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Aerobic Oxidation Of Hydrocarbons With Ir(iii) Pincer Complexes
Get PDFThe development of transition-metal catalyzed alkane valorization methods under mild conditions is an important component of ongoing efforts to reduce the energy costs and environmental impact of the petrochemical industry. Incorporation of “green” reagents such as molecular oxygen in these types of reactions is a crucial part of developing truly scalable technology because oxygen is abundant, environmentally benign, inexpensive, and non-toxic. In this dissertation, two different aerobic alkane functionalization routes are investigated: dehydrogenation of linear alkanes to olefins and oxygenation of cyclohexane to make cyclohexanone, cyclohexanol, and adipic acid. Olefins, cyclohexanone, cyclohexanol, and adipic acid are all widely used platform chemicals in industry. In chapters 2 – 4 novel n-heterocyclic carbene ligated (CCCMesityl) IrIII pincer complexes are demonstrated to undergo C-H activation of n-octane under mild conditions, and each step of an aerobic octane dehydrogenation cycle is demonstrated and optimized. Kinetic studies on the C-H activation step and O2-mediated catalyst regeneration step were carried out, and the results informed design of a new, less sterically bulky CCCMethyl ligand that shows a lowered barrier to C-H activation of benzene. In chapter 5, the aerobic oxidation of cyclohexane to a mixture of cyclohexanone, cyclohexanol, and adipic acid is shown to be promoted by Phebox-ligated Ir complexes. This aerobic autoxidation reaction was optimized for the oxidation of neat cyclohexane, as well as the concomitant oxidation of a mixture of cyclohexanone, cyclohexanol, and cyclohexane
Intimate Reception: Reading Ordinary Queerness In American Women\u27s Literature
Get PDFThis dissertation connects the aesthetic commitment to the ordinary world in twentieth-century women’s literature to the invention and consolidation of modern sexuality. Owing largely to a political antipathy between “the ordinary” and “the queer,” scholars have not addressed the intersections of literary modernism, ordinary aesthetics, and the emergence of queer sexualities. This project argues that the twentieth-century preoccupation with the ordinary cannot be understood apart from representations of queer figures, desires, and intimacies, which are themselves ordinary—neither hidden nor extravagant. The representations I examine are attuned to the specific forms of gendered insignificance that snag on feminine being, subjectivities, and intimacies. The insignificance attached to feminine figures, this project claims, is not so easily redressed by queer alterity defined as the potential to become something extraordinary and different. What I call “ordinary queerness” is an insignificant feature of a changing sexual landscape that required legible subjects and discernible identities. By rendering queerness insignificant, the writer declines to represent a legible subject for discipline, classification, and even description—in other words, interpretation. Through readings of texts by Sarah Orne Jewett, Gertrude Stein, Gwendolyn Brooks, and Elizabeth Bishop, this project finds that representations of an ordinary queerness raise specific interpretive problems for queer literary studies. This project’s method of an “intimate reception” is addressed to those queer figures (characters as well as authors) who might not seem queer enough according to axiomatic frameworks within queer literary studies. This dissertation offers intimate reception as a reading practice and a literary-historical method that is motivated less by critical opposition or indeed by ardent attachments than it is by ordinary affects, insignificant figures, and the distance that inevitably lies between the reader and the queer worlds they desire in a literary text
Structural Insights On Tfiih In Transcription And Dna Repair
Get PDFTFIIH is an essential, ten protein complex that necessary in both transcription initiation andNucleotide Excision Repair (NER). During transcription initiation, the general transcription factor TFIIH marks RNA polymerase II by phosphorylating Ser5 of the C-terminal domain (CTD) of Rpb1, which is followed by extensive modifications coupled to transcription elongation, mRNA processing, and histone dynamics. We have determined a 3.5 Å resolution cryo-EM structure of the TFIIH kinase module (TFIIK in yeast), which is composed of Kin28, Ccl1, and Tfb3, yeast homologues of CDK7, Cyclin H, and MAT1, respectively. The C-terminal region of Tfb3 was lying at the edge of catalytic cleft of Kin28, where a conserved Tfb3 helix served to stabilize the activation loop in its active conformation. By combining the structure of TFIIK with previous cryo- EM structure of the pre-initiation complex, we extend the previously proposed model of the CTD path to the active site of TFIIK. The versatile NER pathway initiates as the XPC-RAD23B-CETN2 complex first recognizes DNA lesions from the genomic DNA and recruits the general transcription factor complex, TFIIH, for subsequent lesion verification. Here, we present a cryo- EM structure of an NER initiation