UCD Conway Institute of Biomolecular and Biomedical Research

Dublin, Ireland

UCD Conway Institute of Biomolecular and Biomedical Research

Dublin, Ireland
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Chaudhry M.,UCD Conway Institute of Biomolecular and Biomedical Research | Wilson A.G.,UCD Conway Institute of Biomolecular and Biomedical Research
Expert Review of Molecular Diagnostics | Year: 2017

Introduction: Rheumatoid Arthritis (RA) varies from a mild to a severe, unremitting illness characterized by uncontrolled inflammation with consequent damage to cartilage and bone of joints. Individualized therapeutic approaches based on likely outcome would facilitate a personalized therapeutic approach. Areas covered: Genetics is known to contribute a significant component of the variability in RA outcome, estimated at 45–60%. A number of candidate gene studies have been associated with variability in radiologically assessed joint damage; however a more comprehensive genome wide analysis is required to more fully characterize the genetic basis of RA severity. Expert commentary: Genetic profiling of patient presenting with RA has the potential to aid stratification based on predicted prognosis, this would inform the clinical development of a personalized therapeutic approach. It will also result in the identification of novel mediators of tissue damage in RA. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Mukandala G.,UCD Conway Institute of Biomolecular and Biomedical Research | Tynan R.,UCD Conway Institute of Biomolecular and Biomedical Research | Lanigan S.,UCD Conway Institute of Biomolecular and Biomedical Research | O'Connor J.J.,UCD Conway Institute of Biomolecular and Biomedical Research
Brain Sciences | Year: 2016

Normal brain function is highly dependent on oxygen and nutrient supply and when the demand for oxygen exceeds its supply, hypoxia is induced. Acute episodes of hypoxia may cause a depression in synaptic activity in many brain regions, whilst prolonged exposure to hypoxia leads to neuronal cell loss and death. Acute inadequate oxygen supply may cause anaerobic metabolism and increased respiration in an attempt to increase oxygen intake whilst chronic hypoxia may give rise to angiogenesis and erythropoiesis in order to promote oxygen delivery to peripheral tissues. The effects of hypoxia on neuronal tissue are exacerbated by the release of many inflammatory agents from glia and neuronal cells. Cytokines, such as TNF-α, and IL-1β are known to be released during the early stages of hypoxia, causing either local or systemic inflammation, which can result in cell death. Another growing body of evidence suggests that inflammation can result in neuroprotection, such as preconditioning to cerebral ischemia, causing ischemic tolerance. In the following review we discuss the effects of acute and chronic hypoxia and the release of pro-inflammatory cytokines on synaptic transmission and plasticity in the central nervous system. Specifically we discuss the effects of the pro-inflammatory agent TNF-α during a hypoxic event. © 2016 by the authors; licensee MDPI, Basel, Switzerland.

Phelan N.,Adelaide and Meath Hospital | O'Connor A.,UCD Conway Institute of Biomolecular and Biomedical Research | Kyaw Tun T.,Adelaide and Meath Hospital | Correia N.,Adelaide and Meath Hospital | And 3 more authors.
Clinical Endocrinology | Year: 2013

Objectives Low-grade chronic inflammation predicts cardiovascular outcomes and is observed in women with polycystic ovary syndrome (PCOS). Whether this is entirely a cause or consequence of insulin resistance (IR) is unknown. Methods Seventy pairs of women with and without PCOS, matched for age, body mass index (BMI) and IR (HOMA, QUICKI and Avignon index), were generated from a larger cohort of 103 women with and 104 BMI-matched women without PCOS. Women with PCOS were studied in the follicular phase of the menstrual cycle. White cell count (WCC), high-sensitivity CRP (hsCRP) and a series of 12 cytokines and growth factors were measured. These inflammatory markers were also compared between women with PCOS and 10 normal women studied in the follicular, peri-ovulatory and luteal stages. Results When all subjects were compared, WCC (6·75 × 109 vs 5·60 × 109g/l, P < 0·005), hsCRP (4·04 vs 2·90 mg/l, P < 0·05) and IL-6 (1·11 vs 0·72 pg/ml, P < 0·05) were greater in women with PCOS. Pair-matching for IR eliminated between-group differences in hsCRP and cytokines but did not alter the difference in WCC (6·60 × 109 vs 5·60 × 109g/l, P < 0·005). WCC was greater in PCOS compared to normal women at all stages of the menstrual cycle. Conclusions Low-grade inflammation occurs in PCOS. Increased hsCRP and cytokines are associated with IR, but increased WCC is observed even when IR is accounted for. The explanation for this and its clinical significance is unknown. © 2012 Blackwell Publishing Ltd.

