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Title: Assessment of anatomical structures and hemodynamic function of cTnI[193His] transgenic mice with micro-echocardiography.
Creator: Gobara, Nariman., Charles E. Schmidt College of Medicine
Abstract/Description: Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart. My study's objective was to assess cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function was monitored in cTnI193His mice and wild-type littermates for a period of 12 months. It progressed gradually from abnormal relaxation to diastolic dysfunction...
Show moreTransgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart. My study's objective was to assess cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function was monitored in cTnI193His mice and wild-type littermates for a period of 12 months. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with micro- echocardiography by a reversed E/A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. The negative impact of cTnI193His on cardiac function was further demonstrated in isolated mouse working heart preparations. Dobutamine stimulation increased heart rate in cTnI193His mice but did not improve CO. The cTnI193His mice had a phenotype similar to that in human RCM patients carrying the cTnI mutation characterized morphologically by enlarged atria and restricted ventricle and functionally by diastolic dysfunction.
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Date Issued: 2009
PURL: http://purl.flvc.org/FAU/186680
Subject Headings: Mice as laboratory animals, Biochemical markers, Diagnostic use, Cardiovascular system, Pathophysiology, Coronary heart disease, Molecular diagnosis
Format: Document (PDF)

Title: Analyses of neuronal replacement in the neuron-depleted olfactory systems in adult mice.
Creator: Liu, Huan, Charles E. Schmidt College of Medicine
Abstract/Description: New neurons are continuously generated in the olfactory system of adult mice, including olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) and interneurons, produced in the subventricular zone (SVZ) and migrated toward olfactory bulb (OB) along rostral migratory stream (RMS). The present study observed the effects of target neuron loss on the life-span and maturation of adult-born OSNs in the OE and on the proliferation, migration and differentiation of SVZ stem cells in the...
Show moreNew neurons are continuously generated in the olfactory system of adult mice, including olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) and interneurons, produced in the subventricular zone (SVZ) and migrated toward olfactory bulb (OB) along rostral migratory stream (RMS). The present study observed the effects of target neuron loss on the life-span and maturation of adult-born OSNs in the OE and on the proliferation, migration and differentiation of SVZ stem cells in the forebrain after eliminating bulb neurons. We found the life-span of newborn neurons in the absence of synaptic targets was shortened, but the timing of maturation was not delayed. In addition, SVZ cells continued to divide and migrate to the damaged bulb, and the migration of newborn cells in the RMS on the contralateral side was delayed at 2 weeks post-BrdU. Also, the proliferation of cells in dentate gyrus of the hippocampus was not affected by OB damage at 3 weeks post-lesion, though lesion affects occurred in the adult SVZ/RMS.
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Date Issued: 2008
PURL: http://purl.flvc.org/fcla/dt/172671
Subject Headings: Mice as laboratory animals, Neurotransmitter receptors, Sensory neurons, Testing, Cellular control mechanisms
Format: Document (PDF)

Title: Chronic variable stress affects hippocampal neurotrophic factor gene expression in the novelty-seeking phenotype: epigenetic regulation.
Creator: Oztan, Ozge., Charles E. Schmidt College of Medicine
Abstract/Description: Experimentally naive rats exhibit varying degrees of novelty exploration. Some rats display high rates of locomotor reactivity to novelty (high responders; HR), and others display low rates (low responders; LR). The novelty-seeking phenotype (LRHR) is introduced as a model of stress responsiveness. In this thesis I examined effects of chronic variable physical and social stress or control handling on the levels of various neurotrophins in the hippocampus, and changes in mossy fibre terminal...
Show moreExperimentally naive rats exhibit varying degrees of novelty exploration. Some rats display high rates of locomotor reactivity to novelty (high responders; HR), and others display low rates (low responders; LR). The novelty-seeking phenotype (LRHR) is introduced as a model of stress responsiveness. In this thesis I examined effects of chronic variable physical and social stress or control handling on the levels of various neurotrophins in the hippocampus, and changes in mossy fibre terminal fields in LRHR rats. A positive correlation is seen between histone deacetylase 2 and brain-derived neurotrophic factor (BDNF) levels both of which are oppositely regulated in LRHR CA3 fields in response to chronic social stress. Increase in BDNF levels in CA3 field accompanied increase in supra-pyramidal mossy fibre terminal field size (SP-MF) in HRs, and decrease in BDNF levels accompanied decrease in SP-MF volume in LRs. Epigenetic regulation of neurotrophic support underlying these structural changes is discussed.
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Date Issued: 2009
PURL: http://purl.flvc.org/FAU/215290
Subject Headings: Rats as laboratory animals, Cellular signal transduction, Gene expression, Hippocampus (Brain), Physiology, Neural transmission, Genetic regulation
Format: Document (PDF)

