Monday, February 29, 2016

The use of dynamic nuclear polarization 13C-pyruvate MRS in cancer

Gutte, H., et al., The use of dynamic nuclear polarization 13C-pyruvate MRS in cancer. Am J Nucl Med Mol Imaging 2015. 5(5): p. 548-560.

In recent years there has been an immense development of new targeted anti-cancer drugs. For practicing precision medicine, a sensitive method imaging for non-invasive, assessment of early treatment response and for assisting in developing new drugs is warranted. Magnetic Resonance Spectroscopy (MRS) is a potent technique for non-invasive in vivo investigation of tissue chemistry and cellular metabolism. Hyperpolarization by Dynamic Nuclear Polarization (DNP) is capable of creating solutions of molecules with polarized nuclear spins in a range of biological molecules and has enabled the real-time investigation of in vivo metabolism. The development of this new method has been demonstrated to enhance the nuclear polarization more than 10,000-fold, thereby significantly increasing the sensitivity of the MRS with a spatial resolution to the millimeters and a temporal resolution at the subsecond range. Furthermore, the method enables measuring kinetics of conversion of substrates into cell metabolites and can be integrated with anatomical proton magnetic resonance imaging (MRI). Many nuclei and substrates have been hyperpolarized using the DNP method. Currently, the most widely used compound is 13C-pyruvate due to favoring technicalities. Intravenous injection of the hyperpolarized 13C-pyruvate results in appearance of 13C-lactate, 13C-alanine and 13C-bicarbonate resonance peaks depending on the tissue, disease and the metabolic state probed. In cancer, the lactate level is increased due to increased glycolysis. The use of DNP enhanced 13C-pyruvate has in preclinical studies shown to be a sensitive method for detecting cancer and for assessment of early treatment response in a variety of cancers. Recently, a first-in-man 31-patient study was conducted with the primary objective to assess the safety of hyperpolarized 13C-pyruvate in healthy subjects and prostate cancer patients. The study showed an elevated 13C-lactate/13C-pyruvate ratio in regions of biopsy-proven prostate cancer compared to noncancerous tissue. However, more studies are needed in order to establish use of hyperpolarized 13C MRS imaging of cancer.

Friday, February 26, 2016

Stabilization of Gyrotron Frequency by PID Feedback Control on the Acceleration Voltage

Khutoryan, E.M., et al., Stabilization of Gyrotron Frequency by PID Feedback Control on the Acceleration Voltage. J Infrared Milli Terahz Waves, 2015. 36(12): p. 1157-1163.

The results of frequency stabilization by proportional-integral-derivative (PID) feedback control of acceleration voltage in the 460-GHz Gyrotron FU CW GVI (the official name in Osaka University is Gyrotron FU CW GOI) are presented. The experiment was organized on the basis of the frequency modulation by modulation of acceleration voltage of beam electrons. The frequency stabilization during 10 h experiment was better than 10−6, which is compared with the results of the frequency deviation in free-running gyrotron operation.

Wednesday, February 24, 2016

Efficient DNP NMR of membrane proteins: sample preparation protocols, sensitivity, and radical location

Liao, S.Y., et al., Efficient DNP NMR of membrane proteins: sample preparation protocols, sensitivity, and radical location. J Biomol NMR, 2016: p. 1-15.

