Monday, November 28, 2016

Dissolution Dynamic Nuclear Polarization capability study with fluid path


Malinowski, R.M., et al., Dissolution Dynamic Nuclear Polarization capability study with fluid path. J Magn Reson, 2016. 272: p. 141-146.


Signal enhancement by hyperpolarization is a way of overcoming the low sensitivity in magnetic resonance; MRI in particular. One of the most well-known methods, dissolution Dynamic Nuclear Polarization, has been used clinically in cancer patients. One way of ensuring a low bioburden of the hyperpolarized product is by use of a closed fluid path that constitutes a barrier to contamination. The fluid path can be filled with the pharmaceuticals, i.e. imaging agent and solvents, in a clean room, and then stored or immediately used at the polarizer. In this study, we present a method of filling the fluid path that allows it to be reused. The filling method has been investigated in terms of reproducibility at two extrema, high dose for patient use and low dose for rodent studies, using [1-13C]pyruvate as example. We demonstrate that the filling method allows high reproducibility of six quality control parameters with standard deviations 3-10 times smaller than the acceptance criteria intervals in clinical studies.

Friday, November 25, 2016

Cross relaxation in nitroxide spin labels


Marsh, D., Cross relaxation in nitroxide spin labels. J Magn Reson, 2016. 272: p. 172-180.


Cross relaxation, and mI-dependence of the intrinsic electron spin-lattice relaxation rate We, are incorporated explicitly into the rate equations for the electron-spin population differences that govern the saturation behaviour of 14N- and 15N-nitroxide spin labels. Both prove important in spin-label EPR and ELDOR, particularly for saturation recovery studies. Neither for saturation recovery, nor for CW-saturation EPR and CW-ELDOR, can cross relaxation be described simply by increasing the value of We, the intrinsic spin-lattice relaxation rate. Independence of the saturation recovery rates from the hyperfine line pumped or observed follows directly from solution of the rate equations including cross relaxation, even when the intrinsic spin-lattice relaxation rate We is mI-dependent.

Wednesday, November 23, 2016

Reaction monitoring using hyperpolarized NMR with scaling of heteronuclear couplings by optimal tracking


Zhang, G., et al., Reaction monitoring using hyperpolarized NMR with scaling of heteronuclear couplings by optimal tracking. J Magn Reson, 2016. 272: p. 123-128.


Off-resonance decoupling using the method of Scaling of Heteronuclear Couplings by Optimal Tracking (SHOT) enables determination of heteronuclear correlations of chemical shifts in single scan NMR spectra. Through modulation of J-coupling evolution by shaped radio frequency pulses, off resonance decoupling using SHOT pulses causes a user-defined dependence of the observed J-splitting, such as the splitting of 13C peaks, on the chemical shift offset of coupled nuclei, such as 1H. Because a decoupling experiment requires only a single scan, this method is suitable for characterizing on-going chemical reactions using hyperpolarization by dissolution dynamic nuclear polarization (D-DNP). We demonstrate the calculation of [13C, 1H] chemical shift correlations of the carbanionic active sites from hyperpolarized styrene polymerized using sodium naphthalene as an initiator. While off resonance decoupling by SHOT pulses does not enhance the resolution in the same way as a 2D NMR spectrum would, the ability to obtain the correlations in single scans makes this method ideal for determination of chemical shifts in on-going reactions on the second time scale. In addition, we present a novel SHOT pulse that allows to scale J-splittings 50% larger than the respective J-coupling constant. This feature can be used to enhance the resolution of the indirectly detected chemical shift and reduce peak overlap, as demonstrated in a model reaction between p-anisaldehyde and isobutylamine. For both pulses, the accuracy is evaluated under changing signal-to-noise ratios (SNR) of the peaks from reactants and reaction products, with an overall standard deviation of chemical shift differences compared to reference spectra of 0.02ppm when measured on a 400MHz NMR spectrometer. Notably, the appearance of decoupling side-bands, which scale with peak intensity, appears to be of secondary importance.

