Medicine and Health Sciences Commons^™

Translocation And Function Of Akt In The Mitochondria, Keri A. Mans

All ETDs from UAB

The ubiquitously expressed kinase Akt is a known survival protein, and is involved in multiple cell signaling cascades, notably the phosphatidylinositol 3-kinase (PI3K) pathway. Active Akt translocates from the plasma membrane to different subcellular compartments, including mitochondria, where it phosphorylates compartment-specific substrates. The mechanism of this translocation and the specific function of Akt within the mitochondria remains a mystery. The goals of this study were to elucidate the mechanism by which Akt enters the mitochondria and examine the role of Akt in mitochondrial function. Finally, the possibilities of using post-mortem human brain tissue to study mitochondrial function in normal and …

Translation Initiation Signaling Components Altered By Mechanical Load Dictate Skeletal Muscle Hypertrophy, David Lawrence Mayhew

All ETDs from UAB

The regulation of protein synthesis (i.e., mRNA translation) is an energetically costly and extensively regulated process, which is primarily regulated at the initiation step. Mechanical load is a potent stimulus of translation in skeletal muscle, and thus this tissue provides an excellent model system to study the plasticity of the translational apparatus. We investigated the effects of alterations in translation initiation cell signaling pathways in skeletal muscle using a variety of in vitro and in vivo mouse and human model systems. Collectively, our results suggest that, although many proteins in translational signaling pathways are responsive to mechanical load, the response …

The Contribution Of Different Mechanisms Of Viral Sequence Variation To The Evolution Of Positive-Sense Single-Stranded Rna Viruses, Brett Earl Pickett

All ETDs from UAB

The Flaviviridae family of positive-sense single-stranded RNA (+ssRNA) viruses includes viral taxa which greatly impact public health worldwide. To explore how the viruses within the Flaviviridae family evolve, we examined the extent to which these viral taxa use nucleotide covariance, spontaneous mutation, and/or homologous recombination to vary their genotype as well as the resulting phenotype. We developed and used CovarView to assist us in simultaneously viewing and inspecting the results from whole genome covariance analyses. This resulted in the identification of previously-characterized RNA functional structures in the genomes of hepatitis C virus (HCV), as well as a new RNA functional …

Regulation Of Glycogen Synthase Kinase 3 In The Pathophysiology And Treatment Of Mood Disorders, Abigail Marie Polter

All ETDs from UAB

Mood disorders are devastating psychiatric illnesses that will affect as many as one in every five persons worldwide over the course of their lifetime. Significant gaps still remain in our understanding of these illnesses and outcomes for many patients are far from optimal. Glycogen Synthase Kinase 3 (GSK3) is a protein kinase that is increasingly recognized as playing an important role in a number of neuronal functions, as well as in pathological states such as mood disorders. GSK3 is inhibited in the brain by phosphorylation on an N-terminal serine. Several treatments for mood disorders, including lithium, antidepressants, and atypical antipsychotics …

Heparanase Drives The Aggressive Myeloma Phenotype: Preclinical Development Of A Heparanase Inhibitor For The Treatment Of Multiple Myeloma, Joe Ritchie

All ETDs from UAB

Heparanase, an endoglycosidase which cleaves heparan sulfate chains at specific sites, is rarely expressed in normal tissues but becomes evident in many human cancers. We have previously shown that heparanase promotes myeloma growth and angiogenesis through modulation of the tumor microenvironment. Recognition that heparanase drives the aggressive myeloma phenotype has led to new strategies designed to therapeutically target this enzyme. SST0001, a non-anticoagulant heparin that is 100% N-acetylated and 25% glycol split, was previously described as a potent inhibitor of heparanase activity in vitro, and, in limited in vivo experiments, SST0001 was identified to have efficacy as an anti-tumor agent …

