Medical Sciences Commons^™

Deletion Of Shank1 Has Minimal Effects On The Molecular Composition And Function Of Glutamatergic Afferent Postsynapses In The Mouse Inner Ear, Jeremy P. Braude, Sarath Vijayakumar, Katherine Baumgarner, Rebecca Laurine, Timothy A. Jones, Sherri M. Jones, Sonya J. Pyott

Department of Special Education and Communication Disorders: Faculty Publications

Abstract

Shank proteins (1-3) are considered the master organizers of glutamatergic postsynaptic densities in the central nervous system, and the genetic deletion of either Shank1, 2, or 3 results in altered composition, form, and strength of glutamatergic postsynapses. To investigate the contribution of Shank proteins to glutamatergic afferent synapses of the inner ear and especially cochlea, we used immunofluorescence and quantitative real time PCR to determine the expression of Shank1, 2, and 3 in the cochlea. Because we found evidence for expression of Shank1 but not 2 and 3, we investigated the morphology, composition, and function of afferent postsynaptic densities …

The Cell's Antenna And Bending With The Flow, Surya M. Nauli, Kimberly F. Atkinson, Sarmed H. Kathem

Pharmacy Faculty Articles and Research

Polycystic kidney disease (PKD) is the most common life-threatening genetic disease worldwide – affecting about 12.5 million people. Patients with the condition have multiple fluid-filled cysts in their kidneys that lead to a massive enlargement of the organ and gradual worsening of its function, as well as complete failure in many cases. The lack of available treatment means patients may eventually require regular dialysis or a kidney transplant.

Rgs16, A Novel P53 And Prb Cross-Talk Candidate Inhibits Migration And Invasion Of Pancreatic Cancer Cells, Miranda B. Carper, James Denvir, Goran Boskovic, Donald A. Primerano, Pier Paolo Claudio

Biochemistry and Microbiology

Data collected since the discovery of p53 and pRb/RB1 suggests these tumor suppressors cooperate to inhibit tumor progression. Patients who have mutations in both p53 and RB1 genes have increased tumor reoccurrence and decreased survival compared to patients with only one tumor suppressor gene inactivated. It remains unclear how p53 and pRb cooperate toward inhibiting tumorigenesis. Using RNA expression profiling we identified 179 p53 and pRb cross-talk candidates in normal lung fibroblasts (WI38) cells exogenously coexpressing p53 and pRb. Regulator of G protein signaling 16 (RGS16) was among the p53 and pRb cross-talk candidates and has been implicated in inhibiting …

Utilizing Haplotypes For Sensitive Snp Array-Based Discovery Of Somatic Chromosomal Mutations, Selina M. Vattathil

Dissertations and Theses (Open Access)

Somatic copy-number (CN) gains and losses and copy-neutral loss of heterozygosity (CNLOH) frequently occur in tumors and play a major role in the progression of disease by altering gene dosage and unmasking deleterious recessive variants. Characterizing these mutations in an individual tumor sample is therefore critical for research on the relationship of specific mutations to disease outcome and for clinical decision-making based on mutations with known impact. A pervasive hindrance to sensitive detection of these mutations is genetic heterogeneity and high levels of contaminating normal cells in tumor samples, which limit the fraction of cells carrying informative mutations. The method …

Cryptorchidism And Infertility In Rats With Targeted Disruption Of The Adamts16 Locus, Shakila Abdul-Majeed, Blair Mell, Surya M. Nauli, Bina Joe

Pharmacy Faculty Articles and Research

A Disintegrin And Metalloproteinase with ThromboSpondin motifs16 (ADAMTS-16) is a member of a family of metalloproteinases. Using a novel zinc-finger nuclease based gene-edited rat model harboring a targeted mutation of the Adamts16 locus, we previously reported this gene to be linked to blood pressure regulation. Here we document our observation with this model that Adamts16 is essential for normal development of the testis. Absence of Adamts16 in the homozygous Adamts16(mutant) males resulted in cryptorchidism and male sterility. Heterozygous Adamts16(mutant) males were normal, indicating that this is a recessive trait. Testes of homozygous Adamts16(mutant) males were significantly smaller with significant histological …

