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Visible Light Photocatalysis With Quantum Dot Gel For Organic Synthesis
Get PDFThis dissertation presents metal chalcogenide quantum dots (QDs), a group of emerging visible light photocatalysts, for unique organic chemical transformations that are impossible using conventional molecular photocatalysts. The first part of this dissertation focuses on the comparison between ligand-capped CdS QD and CdS gel. CdS QD gel is a three-dimensional network of interconnected QD. CdS gels were found to show more facile charge transfer with substrates than QDs, due to the partial removal of ligands from its surface during gelation. Our study showed that the photocatalytic activity of CdS gels was indeed superior to trioctylphosphine (TOP)- and thioglycolic acid (TGA)-capped CdS QDs for dehalogenation, α-amine, and α-amide arylation reactions. More interestingly, we discovered that the QD gels also offered new chemical reactivity, for example, aryl cyanide isomerization and tetrahydroisoquinoline ring-opening via C-N scission, which was not previously observed using conventional molecular photocatalysts. In the second part of the dissertation, we report that CdS QD gel can act as a direct hydrogen atom transfer (d-HAT) photocatalyst for C(sp3)-H bond functionalization. We observed that photoexcited QD gels exhibited unusual reactivities for generating various radicals, including α-amido radicals, heterocyclic radicals, acyl radicals, and benzylic radicals from their stable molecular precursors such as amides, ethers, and aldehydes with high redox potentials. Such board reactivities enable a large substrate scope and provide easy access to a variety of important synthons. The mechanistic study reveals that photocatalytic radical generation should undergo a direct HAT pathway on the QD gel surface rather than a sequential electron/proton transfer pathway. This d-HAT mechanism is supported by the linear correlation between the logarithm of the C-H bond activation rate constant and the C-H bond dissociation energy with a Brønsted slope α = 0.5. Our findings expand the currently limited direct hydrogen atom transfer photocatalysis toolbox and provide new possibilities for photocatalytic C-H functionalization
Solution Kinetic Study Of Vesicle Trafficking Of Zymogen Granules And Myosin 16a Molecular Motor
No full textZymogen granules (ZGs) are about 1 μm diameter enzymatic vesicles found in the exocrine pancreas and act as inactive precursors of digestive enzymes. Gel electrophoresis and mass spectroscopy had shown presence of myosins motors like myosin 1c, 5c, 6 and 7b at the surface of the ZGs and contribute to ZGs transportation in cells. Myosin motors utilize ATP as an energy to function in the actin filaments. Among different classes of myosins, some motors involve in the vesicle trafficking. Vesicle trafficking motors have special features such as they can move in actin tracks continuously and have high duty ratio. For e.g. myosin 5a transports neuronal vesicles (diameter: 40 nm) and has high duty ratio. The high duty ratio motors bound to actin more than half of the ATPase cycle. In contrast, myosin 1c and myosin 5c are low duty ratio motors and cannot move in the actin filament continuously. From the previous study of two myosin 5c molecules using DNA origami in our lab had shown continuous move in the actin filament and demonstrated the possibility of two myosin 5c to transport ZGs which also have flatter surface curvature than neuronal vesicle. In this study, we measured the key steps of ATPase cycle of purified ZGs for the first time from rat pancreas. The duty ratio for ZG was found to be more than that of a single molecule of two headed myosin 5c. The high duty ratio was contributed by phosphate release and low value of mantADP dissociation.108 Myosin16A (Myo16A) is single headed motor. It has potential function during early neonatal brain development. One of the interesting features of aves and mammalian Myo16A is the presence of cysteine (C) residue at the switch 1 of the ATP binding pocket instead of arginine (R). This residue has demonstrated evolutionary change in the vertebrate development. Our work demonstrated the key rates of actin activated. ATPase cycle for the Myo16A-C552 and substitution Myo16A-C552R were studied. The maximum ATPase and KM of actin were measured as 0.52 s-1 and 2.0 μM for Myo16A-C552R, indicating that Myo16A- C552R is a slow motor and weakly binding to actin filament. Myo16A-C552 showed slower rates for actin binding, mantATP binding, and phosphate release. However, mantADP release showed double exponential such as 180 s-1 fast (~73%) and 22 s-1 (~27%) slow rates for WT and 243 s-1 fast (85%) and 17 s-1 slow (15%) rates for substitution Myo16A-C552R. The substitution C552R had slowed the phosphate release rates by 9 times. This result signified the role of arginine at the ATP binding pocket. The duty ratio of Myo16A-C552 was observed to be \u3c 23% and was lower than high duty ratio myosin 5a (70%) motor
Design, Synthesis, And Evaluation Of Class Iia Histone Deacetylase (hdac) Inhibitors
