Genetics and Genomics Commons^™

Med13 Degradation Defines A New Receptor-Mediated Autophagy Pathway Activated By Nutrient Deprivation, Sara E. Hanley

Graduate School of Biomedical Sciences Theses and Dissertations

Cells are exposed to an enormous amount of diverse extracellular cues but have a limited arsenal of weapons for protecting and maintaining homeostasis. To overcome these restrictions, nature has engineered proteins that have multiple functions. The pleiotropy of using one protein to carry out a variety of functions allows cells to rapidly execute tailored responses to a diverse set of signals. The Cdk8 kinase module (CKM) is a conserved detachable unit of the Mediator complex predominantly known for its role in transcriptional regulation. The CKM is composed of four proteins, the scaffolding proteins Med13 and Med12, as well as the …

A Kinome-Wide Crispr Screen Identifies Ck1Α As A Target To Overcome Enzalutamide Resistance Of Prostate Cancer, Jinghui Liu, Yue Zhao, Daheng He, Katelyn M. Jones, Shan Tang, Derek B. Allison, Yanquan Zhang, Jing Chen, Qiongsi Zhang, Xinyi Wang, Chaohao Li, Chi Wang, Lang Li, Xiaoqi Liu

Markey Cancer Center Faculty Publications

Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1a (CK1a) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1a enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1a phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of …

Identification Of A Nacc1-Regulated Gene Signature Implicated In The Features Of Triple-Negative Breast Cancer, Chrispus Ngule, Hami Hemati, Xingcong Ren, Oluwafunminiyi Obaleye, Amos O. Akinyemi, Felix Oyelami, Xiaofang Xiong, Jianxun Song, Xia Liu, Jin-Ming Yang

Markey Cancer Center Faculty Publications

Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such as tumor heterogeneity and therapy resistance, remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression. Using bioinformatics approaches, we found 55 up- and 9 downregulated genes in TNBC. Out of the 55 upregulated genes, a 5 gene-signature (CDK1, EZH2, CCNB1, CCNA2, and AURKA) involved in cell regeneration was positively correlated …

In Situ Microwave Fixation Provides An Instantaneous Snapshot Of The Brain Metabolome, Jelena A. Juras, Madison B. Webb, Lyndsay E. A. Young, Kia H. Markussen, Tara R. Hawkinson, Michael D. Buoncristiani, Kayli E. Bolton, Peyton T. Coburn, Meredith I. Williams, Lisa P. Y. Sun, William C. Sanders, Ronald C. Bruntz, Lindsey R. Conroy, Chi Wang, Matthew S. Gentry, Bret N. Smith, Ramon C. Sun

Markey Cancer Center Faculty Publications

Brain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. In particular, we demonstrate exhaustion of glycogen and glucose and an increase in lactate production during conventional rapid brain resection and preservation by liquid nitrogen. In contrast, we show that these post- mortem changes are not observed with simultaneous animal sacrifice and in situ fixation with focused, high- power microwave. We further employ microwave fixation to define brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple brain regions, evidenced by …

Targeting Lncrna Ddit4-As1 Sensitizes Triple Negative Breast Cancer To Chemotherapy Via Suppressing Of Autophagy, Ting Jiang, Jiaojiao Zhu, Shilong Jiang, Zonglin Chen, Ping Xu, Rong Gong, Changxin Zhong, Yueying Cheng, Xinyuan Sun, Wenjun Yi, Jinming Yang, Wenhu Zhou, Yan Cheng

Markey Cancer Center Faculty Publications

In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4-AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both …

Neuronal Sirt3 Deletion Predisposes To Female-Specific Alterations In Cellular Metabolism, Memory, And Network Excitability, Jennifer N Pearson-Smith, Ruth Fulton, Christopher Q Huynh, Anna G Figueroa, Gia B Huynh, Li-Ping Liang, Lindsey B Gano, Cole R Michel, Nichole Reisdorph, Richard Reisdorph, Kristofer S Fritz, Eric Verdin, Manisha Patel

Faculty, Staff and Students Publications

Mitochondrial dysfunction is an early event in the pathogenesis of neurologic disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases. Given the unique metabolic demands of neurons, the role of SIRT3 in the brain is only beginning to emerge. Using mass spectrometry-based acetylomics, high-resolution respirometry, video-EEG, and cognition testing, we report targeted deletion of SIRT3 from select neurons …