Although dynamic nuclear polarization (DNP) has dramatically enhanced solid-state NMR spectral sensitivities of many synthetic materials and some biological macromolecules, recent studies of membrane-protein DNP using exogenously doped paramagnetic radicals as polarizing agents have reported varied and sometimes surprisingly limited enhancement factors. This motivated us to carry out a systematic evaluation of sample preparation protocols for optimizing the sensitivity of DNP NMR spectra of membrane-bound peptides and proteins at cryogenic temperatures of ~110 K. We show that mixing the radical with the membrane by direct titration instead of centrifugation gives a significant boost to DNP enhancement. We quantify the relative sensitivity enhancement between AMUPol and TOTAPOL, two commonly used radicals, and between deuterated and protonated lipid membranes. AMUPol shows ~fourfold higher sensitivity enhancement than TOTAPOL, while deuterated lipid membrane does not give net higher sensitivity for the membrane peptides than protonated membrane. Overall, a ~100 fold enhancement between the microwave-on and microwave-off spectra can be achieved on lipid-rich membranes containing conformationally disordered peptides, and absolute sensitivity gains of 105-160 can be obtained between low-temperature DNP spectra and high-temperature non-DNP spectra. We also measured the paramagnetic relaxation enhancement of lipid signals by TOTAPOL and AMUPol, to determine the depths of these two radicals in the lipid bilayer. Our data indicate a bimodal distribution of both radicals, a surface-bound fraction and a membrane-bound fraction where the nitroxides lie at ~10 A from the membrane surface. TOTAPOL appears to have a higher membrane-embedded fraction than AMUPol. These results should be useful for membrane-protein solid-state NMR studies under DNP conditions and provide insights into how biradicals interact with phospholipid membranes.

Monday, February 22, 2016

Sensitivity-enhanced NMR reveals alterations in protein structure by cellular milieus

Frederick, K.K., et al., Sensitivity-enhanced NMR reveals alterations in protein structure by cellular milieus. Cell, 2015. 163(3): p. 620-8.

Biological processes occur in complex environments containing a myriad of potential interactors. Unfortunately, limitations on the sensitivity of biophysical techniques normally restrict structural investigations to purified systems, at concentrations that are orders of magnitude above endogenous levels. Dynamic nuclear polarization (DNP) can dramatically enhance the sensitivity of nuclear magnetic resonance (NMR) spectroscopy and enable structural studies in biologically complex environments. Here, we applied DNP NMR to investigate the structure of a protein containing both an environmentally sensitive folding pathway and an intrinsically disordered region, the yeast prion protein Sup35. We added an exogenously prepared isotopically labeled protein to deuterated lysates, rendering the biological environment "invisible" and enabling highly efficient polarization transfer for DNP. In this environment, structural changes occurred in a region known to influence biological activity but intrinsically disordered in purified samples. Thus, DNP makes structural studies of proteins at endogenous levels in biological contexts possible, and such contexts can influence protein structure.

Saturday, February 20, 2016

Robert Griffin receives the ACS E. Bright Wilson Award

Professor of chemistry and head of the Francis Bitter Magnet Laboratory honored for his pioneering contributions to the field of nuclear magnetic resonance spectroscopy.

MIT professor of chemistry and head of the Francis Bitter Magnet Laboratory (FBML) Robert Griffin will receive the E. Bright Wilson Award in Spectroscopy at the spring awards symposium of the American Chemical Society (ACS) Division of Physical Chemistry. Griffin is being honored for his pioneering contributions to the field of nuclear magnetic resonance (NMR) spectroscopy.

Friday, February 19, 2016

The effect of Gd on trityl-based dynamic nuclear polarisation in solids

Ravera, E., et al., The effect of Gd on trityl-based dynamic nuclear polarisation in solids. Phys Chem Chem Phys, 2015. 17(40): p. 26969-78.

In dynamic nuclear polarisation (DNP) experiments performed under static conditions at 1.4 K we show that the presence of 1 mM Gd(iii)-DOTAREM increases the (13)C polarisation and decreases the (13)C polarisation buildup time of (13)C-urea dissolved in samples containing water/DMSO mixtures with trityl radical (OX063) concentrations of 10 mM or higher. To account for these observations further measurements were carried out at 6.5 K, using a combined EPR and NMR spectrometer. At this temperature, frequency swept DNP spectra of samples with 5 or 10 mM OX063 were measured, with and without 1 mM Gd-DOTA, and again a (13)C enhancement gain was observed due to the presence of Gd-DOTA. These measurements were complemented by electron-electron double resonance (ELDOR) measurements to quantitate the effect of electron spectral diffusion (eSD) on the DNP enhancements and lineshapes. Simulations of the ELDOR spectra were done using the following parameters: (i) a parameter defining the rate of the eSD process, (ii) an "effective electron-proton anisotropic hyperfine interaction parameter", and (iii) the transverse electron spin relaxation time of OX063. These parameters, together with the longitudinal electron spin relaxation time, measured by EPR, were used to calculate the frequency profile of electron polarisation. This, in turn, was used to calculate two basic solid effect (SE) and indirect cross effect (iCE) DNP spectra. A properly weighted combination of these two normalized DNP spectra provided a very good fit of the experimental DNP spectra. The best fit simulation parameters reveal that the addition of Gd(iii)-DOTA causes an increase in both the SE and the iCE contributions by similar amounts, and that the increase in the overall DNP enhancements is a result of narrowing of the ELDOR spectra (increased electron polarisation gradient across the EPR line). These changes in the electron depolarisation profile are a combined result of shortening of the longitudinal and transverse electron spin relaxation times, as well as an increase in the eSD rate and in the effective electron-proton anisotropic hyperfine interaction parameter.

