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Background and aims Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. Methods Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. Results Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. Conclusions These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.

Purpose: Phosphorus saturation-transfer experiments can quantify metabolic fluxes non-invasively. Typically, the forward flux through the creatine-kinase reaction is investigated by observing the decrease in phosphocreatine (PCr) after saturation of $\gamma$-ATP. The quantification of total ATP utilisation is currently under-explored, as it requires simultaneous saturation of inorganic phosphate (Pi) and PCr. This is challenging, as currently available saturation pulses reduce the already-low $\gamma$-ATP signal present. Methods: Using a hybrid optimal-control and Shinnar-Le-Roux method, a quasi-adiabatic RF pulse was designed for the dual-saturation of PCr and Pi to enable determination of total ATP utilisation. The pulses were evaluated in Bloch equation simulations, compared with a conventional hard-cosine DANTE saturation sequence, before application to perfused rat hearts at 11.7 Tesla. Results: The quasi-adiabatic pulse was insensitive to a $>2.5$-fold variation in $B_1$, producing equivalent saturation with a 53% reduction in delivered pulse power and a 33-fold reduction in spillover at the minimum effective $B_1$. This enabled the complete quantification of the synthesis and degradation fluxes for ATP in 30-45 minutes in the perfused rat heart. While the net synthesis flux ($4.24\pm0.8$ mM/s, SEM) was not significantly different from degradation flux ($6.88\pm2$ mM/s, $p=0.06$) and both measures are consistent with prior work, nonlinear error analysis highlights uncertainties in the Pi-to-ATP measurement that may explain a trend suggesting a possible imbalance. Conclusion: This work demonstrates a novel quasi-adiabatic dual-saturation RF pulse with significantly improved performance that can be used to measure ATP turnover in the heart in vivo., Comment: 26 pages, Accepted at Magnetic Resonance in Medicine, 24/11/2020 [This version post reviews]

Visual Abstract, Highlights • HIF-1α is activated following myocardial infarction, and is a critical transcription factor promoting survival in hypoxia. • Type 2 diabetes blunts HIF-1α activation in ischemia and downstream adaptation to hypoxia. • This effect is mediated by increased long-chain fatty acids, which prevent HIF-1α activation in hypoxia. • Succinate promotes HIF-1α activation by inhibiting the regulatory HIF hydroxylases. Fatty acids decrease succinate concentrations in hypoxia, by blocking increased glycolysis and malate-aspartate shuttle activity. • Pharmacologically activating HIF-1α or increasing succinate concentrations restores the hypoxic response and improves functional recovery post-ischemia in diabetes., Summary Hypoxia-inducible factor (HIF)-1α is essential following a myocardial infarction (MI), and diabetic patients have poorer prognosis post-MI. Could HIF-1α activation be abnormal in the diabetic heart, and could metabolism be causing this? Diabetic hearts had decreased HIF-1α protein following ischemia, and insulin-resistant cardiomyocytes had decreased HIF-1α-mediated signaling and adaptation to hypoxia. This was due to elevated fatty acid (FA) metabolism preventing HIF-1α protein stabilization. FAs exerted their effect by decreasing succinate concentrations, a HIF-1α activator that inhibits the regulatory HIF hydroxylase enzymes. In vivo and in vitro pharmacological HIF hydroxylase inhibition restored HIF-1α accumulation and improved post-ischemic functional recovery in diabetes.

All animals have a protective covering of skin, generally supplemented by an additional layer of fur, scales, feathers or body armour. Consequently, we are surrounded by instructive models of protection – applicable to a great variety of environments and hazardous events. This chapter is particularly concerned with protection from injury resulting from impacts to the human body. The goal is the development of apparel (an additional layer designed for humans) that reduces risks of injury whilst maintaining usability and comfort for wearers. Understanding the mechanisms relevant to protection provides a starting-point for designing garments that absorb and diffuse the energies of impacts. However, a user-centred design approach must recognise that impact protection is just one of many factors to be considered during product development.

