury Igneous Complex. We have examined a ~43 cm long channel-cut section, including massive sulfide, chloritic alteration/reaction rim and host gneiss, across the margin of a ~2 m thick sulfide vein.
Our integrated analytical approach includes utilizing optical petrography, mineral chemistry (by scanning electron microscopy and microprobe) and stable sulfur isotope measurements.
Petrographic observations revealed a diverse mineralogy of aggregated platinum-group minerals, and accessory Ag±Bi tellurides within the chalcopyrite-dominated sulfide vein material. Fractured surfaces from the interior of the vein expose decrepitated fluid inclusions, observed as salt evaporate haloes (evaporated ‘liquid’ phase), together with solid halides and ferropyrosmalite [(Fe2+,Mn)8Si6O15(OH,Cl)10] daughter phases. It is noteworthy that there is trace Pd present in a few of the halides, and chlorargyrite (AgCl) is commonly observed associated with the fluid inclusions. Epidote occurs in separate parallel bands within the vein, interpreted to have formed late in the veins crystallization history or during a later regional hydrothermal event. Chlorite exhibits a minor decrease in Fe-Ni concentrations away from the vein. Sulfur isotope
measurements (on chalcopyrite) indicate relatively heavy but homogeneous d34S compositions within the vein and chloritic rim and host rock.
Our findings suggest that chloride complexation played a key role in the localization and enrichment of precious metals within the highly differentiated sulfides in the Podolsky North Zone. By providing new insights into the relationship between volatile components, metal solubility and fluid chemistry, this study contributes to broader models of magmatic-hydrothermal systems, with
potential applications for guiding exploration for precious metal-enriched deposits
L'objet de l'autonomie et le sujet de la légitimité : Une intervention sur le paradoxe des théories de l'art francophone en situation minoritaire au Canada
No full textCette thèse interroge l'apport de l'esthétique dans les réflexions sur les vivre-ensemble francophones en situation minoritaire au Canada. À partir des cas de la francophonie ontarienne et acadienne du Nouveau-Brunswick, elle pose deux questions d'ordre général : d'abord, comment parle-t-on de l'art, du politique et de la culture des communautés francophones en situation minoritaire au Canada? Ensuite, qui et qu'est-ce qui est perçu comme participant à produire la culture de ces groupes? À travers ces questions, la thèse apporte un éclairage théorique sur les inégalités esthétiques qui sous-tendent les principes d'autonomie et de légitimité culturelle privilégiés par les théories de la vitalité et de l'exiguïté. Adoptant une approche historiciste radicale, elle problématise et réfute les fondements substantialistes sur lesquels reposent les processus discursifs par lesquels certaines pratiques et catégories de sujets sont évaluées de façon inégale quant à leur capacité à rendre perceptible une expérience sensible collective. Il est proposé que les présupposés d'égalité esthétique et de multidimensionnalité sociohistorique offrent une orientation nouvelle aux interrogations entourant les processus de subjectivation couramment décrits au sein de ces collectivités.
Faisant appel aux études de la performance, la thèse présente plusieurs études de cas, dont la revue d'art Liaison, l'exposition Écoutez tout[e]s petit[e]s et grand[e]s! de l'artiste multidisciplinaire Rémi Belliveau et les soirées de Bingo avec Johanne animées par les musicien·nes Lisa LeBlanc, Benoit Morier et Kevin McIntyre. J'y développe les concepts de performance archivistique et de performance hétérotopique, argumentant, d'une part, que ces concepts sont des outils heuristiques pertinents afin de rendre compte de l'éclatement des possibilités esthétiques que peut opérer la reconnaissance de l'égale capacité des pratiques culturelles à produire du sens. D'autre part, ces deux concepts servent à déstabiliser les récits normatifs et linéaires par lesquels le paradigme de la minorisation, dans lequel s'inscrit notamment l'angoisse associée à l'anticipation de la disparition de ces groupes, imagine leur composition esthétique. En définitive, la thèse invite la recherche sur les pratiques culturelles des communautés francophones en situation minoritaire à opérer un déplacement épistémologique et esthétique afin de mieux appréhender la multidimensionnalité des réalités socioculturelles à travers lesquelles émerge un sens de communalité
Online Co-National Peer Support Across the Migration Journey: Iranian International Students' Pre- and Post-Arrival Experiences with Telegram in Ottawa
No full textThis thesis explores the role of an online Telegram-based co-national peer support group in shaping the experiences of Iranian international students during the pre-sojourn and early settlement phases in Ottawa. Using a descriptive phenomenological methodology, the study examines how voluntary, peer-driven interactions across these phases provided participants with crucial emotional, informational, and practical support. Long before arrival, students engaged with the Telegram group to reduce uncertainty, foster familiarity, and build a sense of communal belonging. The group served not only as a space for acquiring lived-experience-based guidance, but also as an emotionally safe and empathetic environment where support was offered freely and without expectation. It also helped students navigate foundational cultural differences while maintaining connections to their Iranian identity - fostering an emerging sense of bicultural orientation. Over time, reliance on the group declined as participants formed in-person networks and gained independence, yet its significance as a community remained. This study adds to the literature by offering empirical and theoretical insights into how co-national digital peer networks provide informational, emotional, and instrumental support to international students during the pre-sojourn and early settlement phases of adaptation
Charting Agency in Digital Context: Agents and Networks in the Making of Arabic to English Literary Translations in an Online Magazine
No full textThis study centers around recent developments in the concept of agency in literary translation, particularly within the framework of digital initiatives. It identifies the development of agents in translation theory as a necessity proposed by contemporary sociological approaches to emphasize the roles played by both human and non-human entities involved in the translation of foreign texts. While these approaches define agents as active participants who assert their empowerment within institutional structures, they often fail to explain how agents exercise their agency when operating outside these structures, particularly beyond Western/European paradigms of literary translation.