Anterior And Posterior Tongue Regions And Taste Papillae: Distinct Roles And Regulatory Mechanisms With An Emphasis On Hedgehog Signaling And Antagonism., Archana Kumari, Charlotte M. Mistretta

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Sensory receptors across the entire tongue are engaged during eating. However, the tongue has distinctive regions with taste (fungiform and circumvallate) and non-taste (filiform) organs that are composed of specialized epithelia, connective tissues, and innervation. The tissue regions and papillae are adapted in form and function for taste and somatosensation associated with eating. It follows that homeostasis and regeneration of distinctive papillae and taste buds with particular functional roles require tailored molecular pathways. Nonetheless, in the chemosensory field, generalizations are often made between mechanisms that regulate anterior tongue fungiform and posterior circumvallate taste papillae, without a clear distinction that highlights …

A Single-Cell Gene Expression Atlas Of Human Follicular Aspirates: Identification Of Leukocyte Subpopulations And Their Paracrine Factors, Yohan Choi, Hayce Jeon, Mats Brännström, James W. Akin, Thomas E. Curry, Misung Jo

UK CARES Faculty Publications

Leukocytes are in situ regulators critical for ovarian function. However, little is known about leukocyte subpopulations and their interaction with follicular cells in ovulatory follicles, especially in humans. Single-cell RNA sequencing (scRNA- seq) was performed using follicular aspirates obtained from four IVF patients and identified 13 cell groups: one granulosa cell group, one thecal cell group, 10 subsets of leukocytes, and one group of RBC/platelet. RNA velocity analyses on five granulosa cell populations predicted developmental dynamics denoting two projections of differentiation states. The cell type-specific transcriptomic profiling analyses revealed the presence of a diverse array of leukocyte-derived factors that can …

Latexin Regulates Sex Dimorphism In Hematopoiesis Via Gender-Specific Differential Expression Of Microrna 98-3p And Thrombospondin 1, Xiaojing Cui, Cuiping Zhang, Fang Wang, Xinghui Zhao, Shuxia Wang, Jinpeng Liu, Daheng He, Chi Wang, Feng-Chun Yang, Sheng Tong, Ying Liang

Markey Cancer Center Faculty Publications

Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate to all blood cell types. HSCs and their differentiated progeny show sex/gender differences. The fundamental mechanisms remain largely unexplored. We previously reported that latexin (Lxn) deletion increased HSC survival and repopulation capacity in female mice. Here, we find no differences in HSC function and hematopoiesis in Lxn knockout (Lxn-/- male mice under physiologic and myelosuppressive conditions. We further find that Thbs1, a downstream target gene of Lxn in female HSCs, is repressed in male HSCs. Male-specific high expression of micro- RNA 98-3p (miR98-3p) contributes to Thbs1 suppression in male …

Ferric Chloride-Induced Arterial Thrombosis And Sample Collection For 3d Electron Microscopy Analysis, Smita Joshi, Alexis N. Smith, Kanakanagavalli Shravani Prakhya, Hammodah Rawhi Hammodah Alfar, Joshua Lykins, Ming Zhang, Irina D. Pokrovskaya, Maria A. Aronova, Richard D. Leapman, Brian Storrie, Sidney W. Whiteheart

Saha Cardiovascular Research Center Faculty Publications

Cardiovascular diseases are a leading cause of mortality and morbidity worldwide. Aberrant thrombosis is a common feature of systemic conditions like diabetes and obesity, and chronic inflammatory diseases like atherosclerosis, cancer, and autoimmune diseases. Upon vascular injury, usually the coagulation system, platelets, and endothelium act in an orchestrated manner to prevent bleeding by forming a clot at the site of the injury. Abnormalities in this process lead to either excessive bleeding or uncontrolled thrombosis/insufficient antithrombotic activity, which translates into vessel occlusion and its sequelae. The FeCl3-induced carotid injury model is a valuable tool in probing how thrombosis initiates and progresses …