Monday, November 21, 2016

Theory of solid effect and cross effect dynamic nuclear polarization with half-integer high-spin metal polarizing agents in rotating solids #DNPNMR


Corzilius, B., Theory of solid effect and cross effect dynamic nuclear polarization with half-integer high-spin metal polarizing agents in rotating solids. Phys. Chem. Chem. Phys., 2016. 18(39): p. 27190-27204.


Dynamic nuclear polarization (DNP) is a powerful method to enhance sensitivity especially of solid-state magic-angle spinning (MAS) NMR by up to several orders of magnitude. The increased interest both from a practical as well as theoretical viewpoint has spawned several fields of active research such as the development of new polarizing agents with improved or unique properties and description of the underlying DNP mechanisms such as solid effect (SE) and cross effect (CE). Even though a novel class of unique polarizing agents based on high-spin metal ions such as Gd(iii) and Mn(ii) has already been utilized for MAS DNP a theoretical description of the involved DNP mechanism is still incomplete. Here, we review several aspects of DNP-relevant electron-paramagnetic resonance (EPR) properties of the general class of these half-integer high-spin metal ions with isotropic Zeeman interaction but significant zero-field splitting (ZFS). While the SE can be relatively easily described similar to that of a S = 1/2 system and is assumed to be effective only for polarizing agents featuring a narrow central EPR transitions (i.e., mS = -1/2 [rightward arrow] +1/2) with respect to the nuclear Larmor frequency, the CE between two high-spin ions requires a more detailed theoretical investigation due to a multitude of possible transitions and matching conditions. This is especially interesting in light of recent understanding of CE being induced by MAS-driven level anti-crossings (LACs) between dipolar-coupled electron spins. We discuss the requirements of such CE-enabling LACs to occur due to anisotropy of ZFS, the expected adiabaticity, and the resulting possibilities of high-spin metal ion pairs to act as polarizing agents for DNP. This theoretical description serves as a framework for a detailed experimental study published directly following this work.

Friday, November 18, 2016

Following Metabolism in Living Microorganisms by Hyperpolarized (1)H NMR


Dzien, P., et al., Following Metabolism in Living Microorganisms by Hyperpolarized (1)H NMR. J Am Chem Soc, 2016. 138(37): p. 12278-86.


Dissolution dynamic nuclear polarization (dDNP) is used to enhance the sensitivity of nuclear magnetic resonance (NMR), enabling monitoring of metabolism and specific enzymatic reactions in vivo. dDNP involves rapid sample dissolution and transfer to a spectrometer/scanner for subsequent signal detection. So far, most biologically oriented dDNP studies have relied on hyperpolarizing long-lived nuclear spin species such as (13)C in small molecules. While advantages could also arise from observing hyperpolarized (1)H, short relaxation times limit the utility of prepolarizing this sensitive but fast relaxing nucleus. Recently, it has been reported that (1)H NMR peaks in solution-phase experiments could be hyperpolarized by spontaneous magnetization transfers from bound (13)C nuclei following dDNP. This work demonstrates the potential of this sensitivity-enhancing approach to probe the enzymatic process that could not be suitably resolved by (13)C dDNP MR. Here we measured, in microorganisms, the action of pyruvate decarboxylase (PDC) and pyruvate formate lyase (PFL)-enzymes that catalyze the decarboxylation of pyruvate to form acetaldehyde and formate, respectively. While (13)C NMR did not possess the resolution to distinguish the starting pyruvate precursor from the carbonyl resonances in the resulting products, these processes could be monitored by (1)H NMR at 500 MHz. These observations were possible in both yeast and bacteria in minute-long kinetic measurements where the hyperpolarized (13)C enhanced, via (13)C --> (1)H cross-relaxation, the signals of protons binding to the (13)C over the course of enzymatic reactions. In addition to these spontaneous heteronuclear enhancement experiments, single-shot acquisitions based on J-driven (13)C --> (1)H polarization transfers were also carried out. These resulted in higher signal enhancements of the (1)H resonances but were not suitable for multishot kinetic studies. The potential of these (1)H-based approaches for measurements in vivo is briefly discussed.