The Role Of Map Kinase Cascade In Msp Signaling Response, Youfeng Yang

All ETDs from UAB

The MSP domain is an evolutionarily conserved immunoglobulin-like structure of about 120 amino acids (Miller et al., 2001). A P56S missense mutation in the MSP domain of the human vapb gene is associated with a dominantly inherited form of Amyotropic Lateral Sclerosis (ALS) or Spinal Muscular Atrophy (SMA) (Nishimura et al., 2004). In C. elegans, secreted MSP binds to the VAB-1 Eph receptor and other receptors on oocyte and ovarian sheath cell surfaces (Miller et al., 2003). We have recently shown that the P56S mutation prevents secretion of the VAPB MSP domain, suggesting that the signaling function is important in …

Il-21 Dictates The Quality Of The Cd8 T Cell Response During Acute And Chronic Infections, John Seung-Hoon Yi

All ETDs from UAB

CD8 T cells contribute to the control of intracellular pathogens including viruses and certain bacteria. Recognition of foreign antigens by antigen-specific CD8 T cells initiates a differentiation process by which CD8 T cells gain effector functions including the ability to rapidly produce cytokines and kill infected cells. Currently, it is not well understood what signals dictate the generation of robust CD8 T cell responses, however it has been demonstrated that without CD4 T cell help CD8 T cell responses are compromised. CD4 T cells are the primary producers of interleukin-21 (IL-21), which has broad immunological actions. Thus for this dissertation, …

A Ck2-Dependent Mechanism For Activation Of The Jak-Stat Signaling Pathway: Implications For Cancer Biology, Ying Zheng

All ETDs from UAB

Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) signaling is involved in regulation of cell survival, proliferation and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, while they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In this dissertation, we report the identification of the serine/threonine kinase CK2 as a novel interactor and important regulator of activation of the JAK-STAT signaling …

Effect Of Overexpressing Apolipoprotein A-I In An Animal Model Of Alzheimer's Disease, Terry L. Lewis

All ETDs from UAB

Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoprotein (HDL) in circulation and is expressed mainly by the liver and intestine. The levels of apoA-I/HDL are inversely related to the incidence of cardiovascular disease. Because of the connections between heart disease and Alzheimer's disease (AD), it is conceivable that high levels of apoA-I/HDL may be protective against AD. However, the limited literature shows mixed results on the role of apoA-I/HDL in the development of AD. It is hypothesized that increased expression of human apoA-I will ameliorate the behavioral deficits and characteristic amyloid-ß (Aß) plaque formation in a …

Protective Antibodies To The Proline-Rich And Alpha Helical Regions Of Pneumococcal Surface Protein A And Their Detection In An In Vitro Surrogate Assay, Calvin Clay Daniels

All ETDs from UAB

Current pneumococcal vaccines containing pneumococcal capsular polysaccharide antigens protect against infection by pneumococci. However, this protection is limited to strains expressing the capsule types included in the vaccine. Since the introduction of these vaccines, the increase in incidence of infection by serotypes not targeted by the vaccine, a process called "serotype replacement," and the growing antibiotic resistance of replacement strains both stress the need for vaccines with broader protection. The alpha-helical region of a protein present on all clinical isolates of pneumococci, Pneumococcal Surface Protein A (PspA), elicits protective immunity. Downstream of the alpha-helical region is a highly conserved region …

Poxvirus Evolution: The Role Of Horizontal Gene Transfer, Mary Rebecca Odom

All ETDs from UAB

We have investigated the set of all poxvirus proteins for information about the origins of protein coding genes of the Poxviridae family of viruses. A global assessment of all poxvirus proteins for levels of similarity to proteins of other organisms, including eukaryotes, viruses, and prokaryotes, has suggested trends and relationships informative about poxvirus evolution and poxvirus interactions with hosts. Our research has focused on the poxvirus proteins subset this assessment identified as likely to have evolutionary histories involving horizontal gene transfer (HGT). We have used phylogenetic reconstructions to individually determine the sources of more than 70 horizontally transferred genes present …

Individualized Cognitive Modeling For Close-Loop Task Mitigation, Guangfan Zhang, Roger Xu, Wei Wang, Jiang Li, Tom Schnell, Mike Keller, Thomas E. Pinelli (Ed.)

