• Identification and Characterization of Two New Players in DNA Double-Strand Break Repair - PSF and p54(nrb)

      Udayakumar, Durga; Department of Molecular Medicine (2005-12)
      The stability and integrity of a genome depends on how accurately the genetic information is passed on to each daughter of a dividing cell. This accuracy is compromised when the genome is exposed to various stressful conditions, including ionizing radiation (IR), radiomimetic agents such as bleomycin, neocarzinostatin, and etoposide, free radicals generated from metabolic processes, and also errors during replication. The effect is DNA damage resulting in potentially lethal double-strand breaks (DSBs). The causes are as follows: DSBs are also created as intermediates during specialized recombination processes, such as V(D)J recombination, immunoglobulin class switching and somatic hypermutation.
    • Identification of RAB11-Family Interacting Proteins (RAB11-F1Ps): Integral Components in Plasma Membrane Recycling

      Hales, Chadwick M; Institute of Molecular Medicine and Genetics (2003-05)
      Given the involvement of Rabl la in each of these cellular processes and given the potential impact of Rabl la on human health and disease, we sought to further establish a role for Rabl la in plasma membrane recycling. Since other Rab proteins have numerous characterized interacting proteins and because the repetoire for Rabl la is currently limited to three identified interacting proteins, we hypothesized that other Rabl la binding partners exist as putative downstream effectors for the small GTPase. We therefore proposed the following three aims: Aim 1: Identify R ab lla interacting proteins. Aim 2: Determine the effect of interacting proteins on membrane recycling. Aim 3: Establish an organizational model of a putative Rabl la complex. The progression of studies herein provides insight into the dynamic and complex process of plasma membrane recycling. Yeast two hybrid screening of a parietal cell cDNA library utilizing dominant active Rabl laS20V as the bait identified Rabl 1-Family Interacting Protein 1 (Rabll-FIPl), a novel R ab lla interacting protein. EST database searches with the R abll-FIPl sequence identified three homologous proteins with high carboxyl-terminal identity. Chapter 1 introduces the new family of Rabl la interacting proteins and provides the initial characterization. Interestingly, these studies indicated an interaction between Rabll-Family Interacting Protein 2 (Rabll-FIP2) and myosin Vb tail. Chapter 2 further describes the Rabl l-FIP2/myosin Vb tail binding and provides functional data placing Rabll-FIP2 as an integral component of the plasma membrane recycling system. Finally, recent studies have indicated a recycling system dependence on different kinase activities. Through kinase inhibitor studies and immunofluorescence imaging, evidence presented in Chapter 3 suggests that R ab lla along with multiple Rabll-FIP proteins function as a complex beginning at the process of endocytosis with movement dependent on multiple phosphorylation events. The ultimate goal throughout these studies is to provide a clearer picture of Rabl la function in plasma membrane recycling so that one day a positive impact on human health can be achieved.
    • IGF-1 Induction by Acylated Steryl β-Glucosides Found in a Pre-Germinated Brown Rice Diet Reduces Oxidative Stress in Streptozotocin-Induced Diabetes

      Usuki, Seigo; Tsai, Ying-Ying; Morikawa, Keiko; Nonaka, Shota; Okuhara, Yasuhide; Kise, Mitsuo; Yu, Robert K.; Institute of Molecular Medicine and Genetics (2011-12-14)
      Background: The pathology of diabetic neuropathy involves oxidative stress on pancreatic b-cells, and is related to decreased levels of Insulin-like growth factor 1 (IGF-1). Acylated steryl b-glucoside (PR-ASG) found in pre-germiated brown rice is a bioactive substance exhibiting properties that enhance activity of homocysteine-thiolactonase (HTase), reducing oxidative stress in diabetic neuropathy. The biological importance of PR-ASG in pancreatic b-cells remains unknown.
    • The IL-10 and IFN-gamma pathways are essential to the potent immunosuppressive activity of cultured CD8+ NKT-like cells.

