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Long-lived states (LLSs) have lifetimes TLLS that can be much longer than longitudinal relaxation times T1. In molecules containing several geminal pairs of protons in neighboring CH2 groups, it has been shown that delocalized LLSs can be excited by converting magnetization into imbalances between the populations of singlet and triplet states of each pair. Since the empirical yield of the conversion and reconversion of observable magnetization into LLSs and back is on the order of 10 % if one uses spin-lock induced crossing (SLIC), it would be desirable to boost the sensitivity by dissolution dynamic nuclear polarization (d-DNP). To enhance the magnetization of nuclear spins by d-DNP, the analytes must be mixed with radicals such as 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL). After dissolution, these radicals lead to an undesirable paramagnetic relaxation enhancement (PRE) which shortens not only the longitudinal relaxation times T1 but also the lifetimes TLLS of LLSs. It is shown in this work that PRE by TEMPOL is less deleterious for LLSs than for longitudinal magnetization for four different molecules: 2,2-dimethyl-2-silapentane-5-sulfonate (DSS), homotaurine, taurine, and acetylcholine. The relaxivities rLLS (i.e., the slopes of the relaxation rate constants RLLS as a function of the radical concentration) are 3 to 5 times smaller than the relaxivities r1 of longitudinal magnetization. Partial delocalization of the LLSs across neighboring CH2 groups may decrease this advantage, but in practice, this effect was observed to be small, for example, when comparing taurine containing two CH2 groups and homotaurine with three CH2 groups. Regardless of whether the LLSs are delocalized or not, it is shown that PRE should not be a major problem for experiments combining d-DNP and LLSs, provided the concentration of paramagnetic species after dissolution does not exceed 1 mM, a condition that is readily fulfilled in typical d-DNP experiments. In bullet d-DNP experiments however, it may be necessary to decrease the concentration of TEMPOL or to add ascorbate for chemical reduction.

DNP cross-talk experiments in the thermal mixing regime provide energy transfer rates between the different reservoirs. The dependence of the kinetic parameters on the radical concentration and H/D ratio sheds light onto the nature of “hidden” spins.

In nuclear magnetic resonance (NMR), the lifetimes of long-lived states (LLSs) are exquisitely sensitive to their environment. However, the number of molecules where such states can be excited has hitherto been rather limited. Here, it is shown that LLSs can be readily excited in many common molecules that contain two or more neighboring CH 2 groups. Accessing such LLSs does not require any isotopic enrichment, nor does it require any stereogenic centers to lift the chemical equivalence of CH 2 protons. LLSs were excited in a variety of metabolites, neurotransmitters, vitamins, amino acids, and other molecules. One can excite LLSs in several different molecules simultaneously. In combination with magnetic resonance imaging, LLSs can reveal a contrast upon noncovalent binding of ligands to macromolecules. This suggests new perspectives to achieve high-throughput parallel drug screening by NMR.

This piece highlights the rich scientific legacy of Richard Ernst in the field of magnetic resonance, which encompasses studies of chemical exchange, Overhauser effects, cross-correlated relaxation, quantum computing, and phase encoding in magnetic resonance imaging.

Long-lived states (LLS) involving pairs of magnetically inequivalent but chemically equivalent proton spins in aliphatic (CH$_2$)$_n$ chains can be excited by simultaneous application of weak selective radio-frequency (RF) fields at n chemical shifts by polychromatic spin lock induced crossing (poly-SLIC). The LLS are delocalized throughout the aliphatic chain by mixing of intrapair singlet states and by excitation of LLS comprising products of four or six spins. The measured lifetimes T$_{LLS}$ in a model compound are about 5 times longer than T1, and are strongly affected by interactions with macromolecules.

