Digital Commons Network^™

Probing Binding And Allosteric Mechanisms Of The Kras Interactions With Monobodies And Affimer Proteins : Ensemble-Based Mutational Profiling And Thermodynamic Analysis Of Binding Energetics And Allostery Reveal Diversity Of Functional Hotspots And Cryptic Pockets Linked By Conserved Communication Network, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Guang Hu, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

KRAS, a historically "undruggable" oncogenic driver, has eluded targeted therapies due to its lack of accessible binding pockets in its active state. This study investigates the conformational dynamics, binding mechanisms, and allosteric communication networks of KRAS in complexes with monobodies (12D1, 12D5) and affimer proteins (K6, K3, K69) to characterize the binding and allosteric mechanisms and hotspots of KRAS binding. Through molecular dynamics simulations, mutational scanning, binding free energy analysis and network-based analyses, we identified conserved allosteric hotspots that serve as critical nodes for long-range communication in KRAS. Key residues in β-strand 4 (F78, L80, F82), α-helix 3 (I93, H95, …

Phosphomimetic Substitution Of Serine Residue Ser260 With Aspartate Suggests Regulation Of Activity Of Human Cytosolic Malate Dehydrogenase By Phosphorylation, Charles Pelagalli '25, Luke Tischio, Kathleen Cornely

Chemistry & Biochemistry Faculty Publications

Human cytosolic malate dehydrogenase (MDH1) is a key enzyme involved in the malate-aspartate shuttle of eukaryotic cells, and which catalyzes the reaction of oxaloacetate to malate. As MDH1 is responsible for maintaining redox homeostasis by regeneration of NAD+ for glycolysis, its regulation is of particular interest in pharmaceutical applications, specifically in treating cancer cells that proliferate quickly and hence rely greatly on glycolysis. While the regulation of MDH1 by the phosphorylation of key residues has been previously documented, work still remains in identifying the specific residues involved in regulation of the enzyme by phosphorylation. In this study, we used …

Turn-On Fluorescent Glucose Transport Bioprobe Enables Wash-Free Real-Time Monitoring Of Glucose Uptake Activity In Live Cells And Small Organisms, Monica Soma Hensley, David Hutchings, Abdelrahman Ismail, Marina Tanasova

Michigan Tech Publications

The direct link between sugar uptake and metabolic diseases highlights the iminent need for molecular tools to detect and evaluate alterations in sugar uptake efficiency as approaches to identify disease-relevant metabolic alterations. However, the strict requirements of facilitative glucose transporters regarding substrate binding and translocation pose challenges for developing effective fluorescence molecular probes. Based on the state-of-the-art understanding of glucose recognition by facilitative transporters (GLUTs), we designed a glucopyranoside mimic - GluRho - that delivers the “turn-on” rhodamine B to live cells via glucose transport, including major transporters GLUTs 1-4. The high binding affinity achieved through the secondary interaction between …

Enabling New Synthetic Platforms For Aryne Synthesis With Aryl Thianthrenium Reagents, Riley Augustus Roberts

Dissertations and Theses

The enormous importance of aromatic rings in organic molecules cannot be understated. Aromatic rings are present in the majority of pharmaceuticals, agrochemicals, and consumer products. The way in which these rings are arranged and substituted results in a molecule’s unique properties. Because of this, the current limitations of the chemical methods used to synthesize these molecules results in limited structural diversity and thus missed opportunities for the development of value-added products. To this end, this work demonstrates novel methods of aryne synthesis, aryl thianthrenium synthesis and a unique approach to structural scaffold hopping. The approaches presented herein allow for rapid …

Development Of New Oxidative Methods And Synthesis Of Small Molecules For Modulation Of Biological Systems, Robert Eric Anderson

Dissertations - ALL

Oxoammonium salts have commonly been used to oxidize alcohols to aldehydes and ketones. More recently these reagents have been employed in several different oxidative transformations. Utilizing these reagents a new tandem elimination-oxidation process of tertiary alcohols has been developed. The new process yields an allylic ether which can be transformed to the alcohol easily through a reduction with zinc metal, removing the tetramethylpipyridyl protecting group derived form the oxoammonium salt. Mechanistically the reaction likely proceeds through oxoammonium salt mediated elimination followed by allylic oxidation through an ene-type mechanism. Due to the alcohol being protected by the easily removed oxoammonium salt, …

