Diseases Commons^™

When Old-Order Amish Meet New Order Science: Genetic Maladies And The Amish Dilemma, Kelley Downey

Undergraduate Research Conference

The Old World Amish, an Anabaptist Christian domination in the United States and Canada are know for their plain dress, avoidance of modern technology, and separation from the mainstream society.

A traditional agricultural religious group, the Old World Amish maintains isolation from the rest of the community. Financially well-off, they are homogeneous on education, occupation by gender, age at marriage, religion/ethnicity, and health care.

Although the Amish strongly discourage marriage between close cousins, the Lancaster Amish genealogy is described as mutational - inbreeding from multiple, remote connections rather than close consanguinity (first-cousin marriages).

Amish settlements have been identified with certain …

Paracrine Sonic Hedgehog Signalling By Prostate Cancer Cells Induces Osteoblast Differentiation, Samantha M Zunich, Taneka Douglas, Maria Valdovinos, Tiffany Chang

Dartmouth Scholarship

Sonic hedgehog (Shh) and components of its signalling pathway have been identified in human prostate carcinoma and increased levels of their expression appear to correlate with disease progression and metastasis. The mechanism through which Shh signalling could promote metastasis in bone, the most common site for prostate carcinoma metastasis, has not yet been investigated. The present study determined the effect of Shh signalling between prostate cancer cells and pre-osteoblasts on osteoblast differentiation, a requisite process for new bone formation that characterizes prostate carcinoma metastasis.

Corr4a And Vrt325 Do Not Reduce The Inflammatory Response To P. Aeruginosa In Human Cystic Fibrosis Airway Epithelial Cells, Laleh Talebian, Bonita Coutermarsh, Jacqueline Y. Channon, Bruce A. Stanton

Dartmouth Scholarship

P. aeruginosa chronically colonizes the lung in CF patients and elicits a proinflammatory response. Excessive secretion of IL-6 and IL-8 by CF airway cells in response to P. aeruginosa infection in the CF airway is though to contribute to lung injury. Accordingly, the goal of this study was to test the hypothesis that Corr4a and VRT325, investigational compounds that increase ΔF508-CFTR mediated Cl⁻ secretion in human CF airway cells, reduce the pro-inflammatory response to P. aeruginosa.

Loss Of Ski Expression In Testicular Cancer Leads To An Enhanced Invasive Phenotype Through Both Bmp-Dependent And Bmp-Independent Pathways, Amy N. Nash

Theses, Dissertations and Capstones

The proto-oncogene SKI is a transcription factor and a co-repressor of the TGFβ superfamily, including TGF

β and BMP. However, additional data suggests that SKI may function as a tumor suppressor in some cell types. The TGFβ superfamily has been implicated in cancer progression and germ cell migration. Testicular cancer afflicts men during their peak reproductive years and is the most common cancer among men of this age group. Cisplatin-based chemotherapy is the standard treatment for testicular cancer. This treatment can lead to undesirable side effects, including infertility. We have shown that SKI expression is decreased in testicular germ cell …

Combined Effects Of Hyperglycemic Conditions And Hiv-1 Nef: A Potential Model For Induced Hiv Neuropathogenesis., Edward A Acheampong, Cassandra Roschel, Muhammad Mukhtar, Alagarsamy Srinivasan, Mohammad Rafi, Roger J Pomerantz, Zahida Parveen

Department of Neurology Faculty Papers

Hyperglycemic conditions associated with diabetes mellitus (DM) or with the use of antiretroviral therapy may increase the risk of central nervous system (CNS) disorders in HIV-1 infected patients. In support of this hypothesis, we investigated the combined effects of hyperglycemic conditions and HIV-1 accessory protein Nef on the CNS using both in vitro and in vivo models. Astrocytes, the most abundant glial cell type required for normal synaptic transmission and other functions were selected for our in vitro study. The results show that in vitro hyperglycemic conditions enhance the expression of proinflammatory cytokines including caspase-3, complement factor 3 (C3), and …

Cryo-Electron Tomography Elucidates The Molecular Architecture Of Treponema Pallidum, The Syphilis Spirochete, Jacques Izard, Christian Renken, Chyong-Ere Hsieh, Daniel C. Desrosiers, Star Dunham-Ems, Carson La Vake, Linda L. Gebhardt, Ronald J. Limberger, David L. Cox, Michael Marko, Justin D. Radolf