Purpose Echo planar imaging is an attractive rapid imaging readout that can image hyperpolarized compounds in vivo. By alternating the sign of the phase encoding gradient waveform, spatial offsets arising from uncertain frequency shifts can be determined. We show here that blip-reversed echo planar imaging can also be used to correct for susceptibility and B0 inhomogeneity effects that would otherwise produce image-domain distortion in the heart. Methods Previously acquired blip-reversed cardiac 3D-Spectral-Spatial echo planar imaging volumetric timecourses of hyperpolarized [1-13C]pyruvate were distortion corrected by a deformation field estimated by reconstructing signal-to-noise ratio (SNR)-weighted progressively subsampled temporally summed images of each metabolite. Results Reconstructing blip-reversed data as proposed produced volumetric timecourses that overlaid with proton reference images more consistently than without such corrections. Conclusion The method proposed may form an attractive method to correct for image-domain distortions in hyperpolarized echo planar imaging experiments. Magn Reson Med, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

The Krebs cycle plays a fundamental role in cardiac energy production and is often implicated in the energetic imbalance characteristic of heart disease. In this study, we measured Krebs cycle flux in real time in perfused rat hearts using hyperpolarized magnetic resonance spectroscopy (MRS). [2-(13)C]Pyruvate was hyperpolarized and infused into isolated perfused hearts in both healthy and postischemic metabolic states. We followed the enzymatic conversion of pyruvate to lactate, acetylcarnitine, citrate, and glutamate with 1 s temporal resolution. The appearance of (13)C-labeled glutamate was delayed compared with that of other metabolites, indicating that Krebs cycle flux can be measured directly. The production of (13)C-labeled citrate and glutamate was decreased postischemia, as opposed to lactate, which was significantly elevated. These results showed that the control and fluxes of the Krebs cycle in heart disease can be studied using hyperpolarized [2-(13)C]pyruvate.

To demonstrate the feasibility of imaging the first passage of a bolus of hyperpolarized (13) C urea through the rodent heart using flow-sensitizing gradients to reduce signal from the blood pool.A flow-sensitizing bipolar gradient was optimized to reduce the bright signal within the cardiac chambers, enabling improved contrast of the agent within the tissue capillary bed. The gradient was incorporated into a dynamic golden angle spiral (13) C imaging sequence. Healthy rats were scanned during rest (n = 3) and under adenosine stress-induced hyperemia (n = 3).A two-fold increase in myocardial perfusion relative to rest was detected during adenosine stress-induced hyperemia, consistent with a myocardial perfusion reserve of two in rodents.The new pulse sequence was used to obtain dynamic images of the first passage of hyperpolarized (13) C urea in the rodent heart, without contamination from bright signal within the neighboring cardiac lumen. This probe of myocardial perfusion is expected to enable new hyperpolarized (13) C studies in which the cardiac metabolism/perfusion mismatch can be identified. Magn Reson Med, 2015. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

(31)P MRS was evaluated on normal volunteers at 1.5 and 3 T, and the signal-to-noise ratio (SNR) of the two field strengths was calculated. The in vivo spin-lattice, T(1), relaxation times for PCr and gamma-ATP, which are essential for correcting for the effects of radiofrequency saturation on the PCr/ATP ratio, were determined at 3 T. The T(1) values for six volunteers were 3.8 +/- 0.7 s for PCr (mean +/- SD) and 2.4 +/- 1.1 s for gamma-ATP, which are similar to reported values at 1.5 T, allowing us to use protocols developed at 1.5 T at the new clinical field strength of 3 T. Direct comparison between 1.5 T and 3 T in the same 10 subjects, using coils of identical geometry and identical pulse sequences gave a mean SNR for PCr at 3 T which was 206 +/- 94% of that at 1.5 T. The linewidth for PCr increased from 13 +/- 6 Hz at 1.5 T to 22 +/- 12 Hz at 3 T. The coefficient of variation in the measurement of PCr/ATP, based on the Cramer-Rao lower bounds, was reduced from 32 +/- 25% at 1.5 T to 18 +/- 13% at 3 T. Thus, (31)P MRS at 3 T is greatly improved by the increase in SNR compared with acquisitions at 1.5 T because of the higher field strength.