Wednesday, February 17, 2016

Parahydrogen enhanced NMR reveals correlations in selective hydrogenation of triple bonds over supported Pt catalyst

Zhou, R., et al., Parahydrogen enhanced NMR reveals correlations in selective hydrogenation of triple bonds over supported Pt catalyst. Phys Chem Chem Phys, 2015. 17(39): p. 26121-9.

Parahydrogen induced polarization using heterogeneous catalysis can produce impurity-free hyperpolarized gases and liquids, but the comparatively low signal enhancements and limited scope of substrates that can be polarized pose significant challenges to this approach. This study explores the surface processes affecting the disposition of the bilinear spin order derived from parahydrogen in the hydrogenation of propyne over TiO2-supported Pt nanoparticles. The hyperpolarized adducts formed at low magnetic field are adiabatically transported to high field for analysis by proton NMR spectroscopy at 400 MHz. For the first time, the stereoselectivity of pairwise addition to propyne is measured as a function of reaction conditions. The correlation between partial reduction selectivity and stereoselectivity of pairwise addition is revealed. The systematic trends are rationalized in terms of a hybrid mechanism incorporating non-traditional concerted addition steps and well-established reversible step-wise addition involving the formation of a surface bound 2-propyl intermediate.

Monday, February 15, 2016

Singlet lifetime measurements in an all-proton chemically equivalent spin system by hyperpolarization and weak spin lock transfers

Zhang, Y., et al., Singlet lifetime measurements in an all-proton chemically equivalent spin system by hyperpolarization and weak spin lock transfers. Phys. Chem. Chem. Phys., 2015. 17(37): p. 24370-24375.

Hyperpolarized singlet states provide the opportunity for polarization storage over periods significantly longer than T1. Here, we show how the singlet state in a chemically equivalent proton spin system can be revealed by a weak power spin-lock. This procedure allowed the measurement of the lifetimes of the singlet state in protic solvents. The contributions of different intra- and intermolecular relaxation mechanisms to singlet lifetimes are investigated with this procedure.

Friday, February 12, 2016

Terahertz gyrotrons: State of the art and prospects

Glyavin, M.Y., et al., Terahertz gyrotrons: State of the art and prospects. J. Commun. Technol. Electron., 2014. 59(8): p. 792-797.

The state of the art for terahertz gyrotrons that are needed for various scientific research and practical applications is presented. Powers of 5 kW and 200 kW are obtained at frequencies of 1 and 0.7 THz using pulsed gyrotrons with pulse durations of tens of microseconds. A power of 100 W is demonstrated for cw gyrotrons at frequencies ranging from 0.2 to 0.5 THz.

Wednesday, February 10, 2016

Dynamic Nuclear Polarization Solid-State NMR in Heterogeneous Catalysis Research

Kobayashi, T., et al., Dynamic Nuclear Polarization Solid-State NMR in Heterogeneous Catalysis Research. ACS Catalysis, 2015. 5(12): p. 7055-7062.

This article does not seem to have an abstract, therefore I'm posting the first two paragraphs.

