• Parkinson's disease-related protein, alpha-synuclein, in malignant melanoma.

      Matsuo, Yasuhiro; Kamitani, Tetsu; Center for Molecular Chaperone/Radiobiology & Cancer Virology (2010-05-13)
      BACKGROUND: Melanoma is the major cause of skin cancer death worldwide. Parkinson's disease is a neurodegenerative disorder that is caused by mutation of alpha-synuclein or other genes. Importantly, epidemiological studies have reported co-occurrence of melanoma and Parkinson's disease, suggesting that these two diseases could share common genetic components. METHODOLOGY/PRINCIPAL FINDINGS: Recently, we found that human melanoma cell lines highly express alpha-synuclein, whereas the protein is undetectable in the non-melanoma cancer cell lines tested. To investigate the expression of alpha-synuclein in human melanoma tissues, we immunostained sections of melanoma, nevus, non-melanocytic cutaneous carcinoma, and normal skin. alpha-Synuclein was positively detected in 86% of the primary and 85% of the metastatic melanoma sections, as well as in 89% of nevus sections. However, alpha-synuclein was undetectable in non-melanocytic cutaneous carcinoma and normal skin. CONCLUSIONS/SIGNIFICANCE: The Parkinson's disease-related protein, alpha-synuclein, is expressed in both malignant and benign melanocytic lesions, such as melanomas and nevi. Although alpha-synuclein cannot be used to distinguish between malignant and benign melanocytic skin lesions, it might be a useful biomarker for the diagnosis of metastatic melanoma.
    • Participatory Process for Implementing a Colorectal Cancer Screening Intervention: An Action Plan for Local Intervention Sustainability

      Smith, Selina A.; Ansa, Benjamin E.; Sheats, Joyce Q.; Hamilton, Sandra J.; Whitehead, Mary S.; Augusta University (2015)
    • The Pathological Roles of Ganglioside Metabolism in Alzheimer's Disease: Effects of Gangliosides on Neurogenesis

      Ariga, Toshio; Wakade, Chandramohan; Yu, Robert K.; Institute of Molecular Medicine and Genetics; Institute of Neuroscience (2011-01-9)
      Conversion of the soluble, nontoxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is a key step in the onset of Alzheimer’s disease (AD). It has been suggested that Aβ induces changes in neuronal membrane fluidity as a result of its interactions with membrane components such as cholesterol, phospholipids, and gangliosides. Gangliosides are known to bind Aβ. A complex of GM1 and Aβ, termed “GAβ”, has been identified in AD brains. Abnormal ganglioside metabolism also may occur in AD brains. We have reported an increase of Chol-1α antigens, GQ1bα and GT1aα, in the brain of transgenic mouse AD model. GQ1bα and GT1aα exhibit high affinities to Aβs. The presence of Chol-1α gangliosides represents evidence for genesis of cholinergic neurons in AD brains. We evaluated the effects of GM1 and Aβ1–40 on mouse neuroepithelial cells. Treatment of these cells simultaneously with GM1 and Aβ1–40 caused a significant reduction of cell number, suggesting that Aβ1–40 and GM1 cooperatively exert a cytotoxic effect on neuroepithelial cells. An understanding of the mechanism on the interaction of GM1 and Aβs in AD may contribute to the development of new neuroregenerative therapies for this disorder.
    • Perfluorooctanoic acid reduces viability and gene expression of peroxisome proliferator-activated receptor alpha and estrogen receptor alpha in MCF-7 cells

      Smith, April; College of Science and Mathematics (2015-10-09)
      Perfluorooctanoic acid (PFOA) is an endocrine disrupting compound found in food, water, clothes, and other consumer products. It is known to accumulate in the environment and can be taken up through ingestion, inhalation, or skin contact. It has a half-life of nearly four years in humans. PFOA has been shown to bind and activate peroxisome proliferator-activated receptors (PPARs), which are transcription factors found in mammalian cells. PPARs regulate numerous cellular activities, including proliferation and differentiation. Several studies have suggested crosstalk between PPARs and estrogen receptors (ERs). This study aimed to examine the effects of PFOA on cell viability and on PPAR and ER gene expression in MCF-7 breast cancer cells. The results showed a decline in cell viability after 48h of PFOA treatment. In addition, 24h of treatment with PFOA led to a significant decrease in PPARα and ERα, but not PPARβ, PPARγ, or ERβ. Begin Time: 28:30 End Time: 50:40
    • Physical interaction and functional coupling between ACDP4 and the intracellular ion chaperone COX11, an implication of the role of ACDP4 in essential metal ion transport and homeostasis.

