Biochemistry, Biophysics, and Structural Biology Commons^™

A Homogeneous Time-Resolved Fluorescence Screen To Identify Sirt2 Deacetylase And Defatty-Acylase Inhibitors, Jie Yang, Joel Cassel, Brian C Boyle, Daniel Oppong, Young-Hoon Ahn, Brian P Weiser

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Human sirtuin-2 (SIRT2) has emerged as an attractive drug target for a variety of diseases. The enzyme is a deacylase that can remove chemically different acyl modifications from protein lysine residues. Here, we developed a high-throughput screen based on a homogeneous time-resolved fluorescence (HTRF) binding assay to identify inhibitors of SIRT2's demyristoylase activity, which is uncommon among many ligands that only affect its deacetylase activity. From a test screen of 9600 compounds, we identified a small molecule that inhibited SIRT2's deacetylase activity (IC50 = 7 μM) as well as its demyristoylase activity (IC50 = 37 μM). The inhibitor was composed …

Colocalization Of Odc And Amyloid Plaques In Patients With Alzheimer’S Disease And Down Syndrome, Julia S. Gielczynski

Undergraduate Theses, Capstones, and Recitals

Polyamines, and their rate-limiting enzyme ornithine decarboxylase (ODC), are crucial for many functions in the central nervous system but levels decrease with age. In neurodegenerative diseases, like Alzheimer’s Disease (AD), polyamine levels begin to increase again. Yet, there are still many unanswered questions surrounding polyamine’s possible role in AD, especially in those with Down Syndrome (DS), who also have an extra copy of the amyloid precursor protein (APP) and tend to get AD far earlier than the general population. We aim to investigate if there is colocalization between amyloid plaques and Ornithine Decarboxylase (ODC) in patients with AD and AD/DS, …

Effect Of Plumbagin On Chemo-Resistant Metastatic Retinoblastoma, John J. Soto

Theses and Dissertations

Retinoblastoma, which is an ocular malignancy, usually results in poor prognoses in pediatric patients worldwide. Retinoblastoma in some events, can develop metastatic phenotypes which can lead to secondary tumor formation, furthering deleterious patient outcomes. It is of paramount importance to identify and research potent novel compounds that can be used to increase the likelihood of remission. Plumbagin (PLB) is a plant-derived, neuroprotective agent, which exhibits significant anticancer activities during in vitro study. PLB has been shown to have a high therapeutic efficacy against chemoresistant sublines as well as their normal counterparts. We attempted to show that the chemoresistant ABCC1 could …

Scanless Two-Photon Voltage Imaging, Ruth R Sims, Imane Bendifallah, Christiane Grimm, Aysha S Mohamed Lafirdeen, Soledad Domínguez, Chung Yuen Chan, Xiaoyu Lu, Benoît C Forget, François St-Pierre, Eirini Papagiakoumou, Valentina Emiliani

Faculty, Staff and Students Publications

Two-photon voltage imaging has long been heralded as a transformative approach capable of answering many long-standing questions in modern neuroscience. However, exploiting its full potential requires the development of novel imaging approaches well suited to the photophysical properties of genetically encoded voltage indicators. We demonstrate that parallel excitation approaches developed for scanless two-photon photostimulation enable high-SNR two-photon voltage imaging. We use whole-cell patch-clamp electrophysiology to perform a thorough characterization of scanless two-photon voltage imaging using three parallel illumination approaches and lasers with different repetition rates and wavelengths. We demonstrate voltage recordings of high-frequency spike trains and sub-threshold depolarizations from neurons …

Frontotemporal Dementia-Like Disease Progression Elicited By Seeded Aggregation And Spread Of Fus, Sonia Vazquez-Sanchez, Britt Tilkin, Fatima Gasset-Rosa, Sitao Zhang, Diana Piol, Melissa Mcalonis-Downes, Jonathan Artates, Noe Govea-Perez, Yana Verresen, Lin Guo, Don Cleveland, James Shorter, Sandrine Da Cruz