Latinas And The Traditional Genetic Counseling Model: A Qualitative Study, Stephanie Thompson

Dissertations and Theses (Open Access)

The traditional genetic counseling model reflects an individualized counseling session that includes the presentation of information about genes, chromosomes, personalized risk assessment, and genetic testing and screening options. Counselors are challenged to balance providing educational information with discussion of implications of this information in an allotted amount of time. The aim of this study was to explore the perceptions of pregnant Latinas on the benefits and limitations of the traditional prenatal genetic counseling model and to determine the specific preferences for receiving prenatal genetic counseling. Data were collected through focus groups and one-on-one, semi-structured interviews of twenty-five Spanish speaking Latinas …

How Spinocerebellar Ataxia Affects The Body And The Family, Anthony Simpson

Thinking Matters Symposium Archive

This poster project is a literature review that examines the causes, effects, and research being done to treat and prevent some forms of Ataxia. Ataxia is a disorder of the nervous system that causes tremors, and problems with walking, balance, memory, and mood disorders. There are many forms of Ataxia, all affecting various genes, but all have the devastating effect of the loss of the ability to move around without aid. Mental ability is not affected, yet the patient loses the ability to control their body. Most forms are caused by genetic mutations. For example, Fragile X associated tremor/ataxia syndrome …

Pedigree Structure And Kinship Measurements Of A Mid-Michigan Community: A New North American Population Isolate Identified, Joseph D. Bonner, Rachel Fisher, James Klein, Qing Lu, Ellen Wilch, Karen H. Friderici, Jill L. Elfenbein, Debra L. Schutte, Brian C. Schutte

Human Biology Open Access Pre-Prints

Previous studies identified a cluster of individuals with an autosomal recessive form of deafness that resides in a small region of mid-Michigan. We hypothesized that affected members from this community descend from a defined founder population. Using public records and personal interviews, we constructed a genealogical database that includes the affected individuals and their extended families as descendants of 461 settlers who emigrated from the Eifel region of Germany between 1836 and 1875. The genealogical database represents a 13-generation pedigree that includes 27,747 descendants of these settlers. Among these descendants, 13,784 are presumed living. Many of the extant descendants reside …

Lactase Persistence Variants In Arabia And In The African Arabs, Edita Priehodova, Abdelhay Abdelsawy, Evelyne Heyer, Viktor Cerny

Human Biology Open Access Pre-Prints

Lactase persistence (LP), the state enabling the digestion of milk sugar in adulthood occurs only in some human populations. The convergent and independent origin of this physiological ability in Europe and Africa is linked with animal domestication that had either started in both places independently or had spread from the Near East by acculturation. However, it has recently been shown that at least in its southern parts, the population of Arabia not only has a different LP-associated mutation profile than the rest of Africa and Europe but had also experienced an independent demographic expansion occurring before the Neolithic around the …

Retinoic Acid Regulation Of Thyroid Hormone Action In Bone Cells, Anjali Babbar

Loma Linda University Electronic Theses, Dissertations & Projects

Retinoic acid and thyroid hormone are known to play key roles in the regulation of endochondral ossification. However, the issue of whether these two hormones interact with each other to regulate bone functions remains to be established. We investigated how thyroid hormone and retinoic acid interact to regulate cells involved in endochondral bone formation. We demonstrate that thyroid hormone treatment stimulates differentiation of ATDC5 chondrocytes and promotes formation of mineralized nodules while retinoic acid treatment at high dose inhibits chondrocyte differentiation and formation of mineralized nodules. Furthermore, thyroid hormone induced mineralized nodule formation is inhibited by co-treatment with retinoic acid …

Mapping Genes With Longitudinal Phenotypes Via Bayesian Posterior Probabilities, Anthony Musolf, Alejandro Q. Nato Jr., Douglas Londono, Lisheng Zhou, Tara C. Matise, Derek Gordon

