VictorJuiz/thesis huggingface dataset:
Control of Adult Bone Marrow Erythroid Progenitor Cell Fate by Combinatorial Niche Factor Signals
Keywords: stem cell fate
red blood cell differentiation
niche factor
cell signaling
single-cell analysis
flow cytometry

Stem and progenitor cell fate (self-renewal, proliferation, survival, differentiation) is tightly controlled by niche factors and the interplay of these factors is particularly important to comprehend for the development of stem cell therapies. During erythropoiesis, erythroid progenitors at the colony forming unit-erythroid (CFU-E) stage are responsive to both stem cell factor (SCF) and erythropoietin (EPO); however, the joint action of SCF and EPO in these cells and the underlying mechanisms remain to be defined. In this study, quantitative data on the activation of signaling pathways and gene expression profiles provided definitive evidence for two parallel but complementary mechanisms that resulted in enhanced generation of red blood cells from mouse bone marrow-derived CFU-E culture in the presence of SCF and EPO. First, SCF and EPO signaling intersected within the extracellular signal-regulated kinase (ERK) pathway and the sustained ERK activation was required for the maximal changes in the expression levels of genes that are involved in the proliferation and survival of CFU-Es. Second, the apparent competition between SCF and EPO in regulating c-Kit expression was found to have a dramatic impact on the terminal differentiation of CFU-Es. The latter mechanism was, for the first time, reported in a primary cell system. In addition, a fetal liver-derived conditioned medium further enhanced the survival and proliferation of bone marrow CFU-Es in the presence of SCF and EPO by not only increasing the ERK signaling duration but also, the amplitude. The agents present in the conditioned media possess significant clinical potential to stimulate erythropoiesis both in vivo and in vitro. In conclusion, our study has provided novel insights into the mechanisms by which combinations of niche factors control the fate of erythroid progenitors at a unique transitional stage and highlighted the important role of the ERK signaling dynamics in adult erythropoiesis.
The Role of TNFR Family Members GITR and CD30 on CD8 T Cell Responses
Keywords: CD8 T cell
GITR
influenza
T cell memory
CD30
costimulation
TNFR superfamily

GITR and CD30 are T cell costimulatory members of the TNFR superfamily known to regulate T cell responses. Elucidating the mechanisms whereby these receptors modulate T cell responses is crucial for maximizing their potential for immunotherapy. In this thesis, I examine the role of GITR and CD30 on CD8 T cell responses to influenza virus. I show that CD8 T cell intrinsic GITR is required for both maximal primary and secondary CD8 T cell expansion to influenza, while in contrast, CD30 is dispensable for anti-influenza CD8 T cell responses. GITR does not impact on CD8 T cell proliferation or homing, however, it mediates CD8 T cell survival signaling. GITR induces TRAF2/TRAF5 dependent, but TRAF1 independent, NF-κB activation, resulting in the upregulation of the pro-survival molecule Bcl-xL. Furthermore, I show that GITR on CD8 T cells can augment viral clearance and confer protection from death upon severe influenza infection of mice. Similarly, CD30 also elicits protection from death upon severe influenza infection, although the cells responsible for this effect remain to be elucidated. In this thesis, I also show that in unimmunized mice GITR expression is upregulated to higher than basal levels on a population of CD8 memory phenotype cells in the bone marrow. In contrast, CD8 memory phenotype T cells in the spleen and LN have GITR levels similar to that on naïve T cells. The upregulation of GITR in the bone marrow is IL-15 dependent and therefore, GITR serves as a marker for cells that have recently received an IL-15 signal. Furthermore, GITR is required for the persistence, but not for the homeostatic proliferation of CD8 memory phenotype T cells in the bone marrow. Therefore, GITR plays a key role for CD8 T cell intrinsic responses to influenza, as well as for the persistence of CD8 memory phenotype T cells.
Medial Temporal Lobe Function and the Perceptual Richness of Memory for Complex Personal and Laboratory Events
Keywords: memory
episodic
hippocampus
epilepsy
functional magnetic resonance imaging
recollection

