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Next-Generation Biomedical Implants And Stimuli Responsive Soft Optical Arrays Via Surface Functionalized Elastomeric Materials, John M. Kapitan

Dissertations and Doctoral Documents, University of Nebraska-Lincoln, 2023–

The demands of emerging technologies, such as soft robotics, stretchable electronics, and next generation biomedical implants, has led to the development of diverse polymeric and hybrid organic/inorganic materials specifically tuned to meet these challenges. These materials typically have low Young’s moduli and are inert with high chemical stability. However, this has led to materials that are static in nature, lacking any meaningful way of responding to changes in their environment and adapting to these changes. This has driven a shift towards the design, manufacturing, and characterization of various stimuli responsive surfaces, relying on precise control of surface chemical coatings and …

Discovery Of Strong 3-Nitro-2-Phenyl-2h-Chromene Analogues As Antitrypanosomal Agents And Inhibitors Of Trypanosoma Cruzi Glucokinase, Shane M. Carey, Destiny M. O’Neill, Garrett B. Conner, Julian Sherman, Ana Rodriguez, Edward L. D'Antonio

Natural Sciences Faculty Publications

Chagas disease is one of the world’s neglected tropical diseases, caused by the human pathogenic protozoan parasite Trypanosoma cruzi. There is currently a lack of effective and tolerable clinically available therapeutics to treat this life-threatening illness and the discovery of modern alternative options is an urgent matter. T. cruzi glucokinase (TcGlcK) is a potential drug target because its product, D-glucose-6-phosphate, serves as a key metabolite in the pentose phosphate pathway, glycolysis, and gluconeogenesis. In 2019, we identified a novel cluster of TcGlcK inhibitors that also exhibited anti-T. cruzi efficacy called the 3-nitro-2-phenyl-2H-chromene analogues. This was achieved by performing a target-based …

A Phytochemical Analysis Of Secondary Metabolites In Eupatorium Serotinum, Elise Snow

Theses and Dissertations

Phytochemistry, a subset of Natural Products Chemistry, studies chemically derived products from natural substances. Advances in this field have important applications in medicinal research due to the distinctive and unique properties of natural compounds. All metabolites are produced from the metabolic cycle, which is a pathway that provides energy for the organism. These metabolic compounds vary greatly and are classified based on their function within the organism. Primary metabolites are abundant and contribute to organism growth, development, and maintenance of energy. Secondary metabolites are found in lesser quantity and correlate to natural defense mechanisms. For example, salicylic acid is a …

Discovery, Structure-Activity Relationship And In Vitro Anticancer Activity Of Small-Molecule Inhibitors Of The Protein-Protein Interactions Between Af9/Enl And Af4 Or Dot1l, Xin Li, Xiaowei Wu, Shenyou Nie, Jidong Zhao, Yuan Yao, Fangrui Wu, Chandra Bhushan Mishra, Md Ashraf-Uz-Zaman, Bala Krishna Moku, Yongcheng Song

Faculty, Staff and Students Publications

Simple Summary

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene generate potent fusion oncogenes and cause acute myeloid leukemia or lymphocytic leukemia, which account for ~75% infant and 5–10% child/adult acute leukemia cases with a poor prognosis (5-year survival rates < 45%). Protein–protein interactions between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are critical to malignant gene expression and are therefore a potential drug target for cancer. Compound screening followed by medicinal chemistry studies identified several novel small-molecule inhibitors showing strong inhibition of these protein–protein interactions, significant suppression of characteristic gene expression, and robust cellular anticancer activities with negligible cytotoxicity. These compounds are useful chemical probes for biological studies of these protein–protein interactions, as well as pharmacological leads for further drug development against MLL-rearranged and other leukemias.

Abstract

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC₅₀ values as …

Structure-Activity Relationship And Antitumor Activity Of 1,4-Pyrazine-Containing Inhibitors Of Histone Acetyltransferases P300/Cbp, Shenyou Nie, Fangrui Wu, Jingyu Wu, Xin Li, Chao Zhou, Yuan Yao, Yongcheng Song

Faculty, Staff and Students Publications

Acetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The HAT domain of p300/CBP has been found to be a potential drug target for cancer. Compound screening followed by structure-activity relationship studies yielded a novel series of 1,4-pyrazine-containing inhibitors of p300/CBP HAT with their IC50s as low as 1.4 μM. Enzyme kinetics and other studies support the most potent compound 29 is a competitive inhibitor of p300 HAT against the substrate histone. It exhibited a high selectivity for p300 and CBP, with negligible activity on …