      Zhou, Li; Wang, Hongjie; Zhong, Xing; Jin, Yulan; Mi, Qing-Sheng; Sharma, Ashok; McIndoe, Richard A; Garge, Nikhil; Podolsky, Robert H.; She, Jin-Xiong; et al. (2008-09-05)
      BACKGROUND: CD8+ NKT-like cells are naturally occurring but rare T cells that express both T cell and natural killer cell markers. These cells may play key roles in establishing tolerance to self-antigens; however, their mechanism of action and molecular profiles are poorly characterized due to their low frequencies. We developed an efficient in vitro protocol to produce CD8+ T cells that express natural killer cell markers (CD8+ NKT-like cells) and extensively characterized their functional and molecular phenotypes using a variety of techniques. RESULTS: Large numbers of CD8+ NKT-like cells were obtained through culture of na??ve CD8+ T cells using anti-CD3/anti-CD28-coated beads and high dose IL-2. These cells possess potent activity in suppressing the proliferation of na??ve responder T cells. Gene expression profiling suggests that the cultured CD8+ NKT-like cells and the na??ve CD8+ T cells differ by more than 2-fold for about 3,000 genes, among which 314 are upregulated by more than 5-fold and 113 are upregulated by more than 10-fold in the CD8+ NKT-like cells. A large proportion of the highly upregulated genes are soluble factors or surface markers that have previously been implicated in immune suppression or are likely to possess immunosuppressive properties. Many of these genes are regulated by two key cytokines, IL-10 and IFN-gamma. The immunosuppressive activities of cells cultured from IL-10-/- and IFN-gamma-/- mice are reduced by about 70% and about 50%, respectively, compared to wild-type mice. CONCLUSION: Immunosuppressive CD8+ NKT-like cells can be efficiently produced and their immunosuppressive activity is related to many surface and soluble molecules regulated by IL-10 and IFN-gamma.
    • The impact of general experience with patients on baseline measures of confidence in an SBIRT training program

      Johnson, J. Aaron; Chung, Yunmi; Brown, Shilpa P.; Augusta University (2016-10)
    • Impact of stress reduction on negative school behavior in adolescents.

      Barnes, Vernon A.; Bauza, Lynnette B; Treiber, Frank A.; Georgia Institute for Prevention of Human Diseases and Accidents; Department of Pediatrics; Department of Psychiatry and Health Behavior (2008-01-16)
      BACKGROUND: The purpose of this study was to determine the effect of stress reduction via the Transcendental Meditation program on school rule infractions in adolescents. METHODS: Forty-five African American adolescents (ages 15-18 years) with high normal systolic blood pressure were randomly assigned to either Transcendental Meditation (n = 25) or health education control (n = 20) groups. The meditation group engaged in 15-min sessions at home and at school each day for 4 months. The control group was presented 15-min sessions of health education at school each day for 4 months. Primary outcome measures were changes in absenteeism, school rule infractions and suspension days during the four-month pretest period prior to randomization compared with the four-month intervention period. RESULTS: Comparing the pretest and intervention periods, the meditation group exhibited a mean decrease of 6.4 absentee periods compared to an increase of 4.8 in the control group (p <.05). The meditation group exhibited a mean decrease of 0.1 infractions over the four months compared to an increase of 0.3 in the control group (p <.03). There was a mean reduction of 0.3 suspension days due to behavior-related problems in the meditation group compared to an increase of 1.2 in the control group (p <.04). CONCLUSION: These findings demonstrate that the Transcendental Meditation program conducted in the school setting has a beneficial impact upon absenteeism, rule infractions, and suspension rates in African American adolescents.
    • Impact of Transcendental Meditation on Left Ventricular Mass in African American Adolescents

      Barnes, Vernon A.; Kapuku, Gaston K.; Treiber, Frank A.; Georgia Institute for Prevention of Human Diseases and Accidents; Department of Pediatrics (2012-05-22)
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    • Impaired membrane resealing and autoimmune myositis in synaptotagmin VIIâ deficient mice