Chemical Reversal Of Beta-Lactam Resistance And Induction Of Hyper-Susceptibility In Pseudomonas Aeruginosa By Limiting Horizontal Gene Transfer Under Beta-Lactam Stress, Aimee Iradukunda

Dissertations - ALL

The emergence of antibiotic resistance poses a significant threat to global health, with certain bacterial strains evolving to resist multiple drugs. Urgent action is necessary to develop new antibacterial agents that effectively target these resistant strains; however, no new classes of antibiotics have been approved in recent decades. This research employs innovative biological tools to identify and highlight factors influencing resistance dynamics. Additionally, this study refines the novel approach by utilizing adjuvants to chemically repurpose existing antibiotics and improve their effectiveness against antibiotic-resistant strains. Pseudomonas aeruginosa, recognized for its adaptability, persistent infections—especially in cystic fibrosis patients—and widespread antibiotic resistance, serves …

Diel Patterns Of Biogeochemical Indicators In Tidally-Dominated Creeks, Juliana Calderone

Honors Theses

Marshes and swashes are vital environments as a controlling barrier between land affected by various pollutants and the ocean. Eutrophication and the effects of this process can be detrimental for the areas experiencing it. I am interested in ways areas that have little contact with human interactions compare to areas that are heavily urbanized, and whether either of these locations is at a higher risk for eutrophication. Using spectrophotometry and fluorometry, I analyzed samples collected from the relatively undeveloped and restricted-access locations of Waities Island Beach and Dunn Sound monthly for dissolved nutrients, and chlorophyll. At the time of sampling, …

Impact Of Unconventional Gas Extraction On Tributaries Of Tenmile Creek, Greene County, Pennsylvania: A 12-Year Perspective, Christian L. Beall

Electronic Theses and Dissertations

Much of southwestern Pennsylvania has been central to a rapid increase in development for unconventional natural gas extraction in the past two decades. The continued monitoring of streams over their lifetime as extraction sites is pivotal to understanding the effects of fracking on local waterways and their ability to provide for wildlife and human use. Here, using multiple indices of biotic integrity (IBI), I perform analyses of fish and macroinvertebrate communities as well as water chemistry on two streams, Bates Fork (with shale wells) and Fonner Run (without), as part of a follow-up to work performed there from 2010-2012. Fish …

Synthesis Of Sensitive Oligodeoxynucleotides Containing Acylated Cytosine, Adenine, And Guanine Nucleobases, Komal Chillar, Rohith Awasthy, Marina Tanasova, Shiyue Fang

Michigan Tech Publications

Background/Objective: Oligodeoxynucleotides (ODNs) containing base-labile modifications such as N4-acetyldeoxycytidine (4acC), N6-acetyladenosine (6acA), N2- acetylguanosine (2acG), and N4-methyoxycarbonyldeoxycytidine (4mcC) are highly challenging to synthesize because standard ODN synthesis methods require deprotection and cleavage under strongly basic and nucleophilic conditions, and there is a lack of ideal alternative methods to solve the problem. The objective of this work is to explore the capability of the recently developed 1,3-dithian-2-yl-methoxycarbonyl (Dmoc) method for the incorporation of multiple 4acC modifications into a single ODN molecule and the feasibility of using the method for the incorporation of the 6acA, 2acG and 4mcC modifications into ODNs. Methods: …

Architecture Of Pseudomonas Aeruginosa Glutamyl-Trna Synthetase Defines A Subfamily Of Dimeric Class Ib Aminoacyl-Trna Synthetases, Michael K. Fenwick, Stephen J. Mayclin, Steve Seibold, Amy E. Derocher, Sandhya Subramanian, Isabelle Q. Phan, David M. Dranow, Donald D. Lorimer, Ariel B. Abramov, James M. Bullard

School of Integrative Biological & Chemical Sciences (Formerly Dept. of Chemistry)

