Wednesday, October 30, 2013

Analysis of Cancer Metabolism by Imaging Hyperpolarized Nuclei: Prospects for Translation to Clinical Research

Kurhanewicz, J., et al., Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. Neoplasia, 2011. 13(2): p. 81-97.

A major challenge in cancer biology is to monitor and understand cancer metabolism in vivo with the goal of improved diagnosis and perhaps therapy. Because of the complexity of biochemical pathways, tracer methods are required for detecting specific enzyme-catalyzed reactions. Stable isotopes such as (13)C or (15)N with detection by nuclear magnetic resonance provide the necessary information about tissue biochemistry, but the crucial metabolites are present in low concentration and therefore are beyond the detection threshold of traditional magnetic resonance methods. A solution is to improve sensitivity by a factor of 10,000 or more by temporarily redistributing the populations of nuclear spins in a magnetic field, a process termed hyperpolarization. Although this effect is short-lived, hyperpolarized molecules can be generated in an aqueous solution and infused in vivo where metabolism generates products that can be imaged. This discovery lifts the primary constraint on magnetic resonance imaging for monitoring metabolism-poor sensitivity-while preserving the advantage of biochemical information. The purpose of this report was to briefly summarize the known abnormalities in cancer metabolism, the value and limitations of current imaging methods for metabolism, and the principles of hyperpolarization. Recent preclinical applications are described. Hyperpolarization technology is still in its infancy, and current polarizer equipment and methods are suboptimal. Nevertheless, there are no fundamental barriers to rapid translation of this exciting technology to clinical research and perhaps clinical care.

Tuesday, October 29, 2013

Postdoc position (in vivo hyperpolarized 13C MR)

The University of Maryland School of Medicine is expanding its molecular imaging and interventional research capabilities with the addition of a Dynamic Nuclear Polarizer and High-Intensity Focused Ultrasound as part of the recently established Center for Integration of Metabolic Imaging and Therapeutics (CIMIT). This expansion is aimed to facilitate both basic science and clinical research by exploring novel molecular imaging agent based technologies for screening, early detection, and real-time image-guided interventions.

In this process a postdoctoral research fellowship position is available in the metabolic imaging group led by Dr. Dirk Mayer within the Magnetic Resonance Research Center (MRRC). The primary focus of the position will be on the development and evaluation of new in vivo acquisition methods for hyperpolarized 13C spectroscopic imaging in both animal models and humans. This is an exciting opportunity to work at one of the first sites that will do translational/clinical hyperpolarized 13C MRI/MRS.

The candidate should have a Ph.D. (or equivalent degree) in engineering, physics, physical chemistry, or similar fields. The ideal candidate has a background in NMR physics with particular emphasis on in vivo spectroscopy, data acquisition and processing. Experience in pulse sequence programming (ideally on a GE clinical scanner) is preferred. Knowledge of other computer languages, including C++, Matlab and IDL, and experience in performing small animal imaging experience is also desirable. Qualified applicants should also have a track record of first-author research papers published in peer-reviewed journals.

Interested individuals should send a letter detailing their research interests, an updated CV and contact information for at least two references to Dr. Dirk Mayer at

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Monday, October 28, 2013

Dynamic nuclear polarization-enhanced 1H–13C double resonance NMR in static samples below 20 K

I think I missed this one from 2012

Potapov, A., et al., Dynamic nuclear polarization-enhanced 1H–13C double resonance NMR in static samples below 20 K. J. Magn. Reson., 2012. 221(0): p. 32-40.

