VictorJuiz/thesis huggingface dataset:
Coarse Grained Modeling of Intrinsically Disordered Protein Structures and Dynamics

Contrary to natively folded proteins, which often have a single stable 3D structure, Intrinsically Disordered Protein (IDP) structures dynamically fluctuate between many conformations. This complexity impedes their study and the understanding of their functions. Experimental techniques can probe aspects of the conformations, but often different techniques or conditions offer seemingly contradictory results. In this thesis, I use coarse-grained models and simulations to investigate the structures and dynamics of IDPs. One system I focus on is the Nuclear Pore Complex (NPC): a bidirectional selective gate for cargo traveling across the nuclear envelope of eukaryotic cells. A key functional component of the NPC is the layer of intrinsically disordered FG nucleoporins attached to the interior of the transport channel. Elucidating the mechanism of transport remains elusive due to the size and complexity of the NPC, but will contribute to the understanding of diseases associated with mutations in the NPC, viruses which enter the nucleus via the NPC, and drug delivery into the nucleus, as well as the development of NPC inspired devices for nanotechnological applications. I show how a mean field model for surface grafted FG nups reconciles several conflicting experimental observations and theories of transport. Due to a lack of unique structure, the influence of the amino acid sequence on IDP structures and dynamics is unclear. Various evidence points to the overall importance of general properties of the sequence rather than the atomistic details of the amino acids. Using coarse-grained simulations, I investigate how the effects of several key sequence properties on the polymer dimensions and end-to-end distance dynamics of IDPs. These results have implications for interpreting experimental measurements as well as developing appropriate models of IDPs.

Keywords: IDP
intrinsically disordered proteins
NPC
nuclear pore complex
polymer physics
Advisor: Zilman, Anton
Fabrication of Superhydrophobic Ceramic Coatings via Solution Precursor Plasma Spray Process under Atmospheric and Low-pressure Conditions

In this work, superhydrophobic ytterbium oxide coatings were fabricated via the solution precursor plasma spray process under atmospheric and low-pressure conditions. Firstly, Yb2O3 coatings were deposited via the solution precursor atmospheric plasma spray (SPAPS) process by an injection of Yb(NO3)3 solution into atmospheric plasma. The SPAPS coatings exhibited hierarchical columnar structures composed of micron-sized clusters with nanometer-sized splats/particles on the top surface. The SPAPS coating showed a water contact angle (WCA) of ~163o, a roll-off angle (RA) of ~6o, and multiple complete droplet rebound behavior. Based on the SPAPS process, a novel solution precursor vacuum plasma spray (SPVPS) process was developed by injecting Yb(NO3)3 solution into low-pressure plasma. Highly-dense Yb2O3 coatings with relatively consistent microstructures were deposited at different standoff distances at 150 mbar. The coating showed relatively flat topographies, resulting in a WCA of ~155o and a RA of ~28o. The dense SPVPS coating maintained a high microstructural integrity and relatively consistent hydrophobicity after a comprehensive set of mechanical tests, showing a higher mechanical robustness than the SPAPS coatings. By increasing the chamber pressure to 250 mbar and using a glancing angle deposition method, superhydrophobic coatings with bump-structures and inter-bump gaps were deposited via the SPVPS process, showing a WCA of ~160o and a RA of ~7o. The Yb2O3 coatings showed reversible wetting behaviors. The as-deposited coating was superhydrophilic while it became superhydrophobic after vacuum (1-15 Pa) treatment. The superhydrophobic coating again became superhydrophilic after Ar-plasma cleaning or heat treatment, while it regained the superhydrophobicity after another vacuum treatment. The investigation of the surface composition showed that hydrocarbon species increased significantly after vacuum treatment and decreased dramatically after Ar-plasma cleaning or heat treatment, indicating hydrocarbon adsorption/desorption on the surface was the decisive factor for the reversible wettability of the coating. The surface composition of Yb2O3 coatings after long-term (over 10 months) air exposure, Yb2O3 coatings after ultra-high vacuum (~10-7 Pa) treatment and Al2O3 coatings after vacuum treatment (1-15 Pa) were investigated, showing the WCA variation of all the coatings after different treatments was closely related to the amount of hydrocarbon species adsorbed on the surface.