      Chakrabarti, Sabyasachi; Kobayashi, Koichi S.; Flavell, Richard A.; Marks, Carolyn B.; Miyake, Katsuya; Liston, David R.; Fowler, Kimberly T.; Gorelick, Fred S.; Andrews, Norma W.; Institute of Molecular Medicine and Genetics (2003-08-18)
      Members of the synaptotagmin family have been proposed to function as Ca2+ sensors in membrane fusion. Syt VII is a ubiquitously expressed synaptotagmin previously implicated in plasma membrane repair and Trypanosoma cruzi invasion, events which are mediated by the Ca2+-regulated exocytosis of lysosomes. Here, we show that embryonic fibroblasts from Syt VII-deficient mice are less susceptible to trypanosome invasion, and defective in lysosomal exocytosis and resealing after wounding. Examination of mutant mouse tissues revealed extensive fibrosis in the skin and skeletal muscle. Inflammatory myopathy, with muscle fiber invasion by leukocytes and endomysial collagen deposition, was associated with elevated creatine kinase release and progressive muscle weakness. Interestingly, similar to what is observed in human polymyositis/dermatomyositis, the mice developed a strong antinuclear antibody response, characteristic of autoimmune disorders. Thus, defective plasma membrane repair in tissues under mechanical stress may favor the development of inflammatory autoimmune disease.
    • Impaired Volume Regulation in Cardiovascular Disease in Two Distinct Populations

      Beavers, Melinda L. C.; Georgia Prevention Institute (2012-05)
      Volume dysregulation leads to congestive heart failure and death. The condition has been well-documented in both obesity-related cardiovascular disease and congenital heart disease. Our hypotheses are as follows: 1) Volume dysregulation, in the form of elevated systolic blood pressure and left ventricular mass index, is related to adiposity and aldosterone in adolescent boys but not girls. 2) Volume dysregulation, in the form of decreased nocturnal decline in blood pressure (non-dipping) is present in patients with tetralogy of Fallot, and is related to decreased left and right ventricular function. To test our first hypothesis, 100 healthy adolescents, recruited from area schools, were studied. Subjects were placed on a sodium-controlled diet for 4 days. Blood and urine samples were collected after one hour of rest. The protocol was repeated twice for each individual. Data were averaged between visits for greater statistical power. Adiposity and echocardiography measures were collected within 1 month of testing. Stepwise regression indicated that race and adiposity both contributed to the effects of aldosterone. For example, body mass index and race contributed to the model for aldosterone (Adjusted R2=0.303, p=0.002). In the aldosterone-hypertension risk relationship, stepwise regression indicated that only aldosterone contributed to the model for systolic blood pressure (Adjusted R2=0.098, p=0.023). To test our second hypothesis, 20 patients with repaired tetralogy of Fallot were recruited from clinic. Subjects completed a submaximal exercise test (modified Bruce) with echocardiography, and then wore an ambulatory blood pressure monitor for 24 hours. Of the 20 subjects with tetralogy of Fallot, 60% were 'non-dippers'. Race was significantly different between the dippers and non-dippers, with 1 of 8 African Americans being a dipper, and the remaining 7 African Americans being non-dippers (t=2.188, p=0.042). Right ventricular stroke volume (t=2.392, p=0.028) and ejection fraction (t=3.484, p=0.003) were significantly different between dippers and non-dippers. In a population of healthy adolescents with a well-distributed range of adiposity, increasing adiposity is associated with increasing aldosterone levels in boys but not girls. This is related to increasing systolic blood pressure and left ventricular mass in boys, but not in girls. These results may indicate an underlying volume dysregulation that contributes to hypertension and cardiovascular disease as a result of prolonged exposure to increased adiposity. In a population of 20 adolescents and young adults with repaired tetralogy of Fallot, nondipping is associated with decreased right ventricular stroke volume and ejection fraction, but is not associated with decreased left ventricular function. Patients with repaired tetralogy of Fallot and non-dipping may be at greater risk for failure due to the combination of pulmonary regurgitation with increased nocturnal pressures.
    • Implementing alcohol screening and brief intervention in primary healthcare: identifying barriers, proposing solutions