Through an ethnographic case study of Words Without Borders (WWB)—an online literary translation magazine founded in 2003—this thesis explores how this cultural initiative has broadened the concept of agency in response to cultural and political struggles in the early 21st century. It specifically focuses on the role of agents involved in the translation of contemporary Arabic literary texts outside the dominant Anglo-American publishing industry. Drawing on interviews with translators and editors, alongside analysis of documents and paratextual elements, this study probes how these agents navigate their roles to influence visibility for both themselves and Arabic literature among English-speaking audiences.
The research puts sociological definitions of agency in translation theory to the test, arguing for a deeper, more context-sensitive understanding of agency that aligns with the cultural sociology realities of today. Words Without Borders exemplifies how agency is not a static starting point but an evolving, dialectical process shaped by recognition and negotiation with cultural others. This thesis also critically examines the roles of non-human agents within literary translation, particularly digital platforms and their paratextual affordances, viewing them as extensions of human agency rather than independent actors
Identification of Kinase-Mediated Signaling Pathways Regulating Autophagy in Response to Cellular Stresses
No full textAutophagy is a conserved and highly regulated catabolic process essential for cellular homeostasis, particularly under stress conditions such as nutrient starvation and infection. While bulk autophagy facilitates the indiscriminate degradation of cytosolic components during starvation, selective autophagy targets specific organelles and intracellular pathogens for turnover. A critical component of autophagy is the ATG16L1-containing E3-like enzyme, which drives autophagosome formation. Polymorphisms in ATG16L1, such as the Crohn's disease-associated T300A variant (caATG16L1), have been linked to autophagy dysfunction. Our findings demonstrate that ULK1 kinase directly phosphorylates ATG16L1 in response to infection and starvation, facilitating its localization to bacterial entry sites and promoting anti-bacterial autophagy. However, ULK1-mediated phosphorylation of caATG16L1 leads to its destabilization under stress, highlighting a dual role of ULK1 signaling - enhancing wild-type ATG16L1 function while compromising the stability of its disease-associated variant.
We next sought to further dissect the kinase-mediated regulation of selective autophagy targeting specific organelles. We proposed that selective autophagy may be regulated by distinct upstream signaling from starvation-induced autophagy to promote organelle turn-over. To investigate this hypothesis, we developed a customized kinome-wide CRISPR screening platform designed for the parallel interrogation of multiple stress-induced autophagy pathways. Utilizing a reporter cell line expressing DsRed-IRES-GFP-p62, we were able to monitor basal autophagy, starvation-induced autophagy, ER-phagy, and pexophagy. The Brunello kinome library was employed to maximize on-target gene disruption while minimizing off-target effects, enhancing the overall robustness of the screen. Through this approach, we identified both known and novel kinases involved in autophagy regulation, including condition-specific regulators such as CDK11A and NME3 for ER-phagy, and PAN3 and CDC42BPG for pexophagy.
