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Characterizing Ultrafast Equilibrium Dynamics Using Third-Order Nonlinear Mid-Infrared Spectroscopies
No full textCharacterizing equilibrium dynamics provides new insight into examining structure-function relationship in chemical reactions and understanding physical properties and processes in various systems. Third-order nonlinear mid-infrared spectroscopic techniques are powerful tools for investigating ultrafast dynamics under thermal equilibrium. In this thesis, vibrational energy relaxation and orientational relaxation dynamics were extracted from polarization-dependent pump probe spectroscopy and local environment dynamics surrounding a vibrational probe were detected using two-dimensional infrared spectroscopy.Effects of ligand structural variation on the ultrafast dynamics of a series of copper complexes were investigated. An azide group was attached to model copper complexes to serve as a vibrational probe. It was found that the peripheral phosphinimine ligands of the copper complex confined the orientational motion of azide and the degree of spatial restriction was quantified using the wobbling-in-a-cone model. The addition of phenyl groups in the ligands acted to create more accessible local environmental configurations for the azide group. The binding configuration and intramolecular motion of the vibrational probe can affect the dynamics detected. The dynamics detected by the azide group bound to the copper complexes were compared to those detected by an isothiocyanate group with a different binding angle. Molecular dynamics simulations showed that intramolecular reorientation of azide sampled a larger space leading to faster orientational relaxation compared to isothiocyanate. The local environment dynamics detected by azide were slower than those detected by isothiocyanate due to the change of local environment dynamics induced by the binding of different vibrational probes and the differences in the local environment dynamics detected along different spatial orientations. The ultrafast dynamics of liquid crystal systems were also investigated. The effects of gold nanoparticles and their capping ligands on the dynamics of 4-cyano-4′-pentylbiphenyl (5CB) during the isotropic-to-nematic phase transition were examined. Our preliminary results showed that the addition of impurities accelerated the dynamics of 5CB, and this acceleration effect was more significant for the ligands than the ligand-capped nanoparticles
Understanding The Relationship Between Clot Contraction And Platelet Biology Under Hemodynamic Conditions
Get PDFAs thrombosis proceeds, platelets in a clot can expose phosphatidylserine (PS), providing a negatively charged surface for thrombin generation. These PS+ platelets have been shown to sort to the perimeter of platelet masses via platelet contraction. However, it remains unclear how thrombin and fibrin affect PS+ platelet sorting within a clot. We used an 8-channel microfluidic device to perfuse blood over collagen/TF to evaluate temporal and spatial PS+ platelet sorting. We found that thrombin inhibition, fibrin polymerization inhibition, or fibrinolysis each increased clot contraction and PS sorting. Fibrin attenuated clot contraction and PS sorting. Clots without fibrin had a 3.6-times greater contraction than clots with fibrin. Based on these results, we wanted to study contraction further. We tested the effect of inhibitors of ADP and/or thromboxane A2 (TXA2) signaling on clot contraction. We developed two automated imaging methods to score fluorescent platelet percent contraction: (1) “global” measurement of clot length, and (2) “local” changes in surface area coverage of platelet aggregates within the clot. Total platelet fluorescence and global aggregate contraction were highly correlated (R2 =0.87). Local aggregate contraction was more pronounced than global aggregate contraction across all inhibition conditions. Conditions with TXA2 inhibition were shown to significantly reduce local aggregate contraction relative to conditions without TXA2, unlike conditions with ADP inhibition. Lastly, we recently obtained a glycoprotein VI (GPVI) inhibitor. GPVI is a collagen receptor on platelets that drives platelet activation; however, its role at later stages in clotting remains unclear. We tested the effect of anti-GPVI Fab on PS exposure, which occurs at later stages of platelet activation. On collagen/TF, Fab present at t=0s reduced PS exposure, but had no effect when added 30 or 90 seconds later. Thrombin generated via PS exposure had an important role in driving platelet deposition when Fab was present, since inhibition of PS via annexin V binding in the presence of Fab significantly inhibited platelet deposition. Our results from these studies help elucidate the relationship between platelet activation, PS exposure, fibrin, and clot contraction
Topic Modeling: Optimal Estimation, Statistical Inference, And Beyond