Keywords: rare earth oxides
solution precursor plasma spray
superhydrophobic coatings
Advisor: Mostaghimi, Javad
Coyle, Thomas W
Transcriptional Profiling and Regulation in Survivors of Critical Illness with Muscle Weakness and Meta-analysis across Human Muscle Diseases

ICU acquired weakness (ICUAW) is a common complication of critical illness characterized by decreased muscle mass and function with resulting physical impairment that may persist for years after ICU discharge. Transcriptomic profiling of peripheral muscle biopsies in patients with muscle weakness and healthy controls may detect changes in key biological processes related to muscle impairment. We hypothesized that abnormal expression of mRNAs and miRs related to muscle repair may be an important feature of ICUAW compared to controls. In study 1, we integrated clinical data and mRNA transcriptomic data from quadriceps muscle biopsies from patients with ICUAW at day 7 post-ICU discharge and at follow up at month 6 post-ICU discharge and compared to healthy controls. A gene co-expression network analysis method detected groups of co-expressed genes related to muscle repair that were downregulated in ICUAW compared to healthy controls. In study 2, we aimed to identify miRs that are significant regulators of mRNAs and mRNA networks in ICUAW. Mir-424-5p was found to regulate the greatest number of mRNAs in early ICUAW, including downregulated mRNAs related to striated muscle cell differentiation. At month 6 post-ICU, a differentially expressed miR signature was found between patients that increased quadriceps muscle mass (“Improvers”) from those who did not (“Non-improvers”). In study 3, we performed meta-analysis of mRNA transcriptional profiles from muscle biopsies from human muscle diseases and healthy controls to identify a common signature of genes dysregulated across muscle diseases as well as those genes with expression changes that are unique to ICUAW. We detected a common muscle signature of 131 genes similarly expressed across five categories of muscle diseases. Finally, removing the genes common to muscle disease from meta-analysis of only ICUAW cohorts revealed uniquely down-regulated muscle development and contraction genes specific to ICUAW. In summary, dysregulation of mRNAs and miRs related to muscle repair was detected in ICUAW compared to controls. Transcriptional changes unique to ICUAW versus other categories of muscle disease were detected using meta-analysis strategy.

Keywords: Biomarkers
Intensive Care Medicine
Muscle disease
Transcriptomics
Advisor: dos Santos, Claudia
Indexing Cortical Reactivity with TMS in Major Depressive Disorder and Response to Therapeutic Brain Stimulation

The neuropathophysiology of Major Depressive Disorder (MDD) appears to be linked to aberrant cortical inhibition and excitation. These processes are mediated by -amino butyric acid (GABA) and glutamate, the main inhibitory and excitatory neurotransmitters of the cortex, and modified by therapeutic brain stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). Cortical inhibition and excitation can be indexed via transcranial magnetic stimulation, affording high potential as biomarkers of illness state and response to brain stimulation. When combined with electromyography (TMS-EMG), the motor cortex response is assessed. When combined with electroencephalography (TMS-EEG), TMS indexes cortical inhibition and excitation over other cortical regions, more closely associated with MDD. In study one, cortical inhibition was indexed with TMS-EMG over the motor cortex before and after a course of ECT. A TMS-EMG measure of GABAB receptor-mediated cortical inhibition, the cortical silent period, was shorter at baseline in patients who responded to ECT, when compared to the non-responder group. Contrary to evidence, neither cortical silent period nor short interval cortical inhibition (both TMS-EMG measures of cortical inhibition) were altered by a course of ECT. In study two, TMS-EEG indexed cortical inhibition and excitation over the dorsolateral prefrontal cortex (DLPFC) in healthy subjects and patients with MDD. MDD patients had larger TMS-EEG amplitudes of markers of cortical inhibition (N45 and N100) and excitation (P60 and GMFA Area Under the Curve). In fact, the N45 predicted illness state with high accuracy, and N100 was associated with illness severity. In study three, DLPFC response to rTMS was indexed via TMS-EEG in patients recruited for a trial comparing active rTMS to sham rTMS. Sham rTMS did not alter TMS-EEG markers. Active rTMS resulted in differences in the markers of cortical inhibition. The N100 amplitude, a marker associated with GABAB receptor mediated inhibition, decreased in amplitude after rTMS in association with improvement in depressive symptoms. Moreover, a local dampening of cortical activity over the DLPFC, where rTMS was applied, was noted only with active rTMS. TMS markers of cortical inhibition and excitation therefore demonstrate high potential as biomarkers of MDD and response to therapeutic brain stimulation.

Keywords: Biomarkers
Brain Stimulation
EEG
EMG
Major Depressive Disorder
TMS
Advisor: Daskalakis, Zafiris J
Thinking Through Dilemmas

