Digital Commons Network^™

Analysis Of The Ciliary Genes Gas8 And Mks6 Reveal Conserved Roles In Cilia Motility And Transition Zone Function, Wesley Robert Lewis

All ETDs from UAB

Cilia are microtubule based cellular appendages that are present throughout the hierarchy of the animal kingdom. These appendages are utilized for a wide array of functions such as motility in single celled organisms to coordinating complex cellular signaling pathways in more complex organisms. Though these appendages are well conserved, the exact function of cilia in many cell types remains unknown. Recently, cilia are tied to a myriad of developmental diseases and diseases of adult homeostasis collectively referred to as ciliopathies. Dysfunction in cilia results in a wide array of phenotypes ranging from retinal degeneration to polydactyly, cystic kidney disease, and …

The Mauc Gene Encodes A Versatile Signal Sequence And Redox Protein That Can Be Utilized In Native And Non-Native Protein Expression And Electron Trnasfer Systems, Brian Dow

Electronic Theses and Dissertations

The redox-active type 1 copper site of amicyanin is composed of a single copper ion that is coordinated by two histidines, a methionine, and a cysteine residue. This redox site has a potential of +265 mV at pH7.5. Over ten angstroms away from the copper site resides a tryptophan residue whose fluorescence is quenched by the copper. The effects of the tryptophan on the electron transfer (ET) properties were investigated by site-directed mutagenesis. Lessons learned about the hydrogen bonding network of amicyanin from the aforementioned study were attempted to be used as a model to increase the stability of another …

Role Of Klf8-Cxcr4 Signaling In Breast Cancer Metastasis, Debarati Mukherjee

Electronic Theses and Dissertations

Krüppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. In this study we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. …

Stress Granules And Rna Processing Bodies Are Novel Autoantibody Targets In Systemic Sclerosis, Michael E. Johnson, Andrew V. Grassetti, Jaclyn N. Taroni, Shawn M. Lyons, Devin Schweppe, Jessica K. Gordon, Robert F. Speira, Robert Lafyatis, Paul J. Anderson, Scott A. Gerber, Michael L. Whitfield

Dartmouth Scholarship

Autoantibody profiles represent important patient stratification markers in systemic sclerosis (SSc). Here, we performed serum-immunoprecipitations with patient antibodies followed by mass spectrometry (LC-MS/MS) to obtain an unbiased view of all possible autoantibody targets and their associated molecular complexes recognized by SSc.

Intracellular Ros Mediates Gas Plasma-Facilitated Cellular Transfection In 2d And 3d Cultures, Dehui Xu, Biqing Wang, Yujing Xu, Zeyu Chen, Qinjie Cui, Yanjie Yang, Hailan Chen, Michael G. Kong

Bioelectrics Publications

This study reports the potential of cold atmospheric plasma (CAP) as a versatile tool for delivering oligonucleotides into mammalian cells. Compared to lipofection and electroporation methods, plasma transfection showed a better uptake efficiency and less cell death in the transfection of oligonucleotides. We demonstrated that the level of extracellular aqueous reactive oxygen species (ROS) produced by gas plasma is correlated with the uptake efficiency and that this is achieved through an increase of intracellular ROS levels and the resulting increase in cell membrane permeability. This finding was supported by the use of ROS scavengers, which reduced CAP-based uptake efficiency. In …

An Analysis Of Plasticity In The Rat Respiratory System Following Cervical Spinal Cord Injury And The Application Of Nanotechnology To Induce Or Enhance Recovery Of Diaphragm Function, Janelle Lorien Walker

Wayne State University Dissertations

Second cervical segment spinal cord hemisection (C2Hx) results in ipsilateral hemidiaphragm paralysis. However, the intact latent crossed phrenic pathway can restore function spontaneously over time or immediately following drug administration.

