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Showing papers by "Trinity College, Dublin published in 2002"


Journal ArticleDOI
04 Apr 2002-Nature
TL;DR: It is reported that natural oligomers of human Aβ are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell, indicating that synaptotoxic Aβ oligomers can be targeted therapeutically.
Abstract: Although extensive data support a central pathogenic role for amyloid β protein (Aβ) in Alzheimer's disease1, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Aβ and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Aβ are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Aβ monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Aβ species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Aβ monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Aβ oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with γ-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Aβ oligomers can be targeted therapeutically.

4,315 citations


Journal ArticleDOI
TL;DR: The ASSIST items are reliable and feasible to use as part of an international screening test and can serve as the basis for more extensive validation research.
Abstract: WHO ASSIST Working Group member: Robert Ali for Drug and Alcohol Addiction Services Council, Adelaide, Australia

1,385 citations


Journal ArticleDOI
TL;DR: In this paper, the authors define and explore the legitimacy of an action-oriented research approach in OM, and the particular logic and value of applying action research (AR) to the description and understanding of issues in OM.
Abstract: A fundamental methodological question guides this paper: How can operations managers and researchers learn from the applied activity that characterises the practice of OM? To address this question, defines and explores the legitimacy of an action‐oriented research approach in OM, and the particular logic and value of applying action research (AR) to the description and understanding of issues in OM. Begins with a review of the role of empirical research in OM and how AR features within the OM research literature. Introduces the theory and practice of AR and outlines the AR cycle and how AR is implemented. Finally, describes the skills required to engage in AR and explores issues in generating theory. Concludes with the assertion that AR is relevant and valid for the discipline of OM in its ability to address the operational realities experienced by practising managers while simultaneously contributing to knowledge.

1,344 citations


Journal ArticleDOI
TL;DR: The authors employed event-related fMRI and EEG data to investigate the biological basis of cognitive control of behavior using a GO/NOGO task optimized to produce response inhibitions, frequent commission errors, and the opportunity for subsequent behavioral correction.

931 citations


Journal ArticleDOI
TL;DR: The first demonstration of pathogen-specific T regulatory type 1 (Tr1) cells at the clonal level is provided and it is demonstrated that these cells are induced at a mucosal surface during an infection where local Th1 responses are suppressed.
Abstract: Antigen-specific T helper type 1 (Th1) cells mediate protective immunity against a range of infectious diseases, including that caused by Bordetella pertussis. Distinct T cell subtypes that secrete interleukin (IL)-10 or tumor growth factor (TGF)-β are considered to play a role in the maintenance of self-tolerance. However, the antigens recognized by these regulatory T cells in vivo have not been defined. Here we provide the first demonstration of pathogen-specific T regulatory type 1 (Tr1) cells at the clonal level and demonstrate that these cells are induced at a mucosal surface during an infection where local Th1 responses are suppressed. Tr1 clones specific for filamentous hemagglutinin (FHA) and pertactin were generated from the lungs of mice during acute infection with B. pertussis. The Tr1 clones expressed T1/ST2 and CC chemokine receptor 5, secreted high levels of IL-10, but not IL-4 or interferon (IFN)-γ, and suppressed Th1 responses against B. pertussis or an unrelated pathogen. Furthermore, FHA inhibited IL-12 and stimulated IL-10 production by dendritic cells (DCs), and these DCs directed naive T cells into the regulatory subtype. The induction of Tr1 cells after interaction of a pathogen-derived molecule with cells of the innate immune system represents a novel strategy exploited by an infectious pathogen to subvert protective immune responses in vivo.

693 citations


Journal ArticleDOI
TL;DR: Reductions in respiratory and cardiovascular death rates in Dublin suggest that control of particulate air pollution could substantially diminish daily death.

681 citations


Journal ArticleDOI
TL;DR: A biphasic poroelastic finite element model of a fracture callus is used to simulate the time-course of tissue differentiation during fracture healing to confirm the hypothesis that tissue differentiation phenomena could be governed by the proposed mechano-regulation model.