complex containing Rad4-Rad23-Rad33 (yeast homologue of XPC-RAD23B-CETN2) and 7-subunit coreTFIIH assembled on a carcinogen-DNA adduct lesion at 3.9–9.2 Å resolution. A ~30-bp DNA duplex could be mapped as it straddles between Rad4 and the Ssl2 (XPB) subunit of TFIIH on the 3’ and 5’ side of the lesion, respectively. The simultaneous binding with Rad4 and TFIIH was permitted by an unwinding of DNA at the lesion. Translocation coupled with torque generation by Ssl2 and Rad4 would extend the DNA unwinding at the lesion and deliver the damaged strand to Rad3 (XPD) in an open form suitable for subsequent lesion scanning and verification. These two structural studies have demonstrated some functional conservation in the mechanism of DNA unwinding between transcription and NER and provide the groundwork for further investigations into TFIIH function
An In Situ Study Of Resistance Degradation And Switching Of Bulk Yttria-Stabilized Zirconia And Strontium Titanate Single Crystals
Get PDFUnderstanding resistance changes under a constant or set of bipolar-switching voltage(s) is important for thin-film devices, specifically multilayer capacitors and resistance-switching memory. However, identifying critical locations of changes and failures in thin films is difficult, so this work studies the same phenomena in single crystals of yttria-stabilized zirconia (YSZ) and iron-doped strontium titanate (STO) starting with highly accelerated lifetime tests (HALT) at higher temperatures. Although doped STO is a p-type semiconductor and YSZ a fast oxygen-ion conductor with little electronic conductivity, their DC resistance-degradation curves are remarkably indistinguishable. Yet different mechanisms were revealed by in-situ hot-stage photography and thermal imaging in two test environments—air and silicone oil. In YSZ, DC (electro)reduction does not appreciably alter oxygen stoichiometry; nevertheless, above a threshold voltage, it can raise the chemical potential of electrons to the conduction-band level, thereby triggering a metal-insulator (resistance) transition. In contrast, DC-stressed STO undergoes oxygen-vacancy demixing, forming a p-n junction with elevated electronic conductivity, albeit late-stage-demixing can be so sluggish that the steady state is difficult to reach in low-temperature HALT. In both oxides, an inherent instability in the governing field equation dictates degradation follows filament-like paths, which explains the strong field dependence and large variation of lifetimes. Upon further voltage reversals, degraded crystals exhibit different, large resistance changes. In YSZ, a change in DC voltage can already cause a resistance change, which is unipolar switching. But additional resistance degradation after voltage reversal can facilitate filament fragmentation, thus rendering the crystal bipolarly switchable due to a voltage-sensitive metal-insulator transition in a thin layer of barely metallic YSZ adjacent to the original anode. In STO, voltage reversals broaden/narrow a nanolayer of stoichiometric, ionic STO (called i-region) that straddles the p-n junction, by driving electromigration to act in-concert/against back-diffusion of oxygen ions. Thickening/thinning of such region leads to resistance increase/decrease, resulting in the so-called eightwise” bipolar switching. (Interface-controlled, “counter-eightwise” switching was also observed in more severely degraded STO.) As these phenomena find analogies in thin-film devices, mechanisms revealed above have provided new insight that will help understand and improve the performance and reliability of engineering devices
Dynamic Behavior Of Periodic Media And Elastic Metamaterials
Get PDFPeriodic media and resonant, acoustic/elastic metamaterials possess extraordinary frequency band gaps where no waves may propagate. In this dissertation, we leverage numerical simulations to gain insight into practical ways to effectively measure and characterize the behavior of these materials from experimental observables and also explore physical mechanisms to optimize their performance, particularly in the context of resonant metamaterials. With respect to the former, the finite nature of experiments prevents the usage of Bloch\u27s theorem and unit cell analysis. To circumvent this, an FFT procedure combined with an exponential fitting method are used to extract the real and imaginary part of dispersion relations from real-time simulation data. Difficulties such as sample length and frequency domain resolution, associated with this type of analysis, are examined parametrically using synthetic data from numerical simulations. In addition to this study, an additively manufactured, resonant metamaterial made of a soft PDMS rubber is analyzed using both experimental data and finite element models. By isolating several physical features of the material, a new mechanism for band gap formation is discovered where band gaps associated with different vibrational modes are combined to produce an ultrabroad band gap through the use of a compliant frame
Leveraging Systems Immunology To Understand The Molecular Underpinnings Of Chimeric Antigen Receptor T-Cell Therapy