Di Luca A.,Teagasc | Mullen A.M.,Teagasc | Elia G.,UCD Conway Institute of Biomolecular and Biomedical Research | Davey G.,National University of Ireland | Hamill R.M.,Teagasc
Meat Science | Year: 2011

Achieving an improvement in water-holding capacity (WHC) of pork and a reduction in the incidence of pale, soft and exudative (PSE)- and dark, firm and dry (DFD)-like meat is a major challenge for the swine industry. Using proteomics, we sought to identify proteins associated with WHC and to monitor postmortem protein degradation. Twenty longissimus samples were categorised into WHC phenotypes. The centrifugal drip was subjected to SDS-PAGE and mass-spectrometry. Forty-four proteins were identified in the centrifugal drip proteome. Changes occurred in volume of five bands across the ageing period, with most significant changes representing increases between day 3 and day 7. Seven proteins were identified in these bands, most with functions in glycolysis. One band significantly differed in abundance across WHC phenotypes. Peptide signatures of the heat shock protein family were identified in this band. © 2011 Elsevier Ltd.

Di Luca A.,Teagasc | Elia G.,UCD Conway Institute of Biomolecular and Biomedical Research | Hamill R.,Teagasc | Mullen A.M.,Teagasc
Proteomics | Year: 2013

Variation in water-holding capacity (WHC), which presents a major economic burden to the swine industry, is considered to be underpinned by variation at a molecular and biochemical level. High-resolution 2D DIGE followed by MS analysis and Western blot were used to unravel the proteome of muscle exudate, collected following centrifugation, in the pH 4-7 range. A first 2DE-based protein map of this substrate was produced where 89 spots were successfully characterised. Two phenotypes divergent for WHC plus one intermediate were compared with a view to deciphering the biochemical processes impacting on variation in WHC. Twenty spots were observed to be altered across the phenotypes. Of these, 14 represented sixteen proteins including metabolic enzymes, stress response proteins and structural proteins. Triosephosphate isomerase and transferrin showed a major difference between the two extreme phenotypes, and may have potential as biological markers for WHC prediction. Several members of the HSPs family were highlighted. This proteomic study makes an important contribution towards a more detailed molecular view of the processes behind WHC and will provide a valuable resource for future investigations. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Di Luca A.,Teagasc | Elia G.,UCD Conway Institute of Biomolecular and Biomedical Research | Mullen A.M.,Teagasc | Hamill R.M.,Teagasc
Proteome Science | Year: 2013

Background: Meat quality is a complex trait influenced by a range of factors with post mortem biochemical processes highly influential in defining ultimate quality. High resolution two-dimensional DIfference Gel Electrophoresis (2-D DIGE) and Western blot were applied to study the influence of post mortem meat ageing on the proteome of pork muscle. Exudate collected from the muscle following centrifugation was analysed at three timepoints representing a seven day meat ageing period.Results: The intensity of 136 spots varied significantly (p < 0.05) across this post mortem period and 40 spots were identified using mass spectrometry. The main functional categories represented were metabolic proteins, stress-related proteins, transport and structural proteins. Metabolic and structural proteins were generally observed to increase in abundance post mortem and many likely represent the accumulation of the degradation products of proteolytic enzyme activity. In contrast, stress-related proteins broadly decreased in abundance across the ageing period. Stress response proteins have protective roles in maintaining cellular integrity and a decline in their abundance over time may correlate with a reduction in cellular integrity and the onset of meat ageing. Since cellular conditions alter with muscle ageing, changes in solubility may also contribute to observed abundance profiles.Conclusions: Muscle exudate provided valuable information about the pathways and processes underlying the post mortem ageing period, highlighting the importance of post mortem modification of proteins and their interaction for the development of meat quality traits. © 2013 Di Luca et al.; licensee BioMed Central Ltd.

Ryan M.F.,University College Dublin | Grada C.O.,University College Dublin | Grada C.O.,Nutrigenomics Research Group | Morris C.,University College Dublin | And 9 more authors.
American Journal of Clinical Nutrition | Year: 2013

Background: The response to dietary fat plays a key role in metabolic health. Although this can vary widely between individuals, variation within an individual and the associated contribution of phenotypic and genotypic factors to this variation are less defined. Objectives: The objectives were to quantify within-person variation in triacylglycerol response by means of a novel variation score (Sv) and to explore the phenotypic and genotypic factors associated with this score. Design: Two consecutive 5-h oral-lipid-tolerance tests (OLTTs) were conducted in 51 healthy adults aged 18-60 y with a BMI (in kg/m2) of 18.5 to 49.8. Detailed body composition, physical function, biochemistry, and genotype data were gathered. Results: The postprandial triacylglycerol response profile did not differ (P = 0.64) across OLTTs for the group; nor did average concentrations of functional markers apolipoprotein C2 (P = 0.73) and apolipoprotein C3 (P = 0.74). S v was low in most (82%) of the adults and was significantly (P < 0.05) associated with age, fasting triacylglycerol, triacylglycerol AUC, and fasting nonessential fatty acids. Significant associations were also observed between Sv and single nucleotide polymorphisms in 7 genes (APOA1, IL1a, IL1b, TLR4, TCF7L2, CCK1Rec, and STAT3) after correction for phenotypic differences. Conclusions: This work showed that the within-person variability in postprandial lipemic response is low in most healthy adults. It also showed that variability in this response is associated with a defined set of phenotypic and genotypic characteristics. © 2013 American Society for Nutrition.