The aminoacyl-tRNA synthetases (AaRSs) are an ancient family of structurally diverse enzymes that are divided into two major classes. The functionalities of most AaRSs are inextricably linked to their oligomeric states. While GluRSs were previously classified as monomers, the current investigation reveals that the form expressed in Pseudomonas aeruginosa is a rotationally pseudosymmetrical homodimer featuring intersubunit tRNA binding sites. Both subunits display a highly bent, “pipe strap” conformation, with the anticodon binding domain directed toward the active site. The tRNA binding sites are similar in shape to those of the monomeric GluRSs, but are formed through an approximately 180-degree rotation …

Preparation, And Characterization Of Gypsum-Levan Composites And Evaluation Of Their Preliminary In Vitro And Antibacterial Characteristics, Jamileh Sultan El Arab

Thesis/ Dissertation Defenses

Orthopedic surgery has to contend with a myriad of issues with bones, injuries such as fractures as well as chronic ailments, like osteoporosis. There is a widespread understanding and execution of polymethylmethacrylate (PMMA) bone cement and calcium phosphate cements (CPCs), however their drawbacks like being non-biodegradable, generating heat, low bioactivity, and other issues reserve the development of better substitutes This study intends to develop and incorporate microbial levan squaring as a β-2,6-linked fructan polysaccharide into gypsum-based formulations of bone cements to make them biodegradable, bioactive and amplify their mechanical properties. The research aims to address the performance drawbacks of traditional …

California Red Hummingbird Flowers: Color Convergence Across Four Biochemical Categories, Melissa León-Osper, Victor Rossi, Katie Conrad, Josephine Hernandez Mena, Elaine Meslow, Amelia A. Fuller, Eduardo Narbona, Justen B. Whittall

Chemistry and Biochemistry

There are 129 red-flowered species in western North America that fit the hummingbird pollination syndrome. Theory predicts that these flowers should produce a specific red color that is conspicuous to hummingbirds but not to bees. In a few well-studied cases, red flowers can be produced with pelargonidin, cyanidin, or both—sometimes complemented with the addition of yellow carotenoids and sometimes not. Which pigment combinations are most common in California and whether they affect conspicuousness to hummingbirds and bees remain unknown. To determine the taxonomic distribution of the pigments responsible for red hummingbird-pollinated flowers, we quantified the color of 36 red-flowered species …

High-Quality Factor Phase Gradient Metasurfaces With Dynamic Reconfigurability, Lin Lin

Arts & Sciences Graduate Student Theses and Dissertations

Free-space optical communication holds immense potential for surpassing the bandwidth limitations of conventional physically defined channels. Achieving flexible and efficient communication in free space requires compact, robust optical components capable of dynamically tuning laser light without relying on bulky lenses or mechanically driven mirrors. Metasurfaces, or flat optics, have garnered significant attention due to their densely arranged subwavelength nano-resonators, which impart phase, amplitude, and polarization changes comparable to those of traditional bulky optics. However, conventional phase gradient metasurfaces are constrained by passive designs based on geometric configurations and the weak light-matter interaction inherent in most dielectric materials, limiting their applicability …

Computational Design Of Potent Sirna For Braf Oncogene Silencing For Enhancing Cancer Therapy, Muhammad Hermawan Widyananda, Ricadonna Raissa

Karbala International Journal of Modern Science

The discovery of oncogenic BRAF mutations has prompted the development of inhibitors, yet resistance remains widespread. A more effective strategy involves targeting BRAF mRNA with siRNA to overcome resistance to BRAF inhibitors. This study aims to design potent siRNA for BRAF oncogene silencing using a computational approach. The full coding sequence of BRAF was retrieved from the NCBI database and potential siRNAs were predicted using the Ui-Tei, Reynolds, and Amarzguioui rules. Identified siRNAs were further analyzed using various prediction systems and parameters, including their interaction with the hAgo2 protein. The results identified that seven siRNAs (siRNA 23, siRNA 24, siRNA …

Nifuroxazide And 4-Hydroxybenzhydrazone Derivatives As New Antiparasitic (Trypanosoma Cruzi And Leishmania Mexicana) And Anti-Mycobacterium Tuberculosis Agents, Timoteo Delgado-Maldonado, Diana V. Navarrete-Carriola, Lenci K. Vazquez-Jimenez, Alma D. Paz-Gonzalez, Baojie Wan, Scott Franzblau, Othman Mueen Mohammed, Lorena Rodríguez-Páez, Charmina Aguirre-Alvarado, Debasish Bandyopadhyay

School of Integrative Biological & Chemical Sciences Faculty Publications

Background/Objectives: Nifuroxazide (Nfz) is a drug that has been used as a scaffold for designing antimicrobial and antiparasitic agents. This study aimed to synthesize and evaluate in vitro of Nfz and twenty-five 4-hydroxybenzhydrazone derivatives as potential anti-Trypanosoma cruzi, anti-Leishmania mexicana, and anti-Mycobacterium tuberculosis agents.