      Guo, Dehuang; Ling, Jennifer X; Wang, Mong-Heng; She, Jin-Xiong; Gu, Jianguo; Wang, Cong-Yi; Center for Biotechnology and Genomic Medicine; Department of Physiology (2008-01-16)
      Divalent metal ions such as copper, manganese, and cobalt are essential for cell development, differentiation, function and survival. These essential metal ions are delivered into intracellular domains as cofactors for enzymes involved in neuropeptide and neurotransmitter synthesis, superoxide metabolism, and other biological functions in a target specific fashion. Altering the homeostasis of these essential metal ions is known to connect to a number of human diseases including Alzheimer disease, amyotrophic lateral sclerosis, and pain. It remains unclear how these essential metal ions are delivered to intracellular targets in mammalian cells. Here we report that rat spinal cord dorsal horn neurons express ACDP4, a member of Ancient Conserved Domain Protein family. By screening a pretransformed human fetal brain cDNA library in a yeast two-hybrid system, we have identified that ACDP4 specifically interacts with COX11, an intracellular metal ion chaperone. Ectopic expression of ACDP4 in HEK293 cells resulted in enhanced toxicity to metal ions including copper, manganese, and cobalt. The metal ion toxicity became more pronounced when ACDP4 and COX11 were co-expressed ectopically in HEK293 cells, suggesting a functional coupling between them. Our results indicate a role of ACDP4 in metal ion homeostasis and toxicity. This is the first report revealing a functional aspect of this ancient conserved domain protein family. We propose that ACDP is a family of transporter protein or chaperone proteins for delivering essential metal ions in different mammalian tissues. The expression of ACDP4 on spinal cord dorsal horn neurons may have implications in sensory neuron functions under physiological and pathological conditions.
    • Ploidy status and copy number aberrations in primary glioblastomas defined by integrated analysis of allelic ratios, signal ratios and loss of heterozygosity using 500K SNP Mapping Arrays.

      Gardina, Paul J; Lo, Ken C; Lee, Walter; Cowell, John K.; Turpaz, Yaron; GHSU Cancer Center (2008-10-30)
      BACKGROUND: Genomic hybridization platforms, including BAC-CGH and genotyping arrays, have been used to estimate chromosome copy number (CN) in tumor samples by detecting the relative strength of genomic signal. The methods rely on the assumption that the predominant chromosomal background of the samples is diploid, an assumption that is frequently incorrect for tumor samples. In addition to generally greater resolution, an advantage of genotyping arrays over CGH arrays is the ability to detect signals from individual alleles, allowing estimation of loss-of-heterozygosity (LOH) and allelic ratios to enhance the interpretation of copy number alterations. Copy number events associated with LOH potentially have the same genetic consequences as deletions. RESULTS: We have utilized allelic ratios to detect patterns that are indicative of higher ploidy levels. An integrated analysis using allelic ratios, total signal and LOH indicates that many or most of the chromosomes from 24 glioblastoma tumors are in fact aneuploid. Some putative whole-chromosome losses actually represent trisomy, and many apparent sub-chromosomal losses are in fact relative losses against a triploid or tetraploid background. CONCLUSION: These results suggest a re-interpretation of previous findings based only on total signal ratios. One interesting observation is that many single or multiple-copy deletions occur at common putative tumor suppressor sites subsequent to chromosomal duplication; these losses do not necessarily result in LOH, but nonetheless occur in conspicuous patterns. The 500 K Mapping array was also capable of detecting many sub-mega base losses and gains that were overlooked by CGH-BAC arrays, and was superior to CGH-BAC arrays in resolving regions of complex CN variation.
    • Positive Selection of Cd4+ T Cells Is Induced in Vivo by Agonist and Inhibited by Antagonist Peptides

