VictorJuiz/thesis huggingface dataset:
Characterizing Novel Regulators of MYC-dependent Tumorigenesis
Keywords: cancer
c-MYC
interactome
post-translational modifications

The MYC oncogene has been the subject of intense study for over 30 years due its important role in tumorigenesis. MYC is a nuclear transcription factor that can regulate the expression of a multitude of target genes, and its expression in tumours is often associated with poor prognosis. Recent reports have suggested that both protein complexes and post-translational modification (PTM) of MYC are important for regulating the activity and functions of this potent oncogene. The overall goal of my PhD was to gain novel insights into how MYC drives tumorigenesis by characterizing the MYC Box (MB) interactome using BioID and by identifying novel post-translational modification of MYC. In total, 336 proteins were identified as putative MYC interactors, and a subset of these proteins were identified to have a dependency on a specific MB deletion. Of the six MBs interrogated, MBII was further confirmed, and MB0 was newly identified as being essential for MYC to drive tumorigenesis. MBII and MB0 have distinct interactomes; whereas MBII interacts with TIP60 and STAGA complexes, MB0 interactors include members of the general transcriptional machinery. I have also investigated the role of post-translational modifications in the regulation of MYC activity, including SUMOylation and phosphorylation, and have identified both known and novel post-translational modifications of MYC. Signaling through a pair of newly described phospho-residues, serine-303 and threonine-304, resulted in the negative regulation of MYC activity. Finally, I have identified and characterized a site of MYC SUMOylation on lysine-326. Overall, these studies have provided novel insights into the PTMs and protein interactors that are required for MYC to drive transformation.
Model Fitting for Motion Segmentation
Keywords: Model Fitting
Motion Segmentation

The problem of rigid motion segmentation of trajectory data under orthography has been long solved for non-degenerate motions in the absence of noise. But because real trajectory data often incorporates noise, tracking failures, motion degeneracies and motion dependencies, recently proposed motion segmentation methods resort to non-trivial representations to achieve state of the art accuracies, at the expense of a large computational cost. This thesis proposes a method that dramatically reduces this cost (by two orders of magnitude) with minimal segmentation accuracy loss (from 98.8% achieved by the state of the art, to 97% achieved by our method on the standard Hopkins 155 dataset). Computational efficiency comes from the use of a simple but powerful motion model that explicitly incorporates mechanisms to deal with noise, outliers and motion degeneracies. Subsets of these motion models with the best balance between prediction accuracy and model complexity are efficiently ranked from a pool of candidates. Top scoring model combinations are then merged using an averaging technique to produce the final segmentation result.
QUATERNARY SULFUR CYCLE DYNAMICS
Keywords: geochemical modeling
stable isotopes
sulfur cycle

The past 3 million years of Earth history are characterized by dramatic changes, which greatly affected the biogeochemical cycling of elements like carbon, sulfur and phosphorous. Here I investigate the effect of these changes on sulfur fluxes and microbially mediated sulfur cycling in marine sediments. Climate driven sea level fluctuations and dynamic topography have greatly affected the areal extent of the continental shelf during the Quaternary. In turn this affects organic matter burial rates and the relative importance of different organic matter remineralization pathways. Since microbial sulfur cycling is the dominant organic matter re-mineralization pathway in marine sediments, this must have affected marine sulfur cycling. Furthermore, previous studies suggested that Quaternary sea level fluctuations caused a considerable increase in the erosion of shelf sediments, which is closely tied to the re-oxidation of pyrite. Here, I use the marine barite record of sulfur and oxygen isotope ratios (d34S and d18O) of seawater sulfate for the past 4Ma to evaluate the implications of Quaternary sea level changes on the sulfur cycling. Quantitative interpretation of d34S and d18O data suggests that erosion during sea level lowstands was only partly compensated by increased sedimentation during times of rising sea levels and sea level highstands. Furthermore, my findings indicate that shelf systems reached a new equilibrium state about 700 kyr ago, which considerably slowed or terminated erosion of shelf sediments. Modeling results also show that microbial sulfur cycling changes proportionally with shelf area, resulting in a 15% reduction of microbial sulfur cycling over the last 2 Ma. This results in a 1-1.5 / drop in the marine sulfate d18O isotope value. While further work is needed to understand how shelf area changes affect the cycling of carbon, phosphorous and other elements, results presented here highlight the dynamic role of continental shelves in the global biogeochemical cycles.
Cooperating Oncogenic Alterations in Aggressive Pten-Deficient Breast Cancer
Keywords: Breast
Mouse model
p53
PTEN