Reliving the past requires the integration of multi-modal sensory details into a coherent mental impression of the initial event. In most people, memory for life episodes, or Autobiographical Memory (AM), is rich in sensory-perceptual elements that provide the vivid impression of travelling back in time. Abundant evidence indicates that the hippocampus plays a central role in AM recollection, but much research is still needed to determine which AM attributes engage the hippocampus at retrieval. My work assessed the relationship between hippocampal function and the perceptual richness of memory episodes. I designed a paradigm that captured the complexity of AM, and that manipulated perceptual richness while controlling for other AM confounds, such as recency, rehearsal, personal relevance, and “story” content. Participants studied and recalled perceptually enriched and impoverished laboratory events (film clips and written narratives, respectively) matched for the complexity of their storyline. An AM condition was also included for comparison. I tested healthy individuals and participants with unilateral medial temporal lobe epilepsy (mTLE), a clinical population with well documented hippocampal damage, on this paradigm. Perceptual richness was greatly reduced in people with mTLE, an effect that was most salient in the perceptually enriched conditions (AM and film clips). In a functional MRI version of this paradigm conducted on healthy individuals, I identified neural regions sensitive to the perceptual richness of AM and laboratory events, which included the anterior portion of the right hippocampus and other regions known to play a role in imagery and visual processing. In patients with right-lateralized mTLE, activation in these brain regions was markedly reduced in all memory conditions, which was consistent with the reduced perceptual richness I observed behaviourally. I reveal a clear relationship between hippocampal function and the perceptual richness of episodic memory, suggesting that the hippocampus plays a central role among brain regions that support the integration of multi-modal details into enriched memory experiences. My findings also advance our knowledge of how pathology and the nature of memory representation affect the neural correlates of episodic memory.
The Benefit of Capacity Pooling for Repairable Spare Parts
Keywords: Queueing Theory
Stochastic Processes
Spare Parts Provisioning
Maintenance
Capacity Pooling

Capacity pooling in production systems, in the form of production capacity or inventory pooling, has been extensively studied in the literature. While production capacity pooling has been proven to be beneficial, the impact of inventory pooling has been less significant. These results cannot be easily extended to repairable systems due to fundamental differences between repairable and production systems. For one thing, in repairable systems, the demand rate is a function of the number of operational machines, whereas it is exogenous and constant in production systems. In this Thesis, to serve different fleets of machines possibly at different locations, we study whether repair shop pooling is more cost effective than having dedicated on-site repair shops for each fleet. In the first model, we consider transportation delays and related costs, which have been traditionally ignored in the literature. We include on-site spare-part inventories that operate according to a continuous-review base-stock policy. Our numerical findings indicate that when transportation costs are reasonable, repair shop pooling is a better alternative. Next, we model a pooled repair shop that fixes failed components from different k-out-of-n:G systems. We permit a shared spare parts inventory serving all systems and/or reserved spare parts inventories for each system; we call this a hybrid model. The destination for a repaired component can be chosen either on a first-come-first-served basis or by following a static priority rule. Our findings show that both hybrid policies are more cost effective than having separate repair shops and inventories for each system. We propose implementing the multilevel rationing (MR) policy in systems with shared inventory. The MR policy prioritizes classes, and stops serving a class from inventory if the inventory level is below the inventory threshold identified for that class. When there is no inventory, the repaired component is sent to the highest priority class among those with down machines. To approximate the cost of the MR policy, we study an M/G/1//N queueing system serving multiple classes of customers with an unreliable server. Our numerical findings indicate that the MR policy performs as well as the epsilon-optimal policy and outperforms the hybrid policies.
Reflecting the Other: The Thing Poetry of Marianne Moore and Francis Ponge
Keywords: Modernism
Poetry
Alterity
French literature
American literature