603 citations


Journal ArticleDOI
TL;DR: This review summarises and evaluates the current knowledge concerning the complex role of released mitochondrial proteins in the apoptotic process and identifies members of the Bcl-2 protein family that control the integrity and response of mitochondria to apoptotic signals.
Abstract: Mitochondria are 'life-essential' organelles for the production of metabolic energy in the form of ATP. Paradoxically mitochondria also play a key role in controlling the pathways that lead to cell death. This latter role of mitochondria is more than just a 'loss of function' resulting in an energy deficit but is an active process involving different mitochondrial proteins. Cytochrome c was the first characterised mitochondrial factor shown to be released from the mitochondrial intermembrane space and to be actively implicated in apoptotic cell death. Since then, other mitochondrial proteins, such as AIF, Smac/DIABLO, endonuclease G and Omi/HtrA2, were found to undergo release during apoptosis and have been implicated in various aspects of the cell death process. Members of the Bcl-2 protein family control the integrity and response of mitochondria to apoptotic signals. The molecular mechanism by which mitochondrial intermembrane space proteins are released and the regulation of mitochondrial homeostasis by Bcl-2 proteins is still elusive. This review summarises and evaluates the current knowledge concerning the complex role of released mitochondrial proteins in the apoptotic process.

598 citations


Journal ArticleDOI
TL;DR: A systematic and objective analysis of the draft human genome sequence is reported to identify paralogous chromosomal regions (paralogons) formed during chordate evolution and to estimate the ages of duplicate genes.
Abstract: Opinions on the hypothesis that ancient genome duplications contributed to the vertebrate genome range from strong skepticism to strong credence. Previous studies concentrated on small numbers of gene families or chromosomal regions that might not have been representative of the whole genome, or used subjective methods to identify paralogous genes and regions. Here we report a systematic and objective analysis of the draft human genome sequence to identify paralogous chromosomal regions (paralogons) formed during chordate evolution and to estimate the ages of duplicate genes. We found that the human genome contains many more paralogons than would be expected by chance. Molecular clock analysis of all protein families in humans that have orthologs in the fly and nematode indicated that a burst of gene duplication activity took place in the period 350 650 Myr ago and that many of the duplicate genes formed at this time are located within paralogons. Our results support the contention that many of the gene families in vertebrates were formed or expanded by large-scale DNA duplications in an early chordate. Considering the incompleteness of the sequence data and the antiquity of the event, the results are compatible with at least one round of polyploidy.

532 citations


Journal ArticleDOI
12 Apr 2002-Science
TL;DR: The genetic signatures of its origins, secondary movements, and differentiation through the study of 15 microsatellite loci in 50 indigenous cattle breeds spanning the present cattle distribution in Africa reveal a major entry point through the Horn and the East Coast of Africa and two modes of introgression into the continent.
Abstract: The genetic history of African cattle pastoralism is controversial and poorly understood. We reveal the genetic signatures of its origins, secondary movements, and differentiation through the study of 15 microsatellite loci in 50 indigenous cattle breeds spanning the present cattle distribution in Africa. The earliest cattle originated within the African continent, but Near East and European genetic influences are also identified. The initial expansion of African Bos taurus was likely from a single region of origin. It reached the southern part of the continent by following an eastern route rather than a western one. The B. indicus genetic influence shows a major entry point through the Horn and the East Coast of Africa and two modes of introgression into the continent.

490 citations


Journal ArticleDOI
TL;DR: The fluorescent photoinduced electron transfer chemosensors 2 and 3 were designed for the recognition of anions possessing two binding sides such as dicarboxylates and pyrophosphate; the anion recognition in DMSO takes place through the two charge neutral thiourea receptor sites with concomitant PET quenching of the anthracene moiety.

Journal ArticleDOI
TL;DR: Rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin, and the patient should be monitored for signs and symptoms of myopathy and the statin should be discontinued if necessary.
Abstract: The HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions. Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold. Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.