We demonstrate the feasibility of one-dimensional and two-dimensional 1H–13C double resonance NMR experiments with dynamic nuclear polarization (DNP) at 9.4 T and temperatures below 20 K, including both 1H–13C cross-polarization and 1H decoupling, and discuss the effects of polarizing agent type, polarizing agent concentration, temperature, and solvent deuteration. We describe a two-channel low-temperature DNP/NMR probe, capable of carrying the radio-frequency power load required for 1H–13C cross-polarization and high-power proton decoupling. Experiments at 8 K and 16 K reveal a significant T2 relaxation of 13C, induced by electron spin flips. Carr–Purcell experiments and numerical simulations of Carr–Purcell dephasing curves allow us to determine the effective correlation time of electron flips under our experimental conditions. The dependence of the DNP signal enhancement on electron spin concentration shows a maximum near 80 mM. Although no significant difference in the absolute DNP enhancements for triradical (DOTOPA-TEMPO) and biradical (TOTAPOL) dopants was found, the triradical produced greater DNP build-up rates, which are advantageous for DNP experiments. Additionally the feasibility of structural measurements on 13C-labeled biomolecules was demonstrated with a two-dimensional 13C–13C exchange spectrum of selectively 13C-labeled β-amyloid fibrils.

Friday, October 25, 2013

Proton polarization in photo-excited aromatic molecule at room temperature enhanced by intense optical source and temperature control

Sakaguchi, S., et al., Proton polarization in photo-excited aromatic molecule at room temperature enhanced by intense optical source and temperature control. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 2013(0).

Proton polarization at room temperature, produced in a p-terphenyl crystal by using electron population difference in a photo-excited triplet state of pentacene, was enhanced by utilizing an intense laser with an average power of 1.5 W. It was shown that keeping the sample temperature below 300 K is critically important to prevent the rise of the spin–lattice relaxation rate caused by the laser heating. It is also reported that the magnitude of proton polarization strongly depends on the time structure of the laser pulse such as its width and the time interval between them.

Thursday, October 24, 2013

REMINDER: Course on "Dissolution Dynamic Nuclear Polarization" November 13-15, 2013 at EPFL, Switzerland

This is from the Ampere Magnetic Resonance List:

We would like to announce a three-day course for PhD students and Post-Docs on

"Dissolution Dynamic Nuclear Polarization"

The course will start at 1pm on Wednesday November the 13th and will end at 5pm on Friday 15th, and will be held at the Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland, at the Laboratory of Biomolecular Magnetic Resonance (LRMB).

* Registration
please register at the following adress:
subscription fees: 100 CHF

* Information
geoffrey.bodenhausen (at)
sami.jannin (at)

* Objectives
Dissolution Dynamic Nuclear Polarization (D-DNP) provides a way to enhance NMR signals in liquids by more than 4 orders of magnitude. We present the current state-of-the-art and most recent advances of this technique, and we propose experimental demonstrations with hands-on participation. 

* Content
Lectures and seminars: 11 Hours
Hands-on: 7 Hours
Day 1: Lectures, 1 pm - 5 pm: Theoretical aspects of DNP

- Introduction to DNP-enhanced NMR
- Principles of Dissolution-DNP
- Low temperature DNP mechanisms
- Cross Polarization techniques
- Applications to imaging and chemistry

Day 2: Lectures, 9 am - 12 am: Experimental aspects of DNP

- Hardware for DNP
- Hardware for Cross Polarization 
- Hardware for Dissolution

Experiments, 1 pm - 5 pm

- Sample Preparation
- Preparation of a dissolution DNP experiment

Day 3: Experiments, 9 am - 12 am: Practical DNP at the Laboratory of Biomolecular Magnetic Resonance (LRMB)

- Low temperature DNP
- Cross Polarization with DNP 
- Dissolution DNP

Seminars, 1 pm - 5 pm

- All participants are invited to give a short presentation, possibly on DNP and/or related to their own research subjects.

*Required prior knowledge

Basic understanding of NMR

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Wednesday, October 23, 2013

Overhauser dynamic nuclear polarization-enhanced NMR relaxometry

Franck, J.M., R. Kausik, and S. Han, Overhauser Dynamic Nuclear Polarization-Enhanced NMR Relaxometry. Microporous Mesoporous Mater, 2013. 178(0): p. 113-118.