Across continents and independently of one another, Marianne Moore (1887-1972) and Francis Ponge (1899-1988) both made names for themselves in the twentieth century as poets who gave voice to things. Their entire oeuvres are dominated by poems that attempt to reconstruct an external thing (inanimate object, plant or animal being) through language, while emphasizing the necessary distance that exists between the writing self and the written other. Furthermore, their thing poetry establishes an “essential otherness” to the subject of representation that (ideally) rejects an objectification of that subject, thereby rendering the “thing” a subject-thing with its own being-for-itself. This dissertation argues that the thing poetry of Marianne Moore and Francis Ponge successfully challenged the hierarchy between subject and object in representation by bringing the poet’s self into a dialogue with the encountered thing. The relationship between the writing self and the written other is akin to what Maurice Merleau-Ponty refers to in Le visible et l’invisible when he describes the act of perceiving what is visible as necessitating one’s own visibility to another. The other becomes a mirror of oneself and vice versa, Merleau-Ponty explains, to the extent that together they compose a single image. The type of reflection involving self and others that Moore and Ponge employ in their thing poetry invokes the characteristically modern symbol of the crystal with its kaleidoscopic reflective properties. Self and other are distinct yet indissolubly bound, and rather than a hierarchy between subject and object there are only subjects who exist for-themselves and for-each other, reflecting the kind of reciprocal Pour soi that Merleau-Ponty’s phenomenology envisioned.
Probabilistic Models for the Analysis of Gene Expression Profiles
Keywords: probabilistic models
gene expression profiling
cancer
prognosis prediction
expression evolution
tumor heterogeneity
expression deconvolution
tumor purification
topic models

Gene expression profiles are some of the most abundant sources of data about the cellular state of a collection of cells in an organism. Comparison of the expression profiles of multiple samples allows biologists to find associations between observations at the molecular level and the phenotype of the samples. A key challenge is to distinguish variation in expression due to biological factors of interest from variation due to confounding factors that can arise for unrelated technical or biological reasons. This thesis presents models that can explicitly adjust the comparison of expression profiles to account for specific types of confounding factors. One such confounding factor arises when comparing tissue-specific expression profiles across multiple organisms to identify differences in expression that are indicative of changes in gene function. When the organisms are separated by long evolutionary distances, tissue functions may be re-distributed and introduce expression changes unrelated to changes in gene function. We developed Brownian Factor Phylogenetic Analysis, a model that can account for such re-distribution of function, and demonstrate that removing this confounding factor improves tasks such as predicting gene function. Another confounding factor arises because current protocols for expression profiling require RNA extracts from multiple cells. Often biological samples are heterogeneous mixtures of multiple cell types, so the measured expression profile is an average of the RNA levels of the constituent cells. When the biological sample contains both cells of interest and nuisance cells, the confounding expression from the nuisance cells can mask the expression of the cells of interest. We developed ISOLATE and ISOpure, two models for addressing the heterogeneity of tumor samples. We demonstrated that modeling tumor heterogeneity leads to an improvement in two tasks: identifying the site of origin of metastatic tumors, and predicting the risk of death of lung cancer patients.
Late Transition Metal Complexes Bearing Functionalized N-Heterocyclic Carbenes and the Catalytic Hydrogenation of Polar Double Bonds
Keywords: catalysis
N-heterocyclic carbene
homogeneous hydrogenation
ketones
late transition metals
polar double bonds
metal hydrides
bifunctional catalysis
outer-sphere mechanism
inner-sphere mechanism
amine ligands
hydrolysis of nitriles

