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Snow W.M.,St Boniface Research Center | Snow W.M.,University of Manitoba | Stoesz B.M.,University of Manitoba | Kelly D.M.,University of Manitoba | And 3 more authors.
Molecular Neurobiology | Year: 2014

Although traditionally associated with immune function, the transcription factor nuclear factor kappa B (NF-κB) has garnered much attention in recent years as an important regulator of memory. Specifically, research has found that NF-κB, localized in both neurons and glia, is activated during the induction of long-term potentiation (LTP), a paradigm of synaptic plasticity and correlate of memory. Further, experimental manipulation of NF-κB activation or its blockade results in altered memory and spatial navigation abilities. Genetic knockout of specific NF-κB subunits in mice results in memory alterations. Collectively, such data suggest that NF-κB may be a requirement for memory, although the direction of the response (i.e., memory enhancement or deficit) is inconsistent. A limited number of gene targets of NF-κB have been recently identified in neurons, including neurotrophic factors, calcium-regulating proteins, other transcription factors, and molecules associated with neuronal outgrowth and remodeling. In turn, several key molecules are activators of NF-κB, including protein kinase C and [Ca ++]i. Thus, NF-κB signaling is complex and under the regulation of numerous proteins involved in activity-dependent synaptic plasticity. The purpose of this review is to highlight the literature detailing a role for NF-κB in synaptic plasticity, memory, and spatial navigation. Secondly, this review will synthesize the research evaluating gene targets of NF-κB in synaptic plasticity and memory. Although there is ample evidence to suggest a critical role for NF-κB in memory, our understanding of its gene targets in neurons is limited and only beginning to be appreciated. © 2013 Springer Science+Business Media.


Daymont C.,University of Manitoba | Daymont C.,Manitoba Institute of Child Health | Neal A.,Boston Childrens Hospital | Prosnitz A.,Yale New Haven Childrens Hospital | Cohen M.S.,University of Pennsylvania
Pediatrics | Year: 2013

OBJECTIVE: We sought to describe growth in young children with congenital heart disease (CHD) over time. METHODS: We performed a retrospective matched cohort study, identifying children with CHD in a large primary care network in Pennsylvania, New Jersey, and Delaware and matching them 10:1 with control subjects. The primary endpoint was the difference in mean World Health Organization z score for cases and controls for weight-forage (WFAZ), length-for-age (LFAZ), weight-for-length (WFLZ), and head circumference-for-age (HCFAZ) at traditional ages for preventive visits, stratified by CHD category. RESULTS: We evaluated 856 cases: 37 with single ventricle (SV) physiology, 52 requiring complex repair (CR), 159 requiring simple repair (SR), and 608 requiring no repair. For children in the SV, CR, and SR categories, large, simultaneous, and statistically significant (Student's t test P <05) decreases in WFAZ and LFAZ appeared within the first month of life, peaked near 4 months, and persisted through 24 or 36 months. There were fewer and smaller decreases in the no-repair group between 2 and 18 months. HC data were available between 1 week and 24 months; at those ages, decreases in mean HCFAZ generally paralleled decreases in WFAZ and LFAZ in the SV, CR, and SR groups. CONCLUSIONS: Children with CHD experience early, simultaneous decreases in growth trajectory across weight, length, and head circumference. The simultaneous decrease suggests a role for altered growth regulation in children with CHD. Copyright © 2013 by the American Academy of Pediatrics.


Armistead J.,University of Manitoba | Triggs-Raine B.,University of Manitoba | Triggs-Raine B.,Manitoba Institute of Child Health
FEBS Letters | Year: 2014

Collectively, the ribosomopathies are caused by defects in ribosome biogenesis. Although these disorders encompass deficiencies in a ubiquitous and fundamental process, the clinical manifestations are extremely variable and typically display tissue specificity. Research into this paradox has offered fascinating new insights into the role of the ribosome in the regulation of mRNA translation, cell cycle control, and signaling pathways involving TP53, MYC and mTOR. Several common features of ribosomopathies such as small stature, cancer predisposition, and hematological defects, point to how these diverse diseases may be related at a molecular level. © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Coombs K.M.,University of Manitoba | Coombs K.M.,Manitoba Center for Proteomics and Systems Biology | Coombs K.M.,Manitoba Institute of Child Health
Expert Review of Proteomics | Year: 2011