Title: The effect of ambient temperature on serotonin syndrome.
Creator: Krishnamoorthy, Swapna., Charles E. Schmidt College of Medicine
Abstract/Description: Serotonin syndrome (SS) is a drug-induced toxicity caused by an excess of serotonin (5-HT) in the central nervous system (CNS). The symptoms of the disorder range from mild to severe, with the severe state evoking life-threatening hyperthermia. Autonomic dysfunction is controlled in part by serotonin receptors, with the 5-HT2A receptor responsible for increasing core body temperature (Tcor). Our results show that the 5-HT2A receptors on the preoptic/anterior hypothalamus (PO/AH) and...
Show moreSerotonin syndrome (SS) is a drug-induced toxicity caused by an excess of serotonin (5-HT) in the central nervous system (CNS). The symptoms of the disorder range from mild to severe, with the severe state evoking life-threatening hyperthermia. Autonomic dysfunction is controlled in part by serotonin receptors, with the 5-HT2A receptor responsible for increasing core body temperature (Tcor). Our results show that the 5-HT2A receptors on the preoptic/anterior hypothalamus (PO/AH) and prefrontal cortex (PFC), in particular, are sensitive to changes in ambient temperature (Tamb). The toxic increase of 5-HT is postulated to occur due to the temperature-dependent activation of these receptors that promotes a positive feedback mechanism. Our results suggest that changes in Tamb can either exacerbate or alleviate the symptom and that this is mediated by the 5-HT2A receptors. Understanding the mechanism involved in elevating Tcor is imperative in treating and preventing the disorder.
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Date Issued: 2008
PURL: http://purl.flvc.org/FAU/186297
Subject Headings: Serotoninergic mechanisms, Central nervous system, Physiology, Body temperature, Regulation, Neurotransmitter receptors, Serotonin, Physiological effect
Format: Document (PDF)

Title: FAU Charles E. Schmidt College of Medicine Bulletin, 2013-08.
Creator: Charles E. Schmidt College of Medicine, Florida Atlantic University
Date Issued: 2013-11
PURL: http://purl.flvc.org/fau/fd/FAU_UA00000280
Subject Headings: Florida Atlantic University -- History
Format: Document (PDF)

Title: FAU Charles E. Schmidt College of Medicine Research Day 2012-05-11.
Creator: Charles E. Schmidt College of Medicine, Florida Atlantic University
Date Issued: 2012-05-11
PURL: http://purl.flvc.org/fau/fd/FAU_UA00000275
Subject Headings: Florida Atlantic University -- History
Format: Document (PDF)

Title: FAU Charles E. Schmidt College of Medicine Research Day 2013-05-17.
Creator: Charles E. Schmidt College of Medicine, Florida Atlantic University
Date Issued: 2013-05-17
PURL: http://purl.flvc.org/fau/fd/FAU_UA00000276
Subject Headings: Florida Atlantic University -- History
Format: Document (PDF)

Title: FAU Charles E. Schmidt College of Medicine Bulletin, 2013-05.
Creator: Charles E. Schmidt College of Medicine, Florida Atlantic University
Date Issued: 2013-05
PURL: http://purl.flvc.org/fau/fd/FAU_UA00000277
Subject Headings: Florida Atlantic University -- History
Format: Document (PDF)

Title: FAU Charles E. Schmidt College of Medicine Bulletin, 2013-06.
Creator: Charles E. Schmidt College of Medicine, Florida Atlantic University
Date Issued: 2013-06
PURL: http://purl.flvc.org/fau/fd/FAU_UA00000278
Subject Headings: Florida Atlantic University -- History
Format: Document (PDF)