Methods: The compounds were synthesized by condensing 4-hydroxybenzhydrazide with appropriate aldehydes in acidic conditions and structurally confirmed by spectroscopic techniques. All compounds were evaluated in vitro against T. cruzi strains (NINOA and A1), L. mexicana (M379 and FCQEPS strains), and M. tuberculosis (H37Rv strain), followed by enzymatic assays against T. cruzi …

Vanadyl Phthalocyanine As A Low-Temperature/Low-Pressure Catalyst For The Conversion Of Fructose To Methyl Levulinate, Juan Luna, Mataz Alcoutlabi, Elizabeth M. Fletes, Helia Magali Morales, Jason Parsons

School of Integrative Biological & Chemical Sciences Faculty Publications

In this study, a vanadyl phthalocyanine was synthesized and characterized using XRD, FTIR, and XPS, confirming the successful metalation of the phthalocyanine ring. XRD analysis showed the vanadyl phthalocyanine crystallized in the P-1 crystal lattice, with unit cell parameters a = 12.058 Å, b = 12.598 Å, and c = 8.719 Å, and the lattice angels were 96.203°, 94.941°, and 68.204°. FTIR spectroscopy supported the metalation by the disappearance of the N-H stretch of the non-metalated phthalocyanine. The vanadyl phthalocyanine was tested as a heterogenous catalyst for the conversion of fructose into methyl levulinate in H2SO4–methanol and HCl–methanol systems. The …

Treatment Wastewater Of Oil Refinery By Fe2o3 Nps Produce By The Novel Alishewanella Jeotgali Strain Haq8., Hawraa Qays Al-Assdy, Wijdan Hussein Al-Tamimi, Asia Fadhile Almansoory

Karbala International Journal of Modern Science

Metal oxide nanoparticles like iron oxide (Fe₂O₃) exhibit strong reactivity and photolytic features in wastewater treatment and serve as an effective adsorbent for water purification due to its substantial surface area and affinity for different functionalized groups. Iron oxide nanoparticles) IONPs) are currently applied to treat oil-contaminated water. Fe₂O₃NPs were produced using an extracellular approach utilizing the Alishewanella jeotgali strain HAQ8. IONPs were characterized using UV-vis, FT-IR, XRD, AFM, SEM-EDX, and Zeta potential. λ max for the synthesized nanoparticles observed at (358) nm. The bands at 485 cm⁻¹ in the FT-IR spectrum confirmed the formation of …

Development Of A Mechanochemical Synthesis For A Palladacycle: Exploring Solvent Characteristics And Reaction Kinetics, Kyle Lintzenich

Honors College Theses

Palladacycles are a class of palladium complexes that show utility in catalyzing carbon-carbon cross coupling reactions. Mechanochemistry provides a greener alternative to synthesizing these palladacycles via repeated impacts that transfer mechanical energy into the reaction mixture, promoting formation of the desired complex. Specifically, liquid assisted grinding (LAG) has proven to be a viable tradeoff to neat mechanosynthesis of adding a small amount of liquid to decrease synthesis times or improve conversion. Some liquids actively participate in the reaction in a process termed as non-innocent LAG. This work focuses on the development of a mechanosynthetic method using non-innocent LAG for a …

Toxicity And Biodegradability Of Novel Boronium Vs Conventional Ammonium Based Anti Microbial Compounds In Wastewater Treatment Systems, Noor Shalan

Poster Presentations

Quaternary ammonium compounds (QACs) are highly effective as disinfectants, herbicides, and pesticides; thus, overuse causes elevated levels of residual toxicity in domestic and industrial wastewater. QACs can be toxic to essential bacteria breaking down pollutants in wastewater treatment plants (WWTPs) and can remain untreated in effluent, harming the environment, and contributing to antibiotic resistance, posing risks to human health. Novel boronium-based antimicrobial compounds have demonstrated efficacy in eliminating bacteria, fungi, and viruses. If the boronium compounds exhibit lower residual toxicity, they could offer a promising alternative to QACs. Because these compounds are still in development, their potential toxicity to the …