      Kraj, Piotr; Pacholczyk, Rafal; Ignatowicz, Hanna; Kisielow, Pawel; Jensen, Peter; Ignatowicz, Leszek; Institute of Molecular Medicine and Genetics (2001-08-20)
      The nature of peptides that positively select T cells in the thymus remains poorly defined. Here we report an in vivo model to study the mechanisms of positive selection of CD4+ T cells. We have restored positive selection of TCR transgenic CD4+ thymocytes, arrested at the CD4+CD8+ stage, due to the lack of the endogenously selecting peptide(s), in mice deficient for H2-M and invariant chain. A single injection of soluble agonist peptide(s) initiated positive selection of CD4+ transgenic T cells that lasted for up to 14 days. Positively selected CD4+ T cells repopulated peripheral lymphoid organs and could respond to the antigenic peptide. Furthermore, coinjection of the antagonist peptide significantly inhibited agonist-driven positive selection. Hence, contrary to the prevailing view, positive selection of CD4+ thymocytes can be induced in vivo by agonist peptides and may be a result of accumulation of signals from TCR engaged by different peptides bound to major histocompatibility complex class II molecules. We have also identified a candidate natural agonist peptide that induces positive selection of CD4+ TCR transgenic thymocytes.
    • PPAR-c Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flow

      Sharma, Shruti; Sun, Xutong; Rafikov, Ruslan; Kumar, Sanjiv; Hou, Yali; Oishi, Peter E.; Datar, Sanjeev A.; Raff, Gary; Fineman, Jeffrey R.; Black, Stephen M.; et al. (2012-09-4)
      Objective: Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-c expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-c signaling and carnitine dysfunction, and whether the PPAR-c agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.
    • Predicting Impaired Extinction of Traumatic Memory and Elevated

      Nalloor, Rebecca Ipe; Bunting, Kristopher M.; Vazdarjanova, Almira; Brain & Behavior Discovery Institute; Department of Neurology (2011-05-18)
      Background: Emotionally traumatic experiences can lead to debilitating anxiety disorders,
    • Prenatal alcohol exposure triggers ceramide-induced apoptosis in neural crest-derived tissues concurrent with defective cranial development

      Wang, G; Bieberich, Erhard; Institute of Molecular Medicine and Genetics (2010-05-27)
      Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy. The reason why specific embryonic tissues are sensitive toward ethanol is not understood. We found that in neural crest-derived cell (NCC) cultures from the first branchial arch of E10 mouse embryos, incubation with ethanol increases the number of apoptotic cells by fivefold. Apoptotic cells stain intensely for ceramide, suggesting that ceramide-induced apoptosis mediates ethanol damage to NCCs. Apoptosis is reduced by incubation with CDP-choline (citicoline), a precursor for the conversion of ceramide to sphingomyelin. Consistent with NCC cultures, ethanol intubation of pregnant mice results in ceramide elevation and increased apoptosis of NCCs in vivo. Ethanol also increases the protein level of prostate apoptosis response 4 (PAR-4), a sensitizer to ceramide-induced apoptosis. Prenatal ethanol exposure is concurrent with malformation of parietal bones in 20% of embryos at day E18. Meninges, a tissue complex derived from NCCs, is disrupted and generates reduced levels of TGF-b1, a growth factor critical for bone and brain development. Ethanol-induced apoptosis of NCCs leading to defects in the meninges may explain the simultaneous presence of cranial bone malformation and cognitive retardation in FAS. In addition, our data suggest that treatment with CDP-choline may alleviate the tissue damage caused by alcohol.
    • Prevention and Treatment of Cardiovascular Disease in Adolescents and Adults through the Transcendental Meditation(®) Program: A Research Review Update.

      Barnes, Vernon A.; Orme-Johnson, David W; Georgia Prevention Institute (2012-08)
      The pathogenesis and progression of cardiovascular diseases are thought to be exacerbated by stress. Basic research indicates that the Transcendental Meditation(®) technique produces acute and longitudinal reductions in sympathetic tone and stress reactivity. In adolescents at risk for hypertension, the technique has been found to reduce resting and ambulatory blood pressure, left ventricular mass, cardiovascular reactivity, and to improve school behavior. Research on adults with mild or moderate essential hypertension has reported decreased blood pressure and reduced use of anti-hypertensive medication. The technique has also been reported to decrease symptoms of angina pectoris and carotid atherosclerosis, to reduce cardiovascular risk factors, including alcohol and tobacco use, to markedly reduce medical care utilization for cardiovascular diseases, and to significantly decrease cardiovascular and all-cause morbidity and mortality. These findings have important implications for inclusion of the Transcendental Meditation program in efforts to prevent and treat cardiovascular diseases and their clinical consequences.(®)Transcendental Meditation and TM are trademarks registered in the US. Patent and Trademark Office, licensed to Maharishi Vedic Education Development Corporation and are used with permission.
    • Problem Sets allow for multiple competency acquisition in first year neuroscience course