Late transition metal complexes of silver(I), rhodium(I), ruthenium(II), palladium(II) and platinum(II) containing a nitrile-functionalized N-heterocyclic carbene ligand (C-CN) were prepared. The nitrile group on the C–CN ligand was shown to undergo hydrolysis under basic conditions, leading to a silver(I) carbene complex with a primary-amido functional group, and a trimetallic complex of palladium(II) with a partially hydrolyzed C–N–N–C donor ligand. The reduction of a nitrile-functionalized imidazolium salt in the presence of nickel(II) chloride under mild conditions yielded an axially chiral square-planar nickel(II) complex containing a unique primary-amino functionalized N-heterocyclic carbene ligand (C-NH2). A transmetalation reaction moved this chelating C–NH2 ligand from nickel(II) to ruthenium(II), osmium(II), and iridium(III), yielding important catalysts for the hydrogenation of polar double bonds. The ruthenium(II) complex, [Ru(p-cymene)(C–NH2)Cl]PF6 catalyzed the transfer and H2-hydrogenation of ketones. The bifunctional hydride complex, [Ru(p-cymene)(C–NH2)H]PF6, which contains a Ru–H/N–H couple showed no activity under catalytic conditions unless when activated by a base. The outer-sphere mechanism involving bifunctional catalysis of ketone reduction is disfavored according to experimental and theoretical studies and an inner-sphere mechanism is proposed involving the decoordination of the amine donor from the C–NH2 ligand. The ruthenium(II) complex [RuCp*(C–NH2)py]PF6 showed higher activity than the iridium(III) complex [IrCp*(C–NH2)Cl]PF6 in the hydrogenation of ketones. This ruthenium(II) complex also catalyzes the hydrogenation of an aromatic ester, a ketimine, and the hydrogenolysis of styrene oxide. We proposed an alcohol-assisted outer sphere bifunctional mechanism for both systems based on experimental findings and theoretical calculations. The cationic iridium(III) hydride complex, [IrCp*(C–NH2)H]PF6 , was prepared and this failed to react with a ketone in the absence of base. The crucial role of the alkoxide base was demonstrated in the activation of this hydride complex in catalysis. Calculations support the proposal that the base deprotonates the amine group of this hydride complex and triggers the migration of the hydride to the η5-Cp* ring producing a neutral iridium(I) amido complex. This system contains an active Ir–H/N–H couple required for the outer sphere hydrogenation of ketones in the bifunctional mechanism.
Modification of Carbonaceous Materials with Sulfur and Its Impact on Mercury Capture and Sorbent Regenertion
Keywords: activated carbon
mercury
sulfur dioxide
petroleum coke
gas-solid reaction model
specific surface area
sulfuric acid
carbon-sulfur reactions
gas-phase adsorption
mercury control
porosity
coal combustion

Physical activation of oil-sands fluid coke, a dense carbonaceous material, using sulfur dioxide (SO2) was investigated as a means of utilizing a plentiful and inexpensive waste for elemental mercury (Hg) removal. A new model was developed to elucidate physical activation of dense carbonaceous materials. Experiments and model simulations revealed that, during activation with SO2, a sulfur-rich porous layer is formed around the periphery of the coke particles; this porous layer reaches a maximum thickness as a result of diffusion limitations; the maximum porous layer thickness is controlled by activation conditions and determines the maximum achievable specific surface area (SSA). Pre-oxidation in air prior to activation, acid washing after activation and smaller coke particle size all result in higher SSA. The highest SSA achieved was 530 m2/g, the highest yet found for oil-sands fluid coke with physical activation. If present, oxygen out-competed SO2 for carbon during activation. SO2 activation and porous layer formation did not occur until oxygen was depleted. Sulfur added to coke through SO2 activation is mainly in reduced forms which are more thermally stable than elemental sulfur in commercial sulfur-impregnated activated carbons (SIACs). TGA and elemental analyses revealed that only 17% of sulfur was removed at 800°C from SO2-activated coke under inert conditions, compared with 100% from a commercial SIAC. The role of sulfuric acid (H2SO4) in vapor Hg capture by activated carbon (AC) was studied due to conflicting findings in the recent literature. In the absence of other oxidizing species, it was found that Hg could be oxidized by oxygen which enhanced vapor Hg adsorption by AC and Hg absorption in H2SO4 solution at room and elevated temperatures. At 200°C, AC treated with 20% H2SO4 reached a Hg loading of more than 500 mg/g, which is among the highest Hg capacities yet reported. When oxygen was not present, S6+ in H2SO4 was found to act as an oxidizer of Hg, thus enabling Hg uptake by H2SO4-treated AC at 200°C. Treating the AC with SO2 at 700°C improved the initial rate of Hg uptake, with and without subsequent H2SO4 treatment.
From Ruthenium to Iron for the Catalytic Reduction of Ketones: Catalysis and Mechanistic Insights
Keywords: Catalysis
Reduction