Electrical & Computer Engineering Faculty Publications

An accurate real-time operator functional state assessment makes it possible to perform task management, minimize risks, and improve mission performance. In this paper, we discuss the development of an individualized operator functional state assessment model that identifies states likely leading to operational errors. To address large individual variations, we use two different approaches to build a model for each individual using its data as well as data from subjects with similar responses. If a subject's response is similar to that of the individual of interest in a specific functional state, all the training data from this subject will be used …

Morphological Development Of The Axial Skeletons Of Esox Lucius And Esox Masquinongy (Euteleostei: Esociforms), With Comparisons In Developmental And Mineralization Rates., Amanda Maria Burdi

Master's Theses

Developmental morphology of the axial skeleton of Esox lucius (i.e., northern pike and type species) and E. masquinongy (i.e., muskellunge) was investigated. More than 1,000 specimens were examined ranging in size from approximately 10 mm notochordal length (NL) post-hatching juveniles to over 80 mm standard length (SL) foraging sub-adults. Results show that regardless of individual variation, the relative sequence of bone formation and mineralization is consistent between the two species. This consistent developmental pattern enabled construction of an ontogenetic staging scheme of eight developmental stages, each characterized by one defining criterion. The first appearance in cartilage and/or first sign of …

The Globin Gene Family Of The Cephalochordate Amphioxus: Implications For Chordate Globin Evolution, Bettina Ebner, Georgia Panopoulou, Serge N. Vinogradov, Laurent Kiger, Michael C. Marden, Thorsten Burmester, Thomas Hankeln

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

The lancelet amphioxus (Cephalochordata) is a close relative of vertebrates and thus may enhance our understanding of vertebrate gene and genome evolution. In this context, the globins are one of the best studied models for gene family evolution. Previous biochemical studies have demonstrated the presence of an intracellular globin in notochord tissue and myotome of amphioxus, but the corresponding gene has not yet been identified. Genomic resources of Branchiostoma floridae now facilitate the identification, experimental confirmation and molecular evolutionary analysis of its globin gene repertoire.

Results

We show that B. floridae harbors at least fifteen paralogous globin genes, …

Mapping Haplotype-Haplotype Interactions With Adaptive Lasso, Ming Li, Roberto Romero, Wenjiang J. Fu, Yuehua Cui

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

The genetic etiology of complex diseases in human has been commonly viewed as a complex process involving both genetic and environmental factors functioning in a complicated manner. Quite often the interactions among genetic variants play major roles in determining the susceptibility of an individual to a particular disease. Statistical methods for modeling interactions underlying complex diseases between single genetic variants (e.g. single nucleotide polymorphisms or SNPs) have been extensively studied. Recently, haplotype-based analysis has gained its popularity among genetic association studies. When multiple sequence or haplotype interactions are involved in determining an individual's susceptibility to a disease, it …

Comparison Of Mitotic Cell Death By Chromosome Fragmentation To Premature Chromosome Condensation, Joshua B. Stevens, Batoul Y. Abdallah, Sarah M. Regan, Guo Liu, Steven W. Bremer, Christine J. Ye, Henry H. Heng

Wayne State University Associated BioMed Central Scholarship

Abstract

Mitotic cell death is an important form of cell death, particularly in cancer. Chromosome fragmentation is a major form of mitotic cell death which is identifiable during common cytogenetic analysis by its unique phenotype of progressively degraded chromosomes. This morphology however, can appear similar to the morphology of premature chromosome condensation (PCC) and thus, PCC has been at times confused with chromosome fragmentation. In this analysis the phenomena of chromosome fragmentation and PCC are reviewed and their similarities and differences are discussed in order to facilitate differentiation of the similar morphologies. Furthermore, chromosome pulverization, which has been used almost …