      Johnson, J. Aaron; Seale, J. Paul; Georgia Regents University; Mercer University School of Medicine (2014-10-17)
    • Impossibly Complicated Tales of Dispossession and Betrayal: Thomas Pynchon's Vineland and the Neoliberal Shift in America

      Williams, Daniel; Hayes, Adrienne; Atkins, Hunter; Hoffman, Todd; Pamplin College of Arts, Humanities, and Social Sciences (2015-08-10)
      The 1970s were characterized by the ascendancy of a particular breed of right wing conservatism that advanced neoliberal reforms and precipitated the 1980 election of Ronald Reagan. As an economic theory, neoliberalism proposes that the government de-regulate markets and ease financial burdens on corporations thus enabling wealth to be evenly distributed across the social spectrum by natural market processes. In practice, the process of manufacturing consent for these policies mobilized religious and nationalist rhetoric, caused an abiding cultural shift, and resulted in numerous economic crises and inequitable concentrations of wealth. Our project conducts an analysis of Thomas Pynchon's novel Vineland in order to derive insights into this transformation of America. Published in 1990, the scope of Pynchon’s novel encompasses both the hippy movement that peaks in the late 60s and the rise of neoliberalism up through the middle of the Reagan administration in 1984— the year in which the novel takes place. Pynchon’s work is exemplary of what is called postmodern literature—the defining literary genre of the period which in many ways is unique precisely because of its political engagement with post-industrial capitalism—and, as such, encapsulates perhaps better than any writer the effects of neoliberalism. Our project has produced an essay (and a poster) that is comprised of three sections: An economic, cultural, and historical explanation of neoliberalism— An investigation of Pynchon’s critique of the media as it works to assimilate citizens into the cultural hegemony— And Pynchon’s critique of the ideologies and policy decisions surrounding the then contemporary environmental movement.
    • An Improved Test for Detecting Multiplicative Homeostatic Synaptic Scaling

      Kim, Jimok; Tsien, Richard W.; Alger, Bradley E.; Institute of Molecular Medicine and Genetics; Graduate Program in Neuroscience; Department of Neurology (2012-05-17)
      Homeostatic scaling of synaptic strengths is essential for maintenance of network "gain", but also poses a risk of losing the distinctions among relative synaptic weights, which are possibly cellular correlates of memory storage. Multiplicative scaling of all synapses has been proposed as a mechanism that would preserve the relative weights among them, because they would all be proportionately adjusted. It is crucial for this hypothesis that all synapses be affected identically, but whether or not this actually occurs is difficult to determine directly. Mathematical tests for multiplicative synaptic scaling are presently carried out on distributions of miniature synaptic current amplitudes, but the accuracy of the test procedure has not been fully validated. We now show that the existence of an amplitude threshold for empirical detection of miniature synaptic currents limits the use of the most common method for detecting multiplicative changes. Our new method circumvents the problem by discarding the potentially distorting subthreshold values after computational scaling. This new method should be useful in assessing the underlying neurophysiological nature of a homeostatic synaptic scaling transformation, and therefore in evaluating its functional significance.
    • Inactivation of the WASF3 gene in prostate cancer cells leads to suppression of tumorigenicity and metastases

      Teng, Yong; Ren, MingQiang; Cheney, Richard; Sharma, Shruti; Cowell, John K.; GHSU Cancer Center; Department of Pathology (2010-09-28)
      Background:: The WASF3 protein is involved in cell movement and invasion, and to investigate its role in prostate cancer progression we studied the phenotypic effects of knockdown in primary tumors and cell lines.
    • Incidence and survival trends of colorectal cancer from 2002 to 2011

      Ansa, Benjamin E.; Alema-Mensah, Ernest; Claridy, Mechelle D.; Sheats, Joyce Q.; Smith, Selina A.; School of Medicine; Georgia Regents University; Morehouse College (2015-03)
    • Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes.