WGA bound fluorochromes were administered to identify nuclei associated with diaphragm function in both the acute and chronic C2Hx models. WGA is unique in that it undergoes receptor mediated endocytosis and is transsynaptically transported across select physiologically active synapses. Comparison of labeling in the acutely injured to the chronically injured rat provided an anatomical map of spinal and supraspinal injury induced synaptic plasticity. The plasticity occurs over time in the …

A Few Notes On Nabokov's Childhood Entomology, Victor Fet

Biological Sciences Faculty Research

Nabokov's lepidoptery long posed a question: Was he an amateur or a professional entomologist? Today, it has been amply demonstrated that he was a professional. Kurt Johnson says, "For Nabokov, as with many, fascination with the big picture books of butterflies as a young child grew to concerted collecting as a youngster. As with many scientists, these impressions of youth become a driving life force."³ Nabokov started collecting butterflies in 1906, at age seven, and never ceased; he published his first book of poems ten years later, at age seventeen; his first research paper on butterflies, at age twenty; …

N-Methyl 4-Methyl Amphetamine N-Alkyl Chain Extension Differentially Affects Ion Flux At The Human Dopamine And Norepinephrine Transporters, Alan C. Harris Jr.

Theses and Dissertations

Amphetamine (AMPH) and its derivatives embody a remarkable breadth of pharmacology. These molecules exert their effects, both therapeutic and pathological, at the human monoamine transporters, which tune synaptic dynamics by evacuating monoamine neuromodulators from the synapse subsequent to neuronal impulses. These transporters are electrogenic, and the transporter-mediated current can be correlated to a surrogate measure of the change in membrane voltage: Ca⁺⁺ currents from co-transfected L-type Ca⁺⁺ channels. The present work makes use of this assay, with which it is possible to derive pharmacodynamic metrics from both substrates and inhibitors. This work presents data on a heretofore-unstudied class …

Pharmacological Implications Of Adenosine 2a Receptor- Dopamine Type 2 Receptor Heteromerization, Candice N. Hatcher-Solis

Theses and Dissertations

G protein-coupled receptors (GPCRs) are heptahelical, transmembrane proteins that mediate a plethora of physiological functions by binding ligands and releasing G proteins that interact with downstream effectors. GPCRs signal as monomers, complexes of the same receptor subtype (homomers), or complexes of different receptor subtypes (heteromers). Recently, heteromeric GPCR complexes have become attractive targets for drug development since they exhibit distinct signaling and cell-specific localization from their homomeric counterparts. Yet, the effect of heteromerization on the pharmacology of many GPCR homomers remains unknown. Therefore, we have undertaken the task to examine the effect of heteromerization on G_s signaling through the …

Modeling Early Stage Bone Regeneration With Biomimetic Electrospun Fibrinogen Nanofibers And Adipose-Derived Mesenchymal Stem Cells, Michael P. Francis, Yas M. Moghaddam-White, Patrick C. Sachs, Matthew J. Beckman, Stephen M. Chen, Gary L. Bowlin, Lynne W. Elmore, Shawn E. Holt

School of Medical Diagnostics & Translational Sciences Publications

The key events of the earliest stages of bone regeneration have been described in vivo although not yet modeled in an in vitro environment, where mechanistic cell-matrix-growth factor interactions can be more effectively studied. Here, we explore an early-stage bone regeneration model where the ability of electrospun fibrinogen (Fg) nanofibers to regulate osteoblastogenesis between distinct mesenchymal stem cells populations is assessed. Electrospun scaffolds of Fg, polydioxanone (PDO), and a Fg:PDO blend were seeded with adipose-derived mesenchymal stem cells (ASCs) and grown for 7-21 days in osteogenic differentiation media or control growth media. Scaffolds were analyzed weekly for histologic and molecular …

N-Acetylcysteine Decreases Binge Eating In A Rodent Model, M. M. Hurley, Jon M. Resch, Brian Maunze, M. M. Frenkel, David A. Baker, Sujean Choi

Biomedical Sciences Faculty Research and Publications

Binge-eating behavior involves rapid consumption of highly palatable foods leading to increased weight gain. Feeding in binge disorders resembles other compulsive behaviors, many of which are responsive to N-acetylcysteine (NAC), which is a cysteine prodrug often used to promote non-vesicular glutamate release by a cystine–glutamate antiporter. To examine the potential for NAC to alter a form of compulsive eating, we examined the impact of NAC on binge eating in a rodent model. Specifically, we monitored consumption of standard chow and a high-fat, high carbohydrate western diet (WD) in a rodent limited-access binge paradigm. Before each session, rats received either …

Diagnostics Of Primary Immunodeficiencies Through Next-Generation Sequencing., Vera Gallo, Laura Dotta, Giuliana Giardino, Emilia Cirillo, Vassilios Lougaris, Roberta D'Assante, Alberto Prandini, Rita Consolini, Emily G. Farrow, Isabelle Thiffault, Carol J. Saunders, Antonio Leonardi, Alessandro Plebani, Raffaele Badolato, Claudio Pignata

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Recently, a growing number of novel genetic defects underlying primary immunodeficiencies (PIDs) have been identified, increasing the number of PID up to more than 250 well-defined forms. Next-generation sequencing (NGS) technologies and proper filtering strategies greatly contributed to this rapid evolution, providing the possibility to rapidly and simultaneously analyze large numbers of genes or the whole exome.

