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Search Results: 1 - 10 of 298867 matches for " Harry J. McArdle "
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Cell Cycle Regulation and Cytoskeletal Remodelling Are Critical Processes in the Nutritional Programming of Embryonic Development
Angelina Swali, Sarah McMullen, Helen Hayes, Lorraine Gambling, Harry J. McArdle, Simon C. Langley-Evans
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023189
Abstract: Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common “gatekeepers” which may drive nutritional programming. Both protein and iron deficiency in utero reduced the nephron complement in adult male Wistar and Rowett Hooded Lister rats (P<0.05). This occurred in the absence of damage to the glomerular ultrastructure. Microarray, proteomic and pathway analyses identified diet-specific and strain-specific gatekeeper genes, proteins and processes which shared a common association with the regulation of the cell cycle, especially the G1/S and G2/M checkpoints, and cytoskeletal remodelling. A cell cycle-specific PCR array confirmed the down-regulation of cyclins with protein restriction and the up-regulation of apoptotic genes with iron deficiency. The timing and experimental design of this study have been carefully controlled to isolate the common molecular mechanisms which may initiate the sequelae of events involved in nutritional programming of embryonic development. We propose that despite differences in the individual genes and proteins affected in each strain and with each diet, the general response to nutrient deficiency in utero is perturbation of the cell cycle, at the level of interaction with the cytoskeleton and the mitotic checkpoints, thereby diminishing control over the integrity of DNA which is allowed to replicate. These findings offer novel insight into the primary causes and mechanisms leading to the pathologies which have been identified by previous programming studies.
Processes Underlying the Nutritional Programming of Embryonic Development by Iron Deficiency in the Rat
Angelina Swali, Sarah McMullen, Helen Hayes, Lorraine Gambling, Harry J. McArdle, Simon C. Langley-Evans
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048133
Abstract: Poor iron status is a global health issue, affecting two thirds of the world population to some degree. It is a particular problem among pregnant women, in both developed and developing countries. Feeding pregnant rats a diet deficient in iron is associated with both hypertension and reduced nephron endowment in adult male offspring. However, the mechanistic pathway leading from iron deficiency to fetal kidney development remains elusive. This study aimed to establish the underlying processes associated with iron deficiency by assessing gene and protein expression changes in the rat embryo, focussing on the responses occurring at the time of the nutritional insult. Analysis of microarray data showed that iron deficiency in utero resulted in the significant up-regulation of 979 genes and down-regulation of 1545 genes in male rat embryos (d13). Affected processes associated with these genes included the initiation of mitosis, BAD-mediated apoptosis, the assembly of RNA polymerase II preinitiation complexes and WNT signalling. Proteomic analyses highlighted 7 proteins demonstrating significant up-regulation with iron deficiency and the down-regulation of 11 proteins. The main functions of these key proteins included cell proliferation, protein transport and folding, cytoskeletal remodelling and the proteasome complex. In line with our recent work, which identified the perturbation of the proteasome complex as a generalised response to in utero malnutrition, we propose that iron deficiency alone leads to a more specific failure in correct protein folding and transport. Such an imbalance in this delicate quality-control system can lead to cellular dysfunction and apoptosis. Therefore these findings offer an insight into the underlying mechanisms associated with the development of the embryo during conditions of poor iron status, and its health in adult life.
Developmental Origins of Health and Disease
Simon C. Langley-Evans,Barbara Alexander,Harry J. McArdle,Deborah M. Sloboda
Journal of Nutrition and Metabolism , 2012, DOI: 10.1155/2012/838640
Developmental Origins of Health and Disease
Simon C. Langley-Evans,Barbara Alexander,Harry J. McArdle,Deborah M. Sloboda
Journal of Nutrition and Metabolism , 2012, DOI: 10.1155/2012/838640
HCMV Targets the Metabolic Stress Response through Activation of AMPK Whose Activity Is Important for Viral Replication
Jessica McArdle,Nathaniel J. Moorman,Joshua Munger
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002502
Abstract: Human Cytomegalovirus (HCMV) infection induces several metabolic activities that have been found to be important for viral replication. The cellular AMP-activated protein kinase (AMPK) is a metabolic stress response kinase that regulates both energy-producing catabolic processes and energy-consuming anabolic processes. Here we explore the role AMPK plays in generating an environment conducive to HCMV replication. We find that HCMV infection induces AMPK activity, resulting in the phosphorylation and increased abundance of several targets downstream of activated AMPK. Pharmacological and RNA-based inhibition of AMPK blocked the glycolytic activation induced by HCMV-infection, but had little impact on the glycolytic pathway of uninfected cells. Furthermore, inhibition of AMPK severely attenuated HCMV replication suggesting that AMPK is an important cellular factor for HCMV replication. Inhibition of AMPK attenuated early and late gene expression as well as viral DNA synthesis, but had no detectable impact on immediate-early gene expression, suggesting that AMPK activity is important at the immediate early to early transition of viral gene expression. Lastly, we find that inhibition of the Ca2+-calmodulin-dependent kinase kinase (CaMKK), a kinase known to activate AMPK, blocks HCMV-mediated AMPK activation. The combined data suggest a model in which HCMV activates AMPK through CaMKK, and depends on their activation for high titer replication, likely through induction of a metabolic environment conducive to viral replication.