Get PDFWith the development of computer technology and the internet, increasingly large amounts of textual data are generated and collected every day. It is a significant challenge to analyze and extract meaningful and actionable information from vast amounts of unstructured textual data. This thesis explores several problems in topic modelings and provides new algorithms with theoretical guarantees. The first part of this thesis aims to develop an optimality theory for unsupervised topic modeling under the probabilistic latent semantic indexing (pLSI) model. Novel and computationally fast algorithms for estimation and inference of both the word-topic matrix and the topic-document matrix are proposed and their theoretical properties are investigated. Moreover, a refitting algorithm is proposed to establish asymptotic normality and construct valid confidence intervals for the individual entries of the word-topic and topic-document matrices. In the second part, we study supervised topic modeling, which jointly considers a collection of documents and their paired side information. To take account of the compositional nature of the topic-document matrix, we adapt the log-contrast model and introduce a novel bias-adjusted algorithm to investigate the regression coefficients in the generalized linear model. In addition, a de-biased procedure is proposed to establish an asymptotically unbiased and normally distributed estimator, and hence valid confidence intervals are constructed for the individual entries of regression coefficients. We also investigate the errors-in-variables models under the generalized linear model framework in the third part. We proposed an estimator when the measurement error is small
Regulation Of Genome Topology In Notch-Mutated Cancers
Get PDFSpatiotemporal regulation of gene expression governs cellular development and malignant transformation. Compared to the understanding of cis-regulatory elements on the linear chromatin, our knowledge about the three-dimensional (3D) organization of the human genome is still limited. Recent advances in chromatin conformation capture techniques coupled with high-throughput sequencing and fluorescence in situ hybridization combined with high-content microscopy greatly advanced the mapping of 3D genome at kilo-base resolutions. However, the mechanisms of the establishment and maintenance of genome folding and the implications of their disruption in cancer are largely unexplored. Moreover, besides a few architectural proteins, the roles of other transcription factors in chromatin topology remain elusive. Here, I used three cancer types with oncogenic mutations in the signaling-dependent developmental transcription factor NOTCH1 as models to probe the contributions of genome misfolding to oncogenesis and anti-cancer therapy resistance. By subjecting triple-negative breast cancer and mantle cell lymphoma cells to short-term Notch inhibition and reactivation, I discovered that beyond its known role in activating distal enhancers, Notch can dynamically reposition distal enhancers to the promoters of pro-survival genes such as MYC but has limited impact on higher-order chromatin structures including topologically associated domains (TADs) and compartments. Interestingly, in T-cell acute lymphoblastic leukemia (T-ALL), short-term Notch inhibition only diminishes MYC enhancer activity but not looping to the promoter, suggesting that Notch mediates chromatin loops in a lineage- and locus-specific manner. In contrast to short-term treatment, I identified widespread refolding of compartments, TADs and loops in T-ALL cells that acquire resistance to long-term Notch inhibition. These events closely coincide with redistribution of chromatin activity and architectural protein and are reversible when Notch inhibitor is removed. Finally, using a combination of sequencing, imaging and genetics approaches, I provided direct evidence that the B-cell lineage determining factor EBF1 is repositioned from the transcriptionally repressive nuclear lamina to the interior during long-term Notch inhibition. Activated EBF1 thus instructs reorganization of the linear and 3D genome to promote therapy resistance. My studies in Notch-mutated cancers advanced the mechanistical understanding of non-architectural transcription factors in cancer genome folding, which can potentially provide insights into their functional roles during normal development
Some Investigations Of Phase Transitions In Rod-Like Macro-Molecules And Fibrous Gels