Department of Biochemistry and Molecular Biology Faculty Papers

RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation …

Folate As A Potential Treatment For Lethal Ventricular Arrhythmias In Tango2-Deficiency Disorder, Weiyi Xu, Yingqiong Cao, Sara B Stephens, Maria Jose Arredondo, Yifan Chen, William Perez, Liang Sun, Andy C Yu, Jean J Kim, Seema R Lalani, Na Li, Frank T Horrigan, Francisco Altamirano, Xander Ht Wehrens, Christina Y Miyake, Lilei Zhang

Faculty, Staff and Students Publications

TANGO2-deficiency disorder (TDD) is an autosomal-recessive genetic disease caused by biallelic loss-of-function variants in the TANGO2 gene. TDD-associated cardiac arrhythmias are recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Disease modeling for TDD has been primarily carried out using human dermal fibroblast and, more recently, in Drosophila by multiple research groups. No human cardiomyocyte system has been reported, which greatly hinders the investigation and understanding of TDD-associated arrhythmias. Here, we established potentially novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD. These electrophysiological abnormalities were rescued in iPSC-CMs …

Echocardiogram By Apical-Subcostal Protocol In Prone Position During Invasive Mechanical Ventilation In Cardiovascular Intensive Care Unit, César Del Castillo, Fernando Verdugo, Franco Appiani, Francisca Yáñez, Camila Bontá, Carlos Torres-Herrera, Angela Garcia, Zorba Blázquez-Bermejo, Javier Castrodeza, Daniel Requena, Andreina Rodríguez, Arquimedes Silvio, Agustín Gatica, Arnulfo Begazo, Mario Alfaro

Faculty, Staff and Students Publications

AIMS: To evaluate the feasibility of a transthoracic echocardiogram using an apical-subcostal protocol in invasive mechanical ventilation (IMV) and prone position.

METHODS: Prospective study of adults who required a prone position during IMV. A pillow was placed only under the left hemithorax in the prone position to elevate and ease the apical and subcostal windows. A critical care cardiologist (prone group) acquired and evaluated the images using the apical-subcostal protocol. Besides, we used ambulatory echocardiograms performed as a comparative group (supine group).

RESULTS: 86 patients were included, 43 in the prone and 43 in the supine. In the prone group, …

Computational Analysis Of O6-Methylated Guanine And Thioguanine Complexes, Kirsten Stinson, Michael Bowman

Lux et Fides: A Journal for Undergraduate Christian Scholars

DNA methylation occurring on the O⁶ position of guanine has been linked to the formation of cancer. DNA complexes with O⁶-methylated guanine have been studied experimentally, yet questions remain concerning the carcinogenic properties of O⁶-methylguanine. This present research explored the interaction between O⁶-methylguanine and its potential nucleobase pairs of cytosine and adenine in hopes of elucidating the mutagenic characteristics of O⁶-methylguanine. A variety of computational methods including Density Functional Theory (DFT), Symmetry Adapted Perturbation Theory (SAPT), Noncovalent Interaction (NCI) analysis, and Natural Bond Orbital (NBO) analysis were employed to comprehensively probe …

Cyp3a Mediates An Unusual C(Sp2)-C(Sp3) Bond Cleavage Via Ipso-Addition Of Oxygen In Drug Metabolism, Xuan Qin, Yong Wang, Qiuji Ye, John M Hakenjos, Jin Wang, Mingxing Teng, Lei Guo, Zhi Tan, Damian W Young, Kevin R Mackenzie, Feng Li

Faculty, Staff and Students Publications

Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon–carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H218O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage: one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) …

Molecular Therapy Nucleic Acids, Jasmin Morandell, Alan Monziani, Martina Lazioli, Deborah Donzel, Jessica Döring, Claudio Oss Pegorar, Angela D'Anzi, Miguel Pellegrini, Andrea Mattiello, Dalia Bortolotti, Guendalina Bergonzoni, Takshashila Tripathi, Virginia B Mattis, Marina Kovalenko, Jessica Rosati, Christoph Dieterich, Erik Dassi, Vanessa C Wheeler, Zdenka Ellederová, Jeremy E Wilusz, Gabriella Viero, Marta Biagioli