No full textChimeric Antigen Receptor (CAR) T-cell therapy is a promising strategy for the treatment of human cancers, and in the last decade has progressed from breakthrough early trials to first in class FDA approvals for B-cell leukemias and lymphomas. Concurrent with the promise and challenges in cancer immunotherapy, there have been exciting technological advances in the field of genomics and systems biology, including approaches to capture and analyze RNA expression, protein expression, and chromatin accessibility at a single-cell resolution. In this dissertation, I investigate the molecular basis of CAR T-cell therapy response and resistance using a systems immunology approach, leveraging these technologies and computational analysis to shed new light on key clinical questions. First, I discuss our work investigating the molecular differences between pre-manufacture T-cells in a cohort of pediatric patients on trial to receive CAR T-cell therapy, in which we identified subtype-specific factors associated with clinical CAR T-cell persistence. Next, I discuss our work studying CAR T-cells from two of the earliest cancer patients successfully treated with CAR T-cell therapy, in which we discovered novel populations of long-persisting CD4+ CAR T-cells nearly a decade post-infusion. Finally, I discuss our work in understanding the genomic fate of leukemic cells in patients undergoing anti-CD19 CAR T-cell therapy and discuss the broader insights that have arisen from this work. Together, these data expand our understanding of the T-cell and cancer cell characteristics involved in successful CAR T-cell therapy, and highlight the power of integrative genomics and computational biology in spearheading the discovery process in cancer therapy
Ultra-High-Resolution Patterning And Pattern Transfer Via Nanocrystal Colloidal Lithography
Get PDFThe ability to design, pattern, and process materials at the nanoscale has enabled vast research opportunities ranging from fundamental science to technological applications and device integration. The continued development of nanoscience and nanotechnology relies on pushing the limits of nanoscale fabrication capabilities. After decades of development, this frontier has moved to the sub-10 nm length scale to explore novel physical properties and functionalities for next-generation technology. However, conventional “top-down” strategies that have carried nanofabrication to this point have severe limitations for practically improving the resolution capabilities of deep nanoscale fabrication. In this dissertation, we demonstrate ultra-high-resolution patterning and pattern transfer using nanocrystal (NC) colloidal lithography. This innovative nanofabrication platform integrates bottom-up methods, that combine NC synthesis and self-assembly approaches, with well-established top-down techniques such as dry etching and thin film deposition.
We employ monodisperse NC building blocks with self-assembly methods to establish high-density, well-ordered patterns, where the inorganic core of each NC serves as a discrete hard mask used for high-fidelity pattern transfer into a desired substrate material. We demonstrate the use of isotropic NCs to establish various sub-10 nm pattern morphologies and examine the stability of the NC pattern upon dry etching, comparing NC monolayers and bilayers. We extend the NC colloidal lithography scheme using anisotropic NCs to demonstrate high-density, anisotropic pattern transfer into various substrate materials down to the sub-5 nm regime. The presented fabrication strategy offers further opportunities to leverage various combinations of NC morphologies and materials afforded by the extensive NC library for more complex pattern design. Additionally, this approach can be extended to process various substrate material classes at the deep nanoscale. The NC colloidal lithography platform enables broader access to single-digit nanoscale fabrication for the scientific community worldwide, which could impact various research sectors ranging from integrated circuits to memory devices, optoelectronics, metasurfaces, quantum devices and more
Lightweight Structures Enabled By Microfabrication
Get PDFLightweight structures are the product of the science of making things as light as possible with constraints, which is conventionally referred to light yet sufficiently strong or stiff. The recent advancements in microfabrication have allowed the manufacture of structures with unprecedented properties. In this work, three strategies of achieving lightweight structures are explored: (1) hollowing, (2) folding, and (3) lightweight composites. The first strategy is demonstrated by creating a hollow flexural atomic force microscopy (AFM) cantilever. The hollow cantilevers are made by conformally depositing a thin layer of alumina on a solid beam and hollowing out the internal mold, resulting in the same overall dimensions with nanoscale wall thickness. Due to their significantly reduced weight, these hollow cantilevers exhibit low quality factors and comparable resonant frequencies to the solid cantilever, resulting in increased bandwidth and, correspondingly, capabilities for high imaging rate. In the second strategy, a