Wednesday, November 16, 2016

Phenylazide Hybrid-Silica - Polarization Platform for Dynamic Nuclear Polarization at Cryogenic Temperatures #DNPNMR


Grüning, W.R., et al., Phenylazide Hybrid-Silica - Polarization Platform for Dynamic Nuclear Polarization at Cryogenic Temperatures. Helvetica Chimica Acta, 2016: p. n/a-n/a.


Hyperpolarization of NMR-active nuclei is key to gather high quality spectra of rare species and insensitive isotopes. We have recently established that silica-based materials containing regularly distributed nitroxyl radicals connected to the silica matrix by flexible linkers can serve as promising polarization matrices in DNP. Here we investigate the influence of the linker on the efficiency of the polarization. The materials were fully characterized and exhibit high surface areas and narrow pore size distributions with a tunable amount of phenyl azide groups over a broad range of concentrations. The phenyl azide groups can be easily functionalized via a two-step procedure into 4-carboxy-2,2,6,6-tetramethyl-1-oxyl-piperidine (TEMPO) to give polarizing matrices with controllable radical content. The DNP efficiency was found to be similar as in materials with flexible linkers, both for MAS at 105 K and dissolution DNP at 4 K. This article is protected by copyright. All rights reserved.

Monday, November 14, 2016

Open Position at Bridge12: Scientist - Magnetic Resonance #DNPNMR

Bridge12 has an open position for a Scientist - Magnetic Resonance.



Open Position: Scientist - Magnetic Resonance Spectroscopy


Bridge12 is a small business focused on the development of cutting-edge microwave and terahertz (THz) instrumentation for use in scientific research such as Nuclear Magnetic Resonance (NMR), Electron Paramagnetic Resonance (EPR) and Dynamic Nuclear Polarization (DNP) spectroscopy. The company has a worldwide customer base and conducts groundbreaking research on applications of microwave/THz radiation in novel fields, often in collaboration with leading academic institutes.

Position Overview

As a scientist at Bridge12, you will work on multidisciplinary projects covering large aspects of magnetic resonance, instrumentation design, development of prototypes and conduct research. The position requires creativity in a wide range of areas of magnetic resonance spectroscopy including NMR and EPR spectroscopy, imaging, and instrument development. We are looking for a highly motivated, highly organized individual who enjoys an innovative, interdisciplinary environment and the challenges that come with the manufacturing of high-tech, scientific instrumentation. You will work out of the Bridge12 facilities in Framingham, MA with only occasional travel (conferences, tradeshows etc.).

Responsibilities

  • Instrument development with a strong focus on Magnetic Resonance Spectroscopy (NMR, EPR, DNP, MRI). This includes the electrical and mechanical design and fabrication of NMR, EPR and DNP probes. Design of passive microwave/THz components (e.g. transmission lines, mirrors, bends, quasi-optical components) and the design of RF circuits
  • Design and conduct research to support product development
Required Skills & Experience
  • In-depth understanding of the principles of magnetic resonance spectroscopy with a strong emphasis on NMR and EPR spectroscopy
  • Experience in performing solution-state and solid-state NMR experiments, preferably on an Agilent/Varian spectrometer running VnmrJ
  • Experience in performing electromagnetic simulations for RF and microwave/THz circuits using finite element analysis tools (e.g. Ansys HFSS and Maxwell)
  • In-depth knowledge of LabVIEW and Matlab
  • Experience with 3D CAD tools for mechanical design such as Autodesk Inventor
  • Excellent verbal and written communication skills and good teamwork ethics
  • Printed Circuit Board design and prototyping (advantage)
  • Experience in designing cryogenic instrumentation (advantage)

Qualification: ​Ph.D. degree in chemistry, chemical engineering, physical chemistry, physics or equivalent or Master degree and at least 3 years of professional experience.

This is a full-time position. Bridge12 is an equal opportunity employer, and offers a competitive compensation package with excellent benefits and healthcare. In compliance with federal law, all persons hired will be required to verify identity and eligibility to work in the United States and to complete the required employment eligibility verification document form upon hire.