New magnetic real time shape control for MAST
L Pangione,G McArdle,J Storrs
Physics , 2013, DOI: 10.1016/j.fusengdes.2013.01.048
Abstract: The MAST (Mega Ampere Spherical Tokamak) real time plasma position controller is based on an optical linear camera placed on the mid plane of the vessel. This solution has the advantage of being a direct observation of the D [alpha]emissions coming from the interaction between the boundary of the plasma and neutral gas, but, on the other hand, it restricts the control to the outer radius of the plasma only. A complete chain of tools has been set up to implement, test and simulate a new real time magnetic plasma shape controller based on the rtEFIT code. The complete working path consists of three elements: a linear static relationship between control parameters and current demands, a linear state space model needed to represent the plasma dynamic response in closed loop simulations, and the possibility to run simulations inside the Plasma Control System (PCS). The linear relationship has been calculated using the FIESTA code, which is developed using Matlab at CCFE. The linear state space model was generated using the CREATE-L code developed by the CREATE Consortium. It has already been successfully used to model JET, FTU and TCV tokamaks. Using this working path many simulations have been carried out allowing fine tuning of the control gains before the real experiment. The simulation testing includes the plasma shape control law as implemented in PCS itself, so intensive debugging has been possible prior to operation. Successful control using rtEFIT was established in the second dedicated experiment during the MAST 2011-12 campaign. This work is a stepping stone towards divertor control which is ultimately intended for application to the super-X divertor in the MAST Upgrade experiment.
Reduced leakage current in Josephson tunnel junctions with codeposited barriers
Paul B. Welander,Timothy J. McArdle,James N. Eckstein
Physics , 2008, DOI: 10.1063/1.3518983
Abstract: Josephson junctions were fabricated using two different methods of barrier formation. The trilayers employed were Nb/Al-AlOx/Nb on sapphire, where the first two layers were epitaxial. The oxide barrier was formed either by exposing the Al surface to O2 or by codepositing Al in an O2 background. The codeposition process yielded junctions that showed the theoretically predicted subgap current and no measurable shunt conductance. In contrast, devices with barriers formed by thermal oxidation showed a small shunt conductance in addition to the predicted subgap current.
tacg – a grep for DNA
Harry J Mangalam
BMC Bioinformatics , 2002, DOI: 10.1186/1471-2105-3-8
Abstract: I describe a small application which allows searching for all the above pattern types individually, which further allows these atomic motifs to be assembled into logical rules for more sophisticated analysis.tacg is small, portable, faster and more capable than most alternatives, relatively easy to modify, and freely available in source code.String searching is a well-developed field of computer science, with highly optimized algorithms implemented in a variety of applications to efficiently search large collections of text [12,15]. Many of these algorithms are intuitive; some of them are beautiful, the best of them are quite extraordinarily efficient [1,3,6]. Many of these algorithms have been applied to the field of searching genomic sequences and associated databases, either for exact [2,17,18] or probablistic [11,4] matches, but it is striking that many useful algorithms in combinatorial pattern matching have not made their way into tools designed explicitly for bioinformaticists.Most of the tools that have been developed for pattern matching in molecular biology have been prototyped on Unix systems but there has been a perplexing deficit of free bioinformatics tools (comparable to the GNU text utilities [9]) for this platform. Recently, however, the EMBOSS suite of about 100 tools [20] has approached the commercial GCG application suite for breadth of utility. There are other good tools (ie. SEALS [24]) that can be coerced into providing searching capability although often at the cost of non-standard interfaces, large installation or maintenance overhead, or that provide considerable utility but at the cost of building the application yourself, such as the Bio* toolkits [5].A useful utility would be a grep[13] for DNA, a command line program requiring a short learning curve and few resources, but providing sophisticated search abilities as well as being easily extensible. tacg was developed to provide this functionality. For example, tacg -pName, pattern, err#
Exotic Hadrons in the Constituent Quark Model
Lipkin, Harry J.
High Energy Physics - Phenomenology , 2007, DOI: 10.1143/PTPS.168.15
Abstract: Exotic hadrons are important because their existence or absence can provide important clues to understanding how QCD makes hadrons from quarks and gluons. The first experimentally confirmed exotic will be the first hadron containing both $qq$ and $\bar q q$ pairs and the first hadron containing color sextet and color octet pairs. Theoretical models are not very useful because there is no accepted model for multiquark systems with color-space correlations. The constituent quark model is the only phenomenological model with predictive power that has given experimentally tested universal predictions for both mesons and baryons. This paper reviews its explanation for why there are no bound exotics and its guidance to the search for heavy-flavored exotic tetraquarks and pentaquarks. A possible supersymmetry between mesons and baryons leading to meson-baryon mass relations not easily obtained otherwise is discussed.
New systematics in charmless strange $B^+ \to VP$ decays
Lipkin, Harry J.
High Energy Physics - Phenomenology , 2007,
Abstract: Latest data on charmless strange vector-pseudoscalar $B^+$ decays now including $B^+\to \rho^+ K^o$ confirm a simple penguin model in which the gluon $G$ in an initial $\bar s u G$ state fragments equally into $u \bar u$, $d \bar d$ and $s \bar s$ and all form factors are equal. A search for possible additional contributions shows only a few signals not obscured by experimental errors whose implications are discussed. The experimental value of $0.25 \pm 0.11$ for the ratio of the branching ratios $BR(B^+ \to K^{*+}\eta)$ to $BR(B^+\to K^{*+}\eta')$ confirms the parity selection rule prediction 0.32. Large violations arise in a new sum rule for the sum of these branching ratios, analogous to the similar pseudoscalar sum rule including $K^+\eta$ and $K^+\eta'$. Indications for either an electroweak penguin contribution or additional admixtures like instrinsic charm in the $\eta-\eta'$ system remain to be clarified. An alternative symmetry description with new predictive power clarifies the simple penguin approximation and presents new predictions which can be tested experimentally. The fragmentation of the $\bar s u G$ state into two mesons is described by a strong interaction S-matrix dominated by nonexotic hadron resonances in multiparticle intermediate states.
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