Water Proton Research Articles

Cover Feature: Harnessing Water to Enhance Quadrupolar NMR Spectroscopy and Imaging (Chem. Eur. J. 58/2022)

17O and 14N are attractive targets for in vivo NMR spectroscopy and imaging, but low gyromagnetic ratios and fast spin relaxation complicate their observations. In their Research Article (DOI: 10.1002/chem.202201490), R. P. Martinho and L. Frydman explore indirect ways for detecting these sites with the help of proton detection, amplified by chemical exchanges with the abundant water 1H signal. These amplifications are mediated by spontaneous exchanges that the labile 1Hs bound to 17O or 14N undergo with the water protons, opening new avenues in spectroscopic MRI.

Advanced Proton-Conducting Ceramics Based on Layered Perovskite BaLaInO4 for Energy Conversion Technologies and Devices.

Production of high efficiency renewable energy source for sustainable global development is an important challenge for humans. Hydrogen energy systems are one of the key elements for the development of sustainable energy future. These systems are eco-friendly and include devices such as protonic ceramic fuel cells, which require advanced proton-conducting materials. In this study, we focused on new ceramics with significantly improved target properties for hydrogen energy purposes. Neodymium-doped phase based on layered perovskite BaLaInO4 was obtained for the first time. The ability for water intercalation and proton transport was proved. It was shown that the composition BaLa0.9Nd0.1InO4 is the predominant proton conductor below 400 °C under wet air. Moreover, isovalent doping of layered perovskites AA′BO4 is the promising method for improving transport properties and obtaining novel advanced proton-conducting ceramic materials.

ATP-dependent polymerization dynamics of bacterial actin proteins involved in Spiroplasma swimming.

MreB is a bacterial protein belonging to the actin superfamily. This protein polymerizes into an antiparallel double-stranded filament that determines cell shape by maintaining cell wall synthesis. <i>Spiroplasma eriocheiris</i>, a helical wall-less bacterium, has five MreB homologous (SpeMreB1-5) that probably contribute to swimming motility. Here, we investigated the structure, ATPase activity and polymerization dynamics of SpeMreB3 and SpeMreB5. SpeMreB3 polymerized into a double-stranded filament with possible antiparallel polarity, while SpeMreB5 formed sheets which contained the antiparallel filament, upon nucleotide binding. SpeMreB3 showed slow P_i release owing to the lack of an amino acid motif conserved in the catalytic centre of MreB family proteins. Our SpeMreB3 crystal structures and analyses of SpeMreB3 and SpeMreB5 variants showed that the amino acid motif probably plays a role in eliminating a nucleophilic water proton during ATP hydrolysis. Sedimentation assays suggest that SpeMreB3 has a lower polymerization activity than SpeMreB5, though their polymerization dynamics are qualitatively similar to those of other actin superfamily proteins, in which pre-ATP hydrolysis and post-P_i release states are unfavourable for them to remain as filaments.

직접메탄올 연료전지를 위한 Poly(vinyl alcohol-co-styrenesulfonic acid) 기반의 양성자 교환막의 제법 및 특성 연구

Development of proton conducting membrane electrolyte is one of the most important research area within the domain of direct methanol fuel cells (DMFCs). This study reports the preparation of glutaraldehyde-crosslinked poly(vinyl alcohol-co-styrenesulfonic acid) proton exchange membrane (PEM) for DMFC. In order to understand the effect of the extent of crosslinking on the PEM properties, varying concentration of glutaraldehyde was used. Key properties of PEMs such as water uptake, swelling behavior, ion-exchange capacity, proton conductivity, and methanol permeability were thoroughly analyzed. PEM formed using 0.5 M glutaraldehyde solution resulted in a crosslinked PEM with the moderate properties, such as swelling, water uptake, proton conductivity and mechanical strength, along with the exhibition of high proton conductivity and lower methanol permeability compared to commercial Nafion-117. In addition, optimized PEM produced a peak power density of 58 W/㎡ at a current density of 300 A/㎡, when DMFC fed with 2 M methanol solution at 60 °C.