An Improved Germline Genome Assembly For The Sea Lamprey Petromyzon Marinus Illuminates The Evolution Of Germline-Specific Chromosomes, Nataliya Timoshevskaya, Kaan İ. Eşkut, Vladimir A. Timoshevskiy, Sofia M.C. Robb, Carson Holt, Jon E. Hess, Hugo J. Parker, Cindy F. Baker, Allison K. Miller, Cody Saraceno, Mark Yandell, Robb Krumlauf, Shawn R. Narum, Ralph T. Lampman, Neil J. Gemmell, Jacquelyn Mountcastle, Bettina Haase, Jennifer R. Balacco, Giulio Formenti, Sarah Pelan, Ying Sims, Kerstin Howe, Olivier Fedrigo, Erich D. Jarvis, Jeramiah James Smith

Markey Cancer Center Faculty Publications

Programmed DNA loss is a gene silencing mechanism that is employed by several vertebrate and nonvertebrate lineages, including all living jawless vertebrates and songbirds. Reconstructing the evolution of somatically eliminated (germline-specific) sequences in these species has proven challenging due to a high content of repeats and gene duplications in eliminated sequences and a corresponding lack of highly accurate and contiguous assemblies for these regions. Here, we present an improved assembly of the sea lamprey (Petromyzon marinus) genome that was generated using recently standardized methods that increase the contiguity and accuracy of vertebrate genome assemblies. This assembly resolves highly contiguous, somatically …

Chalcone Derivative Cx258 Suppresses Colorectal Cancer Via Inhibiting The Top2a/Wnt/Β-Catenin Signaling, Xi Chen, Xiaocheng Lv, Lijie Gao, Jiawei Liu, Wei Wang, Lichao Guo, Mykhaylo S. Frasinyuk, Wen Zhang, David S. Watt, Chunming Liu, Xifu Liu

Markey Cancer Center Faculty Publications

The deregulation in the Wnt/β-catenin signaling pathway is associated with many human cancers, particularly colorectal cancer (CRC) and, therefore, represents a promising target for drug development. We have screened over 300 semisynthetic and natural compounds using a Wnt reporter assay and identified a family of novel chalcone derivatives (CXs) that inhibited Wnt signaling and CRC cell proliferation. Among them, we selected CX258 for further in vitro and in vivo study to investigate the molecular mechanisms. We found that CX258 significantly inhibited β-catenin expression and nuclear translocation, inducing cell cycle arrest at the G2/M phase in CRC cells. Additionally, CX258 reduced …

Dpc29 Promotes Post-Initiation Mitochondrial Translation In Saccharomyces Cerevisiae, Kyle A. Hubble, Michael F. Henry

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Mitochondrial ribosomes synthesize essential components of the oxidative phosphorylation (OXPHOS) system in a tightly regulated process. In the yeast Saccharomyces cerevisiae, mitochondrial mRNAs require specific translational activators, which orchestrate protein synthesis by recognition of their target gene's 5'-untranslated region (UTR). Most of these yeast genes lack orthologues in mammals, and only one such gene-specific translational activator has been proposed in humans-TACO1. The mechanism by which TACO1 acts is unclear because mammalian mitochondrial mRNAs do not have significant 5'-UTRs, and therefore must promote translation by alternative mechanisms. In this study, we examined the role of the TACO1 orthologue in yeast. We …

Effects Of Post-Translational Histone Modifications On Transcription Rate, Aaron Bohn

Annual Research Symposium

No abstract provided.

Deepbend: An Interpretable Model Of Dna Bendability, Samin Rahman Khan, Sadman Sakib, M Sohel Rahman, Md Abul Hassan Samee

Faculty, Staff and Students Publications

The bendability of genomic DNA impacts chromatin packaging and protein-DNA binding. However, we do not have a comprehensive understanding of the motifs influencing DNA bendability. Recent high-throughput technologies such as Loop-Seq offer an opportunity to address this gap but the lack of accurate and interpretable machine learning models still remains. Here we introduce DeepBend, a convolutional neural network model with convolutions designed to directly capture the motifs underlying DNA bendability and their periodic occurrences or relative arrangements that modulate bendability. DeepBend consistently performs on par with alternative models while giving an extra edge through mechanistic interpretations. Besides confirming the known …