Faculty, Staff and Students Publications

Circular RNA (circRNA) molecules have critical functions during brain development and in brain-related disorders. Here, we identified and validated a circRNA, circHTT(2,3,4,5,6), stemming from the Huntington’s disease (HD) gene locus that is most abundant in the central nervous system (CNS). We uncovered its evolutionary conservation in diverse mammalian species, and a correlation between circHTT(2,3,4,5,6) levels and the length of the CAG-repeat tract in exon-1 of HTT in human and mouse HD model systems. The mouse orthologue, circHtt(2,3,4,5,6), is expressed during embryogenesis, increases during nervous system development, and is aberrantly upregulated in the presence of the expanded CAG tract. …

Rewiring The Sex-Determination Pathway During The Evolution Of Self-Fertility., Yongquan Shen, Shin-Yi Lin, Jonathan Harbin, Richa Amin, Allison Vassalotti, Joseph Romanowski, Emily Schmidt, Alexis Tierney, Ronald E Ellis

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Although evolution is driven by changes in how regulatory pathways control development, we know little about the molecular details underlying these transitions. The TRA-2 domain that mediates contact with TRA-1 is conserved in Caenorhabditis. By comparing the interaction of these proteins in two species, we identified a striking change in how sexual development is controlled. Identical mutations in this domain promote oogenesis in Caenorhabditis elegans but promote spermatogenesis in Caenorhabditis briggsae. Furthermore, the effects of these mutations involve the male-promoting gene fem-3 in C. elegans but are independent of fem-3 in C. briggsae. Finally, reciprocal mutations in these genes show …

Positron Emission Tomography In Oncology And Environmental Science, Samantha Delaney

Dissertations, Theses, and Capstone Projects

The last half century has played witness to the onset of molecular imaging for the clinical assessment of physiological targets. While several medical imaging modalities allow for the visualization of the functional and anatomical properties of humans and living systems, few offer accurate quantitation and the ability to detect biochemical processes with low-administered drug mass doses. This limits how physicians and scientists may diagnose and treat medical issues, such as cancer, disease, and foreign agents.

A promising alternative to extant invasive procedures and suboptimal imaging modalities to assess the nature of a biological environment is the use of positron emission …

Single-Cell Analysis Identifies Plk1 As A Driver Of Immunosuppressive Tumor Microenvironment In Luad, Yifan Kong, Chaohao Li, Jinpeng Liu, Sai Wu

Markey Cancer Center Faculty Publications

PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immuno- therapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single- cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coin- cides with increased secretion of CXCL2 …

Intravascular Imaging-Guided Versus Coronary Angiography-Guided Complex Pci: A Meta-Analysis Of Randomized Controlled Trials, Mohamed Hamed, Sheref Mohamed, Mohamed Mahmoud, Jonathan Kahan, Amr Mohsen, Faisal Rahman, Waleed Kayani, Fernando Alfonso, Emmanuel S Brilakis, Islam Y Elgendy, Mamas A Mamas, Ayman Elbadawi

Faculty, Staff and Students Publications

INTRODUCTION: Trials evaluating the role of intravascular imaging in percutaneous coronary intervention (PCI) for complex coronary artery disease have yielded mixed results. This study aimed to compare the outcomes of intravascular imaging specifically intravascular ultrasound (IVUS) with those from conventional coronary angiography in complex PCI.

METHODS: Comprehensive electronic search of MEDLINE, EMBASE, and Cochrane databases was performed until March 2023 for randomized clinical trials (RCTs) comparing intravascular imaging with coronary angiography in patients undergoing complex PCI. Complex PCI was defined per each study, and included PCI for American College of Cardiology/American Heart Association (ACC/AHA) type B2/C lesions, unprotected left main …

Bacillary Angiomatosis In A Patient With Hiv And Disseminated Mycobacterium Avium Complex Infection, Ibeth P Caceres, Angelique Ruml, Rubi Montejano, Omid Jalali, Theodore Rosen

Faculty, Staff and Students Publications

Bartonella is a genus of arthropod-borne bacterial pathogens that typically cause persistent infections of erythrocytes and endothelial cells in mammalian hosts. The species that primarily infect humans are Bartonella henselae and Bartonella quintana. Depending on immune status, the clinical presentation of B. henselae may differ, manifesting as cat-scratch disease in immunocompetent individuals or bacillary angiomatosis (BA) and peliosis in immunocompromised patients. The cutaneous manifestations of BA are typically characterized by occasionally painful, angiomatous papules and nodules, often with a chronic, persistent course. Herein, we present a case of biopsy-confirmed B. henselae infection in a 32-year-old HIV-positive female with acquired immunodeficiency …