      Lameka, Megan; Department of Cellular Biology and Anatomy (2016-03)
      Self-directed learning (SDL) is an expected element of medical education programs. LCME standard 6.3 requires that students engage in all the following components of SDL as a unified sequence: identify, analyze, and synthesize information relevant to their learning needs, assess the credibility of information sources, share the information with their peers and supervisors, and receive feedback on their information-seeking skills. A classic tradeoff of problem-based learning (PBL) and lecture oriented pedagogies lies between life-long learning skills and content coverage. Problem sets were developed to ensure coverage of learning objectives while allowing students to engage in SDL as defined by the LCME. The neuroscience curriculum for first year medical students at the Medical College of Georgia was restructured to include problem sets in place of lectures related to special senses, somatosensory, motor systems and mental health. The purpose o f this study was to document whether problem sets provided students effective engagement in SDL, and to determine if medical knowledge competency suffered as a result of this shift in pedagogical strategy. Small groups of four students met to evaluate, solve, and discuss each problem set in a series of three meetings. Students were provided learning objectives, cases, and associated discussion and supporting questions. Students initiated a problem set by reviewing learning objectives and cases, identifying individual learning needs, and developing an individual inquiry strategy. During the subsequent meeting, students shared information learned and discussed responses to discussion questions. The final meeting involved a discussion of the problem sets between two groups with a faculty facilitator. Groups were randomly assigned discussion questions and students took turns presenting their findings. Over the course of four problem sets, each student presented findings for two discussion questions. Faculty facilitators used rubrics to assess student competency in all SDL domains. To document student engagement in SDL, data from student assessments were tabulated. To determine whet her medical knowledge was negatively affected by replacing lectures with SDL, student performance on 19 test items mapped to learning objectives covered in problem sets was compared with the same test items mapped to learning objectives covered in lecture in the previous year. Students scored 4.8 ±± 0.5 out of 5 on their ability to identify and analyze information relevant to learning needs, 4.6 ±± 0.6 out of 5 on their ability to use credible sources, and 4.7 ±± 0.6 out of 5 on their ability to effectively communicate information. A two-tailed t-test of percentage correct for all test items indicated no statistically significant differences in student performance on test items mapped to learning objectives (84.4±±10.4 % [lectures] vs. 85.7±±11.5[SDL], p=.71, d=.12). This study shows that students effectively engaged in SDL using problem sets without negatively impacting coverage of medical knowledge. More study is needed to determine if SDL skills improved as a result of problem sets. Future steps include assessment of long term retention of medical knowledge resulting from SDL vs. lecture. In conclusion, problem sets as a pedagogical approach achieved multiple competency-based objectives by providing students an opportunity to develop life-long learning skills and acquire medical knowledge.
    • Promotion of plasma membrane repair by vitamin E

      Howard, Amber Cyran; McNeil, Anna K.; McNeil, Paul L.; Institute of Molecular Medicine and Genetics; Department of Cellular Biology and Anatomy (2011-12-20)
      Severe vitamin E deficiency results in lethal myopathy in animal models. Membrane repair is an important myocyte response to plasma membrane disruption injury as when repair fails, myocytes die and muscular dystrophy ensues. Here we show that supplementation of cultured cells with α-tocopherol, the most common form of vitamin E, promotes plasma membrane repair. Conversely, in the absence of α-tocopherol supplementation, exposure of cultured cells to an oxidant challenge strikingly inhibits repair. Comparative measurements reveal that, to promote repair, an anti-oxidant must associate with membranes, as α-tocopherol does, or be capable of α-tocopherol regeneration. Finally, we show that myocytes in intact muscle cannot repair membranes when exposed to an oxidant challenge, but show enhanced repair when supplemented with vitamin E. Our work suggests a novel biological function for vitamin E in promoting myocyte plasma membrane repair. We propose that this function is essential for maintenance of skeletal muscle homeostasis.
    • Protection Against Colonic Inflammation and Colon Cancer by Commensal Bacterial Metabolites: An Obligatory Role for the Short- Chain Fatty Acid Transporter Slc5a8