Department of Food Science and Technology: Faculty Publications

Cryo-electron tomography (CET) was used to examine the native cellular organization of Treponema pallidum, the syphilis spirochete. T. pallidum cells appeared to form flat waves, did not contain an outer coat and, except for bulges over the basal bodies and widening in the vicinity of flagellar filaments, displayed a uniform periplasmic space. Although the outer membrane (OM) generally was smooth in contour, OM extrusions and blebs frequently were observed, highlighting the structure’s fluidity and lack of attachment to underlying periplasmic constituents. Cytoplasmic filaments converged from their attachment points opposite the basal bodies to form arrays that ran roughly …

Regulation Of The Human Parainfluenza Virus (Hpiv3) Fusion Protein, Amanda Ruth Chapman

Theses and Dissertations (ETD)

Paramyxoviruses include a number of important human pathogens, including measles virus, mumps virus, and the human parainfluenza viruses (hPIV) 1-4, as well as several animal pathogens, such as Sendai virus, Nipah virus and Hendra virus. The creation of effective drugs and vaccines against this family of viruses would play an important role in decreasing the prevalence of these viruses and contributing to the health of both humans and animals worldwide. The purpose of this work was to determine how the fusion (F) protein is regulated with a focus on the heptad repeat B (HRB) region of the F protein located …

Immune Evasion By Rabies Viruses Through The Maintenance Of Blood-Brain Barrier Integrity., Anirban Roy, Douglas C. Hooper

Department of Cancer Biology Faculty Papers

The attenuated rabies virus (RV) strain Challenge Virus Standard (CVS)-F3 and a highly pathogenic strain associated with the silver-haired bats (SHBRV) can both be cleared from the central nervous system (CNS) tissues by appropriate antiviral immune mechanisms if the effectors are provided access across the blood-brain barrier (BBB). In the case of SHBRV infection, antiviral immunity develops normally in the periphery but fails to open the BBB, generally resulting in a lethal outcome. To determine whether or not an absence in the CNS targeted immune response is associated with the infection with other pathogenic RV strains, we have assessed the …

Answering The Cdc's Call For Universal Hiv Testing: Assesing The Impact On A Tertiary Care Referral Center Via A Blinded Seroprevalence Study, Margaret Hoffman-Terry Md, Facp, K Nadeem Ahmed Md, Joseph L. Yozviak Do, Facp, Sherrine Eid Mph, Timothy J. Friel Md, Kimberly A. Pacella, Luther Rhodes Iii Md

Department of Medicine

No abstract provided.

Distinct Functions Of Autoreactive Memory And Effector Cd4+ T Cells In Experimental Autoimmune Encephalomyelitis, Wassim Elyaman, Pia Kivisäkk, Jay Reddy, Tanuja Chitnis, Khadir Raddassi, Jaime Imitola, Elizabeth Bradshaw, Vijay K. Kuchroo, Hideo Yagita, Mohamed H. Sayegh, Samia J. Khoury

Jay Reddy Publications

The persistence of human autoimmune diseases is thought to be mediated predominantly by memory T cells. We investigated the phenotype and migration of memory versus effector T cells in vivo in experimental autoimmune encephalomyelitis (EAE). We found that memory CD4⁺ T cells up-regulated the activation marker CD44 as well as CXCR3 and ICOS, proliferated more and produced more interferon-γ and less interleukin-17 compared to effector T cells. Moreover, adoptive transfer of memory T cells into T cell receptor (TCR)αβ^-/- recipients induced more severe disease than did effector CD4⁺ T cells with marked central nervous system inflammation and …

Surface Charge Effects Involved In The Control Of Stability Of Sols Comprising Uniform Cholesterol Particles, Vuk Uskoković

Pharmacy Faculty Articles and Research

The reported is a method for the preparation of stable dispersions of narrowly dispersed cholesterol crystals, which may provide an excellent model for the aggregation studies thereof. The effects of experimental parameters that include concentration, pH, ionic strength, temperature, and aging on the resulting morphologies are acknowledged. Regardless of the cause of destabilization, the multilayered aggregates of cholesterol particles are formed by “face-to-face” stacking of the original platelets, as promoted by higher surface charge density on particle sides comparing to their faces. In accordance with the crucial involvement of surface charge effects in stabilization of cholesterol dispersions produced hereby, aggregation …