Myocardial Infarction Suppresses Protein Synthesis And Causes Decoupling Of Transcription And Translation, Shijie Liu, Vaibhav Deshmukh, Fangfei Wang, Jie Liang, Jenna Cusick, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Gene expression involves transcription, translation, and mRNA and protein degradation. Advanced RNA sequencing measures mRNA levels for cell state assessment, but mRNA level does not fully reflect protein level. Identifying heart cell proteomes and their stress response is crucial. Using a cardiomyocyte-specific mouse model, we tracked protein synthesis after myocardial infarction. Our results showed that myocardial infarction suppresses protein synthesis and unveils a decoupling of translation and transcription regulation in cardiomyocytes.

Humanism Rounds: A Multifaceted "Back To Bedside" Initiative To Improve Meaning At Work For Internal Medicine Residents, Jennifer M Kaplan, Suchi Agrawal, Disha Kumar, Ann Xu, Kristen A Staggers, Anna G Symmes, Reina U Styskel, Brett Styskel, Anoop Agrawal, Stacey R Rose

Faculty, Staff and Students Publications

INTRODUCTION: Burnout is an increasingly prevalent problem among resident physicians. To address this problem, the Accreditation Council on Graduate Medical Education (ACGME) created the Back to Bedside initiative, supporting resident-driven projects focused on increasing direct interactions with patients. In 2017, Baylor College of Medicine (BCM) Internal Medicine Residency received a Back to Bedside grant to develop and implement “Humanism Rounds,” a multifaceted program which sought to promote personal connections between residents and patients and foster reflection about patients’ non-clinical stories, with the hopes of reducing burnout and increasing residents’ sense of meaning at work.

MATERIALS AND METHODS: Between 2018 and …

Using Rapid Protein Degradation To Determine The Effect Of Runx1 Loss-Of- Function On Dna Damage Accumulation And Repair., Jackriel Pina Morales

Theses and Dissertations

Germline mutations in RUNX1 are associated with familial platelet disorder with a predisposition to myeloid malignancy (RUNX1-FPDMM), in which patients present with low platelet counts,excessive bleeding and bruising, and an increased risk of Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome (MDS) development throughout their lifetime. To understand how these loss-of-function mutations in RUNX1 drive predispose to malignancy, it is important to develop a detailed understanding of the molecular basis of RUNX1 function. While RUNX1 is a transcription factor, preliminary data from our group and work from others suggests that RUNX1 also interacts with proteins that are critical for DNA damage …

Novel Role And Mechanisms Of Brd4 In Mediating Mesothelial To Mesenchymal Transition And Pleural Fibrosis, Felix Kankam

Biotechnology Theses

Pleural fibrosis is characterized by myofibroblast accumulation and increased expression of collagen and other extracellular matrices due to injury to the pleura and remodeling. Mesothelial to mesenchymal transition (MesoMT) is an important pathological event that contributes to the pool of myofibroblasts although its regulation remains incompletely understood. Recent research has reported the role of BRD4, a member of the bromodomain extra terminal domain (BET) family, in developing fibrosis in the heart and the lungs. One recent study showed that MEOX1 is a downstream target of BRD4 and mediated cardiac fibroblast activation. Our joint work also demonstrated that NOX4 is implicated …

Maackia Amurensis Seed Lectin (Masl) And Soluble Human Podoplanin (Shpdpn) Sequence Analysis And Effects On Human Oral Squamous Cell Carcinoma (Oscc) Cell Migration And Viability, Ariel C Yin, Cayla J Holdcraft, Eamonn J Brace, Tyler J Hellmig, Sayan Basu, Saumil Parikh, Katarzyna Jachimowska, Evelyne Kalyoussef, Dylan Roden, Soly Baredes, Eugenio M Capitle, David I Suster, Alan J Shienbaum, Caifeng Zhao, Haiyan Zheng, Kevin Balcaen, Simon Devos, Jurgen Haustraete, Mahnaz Fatahzadeh, Gary S Goldberg