Molecular And Therapeutic Implications Of Notch1 Signaling In Pediatric T-Cell Acute Lymphoblastic Leukemia, Amanda Larson Gedman

Wayne State University Dissertations

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of pediatric ALL cases and is associated with early relapse and inferior outcome. The poorer prognosis of T-ALL compared to B-precursor ALL may in part reflect the lack of unique features on which to base therapy. NOTCH1 mutations are of particular interest since these were reported in 37-71% of T-ALLs. The prognostic value of NOTCH1 mutations remains controversial as both favorable and unfavorable associations were reported, whereas in other studies, there were no associations between NOTCH1 mutations and treatment outcome. We explored the impact of mutations in NOTCH1, FBW7 and PTEN on …

The Role Of Synaptically Evoked Plateau Potentials In Retinogeniculate Development, Emily Dilger

Theses and Dissertations

We study the activity-dependent refinement of sensory systems by using the mouse retinogeniculate system as a model. Spontaneous retinal waves lead to robust excitatory post-synaptic activity in developing relay cells in the dorsal lateral geniculate nucleus (dLGN) of the thalamus and are reportedly needed to help guide the segregation of retinal inputs into eye-specific domains as well as for the pruning of extraneous retinal inputs onto single dLGN relay cells. The composition of retinally evoked post-synaptic activity activated by these retinal waves in dLGN is largely unknown, but based on our in vitro recordings, such activity seems well suited to …

Pk/Pd Modelling Of Comb-Shaped Pegylated Salmon Calcitonin Conjugates Of Differing Molecular Weights, Sinead Ryan, Jesus Maria Frias, David H. Haddleton, David J. Brayden

Articles

Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped end-functionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E …

Expanding The Treatment Window Raising The Bar For Patient Safety, Claranne Mathiesen Rn, Msn, Cnrn

Patient Care Services / Nursing

No abstract provided.

The Development Of A Formal Preceptor Model To Improve Departmental Mentorship, Angela Lutz Bs, Rrt-Nps, Kenneth Miller Med, Rrt-Nps, Linda Cornman Bs, Rrt-Nps, Uma Bhatt Rrt, Bryn Surgeoner Rrt

Patient Care Services / Nursing

No abstract provided.

The Nonpsychoactive Cannabinoid Cannabidiol Inhibits 5-Hydroxytryptamine3a Receptor-Mediated Currents In Xenopus Laevis Oocytes, Keun-Hang Susan Yang, Sehamuddin Galadari, Dmytro Isaev, Georg Petroianu, Toni S. Shippenberg, Murat Oz

Mathematics, Physics, and Computer Science Faculty Articles and Research

The effect of the plant-derived nonpsychotropic cannabinoid, cannabidiol (CBD), on the function of hydroxytryptamine (5-HT)3A receptors expressed in Xenopus laevis oocytes was investigated using two-electrode voltage-clamp techniques. CBD reversibly inhibited 5-HT (1 μM)-evoked currents in a concentration-dependent manner (IC50 = 0.6 μM). CBD (1 μM) did not alter specific binding of the 5-HT3A antagonist [3H]3-(5-methyl-1H-imidazol-4-yl)-1-(1-methylindol-3-yl)propan-1-one (GR65630), in oocytes expressing 5-HT3A receptors. In the presence of 1 μM CBD, the maximal 5-HT-induced currents were also inhibited. The EC50 values were 1.2 and 1.4 μM, in the absence and presence of CBD, indicating that CBD acts as a noncompetitive antagonist of 5-HT3 …

Autoimmunity In Transfusion Babesiosis: A Spectrum Of Clinical Presentations., Jay H Herman, Saleh Ayache, Danuta Olkowska