Title: FAU Charles E. Schmidt College of Medicine Bulletin, 2013-07.
Creator: Charles E. Schmidt College of Medicine, Florida Atlantic University
Date Issued: 2013-09
PURL: http://purl.flvc.org/fau/fd/FAU_UA00000279
Subject Headings: Florida Atlantic University -- History
Format: Document (PDF)

Title: Approaches for raising the level of FOXO3a in animal cells.
Creator: Navarro, Diana., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: The turtle is a unique model of anoxic survival. The turtle's brain can tolerate total oxygen deprivation for hours to days as well as prevent high levels of mitochondrial-derived free radicals upon re-oxygenation. Because of its ability to prevent elevated free radical generation, the turtle has also become recognized as a model of exceptional longevity. We are employing the turtle model for an investigation into the regulation of a key antioxidant enzyme system - methionine sulfoxide...
Show moreThe turtle is a unique model of anoxic survival. The turtle's brain can tolerate total oxygen deprivation for hours to days as well as prevent high levels of mitochondrial-derived free radicals upon re-oxygenation. Because of its ability to prevent elevated free radical generation, the turtle has also become recognized as a model of exceptional longevity. We are employing the turtle model for an investigation into the regulation of a key antioxidant enzyme system - methionine sulfoxide reductases (Msrs), primarily MsrA and MsrB. The Msr system is capable of reversing oxidation of methionines in proteins and Msr subtypes have been implicated in protecting tissues against oxidative stress, as well as, enhancing the longevity of organisms from yeast to mammals. Preliminary data, unpublished results, indicate that MsrA protein and transcripts are elevated by anoxia. A recent study on Caenorhabditis elegans demonstrated that FOXO is involved in activation of the MsrA promoter. Using the turtle MsrA promoter sequence we worked to determine which regions in the promoter are necessary for activation by anoxia. The results of the present study were 1) to prepare a TAT-FOXO3a fusion protein which could penetrate animal cells and 2) to construct a FOXO3a expression vector for transcription studies on MsrA expression.
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Date Issued: 2012
PURL: http://purl.flvc.org/FAU/3342243
Subject Headings: Cellular signal transduction, Cell proliferation, Oxidative stress, Prevention, Adaptation (Physiology)
Format: Document (PDF)

Title: Expression of autophagy transcripts and proteins in the ocular lens suggests a role for autophagy in lens cell and cellular differentiation.
Creator: Mattucci, Lyndzie., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: The lens is an avascular organ that focuses light onto the retina where neural signals are transmitted to the brain and translated into images. Lens transparency is vital for maintaining function. The lens is formed through a transition from organelle-rich epithelial cells to organelle-free fiber cells. Lens cell differentiation, leading to the lack of organelles, provides an environment optimal for minimizing light scatter and maximizing the ability to focus light onto the retina. The...
Show moreThe lens is an avascular organ that focuses light onto the retina where neural signals are transmitted to the brain and translated into images. Lens transparency is vital for maintaining function. The lens is formed through a transition from organelle-rich epithelial cells to organelle-free fiber cells. Lens cell differentiation, leading to the lack of organelles, provides an environment optimal for minimizing light scatter and maximizing the ability to focus light onto the retina. The process responsible for orchestrating lens cell differentiation has yet to be elucidated. In recent years, data has emerged that led our lab to hypothesize that autophagy is likely involved in lens cell maintenance, cell differentiation, and maintenance of lens transparency. As a first step towards testing this hypothesis, we used RT-PCR, western blot analysis, immunohistochemistry, confocal microscopy, and next generation RNA-Sequencing (RNA-Seq) to examine autophagy genes expressed by the lens to begin mapping their lens function.
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Date Issued: 2013
PURL: http://purl.flvc.org/fcla/dt/3360958
Subject Headings: Cell differentiation, Protein binding, Research, Cellular control mechanisms, Apoptosis
Format: Document (PDF)

