Digital Commons Network^™

Drug-Induced Plasticity Contributing To Heightened Relapse Susceptibility: Neurochemical Changes And Augmented Reinstatement In High-Intake Rats, Aric Madayag, Kristen S. Kau, Doug Lobner, John R. Mantsch, Samantha Wisniewski, David A. Baker

Biomedical Sciences Faculty Research and Publications

A key in understanding the neurobiology of addiction and developing effective pharmacotherapies is revealing drug-induced plasticity that results in heightened relapse susceptibility. Previous studies have demonstrated that increased extracellular glutamate, but not dopamine, in the nucleus accumbens core (NAcc) is necessary for cocaine-induced reinstatement. In this report, we examined whether drug-induced adaptations that are necessary to generate cocaine-induced reinstatement also determine relapse vulnerability. To do this, rats were assigned to self-administer cocaine under conditions resulting in low (2 h/d; 0.5 mg/kg/infusion, i.v.) or high (6 h/d; 1.0 mg/kg/infusion, i.v.) levels of drug intake since these manipulations produce groups of rats …

Proliferation Of Aneuploid Human Cells Is Limited By A P53-Dependent Mechanism, Sarah L. Thompson, Duane A. Compton

Dartmouth Scholarship

Most solid tumors are aneuploid, and it has been proposed that aneuploidy is the consequence of an elevated rate of chromosome missegregation in a process called chromosomal instability (CIN). However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation. The mechanism for this intolerance of nondiploid genomes is unknown. In this study, we show that in otherwise diploid human cells, chromosome missegregation causes a cell cycle delay with nuclear accumulation of the tumor suppressor p53 and the cyclin kinase inhibitor p21. Deletion of the p53 gene permits the accumulation …

Neural Network Model For Instruments That Store And Retrieve Sequential Information, Philip W. Landfield, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Patents

A method and design is provided for distributing and storing sets of temporally ordered information in a systematic and sequential fashion. This method is based on a model of how the brain functions in the distribution and storage of temporally ordered memories, but it can also be applied to the design of new biological, electronic or optical devices. These devices may be used in the testing and development of new therapeutic drugs, in the detection of toxic agents or impaired performance, or in the development of new industrial and consumer devices in which the orderly storage of sequential information is …

Cd4+ T Cell Regulation Of Cd25 Expression Controls Development Of Short-Lived Effector Cd8+ T Cells In Primary And Secondary Responses, Joshua J. Obar, Michael J. Molloy, Evan R. Jellison, Thomas A. Stoklasek, Weijun Zhang, Edward J. Usherwood, Leo Lefrançois

Dartmouth Scholarship

Both CD4(+) T cell help and IL-2 have been postulated to "program" activated CD8(+) T cells for memory cell development. However, the linkage between these two signals has not been well elucidated. Here we have studied effector and memory CD8(+) T cell differentiation following infection with three pathogens (Listeria monocytogenes, vesicular stomatitis virus, and vaccinia virus) in the absence of both CD4(+) T cells and IL-2 signaling. We found that expression of CD25 on antigen-specific CD8(+) T cells peaked 3-4 days after initial priming and was dependent on CD4(+) T cell help, likely through a CD28:CD80/86 mediated pathway. CD4(+) T …

Metabolic Oscillations In Pancreatic Islets Depend On The Intracellular Ca2+ Level But Not Ca2+ Oscillations, Matthew J. Merrins, Bernard Fendler, Min Zhang, Arthur Sherman, Richard Bertram, Leslie S. Satin

Pharmacology and Toxicology Publications

Abstract

Plasma insulin is pulsatile and reflects oscillatory insulin secretion from pancreatic islets. Although both islet Ca²⁺ and metabolism oscillate, there is disagreement over their interrelationship, and whether they can be dissociated. In some models of islet oscillations, Ca²⁺ must oscillate for metabolic oscillations to occur, whereas in others metabolic oscillations can occur without Ca²⁺ oscillations. We used NAD(P)H fluorescence to assay oscillatory metabolism in mouse islets stimulated by 11.1 mM glucose. After abolishing Ca²⁺ oscillations with 200 μM diazoxide, we observed that oscillations in NAD(P)H persisted in 34% of islets (n = 101). …

A Transposon In Comt Generates Mrna Variants And Causes Widespread Expression And Behavioral Differences Among Mice, Zhengsheng Li, Megan K. Mulligan, Xusheng Wang, Michael F. Miles, Lu Lu, Robert W. Williams

Pharmacology and Toxicology Publications

Background

Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine. COMT activity influences cognitive and emotional states in humans and aggression and drug responses in mice. This study identifies the key sequence variant that leads to differences in Comt mRNA and protein levels among mice, and that modulates synaptic function and pharmacological and behavioral traits.