      Gurav, Ashish; Georgia Cancer Center (2014-11)
      Dietary fiber consumption has long been known to protect against inflammatory bowel diseases and colorectal carcinogenesis. In mammals, large intestinal microorganisms ferment dietary fiber to generate energy, while releasing short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate. Interestingly, SCFAs are also known to protect against intestinal inflammation and colorectal carcinogenesis, although the molecular mechanisms behind these actions are still being investigated. For most of their biological effects, SCFAs must be transported from lumen into the intestinal tissue, where they activate multiple biological processes. We and others have reported Slc5a8 as a high affinity transport mechanism for SCFAs, which would remain fully functional, even when SCFA concentration drops to sub-millimolar range, whereas other transport mechanisms are rendered inefficient. The aim of the current study was to test protective role of Slc5a8 against intestinal inflammation and colorectal carcinogenesis during suboptimal intake of dietary fiber. We observed that Slc5a8 is obligatory for HDAC-inhibition in colonic epithelium and intestinal barrier function, only when the animals were fed a dietary fiber-free diet (FF diet), and not when the animals were fed diet containing optimal amounts of fibers (FC Diet). Compared to WT, Slc5a8-/- animals demonstrated higher susceptibility to AOMDSS- mediated intestinal inflammation and colorectal carcinogenesis under FF dietary conditions, but not under FC dietary conditions. At molecular level, we found that butyrate and propionate could induce potent immunosuppressive enzymes Indoleamine 2,3-dioxygenase and Aldehyde Dehydrogenase 1A2 in dendritic cells obtained from WT animals, but not from Slc5a8-/- animals. Butyrate, transported via Slc5a8 enabled DCs to suppress conversion of naïve T cells to interferon-γ secreting pro-inflammatory T cells and Slc5a8-/- animals harbored higher proportion of interferon-γ+ CD4+ T cells in vivo. Taken together, our data provide crucial evidence for critical role of Slc5a8 mediating protective effects of dietary fiber metabolites, SCFAs in protecting against intestinal inflammation and colorectal carcinogenesis.
    • Psychotropic Medications and Changes in Weight in a Correctional Setting: The Impact on Women’s Health

      Gates, Madison L.; Ballance, Darra; Ferguson, Elizabeth; Wilkins, Thad; Yoo, Wonsuk; Augusta University (2016-03)
    • Quantifiable Biomarkers of Normal Aging in the Japanese Medaka Fish (Oryzias latipes)

      Ding, Lingling; Kuhne, Wendy W.; Hinton, David E.; Song, Jian; Dynan, William S.; Institute of Molecular Medicine and Genetics (2010-10-11)
      Background: Small laboratory fish share many anatomical and histological characteristics with other vertebrates, yet can be maintained in large numbers at low cost for lifetime studies. Here we characterize biomarkers associated with normal aging in the Japanese medaka (Oryzias latipes), a species that has been widely used in toxicology studies and has potential utility as a model organism for experimental aging research.
    • Questionnaire Design and Responsiveness in a Data Capture Tool for Student Sharing of Experiences of Statewide Clerkship Sites

      Zheng, Stephanie; Behrman, David; Agrawal, Parth; Basco, Brian; Ball, Charlotte; Rose, Jennifer; Miller, Samel; Wood, Elena (2017-03)
      Positive clerkship experiences and student performance in the clinical years has been correlated to perceived quality of education and specialty choice amongst medical students [1-3]. The Medical College of Georgia uses a distributed campus model with more than 250 clerkship rotation sites across the state and beyond, making student clerkship choices imperative to their development as physicians. We developed a survey to collect both quantitative and qualitative data from students during their clerkship years and a system to distribute that information to students. The data allowed us to evaluate the effectiveness of various question formats through responsiveness, the length of responses, and time spent on the survey. In addition to this, we looked at the number of responses per clerkship in order to see whether or not our survey was getting information about all of the 3rd year rotations. We aspire to take these findings and utilize them to expand t he program and improve the questionnaire in order to yield more responsiveness from students.