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الجامعة والبحث العلمي كمحرك لتأسيس الشركات : التجربة البريطانية أنموذجا
يتناول هذا الكتاب ما بات يسمى بالمثلث الذهبي الذي يجمع بين الجامعة والبحث العلمي والشركات التجارية وهو مجال تصدرت فيه التجربة البريطانية على فرنسا يوضح هذا العمل أهم مفاصل برنامج الإصلاحات الذي قادته بريطانيا مع نهاية السبعينيات في نظامها للتعليم العالي والبحث العلمي، والذي من بعده باتت الجامعات البريطانية تعد بمثابة علامات تجارية تسهم في تأسيس المشاريع التجارية وذلك عملا بسياسة المثلث الذهبي الذي يربط الجامعة والبحث العلمي بالشركات التجارية.
BOOK
Hyperpolarized 13C-glucose magnetic resonance highlights reduced aerobic glycolysis in vivo in infiltrative glioblastoma
Glioblastoma (GBM) is the most aggressive brain tumor type in adults. GBM is heterogeneous, with a compact core lesion surrounded by an invasive tumor front. This front is highly relevant for tumor recurrence but is generally non-detectable using standard imaging techniques. Recent studies demonstrated distinct metabolic profiles of the invasive phenotype in GBM. Magnetic resonance (MR) of hyperpolarized
13
C-labeled probes is a rapidly advancing field that provides real-time metabolic information. Here, we applied hyperpolarized
13
C-glucose MR to mouse GBM models. Compared to controls, the amount of lactate produced from hyperpolarized glucose was higher in the compact GBM model, consistent with the accepted “Warburg effect”. However, the opposite response was observed in models reflecting the invasive zone, with less lactate produced than in controls, implying a reduction in aerobic glycolysis. These striking differences could be used to map the metabolic heterogeneity in GBM and to visualize the infiltrative front of GBM.
Journal Article
Correlated cryo-SEM and CryoNanoSIMS imaging of biological tissue
Background
The development of nanoscale secondary ion mass spectrometry (NanoSIMS) has revolutionized the study of biological tissues by enabling, e.g., the visualization and quantification of metabolic processes at subcellular length scales. However, the associated sample preparation methods all result in some degree of tissue morphology distortion and loss of soluble compounds. To overcome these limitations an entirely cryogenic sample preparation and imaging workflow is required.
Results
Here, we report the development of a CryoNanoSIMS instrument that can perform isotope imaging of both positive and negative secondary ions from flat block-face surfaces of vitrified biological tissues with a mass- and image resolution comparable to that of a conventional NanoSIMS. This capability is illustrated with nitrogen isotope as well as trace element mapping of freshwater hydrozoan Green Hydra tissue following uptake of
15
N-enriched ammonium.
Conclusion
With a cryo-workflow that includes vitrification by high pressure freezing, cryo-planing of the sample surface, and cryo-SEM imaging, the CryoNanoSIMS enables correlative ultrastructure and isotopic or elemental imaging of biological tissues in their most pristine post-mortem state. This opens new horizons in the study of fundamental processes at the tissue- and (sub)cellular level.
Teaser
CryoNanoSIMS: subcellular mapping of chemical and isotopic compositions of biological tissues in their most pristine post-mortem state.
Journal Article
Hyperpolarization without persistent radicals for in vivo real-time metabolic imaging
Hyperpolarized substrates prepared via dissolution dynamic nuclear polarization have been proposed as magnetic resonance imaging (MRI) agents for cancer or cardiac failure diagnosis and therapy monitoring through the detection of metabolic impairments in vivo. The use of potentially toxic persistent radicals to hyperpolarize substrates was hitherto required. We demonstrate that by shining UV light for an hour on a frozen pure endogenous substance, namely the glucose metabolic product pyruvic acid, it is possible to generate a concentration of photo-induced radicals that is large enough to highly enhance the 13C polarization of the substance via dynamic nuclear polarization. These radicals recombine upon dissolution and a solution composed of purely endogenous products is obtained for performing in vivo metabolic hyperpolarized 13C MRI with high spatial resolution. Our method opens the way to safe and straightforward preclinical and clinical applications of hyperpolarized MRI because the filtering procedure mandatory for clinical applications and the associated pharmacological tests necessary to prevent contamination are eliminated, concurrently allowing a decrease in the delay between preparation and injection of the imaging agents for improved in vivo sensitivity.
Journal Article
Noninvasive rapid detection of metabolic adaptation in activated human T lymphocytes by hyperpolarized 13C magnetic resonance
The metabolic shift induced in human CD4
+
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
13
C magnetic resonance, a technique which can be used for
in vivo
imaging. It was shown that the conversion of hyperpolarized
13
C-pyruvate to
13
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
.
Journal Article
Thermal annihilation of photo-induced radicals following dynamic nuclear polarization to produce transportable frozen hyperpolarized 13C-substrates
Hyperpolarization via dynamic nuclear polarization (DNP) is pivotal for boosting magnetic resonance imaging (MRI) sensitivity and dissolution DNP can be used to perform
in vivo
real-time
13
C MRI. The type of applications is however limited by the relatively fast decay time of the hyperpolarized spin state together with the constraint of having to polarize the
13
C spins in a dedicated apparatus nearby but separated from the MRI magnet. We herein demonstrate that by polarizing
13
C with photo-induced radicals, which can be subsequently annihilated using a thermalization process that maintains the sample temperature below its melting point, hyperpolarized
13
C-substrates can be extracted from the DNP apparatus in the solid form, while maintaining the enhanced
13
C polarization. The melting procedure necessary to transform the frozen solid into an injectable solution containing the hyperpolarized
13
C-substrates can therefore be performed
ex situ
, up to several hours after extraction and storage of the polarized solid.