Programmed Death 1 Ligand Signaling Regulates The Generation Of Adaptive Foxp3+Cd4+ Regulatory T Cells, Li Wang, Kirina Pino-Lagos, Victor C. De Vries, Indira Guleria, Mohamed H. Sayegh, Randolph J. Noelle

Dartmouth Scholarship

Although mature dendritic cells (DCs) are potent initiators of adaptive immune response, immature steady-state DCs contribute to immune tolerance. In this study, we show that ex vivo splenic DCs are capable of inducing conversion of naïve CD4(+) T cells to adaptive Foxp3(+)CD4(+) regulatory T cells (aTreg) in the presence of TGF-beta. In particular, when compared with splenic CD8alpha(-) DCs, the CD8alpha(+) DC subset were superior in inducing higher frequencies of conversion. This was not attributable to the difference in basal level of costimulation, because deficiency of CD40 or CD80/86 signaling did not diminish the differential induction of Foxp3. Conversion was …

Novel Binding Domains Mediate Binding Of Hpv 16 E6 To Fadd And Procaspase 8, Sandy S. Tungteakkhun

Loma Linda University Electronic Theses, Dissertations & Projects

To evade the host response to infection, viruses have developed means to survive and propagate. HPV 16, a causative agent of cervical cancer and of some cases of oropharyngeal cancers, is one example. We have reported that the early viral protein E6 binds to proteins necessary for propagation of the apoptotic signal following receptor/ligand interactions, such as those mediated by FADD DED and procaspase 8 DED. E6 expression leads to the dose-dependent accelerated degradation of FADD and the protection of E6-expressing cells from Fas-induced apoptosis. Surprisingly, the splice isoforms of E6, E6_large and E6*, affect the stability of procaspase …

Insights Into Morphological Nature Of Precipitation Of Cholesterol, Vuk Uskoković

Pharmacy Faculty Articles and Research

Additional effects on the previously reported procedure of precipitation of narrowly dispersed and well-defined, brick-shaped cholesterol particles, including non-solvent addition rate, temperature, solvent purity, aging treatments, ultrasound agitation and fine mechanical effects were investigated. Based on the presented results, significant morphological sensitivity of cholesterol precipitation processes upon variations from the standard established procedure of crystallization is induced. However, the tendency of cholesterol to crystallize in the form of biaxially grown particles was evidenced as dominating the precipitation processes, irrespective of any modifications of experimental parameters involved in the preparation procedure investigated hereby. Prolonged aging time and temperature effects lead to …

Application Of Prodrugs To Inflammatory Diseases Of The Gut, Helieh S. Oz, Jeffrey L. Ebersole

Center for Oral Health Research Faculty Publications

Oral delivery is the most common and preferred route of drug administration although the digestive tract exhibits several obstacles to drug delivery including motility and intraluminal pH profiles. The gut milieu represents the largest mucosal surface exposed to microorganisms with 10^10-12 colony forming bacteria/g of colonic content. Approximately, one third of fecal dry matter is made of bacteria/ bacterial components. Indeed, the normal gut microbiota is responsible for healthy digestion of dietary fibers (polysaccharides) and fermentation of short chain fatty acids such as acetate and butyrate that provide carbon sources (fuel) for these bacteria. Inflammatory bowel disease (IBD) results …

Diabetes Alters Contraction-Induced Mitogen Activated Protein Kinase Activation In The Rat Soleus And Plantaris, Anjaiah Katta, Deborah L. Preston, Sunil K. Kakarla, Shinichi Asano, Sarath Meduru, Sriram P. Mupparaju, Ellie Yokochi, Kevin M. Rice, Devashish H. Desai, Eric R. Blough