Discovery Of Highly Potent And Bmpr2-Selective Kinase Inhibitors Using Dna-Encoded Chemical Library Screening, Ram K Modukuri, Diana Monsivais, Feng Li, Murugesan Palaniappan, Kurt M Bohren, Zhi Tan, Angela F Ku, Yong Wang, Chandrashekhar Madasu, Jian-Yuan Li, Suni Tang, Gabriella Miklossy, Stephen S Palmer, Damian W Young, Martin M Matzuk

Faculty, Staff and Students Publications

The discovery of monokinase-selective inhibitors for patients is challenging because the 500+ kinases encoded by the human genome share highly conserved catalytic domains. Until now, no selective inhibitors unique for a single transforming growth factor β (TGFβ) family transmembrane receptor kinase, including bone morphogenetic protein receptor type 2 (BMPR2), have been reported. This dearth of receptor-specific kinase inhibitors hinders therapeutic options for skeletal defects and cancer as a result of an overactivated BMP signaling pathway. By screening 4.17 billion “unbiased” and “kinase-biased” DNA-encoded chemical library molecules, we identified hits CDD-1115 and CDD-1431, respectively, that were low-nanomolar selective kinase inhibitors of …

Gasdermin D Deficiency In Vascular Smooth Muscle Cells Ameliorates Abdominal Aortic Aneurysm Through Reducing Putrescine Synthesis, Jianing Gao, Yanghui Chen, Huiqing Wang, Xin Li, Ke Li, Yangkai Xu, Xianwei Xie, Yansong Guo, Nana Yang, Xinhua Zhang, Dong Ma, Hong S. Lu, Ying H. Shen, Yong Liu, Jifeng Zhang, Y. Eugene Chen, Alan Daugherty, Dao Wen Wang, Lemin Zheng

Saha Cardiovascular Research Center Faculty Publications

Abdominal aortic aneurysm (AAA) is a common vascular disease associated with significant phenotypic alterations in vascular smooth muscle cells (VSMCs). Gasdermin D (GSDMD) is a pore-forming effector of pyroptosis. In this study, the role of VSMC-specific GSDMD in the phenotypic alteration of VSMCs and AAA formation is determined. Single-cell transcriptome analyses reveal Gsdmd upregulation in aortic VSMCs in angiotensin (Ang) II-induced AAA. VSMC-specific Gsdmd deletion ameliorates Ang II-induced AAA in apolipoprotein E (ApoE)−/− mice. Using untargeted metabolomic analysis, it is found that putrescine is significantly reduced in the plasma and aortic tissues of VSMC-specific GSDMD deficient mice. High putrescine levels …

Genetic Determinants Involved In Acquisition Of Iron In The Opportunistic Pathogen Mycobacterium Abscessus, Manal F. Farhat

Dissertations, Theses, and Capstone Projects

The opportunistic pathogen Mycobacterium abscessus subsp. abscessus (Mab) has become an emerging public health threat due to the increasing number of Mab-associated chronic pulmonary disease cases. Infection cure rates are only 50% due to the complex resistance of Mab to most antimicrobial drugs and chemotherapy.

Deeper knowledge of Mab biology is needed to illuminate potential candidates for development of improved therapeutics against Mab infections. The ESX-3 type VII protein secretion system of Mab plays an important role in host inflammatory and pathological responses during infection.

In this study, we demonstrate a functional link between the ESX-3 secretion …

Clic And Membrane Wound Repair Pathways Enable Pandemic Norovirus Entry And Infection, B. Vijayalakshmi Ayyar, Khalil Ettayebi, Wilhelm Salmen, Umesh C. Karandikar, Frederick H. Neill, Victoria R. Tenge, Sue E. Crawford, Erhard Bieberich, B. V. Venkataram Prasad, Robert L. Atmar, Mary K. Estes

Markey Cancer Center Faculty Publications

Globally, most cases of gastroenteritis are caused by pandemic GII.4 human norovirus (HuNoV) strains with no approved therapies or vaccines available. The cellular pathways that these strains exploit for cell entry and internalization are unknown. Here, using nontransformed human jejunal enteroids (HIEs) that recapitulate the physiology of the gastrointestinal tract, we show that infectious GII.4 virions and virus-like particles are endocytosed using a unique combination of endosomal acidification-dependent clathrin-independent carriers (CLIC), acid sphingomyelinase (ASM)-mediated lysosomal exocytosis, and membrane wound repair pathways. We found that besides the known interaction of the viral capsid Protruding (P) domain with host glycans, the Shell …