A revolution in solid-state nuclear magnetic resonance (SSNMR) spectroscopy is taking place, attributable to the rapid development of high-field dynamic nuclear polarization (DNP), a technique yielding sensitivity improvements of 2–3 orders of magnitude. This higher sensitivity in SSNMR has already impacted materials research, and the implications of new methods on catalytic sciences are expected to be profound.
With their unique sensitivity to the local electronic environment, the nuclear spins can play the role of perfect reporters in the quest for a fundamental understanding of the catalytic processes at the atomic-scale. Indeed, during the last several decades, SSNMR spectroscopy has evolved to become one of the premier analytical methods for structural characterization of heterogeneous catalytic systems, providing in-depth knowledge about catalyst supports, active sites, reacting molecules, and their interactions.(1-3) Noteworthy is also NMR’s ability to investigate a wide range of dynamic processes at solid–liquid and solid–gas interfaces under catalytically relevant pressures and temperatures. The development of sophisticated SSNMR instrumentation, methodology, and advances in theory have endowed the researchers with an ever increasing ability not only to identify and quantify individual chemical sites but also to determine the three-dimensional (3D) catalytic structures, which are often non-periodic and disordered. Of importance are also the active site distribution and the interactions between these sites and the reacting molecules. This area of multidimensional correlation NMR spectroscopy can open new frontiers for the definite characterization of increasingly complex catalytic materials, provided that the issue of low sensitivity can be overcome.

Monday, February 8, 2016

High-resolution NMR of hydrogen in organic solids by DNP enhanced natural abundance deuterium spectroscopy

Rossini, A.J., et al., High-resolution NMR of hydrogen in organic solids by DNP enhanced natural abundance deuterium spectroscopy. J Magn Reson, 2015. 259: p. 192-8.

We demonstrate that high field (9.4 T) dynamic nuclear polarization (DNP) at cryogenic ( approximately 100 K) sample temperatures enables the rapid acquisition of natural abundance (1)H-(2)H cross-polarization magic angle spinning (CPMAS) solid-state NMR spectra of organic solids. Spectra were obtained by impregnating substrates with a solution of the stable DNP polarizing agent TEKPol in tetrachloroethane. Tetrachloroethane is a non-solvent for the solids, and the unmodified substrates are then polarized through spin diffusion. High quality natural abundance (2)H CPMAS spectra of histidine hydrochloride monohydrate, glycylglycine and theophylline were acquired in less than 2h, providing direct access to hydrogen chemical shifts and quadrupolar couplings. The spectral resolution of the (2)H solid-state NMR spectra is comparable to that of (1)H spectra obtained with state of the art homonuclear decoupling techniques.

Friday, February 5, 2016

A peripheral component interconnect express-based scalable and highly integrated pulsed spectrometer for solution state dynamic nuclear polarization

He, Y., et al., A peripheral component interconnect express-based scalable and highly integrated pulsed spectrometer for solution state dynamic nuclear polarization. Rev Sci Instrum, 2015. 86(8): p. 083101.

High sensitivity, high data rates, fast pulses, and accurate synchronization all represent challenges for modern nuclear magnetic resonance spectrometers, which make any expansion or adaptation of these devices to new techniques and experiments difficult. Here, we present a Peripheral Component Interconnect Express (PCIe)-based highly integrated distributed digital architecture pulsed spectrometer that is implemented with electron and nucleus double resonances and is scalable specifically for broad dynamic nuclear polarization (DNP) enhancement applications, including DNP-magnetic resonance spectroscopy/imaging (DNP-MRS/MRI). The distributed modularized architecture can implement more transceiver channels flexibly to meet a variety of MRS/MRI instrumentation needs. The proposed PCIe bus with high data rates can significantly improve data transmission efficiency and communication reliability and allow precise control of pulse sequences. An external high speed double data rate memory chip is used to store acquired data and pulse sequence elements, which greatly accelerates the execution of the pulse sequence, reduces the TR (time of repetition) interval, and improves the accuracy of TR in imaging sequences. Using clock phase-shift technology, we can produce digital pulses accurately with high timing resolution of 1 ns and narrow widths of 4 ns to control the microwave pulses required by pulsed DNP and ensure overall system synchronization. The proposed spectrometer is proved to be both feasible and reliable by observation of a maximum signal enhancement factor of approximately -170 for (1)H, and a high quality water image was successfully obtained by DNP-enhanced spin-echo (1)H MRI at 0.35 T.