Dissolution dynamic nuclear polarization (DDNP) is a versatile tool to boost signal amplitudes in solution-state nuclear magnetic resonance (NMR) spectroscopy. For DDNP, nuclei are spin-hyperpolarized "

In the course of 2019, a new open access journal called Magnetic Resonance was launched by the Groupement Ampère in Zurich. The journal is produced by a small publisher in Göttingen, Germany, that has gathered experience with a palette of journals run by the European Geosciences Union (EGU). The initial idea of Magnetic Resonance was to create a so-called “gold” open access journal: one can freely download all papers, including preliminary and revised versions, reviewers’ critiques and authors’ replies, while the authors’ institutions pay reasonable Article Processing Charges (APCs). The new journal is independent of learned societies like the Royal Society of Chemistry (RSC) and the American Chemical Society (ACS), and it is not exposed to profit-oriented business models of commercial publishers like RLX/Elsevier, Springer/Nature, Cell Press, and Wiley. After about 2 years, it seems appropriate to publish a few remarks about our experience of the strengths and weaknesses of open access publishing. Our discussion draws on a detailed analysis of the Ethics Committee of the French CNRS, and on a debate organized by the Royal Dutch Academy of Science.

International audience; Dipolar or quadrupolar echoes allow one to observe undistorted powder patterns, in contrast to simple Fourier transformations of free induction decays (FIDs). In this work, the build-up of proton polarization due to dynamic nuclear polarization (DNP) is monitored by observing echoes rather than FIDs. When the microwave irradiation is interrupted during the build-up of DNP, the electrons relax back to their Boltzmann distribution at high fields (B0 = 6.7 T) and low temperatures 1.2 < Tsample < 4.0 K, so that dipolar flip-flop-flip terms involving two electrons and one proton become largely ineffective as a mechanism of proton decoherence. This leads to a prolongation of the nuclear coherence lifetime T2'(1 H). The increase in T2'(1 H) leads to transient surges of the amplitudes of spin echoes. Conversely, transient slumps of spin echoes are observed when the microwave irradiation is switched back on, due to a shortening of nuclear coherence lifetimes.

Diffusion processes can be followed directly by recording one-dimensional images of a selected slice at variable intervals after selective inversion of the magnetization. The resulting diffusion coefficients of H

Protein and peptide interactions are characterized in the liquid state by multidimensional NMR spectroscopy experiments, which can take hours to record. We show that starting from hyperpolarized HDO, two-dimensional (2D) proton correlation maps of a peptide, either free in solution or interacting with liposomes, can be acquired in less than 60 s. In standard 2D NMR spectroscopy without hyperpolarization, the acquisition time required for similar spectral correlations is on the order of hours. This hyperpolarized experiment enables the identification of amino acids featuring solvent-interacting hydrogens and provides fast spectroscopic analysis of peptide conformers. Sensitivity-enhanced 2D proton correlation spectroscopy is a useful and straightforward tool for biochemistry and structural biology, as it does not recur to nitrogen-15 or carbon-13 isotope enrichment.

International audience; Water molecules trapped in crystals of barium chlorate monohydrate have been investigated by magic-angle spinning (MAS) proton NMR spectroscopy in the temperature range 110−300 K. At high temperatures, a single spinning sideband pattern is observed. Below 150 K, however, two interleaved spinning sideband manifolds appear, with distinct centerbands that do not coincide with the average isotropic chemical shift seen at high temperatures. This hitherto unknown "cross-term splitting" results from the interplay of the homonuclear dipole−dipole coupling and two anisotropic proton shielding tensors that have identical principal components but nonequivalent orientations. The resulting cross terms cannot be averaged out by rotation about the magic angle. The analysis of the exchange-induced broadening, coalescence, and narrowing of the cross-term splitting in MAS spectra allows one to estimate the rate of exchange of the two protons between 140 and 190 K. The experimental data is compared with 2 H and 1 H NMR studies of the same sample reported in the literature. Density functional theory methods are utilized to estimate the thermal activation energy for a 2-fold hopping process of proton exchange about the H− O−H bisector. The Bell−Limbach model allows one to take into account contributions due to incoherent quantum tunneling in the low-temperature regime.