Journal ArticleDOI
TL;DR: In this article, a self-assembly pyrolytic route to large arrays of aligned n-type nanotubes (15-80 nm OD and <100 μm in length) is presented.
Abstract: Self-assembly pyrolytic routes to large arrays (<2.5 cm2) of aligned CNx nanotubes (15–80 nm OD and <100 μm in length) are presented. The method involves the thermolysis of ferrocene/melamine mixtures (5:95) at 900–1000 °C in the presence of Ar. Electron energy loss spectroscopy (EELS) reveals that the N content varies from 2–10%, and can be bonded to C in two different fashions (double-bonded and triple-bonded nitrogen). The electronic densities of states (DOS) of these CNx nanotubes, using scanning tunneling spectroscopy (STS), are presented. The doped nanotubes exhibit strong features in the conduction band close to the Fermi level (0.18 eV). Using tight-binding and ab initio calculations, we confirm that pyridine-like (double-bonded) N is responsible for introducing donor states close to the Fermi Level. These electron-rich structures are the first example of n-type nanotubes. Finally, it will be shown that moderate electron irradiation at 700–800 °C is capable of coalescing single-walled nanotubes (SWNTs). The process has also been studied using tight-binding molecular dynamics (TBMD). Vacancies induce the coalescence via a zipper-like mechanism, which has also been observed experimentally. These vacancies trigger the organization of atoms on the tube lattices within adjacent tubes. These results pave the way to the fabrication of nanotube heterojunctions, robust composites, contacts, nanocircuits and strong 3D composites using N-doped tubes as well as SWNTs.

Journal ArticleDOI
TL;DR: Activation during "successful inhibition" occurred predominantly in right prefrontal and parietal regions and was more extensive, bilaterally and prefrontally, in the older groups, extending the aging neuroimaging literature into the cognitive domain of inhibition.
Abstract: Inhibitory control, the ability to suppress irrelevant or interfering stimuli, is a fundamental cognitive function that deteriorates during aging, but little is understood about the bases of decline. Thus, we used event-related functional magnetic resonance imaging (fMRI) to study inhibitory control in healthy adults aged 18 to 78. Activation during "successful inhibition" occurred predominantly in right prefrontal and parietal regions and was more extensive, bilaterally and prefrontally, in the older groups. Presupplementary motor area was also more active in poorer inhibitory performers. Therefore, older adults activate areas that are comparable to those activated by young adults during inhibition, as well as additional regions. The results are consistent with a compensatory interpretation and extend the aging neuroimaging literature into the cognitive domain of inhibition.

Journal ArticleDOI
TL;DR: The success and limitations of a formulation approach using lipid-based vehicles are analyzed, potential areas for further research are highlighted and a deeper appreciation of all the mechanisms is still unrealized.

Journal ArticleDOI
TL;DR: Observations that Tr cells can be induced against bacterial, viral and parasite antigens in vivo and might prevent infection-induced immunopathology or prolong pathogen persistence by suppressing protective Th1 responses have significant implications for the understanding of the role of T cells in immunity to infectious diseases.

Journal ArticleDOI
TL;DR: It has been demonstrated that a tiered approach at all three steps can be helpful to optimise the use of the available resources: if relatively crude tools - designed to provide a "worst case" estimate - do not suggest a toxicologically significant exposure (or a relevant deficit of a particular nutrient) it may not be necessary to use more sophisticated tools.

Journal ArticleDOI
TL;DR: McNeill et al. as mentioned in this paper show that there is no evidence supporting the view that the world economy was globally integrated prior to the 1490s; there is also no evidence that this decade had the trading impact that world historians assign to it; but there is abundant evidence that a very big globalisation bang took place in the 1820s.
Abstract: Some world historians attach globalisation ‘big bang’ significance to 1492 and 1498. Such scholars are on the side of Adam Smith who believed that these were the two most important events in recorded history. Other world historians insist that globalisation stretches back even earlier. There is a third view which argues that the world economy was fragmented and completely de-globalised before the early nineteenth century. None of these three competing views has distinguished explicitly between trade expansion driven by booming import demand or export supply, and trade expansion driven by the integration of markets between trading economies. This article makes that distinction, and shows that there is no evidence supporting the view that the world economy was globally integrated prior to the 1490s; there is also no evidence supporting the view that this decade had the trading impact that world historians assign to it; but there is abundant evidence supporting the view that a very big globalisation bang took place in the 1820s.‘The year 1500 marks an important turning point in world history . . . The European discoveries made the oceans of the earth into highways for their commerce . . .’ William H. McNeill 1999, p. 295.

Journal ArticleDOI
01 Jul 2002-Immunity
TL;DR: It is found that these Th2 cytokines are not essential for fetal survival even during allogeneic pregnancy, and a threshold is reached at which IL-4 alone can activate all Th2 effector functions.