Title: DNAJC25 Pro90Leu J-domain mutation demonstrates decreased chaperone activity in vitro.
Creator: Chauss, Daniel C., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: Molecular chaperones guide peptide fold conformation throughout the lifetime of the peptide. One network of chaperone proteins involved in this activity, Heat shock protein 70s (Hsp70s), are well characterized at restoring peptide fold, utilizing J-domain containing protein chaperone cofactors to activate Hsp70 activity. DnaJ (Hsp40) homolog, subfamily C, member 25 (DNAJC25) is a class III transmembrane J-domain containing protein that to date is underrepresented in the literature. Recently,...
Show moreMolecular chaperones guide peptide fold conformation throughout the lifetime of the peptide. One network of chaperone proteins involved in this activity, Heat shock protein 70s (Hsp70s), are well characterized at restoring peptide fold, utilizing J-domain containing protein chaperone cofactors to activate Hsp70 activity. DnaJ (Hsp40) homolog, subfamily C, member 25 (DNAJC25) is a class III transmembrane J-domain containing protein that to date is underrepresented in the literature. Recently, Hejtmancik et al. 2012. (unpublished data) have revealed that missense mutation to DNACJ25 at Pro90Leu (P90L) is strongly correlated with inherited Closed-Angle Glaucoma. Inherited mutations are well characterized for Open-Angle Glaucoma, however, prior to this finding, were unknown for Closed-Angle Glaucoma. In this report, analysis of the in vitro chaperone activity of DNAJC25 w+ and P90L is assessed utilizing an Hsp70 mediated Glucose-6-Phosphate Dehydrogenase refolding system, SWISS-MODEL predictions are performed for the J-domain structure of DNAJC25 w+ and P90L with consequent analysis of DNAJC25 Pro90 conservation relative to other type I, II, and III J-domain containing proteins. DNAJC25 P90L demonstrated decreased chaperone activity in vitro compared to w+ DNAJC25.
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Date Issued: 2012
PURL: http://purl.flvc.org/FAU/3342040
Subject Headings: Cell physiology, Methodology, Molecular chaperones, Physiological effect, Cellular signal transduction, Proteolytic enzymes
Format: Document (PDF)

Title: GAD 65 and its role in pancreatic tissue survival.
Creator: Kumari, Neeta., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: We employed three genotypes of GAD 65, wildtype (GAD 65 +/+), heterozygous (GAD 65 +/-) and knockout (GAD 65 -/-) to investigate the role of GAD 65 in survival of pancreatic islets. We analyzed the mRNA expression of pro-survival proteins including Bcl2 and Bax in pancreas of wildtype, heterozygous and knockout using Reverse Transcriptase Polymerase Chain Reaction (RTPCR). The level of expression of Bcl2 mRNA was down regulated in knockout mice pancreas and Bax to Bcl2 ratio was found higher...
Show moreWe employed three genotypes of GAD 65, wildtype (GAD 65 +/+), heterozygous (GAD 65 +/-) and knockout (GAD 65 -/-) to investigate the role of GAD 65 in survival of pancreatic islets. We analyzed the mRNA expression of pro-survival proteins including Bcl2 and Bax in pancreas of wildtype, heterozygous and knockout using Reverse Transcriptase Polymerase Chain Reaction (RTPCR). The level of expression of Bcl2 mRNA was down regulated in knockout mice pancreas and Bax to Bcl2 ratio was found higher in knockout mice pancreas suggesting higher cell death rate. However, further studies are required to recognize and understand the specific connections between apoptotic pathways and GAD 65 in pancreatic islets.
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Date Issued: 2012
PURL: http://purl.flvc.org/FAU/3342206
Subject Headings: Glutamic acids, Antagonists, Cellular signal transduction, Glutamic acid, Metabolism
Format: Document (PDF)