PTEN is one of the most frequently inactivated tumor suppressors in human malignancies including breast cancer, and its mutation or loss is often implicated in advanced cancers and therapy resistance. Yet, germline mutations in PTEN induce non-malignant hamartomas in humans and mouse tumors with a wide spectrum of aggressiveness, indicating context-dependent effects. To develop effective anti-cancer therapies, a better understanding of how mutational events cooperate with PTEN-loss is required. In this thesis, I show that most tumors derived from Pten-deleted mammary epithelium were highly differentiated and lacked transplantable tumor initiating cells following FACS isolation or transient propagation under non-adherent conditions. Surprisingly, a rare group of Pten-deficient tumors with distinct histology did contain transplantable TICs. In comparing these two tumor groups, I identified low miR-143/145 expression as a critical factor that determined transplantability. Knockdown of miR-143/145 in Pten-deficient tumor cells promoted secondary tumor engraftment, RAS pathway activation and sensitivity to MEK inhibitors. In basal-like breast cancer, 7% showed combined loss of PTEN and miR-145 as well as poor clinical outcomes. Thus, Pten loss can initiate benign or aggressive mammary tumors depending on miR-143/145 status. Patients with basal-like tumors and low-Pten/miR-143/145 expression should be identified and prioritized for aggressive therapy. Pten-deletion also cooperated with p53R270H mutation, resulting in diverse tumors including basal-like and claudin-low. Compared to mammary tumors arising from Ptenf:p53f mice, Ptenf:p53R270H mammary tumors were more capable of undergoing mesenchymal-epithelial transition (MET) and possessed greater metastatic potential. Together, these findings identified important oncogenic events that cooperate with PTEN-loss to induce aggressive breast cancer, enhance metastatic progression and influence response to therapy, and have significant implications for personalized breast cancer treatment.
Halogen Bonding Polymers: Synthesis, Binding Studies, and Solution-Phase Assembly
Keywords: Halogen Bonding
Intermolecular Interactions
Inverse Micelles
Multicompartmental
Polymer Nanoparticles
Self Assembly

This work explores interpolymer halogen bonding to direct solution-phase self-assembly. Halogen bonding is an attractive, non-covalent interaction between a halogen bond donor which bears an electron deficient halogen atom and a Lewis basic halogen bond acceptor. The donor halogen receives electron density from the Lewis base acceptor. Halogen bonding has received significant attention in materials chemistry but examples of polymeric donors are infrequent. Solution-phase polymer nanostructures are of interest for catalysis, drug delivery, and stimuli responsive materials. They have previously been formed through other non-covalent interactions but not by halogen bonding. This work contributes to the fields of halogen bonding and polymer chemistry through the synthesis of polymeric donors, the characterization of their interpolymer complexation with a polymeric acceptor, and the establishment of conditions yielding well defined solution-phase assemblies of complementary polymeric halogen bond donors and acceptors. Herein, the first examples of RAFT polymerization of halogen bond donors are described for methacrylate and styrene derivatives. X-ray photoelectron spectroscopy and 19F NMR titrations are employed to characterize interpolymer halogen bonding with polymeric acceptor PDMAEMA. Acceptor chain length dependent trends in binding affinity and occupancy of donor sites are established for polymer solutions. Assembly of the donors with block copolymers of the acceptor (PEO-b-PDMAEMA) was performed by multiple solvent switching protocols. Going from DMSO to water resulted in kinetically controlled morphologies, whereas a slow solvent changing procedure from acetone to acetonitrile to water allowed access to a rich variety of structures, including two infrequently reported inverted morphologies (hexagonal and bicontinuous). To further demonstrate the utility of halogen bonding, multicompartmental assemblies were formed with cores composed of both halogen bonding and non-halogen bonding segments. Halogen bonding and hydrophobic domains were assembled in stages using a multi-step assembly process with a donor homopolymer and a triblock terpolymer bearing an acceptor block, a hydrophobic non-halogen bonding block, and a corona block.
Investigating factors that govern T cell and dendritic cell function as therapeutic strategies for immune therapy
Keywords: cancer
Cbl-b
dendritic cell
HIF-1a
immunotherapy
T cell