Molecular Regulation Of The Salicylic Acid Hormone Pathway In Plants Under Changing Environmental Conditions, Christina A. M. Rossi, Eric J. R. Marchetta, Jong Hum Kim, Christian Castroverde

Biology Faculty Publications

Salicylic acid (SA) is a central plant hormone mediating immunity, growth, and development. Recently, studies have highlighted the sensitivity of the SA pathway to changing climatic factors and the plant microbiome. Here we summarize organizing principles and themes in the regulation of SA biosynthesis, signaling, and metabolism by changing abiotic/biotic environments, focusing on molecular nodes governing SA pathway vulnerability or resilience. We especially highlight advances in the thermosensitive mechanisms underpinning SA-mediated immunity, including differential regulation of key transcription factors (e.g., CAMTAs, CBP60g, SARD1, bHLH059), selective protein–protein interactions of the SA receptor NPR1, and dynamic phase separation of the recently identified …

Molecular And Systemic Epigenetic Inheritance: Integrating Development, Genetics, And Evolution, Robert Lickliter, David S. Moore

Pitzer Faculty Publications and Research

Currently, a central problem for theoretical biology is the integration of development with genetics and evolutionary theory. Through the late 20^th century, biologists held that animals resemble their ancestors strictly because of the transgenerational transmission of DNA. This view effectively wrote development out of evolutionary biology. However, many molecular and developmental biologists now understand that phenotypes—anatomical, physiological, and behavioral traits—are not determined by genes (i.e., DNA segments) alone; instead, they emerge epigenetically from developmental processes involving co-acting genetic factors, environmental factors, molecular epigenetic factors, and other non-genetic factors within organisms’ bodies. This insight forces a rethinking of biological inheritance. …

Molecular Investigation Of Minor Genomic Populations And Biological Exposures In Human Health, Brandon Ned Johnson

Dissertations and Theses

The study of genetics has contributed to countless discoveries related to human health and disease. However, the complexities of human biology reside not only in the genome but also in the contributions from environmental exposures, as measured via the classical twin design. To understand the influence of biological exposures, I implemented study designs to explore both the health associations and propagation of foreign genetic material. Microchimerism has been studied for association with several clinical conditions, and I further investigated if male microchimerism could elucidate the etiology of Mayer-Rokitansky-Küster-Hauser syndrome. Prevalence of male microchimerism in women with no history of pregnancy …

Functional Residues Of Cjpata, Robert Lamont

Theses and Dissertations (Comprehensive)

Antibiotic resistance in pathogenic bacteria continues to challenge clinicians and threaten the lives of infected individuals. For this reason, new classes of antibiotics or new targets for antibiotic therapy are needed to circumvent this global health crisis. In Gram-negative bacteria, the enzymes peptidoglycan O-acetyltransferase A and B (PatA and PatB), are responsible for adding acetyl groups to the C-6 hydroxyl group of N-acetyl muramic acid (MurNAc) in peptidoglycan (PG). These acetyl groups are responsible for inhibiting the activity of lysozyme from host organisms that hydrolyze the β1-4 glycosidic linkage between MurNAc and N-acetylglucosamine (GlcNAc). The acetyl groups …

Identification Of Novel Biosynthetic Gene Clusters Encoding For Polyketide/Nrps-Producing Chemotherapeutic Compounds From Marine-Derived Streptomyces Hygroscopicus From A Marine Sanctuary, Hannah Ruth Flaherty

Honors Theses and Capstones

Nearly one out of six deaths in 2020, around ten million people, were caused by cancer, making it a leading cause of death worldwide (WHO, 2022). This major public health issue, in addition to the rise of multidrug-resistant (MDR) pathogens, provides a high demand for the discovery of new pharmaceutical drugs to be used clinically to treat these conditions. The Streptomyces genus accounts to produce 39% of all microbial metabolites currently approved for human health, indicating its potential as an important species to study for antimicrobial and anticancer agents. The long linear genome of Streptomyces contains specialized sequences known as …

Dna Methylation And The Response To Infection In Introduced House Sparrows, Melanie Gibson