OBJECTIVE: To evaluate the role of targeted NGS and whole exome sequencing (WES) in the diagnosis of a case series, characterized by complex or atypical clinical features suggesting a PID, difficult to diagnose using the current diagnostic procedures.

METHODS: We retrospectively analyzed …

Structural Basis For Lipid-And Calmodulin-Mediated Akt Activation In Breast Cancer Cells, Constance Agamasu

All ETDs from UAB

Growth and survival signals initiated at the cell surface by receptor-ligand interactions often involve a downstream activation of Akt, a serine/threonine kinase critical in regulating cell survival, apoptosis and oncogenesis. Hyper-activation of Akt is a common tumorigenic event, thereby making the Akt activation pathway a prime target for cancer therapy. The translocation of Akt to the plasma membrane (PM) for phosphorylation is a critical step in the Akt activation pathway. It has been established that membrane binding of Akt is mediated by direct interactions between its pleckstrin homology domain (PHD) and membrane lipid phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3]. There is now emerging …

Mechanisms Of Innate And Adaptive Immune Function In Parkinson Disease, Heather Elizabeth Allen

All ETDs from UAB

Parkinson disease (PD) is a common neurodegenerative movement disorder characterized pathologically by loss of dopaminergic neurons in the substantia nigra and aggregation of alpha-synuclein (α-syn) into large inclusions. The association of mutations and gene multiplications in SNCA, the gene encoding α-syn, with rare familial forms of PD led to the discovery that α-syn plays a key role in the pathogenesis of PD. The mechanism by which α-syn mediates its toxicity remains uncertain. A leading hypothesis states that the toxic effects of α-syn are mediated by activation of both the innate and adaptive immune systems within the central nervous system. Supporting …

Copper Chaperone In Streptococcus Mutans Biofilm Formation And Dispersion Of Biofilms By Small Molecules, Sandra Stephanie Garcia

All ETDs from UAB

program pilot study randomly assigned 100 women, aged 19 to 25 to two groups. One

Neurobiological Consequences Of Perinatal Ssri Exposure, Matthew Edward Glover

All ETDs from UAB

Selective serotonin reuptake inhibitors (SSRIs) have been a mainstay pharmacological treatment for women experiencing depression during pregnancy and postpartum for nearly three decades. Recently, though, growing evidence indicates that early-life SSRI exposure triggers long-lasting behavioral abnormalities. Clinically, children exposed to SSRIs in early life exhibit increased internalizing behavior, reduced social behavior, and increased risk for depression in adolescence. Similarly, in rodents, perinatal SSRI exposure leads to increased traits of anxiety- and depression-like behavior. Interestingly, certain individuals are more susceptible to early-life SSRI exposure than others, suggesting that perinatal SSRI exposure poses greater risks for negative outcome within certain populations; however, …

Exploring Bacteriophage P22 As A Selective Molecular Scaffold And Molecular Sensor, Gregory Joseph Bedwell

All ETDs from UAB

The virus capsids of many dsDNA bacteriophage are finely tuned macromolecular machines. Their functionality begins at assembly, when their capsids are built under the guidance of a class of proteins referred to as scaffolding proteins. The scaffolding protein of bacteriophage P22 is a flexible, highly elongated protein that binds to the interior surface of the P22 procapsid via its C-terminal domain. The finding that N-terminus is dispensable for procapsid binding prompted the development of chimeric scaffolding protein molecules, wherein N-terminal residues of scaffold are replaced with a variety of different peptide sequences or functional proteins that are then encapsidated within …

Structure-Function Relationships In The Sec7 Guanine Nucleotide Exchange Factor Gbf1, Jay Manoj Bhatt