Structure, Function And Inhibition Of Critical Protein-Protein Interactions Involving Mixed Lineage Leukemia 1 And Its Fusion Oncoproteins, Xin Li, Yongcheng Song

Faculty, Staff and Students Publications

Mixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5-10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains …

Synthesis, Structure-Activity Relationships, And Antiviral Activity Of Allosteric Inhibitors Of Flavivirus Ns2b-Ns3 Protease, Shenyou Nie, Yuan Yao, Fangrui Wu, Xiaowei Wu, Jidong Zhao, Yuanda Hua, Jingyu Wu, Tong Huo, Yi-Lun Lin, Alexander R Kneubehl, Megan B Vogt, Josephine Ferreon, Rebecca Rico-Hesse, Yongcheng Song

Faculty, Staff and Students Publications

Flaviviruses, including Zika, dengue and West Nile virus, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screen followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile virus and their inhibitory activities are correlated. The most potent compounds 47 and 103 potently inhibited Zika virus …

Study Of Student Resource Use In Introductory Chemistry Courses, Sarah E. Melvin

College of Graduate Studies: Theses & Dissertations

According to the U.S. Government Accountability Office (GAO), college textbook prices have increased by 186% from 1986 to 2004.1 The impact of rising cost of textbooks is increasingly apparent as students are becoming more selective in the courses they enroll in, as well as more concerned with the quality of the learning experience they receive once enrolled in a course.¹ In response to high textbook prices, open-education resources (OER) are increasingly becoming more accepted for student use as an alternative to traditional textbook options. OERs are open-source textbook and/or materials that are free to use without worrying about copyright …

Small-Molecule Inhibitor Of Af9/Enl-Dot1l/Af4/Aff4 Interactions Suppresses Malignant Gene Expression And Tumor Grow, Fangrui Wu, Shenyou Nie, Yuan Yao, Tong Huo, Xin Li, Xiaowei Wu, Jidong Zhao, Yi-Lun Lin, Yinjie Zhang, Qianxing Mo, Yongcheng Song

Faculty, Staff and Students Publications

Chromosome translocations involving mixed lineage leukemia (MLL) gene cause acute leukemia with a poor prognosis. MLL is frequently fused with transcription cofactors AF4 (~35%), AF9 (25%) or its paralog ENL (10%). The AHD domain of AF9/ENL binds to AF4, its paralog AFF4, or histone-H3 lysine-79 (H3K79) methyltransferase DOT1L. Formation of AF9/ENL/AF4/AFF4-containing super elongation complexes (SEC) and the catalytic activity of DOT1L are essential for MLL-rearranged leukemia. Protein-protein interactions (PPI) between AF9/ENL and DOT1L/AF4/AFF4 are therefore a potential drug target.

Methods: Compound screening followed by medicinal chemistry was used to find inhibitors of such PPIs, which were examined for their biological …

Phosphorylation Of Adp-Glucose Pyrophosphorylase During Wheat Seeds Development, Danisa M. L. Ferrero, Claudia V. Piattoni, Matías D. Asencion Diez, Bruno E. Rojas, Matías D. Hartman, Miguel A. Ballicora, Alberto A. Iglesias

Chemistry: Faculty Publications and Other Works

Starch is the dominant reserve polysaccharide accumulated in the seed of grasses (like wheat). It is the most common carbohydrate in the human diet and a material applied to the bioplastics and biofuels industry. Hence, the complete understanding of starch metabolism is critical to design rational strategies to improve its allocation in plant reserve tissues. ADP-glucose pyrophosphorylase (ADP-Glc PPase) catalyzes the key (regulated) step in the synthetic starch pathway. The enzyme comprises a small (S) and a large (L) subunit forming an S2L2 heterotetramer, which is allosterically regulated by orthophosphate, fructose-6P, and 3P-glycerate. ADP-Glc PPase was found in a phosphorylated …

Green Chemistry In United States Science Policy, Emily Jarvis

Chemistry and Biochemistry Faculty Works

Although optimizing each of the Twelve Principles of Green Chemistry is necessary for achieving the greenest possible chemistry in the lab, there are additional creative ways to promote green chemistry not encompassed by these. Communicating to society the importance of green chemistry beyond the laboratory is essential. Of course, doing this effectively presents distinct challenges to those encountered when designing chemical syntheses. Here, I discuss several observations from my time working in federal science policy as an American Association for the Advancement of Science/American Chemical Society Congressional Science Fellow in the United States Senate. I suggest a practical science policy …