Biochemistry and Microbiology

Most association studies focus on disease risk, with less attention paid to disease progression or severity. These phenotypes require longitudinal data. This paper presents a new method for analyzing longitudinal data to map genes in both population-based and family-based studies. Using simulated systolic blood pressure measurements obtained from Genetic Analysis Workshop 18, we cluster the phenotype data into trajectory subgroups. We then use the Bayesian posterior probability of being in the high subgroup as a quantitative trait in an association analysis with genotype data. This method maintains high power (>80%) in locating genes known to affect the simulated phenotype …

Assessing Function And Endurance In Adults With Spinal And Bulbar Muscular Atrophy: Validity Of The Adult Myopathy Assessment Tool., Michael O. Harris-Love, Lindsay Fernandez-Rhodes, Galen Joe, Joseph A. Shrader, Angela Kokkinis, Alison La Pean Kirschner, Sungyoung Auh, Cheunju Chen, Li Li, Ellen Levy, Todd E. Davenport, Nicholas A. Di Prospero, Kenneth H. Fischbeck

Exercise and Nutrition Sciences Faculty Publications

Purpose. The adult myopathy assessment tool (AMAT) is a performance-based battery comprised of functional and endurance subscales that can be completed in approximately 30 minutes without the use of specialized equipment. The purpose of this study was to determine the construct validity and internal consistency of the AMAT with a sample of adults with spinal and bulbar muscular atrophy (SBMA).

Methods. AMAT validity was assessed in 56-male participants with genetically confirmed SBMA (mean age, 53 ± 10 years). The participants completed the AMAT and assessments for disease status, strength, and functional status. Results. Lower AMAT scores were associated with longer …

Immobilizing Mutation In An Unconventional Myosin15a Affects Not Only The Structure Of Mechanosensory Stereocilia In The Inner Ear Hair Cells But Also Their Ionic Conductances, Diana Syam

Theses and Dissertations--Medical Sciences

In the inner and outer hair cells (OHCs) of the inner ear, an unconventional myosin 15a localizes at the tips of mechanosensory stereocilia and plays an important role in forming and maintaining their normal structure. A missense mutation makes the motor domain of myosin 15a dysfunctional and is responsible for the congenital deafness DFNB3 in humans and deafness and vestibular defects in Shaker-2 (Sh2) mouse model. All hair cells of homozygous Shaker-2 mice (Myo15^sh2/sh2) have abnormally short stereocilia, but, only stereocilia of Myo15^sh2/sh2OHCs start to degenerate after the first few days of postnatal development …

Chemopreventive Effects Of Pterostilbene In Metastatic Prostate Cancer Cells, Phillip A. Zook

PCOM Biomedical Studies Student Scholarship

Recent studies find that pterostilbene (PTS) exhibits more favorable drug properties and similar chemopreventive effects to its structural analogue resveratrol (RSV). However, few studies describe the activity of PTS in prostate cancer (PCa). Here, we conducted cell count experiments to assess the effects of PTS on metastatic PCa cell viability and to compare the potency of PTS to RSV in this respect. We also performed experiments to assess the effects of PTS on the androgen receptor (AR) and AR-mediated events. We used qPCR to measure the mRNA levels of the androgenresponsive gene (ARG), prostate-specific antigen (PSA), and Western blots to …

Conformational Changes And Translocation Of Tissue-Transglutaminase To The Plasma Membranes: Role In Cancer Cell Migration, Ambrish Kumar, Jianjun Hu, Holly A. Lavoie, Kenneth B. Walsh, Donald J. Dipette, Ugra S. Singh

Faculty Publications

Background

Tissue-transglutaminase (TG2), a dual function G-protein, plays key roles in cell differentiation and migration. In our previous studies we reported the mechanism of TG2-induced cell differentiation. In present study, we explored the mechanism of how TG2 may be involved in cell migration.