Richard Ernst, professor at the Swiss Federal Institute of Technology in Zurich (ETH Zurich), Nobel laureate, and groundbreaking scientist, died on 4 June. He was 87. By working at the interfaces between chemistry, physics, and biology, Ernst opened the door to magnetic resonance of materials, proteins, and nucleic acids. His work on magnetic resonance imaging (MRI) revolutionized medical diagnosis. Born on 14 August 1933 and raised in Winterthur near Zurich, Switzerland, Ernst graduated with a diploma (BA) in chemistry from ETH Zurich, followed by a PhD from the same institution under the supervision of Hans Primas and Hans Gunthard. Except for a few years with Varian Associates in Palo Alto, California, he spent his entire career as a member of the ETH Zurich faculty. He had a rare talent for picking graduate students and postdoctoral associates, many of whom now hold faculty positions. In 1945, physicists Felix Bloch at Stanford University and Edward M. Purcell at Harvard University discovered nuclear magnetic resonance in bulk matter by observing very weak signals that emanate from the nuclei of atoms, which possess magnetization like the needle of a compass. Ernst transformed magnetic resonance from an academic curiosity into a universal tool by making it possible to observe all nuclei in a molecule or a human body simultaneously rather than sequentially. The resulting signals can be analyzed by Fourier transformation, a mathematical operation that retrieves with clarity all frequencies in seemingly inextricable signals. Ernst developed methods to unravel signals that overlap in several dimensions, to correlate frequencies of different nuclei in a molecule, and to separate different spatial dimensions in a body. Simultaneous observation of all nuclei drastically improved the sensitivity of magnetic resonance. Information-rich images that are generated allow researchers and radiologists to observe all magnetic nuclei in a molecule or human body. Ernst's breakthrough applies to work in a variety of fields. In biology, simultaneous observation of magnetic resonance signals allows the structure and dynamics of biomolecules such as proteins and nucleic acids (DNA or RNA) to be determined in solution as well as in microcrystals, fibrils, sediments, and other solids. Magnetic resonance not only circumvents the need for obtaining crystals for diffraction but also opens the way to the study of the flexibility and structural adaptability of biomolecules. In materials science, simultaneous observation of magnetic resonance signals has been exploited with great success in batteries, catalysts, polymers, and porous materials of all sorts, as improved sensitivity makes it possible to determine the arrangement of atoms and ions in space and their ability to move around. Ernst was honored as the sole recipient of the Nobel Prize in Chemistry in 1991, which coincided with the extravagantly celebrated 90th anniversary of the death of Alfred Nobel and the 700th anniversary of the Swiss Confederation. Upon his return to Switzerland from Stockholm, Ernst was celebrated like a national hero, with spectacular fireworks and many television and radio interviews. He had mixed feelings about his award and the related celebrations, as he was well aware that others had paved the way for his success: Paul Lauterbur and Peter Mansfield, who had made images of humans, and Weston Anderson, Jean Jeener, Ray Freeman, Kurt Wuthrich, and others, who had contributed to obtaining structures of molecules. Three of these scientists would be awarded Nobel Prizes in later years, but Ernst was disappointed that the others did not receive proper recognition. Ernst also received the Marcel Benoist Prize in Switzerland, the Wolf Prize in Israel, and the first of more than a dozen honorary doctorates from the Swiss Federal Institute of Technology in Lausanne. His autobiography, Nobelpreistrager aus Winterthur (Nobel laureate from Winterthur), richly illustrated with works of Tibetan art that he collected, was published in German in 2020. An English translation will be released soon. Ernst's influence went far beyond the field of physical chemistry. He was for many years one of the most cited Nobel laureates. As a guest speaker at universities around the world, especially after his retirement in 1998, he deftly associated science with other concerns, including Tibetan art and Buddhism. In his talks, he also expressed a biting criticism of university education, which he believed should focus on instilling a sense of responsibility beyond mere knowledge and technical skills, and he sharply denounced inequalities and injustice. His fiery speeches against the evils of US imperialism earned him the enmity of his critics. The richness of Ernst's career reflects the complexity of the man. Always on the lookout for new methods to probe the secrets of matter, he also sought to unravel the mysteries of music and art. Even though he had given up playing Bach's cello suites because “his fingers did not obey his ear,” he continued to study intricate works of 18th-century composers. He also explored the Buddhist painting schools of Tibetan monasteries as well as the pantheon of deities represented on thangkas that he ardently collected. I began working with Ernst as a postdoc in 1980. His support helped me earn the title of privatdozent before departing ETH Zurich in 1985. While there, I h elped him complete a book on the principles of nuclear magnetic resonance that took many years to write. Owing in large part to Ernst's demanding sense of breadth and farsighted vision, the book continues to be widely cited as a reference for practitioners of magnetic resonance, even decades after its publication. Along with his students and other collaborators, I appreciated Ernst's rigor, tinged with a certain stiffness; his incorruptible intransigence; and his oscillations between moods of arrogance and humility, forever unsatisfied and in search of balance. Like the spirits transmitted by reincarnation according to the Tibetan traditions that he admired so much, the spirit of this great scientist will undoubtedly enrich future generations.