MIIR Faculty Research

The prescription of anaerobic exercise has recently been advocated for the management of diabetes; however exercise-induced signaling in diabetic muscle remains largely unexplored. Evidence from exercise studies in nondiabetics suggests that the extracellular-signal-regulated kinases (Erk1/2), p38, and c-JUN NH2-terminal kinase (Jnk) mitogen-activated protein kinases (MAPKs) are important regulators of muscle adaptation. Here, we compare the basal and the in situ contraction-induced phosphorylation of Erk1/2- p38- and Jnk-MAPK and their downstream targets (p90rsk and MAPKAP-K2) in the plantaris and soleus muscles of normal and obese (fa/fa) Zucker rats. Compared to lean animals, the time course and magnitude of Erk1/2, p90rsk and …

The Mind-Body Connection: The Association Between Adolescent Locus Of Control And Indicators Of Physical Health, C. Jayne Brahler, James Cropper

Physical Therapy Faculty Publications

Locus of control (LOC) describes an individual’s generalized beliefs or expectancies that their reinforcements are under internal versus external control (1). An individual exhibits either an internal or external LOC. This study examines the link between LOC and selected health risk factors in adolescents. A convenience sample of 167 high school physical education students completed a 13-item LOC questionnaire based on Rotter’s 1966 instrument.

Various anthropometric measurements, blood pressure, body mass index (BMI), and body fat were recorded on all subjects. A subsample of 61 female students received blood chemistry analysis that included a lipid profile, hemoglobin A1c (HbA1c), Apo …

Composites Comprising Cholesterol And Carboxymethyl Cellulose, Vuk Uskoković

Pharmacy Faculty Articles and Research

Whereby cholesterol presents one of the major fatty substances in human body, carboxymethyl cellulose is a water-soluble derivative of cellulose, the most abundant dietary fiber. Whereas on one hand in vivo precipitation of cholesterol is the major cause of atherosclerosis, dietary fibers are on the other hand known for their ability to clean the fatty plaque deposited on intestinal pathways, and prevent its build-up in other critical areas within the organism. In this work, a method for the preparation of a composite material comprising cholesterol and carboxymethyl cellulose from 1-hexanol/water biphase mixtures is reported. Specificity of the interaction between the …

Association Of Epstein-Barr Virus With Nasopharyngeal Carcinoma And Current Status Of Development Of Cancer-Derived Cell Lines, Charles A. Gullo Phd, Wong Kein Low, Gerrard Teoh

Biochemistry and Microbiology

It is well known that the Epstein-Barr virus (EBV) contributes directly to tumourigenesis in nasopharyngeal carcinoma (NPC), primarily in the undifferentiated form of NPC (WHO type III; UNPC or UC), which is commonly found in South East Asia. Unfortunately, research in NPC has been severely hampered by the lack of authentic EBV-positive (EBV+) human NPC cell lines for study. Since 1975, there have been more than 20 reported NPC cell lines. However, many of these NPC-derived cell lines do not express EBV transcripts in long-term culture, and therefore that finding may dispute the fundamental theory of NPC carcinogenesis. In fact, …

A Novel And Generalizable Organotypic Slice Platform To Evaluate Stem Cell Potential For Targeting Pediatric Brain Tumors., Shengwen Calvin Li, William Gunter Loudon

Department of Cancer Biology Faculty Papers

Brain tumors are now the leading cause of cancer-related deaths in children under age 15. Malignant gliomas are, for all practical purposes, incurable and new therapeutic approaches are desperately needed. One emerging strategy is to use the tumor tracking capacity inherent in many stem cell populations to deliver therapeutic agents to the brain cancer cells. Current limitations of the stem cell therapy strategy include that stem cells are treated as a single entity and lack of uniform technology is adopted for selection of clinically relevant sub-populations of stem cells. Specifically, therapeutic success relies on the selection of a clinically competent …

A Comprehensive Analysis Of The Naturally Occurring Polymorphisms In Hiv-1 Vpr: Potential Impact On Ctl Epitopes., Alagarsamy Srinivasan, Velpandi Ayyavoo, Sundarasamy Mahalingam, Aarthi Kannan, Anne Boyd, Debduti Datta, Vaniambadi S Kalyanaraman, Anthony Cristillo, Ronald G Collman, Nelly Morellet, Bassel E Sawaya, Ramachandran Murali