Methodology/Principal Findings

We examined Comt expression in multiple tissues in over 100 diverse strains and several genetic crosses. Differences in expression map back to Comt and are generated by a 230 nt insertion of a B2 short interspersed element (B2 …

Development Of A Syngeneic Mouse Model Of Epithelial Ovarian Cancer, Bridget A. Quinn, Fang Xiao, Laura Bickel, Lainie Martin, Xiang Hua, Andres Klein-Szanto, Denise C. Connolly

Human and Molecular Genetics Publications

Background

Most cases of ovarian cancer are epithelial in origin and diagnosed at advanced stage when the cancer is widely disseminated in the peritoneal cavity. The objective of this study was to establish an immunocompetent syngeneic mouse model of disseminated epithelial ovarian cancer (EOC) to facilitate laboratory-based studies of ovarian tumor biology and preclinical therapeutic strategies.

Methods

Individual lines of TgMISIIR-TAg transgenic mice were phenotypically characterized and backcrossed to inbred C57BL/6 mice. In addition to a previously described line of EOC-prone mice, two lines (TgMISIIR-TAg-Low) were isolated that express the oncogenic transgene, but have little or no …

Treatment Strategies In Acute Myelogenous Leukemia : Investigating Hsp90 And P53 As Targets, Jennifer M. Napper

Theses, Dissertations and Capstones

Acute myelogenous leukemia (AML) is the deadliest of the lymphatic and bone marrow cancers. Patients diagnosed with AML have a five year survival rate of 23.4%. AML is characterized by an accumulation of undifferentiated and functionless myeloid precursors in the bone marrow and blood. Heat shock protein 90 (Hsp90) inhibitors, such as 17-AAG, an analog of geldanamycin (GM), are currently undergoing phase I, and II and III clinical trials for various cancers with mixed results. I found distinct responses to 17-AAG treatment among the AML cell lines tested. I also discovered two mutant TP53 alleles in Kasumi-3 cells, an AML …

Age- And Sex-Associated Changes In Mrna Expression Of Neurodegenerative Disorder-Related Molecules In The Hippocampus And Cerebellum Of Rat Brain, Srinivasarao Thulluri

Theses, Dissertations and Capstones

Age-associated oxidative stress is involved in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, and sex-associated differences may also affect the risk for these neurodegenerative diseases. We compared the effects of aging and sex on the mRNA expression of five molecules that are closely related to oxidative stress, along with Alzheimer’s and Parkinson’s diseases in the hippocampus of both male and female Fischer 344xBrown Norway (F344BN) rats. The reverse transcription polymerase chain reaction was used to determine the mRNA expression level of superoxide dismutase 2 (SOD2), heme oxygenase 1 (HO1), amyloid precursor protein (APP), -site APP-cleaving enzyme 1 (BACE1), and …

Genetic And Environmental Factors Suggest That Dietary Fatty Acid Content, Lipid Metabolism, And Bone Properties Are Key Regulators Of Myeloid Progenitor Cell Frequency, Melinda E. Varney

Theses, Dissertations and Capstones

Acute myelogenous leukemia (AML) and its precursors are the result of the dysregulation of hematopoiesis. Hematopoiesis proceeds in a stepwise manner, beginning with hematopoietic stem cells, continuing to develop into various stages of progenitor cells, and finally becoming fully functional blood cells. As this process goes awry, immature, functionless cells of the myeloid lineage proliferate out of control. Discerning how myeloid progenitor frequency is regulated allows for a better understanding of how the process may lose control. Hematopoiesis has been shown to depend on genetic and environmental factors. In this work, I have added to this knowledge base by providing …

The Expression And Function Of Hypoxia Inducible Factor-1Α In Human Melanoma, Sandeep S. Joshi

Theses, Dissertations and Capstones

Hypoxia inducible factor-1α (HIF-1α) protein, a key regulator of oxygen homeostasis, is stabilized under hypoxia and degraded under normal oxygen tension. Here, the human melanoma cells were found to express an elevated amount of HIF-1α mRNA and protein relative to normal human melanocytes under normoxic conditions. The amount of HIF-1α expressed is roughly correlated with the stage of melanoma from which the cell line was established. In addition, a splice variant mRNA of HIF-1α785 is expressed at higher levels than full-length HIF-1α mRNA in the more aggressive melanoma cells. This splice variant lacks part of the oxygen regulation domain. Ectopic …