Methods

To study the mechanism of TG2-mediated cell migration, we used neuroblastoma cells (SH-SY5Y) which do not express TG2, neuroblastoma cells expressing exogenous TG2 (SHY_TG2), and pancreatic cancer cells which express high levels of endogenous TG2. Resveratrol, a natural compound previously shown to inhibit neuroblastoma and pancreatic cancer in the animal models, was utilized to …

Caspase-12 And Rheumatoid Arthritis In African-Americans, Laura Marshall, Mohammad Obaidullah, Trista Fuchs, Naomi S. Fineberg, Garland Brinkley, Ted R. Mikuls, Evan Hermel

Faculty Publications & Research of the TUC College of Osteopathic Medicine

CASPASE-12 (CASP12) has a downregulatory function during infection and thus may protect against inflammatory disease. We investigated the distribution of CASP12 alleles (#rs497116) in African-Americans (AA) with rheumatoid arthritis (RA). CASP12 alleles were genotyped in 953 RA patients and 342 controls. Statistical analyses comparing genotype groups were performed using Kruskal–Wallis non-parametric ANOVA with Mann–Whitney U tests and chi-square tests. There was no significant difference in the overall distribution of CASP12 genotypes within AA with RA, but CASP12 homozygous patients had lower baseline joint-narrowing scores. CASP12 homozygosity appears to be a subtle protective factor for some aspects of RA in AA …

Analysis Of The Role Of Astrocyte Elevated Gene-1 In Normal Liver Physiology And In The Onset And Progression Of Hepatocellular Carcinoma, Chadia L. Robertson

Theses and Dissertations

First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction …

In Vivo Bioluminescence Imaging To Evaluate Systemic And Topical Antibiotics Against Community-Acquired Methicillin-Resistant Staphylococcus Aureus-Infected Skin Wounds In Mice, Yi Guo, Romela Irene Ramos, John S. Cho, Niles P. Donegan, Ambrose L. Cheung, Lloyd S. Miller

Dartmouth Scholarship

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) frequently causes skin and soft tissue infections, including impetigo, cellulitis, folliculitis, and infected wounds and ulcers. Uncomplicated CA-MRSA skin infections are typically managed in an outpatient setting with oral and topical antibiotics and/or incision and drainage, whereas complicated skin infections often require hospitalization, intravenous antibiotics, and sometimes surgery. The aim of this study was to devel

Developmental Genes Targeted For Epigenetic Variation Between Twin-Twin Transfusion Syndrome Children, Carmen J. Marsit, Devin C. Koestler, Debra Watson-Smith, Charlotte M. Boney

Dartmouth Scholarship

Background: Epigenetic mechanisms are thought to be critical in mediating the role of the intrauterine environment on lifelong health and disease. Twin-twin transfusion syndrome (TTTS) is a rare condition wherein fetuses share the placenta and develop vascular anastomoses, which allow blood to flow between the fetuses. The unequal flow results in reciprocal hypo- and hypervolemia in the affected twins, striking growth differences and physiologic adaptations in response to this significant stressor. The donor twin in the TTTS syndrome can be profoundly growth restricted and there is likely a nutritional imbalance between the twins. The consequences of TTTS on fetal programming …

A Simple And Computationally Efficient Approach To Multifactor Dimensionality Reduction Analysis Of Gene-Gene Interactions For Quantitative Traits, Jiang Gui, Jason H. Moore, Scott M. Williams, Peter Andrews, Hillege, Hans L. Hillege, Hans L., Pim Van Der Harst, Gerjan| Navis, Wiek H. Van Gilst, Folkert W. Asselbergs, Diane| Gilbert-Diamond

Dartmouth Scholarship

We present an extension of the two-class multifactor dimensionality reduction (MDR) algorithm that enables detection and characterization of epistatic SNP-SNP interactions in the context of a quantitative trait. The proposed Quantitative MDR (QMDR) method handles continuous data by modifying MDR’s constructive induction algorithm to use a T-test. QMDR replaces the balanced accuracy metric with a T-test statistic as the score to determine the best interaction model. We used a simulation to identify the empirical distribution of QMDR’s testing score. We then applied QMDR to genetic data from the ongoing prospective Prevention of Renal and Vascular End-Stage Disease (PREVEND) study.