Airborne Measurements Of Western U.S. Wildfire Emissions: Comparison With Prescribed Burning And Air Quality Implications, Xiaoxi Liu, L. Gregory Huey, Robert J. Yokelson, Vanessa Selimovic, Isobel J. Simpson, Markus Müller, Jose L. Jimenez, Pedro Campuzano-Jost, Andreas J. Beyersdorf, Donald R. Blake, Zachary Butterfield, Yonghoon Choi, John D. Crounse, Douglas A. Day, Glenn S. Diskin, Manvendra K. Dubey, Edward Fortner, Thomas F. Hanisco, Weiwei Hu, Laura E. King, Lawrence Kleinman, Simone Meinardi, Tomas Mikoviny, Timothy B. Onasch, Brett B. Palm, Jeff Peischl, Ilana B. Pollack, Thomas B. Ryerson, Glen W. Sachse, Arthur J. Sedlacek, John E. Shilling, Stephen Springston, Jason M. St. Clair

Chemistry and Biochemistry Faculty Publications

Wildfires emit significant amounts of pollutants that degrade air quality. Plumes from three wildfires in the western U.S. were measured from aircraft during the Studies of Emissions and Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys (SEAC4RS) and the Biomass Burning Observation Project (BBOP), both in summer 2013. This study reports an extensive set of emission factors (EFs) for over 80 gases and 5 components of submicron particulate matter (PM1) from these temperate wildfires. These include rarely, or never before, measured oxygenated volatile organic compounds and multifunctional organic nitrates. The observed EFs are compared with previous measurements of temperate …

Frontiers In Otolith Chemistry: Insights, Advances And Applications, B. D. Walther, K. E. Limburg, C. M. Jones, J. J. Schaffler

OES Faculty Publications

The rapid proliferation of publications employing chemical assays of fish hard parts, and otoliths in particular, has led to many novel insights into the migration patterns, life history strategies and mixed stock dynamics of fishes across the globe (Campana et al., 2000; Elsdon et al., 2008; Walther & Limburg, 2012). These insights include uncovering diverse migratory strategies within species and populations (Kerr et al., 2009; Hogan et al., 2014; Schoen et al., 2016), quantifying rates of mixing among stocks across management boundaries (Rooker et al., 2008; Walther & Thorrold, 2010) and estimating the relative …

Beyond Zar: The Use And Abuse Of Classification Statistics For Otolith Chemistry, C. M. Jones, M. Palmers, J. J. Schaffler

OES Faculty Publications

Classification method performance was evaluated using otolith chemistry of juvenile Atlantic menhaden Brevoortia tyrannus when assumptions of data normality were met and were violated. Four methods were tested [linear discriminant function analysis (LDFA), quadratic discriminant function analysis (QDFA), random forest (RF) and artificial neural networks (ANN)] using computer simulation to determine their performance when variable-group means ranged from small to large and their performance under conditions of typical skewness to double the amount of skewness typically observed. Using the kappa index, the parametric methods performed best after applying appropriate data transformation, gaining 2% better performance with LDFA performing slightly better …

Characterization And Target Identification Of Non-Toxic Ikkβ Inhibitors For Anticancer Therapy, Elizabeth Blowers

Theses & Dissertations

IKKβ is a key kinase in the canonical NF-κB pathway. Transient activation of IKKβ is required for normal immune response while sustained activation has been implicated in cancer. To date, no IKKβ inhibitor has been approved for clinical use as a chemotherapeutic, likely due to unexpected toxicities associated with blocking the transient activation of IKKβ. We hypothesized that an IKKβ inhibitor that allows transient activation of IKKβ, but not sustained activation of IKKβ, could inhibit cancer growth without inducing toxicity.