Please email your Resume or CV together with a cover letter to: careers@bridge12.com.


You can also find the job posting by visiting our website.

Simultaneous PET/MRI with (13)C magnetic resonance spectroscopic imaging (hyperPET): phantom-based evaluation of PET quantification


Hansen, A.E., et al., Simultaneous PET/MRI with (13)C magnetic resonance spectroscopic imaging (hyperPET): phantom-based evaluation of PET quantification. EJNMMI Phys, 2016. 3(1): p. 7.


BACKGROUND: Integrated PET/MRI with hyperpolarized (13)C magnetic resonance spectroscopic imaging ((13)C-MRSI) offers simultaneous, dual-modality metabolic imaging. A prerequisite for the use of simultaneous imaging is the absence of interference between the two modalities. This has been documented for a clinical whole-body system using simultaneous (1)H-MRI and PET but never for (13)C-MRSI and PET. Here, the feasibility of simultaneous PET and (13)C-MRSI as well as hyperpolarized (13)C-MRSI in an integrated whole-body PET/MRI hybrid scanner is evaluated using phantom experiments. METHODS: Combined PET and (13)C-MRSI phantoms including a NEMA [(18)F]-FDG phantom, (13)C-acetate and (13)C-urea sources, and hyperpolarized (13)C-pyruvate were imaged repeatedly with PET and/or (13)C-MRSI. Measurements evaluated for interference effects included PET activity values in the largest sphere and a background region; total number of PET trues; and (13)C-MRSI signal-to-noise ratio (SNR) for urea and acetate phantoms. Differences between measurement conditions were evaluated using t tests. RESULTS: PET and (13)C-MRSI data acquisition could be performed simultaneously without any discernible artifacts. The average difference in PET activity between acquisitions with and without simultaneous (13)C-MRSI was 0.83 (largest sphere) and -0.76 % (background). The average difference in net trues was -0.01 %. The average difference in (13)C-MRSI SNR between acquisitions with and without simultaneous PET ranged from -2.28 to 1.21 % for all phantoms and measurement conditions. No differences were significant. The system was capable of (13)C-MRSI of hyperpolarized (13)C-pyruvate. CONCLUSIONS: Simultaneous PET and (13)C-MRSI in an integrated whole-body PET/MRI hybrid scanner is feasible. Phantom experiments showed that possible interference effects introduced by acquiring data from the two modalities simultaneously are small and non-significant. Further experiments can now investigate the benefits of simultaneous PET and hyperpolarized (13)C-MRI in vivo studies.

Friday, November 11, 2016

35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients #DNPNMR


Hirsh, D.A., et al., 35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients. Phys Chem Chem Phys, 2016. 18(37): p. 25893-25904.


In this work, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced 35Cl solid-state NMR (SSNMR) spectra at 9.4 T and demonstrate how they can be used to characterize the molecular-level structure of hydrochloride salts of active pharmaceutical ingredients (APIs) in both bulk and low wt% API dosage forms. 35Cl SSNMR central-transition powder patterns of chloride ions are typically tens to hundreds of kHz in breadth, and most cannot be excited uniformly with high-power rectangular pulses or acquired under conditions of magic-angle spinning (MAS). Herein, we demonstrate the combination of DNP and 1H-35Cl broadband adiabatic inversion cross polarization (BRAIN-CP) experiments for the acquisition of high quality wideline spectra of APIs under static sample conditions, and obtain signals up to 50 times greater than in spectra acquired without the use of DNP at 100 K. We report a new protocol, called spinning-on spinning-off (SOSO) acquisition, where MAS is applied during part of the polarization delay to increase the DNP enhancements and then the MAS rotation is stopped so that a wideline 35Cl NMR powder pattern free from the effects of spinning sidebands can be acquired under static conditions. This method provides an additional two-fold signal enhancement compared to DNP-enhanced SSNMR spectra acquired under purely static conditions. DNP-enhanced 35Cl experiments are used to characterize APIs in bulk and dosage forms with Cl contents as low as 0.45 wt%. These results are compared to DNP-enhanced 1H-13C CP/MAS spectra of APIs in dosage forms, which are often hindered by interfering signals arising from the binders, fillers and other excipient materials.