According to the sociological dual process model (SDPM), all thoughts occur either automatically and unconsciously or deliberately and consciously. However, by analyzing three empirical cases where individuals often engage in great amounts of deliberation – death and dying, pedophilia, and career decision-making – I find that individuals engage in what I term automatic deliberation: a mode of thinking which is both habitual and effortful. Given the high levels of emotional resonance of these topics for many individuals, schemas and frames for thinking about and through these topics are frequently alternated between in ways which demonstrate a blend of habituated understandings and conscious deliberation. Recent innovations in dual process theorizing are utilized to help support my argument. Specifically, the hybrid and parallel dual process models – two models which assume strong interconnections between automatic or Type 1 and deliberate or Type 2 processes. The data analyzed in this dissertation support this blended view of cognition by demonstrating how individuals think through complex topics in patterned yet personalized ways as they draw on schemas and frames to arrive at their final conclusions. Individuals’ thought processes are mapped out using the concept of cognitive paths: the routes that individuals tend to take when reasoning through particular topics which can fruitfully be unpacked in terms of which ideas are called upon, how they are used, and how they take shape throughout an individual’s overall response trajectory. The patterned yet personalized nature of thought as made evident through the analysis of automatic deliberation and cognitive paths implies that, rather than being purely Type 1 or Type 2 in any given instance, cognition has both automatic and deliberate dimensions to it. By framing cognition in such a manner and mapping it out using cognitive paths, sociologists can more accurately gauge the extent to which culture shapes cognition in any given empirical domain.

Keywords: Careers
Cognition
Death and Dying
Dilemmas
Dual Process Models
Pedophilia
Advisor: Leschziner, Vanina
Free Will in Malebranche and Leibniz

This dissertation explores two aspects of freedom in Malebranche and Leibniz. The first concerns the freedom with which God creates. Malebranche and Leibniz both think that God sees reasons to create a world, and that God freely decides to create a world in light of those reasons. They disagree, though, both about what the reasons are for why God creates and the sense in which God is free in creating. The second issue concerns their agreement that God and humans are free in the same sense, a controversial position in the period. I argue that Malebranche’s God creates a world with the purpose of glorifying himself. Furthermore, Malebranche’s God’s decision to create instead of doing nothing whatsoever involves the indifference of equilibrium. This is because God glorifies himself whether he creates a world or not. An implication of this position is that there is no contrastive explanation for why God creates a world instead of doing nothing whatsoever. A notoriously difficult question for Malebranche is how his account of human freedom is consistent with his commitment to occasionalism. I argue that recognizing that human freedom for Malebranche, too, involves an indifference of equilibrium allows an interpretation of Malebranche’s account of freedom that does not undermine his commitment to occasionalism. A problem for Leibniz is that it is unclear how the existence of the best possible world can be contingent if it is metaphysically necessary that God chooses whatever seems best to him. I deny that it is metaphysically necessary that God chooses whatever seems best to him. Instead, for Leibniz, God’s decision to create the best possible world is free and contingent because it is founded on his free decision to set his will to always choose whatever is best. This decision is free because it is formally indemonstrable from God’s nature. Recognizing that this decision is free shows how it can be that unactualized possibles strive for existence in their very nature, while also maintaining that the existence of the best set of them is contingent. Finally, I argue that, against what Leibniz’s 1686 essay “On Necessary and Contingent Truths” may suggest, Leibniz maintains that there is a univocal sense in which all intelligent agents are free.

Advisor: Rozemond, Marleen
Epigenetic Basis for Heterogeneity in Vascular Cell Adhesion Molecule 1 Gene Expression in the Cytokine Activated Vascular Endothelium

Homogeneous populations of mature differentiated primary cell types can display variable responsiveness to extracellular stimuli, though little is known about the underlying mechanisms that govern such heterogeneity at the level of gene expression. Here we show that morphologically homogenous human endothelial cells exhibit heterogeneous expression of VCAM1 after TNFα stimulation. Variability in VCAM1 expression was not due to heterogeneity of intracellular signal transduction, but rather to preexisting established heterogeneous states of promoter DNA methylation that were generationally conserved through mitosis. Variability in DNA methylation of the VCAM1 promoter resulted in graded RelA and RNA polymerase II binding that gave rise to a distribution of VCAM1 transcription in the population after TNFα stimulation. Microarray analysis and single cell RNA sequencing revealed that a number of cytokine-inducible genes shared this heterogeneous response pattern. These results show that heritable epigenetic heterogeneity is fundamental in inflammatory signalling and highlight VCAM1 as a metastable epiallele.

Keywords: DNA methylation
Epigenetics
Gene regulation
Heterogeneity
Vascular biology
VCAM1
Advisor: Marsden, Philip A
Incorporating Youth into the Political Arena: Elite Structures, Elite-youth Linkages, and Youth (De-) mobilization in post-1960 Turkey (1960-2016)