A novel method dubbed ZULF-TOCSY results from the combination of Zero and Ultra-Low Field (ZULF) with high-field, high-resolution NMR, leading to a generalization of the concept of total correlation spectroscopy (TOCSY). ZULF-TOCSY is a new building block for NMR methods, which has the unique property that the polarization is evenly distributed among all NMR-active nuclei such as 1H, 13C, 15N, 31P, etc., provided that they belong to the same coupling network, and provided that their relaxation is not too fast at low fields, as may occur in macromolecules. Here, we show that ZULF-TOCSY correlations can be observed for peptides at natural isotopic abundance, such as the protected hexapeptide Boc-Met-enkephalin. The analysis of ZULF-TOCSY spectra readily allows one to make sequential assignments, thus offering an alternative to established heteronuclear 2D experiments like HMBC. For Boc-Met-enkephalin, we show that ZULF-TOCSY allows one to observe all expected cross-peaks between carbonyl carbons and α-CH protons, while the popular HMBC method provides insufficient information.

International audience; The 17 O resonances of Zirconium-oxo clusters that can be found in porous Zr carboxylate metal-organic frameworks (MOFs) have been investigated by magic-angle spinning (MAS) NMR spectroscopy enhanced by dynamic nuclear polarization (DNP). High-resolution 17 O spectra at 0.037 % natural abundance could be obtained in 48 hours, thanks to DNP enhancement of the 1 H polarization by factors   = S with /S without = 28, followed by 1 H 17 O cross-polarization, allowing a saving in experimental time by a factor of ca. 800. The distinct 17 O sites from the oxo-clusters can be resolved at 18.8 T. Their assignment is supported by density functional theory (DFT) calculations of chemical shifts and quadrupolar parameters. Protonation of 17 O sites seems to be leading to large characteristic shifts. Markedly, natural abundance 17 O NMR spectra of diamagnetic MOFs can thus be used to probe and characterize the local environment of different 17 O sites on an atomic scale.

SPatio-temporal ENcoding (SPEN) MRI is a non-Fourier imaging technique that encodes the spatial information in such a way that there is a one-to-one correspondence between the signal intensity as a function of time and the spin density at the corresponding position. In current spatio-temporal encoding methods imparting a quadratic phase – that is the phase of the transverse magnetization depends as a quadratic function of the spatial coordinates – onto the transverse magnetization is the first crucial step. Usually, this is achieved by simultaneous application of a frequency-swept (chirp) pulse and a linear magnetic field gradient. In this work, we show that it can be advantageous to use quadratic encoding gradients for this purpose. By avoiding chirp pulses one can achieve much smaller specific absorption rates (SARs), and shorter echo times (TEs), while the spatial resolution, the field of view (FOV), and the signal-to-noise ratio (SNR) are the same as in SPEN if one uses similar parameters. In addition, the proposed sequence can readily be used for multi-slice applications.

About a year after launching Magnetic Resonance it seems appropriate to publish a few editorial remarks about the strengths, weaknesses, opportunities, and threats of Open Access, motivated by an analysis of the Ethics Committee of the French CNRS and by a debate organized by the Royal Dutch Academy of Science.