Hyperpolarized molecules provide unique contrast for MRI but due to their short relaxation time need to be prepared shortly before injection. Here the authors report a method for eliminating the main source of relaxation and producing frozen polarized substances that can be stored and transported.
Journal Article
13Cbicarbonate labelled from hyperpolarized 1-13Cpyruvate is an in vivo marker of hepatic gluconeogenesis in fasted state
Hyperpolarized [1-
13
C]pyruvate enables direct in vivo assessment of real-time liver enzymatic activities by
13
C magnetic resonance. However, the technique usually requires the injection of a highly supraphysiological dose of pyruvate. We herein demonstrate that liver metabolism can be measured in vivo with hyperpolarized [1-
13
C]pyruvate administered at two- to three-fold the basal plasma concentration. The flux through pyruvate dehydrogenase, assessed by
13
C-labeling of bicarbonate in the fed condition, was found to be saturated or partially inhibited by supraphysiological doses of hyperpolarized [1-
13
C]pyruvate. The [
13
C]bicarbonate signal detected in the liver of fasted rats nearly vanished after treatment with a phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, indicating that the signal originates from the flux through PEPCK. In addition, the normalized [
13
C]bicarbonate signal in fasted untreated animals is dose independent across a 10-fold range, highlighting that PEPCK and pyruvate carboxylase are not saturated and that hepatic gluconeogenesis can be directly probed in vivo with hyperpolarized [1-
13
C]pyruvate.
Can et al. demonstrate the ability to use hyperpolarized [1-13C]pyruvate at nearphysiological concentrations to directly assess liver enzymatic activities by 13C magnetic resonance. While in the fed state, the normalized [13C]bicarbonate signal produced from hyperpolarized [1-13C]pyruvate derives from PDH activity, which is saturated at supraphysiological doses, it results from PEPCK in the fasted state and is dose-independent, allowing non-invasive in vivo detection of hepatic gluconeogenesis.”
Journal Article
A method to disentangle and quantify host anabolic turnover in photosymbiotic holobionts with subcellular resolution
A wide range of organisms host photosynthesizing symbionts. In these animals the metabolic exchange between host and symbionts has prevented in situ host anabolic turnover to be studied without the confounding effect of translocated photosynthates. Using the symbiotic coral
Stylophora pistillata
as a model organism and [1-
13
C]-pyruvate and [2,3-
13
C]-pyruvate in different incubation conditions (light, light + DCMU, and darkness), we employed NanoSIMS isotopic imaging to quantify host anabolism, with and without translocated metabolites from their photosynthesizing dinoflagellate symbionts. Under our experimental conditions, host de novo lipid synthesis accounted for ~40% of the total holobiont lipid reserve, and dinoflagellate recycling of metabolic
13
CO
2
enhanced host tissue
13
C-enrichment by 13–22% in the epidermis, 40–58% in the gastrodermis, and 135–169% in host lipid bodies. Furthermore, we show that host anabolic turnover in different tissue structures differs, in a manner consistent with the localisation, function and cellular composition of these structures.
Gibbin et al. use [1–13C]-pyruvate and [2,3–13C]-pyruvate in different incubation conditions (light, light+DCMU, and dark) to discern and quantify coral host anabolism, with and without translocated metabolites from their photosynthesizing symbionts.
Journal Article
Thermal annihilation of photo-induced radicals following dynamic nuclear polarization to produce transportable frozen hyperpolarized 13 C-substrates
Hyperpolarization via dynamic nuclear polarization (DNP) is pivotal for boosting magnetic resonance imaging (MRI) sensitivity and dissolution DNP can be used to perform in vivo real-time
C MRI. The type of applications is however limited by the relatively fast decay time of the hyperpolarized spin state together with the constraint of having to polarize the
C spins in a dedicated apparatus nearby but separated from the MRI magnet. We herein demonstrate that by polarizing
C with photo-induced radicals, which can be subsequently annihilated using a thermalization process that maintains the sample temperature below its melting point, hyperpolarized
C-substrates can be extracted from the DNP apparatus in the solid form, while maintaining the enhanced
C polarization. The melting procedure necessary to transform the frozen solid into an injectable solution containing the hyperpolarized
C-substrates can therefore be performed ex situ, up to several hours after extraction and storage of the polarized solid.
Journal Article
In Vivo Detection of Brain Krebs Cycle Intermediate by Hyperpolarized Magnetic Resonance
The Krebs (or tricarboxylic acid (TCA)) cycle has a central role in the regulation of brain energy regulation and metabolism, yet brain TCA cycle intermediates have never been directly detected in vivo. This study reports the first direct in vivo observation of a TCA cycle intermediate in intact brain, namely, 2-oxoglutarate, a key biomolecule connecting metabolism to neuronal activity. Our observation reveals important information about in vivo biochemical processes hitherto considered undetectable. In particular, it provides direct evidence that transport across the inner mitochondria membrane is rate limiting in the brain. The hyperpolarized magnetic resonance protocol designed for this study opens the way to direct and real-time studies of TCA cycle kinetics.
Journal Article