All ETDs from UAB

All eukaryotic cells contain a secretory pathway composed of membrane-bound compartments connected by vesicles that transport cargo from the endoplasmic reticulum (ER) through the Golgi apparatus to various destination within and outside the cell. The Golgi Brefeldin A-resistant Factor 1 (GBF1) is required for protein traffic between ER and Golgi and within the Golgi. GBF1 belongs to a family of Guanine nucleotide Exchange Factors (GEFs) that stimulate the nucleotide exchange of GDP for GTP on small GTPases called ADP-ribosylation factors (ARFs). Once GTP-bound, ARFs become active and initiate a cascade of events that lead to vesicle formation. Thus, GBF1 is …

The Function Of Prmt1 In Normal And Abnormal Megakaryopoiesis, Hairui Su

All ETDs from UAB

Protein arginine methylation is a common type of post-translational modifications. Protein arginine methyltransferase 1 (PRMT1) is the predominant PRMT that is involved in diverse physiological and pathological processes in mammalian cells. Dysregulation of PRMT1 is often positively correlated with cancer development, yet many aspects of PRMT1’s role in cancer, especially in acute megakaryoblastic leukemia (AMKL) remain unclear. We identified two PRMT1-methylated substrates and how they impact normal and abnormal megakaryopoiesis. In this dissertation, we demonstrate that dual-specificity protein phosphatase 4 (DUSP4) and RNA binding motif protein 15 (RBM15), two crucial factors for megakaryocytic (MK) differentiation, are methylated by PRMT1 and …

The Roles Of Il-21 And Il-10 In Cellular And Humoral Immune Responses, Yuan Tian

All ETDs from UAB

values, it may be more appropriate to use CH

Regulation Of Breast Cancer Metastasis By Sin3 Chromatin Remodeling Complexes, Monica Jeanene Lewis

All ETDs from UAB

Metastasis continues to be the most difficult clinical challenge for breast cancer. Survival rates for patients with metastatic breast cancer have not significantly changed in the past 20 years. Therefore, we need a better understanding of the molecular mechanisms that regulate breast cancer metastasis to develop effective therapies. SIN3 chromatin remodeling complexes have been implicated in breast cancer progression. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions during development. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. To better understand how …

Development Of A Split Luciferase Complementation Assay To Investigate Growth Hormone Receptor/ Prolactin Receptor Homo-/ Hetero-Association, Ying Liu

All ETDs from UAB

Growth hormone receptor (GHR) and prolactin receptor (PRLR) are transmembrane glycoproteins cytokine receptors that are structurally homologous. Each can pre-homodimerize and ligand binding of each activates JAK2-STAT signaling pathways by inducing conformational change within the receptor homodimer. Human GHR can be activated by growth hormone (GH) while human PRLR can be activated by both GH and prolactin (PRL). We devised a split luciferase complementation assay, in which one receptor is fused to the N-terminal fragment of luciferase and the other receptor is fused to the C-terminal fragment of luciferase. When the two receptors approximate, luciferase activity (complementation) results. Using this …

Cell-Specific Pgc-1Α-Dependent Transcription: Implications For Cognitive And Motor Dysfunction, Laura Mcmeekin

All ETDs from UAB

health beliefs in young women. The Prevention of Osteoporosis in Women (POW)

Early-Life Programming Of Emotional Behaviors And Cardiovascular Function, Samir Rana

All ETDs from UAB

Extensive evidence implicates bi-directional relationship between mood disorders and cardiovascular disorders. Early-life experience can have strong effects both on emotional development and cardiovascular function throughout life. Studies in humans are limited to correlational analyses, which are necessarily limited in terms of revealing mechanistic underpinnings of these associations. Thus, various pre-clinical models are utilized to investigate the effects of early-life experience in various domains, such as behavior and cardiovascular function, which are likely mediated by epigenetic mechanisms. Previous studies have used maternal separation and neonatal handling in developing rodents as a way to model differences in early-life experience. The effect of …

Reorganization Of The Golgi Apparatus During Human Cytomegalovirus Infection, George Michael Rebmann

All ETDs from UAB

Human cytomegalovirus (HCMV) is the largest and most structurally complex of all the herpesviruses. HCMV is an important human pathogen that results in significant morbidity and disease in immunocompromised individuals. The assembly of herpesviruses is complex and involves a nuclear and cytoplasmic phase. The nuclear events of capsid assembly and genome incorporation as well as nuclear egress are believed to be similar in all herpesviruses and as such, are more clearly defined then the cytoplasmic phase; including the process of tegument and envelope acquisition. Human Cytomegalovirus induces the reorganization of the cellular secretory pathway including the Golgi apparatus and membranes …