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Maackia amurensis lectins serve as research and botanical agents that bind to sialic residues on proteins. For example, M. amurensis seed lectin (MASL) targets the sialic acid modified podoplanin (PDPN) receptor to suppress arthritic chondrocyte inflammation, and inhibit tumor cell growth and motility. However, M. amurensis lectin nomenclature and composition are not clearly defined. Here, we sought to definitively characterize MASL and its effects on tumor cell behavior. We utilized SDS-PAGE and LC-MS/MS to find that M. amurensis lectins can be divided into two groups. MASL is a member of one group which is composed of subunits that form dimers, …

Ciliary Tip Actin Dynamics Regulate Photoreceptor Outer Segment Integrity, Roly Megaw, Abigail Moye, Zhixian Zhang, Fay Newton, Fraser Mcphie, Laura C Murphy, Lisa Mckie, Feng He, Melissa K Jungnickel, Alex Von Kriegsheim, Peter A Tennant, Chloe Brotherton, Christine Gurniak, Alecia K Gross, Laura M Machesky, Theodore G Wensel, Pleasantine Mill

Faculty, Staff and Students Publications

As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily. Defects in this process, due to mutations, cause retinitis pigmentosa (RP). Whilst fundamental for vision, the mechanism of photoreceptor disc generation is poorly understood. Here, we show membrane deformation required for disc genesis is driven by dynamic actin changes in a process akin to ectocytosis. We show RPGR, a …

An Unexpected Path For Malat1 In Neurons: Trafficking Out Of The Nucleus For Translation, Bradley W Wright, Jeremy E Wilusz

Faculty, Staff and Students Publications

The Malat1 (metastasis-associated lung adenocarcinoma transcript 1) long noncoding RNA is highly and broadly expressed in mammalian tissues, accumulating in the nucleus where it modulates expression and pre-mRNA processing of many protein-coding genes. In this issue of Genes & Development, Xiao and colleagues (doi:10.1101/gad.351557.124) report that a significant fraction of Malat1 transcripts in cultured mouse neurons are surprisingly exported from the nucleus. These transcripts are packaged with Staufen proteins in RNA granules and traffic down the lengths of neurites. They then can be released in a stimulus-dependent manner to be locally translated into a microprotein that alters neuronal gene …

Towards A New Role Of Mitochondrial Hydrogen Peroxide In Synaptic Function, Cliyahnelle Z. Alexander

Student Theses and Dissertations

Aerobic metabolism is known to generate damaging ROS, particularly hydrogen peroxide. Reactive oxygen species (ROS) are highly reactive molecules containing oxygen that have the potential to cause damage to cells and tissues in the body. ROS are highly reactive atoms or molecules that rapidly interact with other molecules within a cell. Intracellular accumulation can result in oxidative damage, dysfunction, and cell death. Due to the limitations of H₂O₂ (hydrogen peroxide) detectors, other impacts of ROS exposure may have been missed. HyPer7, a genetically encoded sensor, measures hydrogen peroxide emissions precisely and sensitively, even at sublethal levels, during …

Exploring The Design Space Of Antifungal Peptides, Miryam Kikhwa

Seton Hall University Dissertations and Theses (ETDs)

The synthesis, characterization, and evaluation of antifungal activity of peptides FQ15 and FG10 will be conducted to address the hypothesis. The hypothesis of this thesis is that a peptide with similar properties to AS15 would have similar activity against Cryptococcus neoformans. This study addresses the challenge of drug- resistant microbes by developing inhibitors targeting lipid flippase and exploring their potential as antimicrobial agents against Cryptococcus neoformans. Chapter 1 provides a historical context of the background on the development of antimicrobials and common antifungal treatments, as well as an introduction about C. neoformans and its resistance mechanism. Chapter 2 introduces the …

Antiseizure Properties Of Fenamate Nsaids Determined In Mature Human Stem-Cell Derived Neuroglial Circuits., Hamed Salmanzadeh, Robert F. Halliwell

