Measuring changes in substrate utilization in the myocardium in response to fasting using hyperpolarized [1-(13)C]butyrate and [1-(13)C]pyruvate.

Cardiac dysfunction is often associated with a shift in substrate preference for ATP production. Hyperpolarized (HP) (13)C magnetic resonance spectroscopy (MRS) has the unique ability to detect real-time metabolic changes in vivo due to its high sensitivity and specificity. Here a protocol using HP [1-(13)C]pyruvate and [1-(13)C]butyrate is used to measure carbohydrate versus fatty acid metabolism in vivo. Metabolic changes in fed and fasted Sprague Dawley rats (n = 36) were studied at 9.4 T after tail vein injections. Pyruvate and butyrate competed for acetyl-CoA production, as evidenced by significant changes in [(13)C]bicarbonate (-48%), [1-(13)C]acetylcarnitine (+113%), and [5-(13)C]glutamate (-63%), following fasting. Butyrate uptake was unaffected by fasting, as indicated by [1-(13)C]butyrylcarnitine. Mitochondrial pseudoketogenesis facilitated the labeling of the ketone bodies [1-(13)C]acetoacetate and [1-(13)C]β-hydroxybutyryate, without evidence of true ketogenesis. HP [1-(13)C]acetoacetate was increased in fasting (250%) but decreased during pyruvate co-injection (-82%). Combining HP (13)C technology and co-administration of separate imaging agents enables noninvasive and simultaneous monitoring of both fatty acid and carbohydrate oxidation. This protocol illustrates a novel method for assessing metabolic flux through different enzymatic pathways simultaneously and enables mechanistic studies of the changing myocardial energetics often associated with disease

Magnetic properties of pure and Gd doped EuO probed by NMR

An Eu NMR study in the ferromagnetic phase of pure and Gd doped EuO was performed. A complete description of the NMR lineshape of pure EuO allowed for the influence of doping EuO with Gd impurities to be highlighted. The presence of a temperature dependent static magnetic inhomogeneity in Gd doped EuO was demonstrated by studying the temperature dependence of the lineshapes. The results suggest that the inhomogeneity in 0.6% Gd doped EuO is linked to colossal magnetoresistance. The measurement of the spin-lattice relaxation times as a function of temperature led to the determination of the value of the exchange integral J as a function of Gd doping. It was found that J is temperature independent and spatially homogeneous for all the samples and that its value increases abruptly with increasing Gd doping.Comment: 14 pages, 10 figures, to be published in Physical Review

The phase transition in the localized ferromagnet EuO probed by muSR

We report results of muon spin rotation measurements performed on the ferromagnetic semiconductor EuO, which is one of the best approximations to a localized ferromagnet. We argue that implanted muons are sensitive to the internal field primarily through a combination of hyperfine and Lorentz fields. The temperature dependences of the internal field and the relaxation rate have been measured and are compared with previous theoretical predictions.Comment: 4 pages, 4 figure

Modeling Adaptive Regulatory T-Cell Dynamics during Early HIV Infection

Regulatory T-cells (Tregs) are a subset of CD4+ T-cells that have been found to suppress the immune response. During HIV viral infection, Treg activity has been observed to have both beneficial and deleterious effects on patient recovery; however, the extent to which this is regulated is poorly understood. We hypothesize that this dichotomy in behavior is attributed to Treg dynamics changing over the course of infection through the proliferation of an ‘adaptive’ Treg population which targets HIV-specific immune responses. To investigate the role Tregs play in HIV infection, a delay differatial equation model was constructed to examine (1) the possible existence of two distinct Treg populations, normal (nTregs) and adaptive (aTregs), and (2) their respective effects in limiting viral load. Sensitivity analysis was performed to test parameter regimes that show the proportionality of viral load with adaptive regulatory populations and also gave insight into the importance of downregulation of CD4+ cells by normal Tregs on viral loads. Through the inclusion of Treg populations in the model, a diverse array of viral dynamics was found. Specifically, oscillatory and steady state behaviors were both witnessed and it was seen that the model provided a more accurate depiction of the effector cell population as compared with previous models. Through further studies of adaptive and normal Tregs, improved treatments for HIV can be constructed for patients and the viral mechanisms of infection can be further elucidated

Measuring glucose cerebral metabolism in the healthy mouse using hyperpolarized ¹³C magnetic resonance.