Overall, our study emphasizes the central role of kinase signaling in coordinating selective autophagy. We demonstrate that ULK1 differentially affects autophagic outcomes depending on the ATG16L1 allele, revealing an additional layer of regulatory complexity. Additionally, the datasets generated from our optimized screening strategy provide valuable insight into the distinct regulatory networks governing bulk versus selective autophagy, offering a foundation for future mechanistic and therapeutic studies
A Paleolimnological Perspective on Avian Population Dynamics and Their Effect on Lake Productivity in a Rapidly Warming Arctic
No full textRapid warming is radically transforming the Arctic, including its freshwater ecosystems. Regionally, warmer temperatures and greater nutrient inputs from a greening landscape are increasing waterbodies' productivity. However, nutrients from the feces produced by growing avian nesting colonies in some locations can have a much greater effect on aquatic primary production, as undisturbed Arctic catchments otherwise provide little nutrients to waterbodies. Therefore, a more complete assessment of climate warming's influence on Arctic waterbodies should consider how warming may influence avian population dynamics. In this thesis, markers for primary production (chlorophyll a, C/N ratio), avian fecal inputs (δ¹⁵N, sterols/stanols), and paleotemperature (branched glycerol diakyl glycerol tetraethers (brGDGTs)) are analyzed in lake sediment cores from the Arctic Archipelago to explore whether these variables are related. Chapter 2 looks at a sediment core from a known seabird-impacted pond on Cape Vera (Devon Island, Nunavut), where previous studies had suggested that warming may be responsible for the significant Northern Fulmar (Fulmarus glacialis) population growth inferred from lacustrine sedimentary depth profiles of avian markers. Our brGDGT-based paleotemperature reconstructions show rapid months above freezing (MAF) warming, which is corroborated by a short temperature record and a longer-term warming trend seen in ice core records from the nearby Devon Ice Cap and tracks the seabird population increase also inferred from sedimentary markers. Chapter 3 examines whether primary production in Cambridge Bay region (Nunavut) lakes is determined by climate warming and/or nutrient inputs from goose droppings using sediment cores from three lakes, including the only known eutrophic lake from the region. Paleotemperature reconstructions largely indicate non-significant MAF warming in all lakes, and significant increases in primary production markers tracking goose fecal markers are observed in 2 lakes. The lack of a primary production increase in the third, non-goose-impacted lake suggests that warming has had a minimal impact on primary production compared to avian-derived nutrients. Altogether, this thesis highlights the impact warming may have on lake primary production by positively influencing migratory bird populations. This work also provides some of the first paleotemperature reconstructions relying on the sedimentary relative abundances of brGDGTs from the Arctic Archipelago and showcases their validity, as we were able to correctly discern two distinct local temperature trends
Efficient Text-Driven 3D Scene Editing Based on Gaussian Splatting
No full textText-guided 3D scene editing has advanced with diffusion models and neural rendering. While Neural Radiance Fields (NeRF) excel at 3D reconstruction and novel view synthesis, they face key challenges: computational inefficiency, multi-view inconsistency, and poor handling of motion blur. To overcome these limitations, we introduce a 3D Gaussian Splatting (3DGS)-based framework for efficient and consistent 3D editing. 3DGS offers real-time rendering and a more practical alternative to NeRF. We enhance its performance with two key components: (1) a Complementary Information Mutual Learning Network (CIMLN) for refining 3DGS-derived depth maps, enabling depth-aware image editing; and (2) a Wavelet Consensus Attention mechanism that aligns latent codes across views during diffusion denoising, ensuring consistent multi-view outputs. We also address motion-blurred scene reconstruction by applying low-pass filtering and jointly optimizing Gaussian parameters with camera trajectories. Experiments show that our method achieves photorealistic, structurally consistent re- sults while maintaining real-time performance and significantly reducing computational overhead compared to prior methods
Effectiveness of wellness program interventions to improve physician wellness: a systematic review
No full textAbstract Background Physician wellness programs are being implemented to offset rises in physician burnout. Insight into the effectiveness of these programs and to whom they are being offered, remains unclear. Objectives To identify and characterize wellness program interventions to improve physician wellness. Methods A PRISMA-P 2020-compliant systematic review as conducted, searching PubMed, Scopus, and Medline from May 2006 to July 2024. Search terms included Medical Subject Headings terms and keywords related to physicians and wellness program interventions. Peer reviewed published studies that qualitatively and/or quantitively measured outcomes of wellness interventions for practicing physicians were included. Results Thirty-six studies involving 6,708 total participants were included. Interventions were heterogenous and included group therapy, stress reduction strategies, time off/workload reductions, education, and peer support. The efficacy of interventions varied, with sixteen studies (44.4%) demonstrating some measurable degree of effectiveness, with statistically significant changes (p < 0.05) post-intervention. Few studies reported improvements by physician sex, age groups, or comparisons across specialities. Conclusion Studies examining physician wellness program interventions are highly heterogenous in terms of intervention, study design and methods of outcome assessment, limiting definitive conclusions about their general effectiveness. Trial registration The review protocol has been registered on Open Science Framework ( https://doi.org/10.17605/OSF.IO/8SDM9 )