We present a new methodological basis for selectively illuminating a dilute population of fluid within a porous medium. Specifically, transport in porous materials can be analyzed by now-standard nuclear magnetic resonance (NMR) relaxometry and NMR pulsed field gradient (PFG) diffusometry methods in combination with with the prominent NMR signal amplification tool, dynamic nuclear polarization (DNP). The key components of the approach introduced here are (1) to selectively place intrinsic or extrinsic paramagnetic probes at the site or local volume of interest within the sample, (2) to amplify the signal from the local solvent around the paramagnetic probes with Overhauser DNP, which is performed in situ and under ambient conditions, and (3) to observe the ODNP-enhanced solvent signal with 1D or 2D NMR relaxometry methods, thus selectively amplifying only the relaxation dynamics of the fluid that resides in or percolates through the local porous volume that contains the paramagnetic probe. Here, we demonstrate the proof of principle of this approach by selectively amplifying the NMR signal of only one solvent population, which is in contact with a paramagnetic probe and occluded from a second solvent population. An apparent one-component T 2 relaxation decay is shown to actually contain two distinct solvent populations. The approach outlined here should be universally applicable to a wide range of other 1D and 2D relaxometry and PFG diffusometry measurements, including T 1-T 2 or T 1-D correlation maps, where the occluded population containing the paramagnetic probes can be selectively amplified for its enhanced characterization.

Friday, October 18, 2013

Evidence for Coherent Transfer of para-Hydrogen-Induced Polarization at Low Magnetic Fields

Kiryutin, A.S., et al., Evidence for Coherent Transfer of para-Hydrogen-Induced Polarization at Low Magnetic Fields. The Journal of Physical Chemistry Letters, 2013. 4(15): p. 2514-2519.

We have investigated the mechanism of para-hydrogen-induced polarization (PHIP) transfer from the original strongly aligned protons to other nuclei at low external magnetic fields. Although it is known that PHIP is efficiently transferred at low fields, the nature of the transfer mechanism, that is, coherent spin mixing or cross-relaxation, is not well established. Polarization transfer kinetics for individual protons of styrene was, for the first time, measured and modeled theoretically. Pronounced oscillations were observed indicating a coherent transfer mechanism. Spin coherences were excited by passing through an avoided level crossing of the nuclear spin energy levels. Transfer at avoided level crossings is selective with respect to spin order. Our work provides evidence that the coherent PHIP transfer mechanism is dominant at low magnetic fields.

Wednesday, October 16, 2013

Asymmetric Collapse in Biomimetic Complex Coacervates Revealed by Local Polymer and Water Dynamics

Ortony, J.H., et al., Asymmetric Collapse in Biomimetic Complex Coacervates Revealed by Local Polymer and Water Dynamics. Biomacromolecules, 2013. 14(5): p. 1395-1402.

Complex coacervation is a phenomenon characterized by the association of oppositely charged polyelectrolytes into micrometer-scale liquid condensates. This process is the purported first step in the formation of underwater adhesives by sessile marine organisms, as well as the process harnessed for the formation of new synthetic and protein-based contemporary materials. Efforts to understand the physical nature of complex coacervates are important for developing robust adhesives, injectable materials, or novel drug delivery vehicles for biomedical applications; however, their internal fluidity necessitates the use of in situ characterization strategies of their local dynamic properties, capabilities not offered by conventional techniques such as X-ray scattering, microscopy, or bulk rheological measurements. Herein, we employ the novel magnetic resonance technique Overhauser dynamic nuclear polarization enhanced nuclear magnetic resonance (DNP), together with electron paramagnetic resonance (EPR) line shape analysis, to concurrently quantify local molecular and hydration dynamics, with species- and site-specificity. We observe striking differences in the structure and dynamics of the protein-based biomimetic complex coacervates from their synthetic analogues, which is an asymmetric collapse of the polyelectrolyte constituents. From this study we suggest charge heterogeneity within a given polyelectrolyte chain to be an important parameter by which the internal structure of complex coacervates may be tuned. Acquiring molecular-level insight to the internal structure and dynamics of dynamic polymer complexes in water through the in situ characterization of site- and species-specific local polymer and hydration dynamics should be a promising general approach that has not been widely employed for materials characterization.