Journal ArticleDOI
06 Sep 2002-Science
TL;DR: These data provide evidence that many bacteria possess a DNA DSB repair apparatus that shares many features with the NHEJ system of eukarya and suggest that this DNA repair pathway arose before the prokaryotic and eukaryotic lineages diverged.
Abstract: In eukaryotic cells, double-strand breaks (DSBs) in DNA are generally repaired by the pathway of homologous recombination or by DNA nonhomologous end joining (NHEJ). Both pathways have been highly conserved throughout eukaryotic evolution, but no equivalent NHEJ system has been identified in prokaryotes. The NHEJ pathway requires a DNA end-binding component called Ku. We have identified bacterial Ku homologs and show that these proteins retain the biochemical characteristics of the eukaryotic Ku heterodimer. Furthermore, we show that bacterial Ku specifically recruits DNA ligase to DNA ends and stimulates DNA ligation. Loss of these proteins leads to hypersensitivity to ionizing radiation in Bacillus subtilis. These data provide evidence that many bacteria possess a DNA DSB repair apparatus that shares many features with the NHEJ system of eukarya and suggest that this DNA repair pathway arose before the prokaryotic and eukaryotic lineages diverged.

Journal ArticleDOI
TL;DR: S. aureus has multiple mechanisms for stimulating platelet aggregation, and functional redundancy suggests that this phenomenon may be important in the pathogenesis of invasive diseases such as infective endocarditis.
Abstract: The ability of Staphylococcus aureus cells to induce platelet aggregation has long been recognized. However, despite several attempts to identify the mechanisms involved in this interaction, the nature of the bacterial receptors required remains poorly understood. Using genetic manipulation, this study for the first time provides clear evidence that several S. aureus surface proteins participate in the inter-action with platelets. Mutants of S. aureus strain Newman lacking one or more surface proteins were tested for their ability to stimulate platelet aggregation. This approach was complemented by the expression of a number of candidate proteins in the non-aggregating Gram-positive bacterium Lacto-coccus lactis. S. aureus-induced aggregation was monophasic and was dependent on the platelet receptor GPIIb/IIIa. The fibrinogen-binding proteins, clumping factors A and B and the serine-aspartate repeat protein SdrE could each induce aggregation when expressed in L. lactis. Although protein A expressed in L. lactis was not capable of inducing aggregation independently, it enhanced the aggregation response when expressed on the surface of S. aureus. Thus, S. aureus has multiple mechanisms for stimulating platelet aggregation. Such functional redundancy suggests that this phenomenon may be important in the pathogenesis of invasive diseases such as infective endocarditis.

Journal ArticleDOI
TL;DR: In this paper, a review of magnet applications is presented, classifying the magnet applications in terms of the nature of the field, the effect on the magnet and the physical effect exploited.

Journal ArticleDOI
TL;DR: The results suggest that providing environmental support to one aspect of executive function may facilitate monitoring and behavioural flexibility--and therefore the useful expression of other skills that may be relatively intact.

Journal ArticleDOI
TL;DR: The results indicate that stress exists for students in both the clinical and academic aspects of the programme, and financial constraints and academic-related concerns emerged as the most stressful areas for students.

Book ChapterDOI
TL;DR: Differences between signals generated by TLRs are emerging, with TLR-4 signalling requiring an additional adapter termed MyD88-adapter-like (Mal), which may regulate the expression of genes specific for the response required to eliminate infection by Gram-negative bacteria.
Abstract: Toll-like receptors (TLRs) are an important point of first contact between host and microbe, and once activated generate signals which culminate in the induction of genes important for host defence. TLRs respond to different microbial products, and the signalling pathways activated are very similar to that generated by the pro-inflammatory cytokine interleukin-1 (IL-1). This is because the Type I IL-1 receptor and TLRs are highly homologous in their cytosolic portions, possessing a Toll/IL-1 receptor (TIR) domain. Signals triggered include the important transcription factor NF-кB and two MAP kinases, p38 and Jun N-terminal kinase. Receptor-proximal proteins involved include the adapter MyD88, IRAK, IRAK-2, Tollip, TRAF6 and TAK-1. These latter two proteins need to be ubiquitinated in order to be active. Differences between signals generated by TLRs are emerging, with TLR-4 signalling requiring an additional adapter termed MyD88-adapter-like (Mal), which may regulate the expression of genes specific for the response required to eliminate infection by Gram-negative bacteria. Future studies on TLR signalling may reveal hitherto unsuspected specificities in the innate immune response to infection.