Get PDFTwo problems pertaining to solid-solid phase transitions are presented here.First, we conduct Langevin dynamics calculations on a chain of masses and bistable springs in a viscous fluid, and extract a temperature dependent kinetic relation by observing that the dissipation at a phase boundary can be estimated by performing an energy balance. Using this kinetic relation we solve boundary value problems for a bistable bar immersed in a constant temperature bath and show that the resultant force-extension relation matches very well with the Langevin dynamics results. We estimate the force fluctuations at the pulled end of the bar due to thermal kicks from the bath by using a partition function. We also show rate dependence of hysteresis in cyclic loading of the bar arising from the stick-slip kinetics. we also extract equilibrium and non-equilibrium information from an over-damped Langevin system using fluctuation theorems. Second, we use a double-well stored energy function in a chemo-elastic model of gels to capture the existence of two phases of the network. We model cyclic compression/decompression experiments on fibrous gels and show that they exhibit propagating interfaces and hysteretic stress-strain curves that have been observed in experiments. We can capture features in the rate-dependent response of these fibrous gels without recourse to finite element calculations. We also use the model to study the rheological behavior of fibrous gels. We obtain the storage and loss modulus of fibrous gels by performing small amplitude oscillatory compression around various levels of deformation
Single Molecule Approaches To Studying Tau Function And Dysfunction
Get PDFTau is an intrinsically disordered protein found mainly in neurons, composed of four main domains, the N-terminal domain, the proline rich region, the microtubule binding region, and the C-terminal domain. Tau regulates the dynamic instability of microtubules by facilitating the polymerization of tubulin. Tau is also a key component of the aggregates found in several neurodegenerative diseases collectively known as tauopathies, the most prevalent of which is Alzheimer’s disease. In this disease pathology, normally soluble tau aggregates to form insoluble neurofibrillary tangles. The presence of aggregated tau spreads from one region of the brain to another suggesting that tau propagates from cell to cell. Understanding the mechanisms by which tau interacts with microtubules and the aggregation pathway leading to the spread of disease pathology is vital for diagnosis and treatment of tauopathies. In this work, we primarily use single molecule fluorescence techniques to study three mechanisms of tau. We studied the initiation of aggregation of tau in the presence of polyphosphates, a biologically relevant polyanionic molecule. We find that the proline rich region contains multiple binding sites and contributes to the three mechanisms by which polyphosphates can initiation aggregation; a change in conformation towards a more aggregation-prone conformation, charge-screening to increase local concentrations of tau, and intermolecular crosslinking. We also studied the propagation of monomer tau between neuronal cells. We find that the proline rich region of tau has a unique ability to diffuse passively through a lipid membrane, and that tau has higher affinity to lipid membranes with more ordered structure, higher cholesterol content mimicking lipid rafts. Lastly, we investigated the effects of the R5L mutation on tau’s binding to tubulin. We find that the mutation found on the N-terminal domain of the protein doesn’t affect binding affinity to microtubules or tubulin in high molarity buffers but has a higher affinity for tau in the 3R isoform of tau in a low salt buffer. Together, this provides us with an insight into the importance of the domain dependence of tau in its functions and dysfunctions, as well as an insight into tau’s preference for binding partners
Essays In Finance And Inequality
Get PDFStudents of lower-income families invest much less in college education than higher-income families. To assess the role of financing constraints and subsidy schemes in explaining this gap, I structurally estimate a model of college choice in the presence of financing frictions. The estimation uses novel nationally representative data on US high-school and college students. I propose a novel identification strategy that relies on bunching at federal Stafford loan limits and differences between in- and out-of-state tuition. I find that the college investment gap is mainly due to fundamental factors: heterogeneity in preparedness for college and the (perceived) value-added of college. Frictionless access to student loans would substantially increase consumption during college but would leave the investment in college education mainly unaffected. I show that making public colleges tuition-free would mitigate financing constraints, but it would overall entail more than $15B deadweight loss per year and would disproportionately benefit wealthier students. Expanding Pell grants, in contrast, would benefit lower-income students at a much lower cost
Leveraging Macrophage Immune Checkpoint Blockade To Link Innate And Adaptive Immunity Against Solid Tumors
