Mathematical modelling of metabolic pathways in pig muscle

Improving efficiency within the agricultural industry is vital to maintain the food demands of the increasing population, as well the current preference for a more protein rich diet. One avenue for addressing these issues is to study animal-based growth to determine if the efficiency of the production system can be improved by increasing lean muscle mass. The aim of this thesis is to provide an alternative exploration to experimental work to provide an insight into how muscle metabolism in pigs is altered by the administration of a beta-agonist which induces muscle hypertrophy. This will be incorporated into a wider body of work to determine specific pathways to target for improving feed conversion efficiency, contributing to the necessary research into global food security. We begin by compiling a selection of statistical methods to analyse muscle microarray data, which enables the identification of a selection of genes whose expressions are altered by the exposure to a beta-agonist. These differentially expressed transcripts are then grouped via a k-means algorithm, with log likelihood and the Bayesian Inference Criterion calculations providing an optimal selection of clusters. This results in selecting a group of 51 transcripts and partitioning them into 9 clusters, and identifying several pathways which appear key to the regulation of muscle metabolism in the presence of beta-agonist. We have proceeded to incorporate this information into a mathematical model for glycolysis and the TCA cycle, in an effort to analyse biological hypotheses about how the promoters work. The equations describe the concentrations of metabolites within the cytosolic and mitochondrial compartments of a cell using mass balance ODEs. An initial model is presented, which is then increased in complexity, to keep up with developments in the experimental side of the overarching project. We make use of a selection of methods to analyse the model in an attempt to determine the effects that the different parameters cause. Through steady state analysis, we determine parameter ranges which permit positive steady states. In finding these regions, we also determine the existence of time dependent solutions, which occur when critical values of certain parameters are exceeded, and result in the build up of specific metabolites. We use asymptotic analysis to generate approximate solutions when steady states do not exist. The model parameters of most interest are those which were identified through the microarray work, namely the upregulated transcripts of PCK2 and those within the serine synthesis pathway, the control mechanism for the first half of the TCA cycle, the proportion of GTP producing enzyme from the second half of the TCA cycle, and the flux into the glycolytic pathway. We find that critical values for the glycolytic flux, and the GTP production parameter exist, determining whether the model lies within the steady state regime. In a large number of cases, the parameters we choose to represent the beta-agonist case push the system into the time dependent state. The model does not exhibit any interesting behaviour when the parameter controlling the PCK2 pathway is studied, indicating that initial intuition of the key controlling reaction mechanisms were incomplete. Whilst there are shortfalls in the model, which highlight areas for investigation, the system is set up for validation and parameter fitting when appropriate experimental data become available. We have been able to determine specific metabolic pathways within the cell which may be of significance to improving feed efficiency

Incidence of anaemia among HIV-infected patients treated with zidovudine-containing antiretroviral therapy in northeastern Nigeria

Background: Zidovudine (AZT) is a common component of antiretroviral therapy (ART) in resource-limited settings. However, AZT is associated with myelotoxity that often presents with anaemia. The aim of this study was to determine the incidence of anaemia among patients initiated on AZT-containing and non-AZT containing ART regimens.Methods: In this retrospective analysis, records from 800 ART-naïve HIV-infected patients were abstracted by simple random sampling from program databases. Rates of anaemia were compared between patients initiated on AZT- versus non- AZT-containing ART regimens. Patients were stratified according to absence (Group A) or presence (Group B) of baseline anaemia defined as haemoglobin < 10.5g/dl. Incidence was calculated as total cases of AZT-induced anaemia (group A) or worsening of anaemia (group B) during the study period divided by person-time at risk and adjusted per 100 person-years. Average time-to-event and survival curve were estimated using Kaplan Meier survival analysis.Results: In group A (without baseline anaemia), the incidence of anaemia in the AZT-exposed versus non-exposed cohorts was 73.3 and 17.6 per 100 patient years at 6 months, and 60.5 and 8.5 per 100 patient years at 12 months, respectively. In group B, the incidence of worsening anaemia was 65.9 and 26.2 per 100 patient years at 6 months, and 57.5 and 17.9 per 100 patient years after 12 months in AZT-exposed and AZT-unexposed cohorts, respectively. The estimated time to event (developing anaemia) was 2.3 (1.5 – 3.4) months, while estimated to event (worseninig anaemia) was 2.0 (1.5 – 4.0).Conclusions: HIV-infected patients initiated on AZT-containing ART are 2.7 and 4.5 more likely to develop anaemia at 6 and 12 months, respectively, compared to those initiating a non-AZT containing regimen. When censored at 12 months the overall incidence of AZT-related anaemia was estimated at 22.3% (38.2 incidences per person years). Majority (75%) of the AZT-related anaemia occurred early with estimated time-to-event occurring within the first 3.8 monthsKeywords: Anaemia, Zidovudine, Antiretroviral therapy, Incidenc