Truncation Of Type Iv Pilin Induces Mucoidy In Pseudomonas Aeruginosa Strain Pao579, T. Ryan Withers, F. Heath Damron, Yeshi Yin, Hongwei D. Yu

Biochemistry and Microbiology

Pseudomonas aeruginosa is a Gram negative, opportunistic pathogen that uses the overproduction of alginate, a surface polysaccharide, to form biofilms in vivo. Overproduction of alginate, also known as mucoidy, affords the bacterium protection from the host's defenses and facilitates the establishment of chronic lung infections in individuals with cystic fibrosis. Expression of the alginate biosynthetic operon is primarily controlled by the alternative sigma factor AlgU (AlgT/σ²²). In a nonmucoid strain, AlgU is sequestered by the transmembrane antisigma factor MucA to the cytoplasmic membrane. AlgU can be released from MucA via regulated intramembrane proteolysis by proteases AlgW and MucP …

Influence Of Genetic Variation On Birth Defects In Caenorhabditis Elegans, Daniel Robert Kepple

Renée Crown University Honors Thesis Projects - All

In my Renee Crown Honors Capstone project, I studied how genetic variation influences birth defects that cause death in C. elegans embryos. I performed high-throughput hatching assay experiments of recombinant inbred advance intercross lines of C. elegans. These lines are genetically distinct from each other. I found significant variation in birth defects causing embryo death in these recombinant inbred advanced intercross lines. My results give evidence that gene interaction may play a significant role in causing birth defects resulting in death. My data also provides a starting point for studies making statistical arguments linking these birth defects to specific …

Systems Biology Of The Functional And Dysfunctional Endothelium, Jennifer Frueh, Nataly Maimari, Takayuki Homma, Sandra M. Bovens, Ryan M. Pedrigi, Leila Towhidi, Rob Krams

Department of Mechanical and Materials Engineering: Faculty Publications

This review provides an overview of the effect of blood flow on endothelial cell (EC) signalling pathways, applying microarray technologies to cultured cells, and in vivo studies of normal and atherosclerotic animals. It is found that in cultured ECs, 5–10% of genes are up- or down-regulated in response to fluid flow, whereas only 3–6% of genes are regulated by varying levels of fluid flow. Of all genes, 90%are regulated by the steady part of fluid flow and 10% by pulsatile components. The associated gene profiles show high variability from experiment to experiment depending on experimental conditions, and importantly, the bioinformatical …

The Roles Of Primary Cilia In Polycystic Kidney Disease, Samred H. Kathem, Ashraf M. Mohieldin, Surya M. Nauli

Pharmacy Faculty Articles and Research

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disorder that results in progressive renal cyst formation with ultimate loss of renal function and other systemic disorders. These systemic disorders include abnormalities in cardiovascular, portal, pancreatic and gastrointestinal systems. ADPKD is considered to be among the ciliopathy diseases due to the association with abnormal primary cilia function. In order to understand the full course of primary cilia and its association with ADPKD, the structure, functions and role of primary cilia have been meticulously investigated. As a result, the focus on primary cilia has emerged to support the vital roles …

Acute Hypersensitivity Of Pluripotent Testicular Cancer-Derived Embryonal Carcinoma To Low-Dose 5-Aza Deoxycytidine Is Associated With Global Dna Damage-Associated P53 Activation, Anti-Pluripotency And Dna Demethylation, Bijesh K. Biswal, Maroun J. Beyrouthy, Mary P. Hever-Jardine, David Armstrong, Craig R. Tomlinson, Brock C. Christensen, Carmen J. Marsit, Michael J. Spinella

Dartmouth Scholarship

Human embryonal carcinoma (EC) cells are the stem cells of nonseminoma testicular germ cells tumors (TGCTs) and share remarkable similarities to human embryonic stem (ES) cells. In prior work we found that EC cells are hypersensitive to low nanomolar doses of 5-aza deoxycytidine (5-aza) and that this hypersensitivity partially depended on unusually high levels of the DNA methyltransferase, DNMT3B. We show here that low-dose 5-aza treatment results in DNA damage and induction of p53 in NT2/D1 cells. In addition, low-dose 5-aza results in global and gene specific promoter DNA hypomethylation. Low- dose 5-aza induces a p53 transcriptional signature distinct from …