Journal ArticleDOI
TL;DR: SJW increased expression and enhanced the drug efflux function of the multi drug transporter P-glycoprotein in PBMCs of healthy volunteers and may represent a second mechanism for the drug-herb interactions seen in clinical practice and account for the discrepancies between in vitro and in vivo data.
Abstract: Aims St John's Wort (SJW) is widely used in the treatment of depression but concerns have been raised about its potential to interact with other drugs. Co-administration with SJW has resulted in significant reductions in trough plasma concentrations of indinavir and cyclosporin [1, 2]. Induction of cytochrome P450 3A4 (CYP3A4) has been implicated as the most likely interaction mechanism. However, the magnitude of the interaction seen in clinical practice is greater than that predicted by in vitro studies suggesting additional interaction mechanisms may exist. As indinavir and cyclosporin are substrates for both CYP3A4 and the multi drug transporter P-glycoprotein we hypothesized that modulation of P-glycoprotein expression and function by SJW may contribute to the development of potentially harmful drug–drug interactions.

Journal ArticleDOI
TL;DR: In this article, a new approach is proposed by Working Group 1 of the European COST Action 620 on "Vulnerability mapping for the protection of carbonate (karst) aquifers".
Abstract: In order to achieve some consistency in the establishment of groundwater intrinsic vulnerability maps in Europe, a new approach is proposed by Working Group 1 of the European COST Action 620 on "Vulnerability mapping for the protection of carbonate (karst) aquifers". A general procedure is offered which provides consistency while allowing the required flexibility for application to a continent and under conditions of varying geology, scale, information availability, time, and resources.

Journal ArticleDOI
TL;DR: It is demonstrated that T helper type 1 and regulatory T cells are induced against the same epitopes on the core protein during HCV infection.
Abstract: The factors that determine persistence or clearance of hepatitis C virus (HCV) infection are poorly understood. The CD4 T cell responses to the HCV core protein were examined in a cohort of women infected with a single genotype of HCV. CD4 T cells from HCV-infected patients secreted interferon (IFN)-gamma in response to peptides from 4 immunodominant regions of the core protein, and these responses were stronger in persistently infected women. Interleukin (IL)-10 was also produced by CD4 T cells from HCV-infected subjects in response to the same core peptides. Furthermore, HCV core-specific CD4 T cell clones secreted either IFN-gamma or IL-10 but not IL-4. These findings demonstrate that T helper type 1 and regulatory T cells are induced against the same epitopes on the core protein during HCV infection.

Journal ArticleDOI
TL;DR: This work established whether workers of the bumblebee, Bombus terrestris (L.) (Hymenoptera; Apidae), exhibit alloethism, and quantified the size of workers engaging in foraging compared to those that remain in the nest, and confirmed that it is the larger bees that tend to forage.

Journal ArticleDOI
TL;DR: It is demonstrated that CLA supplementation significantly improves plasma TAG and VLDL metabolism in human subjects and confirms that some of the cardio-protective effects of CLA that were shown in animal studies are relevant to man.
Abstract: Conjugated linoleic acid (CLA) refers to a group of positional and geometric isomers of linoleic acid. Studies using animal models have shown that CLA reduces adiposity, improves plasma lipoprotein metabolism and insulin sensitivity and reduces arteriosclerosis. Whilst CLA may have therapeutic potential with regard to coronary artery disease risk factors in human subjects, there has been little investigation into its effects in human subjects. This current study investigated the effects of dietary supplementation using two isomeric blends of CLA on triacylglycerol (TAG)-rich lipoprotein metabolism and reverse cholesterol transport in human subjects and evaluates whether CLA modulated cardiovascular disease risk factors. Fifty-one normolipidaemic subjects participated in this randomised double-blind placebo-controlled intervention trial. Subjects were randomly assigned to receive 3 g cis-9,trans-11-trans-10,cis-12 isomeric blend (50 : 50) or a cis-9,trans-11-trans-10,cis-12 isomeric blend (80 : 20) CLA or linoleic acid (control)/d for 8 weeks. The 50 : 50 CLA isomer blend significantly reduced (P