Measurement of biologically important effector protein molecules has been a long-standing essential component of biological research. Advances in biotechnology, in the form of high-resolution mass spectrometers, and in bioinformatics, now allow the simultaneous quantitative analysis of thousands of proteins. While these techniques still do not allow definitive identification of the entire proteome of complex mixtures, such as cells, quantitative analyses of hundreds to thousands of proteins in such complex mixtures provides a means to elucidate molecular alterations that occur during perturbation of cellular systems. This article will outline considerations of reducing sample complexity, by strategies such as multidimensional separations (gel-based and chromatography-based, including multidimensional protein identification technology). In addition, some of the most common methods used to quantitatively measure proteins in complex mixtures (2D difference in-gel electrophoresis, isotope-coded affinity tags, isotope-coded protein labeling, tandem mass tags, isobaric tags for relative and absolute quantitation, stable isotope labeling of amino acids in cell culture and label-free), as well as recent examples of each strategy, are described. © 2011 Expert Reviews Ltd.


El-Matary W.,Manitoba Institute of Child Health | Moroz S.P.,Manitoba Institute of Child Health | Bernstein C.N.,University of Manitoba
Journal of Pediatric Gastroenterology and Nutrition | Year: 2014

Objectives: The aim of this study was to describe the incidence and prevalence of inflammatory bowel disease (IBD) in children <17 years of age in 30 years from 1978 to 2007.Methods: From January 1, 1978, to December 31, 2007, the sex- and ageadjusted annual incidence and prevalence of pediatric IBD per 100,000 population were calculated based on the pediatric IBD database of the only pediatric tertiary center in the province. The annual health statistics records for the Province of Manitoba were used to calculate population estimates for the participants. To ensure validity of data, the University of Manitoba IBD Epidemiology Database was analyzed for patients <17 years of age from 1989 to 2000.Results: The sex- and age-adjusted incidence of pediatric Crohn disease has increased from 1.2/100,000 in 1978 to 4.68/100,000 in 2007 (P<0.001). For ulcerative colitis, the incidence has increased from 0.47/100,000 in 1978 to 1.64/100,000 in 2007 (P<0.001). During the same time period, the prevalence of Crohn disease has increased from 3.1 to 18.9/100,000 (P<0.001) and from 0.7 to 12.7/100,000 for ulcerative colitis (P<0.001). During the last 5 years of the study the average annual incidence of IBD in urban patients was 8.69/100,000 as compared with 4.75/100,000 for rural patients (P<0.001).Conclusions: The incidence and prevalence of pediatric IBD are increasing. The majority of patients were residents of urban Manitoba, confirming the important role of environmental factors in the etiopathogenesis of IBD. Copyright © 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.


Comer B.S.,University of South Alabama | Camoretti-Mercado B.,University of South Florida | Kogut P.C.,University of Chicago | Halayko A.J.,University of Manitoba | And 3 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2014

MicroRNA (miR)-146a and miR-146b are negative regulators of inflammatory gene expression in lung fibroblasts, epithelial cells, monocytes, and endothelial cells. The abundance of cyclooxygenase-2 (COX-2) and IL-1β is negatively regulated by the miR-146 family, suggesting miR-146a and/or miR-146b might modulate inflammatory mediator expression in airway smooth muscle thereby contributing to pathogenesis of asthma. To test this idea we compared miR-146a and miR-146b expression in human airway smooth muscle cells (hASMCs) from nonasthmatic and asthmatic subjects treated with cytomix (IL-1β, TNF-α, and IFNγ) and examined the miRNAs' effects on COX-2 and IL-1β expression. We found that cytomix treatment elevated miR-146a and miR-146b abundance. Induction with cytomix was greater than induction with individual cytokines, and asthmatic cells exhibited higher levels of miR-146a expression following cytomix treatment than nonasthmatic cells. Transfection of miR-146a or miR-146b mimics reduced COX-2 and IL-1β expression. A miR-146a inhibitor increased COX-2 and IL-1β expression, but a miR-146b inhibitor was ineffective. Repression of COX-2 and IL-1β expression by miR-146a correlated with reduced abundance of the RNA-binding protein human antigen R. These results demonstrate that miR-146a and miR-146b expression is inducible in hASMCs by proinflammatory cytokines and that miR-146a expression is greater in asthmatic cells. Both miR-146a and miR-146b can negatively regulate COX-2 and IL-1β expression at pharmacological levels, but loss-of-function studies showed that only miR-146a is an endogenous negative regulator in hASMCs. The results suggest miR-146 mimics may be an attractive candidate for further preclinical studies as an anti-inflammatory treatment of asthma. © 2014 the American Physiological Society.