Monday, October 14, 2013

Computation of DNP coupling factors of a nitroxide radical in toluene: seamless combination of MD simulations and analytical calculations

Sezer, D., Computation of DNP coupling factors of a nitroxide radical in toluene: seamless combination of MD simulations and analytical calculations. Phys. Chem. Chem. Phys., 2013. 15(2): p. 526-540.

Dynamic nuclear polarization (DNP) employs paramagnetic species to increase the NMR signal of nuclear spins. In liquids, the efficiency of the effect depends on the strength of the interaction between the electron and nuclear spins and the time scales on which this interaction is modulated by the physical motion of the spin-bearing molecules. An approach to quantitatively predict the contribution of molecular motions to the DNP enhancement using molecular dynamics (MD) simulations is developed and illustrated for the nitroxide radical TEMPOL in liquid toluene. A multi-resolution strategy that combines explicit treatment of the solvent at short distances from the free radical with implicit description at large intermolecular distances is adopted. Novel analytical expressions are obtained to correct for the finite spatial extent of the MD simulations. The atomistic and analytical descriptions are sewn seamlessly together by ensuring that for molecular trajectories that start in the near (explicit) region and end in the distant (implicit) region the analytical dipolar spectral densities reproduce the MD estimates. The spectral densities obtained from the developed approach are used to calculate DNP coupling factors separately for the ring and methyl protons of toluene. The agreement with previously reported experimental DNP data at a magnetic field of 3.4 T is noteworthy and encouraging. Maximum obtainable DNP enhancements at other magnetic fields are predicted.

Friday, October 11, 2013

Optimal variable flip angle schemes for dynamic acquisition of exchanging hyperpolarized substrates

Xing, Y., et al., Optimal variable flip angle schemes for dynamic acquisition of exchanging hyperpolarized substrates. J. Magn. Reson., 2013. 234(0): p. 75-81.

In metabolic MRI with hyperpolarized contrast agents, the signal levels vary over time due to T1 decay, T2 decay following RF excitations, and metabolic conversion. Efficient usage of the nonrenewable hyperpolarized magnetization requires specialized RF pulse schemes. In this work, we introduce two novel variable flip angle schemes for dynamic hyperpolarized MRI in which the flip angle is varied between excitations and between metabolites. These were optimized to distribute the magnetization relatively evenly throughout the acquisition by accounting for T1 decay, prior RF excitations, and metabolic conversion. Simulation results are presented to confirm the flip angle designs and evaluate the variability of signal dynamics across typical ranges of T1 and metabolic conversion. They were implemented using multiband spectral-spatial RF pulses to independently modulate the flip angle at various chemical shift frequencies. With these schemes we observed increased SNR of [1-(13)C]lactate generated from [1-(13)C]pyruvate, particularly at later time points. This will allow for improved characterization of tissue perfusion and metabolic profiles in dynamic hyperpolarized MRI.

Wednesday, October 9, 2013

Nanoemulsion Contrast Agents with Sub-picomolar Sensitivity for Xenon NMR

Stevens, T.K., R.M. Ramirez, and A. Pines, Nanoemulsion Contrast Agents with Sub-picomolar Sensitivity for Xenon NMR. J. Am. Chem. Soc., 2013. 135(26): p. 9576-9579.

A new type of contrast agent for Xe NMR based on surfactant-stabilized perfluorocarbon-in-water nanoemulsions has been produced. The contrast agent uses dissolved hyperpolarized xenon gas as a nonperturbing reporting medium, as xenon freely exchanges between aqueous solution and the perfluorocarbon interior of the droplets, which are spectroscopically distinguishable and allow for chemical exchange saturation transfer (CEST) detection of the agent. Nanoemulsions with droplet diameters between 160 and 310 nm were produced and characterized using hyperpolarized 129Xe combined with CEST detection. Saturation parameters were varied and data were modeled numerically to determine the xenon exchange dynamics of the system. Nanoemulsion droplets were detected at concentrations as low as 100 fM, corresponding to <1 ?L of perfluorocarbon per liter of solution. The straightforward, inexpensive production of these agents will facilitate future development toward molecular imaging and chemical sensing applications.