College of Graduate Studies: Theses & Dissertations

Epigenetics is the study of molecular modification of a genome without changing its base pairs. The most studied type of epigenetic mechanism is DNA methylation, which is capable of turning a gene “on” or “off.” Epigenetic potential is the capacity to which an individual can have methylation on its genome. The more CpGs available, the greater the epigenetic potential. In invasive species, genetic variation has been observed to be paradoxical: not much of it exists on a genomic level, but epigenetically, phenotypic variation can occur. The focus on shift in gene expression in this study is on Toll-Like Receptor 4 …

Generation Of Chimeric Rhinoviruses Presenting Sars-Cov-2 Broadly Neutralizing Epitopes And Their Antigenicity Characterization, Danish Ansari

Biotechnology Theses

The global COVID pandemic is not yet fully under control as there were over 21 million new cases of SARS-CoV-2 infections and over 50,000 deaths globally as of January of 2022. A heavily mutated variant of concern, Omicron is responsible for most of these cases which demands an urgency for a new vaccine. NIH reports over 180 vaccine candidates that use various strategies currently in development. However, a recurring concern with these vaccines is that the continuous viral mutations decrease the efficacy of vaccines. Therefore, we proposed to construct a human rhinovirus (HRV) based chimeric virus containing highly conserved, broadly …

A Monoadduct Generating Ru(Ii) Complex Induces Ribosome Biogenesis Stress And Is A Molecular Mimic Of Phenanthriplatin, Richard Joseph Mitchell, Sarah M. Kriger, Alexander D. Fenton, Dmytro Havrylyuk, Ankit Pandeya, Yang Sun, Tami Smith, Jason E. Derouchey, David K. Heidary, Edith C. Glazer

Markey Cancer Center Faculty Publications

Ruthenium complexes are often investigated as potential replacements for platinum-based chemotherapeutics in hopes of identifying systems with improved tolerability in vivo and reduced susceptibility to cellular resistance mechanisms. Inspired by phenanthriplatin, a non-traditional platinum agent that contains only one labile ligand, monofunctional ruthenium polypyridyl agents have been developed, but until now, few demonstrated promising anticancer activity. Here we introduce a potent new scaffold, based on [Ru(tpy)(dip)Cl]Cl (tpy = 2,20:60,200-terpyridine and dip = 4,7-diphenyl-1,10-phenanthroline) in pursuit of effective Ru(II )-based monofunctional agents. Notably, the extension of the terpyridine at the 40 position with an aromatic ring resulted in a molecule that …

Dysregulated Polycomb Repressive Complex 2 Contributes To Chronic Obstructive Pulmonary Disease By Rewiring Stem Cell Fate, Aria Byrd, Xufeng Qu, Alexsandr Lukyanchuk, Jinpeng Liu, Fan Chen, Kassandra J. Naughton, Tanner Ducote, Xiulong Song, Hannah Bowman, Yanming Zhao, Abigail R Edgin, Chi Wang, Jinze Liu, Christine Fillmore Brainson

Markey Cancer Center Faculty Publications

Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self- renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of in vivo models revealed that heterozygosity of Ezh2 …

Polycomb Deficiency Drives A Foxp2-High Aggressive State Targetable By Epigenetic Inhibitors, Fan Chen, Aria Byrd, Jinpeng Liu, Robert M. Flight, Tanner Ducote, Kassandra J. Naughton, Xiulong Song, Abigail R Edgin, Alexsandr Lukyanchuk, Danielle T. Dixon, Christian M. Gosser, Dave-Preston Esoe, Rani Jayswal, Stuart H. Orkin, Hunter N. B. Moseley, Chi Wang, Christine Fillmore Brainson

Markey Cancer Center Faculty Publications

Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 loss/inhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 …

Use Of Foreign Edna Tracers To Resolve Site- And Time-Specific Edna Distributions In Natural Streams, Braden A. Herman

Cal Poly Humboldt theses and projects

Substantial uncertainty in how to interpret eDNA observations motivates a need for a technique to effectively and efficiently measure of system- and time-specific eDNA distributions. Using a technique to robustly calibrate eDNA dynamics in a given system would improve established eDNA methods such as presence and absence and has the potential to refine estimates of organism abundance using eDNA concentration that are less well understood. Particles of eDNA are present in a wide variety of size and type resulting in varying transport dynamics, persistence, decay, among others. This variation likely makes eDNA transport more complex than that of conservative tracers …