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Transfusion-acquired babesiosis can be an asymptomatic or self-limited febrile hemolytic illness in a healthy host. A persistent, relapsing, and/or fulminant course with the development of life-threatening complications may be seen in immunocompromised or splenectomized patients. As in malaria, erythrocyte parasitemia is often associated with nonimmune hemolysis, and can be treated with erythrocytapheresis. Just as warm autoantibodies have been reported in malaria infection, the development of autoantibody-mediated immune hemolysis has been reported in babesiosis. We treated a previously healthy male with multiple injuries from a motor vehicle accident necessitating massive transfusion. Late in the hospitalization, his blood smear revealed Babesia microti, …

Sustained Expression Of Tdp-43 And Fus In Motor Neurons In Rodent's Lifetime., Cao Huang, Pedro Yuxing Xia, Hongxia Zhou

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) are two highly conserved ribonucleoproteins. Pathogenic mutations of the TDP-43 or the FUS gene are all linked to amyotrophic lateral sclerosis (ALS) that is characterized by progressive degeneration of motor neurons. To better understand the correlation of ALS disease genes with the selectivity of chronic motor neuron degeneration, we examined the longitudinal expression of the TDP-43 and the FUS genes in C57BL6 mice and in Sprague-Dawley rats. TDP-43 and FUS were robustly and ubiquitously expressed in the postnatal mice and rats, but were markedly decreased in the adult rodents. In adulthood, …

Outcome Of Traumatic Aortic Rupture: A 14-Year Experience, Matthew Wilson, James K. Wu, Sanjay M. Mehta Md, Theodore G. Phillips Md, Raymond L. Singer Md, Michael F. Szwerc Md, Gary W. Szydlowski Md

Department of Medicine

No abstract provided.

The Impact Of A Mental Health-Related Diagnosis On Readmission Rates For Heart Failure, Ronald S. Freudenberger Md, Carol A. Foltz Phd, Lou A. Lukas Md, Donna F. Petruccelli Crnp, Hannah D. Paxton Rn, Mph, Victoria Sabella Bsn

Department of Medicine

No abstract provided.

Recent Advances On Skin-Resident Stem/Progenitor Cell Functions In Skin Regeneration, Aging And Cancers And Novel Anti-Aging And Cancer Therapies., Murielle Mimeault, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Recent advances in skin-resident adult stem/progenitor cell research have revealed that these immature and regenerative cells with a high longevity provide critical functions in maintaining skin homeostasis and repair after severe injuries along the lifespan of individuals. The establishment of the functional properties of distinct adult stem/progenitor cells found in skin epidermis and hair follicles and extrinsic signals from their niches, which are deregulated during their aging and malignant transformation, has significantly improved our understanding on the etiopathogenesis of diverse human skin disorders and cancers. Particularly, enhanced ultraviolet radiation exposure, inflammation and oxidative stress and telomere attrition during chronological aging …

When You Hear Hoof Beats, It Might Be A Zebra: Lupus Patient With Fever And Leukopenia, Erica Peart Do, James Ross Md, Facp

Department of Medicine

No abstract provided.

Immunologic Therapy With Cadi-05 For The Treatment Of Advanced Melanoma, Paul J. Mosca Md, Phd, Suresh G. Nair Md, Susan K. Ayre Rn, Ma, Wenjing Shi Rn, Ms, Sherrine Eid Mph, Shantu Amin Phd, Dhimant Desai Phd, Joseph J. Drabick Md, Facp, Bakulesh M. Khamar Md, Arati Sharma Phd, Svetomir N. Markovic Md, Gavin P. Robertson Phd

Department of Medicine

No abstract provided.

Using Technology And Collaborative Partners For A 2010 Needs Assessment In Tobacco Control, Alice Dalla-Palu Mpa, Ctts-M, Cac, Jeanne Fignar Aas, Meredith Casey B.S.E., Ctts-M, Andreea Ambrus Ms, Anthony Nerino, Deborah Youngfelt Bs,Ches, Ctts,, Trudy Coleman Phd

Department of Medicine

No abstract provided.