The Prevalence Of Essential Hypertension In Kasigau, Kenya, Lindsay Williams

Mahurin Honors College Capstone Experience/Thesis Projects

Hypertension is the leading cause of cardiovascular disease worldwide. Cardiovascular disease (CVD) is a widespread chronic non-communicable disease (NCD) which is on the rise in developing countries. Evidence based on extensive research studies on risk factors for NCDs suggests that they could be easily significantly decreased by simply controlling their risk factors. Although high blood pressure has been recognized as a leading risk factor for CVD, little research has been done to document the prevalence and incidence of essential hypertension (EH) in lower socioeconomic developing countries. One such country is Kenya. It was found in our research study that Kasigau …

Epigenetics: A Possible Mechanism Of Memory, Aliza Grossman Rubenstein

The Science Journal of the Lander College of Arts and Sciences

The following is an excerpt from the introduction to this article: The mind-body connection has fascinated philosophers and scientists for centuries. How is it possible that consciousness arises from a lump of matter known as the brain? How does neurons’ firing affect choice and beliefs? How do the electrochemical properties of the brain allow for the memory of events long after they’ve occurred? One of the most studied of these areas is that of memory. Researchers seek to understand the biological basis behind memory and how that biology is affected in individuals suffering from memory disorders.

Higher Il-6 And Il6:Igf Ratio In Patients With Barth Syndrome, Lori D. Wilson, Sadeeka Al-Majid, Cyril Rakovski, Christina D. Schwindt

Mathematics, Physics, and Computer Science Faculty Articles and Research

Background: Barth Syndrome (BTHS) is a serious X-linked genetic disorder associated with mutations in the tafazzin gene (TAZ, also called G4.5). The multi-system disorder is primarily characterized by the following pathologies: cardiac and skeletal myopathies, neutropenia, growth delay, and exercise intolerance. Although growth anomalies have been widely reported in BTHS, there is a paucity of research on the role of inflammation and the potential link to alterations in growth factors levels in BTHS patients.

Methods: Plasma from 36 subjects, 22 patients with Barth Syndrome (0.5 - 24 yrs) and 14 healthy control males (8 - 21 yrs) was …

Overt Cleft Palate Phenotype And Tbx1 Genotype Correlations In Velo-Cardio-Facial/Digeorge/22q11.2 Deletion Syndrome Patients, Sean Herman, Tingwei Guo, Donna M. Mcdonald Mcginn, Anna Blonska, Alan L. Shanske, Anne S. Bassett, Eva Chow, Mark Bowser, Molly Sheridan, Frits Beemer, Koen Devriendt, Ann Swillen, Jeroen Breckpot, Maria Christina Digilio, Bruno Marino, Bruno Dallapiccola, Courtney Carpenter, Xin Zheng, Jacob Johnson, Jonathan Chung, Anne Marie Higgins, Nicole Philip, Tony J. Simon, Karlene Coleman, Damian Heine Suñer, Jordi Rosell, Wendy R. Kates, Marcella Devoto, Elaine Zackai, Tao Wang, Robert J. Shprintzen, Beverly Emanuel, Bernice Morrow, International Chromosome 22q11.2 Consortium

Communication Disorders Faculty Publications

Velo-cardio-facial syndrome/DiGeorge syndrome, also known as 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome, with an estimated incidence of 1/2,000 – 1/4,000 live births. Approximately 9–11% of patients with this disorder have an overt cleft palate (CP), but the genetic factors responsible for CP in the 22q11DS subset are unknown. The TBX1 gene, a member of the T-box transcription factor gene family, lies within the 22q11.2 region that is hemizygous in patients with 22q11DS. Inactivation of one allele of Tbx1 in the mouse does not result in CP, but inactivation of both alleles does. Based on these data, …

P40: The Missing Link Between Autophagy And Cancer?, Mittul Patel

Kaleidoscope

No abstract provided.