Wednesday, February 3, 2016

[NMR] PhDs & Postdocs in MAS-DNP at CEA Grenoble (France)

From the Ampere Magnetic Resonance list

PhDs & Postdocs in MAS-DNP at CEA Grenoble (France)

Contact Gaël De Paëpe (

PhD and Postdoc positions are now available at CEA-INAC (twinned with the Univ. Grenoble Alpes), France. The ERC-funded project will focus on the further development of an emerging hyperpolarization technique called MAS-DNP (Magic Angle Spinning Dynamic Nuclear Polarization). Combining hardware development, computational/theoretical approaches and sophisticated NMR experiments, we will apply the newly developed methodology to improve the understanding of challenging systems (both materials and biomolecules).

Line of research / welcomed fields of expertize:
- Designing and conducting advanced DNP/NMR experiments
- Spin dynamics simulations for pulse sequence development
- Hardware development for cryogenic helium spinning
- RF/MW engineering
- Quantum Chemical Calculations and Molecular Dynamics simulations
- Experience with material and/or biomolecular sample preparation
- Basic knowledge in radical chemistry
- Matlab programming
- EPR experiments

The funded project is part of a larger ongoing activity involving a strong partnership between our lab and LNCMI/CNRS (for high-field EPR) as well as an industrial partner (Bruker Biospin). Motivated candidates must have a good command (written / spoken) of English and should send a detailed CV and a letter of motivation, as well as any questions, to

Grenoble is one of the major cities in Europe for research with a large international scientific community. In addition, Grenoble has a large international student population, is a very pleasant city to live in, and is known as the “Capital of the Alps” with easy access to great skiing and hiking. It’s also only 2 hours’ drive to the Mediterranean Sea, Italy, or Switzerland. Grenoble, Lyon, and Geneva airports are nearby and permit straightforward international travel. 

Selected references from the group:

1 – Enhanced Solid-State NMR Correlation Spectroscopy of Quadrupolar Nuclei Using Dynamic Nuclear Polarization, Lee D., Takahashi H., Thankamony A. S. L., Dacquin J.-P., Bardet M., Lafon O., De Paëpe G., Journal of the American Chemical Society, 134, 18491-18494, 2012

2 – Rapid Natural-Abundance 2D C13-C13 Correlation Spectroscopy Using Dynamic Nuclear Polarization Enhanced Solid-State NMR and Matrix-Free Sample Preparation, Takahashi H., Lee D., Dubois L., Bardet M., Hediger S. De Paëpe G., Angewandte Chemie International Edition, 51, 11766-11769, 2012

3 – Towards Structure Determination of Self-Assembled Peptides by Dynamic Nuclear Polarization Enhanced Solid-State NMR, Takahashi H., Viverge B., Lee D., Rannou P., De Paëpe G., Angewandte Chemie International Edition, 52, 6979-6982, 2013

4 – Solid-State NMR on Bacterial Cells: Selective Cell-Wall-Signal Enhancement and Resolution Improvement using Dynamic Nuclear Polarization, Takahashi H., Ayala I., Bardet M., De Paëpe G., Simorre J.P., Hediger S., Journal of the American Chemical Society, 135, 5105-5110, 2013

5 – Untangling the Condensation Network of Organosiloxanes on Nanoparticles using 2D 29Si- 29Si Solid-State NMR enhanced by Dynamic Nuclear Polarization, D Lee, G Monin, NT Duong, IZ Lopez, M Bardet, V Mareau, L Gonon, G. De Paëpe, Journal of the American Chemical Society, 136, 13781-13788, 2014

6 – Nuclear Depolarization and Absolute Sensitivity in Magic-Angle Spinning Cross-Effect Dynamic Nuclear Polarization, Mentink-Vigier F., Paul S., Lee D., Feintuch A., Hediger S., Vega S., De Paëpe G., Physical Chemistry Chemical Physics, 17, 21824-21836, 2015