Shulyakov A.V.,Manitoba Institute of Child Health | Buist R.J.,University of Manitoba | Del Bigio M.R.,Manitoba Institute of Child Health | Del Bigio M.R.,University of Manitoba
Neurosurgery | Year: 2012

BACKGROUND: The mechanisms of hydrocephalus formation remain unclear. OBJECTIVE: To measure intracranial biomechanical changes in rats with hydrocephalus. METHODS: Stress-strain relationships were determined by using force-controlled indentation through a craniotomy. Cortical blood flow and intracerebral pressures were monitored. In normal rats, deformability of intracranial contents was examined by applying 100 (20-100 mN) indentation cycles and during a 2-hour stress (100 mN) holding test. Hydrocephalus was induced in 56-day rats by cisternal kaolin injection. Magnetic resonance imaging was used to measure ventricle size and cortical blood flow. RESULTS: Application of a constant small force for 2 hours or 100 cycles of a small indentation caused progressive intracranial deformation. Following kaolin injection, the ventricles of 3-to 4-day, 7-to 9-day, and 12-to 15-day hydrocephalic rats progressively enlarged, the dorsal cerebrum thickness decreased by >40%, and cortical blood flow decreased by ∼20%. After 3 to 4 days, intracranial pressure and intraparenchymal pulse pressure increased significantly by ∼85%, and diminished thereafter. After 7 to 9 days, there was a transient significant increase of the intracranial stiffness (indentation modulus). Viscoelastic strain during application of a constant force significantly increased by >50% at 7 to 9 and 12 to 15 days. CONCLUSION: The observation that very small forces applied exogenously or endogenously (through pulsatile brain micromotions) cause progressive intracranial deformation suggests that the brain behaves in a poroviscoelastic manner. Intracranial pulsatility is increased during the early phases of ventriculomegaly. Small viscoelastic property changes of the intracranial contents accompany the ventriculomegaly. Consolidation of brain tissue by the pulsatile forces likely occurs through displacement of intraparenchymal fluids. Copyright © 2012 by the Congress of Neurological Surgeons.


Pydi S.P.,University of Manitoba | Bhullar R.P.,University of Manitoba | Chelikani P.,University of Manitoba | Chelikani P.,Manitoba Institute of Child Health
Journal of Neurochemistry | Year: 2012

The human bitter taste receptors (T2Rs) belong to the G-protein coupled receptor (GPCR) superfamily. T2Rs share little homology with the large subfamily of Class A G-protein coupled receptors, and their mechanisms of activation are poorly understood. Guided by biochemical and molecular approaches, we identified two conserved amino acids Gly281.46 and Ser2857.47 present on transmembrane (TM) helices, TM1 and TM7, which might play important roles in T2R activation. Previously, it was shown that naturally occurring Gly511.46 mutations in the dim light receptor, rhodopsin, cause autosomal dominant retinitis pigmentosa, with the mutants severely defective in signal transduction. We mutated Gly281.46 and Ser2857.47 in T2R4 to G28A, G28L, S285A, S285T, and S285P, and carried out pharmacological characterization of the mutants. No major changes in signaling were observed upon mutation of Gly281.46 in T2R4. Interestingly, S285A mutant displayed agonist-independent activity (approximately threefold over basal wild-type T2R4 or S285T or S285P). We propose that Ser2857.47 stabilizes the inactive state of T2R4 by a network of hydrogen-bonds connecting important residues on TM1-TM2-TM7. We compare and contrast this hydrogen-bond network with that present in rhodopsin. Thus far, S285A is the first constitutively active T2R mutant reported, and gives novel insights into T2R activation. Constitutively active bitter taste receptor mutant. €Â̈Mechanisms of activation of bitter taste receptors (T2Rs) are poorly understood. In this study, we show that Ser2857.47 is crucial in maintaining the inactive state of T2R4 and the S285A mutant displayed constitutive activity. Constitutively active mutants (CAMs) can act as pharmacological tools for characterizing novel bitter taste blockers. © 2012 International Society for Neurochemistry.