School of Pharmacy Faculty Articles

Repeated and uncontrolled seizures in epilepsy result in brain cell loss and neural inflammation. Current anticonvulsants primarily target ion channels and receptors implicated in seizure activity. Identification of neurotherapeutics that can inhibit epileptiform activity and reduce inflammation in the brain may offer significant benefits in the long-term management of epilepsy. Fenamates are unique because they are both non-steroidal anti-inflammatory drugs (NSAIDs) and highly subunit selective modulators of GABA_A receptors. In the current study we have investigated the hypothesis that fenamates have antiseizure properties using mature human stem cell-derived neuro-glia cell cultures, maintained in long-term culture, and previously shown to …

Novel Tetrazolium-Based Colorimetric Assay For Helicase Nsp13 In Sars-Cov-2, Triet M. Pham, Morgan G. Howard, Shane M. Carey, Lindsey R. Baker, Edward L. D'Antonio

Natural Sciences Faculty Publications

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a human pathogenic virus that encodes for a helicase (SC2Hel) that is essential for viral replication. SC2Hel has the ability to unravel dsRNA or dsDNA in an NTP-dependent manner from the 5′ to 3′ directionality. The standard helicase assay from studies involving SARS-CoV and SARS-CoV-2 have relied on the concept of fluorescence resonance energy transfer. Adding to the collection of helicase assays, herein, we have developed a novel tetrazolium-based colorimetric assay system for the detection of ADP that is produced via SC2Hel activity. This SC2Hel assay combines three enzyme-coupled steps involving the …

Unveiling The Nexus Of Cellular Quality Control: Exploring The Interplay Between Ribosome-Associated Protein Quality Control And Mitochondrial Quality Control Pathways, Foozhan Tahmasebinia

Biological Sciences Theses and Dissertations

In eukaryotic cells, the intricate interplay between cellular quality control mechanisms is crucial for maintaining homeostasis and safeguarding the integrity of vital processes, spanning from macromolecule synthesis to the renewal of entire cellular organelles.

Disruption of these networks can lead to severe diseases such as metabolic disorders, underscoring the interconnected nature and feedback control mechanisms inherent in biological systems, including cellular quality control systems. This interconnectedness extends to the intricate communication between organelles, enabling coordinated functioning and adaptation to changing cellular conditions, particularly in response to stressors.

While the exact mechanisms governing these communications within cellular quality control systems remain …

Protein Oxidation In Aging And Alzheimer’S Disease Brain, Rukhsana Sultana, D. Allan Butterfield

Markey Cancer Center Faculty Publications

Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review, we summarize the role of protein oxidation in normal aging and Alzheimer’s disease (AD). The major emphasis of this review article is on the carbonylation and nitration of proteins in AD and mild cognitive impairment (MCI). The oxidatively modified proteins showed a strong correlation with the reported changes in brain structure, carbohydrate …

Predicting The Pathway Involvement Of Metabolites Based On Combined Metabolite And Pathway Features, Erik D. Huckvale, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

A major limitation of most metabolomics datasets is the sparsity of pathway annotations for detected metabolites. It is common for less than half of the identified metabolites in these datasets to have a known metabolic pathway involvement. Trying to address this limitation, machine learning models have been developed to predict the association of a metabolite with a “pathway category”, as defined by a metabolic knowledge base like KEGG. Past models were implemented as a single binary classifier specific to a single pathway category, requiring a set of binary classifiers for generating the predictions for multiple pathway categories. This past approach …

Identification Of Potent Pan-Ephrin Receptor Kinase Inhibitors Using Dna-Encoded Chemistry Technology, Chandrashekhar Madasu, Zian Liao, Sydney E Parks, Kiran L Sharma, Kurt M Bohren, Qiuji Ye, Feng Li, Murugesan Palaniappan, Zhi Tan, Fei Yuan, Chad J Creighton, Suni Tang, Ramya P Masand, Xiaoming Guan, Damian W Young, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

EPH receptors (EPHs) are highly sought-after drug targets owing to their essential roles in maintaining appropriate cellular functions in both physiological and disease conditions. However, limited potency and specificity pose significant obstacles to the development of small-molecule inhibitors for EPHs. Here, using high-throughput DNA-encoded chemical library screenings, we developed potent and selective inhibitors of the EPH receptor kinase family. Our results also emphasize the therapeutic potential of our EPH inhibitors in cancer and endometriosis, a global health concern that causes chronic pain and often leads to infertility in women. This study showcases the robust pipeline of using DNA-encoded chemistry technology …