self-deployable silicon-based propeller for microflyer is made with lightweight polymeric film. The propeller can be initially folded and then deployed by the apparent centrifugal force from rotation. The propeller exhibits lightweight yet sufficient thrust for flight which is promising for application in micro-aerial vehicles (MAVs) with potential to integrate MEMS sensors. Lastly, the last strategy is currently being explored by making thin composites. Thin composites can be made with a sandwich plate structure of materials with microscale thicknesses. Materials like carbon fiber and Mylar provides lightweight potentials that can be mechanical enhanced when reinforced by supplementary materials such as aluminum or alumina. These developments demonstrate the use of microfabrication to create lightweight structures with unique functionalities
Neuronal Codes And Circuits Underlying Audiovisual Integration
Get PDFWe rely on interactions between our sensory systems to help us communicate with each other and navigate our world. This multisensory integration can improve the accuracy of the sensory systems involved. However, many questions remain on how multisensory integration, specifically audiovisual integration, is mediated within the brain. In Chapter 2, we tested whether sound improves visual processing in the primary visual cortex. We found that both individual and populations of neurons encoded visual stimuli better with simultaneous auditory input. Importantly, we also found that this effect was due to sound and not mediated by sound-induced movements, an independent modulator of visual responses. These results clarify the codes underlying this tripartite interaction in this visual region. In Chapter 3, we probed the cortical circuits that support the audiovisual integration in the primary visual cortex. We found that the auditory cortex sends excitatory projections to the visual cortex, and stimulation of these fibers enhances visual response magnitude. However, suppression of this pathway failed to impair audiovisual integration in the primary visual cortex, suggesting the presence of parallel or compensatory mechanisms in this region. In Chapter 4, we explored the subcortical visual circuits that project to the inferior colliculus. We found that the superior colliculus synapses with neurons in the external shell of the inferior colliculus, and stimulation of these projections evokes activity in this auditory midbrain. However, neurons in the inferior colliculus failed to exhibit consistent responses to looming or static audiovisual stimuli, suggesting specificity in the visual tuning of these auditory neurons. Together, these results improve our knowledge of the coding and circuitry principles underlying audiovisual integration in both cortical and subcortical regions, and expand our understanding of how the brain integrates sensory information to generate our smooth perceptual experience
The Rational Design, Synthesis, And Biological Evaluation Of Small Molecule Cd4 Mimetic Families For Hiv-1 Viral Entry Inhibition
Get PDFDespite extensive research and a number of approved therapeutic approaches, a preventative and curative treatment for HIV infection and AIDS still remains a prominent global health need. A strategy employed for more than a decade within the Smith Laboratory, in collaboration with multiple collaborators within a NIH-funded P01 project (P01 AI 150471), has been to target the HIV-1 viral envelope as a means to prevent HIV-1 viral entry and subsequent infection. The small molecules developed in the Smith Laboratory, based on initial findings by Debnath and coworkers, act as mimics of the natural immune system receptor CD4, which binds within the viral envelope’s gp120 glycoprotein subunit. Binding of CD4 and gp120 elicits a cascade of events that ultimately results in viral entry into host cells. The small molecule CD4 mimetics developed by the Smith laboratory are able to bind within the gp120-CD4 binding pocket, and thus prevent the events that would result in viral entry. Through extensive SAR work, a lead CD4 mimetic compound BNM-III-170 containing an indanone core has been identified with a micromolar potency value of inhibition (IC50 JR-FL: 13.9 µM); however, for a CD4 mimetic to be seriously considered for clinical consideration, a 10- to 100-fold increase in potency is required. It was hypothesized that the potency of these CD4 mimetics could be improved upon both by maintaining the hydrogen-bonding interactions with highly conserved amino acid residues that lead CD4 mimetic BNM-III-170 engages with in the gp120 binding cavity but also by branching into new chemical space to establish hydrogen-bonding interactions with other additional, conserved amino acid residues. With the aid of computational modeling, three different families of CD4 mimetics were rationally designed, synthesized, and evaluated in vitro for HIV-1 inhibitory activity. These families explore bioisoteric replacement of the lead’s guanidinium group at the 2-position of the indanone (Chapter 2), a 5,7-disubstituted pattern around the lead BNM-III-170 indanone core (Chapter 3), and incorporation of heterocyclic amines at C(5) of BNM-III-170