The mammalian brain relies primarily on glucose as a fuel to meet its high metabolic demand. Among the various techniques used to study cerebral metabolism, <sup>13</sup> C magnetic resonance spectroscopy (MRS) allows following the fate of <sup>13</sup> C-enriched substrates through metabolic pathways. We herein demonstrate that it is possible to measure cerebral glucose metabolism in vivo with sub-second time resolution using hyperpolarized <sup>13</sup> C MRS. In particular, the dynamic <sup>13</sup> C-labeling of pyruvate and lactate formed from <sup>13</sup> C-glucose was observed in real time. An ad-hoc synthesis to produce [2,3,4,6,6- <sup>2</sup> H <sub>5</sub> , 3,4- <sup>13</sup> C <sub>2</sub> ]-D-glucose was developed to improve the <sup>13</sup> C signal-to-noise ratio as compared to experiments performed following [U- <sup>2</sup> H <sub>7</sub> , U- <sup>13</sup> C]-D-glucose injections. The main advantage of only labeling C3 and C4 positions is the absence of <sup>13</sup> C- <sup>13</sup> C coupling in all downstream metabolic products after glucose is split into 3-carbon intermediates by aldolase. This unique method allows direct detection of glycolysis in vivo in the healthy brain in a noninvasive manner

A link between short-range and long-range properties of random sphere packings

We present a high precision particle-by-particle 3D reconstruction of granular systems composed of monodispersed spheres (sphere packings); the experimental approach is based on magnetic resonance imaging techniques. Our measurements revealed a strong correlation between the volume defined by the distance to the first nearest neighbor and the long-range average density. The main contribution to the amplitude decay of the correlation function can be described as exponential rather than power law up to a range equal to 7 sphere diameters. No evidence of geometrical structural changes as a function of the density was observed and neither regular crystallites nor any other statistically significant structures could be ascribed to a specific local arrangement. We concluded that granular compaction is the result of a process through which the system changes the average size of local structures without changing their local geometrical characteristics. These conclusions are supported by two-body correlation functions and Voronoi polyhedra space decomposition. The results provide a different perspective on the mechanisms underlying compaction with respect to previous works, and allow to discriminate between the different existing theoretical approache

Noninvasive rapid detection of metabolic adaptation in activated human T lymphocytes by hyperpolarized ¹³C magnetic resonance.

The metabolic shift induced in human CD4 <sup>+</sup> T lymphocytes by stimulation is characterized by an upregulation of glycolysis, leading to an augmentation in lactate production. This adaptation has already been highlighted with various techniques and reported in several previous studies. We herein propose a method to rapidly and noninvasively detect the associated increase in flux from pyruvate to lactate catalyzed by lactate dehydrogenase using hyperpolarized <sup>13</sup> C magnetic resonance, a technique which can be used for in vivo imaging. It was shown that the conversion of hyperpolarized <sup>13</sup> C-pyruvate to <sup>13</sup> C-lactate during the one-minute measurement increased by a mean factor of 3.6 in T cells stimulated for 5 days as compared to resting T cells. This method can be extended to other metabolic substrates and is therefore a powerful tool to noninvasively analyze T cell metabolism, possibly in vivo