A range of air- and moisture-stable phosphonium salts was prepared. Compounds were isolated in high yield and fully characterized. The properties of these compounds and the nature of their formation were explored. The phosphonium salts react with base to give phosphino-aldehydes which are important building blocks in the synthesis of PNNP ligands. The condensation reaction between phosphino-aldehydes and a diamine usually employed for the preparation of PNNP ligands was not applicable to the phosphino-aldehydes derived from these phosphonium salts as a result of the high reactivity of the nucleophilic phosphorus causing uncontrollable side-reaction. In order to resolve this problem, a template reaction with iron(II) Lewis acid was used to suppress the reactivity of the phosphorus via coordination. The reaction was successful and gave rise to bis-tridentate complexes with PNN ligands ([Fe(Ph2PCH2CH=N---NH2)2][BPh4]2, where N---NH2 depends on diamine used) as the kinetic product and to desired tetradentate complexes with PNNP ligands (trans-[Fe(Ph2PCH2CH=N---N=CHCH2PPh2)(CH3CN)2][BPh4]2, where N---N depends on diamine used) as a thermodynamic product of the reaction. The reaction appeared to be very general; complexes iii with various diamines incorporated in the ligand backbone were prepared in high yield and fully characterized. Mono-carbonylation reaction of the complexes containing tetradentate PNNP ligands resulted in the formation of the precatalysts with a general formula (trans-[Fe(Ph2PCH2CH=N---N=CHCH2PPh2)(CO)(Br)][BPh4]. These precatalysts give active (TOF up to 28000 h-1) and enantioselective (up to 95 % ee) catalytic systems for the ATH of ketones when activated with base in a solution of 2-propanol as the reducing agent. On the basis of a kinetic study and other evidence, we propose a mechanism of activation and operation of the catalytic system involving the precatalyst trans-[Fe(CO)(Br)(Ph2CH2CH=N-((S,S)-C(Ph)H-C(Ph)H)-N=CHCH2PPh2)][BPh4] and acetophenone as a model substrate. We determined that the activation of the precatalyst to the active species involves the stereoselective reduction of one imine group of the ligand, since when the active species are quenched with acid, the complex trans-[Fe(CO)(Cl)(Ph2CH2CH-(H)N-((S,S)-C(Ph)H-C(Ph)H)-N=CHCH2PPh2)][BPh4] containing amine and imine functionalities in the backbone is produced.
In Each Other&rsquo;s Arms: France and the St. Lawrence Mission Villages in War and Peace, 1630-1730
Keywords: New France
Missions
Aboriginals
Native Americans
Ethnohistory
War

Beginning in the late 1630s, a diversity of Algonquian and Iroquoian peoples established under the auspices of Jesuit and, later, Sulpician missionaries a string of village communities in the St. Lawrence Valley. A diversity of peoples, whom the French lumped under the rubrics of “Algonquins”, “Montagnais”, “Hurons”, “Iroquois”, “Abenakis” and “Loups”, migrated to these villages in the hope of bettering their lives in trying times. This dissertation retraces the formation and the early development of these communities, exploring the entangled influence of armed conflict, diplomacy, kinship, and leadership on migration, community-building, and identity formation. The historiography of the St. Lawrence Valley – the French colonial heartland in North America – has tended to relegate these Aboriginal communities to the margins. Moreover, those scholars who have considered the formation of mission villages have tended to emphasize missionary initiative. Here, these villages are reimagined as a joint creation, the result of intersecting French and Aboriginal desires, needs, and priorities. The significance of these villages as sites of refuge becomes readily apparent, the trajectories of individual communities corresponding with the escalation of conflict or with its tense aftermath. What also becomes clear is that the course of war and peace through the region cannot be accounted solely by the relations of the French and Iroquois, or of the French and British crowns. Paying close attentions to the nuanced personal and collective identities of the residents of the mission villages and their neighbours allows us to gain a better understanding of the geopolitics of the northeastern woodlands during the seventeenth and early eighteenth centuries.