The purpose of this work was to take advantage of the new clinical field strength of 3 T to implement and optimize a chemical shift imaging (CSI) acquisition protocol to produce spectra of high quality with high specificity to the myocardium within a clinically feasible scan time. Further, an analysis method was implemented dependent purely on anatomical location of spectra, and as such free from any potential user bias caused by inference from spectral information. Twenty healthy male subjects were scanned on two separate occasions using the optimized CSI protocol at 3 T. Data were analyzed for intra- and inter-subject variability, as well as intra- and inter-observer variability. The average phosphocreatine (PCr)/adenosine triphosphate (ATP) value for scan 1 was 2.07 +/- 0.38 and for scan 2 was 2.14 +/- 0.46, showing no significant difference between scans. Intra-subject variability was 0.43 +/- 0.35 (percentage difference 20%) and the inter-subject coefficient of variation was 18%. The intra-observer variability, assessed as the absolute difference between analyses of the data by a single observer, was 0.14 +/- 0.24 with no significant difference between analyses. The inter-observer variability showed no significant differences between the PCr/ATP value measured by four different observers as demonstrated by an intra-class correlation coefficient of 0.763. The increased signal available at 3 T has improved spatial resolution and thereby increased myocardial specificity without any significant decrease in reproducibility over previous studies at 1.5 T. We present an acquisition protocol that routinely provides high quality spectra and a robust analysis method that is free from potential user bias.

Pyruvate dehydrogenase (PDH) is a key regulator of cardiac substrate selection and is regulated by both pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation and feedback inhibition. The extent to which chronic upregulation of PDK protein levels, acutely increased PDK activity and acute feedback inhibition limit PDH flux remains unclear because existing in vitro assessment methods inherently disrupt the regulation of the enzyme complex. We have demonstrated previously that hyperpolarised (13)C-labelled metabolic tracers coupled with MRS can monitor flux through PDH in vivo. The aim of this study was to determine the relative contributions of acute and chronic changes in PDK and PDH activities to in vivo myocardial PDH flux. We examined both fed and fasted rats with either hyperpolarised [1-(13)C]pyruvate alone or hyperpolarised [1-(13)C]pyruvate co-infused with malate [to modulate mitochondrial nicotinamide adenine dinucleotide (NADH/NAD(+)) and acetyl-coenzyme A (acetyl-CoA)/CoA ratios, which alter both PDH activity and flux]. To confirm the metabolic fate of infused malate, we performed in vitro (1)H NMR spectroscopy on cardiac tissue extracts. We observed that, in fed rats, where PDH activity was high, the presence of malate increased PDH flux by 27%, whereas, in the fasted state, malate infusion had no effect on PDH flux. These observations suggest that pyruvate oxidation is limited by feedback inhibition from acetyl-CoA only when PDH activity is high. Therefore, in the case of PDH, and potentially other enzymes, hyperpolarised (13)C MRI can be used to assess noninvasively enzymatic regulation.

Purpose Hyperpolarized metabolic imaging has the potential to revolutionize the diagnosis and management of diseases where metabolism is dysregulated, such as heart disease. We investigated the feasibility of imaging rodent myocardial metabolism at high resolution at 7 T. Methods We present here a fly‐back spectral‐spatial radiofrequency pulse that sidestepped maximum gradient strength requirements and enabled high resolution metabolic imaging of the rodent myocardium. A 3D echo‐planar imaging readout followed, with centric ordered z‐phase encoding. The cardiac gated sequence was used to image metabolism in rodents whose metabolic state had been manipulated by being fasted, fed, or fed and given the pyruvate dehydrogenase kinase inhibitor dichloroacetate. Results We imaged hyperpolarized metabolites with a spatial resolution of 2×2×3.8 mm3 and a temporal resolution of 1.8 s in the rat heart at 7 T. Significant differences in myocardial pyruvate dehydrogenase flux were observed between the three groups of animals, concomitant with the known biochemistry. Conclusion The proposed sequence was able to image in vivo metabolism with excellent spatial resolution in the rat heart. The field of view enabled the simultaneous multi‐organ acquisition of metabolic information from the rat, which is of great utility for preclinical research in cardiovascular disease. Magn Reson Med 000:000–000, 2015. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Magn Reson Med 75:1515–1524, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance.

Purpose: To demonstrate the feasibility of mapping intracellular pH within the in vivo rodent heart. Introduction: Alterations in cardiac acid-base balance can lead to acute contractile depression and alterations in Ca2+ signalling. The transient reduction in ATP consumption and cardiac contractility may be initially beneficial; however, sustained pH changes can be maladaptive, leading to myocardial damage and electrical arrhythmias. Methods: Spectrally-selective RF pulses were used to excite the HCO3- and CO2 resonances individually while preserving signal from the injected hyperpolarized [1-13C]pyruvate. The large flip angle pulses were placed within a 3D imaging acquisition which exploited CA-mediated label exchange between HCO3- and CO2. Images at 4.5x4.5x5 mm3 resolution were obtained in the in vivo rodent heart. The technique was evaluated in healthy rodents scanned at baseline and during high cardiac workload induced by dobutamine infusion. Results: The intracellular pH was measured to be 7.15±0.04 at baseline, and decreased to 6.90±0.06 following 15 minutes of continuous β-adrenergic stimulation. Conclusion: Volumetric maps of intracellular pH can be obtained following an injection of hyperpolarized [1-13C]pyruvate. The new method is anticipated to enable assessment of stress-inducible ischaemia and potential ventricular arrythmogenic substrates within the ischaemic heart.