A study of long-lived spin order in chlorothiophene carboxylates at both high and low magnetic fields is presented. Careful sample preparation (removal of dissolved oxygen in solution, chelating of paramagnetic impurities, reduction of convection) allows one to obtain very long-lived singlet order of the two coupled protons in chlorothiophene derivatives, having lifetimes of about 130 s in D2 O and 240 s in deuterated methanol, which are much longer than the T1 -relaxation times (18 and 30 s, respectively, at a field B 0 =9.4 T). In protonated solvents the relaxation times become shorter, but the lifetime is still substantially longer than T 1 . In addition, long-lived coherences are shown to have lifetimes as long as 30 s. Thiophene derivatives can be used as molecular tags to study slow transport, slow dynamics and slow chemical processes, as has been shown in recent years.

International audience; Dynamic nuclear polarization of samples at low temperatures, typically between 1.2 and 4.2 K, allows one to achieve spin temperatures of as low as 2 mK so that for many nuclear isotopes the high-temperature approximation is violated for the nuclear Zeeman interaction. This leads to characteristic asymmetries in powder spectra. We show that the line shapes due to the quadrupolar couplings of deuterium spins present in virtually all solvents used for such experiments (DNP juice) allow the quick yet accurate determination of the deuterium spin temperature or, equivalently, the deuterium polarization. The observation of quadrupolar echoes excited by small flip-angle pulses allows one to monitor the build-up and decay of the positive or negative deuterium polarization.

Signal enhancements of up to two orders of magnitude in protein NMR can be achieved by employing HDO as a vector to introduce hyperpolarization into folded or intrinsically disordered proteins. In this approach, hyperpolarized HDO produced by dissolution-dynamic nuclear polarization (D-DNP) is mixed with a protein solution waiting in a high-field NMR spectrometer, whereupon amide proton exchange and nuclear Overhauser effects (NOE) transfer hyperpolarization to the protein and enable acquisition of a signal-enhanced high-resolution spectrum. To date, the use of this strategy has been limited to 1D and 1H-15N 2D correlation experiments. Here we introduce 2D 13C-detected D-DNP, to reduce exchange-induced broadening and other relaxation penalties that can adversely affect proton-detected D-DNP experiments. We also introduce hyperpolarized 3D spectroscopy, opening the possibility of D-DNP studies of larger proteins and IDPs, where assignment and residue-specific investigation may be impeded by spectral crowding. The signal enhancements obtained depend in particular on the rates of chemical and magnetic exchange of the observed residues, thus resulting in non-uniform ‘hyperpolarization-selective’ signal enhancements. The resulting spectral sparsity, however, makes it possible to resolve and monitor individual amino acids in IDPs of over 200 residues at acquisition times of just over a minute. We apply the proposed experiments to two model systems: the compactly folded protein ubiquitin, and the intrinsically disordered protein (IDP) osteopontin (OPN). Electronic supplementary material The online version of this article (10.1007/s10858-020-00301-5) contains supplementary material, which is available to authorized users.

International audience; The isomerisation of 6-phosphogluconolactones and their hydrolyses into 6-phosphogluconic acid form a non enzymatic side cycle of the pentose-phosphate pathway (PPP) in cells. We show that dissolution dynamic nuclear polarization can be used for determining the kinetic rates of the involved transformations in real time. It is found that the hydrolysis of both lactones is significantly slower than the isomeration process, thereby shedding new light onto this subtle chemical process.

International audience; Dynamic nuclear polarization (DNP) embraces a family of methods to increase signal intensities in nuclear magnetic resonance (NMR) spectroscopy. Despite extensive theoretical work that allows one to distinguish at least five distinct mechanisms, it remains challenging to determine the relative weights of the processes that are responsible for DNP in state-of-the-art experiments operating with stable organic radicals like nitroxides at high magnetic fields and low temperatures. Specifically, determining experimental conditions where DNP involves thermal mixing, which denotes a spontaneous heat exchange between different spin reservoirs, remains challenging. We propose an experimental approach to ascertain the prevalence of the thermal mixing regime by monitoring characteristic signature properties of the time evolution of the hyperpolarization. We find that thermal mixing is the dominant DNP mechanism at high nitroxide radical concentrations, while a mixture of different mechanisms prevails at lower concentrations.