Title: Effects of adolescent stress on depressive- and anxiety-like behaviors and hippocampal mossy fibre-CA3 remodeling in the novelty-seeking phenotype: implications for epigenetic regulation of the BDNF gene.
Creator: Oztan, Ozge., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: Experimentally naive rats show variance in their locomotor reactivity to novelty, some displaying higher (HR) while others displaying lower (LR) reactivity, associated with vulnerability to stress. LRHR phenotype is proposed as an antecedent to the development of stress hyper responsiveness. Results presented here show emergence of antidepressive-like behavior following peripubertal-juvenile exposure to chronic variable physical (CVP) and chronic variable social stress (CVS) in HR rats, and...
Show moreExperimentally naive rats show variance in their locomotor reactivity to novelty, some displaying higher (HR) while others displaying lower (LR) reactivity, associated with vulnerability to stress. LRHR phenotype is proposed as an antecedent to the development of stress hyper responsiveness. Results presented here show emergence of antidepressive-like behavior following peripubertal-juvenile exposure to chronic variable physical (CVP) and chronic variable social stress (CVS) in HR rats, and depressive-like behavior following CVP in the LRs. The antidepressive-like behavior in HR rats was accompanied by increased levels of acetylated Histone3 (acH3) and acetylated Histone4 (acH4) at the hippocampal brain-derived neurotrophic factor (BDNF) P2 and P4 promoters respectively. This effect may mediate increased mossy fibre (MF) terminal field size, particularly the suprapyramidal mossy fibre projection volume (SP-MF), in the HR animals following both stress regimens. These findings show that chronic variable stress during adolescence induces individual differences in molecular, neuromorphological and behavioral parameters between LRs and HRs, which provides further evidence that individual differences in stress responsiveness is an important factor in resistance or vulnerability to stress-induced depression and/or anxiety.
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Date Issued: 2013
PURL: http://purl.flvc.org/fcla/dt/3360950
Subject Headings: Rats as laboratory animals, Anxiety in adolescence, Depression in adolescence, Stress (Psychology), Cellular signal transduction, Hippocampus (Brain), Physiology, Genetic regulation, Gene expression
Format: Document (PDF)

Title: Determining the subcellular localization of a group II p21-activated kinase - PAK6.
Creator: John, Ciny, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: p-21-activated kinase 6 (PAK6) is a serine-threonine protein kinase originally identified as an Androgen Receptor (AR) interacting protein. In current study, we determined the subcellular localization of PAK6 through mutational analysis. We have found that the N-terminal CRIB domain is partly responsible for plasma membrane targeting, the region between amino acid residues #292 to #368 is functionally relevant to plasma membrane localization and that amino acid residues #119 through #190 are...
Show morep-21-activated kinase 6 (PAK6) is a serine-threonine protein kinase originally identified as an Androgen Receptor (AR) interacting protein. In current study, we determined the subcellular localization of PAK6 through mutational analysis. We have found that the N-terminal CRIB domain is partly responsible for plasma membrane targeting, the region between amino acid residues #292 to #368 is functionally relevant to plasma membrane localization and that amino acid residues #119 through #190 are responsible for nuclear targeting of PAK6, in addition to a stretch of positively charged N-terminal residues (#2-#11) since mutants lacking this sequence mis-localizes to cytoplasm. In junction forming epithelial cells, PAK6 is demonstrated to co-localize with B-catenin at adherens junctions, suggesting that PAK6 is an activation-dependent event and that PAK6 translocates from plasma membrane to the cytoplasm in response activation via the PKA signal pathway.
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Date Issued: 2012
PURL: http://purl.flvc.org/FAU/3355569
Subject Headings: Cellular signal transduction, Serine proteinases, Phosphorylation, Protein kinases, Pathophysiology, Phosphoroproteins, Metabolism
Format: Document (PDF)