Wednesday, November 9, 2016

Selective High-Resolution Detection of Membrane Protein-Ligand Interaction in Native Membranes Using Trityl-Nitroxide PELDOR


Joseph, B., et al., Selective High-Resolution Detection of Membrane Protein-Ligand Interaction in Native Membranes Using Trityl-Nitroxide PELDOR. Angew Chem Int Ed Engl, 2016. 55(38): p. 11538-42.


The orchestrated interaction of transmembrane proteins with other molecules mediates several crucial biological processes. Detergent solubilization may significantly alter or even abolish such hetero-oligomeric interactions, which makes observing them at high resolution in their native environment technically challenging. Dipolar electron paramagnetic resonance (EPR) techniques such as pulsed electro-electron double resonance (PELDOR) can provide very precise distances within biomolecules. To concurrently determine the inter-subunit interaction and the intra-subunit conformational changes in hetero-oligomeric complexes, a combination of different spin labels is required. Orthogonal spin labeling using a triarylmethyl (TAM) label in combination with a nitroxide label is used to detect protein-ligand interactions in native lipid bilayers. This approach provides a higher sensitivity and total selectivity and will greatly facilitate the investigation of multimeric transmembrane complexes employing different spin labels in the native lipid environment.

Tuesday, November 8, 2016

[NMR] Symposium in Honor of Prof. Jacob Schaefer - Jan. 6, 2017

From the Ampere Magnetic Resonance List


Could you please announce: at Washington University we are holding a special symposium in Jake Schaefer’s honor—after the release of a special issue of the Elsevier journal, Solid State Nuclear Magnetic Resonance, in his honor, to celebrate the developments of CPMAS and REDOR. 

Symposium in Honor of Jacob Schaefer

Date: Friday Jan. 6, 2017
Location: Chemistry Department, Washington University, St. Louis
Website for more information: https://sites.google.com/site/stlnmrdg/

Confirmed Speakers

Alexander Barnes, Washington University
Technology for Electron Decoupling and Pulsed DNP in Rotating Solids

Lynette Cegelski, Stanford University
CPMAS and REDOR: Bugs, Films, and Leaves

Hellmut Eckert, WWU Muenster, Germany
Inspired by Rochester 1988: Using REDOR for Structural Studies of Inorganic Glasses

Joel Garbow, Washington University School of Medicine
Monsanto to Washington University: Tales of a Schaefer Post-doc

Terry Gullion, West Virginia University
Some Recollections of REDOR and Some Observations of Peptides on Gold Nanoparticles

Joon Kim, Baylor University
How mosquitoes and algae get fat: carbon metabolic fluxes by solid-state NMR

Matt Merritt, Univ. of Florida, Gainesville
Paths Less Traveled: Using NMR to Understand Metabolism

Gary Patti, Washington University
Metabolic Anachronisms from Jake Schaefer's 1985 Lab Notebook

Ayyalusamy Ramamoorthy, Univ. of Michigan
Dynamic Structural Interactions between Membrane-Bound Cytochrome-P450 and Redox Partners by NMR

Asher Schmidt, Technion University, Israel
Bominerals interfaces and mesoporous materials surfaces: the molecular REDOR eyes expose mechanistic pathways in functional materials.

David Weliky, Michigan State University
Solid-State NMR of Viral Fusion Proteins


Sophia E. Hayes
Professor, Department of Chemistry, Washington University, 1 Brookings Dr., St. Louis, MO 63130
Office location: 407 McMillen Lab Bldg.
(314) 935-4624

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Monday, November 7, 2016

Gyrotrons for High-Power Terahertz Science and Technology at FIR UF #DNPNMR


Idehara, T. and S.P. Sabchevski, Gyrotrons for High-Power Terahertz Science and Technology at FIR UF. J Infrared Milli Terahz Waves, 2016: p. 1-25.