The Impact Of Rrna And Trna Synthesis On Chromatin Structure And Cell Fate, Jessica Makofske Woolnough

All ETDs from UAB

The Central Dogma of molecular biology describes the process by which genetic material is faithfully converted into functional molecules across all domains of life. Originally, RNA was solely understood as an intermediate in this process. However, mounting evidence over the past 50 years has made clear that RNA have diverse functional roles as a class of molecule termed non-coding RNA. Two of the first described non-coding RNA have essential roles within the Central Dogma, itself: ribosomal RNA (rRNA) and transfer RNA (tRNA). These two non-coding RNA are highly abundant, collectively accounting for up to 90% of the total transcript in …

Leukemia Stem Cell Markers And Inv(16) In Acute Myeloid Leukemia, Jason Legrand

All ETDs from UAB

Although greater than 85% of inv(16) acute myeloid leukemia patients are able to achieve first complete remission after anthracycline- and cytarabine-based therapy, only about 60% of patients survive the disease long-term due to relapsed disease or treatment-related mortality. Multiple studies have shown that acute myeloid leukemia is composed of heterogeneous populations of leukemic clones that can exhibit a wide degree of genetic, epigenetic, and functional diversity, accounting for different outcomes in response to therapy. Genomic analysis of leukemic clones in paired diagnostic and relapse samples of acute myeloid leukemia has shown that all relapses stem from surviving leukemic or ancestral …

The Effect Of Proinflammatory Cytokines On Thioredoxin-Interacting Protein In Pancreatic Beta-Cells, Kyunghee Hong

All ETDs from UAB

Pro-inflammatory cytokines, such as Interleukin (IL)-1β, Tumor necrosis factors (TNF) α, and Interferon (IFN)γ, have been implicated as critical mediators of β-cell destruction in diabetes. In addition, although a combination of these three cytokines has been used to mimic the inflammatory conditions of type 1 diabetes in vitro, the mechanisms underlying the effect are not fully understood. Previously, we discovered Thioredoxin-interacting protein (TXNIP) as a key regulator of glucotoxicity-induced β-cell apoptosis and β-cell dysfunction, while deletion of TXNIP prevented type 1 (T1D) and type 2 diabetes (T2D). However, the effects of proinflammatory cytokines on the regulation of TXNIP have not …

The Eff-1a Cytoplasmic Domain Influences Hypodermal Cell Fusions In C. Elegans But Is Not Dependent On 14-3-3 Proteins., Jessica H Shinn-Thomas, Jacob J Del Campo, Jianjun Wang, William A Mohler

Department of Biochemistry and Molecular Biology Faculty Papers

BACKGROUND: Regulatory and biophysical mechanisms of cell-cell fusion are largely unknown despite the fundamental requirement for fused cells in eukaryotic development. Only two cellular fusogens that are not of clear recent viral origin have been identified to date, both in nematodes. One of these, EFF-1, is necessary for most cell fusions in Caenorhabditis elegans. Unregulated EFF-1 expression causes lethality due to ectopic fusion between cells not developmentally programmed to fuse, highlighting the necessity of tight fusogen regulation for proper development. Identifying factors that regulate EFF-1 and its paralog AFF-1 could lead to discovery of molecular mechanisms that control cell fusion …

China Suboptimal Health Cohort Study: Rationale, Design And Baseline Characteristics, Youxin Wang, Siqi Ge, Yuxiang Yan, Anxin Wang, Zhongyao Zhao, Xinwei Yu, Jing Qui, Mohamed Ali Alzain, Hao Wang, Honghong Fang, Qing Gao, Manshu Song, Jie Zhang, Yong Zhou, Wei Wang

Research outputs 2014 to 2021

Background:

Suboptimal health status (SHS) is a physical state between health and disease, characterized by the perception of health complaints, general weakness, chronic fatigue and low energy levels. SHS is proposed by the ancient concept of traditional Chinese medicine (TCM) from the perspective of preservative, predictive and personalized (precision) medicine. We previously created the suboptimal health status questionnaire 25 (SHSQ-25), a novel instrument to measure SHS, validated in various populations. SHSQ-25 thus affords a window of opportunity for early detection and intervention, contributing to the reduction of chronic disease burdens.

Methods/design:

To investigate the causative effect of SHS in non-communicable …