Batti L.,UCD Conway Institute of Biomolecular and Biomedical Research | O'Connor J.J.,UCD Conway Institute of Biomolecular and Biomedical Research
Journal of Neuroimmunology | Year: 2010

Cerebral ischaemia is a common occurrence in a range of pathological conditions, including stroke and traumatic brain injury. Two of the components in ischaemia are tissue hypoxia and the release of pro-inflammatory agents such as TNF-α. The role of TNF-α in an ischaemic/hypoxic episode is still controversial, although deleterious effects of pro-inflammatory cytokines in the area of injury are well documented. One of the prime adaptive mechanisms in response to hypoxia is the cellular activation of adenosine 1 receptors (A1Rs), which inhibits excitatory synaptic transmission. In the present study we have examined the effect of TNF-α application on synaptic transmission during hypoxic exposure and re-oxygenation using extracellular recordings in the CA1 region of the rat hippocampal slice. Hypoxia caused a reversible depression of the field EPSP (29.6 ± 9.7% of control, n = 5), which was adenosine A1 receptor-dependent (85.7 ± 4.3%, in the presence of DPCPX (200 nM), the adenosine A1 receptor antagonist). DPCPX inhibited the maintenance of long-term potentiation obtained 30 min post hypoxia (143.8 ± 8.2% versus 96.4 ± 10.6% respectively, 1 h post tetanus; n = 5; p < 0.005). In TNF-α (150 pM) treated slices hypoxic depression was similar to controls but a reduction in fEPSP slope was observed during re-oxygenation (66.8 ± 1.4%, n = 5). This effect was reversed by pre-treatment with SB 203580 (1 μM), a p38 MAP kinase inhibitor (91.8 ± 6.9%, n = 5). These results demonstrate a novel p38 MAPK dependent role for TNF-α in attenuating synaptic transmission after a hypoxic episode. © 2009 Elsevier B.V. All rights reserved.

Sandin P.,UCD Conway Institute of Biomolecular and Biomedical Research | Fitzpatrick L.W.,UCD Conway Institute of Biomolecular and Biomedical Research | Simpson J.C.,University College Dublin | Dawson K.A.,UCD Conway Institute of Biomolecular and Biomedical Research
ACS Nano | Year: 2012

Despite the increased application of nanomaterials in diagnostics and therapeutics, methods to study the interactions of nanoparticles with subcellular structures in living cells remain relatively undeveloped. Here we describe a robust and quantitative method that allows for the precise tracking of all cell-associated nanoparticles as they pass through endocytic compartments in a living cell. Using rapid multicolor 3D live cell confocal fluorescence microscopy, combined with transient overexpression of small GTPases marking various endocytic membranes, our studies reveal the kinetics of nanoparticle trafficking through early endosomes to late endosomes and lysosomes. We show that, following internalization, 40 nm polystyrene nanoparticles first pass through an early endosome intermediate decorated with Rab5, but that these nanoparticles rapidly transfer to late endosomes and ultimately lysosomes labeled with Rab9 and Rab7, respectively. Larger nanoparticles of 100 nm diameter also reach acidic Rab9- and Rab7-positive compartments although at a slower rate compared to the smaller 40 nm nanoparticles. Our work also reveals that relatively few nanoparticles are able to access endocytic recycling pathways, as judged by lack of significant colocalization with Rab11. Finally, we demonstrate that this quantitative approach is sufficiently sensitive to be able to detect rare events in nanoparticle trafficking, specifically the presence of nanoparticles in Rab1A-labeled structures, thereby revealing the wide range of intracellular interactions between nanoparticles and the intracellular environment. © 2012 American Chemical Society.

O'Shea L.,University College Dublin | Fair T.,UCD Conway Institute of Biomolecular and Biomedical Research | Hensey C.,University College Dublin
Cell Death and Disease | Year: 2013

We have analyzed the expression and function of the cell death and cell cycle regulator Aven in Xenopus. Analysis of Xenopus Aven expression in oocytes and embryos revealed a band close to the predicted molecular weight of the protein (36 kDa) in addition to two bands of higher molecular weight (46 and 49 kDa), one of which was determined to be due to phosphorylation of the protein. The protein is primarily detected in the cytoplasm of oocytes and is tightly regulated during meiotic and mitotic cell cycles. Progesterone stimulation of oocytes resulted in a rapid loss of Aven expression with the protein levels recovering before germinal vesicle breakdown (GVBD). This loss of Aven is required for the G2-M1 cell cycle transition. Aven morpholino knockdown experiments revealed that early depletion of the protein increases progesterone sensitivity and facilitates GVBD, but prolonged depletion of Aven results in caspase-3 activation and oocyte death by apoptosis. Phosphorylated Aven (46 kDa) was found to bind Bcl-xL in oocytes, but this interaction was lost in apoptotic oocytes. Thus, Aven alters progesterone sensitivity in oocytes and is critical for oocyte survival. © 2013 Macmillan Publishers Limited All rights reserved.

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