      Ergul, Adviye; Elgebaly, Mostafa M; Middlemore, Mary-Louise; Li, Weiguo; Elewa, Hazem; Switzer, Jeffrey A; Hall, Christiana; Kozak, Anna; Fagan, Susan C.; Vascular Biology Center; et al. (2007-11-29)
      BACKGROUND: Interruption of flow through of cerebral blood vessels results in acute ischemic stroke. Subsequent breakdown of the blood brain barrier increases cerebral injury by the development of vasogenic edema and secondary hemorrhage known as hemorrhagic transformation (HT). Diabetes is a risk factor for stroke as well as poor outcome of stroke. The current study tested the hypothesis that diabetes-induced changes in the cerebral vasculature increase the risk of HT and augment ischemic injury. METHODS: Diabetic Goto-Kakizaki (GK) or control rats underwent 3 hours of middle cerebral artery occlusion and 21 h reperfusion followed by evaluation of infarct size, hemorrhage and neurological outcome. RESULTS: Infarct size was significantly smaller in GK rats (10 +/- 2 vs 30 +/- 4%, p < 0.001). There was significantly more frequent hematoma formation in the ischemic hemisphere in GK rats as opposed to controls. Cerebrovascular tortuosity index was increased in the GK model (1.13 +/- 0.01 vs 1.34 +/- 0.06, P < 0.001) indicative of changes in vessel architecture. CONCLUSION: These findings provide evidence that there is cerebrovascular remodeling in diabetes. While diabetes-induced remodeling appears to prevent infarct expansion, these changes in blood vessels increase the risk for HT possibly exacerbating neurovascular damage due to cerebral ischemia/reperfusion in diabetes.
    • Inflammation and diabetic retinal microvascular complications

      Zhang, Wenbo; Liu, Hua; Al-Shabrawey, Mohamed; Caldwell, Robert William; Caldwell, Ruth B.; Vascular Biology Center; Vision Discovery Institute; Department of Pharmacology and Toxicology; Department of Oral Biology; Department of Cellular Biology and Anatomy; et al. (2011-04)
      Diabetic retinopathy (DR) is one of the most common complications of diabetes and is a leading cause of blindness in people of the working age in Western countries. A major pathology of DR is microvascular complications such as non-perfused vessels, microaneurysms, dot/blot hemorrhages, cotton-wool spots, venous beading, vascular loops, vascular leakage and neovascularization. Multiple mechanisms are involved in these alternations. This review will focus on the role of inflammation in diabetic retinal microvascular complications and discuss the potential therapies by targeting inflammation.
    • Influence of common variants in FTO and near INSIG2 and MC4R on growth curves for adiposity in Africanâ and Europeanâ American youth

      Liu, Gaifen; Zhu, Haidong; Dong, Yanbin; Podolsky, Robert H.; Treiber, Frank A.; Snieder, Harold; Center for Biotechnology and Genomic Medicine (2011-06-5)
      Electronic supplementary material: The online version of this article (doi:10.1007/s10654-011-9583-4) contains supplementary material, which is available to authorized users.
    • Influence of DNA Ends on Structure and Function of the DNA-dependent Protein Kinase

      Jovanovic, Marko; Institute of Molecular Medicine and Genetics (2006-12)
      Non-homologous end joining is a major DNA double-strand break repair pathway in mammalian cells. The DNA-dependent protein kinase (DNA-PK), consisting of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ku heterodimer, is hypothesized to be a key regulator of the pathway. Available data suggest DNA-PKcs may exert this regulatory function by controlling access to the DNA termini and by phosphorylation of itself and other proteins. I further characterized DNA-PK-DNA interaction by studying binding of DNA-PKcs and Ku to oligonucleotides with chemically defined end structures under conditions that preclude synapsis between opposing DNA ends. Binding of DNA-PKcs to DNA varied with the end structure in a manner that suggests that partial melting of DNA ends is necessary for the formation of a stable, enzymatically active complex. Unexpectedly, these studies also revealed that ATP, as well as its nonhydrolyzable analog AMP-PNP, have an allosteric effect on the interaction of DNA-PKcs with DNA.