This dissertation investigates why the Turkish state encountered sustained youth contention and failed to contain it in the 1960s and the 1970s, while it proved more capable in preventing the emergence/escalation of youth dissent in the post-1980 period. Studies on social movements have not treated youth as a central category (Bayat 2010) and have under-theorized the processes of youth mobilization and demobilization. Besides, scholars of state-society relations in the Global South have paid scant attention to the political role of youth and elite attempts at incorporating young people into the political and economic structures. This study undertakes a comparative-historical analysis of political elite-youth linkages to explain the trajectory of youth political participation in post-1960 Turkey. By elite-youth linkages, I refer to the attempts of the power-holder elites at regulating youth political participation in accordance with their particular interests and to the ways young people benefit from, negotiate, or at times challenge elite claims to exert control over youth political agency. This study contends that the more fragmented the Turkish elites in the period from 1960 to 1980, the more they turned to participate themselves in youth mobilization via the process of partisan incorporation. Elite fragmentation in part facilitated militant youth behavior, left the Turkish state vulnerable to youth contention, and created youth mobilization that was sustained over a long period. The more cohesive the Turkish elites in the post-1980 coup period, the more they turned away from establishing partisan linkages with youth and the more they subscribed to incorporation as moderation and control. Elite cohesion curbed the mobilizational capacity of youth and ultimately triggered youth political disengagement. Finally, the more the ruling party elites perceived threats to emerging elite hegemony in the post-2010 period, the more they adopted hybrid incorporation to secure incumbency and sustain political hegemony. Elite hegemony weakened oppositional youth politics and politically empowered pro-government youth.

Keywords: elite studies
state-society relations
Turkish Politics
Youth politics
Advisor: Kingston, Paul
The Key of Ordering: Reading Musical Manuscripts of the Thirteenth and Fourteenth Centuries

This is a study of a complex attitude toward manuscript production and an associated reading practice in musical manuscripts from thirteenth- and fourteenth-century France. The practice is based on the idea that music was not only defined as a sonic phenomenon received through hearing but it could also be received through the intellectual perception of the order of things. Some manuscripts were designed based on the idea of musica mundana, or the harmony of the spheres, and reading such books was seen as a way to exercise this type of hearing, which enacted the mystical ascent of the reader to beatific vision. The three manuscripts examined exhibit this practice in their ordering and content: Roman de la Poire (Paris, Bibliothèque nationale de France, MS fr. 2186), Roman de Fauvel (Paris, BnF, MS fr. 146), and Guillaume de Machaut’s MS A (Paris, BnF, MS fr. 1584). After a methodological introduction, chapter two defines the manuscript production and reading practice using medieval metaphysics and a novel understanding of the medieval definition of musica as a basis. The three manuscripts’ diverse contents of poetry, music, and art were composed and ordered based on precise mathematical proportions and these proportions highlight content throughout the manuscripts. Chapter three examines the ordering scheme of the Roman de la Poire manuscript. It is designed based on an elaborate ordering scheme that is meant to lead the reader to understand the transcendent order of Love. Chapters four and five examine the ordering scheme of the Roman de Fauvel manuscript. The Complainte d’amor at the beginning of the manuscript contains a hidden map that reveals the ordering scheme of the whole manuscript. Chapters six and seven examine the ordering scheme of Guillaume de Machaut’s MS A. The Prologue is a cryptic puzzle that reveals a task for the reader to undertake and a map for him or her to navigate through the ordering of the manuscript. The conclusion suggests that this manuscript production and related reading practice is based on the idea of hylomorphism—that the form (ordering) and the matter (content) must be considered as one substance.

Keywords: Guillaume de Machaut
History of the Book
Medieval manuscripts
Reading practices
Roman de Fauvel
Roman de la Poire
Advisor: Haines, John
Mechanisms of Centriole Duplication and Spindle Assembly in Human Cells

The centrosome is the major microtubule-organizing center in animal cells. Centrosomes duplicate once and only once per cell cycle thereby ensuring that two centrosomes are present in mitosis, each of them organizing one of the two spindle poles. Numerical and structural centrosomal abnormities lead to a number of devastating human diseases, including ciliopathies, microcephaly and cancer. Despite extensive effort at elucidating the molecular mechanisms underpinning centriole assembly, our understanding of this process remains incomplete and many novel factors remain to be identified. Here, using a high-throughput, semi-automated centriole duplication screen, I identified TRIM36 as a novel regulator of centriole duplication and mitotic spindle assembly. TRIM36 is a microtubule-binding RING-type E3 ligase. In centriole duplication, TRIM36 regulates daughter centriole assembly in a manner that is dependent on the RING domain. Using super-resolution microscopy, I discovered that TRIM36 plays a role in the early steps of centriole formation, where it mediates the recruitment of SAS6. TRIM36 depletion also caused severe defects in mitotic spindle assembly and chromosome congression. My results indicated that the dual role of TRIM36 in centriole duplication and spindle formation involves, at least in part, the recruitment of γ-tubulin to centrosomes. Co-depletion of RBM14, a negative regulator of centriole duplication, compensated for the loss of γ-tubulin recruitment and rescued both the centriole duplication and spindle assembly defects. These results provide insights into the critical role of the E3 ligase TRIM36 in centriole duplication, mitotic spindle assembly and cell cycle progression.

Keywords: Centriole duplication
Spindle assembly
TRIM36
Advisor: Pelletier, Laurence