As such, we identified a small molecule inhibitor, 13-197, that allows the transient activation of IKKβ but not the sustained …

Identification And Differentiation Of Tier 1 Bacterial Agents Using Gas Chromatography-Mass Spectrometry, Dan Li

Theses and Dissertations

A simple method was developed for detection and differentiation of five Tier 1 bacterial agents, including Bacillus anthracis, Francisella tularensis, Yersinia pestis, Burkholderia pseudomallei and Burkholderia mallei as well as their closely related near neighbors by gas chromatography-mass spectrometry (GC-MS). Generally, different classes of compounds can be used as biomarkers for biowarfare agent detection, including nucleic acids (i.e., DNA or RNA), proteins (i.e., antibodies), carbohydrates (i.e., sugars), lipopolysaccharides, lipids (i.e., fatty acids) and small molecules. One-step thermochemolysis (TCM) was developed to provide GC-MS detectable biomarker signatures, including sugars, fatty acids and small molecules. Solid phase micro-extraction (SPME) was used for …

Ferritin Diversity: Mechanistic Studies, Disease Implications, And Materials Chemistry, Robert Joseph Hilton

Theses and Dissertations

The study of ferritin includes a rich history of discoveries and scientific progress. Initially, the composition of ferritin was determined. Soon, it was shown that ferritin is a spherical, hollow protein. Eventually, over several decades of research, the structure and some function of this interesting protein was elucidated. However, the ferritin field was not completely satisfied. Today, for example, researchers are interested in refining the details of ferritin function, in discovering the role of ferritin in a variety of diseases, and in using ferritin for materials chemistry applications. The work presented in this dissertation highlights the progress that we have …

Enzymology And Medicinal Chemistry Of N5-Carboxyaminoimidazole Ribonucleotide Synthetase : A Novel Antibacterial Target, Hanumantharao Paritala

Wayne State University Dissertations

N5-Carboxyaminoimidazole ribonucleotide synthetase (N5-CAIR synthetase), a key enzyme in microbial de novo purine biosynthesis, catalyzes the conversion of aminoimidazole ribonucleotide (AIR) to N5-CAIR. To date, this enzyme has been observed only in microorganisms, and thus, it represents an ideal target for antimicrobial drug development. Here we report structural and functional studies on the Aspergillus clavatus N5-CAIR synthetase and identification of inhibitors for the enzyme. In collaboration with Dr. Hazel Holden of the University of Wisconsin, the three-dimensional structure of Aspergillus clavatus N5-CAIR synthetase was solved in the presence of either Mg2ATP or MgADP and AIR. These structures, determined to 2.1 …

Comprehensive Laboratory Measurements Of Biomass-Burning Emissions: 2. First Intercomparison Of Open-Path Ftir, Ptr-Ms, And Gc-Ms/Fid/Ecd, Ted J. Christian, B. Kleiss, Robert J. Yokelson, R. Holzinger, P. J. Crutzen, Wein Min Hao, T. Shirai, Donald R. Blake

Chemistry and Biochemistry Faculty Publications

No abstract provided.

The Effects Of Student Manipulated Lewis Structure Models On Chemistry Achievement According To Cognitive Level, Kimberly M. Ross

Dissertations and Theses @ UNI

The purpose of this study was to determine if there was a correlation between teaching method or cognitive development and achievement in a unit on Lewis electron dot structures. Forty-six students were taught a unit on Lewis electron dot structures using the traditional paper and pencil method. Thirty-eight students were taught the same unit using a manipulative model instead of the traditional method. Both groups of students were given pre and post-tests on Lewis electron dot structures and their gains after instruction were measured. The Group Assessment of Logical Thinking measured student's cognitive level. Students were categorized as concrete, transitional …

Micronutrients And Biological Patterns In Lake Mead, Hasan K. Qashu, Lorne G. Everett, J. S. Carlson, Bureau Of Reclamation

Publications (WR)

Progressive increases in concentration of dissolved solids in the Colorado River water from Lake Powell to Imperial Dam seem to alter plankton dynamics and biological productivity of the river. Also, changes in biological productivity and micronutrients concentrations occur within the same reservoir. Development of a digital simulation model to predict micronutrients concentrations and biological productivity is necessary for diagnosing changes in plankton population and effluent-carrying capacity of the system. The objectives of the study are: (1) to determine trace metal balance at different locations in Lake Mead, (2) to measure biological productivity and conduct plankton population counts at each sampling …

Water Chemistry Survey Of Boulder Basin, Lake Mead, P. R. Tramutt, Bureau Of Reclamation

Publications (WR)

The survey results indicate that the impoundment of water behind Hoover Dam has not adversely affected the dissolved oxygen (DO) content and that water quality and DO content were uniform regardless of depth. The study made in April-May 1964 will provide water quality data of Lake Mead prior to releases from Lake Powell as a basis for evaluating Lake Powell's effect on water quality and limnology of Lake Mead. The performance of a DO analyzer was tested and found unsatisfactory at depths below 150 ft. Parameters tested by standard chemical analyses of water samples in the Denver Laboratory and by …