Electrospun Nanofibers For Neural Tissue Engineering, Jingwei Xie, Matthew R. Macewan, Andrea G. Schwartz, Younan Xia

MIIR Faculty Research

Biodegradable nanofibers produced by electrospinning represent a new class of promising scaffolds to support nerve regeneration. We begin with a brief discussion on electrospinning of nanofibers and methods for controlling the structure, porosity, and alignment of the electrospun nanofibers. The methods include control of the nanoscale morphology and microscale alignment for the nanofibers, as well as the fabrication of macroscale, three-dimensional tubular structures. We then highlight recent studies that utilize electrospun nanofibers to manipulate biological processes relevant to nervous tissue regeneration, including stem cell differentiation, guidance of neurite extension, and peripheral nerve injury treatments. The main objective of this feature …

Fluprostenol-Induced Mapk Signaling Is Independent Of Aging In Fischer 344/Nniahsd X Brown Norway/Binia Rat Aorta, Kevin M. Rice, Ernest M. Walker, Sunil K. Kakarla, Satyanarayana Paturi, Miaozong Wu, Sumit Narula, Eric R. Blough

MIIR Faculty Research

The factors that regulate vascular mechanotransduction and how this process may be altered with aging are poorly understood and have not been widely studied. Recent data suggest that increased tissue loading can result in the release of prostaglandin F2 alpha (PGF2α) and other reports indicate that aging diminishes the ability of the aged aorta to activate mitogen activated protein kinase (MAPK) signaling in response to increased loading. Using ex vivo incubations, here we investigate whether aging affects the ability of the aorta to induce phosphorylation of extracellular signal-regulated kinase 1/2 (ERK½-MAPK), p38-MAPK, and Jun N-terminal kinase (JNK-MAPK) activation following stimulation …

Prevention Of Fetal Alcohol Damage In Northern Native Communities: A Practical School-Based Approach, Steven Jacquier, Judith Kleinfeld, David Gilliam

SPS Faculty Publications

This article describes a Fetal Alcohol Syndrome prevention program, "FASD in Lab Mice," that had a dramatic effect in increasing Alaska Native students' understanding of the lifelong neurological and physical damage caused by drinking during pregnancy and, more importantly, led them to engage in active prevention efforts in their own and other Native communities. Informational programs typically used in the schools create little student interest and students often do not see connections between their own experience and the atypically extreme examples such prevention programs tend to emphasize. The "FASD in Lab Mice" prevention program, using actual experiments conducted by the …

To Live And Die In Ca, Jane Frances Curnutt

Theses Digitization Project

This thesis investigates the nature of elementary cellular automata to better understand their relationship of the models they support to the biological organisms that create the mats and soil crusts found in extreme environments here on earth. Cellular automata have been used to study growth and patterns in forests, arid desert environments, predator-prey problems, and sea shells. It has also been used to study areas of diverse epidemiology and linguistics. Cellular automata have been used as the core of computer games as well. This investigation has led to develop a graphical grammar for simple cellular automata, using L-systems, a grammar …

Practical Considerations In Regenerative Medicine Research: Iacucs, Ethics, And The Use Of Animals In Stem Cell Studies, Susan Vandewoude, Bernard E. Rollin

Biomedicine and Animal Models in Research Collection

The intent of US federal laws mandating IACUC review of animal-related activities was to satisfy contemporary socioethical concerns by introducing deliberations about ethics and animal welfare into the research process when animals are used. These laws and the system they chartered have worked well for the most part in providing opportunities for consideration of animal welfare as a vital part of animal research. As a result, investigators today are far less naïve about the ethical issues raised by research on animals and typically more sympathetic about the need for such consideration. As evidence of this growing awareness, the literature on …

Use Of Electronic Anatomy Practical Examinations For Remediating “At Risk” Students, Frank J. Daly

Biomedical Sciences Faculty Publications

Restrictive laboratory scheduling, an increasing number of human cadaver-based anatomy courses and a reduction in the curricular time allotted to anatomy courses have created problems with cadaver laboratory access at the University of New England. This article describes a combination of anatomy testing and grading strategies to allow “at risk” (borderline failing) students an opportunity to remediate their lowest set of examination scores and pass their anatomy course. An alternative electronic practical examination for these students provided flexibility in laboratory scheduling, thereby increasing laboratory access for other students taking concurrent courses. Specifically, the electronic examinations allowed for a reduction in …