Get PDFHistone deacetylase (HDAC) proteins are linked to disease states, including cancer, and have become important targets for therapeutic development. Many inhibitors have been developed to target HDAC proteins, including FDA-approved inhibitors Vorinostat (SAHA), Belinostat, Romidepsin, and Panobinostat. These inhibitors non-specifically influence most of the 11 metal-dependent HDAC isoforms, which might contribute to the side effects that patients experience during treatment. The lack of selectivity also diminishes the use of HDAC inhibitors as biomedical research tools. To address these drawbacks, the development of selective inhibitors has been heavily studied. Yet, reported inhibitors are predominantly selective for class I HDAC isoforms (HDACs 1, 2, 3 and 8) or the entirety of class I. There is a lack of selective inhibitors for class IIa HDAC isoforms (HDACs 4, 5, 7 and 9), which have been linked to disease states, including cancer and neurodegenerative disorders. With class IIa HDAC proteins as necessary targets for selective HDAC inhibitor development, one long-term goal of this project is to develop and synthesize potent class IIa isoform selective HDAC inhibitors based on previous work and docking studies.HDAC inhibitors are generally tested for potency and selectivity using a deacetylation activity assay. However, a challenge with testing HDAC4, HDAC5, HDAC7, and HDAC9 is their low enzymatic activity. To overcome the low enzymatic activity of class IIa HDAC proteins in this activity assay, an unnatural trifluoro acetyl substrate is used to encourage deacetylation. Additionally, the activity assay uses recombinant protein rather than cellular proteins. These limitations of low enzymatic activity and use of purified protein suggest a need for a physiologically relevant binding assay to compliment the necessary activity assay. A second long term goal of this project is development of a simple, accessible, and cell-based activity assay for inhibitor screening. The significant outcomes of this project are isoform selective class IIa HDAC inhibitors and a cellular binding assay
Development Of Essential Oil-Based Silver Nanoparticle Conjugates And Their Effect On Listeria Monocytogenes Biofilms
No full textThe study aimed to assess the effectiveness of essential oil silver nanoparticles (EOAgNPs) conjugates against L. monocytogenes biofilms and explore potential applications in food processing systems. The oils used for this study were cinnamon, oregano, clove, eucalyptus, and rosemary extracts. EOAgNPs were individually screened against L. monocytogens (ATCC 19115) using broth micro dilution. Cinnamon EOAgNPs showed the highest antimicrobial efficacy against the test organism, as determined by the minimum inhibitory concentration (MIC). Oregano had the second-highest efficacy, while the other oils exhibited marginal antimicrobial activities. To determine the effect of the EOAgNPs on listeria biofilms, glass slide biofilm assays were performed. Results similar to the micro broth dilution method were observed, where cinnamon and oregano exhibited the highest cell death in the biofilm biomass. As the EOAgNPs presented promising use in controlling listeria biofilms, their potential toxicity was determined by preliminarily exposing them to brine shrimp. Followed by rat and human hepatic cell exposure in increasing concentrations, LDH assay was used to determine toxicity in cells. LC50 for all EOAgNPs was above four logs their respective concentrations. Finally, to assess the pathways the EOAgNPs might have affected a biosensor assay was conducted using V. harvyie, and a reduction in bioluminescence was observed, indicating interruption of autoinducer-mediated quorum sensing. To confirm these observations, qPCR analysis of agr A and agr C genes of the agr operon was performed, and up to a 12-fold reduction was observed. These results suggest that EOAgNPs have the potential to be used as antimicrobial agents to enhance food safety
MEDICATIONS FOR OPIOID USE DISORDER & IMPLICATIONS FOR MOBILE METHADONE UNITS
No full textResearch has shown the urgent need for updates to guidelines regulating opioid treatment programs (OTPs), especially as the COVID-19 pandemic exacerbated overdose rates and the drug supply became increasingly contaminated with fentanyl, synthetic opioids, and xylazine (Moghtaderi et al., 2023)(DEA, 2022). Part 8 of Title 42 of the Code of Federal Regulations (CFR), originally enacted in 2001, includes regulations that guide OTPs. The 42 CFR Part 8 final rule, issued by SAMHSA, updates these federal regulations. It is the first major revision since 2001, aimed at expanding access to care, improving patient outcomes, and integrating lessons learned from the COVID-19 pandemic (SAMHSA, 2024a). These updates are in response to the long-voiced concerns of both practitioners and patients on the opioid epidemic\u27s front lines. They aim to make temporary flexibilities from the COVID-19 public health emergency permanent, enhance OTP accessibility, and adapt to evolving standards and practices. The emphasis on mobile units and harm reduction measures reflects a commitment to reducing barriers to care and improving outcomes for individuals with opioid use disorder (OUD). The final rule removes stigmatizing language and supports a patient-centered approach, as well as practitioner autonomy (SAMHSA, 2024a). Support for these changes was reinforced by studies demonstrating that pandemic-era flexibilities, such as relaxing take-home guidelines, did not increase diversion but instead increased retention, improved access to treatment, and enhanced patient outcomes, particularly for those with transportation barriers and daily dosing demands (Hoffman et al., 2022)(Krawczyk et al., 2023). The final rule went into effect on April 2, 2024. OTPs have 6 months to integrate these changes and are expected to comply with all final rule standards by October 2, 2024