In this review paper, we present the recent progress in the development of a series of gyrotrons at the Research Center for Development of Far-Infrared Region, University of Fukui, that have opened the road to many novel applications in the high-power terahertz science and technology. The current status of the research in this actively developing field is illustrated by the most representative examples in which the developed gyrotrons are used as powerful and frequency-tunable sources of coherent radiation operating in a continuous-wave regime. Among them are high-precision spectroscopic techniques (most notably dynamic nuclear polarization-nuclear magnetic resonance, electron spin resonance, X-ray detected magnetic resonance, and studies of the hyperfine splitting of the energy levels of positronium), treatment and characterization of advanced materials, and new medical technologies.

Friday, November 4, 2016

Difference between Extra- and IntracellularT1Values of Carboxylic Acids Affects the Quantitative Analysis of Cellular Kinetics by Hyperpolarized NMR


Karlsson, M., et al., Difference between Extra- and IntracellularT1Values of Carboxylic Acids Affects the Quantitative Analysis of Cellular Kinetics by Hyperpolarized NMR. Angewandte Chemie, 2016. 128(43): p. 13765-13768.


Incomplete knowledge of the longitudinal relaxation time constant (T1) leads to incorrect assumptions in quantitative kinetic models of cellular systems, studied by hyperpolarized real-time NMR. Using an assay that measures the intracellular signal of small carboxylic acids in living cells, the intracellular T1 of the carboxylic acid moiety of acetate, keto-isocaproate, pyruvate, and butyrate was determined. The intracellular T1 is shown to be up to four-fold shorter than the extracellular T1. Such a large difference in T1 values between the inside and the outside of the cell has significant influence on the quantification of intracellular metabolic activity. It is expected that the significantly shorter T1 value of the carboxylic moieties inside cells is a result of macromolecular crowding. An artificial cytosol has been prepared and applied to predict the T1 of other carboxylic acids. We demonstrate the value of this prediction tool.

Wednesday, November 2, 2016

Gd(iii) and Mn(ii) complexes for dynamic nuclear polarization: small molecular chelate polarizing agents and applications with site-directed spin labeling of proteins #DNPNMR


Kaushik, M., et al., Gd(iii) and Mn(ii) complexes for dynamic nuclear polarization: small molecular chelate polarizing agents and applications with site-directed spin labeling of proteins. Phys Chem Chem Phys, 2016. 18(39): p. 27205-27218.


We investigate complexes of two paramagnetic metal ions Gd3+ and Mn2+ to serve as polarizing agents for solid-state dynamic nuclear polarization (DNP) of 1H, 13C, and 15N at magnetic fields of 5, 9.4, and 14.1 T. Both ions are half-integer high-spin systems with a zero-field splitting and therefore exhibit a broadening of the mS = -1/2 <--> +1/2 central transition which scales inversely with the external field strength. We investigate experimentally the influence of the chelator molecule, strong hyperfine coupling to the metal nucleus, and deuteration of the bulk matrix on DNP properties. At small Gd-DOTA concentrations the narrow central transition allows us to polarize nuclei with small gyromagnetic ratio such as 13C and even 15N via the solid effect. We demonstrate that enhancements observed are limited by the available microwave power and that large enhancement factors of >100 (for 1H) and on the order of 1000 (for 13C) can be achieved in the saturation limit even at 80 K. At larger Gd(iii) concentrations (>/=10 mM) where dipolar couplings between two neighboring Gd3+ complexes become substantial a transition towards cross effect as dominating DNP mechanism is observed. Furthermore, the slow spin-diffusion between 13C and 15N, respectively, allows for temporally resolved observation of enhanced polarization spreading from nuclei close to the paramagnetic ion towards nuclei further removed. Subsequently, we present preliminary DNP experiments on ubiquitin by site-directed spin-labeling with Gd3+ chelator tags. The results hold promise towards applications of such paramagnetically labeled proteins for DNP applications in biophysical chemistry and/or structural biology.