Get PDFImmunotherapies harness the power of the immune system, broadly, to identify, suppress, or otherwise control disease progression. Potent immune checkpoints, such as PD-1/PD-L1, CTLA4, and here, CD47-SIRPα restrain immunity in normal regulation to protect healthy ‘self’ cells, yet can become dysregulated in the progression of diseases. Antibody-based blockade of such checkpoints has emerged as a powerful tool to retrain and re-energize immune surveillance, but significant barriers to efficacy and safety remain. CD47-SIRPα is the macrophage immune checkpoint that enables macrophages, a first line of defense in innate cellular immunity, to discriminate ‘self’ vs. ‘foreign’, which many cancers utilize to evade clearance. Consequently, CD47 is now a clinical target for antibody-based blockade in early and late phase clinical trials in many liquid tumors and some solid tumors. However, clinically targeting a ubiquitously expressed surface marker presents numerous challenges, including a large antigen sink, on-target but off-tumor clearance, and mass permeation of solid tissues that are yet to be answered (Chapter 1 and Chapter 4). Here, we demonstrate that efficacy of molecular and cell-based therapies targeting CD47-SIRPα requires complete ablation of signaling and a pro-phagocytic signal to drive tumor-specific macrophage phagocytosis in solid tumors (Chapter 2). We further delineate and provide evidence for a novel phenomenon of “cooperative phagocytosis” in these tumors, whereby macrophages that are maximally activated along the CD47-SIRPα paradigm, work together to disrupt solid tumor adhesions and durably eliminate tumoroids in vitro and tumors in vivo (Chapter 3). Finally, we highlight a significant role for macrophages as potent immune effectors to clear tumors and induce a de novo, endogenous antibody response that strengthens macrophage phagocytosis and cooperativity with high tumor antigen-binding and -specificity (Chapter 3). These results position macrophages as potent immune effectors in solid tumors with the potential to overcome long-standing challenges in immuno-oncology (Chapter 5)
Ancient Solutions Of The Ricci Flow On Compact Homogeneous Spaces
Get PDFWe investigate the behaviour of the Ricci flow for homogeneous metrics on spheres and on general compact homogeneous spaces. In particular we complete the classification of ancient homogeneous solutions on spheres and discover a new 1-parameter family of ancient solutions. These solutions can be described in terms of shrinking the fibers of the Hopf fibration while varying the metric on the base. Precisely one solution collapses along the backwards flow to the Fubini-Study metric while the rest collapse to Ziller\u27s second Einstein metric on . We then proceed to determine a general criterion for the existence of collapsed ancient solutions on compact homogeneous spaces. In particular, we show that whenever is the total space of a homogeneous fibration where is a maximal torus in a compact complement of in , then for every Einstein metric on the base there exists a family of ancient solutions on which collapse to the given Einstein metric under the backwards flow. This construction generalizes all previously known examples of collapsed homogeneous ancient solutions in the literature, and also leads to many new families of examples
Surface Modification Of Solid Oxide Cell Electrodes To Improve The Electrochemical Performance
Get PDFSolid Oxide Fuel Cells are high temperature, solid-state, electrochemical devices that can convert fuels into electricity or produce fuels from excess electricity. Oxygen is reduced at the cathode to oxygen ions which move through the ceramic to the anode. These oxygen ions are used to oxidize fuels at the anode compartment, producing heat and electrons that will move through an external circuit to produce power.At the cathode the sluggish oxygen reduction kinetics impede the performance of the electrode. A common approach to enhance the cathode performance is infiltration. Often the performance of a cathode is enhanced after the addition of a variety of metal-oxide materials. The common claim is that the infiltrated materials enhance catalytic activity or conductivity. With infiltration however, it is impossible to control for changes in surface area or conductivity. Atomic Layer Deposition (ALD) was employed to change the surface chemistry of the electrode, without changing the conductivity, or surface area of the electrode. Perovskite anodes are of interest due to their resistance to many of the issues that plague Ni-cermet (ceramic metal) anode. Their catalytic activity is often lacking, and as such a variety of methods are employed to enhance this. The most efficient approach is surface modification which allows for increases in activity with minimal metal loadings. ALD was employed to deposit highly disperse oxidation catalysts inorder to minimize the metal loadings while maximizing performance. At the Ni-cermet anode, undesirable reactions, such as carbon fiber formation and Ni oxidation to NiO, limit the lifetime of the electrode. Surface modification approaches are often vi employed to protect the Ni surface against these processes. We investigated the use of CeO2 ALD to overcome these challenges. Perovskites with exclusively 2 + cations (Ba and Sr) in the A-site and Fe in the B-site have recently exhibited great performance as SOFC anodes. The reasoning behind the high catalytic activity of these anodes has not been thoroughly studied. To elucidate the origin of the high activity of these anodes, the performance and thermodynamics of Ba0.5Sr0.5FeO3 (BSF) anodes was investigated