Department of Microbiology and Immunology Faculty Papers

The enormous genetic variability reported in HIV-1 has posed problems in the treatment of infected individuals. This is evident in the form of HIV-1 resistant to antiviral agents, neutralizing antibodies and cytotoxic T lymphocytes (CTLs) involving multiple viral gene products. Based on this, it has been suggested that a comprehensive analysis of the polymorphisms in HIV proteins is of value for understanding the virus transmission and pathogenesis as well as for the efforts towards developing anti-viral therapeutics and vaccines. This study, for the first time, describes an in-depth analysis of genetic variation in Vpr using information from global HIV-1 isolates …

Autoimmune-Induced Preferential Depletion Of Myelin-Associated Glycoprotein (Mag) Is Genetically Regulated In Relapsing Eae (B6 × Sjl) F1 Mice, Dusanka S. Skundric, Rujuan Dai, Vaagn L. Zakarian, Weili Zhou

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Experimental autoimmune encephalomyelitis (EAE) is commonly used to investigate mechanisms of autoimmune-mediated damage to oligodendrocytes, myelin, and axons in multiple sclerosis (MS). Four distinct autoimmune mechanisms with subsequently distinct patterns of demyelination have been recognized in acute MS lesions. EAE correlates for those distinct patterns of MS lesions are unknown. An excessive loss of myelin-associated glycoprotein (MAG), as a result of distal oligodendrogliopathy, is found exclusively in the subtype III lesion. We sought to answer if types of demyelination in acute lesions during onset and relapse of EAE can replicate the specific patterns observed in MS acute lesions. …

Hiv-1 Tat Protein Alter The Tight Junction Integrity And Function Of Retinal Pigment Epithelium: An In Vitro Study., Ling Bai, Zhenping Zhang, Hui Zhang, Xiumei Li, Qiurong Yu, Haotian Lin, Wenhui Yang

Department of Medicine Faculty Papers

BACKGROUND: How HIV-1 enter into the eyes remains obscure. We postulated that HIV-1 Tat protein can alter the expression of specific tight-junction proteins and disturb the blood retinal barrier, and contributes to HIV trafficking into the eyes. This study is to determine the effects of HIV-1 Tat proteins on the barrier function and tight-junction protein expression of retinal pigment epithelial cell (RPE). METHODS: A human RPE cell line (D407) cultured on microporous filter-supports was used. After treating with HIV-1 Tat protein, transepithelial electrical resistance (TER) of confluent RPE cells was measured by epithelial voltmeter. The permeability of the RPE cells …

Direct Inhibition Of Cdk9 Blocks Hiv-1 Replication Without Preventing T Cell Activation In Primary Human Peripheral Blood Lymphocytes, Dominic Salerno, Muneer G Hasham, Renee Marshall Demarest, Judit Garriga, Alexander Y Tsygankov, Xavier Graña

Rowan-Virtua School of Osteopathic Medicine Departmental Research

HIV-1 transcription is essential for the virus replication cycle. HIV-1 Tat is a viral transactivator that strongly stimulates the processivity of RNA polymerase II (RNAPII) via recruitment of the cyclin T1/CDK9 positive transcription elongation factor, which phosphorylates the C-terminal domain (CTD) of RNAPII. Consistently, HIV-1 replication in transformed cells is very sensitive to direct CDK9 inhibition. Thus, CDK9 could be a potential target for anti-HIV-1 therapy. A clearer understanding of the requirements for CDK9 activity in primary human T cells is needed to assess whether the CDK9-dependent step in HIV-1 transcription can be targeted clinically. We have investigated the effects …

Uncovering P53 Mutations And Abnormal Gene Expression In Pediatric Adrenocortical Cancer, Alina Nico West

Theses and Dissertations (ETD)

Pediatric adrenocortical cancer is extremely rare and often fatal (approximately 0.3-0.4 cases per million worldwide; 50% 5-year survival). The incidence of pediatric adrenocortical cancer in southern Brazil is 10-15 times higher than the worldwide incidence. Due to the rarity of adrenocortical cancer, especially in children, underlying gene dysregulation and mechanisms of tumorigenesis of the adrenal gland are very poorly described in the literature. However, it is well-known that the tumor suppressor p53, which is mutated in over 50% of all human cancers, is commonly mutated in pediatric adrenocortical cancer. In addition, evidence strongly suggests that if a child has adrenocortical …