7 – Pushing NMR sensitivity limits using dynamic nuclear polarization with closed-loop cryogenic helium sample spinning, E. Bouleau, P. Saint-Bonnet, F. Mentink-Vigier, H. Takahashi, J.-F. Jacquot, M. Bardet, F. Aussenac, A. Purea, F. Engelke, S. Hediger, D. Lee, G. De Paëpe, Chemical Science, 6, 6806-6812, 2015

8 – A New Tool for NMR Crystallography: Complete 13C/15N Assignment of Organic Molecules at Natural Isotopic Abundance Using DNP-Enhanced Solid-state NMR, K. Märker, M. Pingret, Jean-Marie Mouesca, Didier Gasparutto, Sabine Hediger, Gaël De Paëpe, Journal of the American Chemical Society, 137, 13796-13799, 2015

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Gutte, H., et al., Simultaneous Hyperpolarized 13C-Pyruvate MRI and 18F-FDG PET (HyperPET) in 10 Dogs with Cancer. J Nucl Med, 2015. 56(11): p. 1786-92.

With the introduction of combined PET/MR spectroscopic (MRS) imaging, it is now possible to directly and indirectly image the Warburg effect with hyperpolarized (13)C-pyruvate and (18)F-FDG PET imaging, respectively, via a technique we have named hyperPET. The main purpose of this present study was to establish a practical workflow for performing (18)F-FDG PET and hyperpolarized (13)C-pyruvate MRS imaging simultaneously for tumor tissue characterization and on a larger scale test its feasibility. In addition, we evaluated the correlation between (18)F-FDG uptake and (13)C-lactate production. METHODS: Ten dogs with biopsy-verified spontaneous malignant tumors were included for imaging. All dogs underwent a protocol of simultaneous (18)F-FDG PET, anatomic MR, and hyperpolarized dynamic nuclear polarization with (13)C-pyruvate imaging. The data were acquired using a combined clinical PET/MR imaging scanner. RESULTS: We found that combined (18)F-FDG PET and (13)C-pyruvate MRS imaging was possible in a single session of approximately 2 h. A continuous workflow was obtained with the injection of (18)F-FDG when the dogs was placed in the PET/MR scanner. (13)C-MRS dynamic acquisition demonstrated in an axial slab increased (13)C-lactate production in 9 of 10 dogs. For the 9 dogs, the (13)C-lactate was detected after a mean of 25 s (range, 17-33 s), with a mean to peak of (13)C-lactate at 49 s (range, 40-62 s). (13)C-pyruvate could be detected on average after 13 s (range, 5-26 s) and peaked on average after 25 s (range, 13-42 s). We noticed concordance of (18)F-FDG uptake and production of (13)C-lactate in most, but not all, axial slices. CONCLUSION: In this study, we have shown in a series of dogs with cancer that hyperPET can easily be performed within 2 h. We showed mostly correspondence between (13)C-lactate production and (18)F-FDG uptake and expect the combined modalities to reveal additional metabolic information to improve prognostic value and improve response monitoring.

Monday, February 1, 2016

Dynamic Nuclear Polarization as an Enabling Technology for Solid State Nuclear Magnetic Resonance Spectroscopy

Smith, A.N. and J.R. Long, Dynamic Nuclear Polarization as an Enabling Technology for Solid State Nuclear Magnetic Resonance Spectroscopy. Analytical Chemistry, 2016. 88(1): p. 122-132.

(This article does not seem to have an abstract, so I'm just posting the first paragraph here)

Magic angle spinning (MAS) solid state nuclear magnetic resonance spectroscopy (ssNMR) can yield unique and insightful information for complex systems; most notably structural and dynamical information can be obtained at atomic resolution.1−23 A particular strength of MAS ssNMR is it can be applied to heterogeneous systems, which are not amenable to study by other high-resolution experimental techniques due to sample characteristics. For example biomolecular assemblies, such as membrane proteins, are often not tractable for solubilization, a requisite for standard solution state NMR experiments, or crystallization, as needed for diffraction studies.1,24 Solid state materials with limited global order are often difficult to characterize by diffraction or other spectroscopic methods (e.g., UV− vis, IR, etc.), and information on reactive moieties, of particular interest for chemical and functional insight, can be difficult to differentiate from bulk signals.