Whilst good impact protection using materials of 5-10 mm thickness can be achieved, the thickness of the resulting assemblage often creates difficulties of appearance, stiffness and loss of comfort. This creates problems for product developers and users. In the quest for efficient impact protection using thinner materials, research has been directed to understanding the mechanisms that provide protection. This has led to the adoption of a biomimetic approach, with consideration being given to composite materials. The research reported concerns the ability of composites to enhance impact protection without being bulky. The materials under investigation in this research are primarily commercially available in a variety of thicknesses and densities. The composites have been formed using double-sided adhesive tape. The testing work is undertaken using a customised rig that allows the forces and timescales of impacts to be recorded. The performances of the composites are compared with the test results of a variety of alternative materials, and conclusions are drawn about the mechanisms of achieving enhanced protection. Design principles are identified to assist the designers and product developers of functional apparel.

We present the results of a recent review of fibre identification technologies for apparel recycling. The review focuses on tagging and labelling approaches that can help apparel recyclers identify the material composition of the recycling grades of apparel, in preparation for the introduction of more material-specific recycling technologies. We conclude that the adoption of the 2D barcode linked to an external database will both contain sufficient bits to encode useful information, and that such an approach could also give consumer (and hence brand) benefits that would help make the business case for their introduction.

Recently there had been a widespread use of high performance materials in sports wear with enhanced functionality. In sportswear, protection against impact is featured in products for skiwear, snowboarding, rugby, football, basketball, cycling, running shoes, and many others. There is a dearth of technical information about the range of materials being used and quantifiable measures of their effectiveness are rarely disseminated. An experimental set up is discussed with the scope of obtaining reliable and valid data relating to materials and commercial products. Two experimental methods have been used to gain understanding of material properties: an impact attenuation test (which captures peak forces over time) and Tekscan® pressure sensors (which capture the areal dispersal of impact forces). Alongside these dynamic tests are measures of thickness, flexural rigidity and bulk density. It was found that thicker materials (10 mm) were effective in protecting against 5J impacts. However bulky inserts resrticted free movement, which was a concern in designing garments. The outcomes from pressure sensors enabled to precisely measure and monitor profile of impact force applied on to the substrate. Based on this work, three parameters identified which would determine the characteristics of materials, the energy absorption properties, the ability of materials to extend the duration of an impact and the ability of materials to broaden the area affected by an impact. Using the above parameters the research is able to design smart protective garments which will have materials to prevent impact injury by absorbing the impact, delaying the point impact force and distributing it across a wider area.

This paper highlights the significance of impact resistant materials which are incorporated in sportswear and functional outdoor applications. In recent years, there have been interesting explorations on a wide range of composite materials such as coir/EVA as nonwoven impact protectors, polypropylene and flax fibre laminate, cellular textile materials as sports protectors for helmets. 3D spacer fabrics were explored by Dow Corning on varying thicknesses and levels of protection. In addition materials such as, D3O and visco-elastic polymer dough were also reported to have potential in sportswear applications such as the market for knee pads. In addition, Dow Corning's helical auxetic system is made up of an inelastic fibre spirally wound around a thicker elastic fibre that expands to absorb the shock while the inelastic one limited the expansion. Some concerns noted by researchers are that it has limited applications and the benefits of the impact resistant materials should be evaluated using precise monitoring systems. In this context, the authors have critically evaluated the literature, explored the importance of such materials in the context of functional clothing used for sportswear, and reported their limitations and implications. The study also is informed by experimentation using a custom-built measurement device to precisely monitor the pressure profile of various materials. This device is modelled on some of the ISO test procedures for assessing impact protection. The pressure sensors are located below the sample material and forces transmitted through the material by an impactor are recorded in the form of a load-vs-time dataset. Quantitative comparisons of a range of commercial materials used for impact protection have been obtained.

Developments in computerised management information systems (MIS)have been very rapid during the past decade, with advances in both hardware technology and software engineering. This paper captures the experience of a factory manager who invested in a real-time MIS.