An Electron Paramagnetic Resonance (EPR) spectroscopy study on the γ-irradiation sterilization of the pharmaceutical excipient l-histidine: Regeneration of the radicals in solution

The effects of γ-radiation sterilization on the parenteral excipient L-histidine were analysed by means of EPR spectroscopy. The irradiation process was found to induce the formation of a deamination radical which was persistent in the solid state. The nature and reactivity of the radicals following dissolution in water was evaluated using spin-trapping EPR experiments. The deamination radical was found to regenerate in solution in the presence of trace metals, potentially leading to radical induced degradation reactions occurring up to an hour after the dissolution process. Understanding this process is significant for the improved design of parental pharmaceutical formulations in which unwanted radical reactions after γ radiation sterilization could lead to degradation of active ingredients

Organic Digital Logic and Analog Circuits Fabricated in a Roll-to-Roll Compatible Vacuum-Evaporation Process

We report the fabrication of a range of organic circuits produced by a high-yielding, vacuum-based process compatible with roll-to-roll production. The circuits include inverters, NAND and NOR logic gates, a simple memory element (set-reset latch), and a modified Wilson current mirror circuit. The measured circuit responses are presented together with simulated responses based on a previously reported transistor model of organic transistors produced using our fabrication process. Circuit simulations replicated all the key features of the experimentally observed circuit performance. The logic gates were capable of operating at frequencies in excess of 1 kHz while the current mirror circuit produced currents up to 18 μA

A high-yield vacuum-evaporation-based R2R-compatible fabrication route for organic electronic circuits

Advances are described in a vacuum-evaporation-based approach for the roll-to-roll (R2R) production of organic thin film transistors (TFTs) and circuits. Results from 90-transistor arrays formed directly onto a plasma-polymerised diacrylate gate dielectric are compared with those formed on polystyrene-buffered diacrylate. The latter approach resulted in stable, reproducible transistors with yields in excess of 90%. The resulting TFTs had low turn-on voltage, on-off ratios ∼106 and mobility ∼1 cm2/V s in the linear regime, as expected for dinaphtho[2,3-b: 2′,3′-f] thieno[3,2-b]thiophene the air stable small molecule used as the active semiconductor. We show that when device design is constrained by the generally poor registration ability of R2R processes, parasitic source-drain currents can lead to a >50% increase in the mobility extracted from the resulting TFTs, the increases being especially marked in low channel width devices. Batches of 27 saturated-load inverters were fabricated with 100% yield and their behaviour successfully reproduced using TFT parameters extracted with Silvaco's UOTFT Model. 5- and 7-stage ring oscillator (RO) outputs ranged from ∼120 Hz to >2 kHz with rail voltages, VDD, increasing from -15 V to -90 V. From simulations an order of magnitude increase in frequency could be expected by reducing parasitic gate capacitances. During 8 h of continuous operation at VDD = -60 V, the frequency of a 7-stage RO remained almost constant at ∼1.4 kHz albeit that the output signal amplitude decreased from ∼22 V to ∼10 V. Over the next 30 days of intermittent operation further degradation in performance occurred although an unused RO showed no deterioration over the same period. © 2014 The Authors. Published by Elsevier B.V

Biological life-history and farming scenarios of marine aquaculture to help reduce wild marine fishing pressure

Aquaculture (freshwater and marine) has largely supplemented fisheries, but in theory could help reduce fishing pressure on wild stocks. Although not the sole factors, some potential benefits depend on aquaculture pressures on fished species, including collection of wild ‘seed’ material—earlier to later life stages—for rearing in captivity and the capacity of aquaculture to increase. Here we first classify 203 marine (saltwater and brackish) animal species as being produced by either open-cycle capture-based aquaculture (CBA) or closed-cycle domesticated aquaculture (DA)—based on their likely reliance on wild seed—and assess the extent to which these forms of aquaculture could support seafood production and greater wild biomass. Using a data-limited modelling approach, we find evidence that current aquaculture practices are not necessarily helping reduce fishing to sustainable levels for their wild counterparts—consistent with emerging scientific research. However, if some wild capture species (87 equivalent spp.) were instead produced through CBA, almost a million extra tonnes could theoretically be left in the wild, without reducing seafood production. Alternatively, if reliance on wild seed inputs is further reduced by shifting to DA production, then a little less than doubling of aquaculture of the overexploited species in our study could help fill the ‘production gap’ to support fishing at maximum sustainable levels. While other ecological (e.g. escapes), social and economic considerations (e.g. market substitution) are important, we focused on a critical biological linkage between wild fisheries and aquaculture that provides another aspect on how to improve management alignment of the sectors