In 1909, Paul Ehrlich first suggested that the immune system protects against cancer. Over a century later, significant progress has been made towards understanding the interplay between the immune system and cancer, as well as many other diseases. Cancer immunotherapy is a burgeoning field of research that has great potential to complement or replace existing treatments. However, much remains to be understood in defining the precise factors that regulate immune function, particularly in the context of the complex tumor microenvironment. Dendritic cells and T cells, the prototypical immune populations involved in the generation of an adaptive, cytotoxic T cell response, play an important role in tumor immune surveillance. The activity of these immune subsets in a tumor, however, is frequently inhibited. Thus, identifying strategies to restore immune activity in the immunosuppressive tumor environment will serve to augment immune therapies for cancer. In the first part of this thesis, we show that Casitas B lymphoma b (Cbl-b), a crucial negative regulator of T cell activation, is regulated downstream of the phosphoinositol 3-kinase (PI3K)-protein kinase B/Akt (PKB) signaling pathway in T cells. Glycogen synthase kinase 3 (GSK-3), one of the first targets identified for PKB, was found to phosphorylate Cbl-b, modulating its expression. In the second part of this thesis, we clarify the role of the master cellular sensor of hypoxia, hypoxia-inducible factor 1 alpha (HIF-1Îą), in dendritic cells. HIF-1Îą plays an important role in cancer biology, but has also been shown to have opposing effects on immune function in a cell- and context-dependent manner. We found that enforced HIF-1Îą expression in bone marrow-derived dendritic cell (BMDC) cultures promotes the differentiation of myeloid-derived suppressor cells (MDSCs), an immunosuppressive population. Altogether, these data suggest two potential targets for modulating immune function and augmenting anti-tumor responses in immune therapy.
Development of a More Robust Near-Infrared Spectroscopy Brain Computer Interface: Single-Trial Classification of Near-Infrared Spectroscopy Signals Arising from Multiple Cortical Regions
Keywords: brain-computer interface
near-infrared spectroscopy
online
parietal
prefrontal
single-trial classification

Near-infrared spectroscopy (NIRS) has been gaining increasing attention as a brain-computer interface (BCI) modality. However, communication rates offered by this technology are not yet practical for clinical implementation. This thesis investigates the feasibility of enhancing the speed and accuracy attainable by NIRS-BCIs. To date, most studies have utilized activity from a single cortical region, particularly the anterior prefrontal cortex (aPFC), to discern two non-motor-based mental states. However, cognitive processes require coordination between several, spatially-distributed areas. Additional cortical information may help improve classification of mental states, particularly combinations of more than two. Furthermore, testing has largely focused on offline analyses, despite the possibility of enhanced cortical control attainable with feedback. Lastly, NIRS-BCI work has primarily involved able-bodied participants, most of which were offline. In an initial offline study, we investigated the value of utilizing cortical activity measured from multiple brain regions to differentiate all possible combinations of two cognitive tasks and rest. With prefrontal and parietal measurements, average binary and ternary accuracies exceeded 80% and 70%, respectively. Accuracies and information transfer rates (ITRs) improved significantly with the inclusion of measurements beyond the aPFC. A second study was conducted to evaluate ternary classification accuracies achievable in an online system that offered classification feedback. An average online accuracy of 74.2 Âą 14.8% was attained, representing further improvements in NIRS-BCI speed and accuracy. In a final study, we tested an online system developed for a candidate BCI user with severe, congenital muscular impairments. The binary system made use of prefrontal measurements beyond the aPFC and was tailored for the user prior to each online session. Offline and online accuracies of 66.9 Âą 9.11% and 63.33%, respectively, were achieved. Collectively, these findings demonstrate the value of considering multiple brain regions and offering online classification feedback to realize a faster and more accurate NIRS-BCI.
Sanctuary Lost? Exposing the Reality of the “Sanctuary-City” Debate Liberal States-Rights’ Litigation
Keywords: Executive Order 13
768
immigration federalism
sanctuary cities
states' rights
Tenth Amendment