Humanized Chimeric Receptors In The Therapy Of Multiple Sclerosis, Ioana Moisini

Theses and Dissertations (ETD)

The role of autoreactive, antigen-specific T-cells in the development of autoimmunity has long been documented. T-cells expressing chimeric receptors are specifically redirected against such cells and have been proven to suppress autoimmune encephalomyelitis, the murine model of multiple sclerosis. We here demonstrate the ability of humanized chimeric receptors to suppress experimental autoimmune encephalomyelitis (EAE) in a humanized mouse model by redirecting T lymphocytes against autoreactive T-cells. The receptors were synthesized by linking the 84-102 epitope of human myelin basic protein (MBP) to the extracellular and transmembrane domains of the beta chain of human major histocompatibility complex (MHC) class II molecule …

Uniform Particles Of Pure And Silica Coated Cholesterol, Vuk Uskoković, Egon Matijević

Pharmacy Faculty Articles and Research

Uniform crystalline colloidal cholesterol particles of narrow size distribution were obtained by precipitation. The method consisted of adding a miscible non-solvent (water) into cholesterol solutions of different alcohols and acetone, without any additives. The properties of the resulting particles depended in a sensitive way on the concentration of all reactants, temperature, pH, ionic strength, and aging time. The major observed effects were due to the solubility of cholesterol, which was strongly affected by the solvent mixture and temperature. Precipitation in 1-propanol/water system yielded stable dispersions of well-defined particles, which were used to evaluate the effects of different experimental parameters on …

The Neural Correlates Of Non-Spatial Working Memory In Velocardiofacial Syndrome (22q11.2 Deletion Syndrome), Wendy R. Kates, Beth R. Krauss, Nuria Abdulsabur, Dierdre Colgan, Kevin M. Antshel, Anne Marie Higgins, Robert J. Shprintzen

Communication Disorders Faculty Publications

Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a neurogenetic disorder that is associated with both learning disabilities and a consistent neuropsychological phenotype, including deficits in executive function, visuospatial perception, and working memory. Anatomic imaging studies have identified significant volumetric reductions in the parietal lobe of individuals with VCFS, but several studies have reported that the frontal lobe is relatively preserved. We used functional magnetic resonance imaging to investigate the neural correlates of non-spatial working memory in 17 youths with VCFS, 10 of their unaffected siblings, and 10 community controls (with the same proportion of learning disabilities as …

Selective Repression Of Retinoic Acid Target Genes By Rip140 During Induced Tumor Cell Differentiation Of Pluripotent Human Embryonal Carcinoma Cells, Kelly C. Heim, Kristina A. White, Dexin Deng, Craig R. Tomlinson, Jason Moore, Sarah Freemantle, Michael Spinella

Dartmouth Scholarship

The use of retinoids as anti-cancer agents has been limited due to resistance and low efficacy. The dynamics of nuclear receptor coregulation are incompletely understood. Cell-and context-specific activities of nuclear receptors may be in part due to distinct coregulator complexes recruited to distinct subsets of target genes. RIP140 (also called NRIP1) is a ligand-dependent corepressor that is inducible with retinoic acid (RA). We had previously shown that RIP140 limits RA induced tumor cell differentiation of embryonal carcinoma; the pluriopotent stem cells of testicular germ cell tumors. This implies that RIP140 represses key genes required for RA-mediated tumor cell differentiation. Identification …

Let-7 Expression Defines Two Differentiation Stages Of Cancer, Scott Shell, Sun-Mi Park, Amir Reza Radjabi, Robert Schickel, Emily Kistner, David Jewell

Dartmouth Scholarship

The early phases of carcinogenesis resemble embryonic development, often involving the reexpression of embryonic mesenchymal genes. The NCI60 panel of human tumor cell lines can genetically be subdivided into two superclusters (SCs) that correspond to CD95 Type I and II cells. SC1 cells are characterized by a mesenchymal and SC2 cells by an epithelial gene signature, suggesting that SC1 cells represent less differentiated, advanced stages of cancer. miRNAs are small 20- to 22-nucleotide-long noncoding RNAs that inhibit gene expression at the posttranscriptional level. By performing miRNA expression analysis on 10 Type I and 10 Type II cells, we have determined …