Lu C.,University of Manitoba | Xing M.M.Q.,University of Manitoba | Xing M.M.Q.,Manitoba Institute of Child Health | Zhong W.,University of Manitoba
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2011

Hepatocyte-targeting and shell cross-linked nanoparticles with lactose moiety on the surface and doxorubicin (DOX) in the core were prepared from lactose-PEG-DOX conjugate. The process consists of the synthesis of a novel α-hydrazine- ω-propargyl poly(ethylene glycol) (PEG) with a double bond in the PEG backbone, followed by the bonding of a lactose molecule containing an azide group to the α-end of PEG via "click" chemistry, and finally, the conjugation of DOX to the ω-end of PEG via an acid-labile, hydrazone linkage. The resultant conjugate can be self-assembled into nanoparticles. Thiolated tri(ethylene glycol) was introduced into the shell of nanoparticles as a cross-linking agent. The release of DOX is more rapid from lactose-PEG-DOX at pH 5.0 than at pH 7.4. Fluorescent microscope studies suggest that the lactose-DOX nanoparticles are internalized by hepatoma cells through a lactose receptor-mediated mechanism, whereas the lactose-free nanoparticles are not endocytosed as rapidly as lactose-DOX nanoparticles. MTT assay also shows that lactose-DOX nanoparticles have a stronger inhibition against hepatoma cells than DOX nanoparticles and pure DOX. From the Clinical Editor: In this basic science study, a highly efficient targeted doxorubicin delivery method to hepatocytes is presented. © 2011 Elsevier Inc.


Chen J.,University of Manitoba | Chen J.,Manitoba Institute of Child Health | Xing M.M.Q.,University of Manitoba | Xing M.M.Q.,Manitoba Institute of Child Health | Zhong W.,University of Manitoba
Polymer | Year: 2011

Micelles based on a low-toxic and hydrolytically degradable poly(β-amino ester)-g-octadecyl acrylate (PAE-g-ODA) amphiphilic copolymer were developed for doxorubicin (DOX) delivery. A two-step reaction pathway was used to synthesize PAE-g-ODA copolymers with poly(ethylene glycol) segments in the backbone via Michael-type addition reaction. Copolymers with various grafting degrees were obtained by tuning the feeding molar ratios of acrylate/formed secondary amine and the grafting reaction time. Among this series of copolymers, PAE-g-ODA-2 (PAE-g-ODA with 45% ODA side chains) were found to form spherical micelles with an average size of 72.5 nm, as determined by dynamic light scattering (DLS) and transmission electron microscope (TEM), whereas the other PAE-g-ODA copolymers fail to form stable micelles with a narrow size distribution in an aqueous solution. The titration curve illustrated that PAE-g-ODA-2 has a high buffer capacity in the pH range of 7.5-5. The hydrolytic degradation of PAE-g-ODA-2 copolymer in PBS buffer (pH 7.4, 37 °C) was monitored by 1H NMR. It was found that up to 70% ester groups in the backbones were hydrolyzed in 48 h. The DOX-loaded micelles release about 70% trapped DOX within 48 h in physiological condition. Cytotoxicity assay showed a low cytotoxicity of PAE-g-ODA-2 micelles as well as a higher inhibition against HepG2 tumor cells of DOX-loaded micelles than free DOX. © 2010 Elsevier Ltd. All rights reserved.

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