The Trump Administration seeks to withhold federal funding from “sanctuary cities.” It also has returned to the Secure Communities Program, which has led to a 150% arrest-rate increase of the migrants who would otherwise be integrated into “sanctuary” jurisdictions. Liberal voices have responded in legal and academic terms, but they have not reframed the administration’s powerful anti-immigrant narrative. This rhetorical mismatch has obscured fundamental aspects of the debate—namely, the power of states to make community policing decisions and the effectiveness of such policies. Moreover, liberals’ approach to states-rights’ litigation is incomplete. The aspects of Executive Order 13,768 that are receiving the most attention (funding) can be rebuffed, yet aspects that pose grave, indirect harm to integrationist policies (S-Comm) are not being addressed. Liberals should continue states-rights’ litigation but also assert an integrationist counter-narrative and use litigation as a form of non-cooperation designed to prompt a return to enforcement priorities.
Controlled Generation of Hematopoietic Progenitor Cells from Human Pluripotent Stem Cells
Keywords: Hematopoiesis
Hematopoietic Stem Cells
Human Embryonic Stem Cells
Micropatterning
Niche Engineering
T-cells

Human pluripotent stem cells (hPSCs) provide an exciting source for regenerative therapy because they have the potential to differentiate towards specialized tissues. However, in vitro generation of hPSC-derived cell lineages, such as definitive hematopoietic cells, remains challenging and typically only generates primitive blood cells. In the developing embryo, blood cell emergence is coordinated by spatial and temporal cues that include autocrine/paracrine signaling, oxygen tension, local cell density, and immobilized growth factors. We hypothesize that engineering aspects of the native definitive blood niche in vitro will enable robust generation of adult-like blood progenitor cells. To this end, we have investigated whether hPSC-derived hemogenic endothelial (HE) cells seeded into engineered niches of controlled size, distribution and composition could be optimized to promote differentiation towards phenotypical CD45+ blood cells, including definitive blood precursors. First, we used microwells to initiate hPSC differentiation as size-controlled cell aggregates in serum-free conditions to promote HE induction. These cells display multi-lineage differentiation capabilities (myeloid and lymphoid) and short-term engraftment. HE cells served as our starting population to study the effects of lithography-based micropatterned (MP) controlled culture parameters such as colony size, spacing and clustering on the endothelial-to-hematopoietic transition. MP treatments yield 5.5-fold greater enhancement in CD45+ progenitors compared to unpatterned treatments and demonstrate endogenous inhibitors at play during hematopoietic differentiation. We show that deficiencies in hematopoietic induction can be overcome via MP niches and link the induced interferon gamma protein (IP-10)/p-38 MAPK signaling pathway as a mechanism for hematopoietic inhibition. Using this platform, we identified interferon-gamma (IFN-Ę ), interleukin-3 (IL-3), VX-702 (p38 MAPK inhibitor) and Fasudil HCl (Rho-kinase inhibitor) as key modulators for definitive hematopoietic induction from hPSC-derived sources that confer long-term splenic engraftment in immunocompromised mice. This demonstrates that in vitro niche engineering can mimic in vivo embryonic development and provides a model to investigate blood cell emergence.
The role of NKR-P1:Clr family interactions in murine cytomegalovirus infection
Keywords: Cytomegalovirus
Innate immunity
Missing-self
Natural killer cells
NK1.1
Nkrp1-Clr

Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKR). Here, an MHC-I-independent NK cell recognition mechanism that involves modulation of NKR-P1:Clr receptor-ligand function upon mouse cytomegalovirus (MCMV) infection is characterized. Expression of host “self” Clr-b ligand is rapidly lost on MCMV-infected cells, invoking “missing-self” NK recognition. Cross-species viral infections using rodent fibroblasts suggest this response is evolutionarily conserved. Active viral infection is necessary for Clr-b loss, as inactivated virus and innate signalling agonists fail to elicit Clr-b downregulation. Clr-b loss is partially blocked by cycloheximide, suggesting early viral or nascent host proteins are required for Clr-b downregulation. Further investigation using CD3/NKR-P1 reporter cell assays identified a novel Clr-b-independent MCMV-encoded decoy immunoevasin, m12, that directly engages the paired NKR-P1A/B/C receptor clade. Thus, MCMV m12 is the first physiological ligand for the prototypical NK1.1 orphan receptors (NKR-P1B/C). MCMV m12 restrains NK effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Independent structural analyses reveal that m12 is IgV-like and sequesters a large surface area of the C-type lectin-like NKR-P1 protein via a "polar claw" docking mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. This work identifies the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay. Additional work provides evidence that the MCMV m153 immunoevasin stabilizes host Clr-b surface levels. In contrast, infections using m153-deficient MCMV mutants show exacerbated Clr-b downregulation. Importantly, enhanced Clr-b loss by MCMV m153-mutant infection is reversed by exogenous m153 complementation. Intracellular m153 localization suggests the Clr-b stabilization effect may be indirect. This is confirmed by m153 tetramer staining of dendritic cells, and in vivo analyses showing that m153 MCMV exhibits enhanced virulence, in an Nkrp1b/Clrb-independent manner. Thus, m153 may bind an activating immunoreceptor. Together, these data demonstrate that the NKR-P1:Clr recognition axis is subverted by multiple MCMV immune evasion strategies.
The Paromomyidae (Primates, Mammalia): Systematics, Evolution, and Ecology
Keywords: Ecology
Evolution
Mammalia
Paromomyidae
Primates
Systematics

Plesiadapiforms represent the first radiation of Primates, appearing near the Cretaceous-Paleogene boundary. Eleven families of plesiadapiforms are recognized, including the Paromomyidae. Questions surrounding this family explored in this thesis include its pattern of extinction, its phylogeny and migration, and its dietary ecology. Firstly, there is a record of misclassifying small-sized omomyoid euprimates as late-occurring paromomyid plesiadapiforms. Here, a new omomyoid from the Uintan of California is described. This material was previously thought to pertain to a paromomyid, similar to previously named supposed paromomyids Phenacolemur shifrae and Ignacius mcgrewi. The new Californian species, Ph. shifrae, and I. mcgrewi are transferred to Trogolemurini, a tribe of omomyoids. The implications of this taxonomic change are that no paromomyids are found between the early Bridgerian and the Chadronian, suggesting that the group suffered near-extinction during a period of particularly warm climate. Secondly, migration of paromomyids between North America and Europe is poorly understood. The European material (genus Arcius) is taxonomically reassessed, including emended diagnoses for all four previously named species, and description of two new Arcius species. A cladistic analysis of the European paromomyids resolves Arcius as monophyletic, implying that the European radiation of paromomyids was a product of a single migration event from North America. Finally, paromomyid diet has only been assessed qualitatively in previous literature. Dental topographic metrics are used to assess diet in paromomyids and observe patterns of evolutionary change in the P4. The results for P4 are consistent with previous literature for inferences about changes within given lineages, but comparisons across different lineages is challenging. The results for M2 suggest a more varied diet that previously thought for paromomyids. The results presented here show a general trend from more insect intake in primitive members to a more frugivorous diet in more derived and/or later occurring members of various lineages.