Title: Influence of sex hormones and genetic predisposition in dry eye in Sjèogren's syndrome: a new clue to the immunopathogenesis of dry eye disease.
Creator: Mostafa, Safinaz, Charles E. Schmidt College of Medicine, Department of Biological Sciences
Abstract/Description: Sjèogren's syndrome (S) is a chronic autoimmune disease characterized by ocular and oral dryness and primarily affects post menopausal women. In the present study we investigated the time course of lymphocytic infiltration, apoptosis, caspase-3 activity and different cytokines levels in the lacrimal glands of both genetically predisposed and control mice to elucidate immunopathological mechanism leading to dry eye. The results of our experiments showed that ovariectomy accelerated...
Show moreSjèogren's syndrome (S) is a chronic autoimmune disease characterized by ocular and oral dryness and primarily affects post menopausal women. In the present study we investigated the time course of lymphocytic infiltration, apoptosis, caspase-3 activity and different cytokines levels in the lacrimal glands of both genetically predisposed and control mice to elucidate immunopathological mechanism leading to dry eye. The results of our experiments showed that ovariectomy accelerated pathological findings of SS by increasing lympocytic infiltration, cytokine production, lacrimal gland cell death and cleaved caspase-3 activity, and these effects were more pronounced and persistent in the genetically predisposed mouse model of SS. In addition, we observed that lymphocytic infiltration occurred earlier compared to apoptosis which may perpetuate immune mediated destruction of lacrimal epithelial cells. Furthermore, treatment with physioloigical doses of 17-B Estradiol (E2) or DIhydrotestosterone (DHT) prevented all these pathological events observed after ovariectomy.
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Date Issued: 2011
PURL: http://purl.flvc.org/FAU/3353086
Subject Headings: Dry eye syndromes, Immunological aspects, Sjèogren's syndrome, Immunological aspects, Disease susceptibility, Human genome, Medical genetics
Format: Document (PDF)

Title: Mutant huntingtin reduces palmitoylation of GAD65 and impairs its vesicular trafficking.
Creator: Rush, Daniel., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: Huntington's disease (HD) is caused by an expanded plyglutamine repeat in the huntingtin protein. In this study, I focused on the effect of the mutant huntingtin protein (mhtt) on the subcellular localization of glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing gama-aminobutyric acid (GABA). Subcellular distribution of GAD65 is significantly altered in two neuronal cell lines that express either the N-terminus or full length mhtt. GAD65 is predominantly associated...
Show moreHuntington's disease (HD) is caused by an expanded plyglutamine repeat in the huntingtin protein. In this study, I focused on the effect of the mutant huntingtin protein (mhtt) on the subcellular localization of glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing gama-aminobutyric acid (GABA). Subcellular distribution of GAD65 is significantly altered in two neuronal cell lines that express either the N-terminus or full length mhtt. GAD65 is predominantly associated with the Golgi membrane in cells expressing normal huntingtin (Htt). However, it diffuses in the cytosol of cells expressing mhtt. Palmitoylation of GAD65 is required for GAD65 trafficking, and I demonstrated the palmitoylation of GAD65 is reduced in the HD model. Overexpression of huntingtin-interacting protein 14 (HIP14), the enzyme that palmitoylates GAD65, rescues GAD65 palmitoylation and vesicle-associated trafficking. This data suggests that impairment of GAD65 palmitoylation by mhtt may alter its localization and lead to altered inhibitory neurotransmission in HD.
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Date Issued: 2012
PURL: http://purl.flvc.org/FAU/3352831
Subject Headings: Glutamic acids, Antagonists, Cellular signal transduction, Proteolytic enzymes, Research, Proteins, Physiological transport, Huntington's chorea, Research
Format: Document (PDF)

Title: The novel function of sJAM-C in promoting cytoskeleton rearrangement and migration in mammary epithelial cells.
Creator: Qureshi, Anila, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: Soluble form of Junctional adhesion molecule C (sJAM-C) has been identified to cause angiogenesis as well as chemotaxis in endothelial cells. However, the role of sJAM-C in the context of cancer has not been elucidated. Our atomic force microscopy (AFM) stiffness measurements of normal mammary epithelial cells (MCF 10A) have shown a two-fold decrease in cell's stiffness in response to sJAM-C. Changes in cell stiffness are indicative of modulations in a cell's mechanical properties. Our...
Show moreSoluble form of Junctional adhesion molecule C (sJAM-C) has been identified to cause angiogenesis as well as chemotaxis in endothelial cells. However, the role of sJAM-C in the context of cancer has not been elucidated. Our atomic force microscopy (AFM) stiffness measurements of normal mammary epithelial cells (MCF 10A) have shown a two-fold decrease in cell's stiffness in response to sJAM-C. Changes in cell stiffness are indicative of modulations in a cell's mechanical properties. Our results indicated that sJAM-C increased the MCF 10A cell migration about two-fold and also promoted a three-fold increase in chemotaxis. Additionally, sJAM-C treatment resulted in considerable filamentous-actin loss and peripheral actin ring breakage. We also found activation of Rho signaling pathway to be the main mechanism behind sJAM-C mediated alterations in MCF 10A cell cytoskeleton and motility. Our data present for the first time that sJAM-C is a pro metastatic mediator for normal mammary epithelial cells.
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Date Issued: 2012
PURL: http://purl.flvc.org/fcla/dt/3362046
Subject Headings: Tight junctions (Cell biology), Cell interaction, Cell junction, Cell adhesion, Microcirculation
Format: Document (PDF)