Molecular Insights: Advances In Single Molecule And Single Particle Detection For Analysis Of Chemical, Physical, And Biological Phenomena, James Ethan Batey

Chemistry & Biochemistry Undergraduate Honors Theses

This thesis is focused on recent advancements made in the field of chemical imaging, optical microscopy, and recent developments that have improved spatial, temporal, or spectral resolution or have made certain techniques more accessible and cost effective for their wider adoption. This thesis is organized based on the systems of interest we studied with each new technique. Although, it is important to note that many of the methods here can be used with a multitude of systems even if not explicitly mentioned. The first chapter of this thesis will discuss the current state of chemical imaging, common terminology, and important …

Development Of Novel Pharmaceutical For Optimization Of Opioid Overdose Treatment, Larae Kram

Celebrating Scholarship and Creativity Day (2018-)

Although opioids are highly effective drugs for pain management, their overuse and addictive nature has caused an opioid epidemic, resulting in many cases of opioid addiction and overdose. There are two current opioid overdose drugs that are FDA approved: naloxone and nalmefene. These drugs have a higher affinity to the active binding pocket on the opioid receptor than opioids do and displace the opioids, preventing any further binding of the opioid and halting the opioid’s effects. However, naloxone is not active long enough to outlast the duration of the opioid and nalmefene causes severe withdrawal symptoms. The development of more …

Synthesis And Characterization Of 3,5 Trifluoromethyl Tpm With A Metal Carbonyl Complex, Emily P. Berkman

Undergraduate Honors Thesis Collection

Tris(pyrazolyl)methane (Tpm) ligands have a central carbon with 3 pyrazole rings attached. These were discovered in 1970 and have since been synthesized with many substituents on the rings. Based on the parent structure, my goal was to synthesize a fluorinated Tpm derivative. By adapting existing procedures, I have synthesized a Tpm derivative with trifluorinated methyl groups in the 3 and 5 positions of the pyrazole ring. The fluorinated ligand is expected to be electron withdrawing and exhibit interesting chemistry when bound to a metal center. Future directions of the project will be discussed.

Disulfide-Cleavable Linkers In Antibody-Drug Conjugates For Targeted Cancer Therapy, Emily Hwang

Undergraduate Honors Thesis Collection

This project aims to discover a way to improve the safety of and reduce adverse side effects of disulfide-linked antibody-drug conjugates. Disulfide-cleavable linkers for antibody-drug conjugates function by exploiting the differential concentrations of dominant thiol species in the blood plasma and in the cytosol of malignant cells. This project aimed to identify a relationship between the stability of disulfide cleavable linkers in the blood plasma and disulfide linker structure, to prevent premature release of the cytotoxic drug. Three disulfide linker analogs with varying carbon chain lengths were synthesized through reaction with 2,2’-dipyridyl disulfide. Each analog was conjugated to a fluorescent …

Cultural Health Benefits And Challenges Of Food Preparation And Consumption: A Comparative Study Of The United States, Italy, And Norway, Natalie G. Link

Undergraduate Honors Thesis Collection

This study aims to investigate the cultural health benefits and challenges associated with food preparation and consumption in the United States, Italy, and Norway, with a particular focus on citizens in lower socioeconomic levels. By examining the dietary habits, social structures, and health outcomes in these three countries, this research aims to uncover broader insights into the health status and well-being of their respective populations. The study will employ secondary data analysis approach examining existing research on cultural practices and social support systems. The findings of this research will contribute to a deeper understanding of the complex interplay between food …

Semiconductors In Space: Data Analysis Of Microgravity's Impact On Crystal Formation, Keegan Jo Jackson

Undergraduate Honors Thesis Collection

Comprehensive data analysis on crystal growth in microgravity is a requisite to inform understanding of prior work. Our research constructed and analyzed a database containing data gathered from research focusing on semiconductors grown in microgravity. Data curation spanned multiple decades, countries, and semiconductor materials. All relevant reported information was recorded in the database, notably data regarding the metrics used to determine the impact space had on crystal growth: size, structure, uniformity, and performance. After data cleaning and data processing, the database was organized and readied for analysis. Data analysis was performed using RStudio and SciKit-learn. RStudio was employed for data …