Role Of Genetics In Prediction Of Coronary Artery Disease, Andrey Yuabov

The Science Journal of the Lander College of Arts and Sciences

The following is the introduction of this article: Coronary arteries disease (CAD) is a leading cause of death in United States and rest of the world. It mostly involves atherogenic formation within the walls of the coronary arteries, which in turn restricts the adequate perfusion to the heart muscle. This leads to myocardial infarction and sudden death. In the past few decades the theories of coronary arteries disease pathogenesis have changed. The facts reveal that the onset of the disease can develop as early as childhood. The degree of the disease gradually progresses in stages and it is regarded as …

Prieurianin Causes Weight Loss In Diet-Induced Obese Mice And Inhibits Adipogenesis In Cultured Preadipocytes, Ahmed Kablan, Rudel A. Saunders, Maria Szkudlarek-Mikho, Andrew J.B. Chin, Raul M. Bosio, Kazuyuki Fujii, Joseph I. Shapiro M.D., Khew-Voon Chin

Biochemistry and Microbiology

The global increase in the incidence of obesity has emerged as one of the most serious public health risks in recent years. Despite the enormity of the obesity pandemic, there are currently only two FDA-approved therapies for its treatment and these drugs exhibit modest effi cacy and have limiting side effects. Prieurianin is a plant limonoid product that deters feeding in insect larvae. We investigated in this study the effects of prieurianin on weight loss and adipogenesis. Our results showed that prieurianin causes weight loss by reducing energy intake in obese mice on highcalorie diet. We also found that prieurianin …

Regulation Of Neuronal Excitability: New Mechanisms For Slow Afterhyperpolarization Activation And Modulation, Claudio Alberto Villalobos

Wayne State University Dissertations

One of the most characteristic features of pyramidal cells in the prefrontal cortex (PFC) is that they present a slow afterhyperpolarizing current (I_sAHP) that plays a critical role in the regulation of neuronal excitability. This current is modulated by receptors acting via GΑ_q/11 G proteins, thus it is thought that neurotransmitters regulate neuronal excitability through the inhibition of this current. I_sAHP is known to be mediated by calcium-activated potassium channels, however, neither the identity of the channel underlying this current nor its mechanism of activation are yet well understood. Recent reports have questioned a direct role …

Raman Spectroscopic Modeling Of T- Lymphocyte Activation And Detection Of Acute Renal Allograft Rejection, Kristian L. Brown

Wayne State University Dissertations

ABSTRACT

RAMAN SPECTROSCOPIC MODELING OF T-LYMPHOCYTE ACTIVATION AND DETECTION OF ACUTE RENAL ALLOGRAFT REJECTION

By

KRISTIAN L. BROWN

2010

Advisor: Gregory Auner, PhD

Major: Biomedical Engineering

Degree: Doctor of Philosophy

Despite the advances made in the area of kidney transplantation, the disparity between the demand and available donated organs remains a dominant and unresolved issue. Given the paucity of available renal allografts the preservation of existing grafts is vital. One factor that has negatively impacted renal allograft survival is acute rejection (AR). Traditionally, kidney transplant centers have used elevations in serum creatinine as a screening tool for detecting AR. However, …

An Epitope From Acanthamoeba Castellanii That Cross-React With Proteolipid Protein 139-151-Reactive T Cells Induces Autoimmune Encephalomyelitis In Sjl Mice, Chandirasegaran Massilamany, David Steffan, Jay Reddy

Jay Reddy Publications

We report here that an epitope (aa, 83-95) derived from Acanthamoeba castellanii (ACA) induces clinical signs of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice reminiscent of the disease induced with myelin proteolipid protein (PLP) 139-151. By using IA^s/tetramers, we demonstrate that both ACA 83-95 and PLP 139-151 generate antigen-specific cross-reactive CD4 T cells and the T cells secrete identical patterns of cytokines and induce EAE with a similar severity. These results may provide insights into the pathogenesis of multiple sclerosis and ACA-induced granulomatous encephalitis.

Starch-Entrapped Microspheres Show A Beneficial Fermentation Profile And Decrease In Potentially Harmful Bacteria During In Vitro Fermentation In Faecal Microbiota Obtained From Patients With Inflammatory Bowel Disease, Devin J. Rose, Koen Venema, Ali Keshavarzian, Bruce R. Hamaker

Devin Rose Publications

The purpose of this research was to test the hypothesis that starch-entrapped microspheres would produce favourable fermentation profiles and microbial shifts during in vitro fermentation with the faecal microbiota from patients with inflammatory bowel disease (IBD). In vitro fermentation was carried out using a validated, dynamic, computer-controlled model of the human colon (Toegepast Natuurwetenschappelijk Onderzoek gastrointestinal model-2) after inoculation with pooled faeces from healthy individuals, patients with inactive IBD (Crohn’s disease (CD)) or patients with active IBD (ulcerative colitis (UC)). Starch-entrapped microspheres fermented more slowly and produced more butyrate than fructooligosaccharides (FOS) when fermented with the faecal microbiota from patients …