Deliberate concealment

Purpose – Welwyn Hatfield Council v Secretary of State for Communities and Local Government [2009] EWHC 966 (Admin), Welwyn Hatfield Council v. Secretary of State for Communities and Local Government [2010] EWCA Civ 26 and Welwyn Hatfield Council v. Secretary of State for Communities and Local Government [2011] UKSC 15 (Beesley hereafter) and Fidler v. Secretary of State for Communities and Local Government [2010] EWHC 143 (Admin), Fidler v. Secretary of State for Communities and Local Government [2011] EWCA civ 1159 (Fidler hereafter) are two recent cases concerning deliberately concealed breaches of planning control. The defendants engaged in dishonest and misleading conduct, in an attempt to rely on a loophole within Section 171B of the Town and Country Planning Act 1990 (T&CPA). This study aims to critically analyse two solutions which were created to close the loophole; in addition, this study analyses various alternative remedies that have been suggested, and finally, whether the present law has been sufficient to remedy the situation. Design/methodology/approach – The T&CPA is a key piece of legislation regulating planning controls; Section 171A-C provides the time limits for taking enforcement action against a breach of planning control. To achieve the above purpose, an evaluation of those provisions will be undertaken in detail. Subsequently, this study will analyse two solutions which were created to close the loophole; firstly, the Supreme Court (SC) decision (Welwyn Hatfield Borough Council v. Secretary of State for Communities and Local Government [2011] UKSC 15) and, secondly, the governments’ decision to amend the T&CPA without awaiting the SC’s decision[1]. Findings – This research concludes that the government should have awaited the SC’s decision before amending statute to prohibit reliance upon the expiration of time where there is an element of deliberate concealment. Additionally, this study suggests that the statutory amendments were not required in light of the SC’s solution in Beesley. As a result of the governments’ ill-considered decision, uncertainty has permeated through the conveyancing process, causing ambiguity, delays and additional expense in transactions at a time when a precarious property market needs anything but uncertainty. Research limitations implications – The scope of this research is limited to deliberate concealment of breaches of planning control and the four-year enforcement period; whilst considering the consequences of the solutions proposed, this study does not provide a detailed overview of the planning system, but rather assumes prior knowledge. Originality/value – This study offers a unique assessment of the law relating to the deliberate concealment of planning breaches and offers a thorough criticism of the law with recommendations for reform. Additionally, a variety of alternative solutions are considered. Both legal academics, planning professionals and those interested in planning law will find the paper a thought-provoking digest

Evolution of magnetic polarons and spin-carrier interactions through the metal-insulator transition in Eu1−x_{1-x}Gdx_{x}O

Raman scattering studies as functions of temperature, magnetic field, and Gd-substitution are used to investigate the evolution of magnetic polarons and spin-carrier interactions through the metal-insulator transition in Eu$_{1-x}$Gd$_{x}$O. These studies reveal a greater richness of phase behavior than have been previously observed using transport measurements: a spin-fluctuation-dominated paramagnetic (PM) phase regime for T $>$ T$^{*}$ $>$ T$_{C}$, a two-phase regime for T $<$ T$^{*}$ in which magnetic polarons develop and coexist with a remnant of the PM phase, and an inhomogeneous ferromagnetic phase regime for T $<$ T$_{C}$

Hyperpolarized ¹³C Magnetic Resonance Spectroscopy Reveals the Rate-Limiting Role of the Blood-Brain Barrier in the Cerebral Uptake and Metabolism of l-Lactate in Vivo.

The dynamics of l-lactate transport across the blood-brain barrier (BBB) and its cerebral metabolism are still subject to debate. We studied lactate uptake and intracellular metabolism in the mouse brain using hyperpolarized &lt;sup&gt;13&lt;/sup&gt; C magnetic resonance spectroscopy (MRS). Following the intravenous injection of hyperpolarized [1- &lt;sup&gt;13&lt;/sup&gt; C]lactate, we observed that the distribution of the &lt;sup&gt;13&lt;/sup&gt; C label between lactate and pyruvate, which has been shown to be representative of their pool size ratio, is different in NMRI and C57BL/6 mice, the latter exhibiting a higher level of cerebral lactate dehydrogenase A ( Ldha) expression. On the basis of this observation, and an additional set of experiments showing that the cerebral conversion of [1- &lt;sup&gt;13&lt;/sup&gt; C]lactate to [1- &lt;sup&gt;13&lt;/sup&gt; C]pyruvate increases after exposing the brain to ultrasound irradiation that reversibly opens the BBB, we concluded that lactate transport is rate-limited by the BBB, with a 30% increase in lactate uptake after its disruption. It was also deduced from these results that hyperpolarized &lt;sup&gt;13&lt;/sup&gt; C MRS can be used to detect a variation in cerebral lactate uptake of &lt;40 nmol in a healthy brain during an in vivo experiment lasting only 75 s, opening new opportunities to study the role of lactate in brain metabolism