The authors thank Lyndon Emsley for making means available.; International audience; We have induced hyperpolarized long-lived states in compounds containing C-13-bearing methyl groups by dynamic nuclear polarization (DNP) at cryogenic temperatures, followed by dissolution with a warm solvent. The hyper polarized methyl long-lived states give rise to enhanced antiphase C-13 NMR signals in solution, which often persist for times much longer than the C-13 and H-1 spin-lattice relaxation times under the same conditions. The DNP-induced effects are similar to quantum-rotor-induced polarization (QRIP) but are observed in a wider range of compounds because they do not depend critically on the height of the rotational barrier. We interpret our observations with a model in which nuclear Zeeman and methyl tunnelling reservoirs adopt an approximately uniform temperature, under DNP conditions. The generation of hyperpolarized NMR signals that persist for relatively long times in a range of methyl-bearing substances may be important for applications such as investigations of metabolism, enzymatic reactions, protein ligand binding, drug screening, and molecular imaging.

International audience; Total correlation spectroscopy (TOCSY) is a key experiment to assign nuclear magnetic resonance (NMR) spectra of complex molecules. Carbon-13 TOCSY experiments are essential to assign signals of protein side chains. However, the performance of carbon-13 TOCSY deteriorates at high magnetic fields since the necessarily limited radiofrequency irradiation fails to cover the broad range of carbon-13 frequencies. Here, we introduce a new concept to overcome the limitations of TOCSY by using two-field NMR spectroscopy. In two-field TOCSY experiments, chemical shifts are labelled at high field but isotropic mixing is performed at a much lower magnetic field, where the frequency range of the spectrum is drastically reduced. We obtain complete correlations between all carbon-13 nuclei belonging to amino acids across the entire spectrum: aromatic, aliphatic and carboxylic. Two-field TOCSY should be a robust and general approach for the assignment of uniformly carbon-13 labelled molecules in high-field and ultra-high field NMR spectrometers beyond 1000 MHz.

Coherent superpositions between nuclear singlet and triplet spin states of pairs of J-coupled nuclei in high magnetic fields can be excited and sustained by oscillating radio-frequency (rf) radiation. The relaxation time constants of these ‘long-lived coherences’ can be up to nine times longer than those of allowed single-quantum coherences. We detail herein the development and early applications of long-lived coherences.

International audience; The longitudinal spin–lattice relaxation properties of water molecules trapped in a static powdered polycrystalline sample of barium chlorate monohydrate are investigated by means of solid-state 1H NMR spectroscopy. Different portions of the inhomogeneous Pake pattern that are associated with crystallites at different orientations with respect to the external magnetic field show either a mono- or a biexponential recovery. At high field (9.4 T), the chemical shift anisotropy is the main interaction that is responsible for the inhomogeneity of the relaxation rates. A theoretical description of rapid two-site hopping about the H–O–H bisector in the framework of Liouville space agrees very well with the experimental evidence. Numerical simulations predict a distribution of monoexponential time constants associated with individual single-crystal orientations. Overlapping signals give rise to biexponential recovery. This is confirmed experimentally by 1H NMR spectra of static single crystals.

International audience; We introduce a method for the detection of weak interactions of small molecules such as metabolites or medicaments that contain deuterated methyl groups with proteins in solution. The technique relies on long-lived imbalances of spin state populations, which are generated by dissolution dynamic nuclear polarization (D-DNP) and feature lifetimes that depend on the frequency of internal rotation of deuterated methyl groups. We demonstrate the technique for interactions between deuterated dimethyl sulfoxide (DMSO-d6) and bovine serum albumin (BSA) or trypsin, where the methyl group rotation is slowed down upon protein binding, which causes a marked reduction in the lifetime of the population imbalances.

To overcome the effects of static field inhomogeneities, single-scan hybrid imaging techniques that use k-space encoding in one direction and spatial encoding in the other have been shown to be superior to traditional imaging techniques based on full k-space encoding. Like traditional imaging methods, hybrid methods can be implemented in different ways that favor different sources of contrast. So far, little attention appears to have been paid to these aspects. By modifying an established hybrid imaging sequence called Rapid Acquisition by Sequential Excitation and Refocusing (RASER) so as to obtain Echo-Shifted RASER sequences, we show that by shifting spin echoes one can tune the contrast due to inhomogeneous T decay.