Enhancing Proton Conductivity of Nafion Membrane by Incorporating Porous Tb-Metal-Organic Framework Modified with Nitro Groups.

A rigid carboxylate ligand with a nitro functional group was selected to coordinate with Tb(III) cation, and Tb-MOF ({[Tb4(L)4(OH)4(H2O)3]·8H2O}n, H2L = 2-nitroterephthalic acid) with large porous and excellent hydrophilicity was obtained successfully. The obtained Tb-MOF was filled into the Nafion matrix to improve its proton conduction performance. The Tb-MOF/Nafion composite membrane was characterized by PXRD, IR, and thermogravimetry (TG) and for water uptake, area swelling, and proton conductivity. The activity energy, Ea, value of the composite membrane, which is a very important factor affecting the proton conduction performance of the membrane, was fitted and calculated. It was revealed that Tb-MOF can improve the proton conductivities of composite membranes, and the improvement degree and Ea value were both affected by Tb-MOF content. When Tb-MOF content was 5%, the proton conductivity of the composite membrane was 1.53 × 10-2 S·cm-1 at 100% RH and 80 °C, which is 1.81 times that of the pure Nafion membrane. A MOF containing a nitro functional group was first doped into Nafion in this study and exhibited excellent performance for improving composite membrane proton conductivity. This study will provide a valuable reference for designing different functionalized MOFs to promote the proton conductivities of proton exchange membranes.

Harnessing Water to Enhance Quadrupolar NMR Spectroscopy and Imaging.

17 O and 14 N are attractive targets for in vivo NMR spectroscopy and imaging, but low gyromagnetic ratios γ and fast spin relaxation complicate observations. This work explores indirect ways of detecting some of these sites with the help of proton-detected double resonance techniques. As standard coherence transfer methods are of limited use for such indirect detection, alternative routes for probing the quadrupolar spectra on 1 H were tested. These centered on modulating the broadening effects imparted onto protons adjacent to the low-γ species through J couplings through either continuous wave or spin-echo double-resonance decoupling/recoupling sequences. As in all cases, the changes imparted by these double-resonance strategies were small due to the fast relaxation undergone by the quadrupoles, the sensitivity of these approaches was amplified by transferring their effects onto the abundant water 1 H signal. These amplifications were mediated by the spontaneous exchanges that the labile 1 Hs bound to 17 O or 14 N undergo with the water protons. In experiments designed on the basis of double-resonance spin echoes, these enhancements were imparted by looping the transverse encodings together with multiple longitudinal storage periods, leading to decoupling-recoupling with exchange (D-REX) sequences. In experiments designed on the basis of continuous on/off quadrupolar decoupling, these solvent exchanges were incorporated into chemical-exchange saturation transfer schemes, leading to decoupling-recoupling with saturation transfer (D-REST) sequences. Both of these variants harnessed sizable proportions of the easily detectable water signals, in order to characterize the NMR spectra and/or to image with atomic-site specificity the 17 O and 14 N species.

Ion influence on surface water dynamics and proton exchange at protein surfaces – A unified model for transverse and longitudinal NMR relaxation dispersion

In all biologically relevant media, proteins interact in the presence of surrounding ions, and such interactions are water-mediated. Water molecules play a crucial role in the restructuring of proteins in solution and indeed in their biological activity. Surface water dynamics and proton exchange at protein surfaces is investigated here using NMR relaxometry, for two well-known globular proteins, lysozyme and bovine serum albumin, with particular attention to the role of surface ions. We present a unified model of surface water dynamics and proton exchange, accounting simultaneously for the observed longitudinal and transverse relaxation rates. The most notable effect of salt (0.1 M) concerns the slow surface water dynamics, related to rare water molecules embedded in energy wells on the protein surface. This response is protein-specific. On the other hand, the proton exchange time between labile protein-protons and water-protons at the protein surface seems to be very similar for the two proteins and is insensitive to the addition of salts at the concentration studied.