Title: Structure-function relationships in eukaryotic and prokaryotic family 6 glycosyltransferases.
Creator: Tumbale, Percy., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: Carbohydrate Active Enzyme family 6 (CA6) glycosyltransferases (GTs) are type II transmembrane proteins localized in the Golgi apparatus. CA6 GTs have a GT-A fold, a type of structure that resembles the Rossman fold and catalyze the transfer either galactose (Gal) or N-acetylgalactosamine (GalNAc) from the UDP nucleotide sugar to an non-reducing terminal Gal or GalNAc on an acceptor via an a-1,3 linkage. In this reaction, the anomeric configuration of the sugar moiety of the donor is retained...
Show moreCarbohydrate Active Enzyme family 6 (CA6) glycosyltransferases (GTs) are type II transmembrane proteins localized in the Golgi apparatus. CA6 GTs have a GT-A fold, a type of structure that resembles the Rossman fold and catalyze the transfer either galactose (Gal) or N-acetylgalactosamine (GalNAc) from the UDP nucleotide sugar to an non-reducing terminal Gal or GalNAc on an acceptor via an a-1,3 linkage. In this reaction, the anomeric configuration of the sugar moiety of the donor is retained in the product. CA6 GTs includes the histo-blood group A and B GTs, a-galactosyltransferase (a3GT), Forssman glycolipid synthase (FS), isogloboside 3 synthase (iGb3) in mammals. a3GT and its products (a-Gal epitode) are present in most mammals but are absent in humans and old world primates because of inactivating mutations. The absence of a3GT and its products results in the production of anti-a-Gal epitope natural antibodies in these species., Up to date, the catalytic mechanisms of the CA6 GTs are not well understood. Based on previous structural and mutagenesis studies of bovine aB3GT, we investigated active site residues (His315, Asp316, Ser318, His319, and Lys359) that are highly conserved among CA6 GTs. We have also investigated the role of the C-terminal region by progressive C-terminal truncations. Findings from these studies clarify the functional roles of these residues in structure, catalysis, and specificity in these enzymes and have implications for their catalytic mechanisms. GTs are useful tools in synthesis of glycans for various applications in science and medicine. Methods for the large scale production of pure glycans are continuously being developed. We created a limited randomized combinatorial library based on knowledge of structural information and sequence analysis of the enzyme and its mammalian homologues., Two GalNAc-specific variants were identified from the library and one Glc-specific variant was identified by site-direct mutagenesis. The glycosyltransferase activities of these variants are expected to be improved by further screens of libraries which are designed using the variants as templates. The mammalian CA6 GTs that have been characterized to date are metal-independent and require the divalent cation, Mn2+ for activity. In some recently-discovered bacterial CA6 GTs, the DXD sequence that is present in eukaryotic GTs is replaced by NXN. We cloned and expressed one of these proteins from Bacteroides ovatus, a bacterium that has been linked with inflammatory bowel disease. Functional characterization shows it is a metal-independent monomeric GT that efficiently catalyzes the synthesis of oligosaccharides similar to human blood group A glycan., Mutational studies indicated that despite the lack of a metal cofactor there are similarities in structure-function relationships between the bacterial and vertebrate family 6 GTs.
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Date Issued: 2009
PURL: http://purl.flvc.org/FAU/186686
Subject Headings: Molecular biology, Mathematical models, Glycotransferase genes, Biological transport, Proteins, Synthesis, Evolutionary genetics
Format: Document (PDF)

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