Monday, October 7, 2013

Dynamic nuclear polarization of water by a nitroxide radical: rigorous treatment of the electron spin saturation and comparison with experiments at 9.2 Tesla

And another great article from 2009 that I missed.

Sezer, D., et al., Dynamic nuclear polarization of water by a nitroxide radical: rigorous treatment of the electron spin saturation and comparison with experiments at 9.2 Tesla. Phys. Chem. Chem. Phys., 2009. 11(31): p. 6638-6653.

The interaction between nuclear and electronic spins is of interest for structural characterization of biomolecules and biomedical imaging based on nuclear magnetic resonance. The polarization of the nuclear spins can be increased significantly if the electron spin polarization is kept out of equilibrium. We employ semiclassical relaxation theory to analyze the electronic polarization of the two-spin system characteristic of nitroxide radicals. Atomistic molecular dynamics simulations of the nitroxide TEMPOL in water are performed to account for the effects of tumbling and spin-rotation coupling on the spin-spin and spin-lattice relaxation times. Concentration effects on the electron saturation are introduced by allowing for Heisenberg spin exchange between two nitroxides. Polarization enhancement profiles, calculated from the computed saturation, are directly compared with liquid-state dynamic nuclear polarization experiments conducted at 260 GHz/400 MHz. The contribution of the separate hyperfine lines to the saturation can be easily disentangled using the developed formalism.

Friday, October 4, 2013

Site-specific dynamic nuclear polarization of hydration water as a generally applicable approach to monitor protein aggregation

This article was already published in 2009 but unfortunately I missed it.

Pavlova, A., et al., Site-specific dynamic nuclear polarization of hydration water as a generally applicable approach to monitor protein aggregation. Phys. Chem. Chem. Phys., 2009. 11(31): p. 6833-6839.

We present a generally applicable approach for monitoring protein aggregation by detecting changes in surface hydration water dynamics and the changes in solvent accessibility of specific protein sites, as protein aggregation proceeds in solution state. This is made possible through the Overhauser dynamic nuclear polarization (DNP) of water interacting with stable nitroxide spin labels tethered to specific proteins sites. This effect is highly localized due to the magnetic dipolar nature of the electron-proton spin interaction, with >80% of their interaction occurring within 5 A between the unpaired electron of the spin label and the proton of water. We showcase our tool on the aggregation of tau proteins, whose fibrillization is linked to neurodegenerative disease pathologies known as taupathies. We demonstrate that the DNP approach to monitor local changes in hydration dynamics with residue specificity and local contrast can distinguish specific and neat protein-protein packing leading to fibers from non-specific protein agglomeration or precipitation. The ability to monitor tau assembly with local, residue-specific, resolution, under ambient conditions and in solution state will help unravel the mechanism and structural characteristics of the gradual process of tau aggregation into amyloid fibers, which remains unclear to this day.

Wednesday, October 2, 2013

Matrix-free dynamic nuclear polarization enables solid-state NMR (13)C-(13)C correlation spectroscopy of proteins at natural isotopic abundance

Takahashi, H., S. Hediger, and G. De Paepe, Matrix-free dynamic nuclear polarization enables solid-state NMR (13)C-(13)C correlation spectroscopy of proteins at natural isotopic abundance. Chem Commun (Camb), 2013. 49(82): p. 9479-81.

We introduce a general approach for dynamic nuclear polarization (DNP) enhanced solid-state NMR that overcomes the current problems in DNP experiments caused by the use of frozen solutions. Notably, we report for the first time a 2D (13)C-(13)C correlation spectrum of a protein without the use of isotopic labeling.