Linking The Past And The Future: Understanding How Pollutants Cause Corrosion During An Oddy Test, Kylie Blair Blake

Undergraduate Honors Thesis Collection

Artifacts and artwork continue to tell a story long after a time or culture has disappeared. Preventive art conservation science involves careful and responsible management of the objects entrusted in the care of the museum staff to ensure environmental and display conditions do not cause damage so future generations can observe and learn about past cultures. An accelerated metal corrosion test, the Oddy test, has been used to help determine the suitability of display and storage materials. The Oddy test is subjective, so newer methods are being developed involving the use of gas chromatography and mass spectrometry to identify specific …

A New Transition Metal Borate, Co6(B24O39(Oh)6(H2O) 6·2.21h2O, Synthesized Via A Mild Hydrothermal Synthesis, Alevtina Maksimova, Patrick Belt, Nilah Whitfield, Mark D. Smith, Gopabandhu Panigrahi, Gregory Morrison, Hans Conrad Zur Loye

Faculty Publications

A new transition metal borate hydrate, Co₆B₂₄O₃₉(OH)₆(H₂O)₆·2.21H₂O, was synthesized via a mild hydrothermal method using boric acid as the melt. The compound crystallizes in the trigonal space group P 3‾ with lattice parameters a = b = 13.17840(10) Å, c = 12.3287(2) Å, and a unit cell volume of 1854.27(4) ų (Z = 2). This borate hydrate crystallizes in a new structure type comprised of layers containing [BO3] trigonal planar units and [BO4] tetrahedra that are linked by CoO6 and Co(OH)2(H2O)4 octahedra via corner-sharing. The …

Atomic Level Characterization For The Transport Cycle Conformational Pathways Of Multidrug Resistance Protein 1 (Mrp1), Samuel Wamwere Mwatha

Graduate Theses and Dissertations

The multidrug resistance-associated protein 1 (MRP1/ABCC1) is an ATP-binding cassette (ABC) transporter that mediates the cellular efflux of endogenous and xenobiotic substrates, including therapeutic drugs. Its overexpression is a major contributor to multidrug resistance in cancer, which tends to result in negative clinical results. Even with considerable progress made in structural biology, the intricate details of how membrane lipid composition affects the conformational changes and functional switches of MRP1 still lack explanation.

This thesis employs long-timescale, all-atom molecular dynamics (MD) simulations to study the influence of various lipids on MRP1 lipid bilayer environments. Both inward-facing and outward-facing conformations of MRP1 …

Development And Characterization Of Aso-Based Ribonuclease Targeting Chimera For The Degradation Of Cug Rna Repeat Expansion In Myotonic Dystrophy Type, Audrey Coons

Chemistry

Myotonic Dystrophy Type 1 is a multisystemic genetic disorder that primarily affects the muscles in the body leading to such pathologies as myotonia, muscle atrophy, insulin resistance and even neurological deficits. This disorder is caused by a series of CUG repeats in the 3’ untranslated region of the DMPK gene; symptoms appear after around 34 repeats. These repeats form foci when MBNL1 protein that deals with alternative splicing of many events in the body, forms aggregations around these repeats. These foci render the MBNL 1 proteins useless. There is no FDA approved therapeutic, but many RNA targeting therapeutics have been …

Synthesis Of Single Chain Polymer Nanoparticle Networks By Reinitiating Raft Polymerization, Dallas Donovan

Honors Theses

Hydrogel materials, which are polymer networks comprised mostly of water, hold significant promise for biomedical applications due to their compatibility with biological systems. Conventional hydrogel materials are often brittle and weak, but most applications in biomedical systems require materials to be strong and tough. The topology of a polymer network dictates its mechanical properties. An important strategy for designing tougher hydrogels is the release of stored length, such as from the unfolding of polyprotein cross-linkers. Inspired by the success of the strategy, we report progress towards a fully synthetic design using single chain nanoparticles (SCNPs) into a hydrogel. SCNPs, which …