Comparison Of Affective Analgesia And Conditioned Place Preference Following Cholinergic Activation Of, Elena Schifirnet

Wayne State University Dissertations

Activation of the dopaminergic mesolimbic reward circuitry that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress affective reactions to noxious stimuli (affective analgesia, AA). VTA dopamine neurons are activated via cholinergic inputs, and we have observed that microinjections of the acetylcholine agonist carbachol suppressed vocalizations of rats that occur following administration of brief (1 sec) tail-shocks (vocalization afterdischarges = VAD). VADs are a validated rodent model of pain affect. In addition, the capacity of carbachol to support reinforcement appears to be regionally dependent within VTA. Ikemoto and Wise (2002) reported that carbachol was self-administered in the …

Study Of The Egfr, Src And Stat3 Pathway In Pancreatic Cancer, Soumya Jaganathan

Electronic Theses and Dissertations

Cancer is associated with many molecular aberrations that support the malignant phenotype. In that regard, aberrant activation of epidermal growth factor receptor (EGFR), Src, and signal transducer and activator of transcription 3 (Stat3) occur concurrently in pancreatic cancer and are implicated in the disease phenotype. Notwithstanding, increasing evidence indicates that therapies that target only EGFR or Src are rather ineffective in modulating the cancer phenotype. The poor therapeutic outcome of the monotherapies targeting EGFR or Src may in part be due to the increased incidence of signaling cross-talks among aberrant signaling pathways in cancer. Molecular details of the signaling integration …

Chronic Inflammatory Responses To Microgel-Based Implant Coatings, Amanda W. Bridges, Rachel E. Whitmire, Neetu Singh, Kellie L. Templeman, Julia E. Babensee, L. Andrew Lyon, Andrés J. García

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Inflammatory responses to implanted biomedical devices elicit a foreign body fibrotic reaction that limits device integration and performance in various biomedical applications. We examined chronic inflammatory responses to microgel conformal coatings consisting of thin films of poly(N-isopropylacrylamide) hydrogel microparticles cross-linked with poly(ethylene glycol) diacrylate deposited on poly(ethylene terephthalate) (PET). Unmodified and microgel-coated PET disks were implanted subcutaneously in rats for 4 weeks and explants were analyzed by histology and immunohistochemistry. Microgel coatings reduced chronic inflammation and resulted in a more mature/organized fibrous capsule. Microgel-coated samples exhibited 22% thinner fibrous capsules that contained 40% fewer cells compared to unmodified PET disks. …

Prognostic Significance Of Trail Death Receptors In Middle Eastern Colorectal Carcinomas And Their Correlation To Oncogenic Kras Alterations, Prashant Bavi, Sarita E Prabhakaran, Jehad Abubaker, Zeeshan Qadri, Thara George, Nasser Al-Sanea, Alaa Abduljabbar, Luai H Ashari, Samar Alhomoud, Fouad Al-Dayel, Azhar Hussain, Shahabuddin, Khawla S Al-Kuraya

Centre for Regenerative Medicine & Stem Cell Research

Background: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4) and TRAIL receptor 2 (DR5). Expression of TRAIL receptors is higher in colorectal carcinoma (CRC) as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells.
Methods: We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological …

Letter To The Editor: Reproductive Toxicology, Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

What Are The Reproductive And Developmental Risks Of Ionizing Radiation?, Robert L. Brent Dr.

The Selected Works of Robert Brent

None

Differential Impact Of Tumor Suppressor Pathways On Dna Damage Response And Therapy-Induced Transformation In A Mouse Primary Cell Model., A Kathleen Mcclendon, Jeffry L Dean, Adam Ertel, Erik S Knudsen

Department of Cancer Biology Faculty Papers

The RB and p53 tumor suppressors are mediators of DNA damage response, and compound inactivation of RB and p53 is a common occurrence in human cancers. Surprisingly, their cooperation in DNA damage signaling in relation to tumorigenesis and therapeutic response remains enigmatic. In the context of individuals with heritable retinoblastoma, there is a predilection for secondary tumor development, which has been associated with the use of radiation-therapy to treat the primary tumor. Furthermore, while germline mutations of the p53 gene are critical drivers for cancer predisposition syndromes, it is postulated that extrinsic stresses play a major role in promoting varying …