Determining the hydronium pKα at platinum surfaces and the effect on pH-dependent hydrogen evolution reaction kinetics

Electrocatalytic hydrogen evolution reaction (HER) is critical for green hydrogen generation and exhibits distinct pH-dependent kinetics that have been elusive to understand. A molecular-level understanding of the electrochemical interfaces is essential for developing more efficient electrochemical processes. Here we exploit an exclusively surface-specific electrical transport spectroscopy (ETS) approach to probe the Pt-surface water protonation status and experimentally determine the surface hydronium pKa [Formula: see text] 4.3. Quantum mechanics (QM) and reactive dynamics using a reactive force field (ReaxFF) molecular dynamics (RMD) calculations confirm the enrichment of hydroniums (H3O[Formula: see text]) near Pt surface and predict a surface hydronium pKa of 2.5 to 4.4, corroborating the experimental results. Importantly, the observed Pt-surface hydronium pKa correlates well with the pH-dependent HER kinetics, with the protonated surface state at lower pH favoring fast Tafel kinetics with a Tafel slope of 30 mV per decade and the deprotonated surface state at higher pH following Volmer-step limited kinetics with a much higher Tafel slope of 120 mV per decade, offering a robust and precise interpretation of the pH-dependent HER kinetics. These insights may help design improved electrocatalysts for renewable energy conversion.

On the Observation of 14N Quadrupole Resonance Transitions in Water Proton NMR Relaxometry Dispersion Curves: The Case of a Labile NH Grouping in a Semirigid Molecular Moiety.

The electric field gradient tensor (considered here at the level of a nitrogen nucleus) can be described by two parameters: the largest element in the (X,Y,Z) principal axis system, denoted by VZZ (leading to the nuclear quadrupole coupling), and the asymmetry parameter η = (|VYY| - |VXX|)/|VZZ| with |VZZ| > |VYY| > |VXX|. The frequencies of the three nitrogen-14 nuclear quadrupole resonance (NQR) transitions depend on both parameters but, for sensitivity reasons, their determination may be especially difficult and time consuming. For a partly rigid NH grouping with a labile proton, water nuclear magnetic resonance (NMR) relaxometry curves may exhibit these three transitions (dubbed quadrupolar dips or quadrupole relaxation enhancement (QRE)), provided that the NH grouping belongs to a moiety possessing a sufficient degree of ordering. Their line shape leads to the correlation time describing mainly the motion of the NH grouping (the proton of which being in exchange with water protons), and their amplitude can be interpreted in terms of an effective NH distance. This approach is applied to a hydrogel, where separate NQR lines are observed for the different types of water existing in this system. Furthermore, the analysis of experimental data allows one to determine the nuclear quadrupole coupling in the protonated and deprotonated forms of this molecular moiety involving a labile NH grouping.

Redox-Responsive MRI Probes Based on First-Row Transition-Metal Complexes.

The presence of multiple oxidation and spin states of first-row transition-metal complexes facilitates the development of switchable MRI probes. Redox-responsive probes capitalize on a change in the magnetic properties of the different oxidation states of the paramagnetic metal ion center upon exposure to biological oxidants and reductants. Transition-metal complexes that are useful for MRI can be categorized according to whether they accelerate water proton relaxation (T1 or T2 agents), induce paramagnetic shifts of 1H or 19F resonances (paraSHIFT agents), or are chemical exchange saturation transfer (CEST) agents. The various oxidation state couples and their properties as MRI probes are summarized with a focus on Co(II)/Co(III) or Fe(II)/Fe(III) complexes as small molecules or as liposomal agents. Solution studies of these MRI probes are reviewed with an emphasis on redox changes upon treatment with oxidants or with enzymes that are physiologically important in inflammation and disease. Finally, we outline the challenges of developing these probes further for in vivo MRI applications.

Changes in Natural Silk Fibres by Hydration, Tensile Loading and Heating as Studied by 1H NMR: Anisotropy in NMR Relaxation Times.

B. mori silkworm natural silk is a fibrous biopolymer with a block copolymer design containing both hydrophobic and hydrophilic regions. Using 1H NMR relaxation, this work studied B. mori natural silk fibres oriented at 0° and 90° to the static magnetic field B0 to clarify how measured NMR parameters reflect the structure and anisotropic properties of hydrated silk fibres. The FTIR method was applied to monitor the changes in the silk I and β-sheet conformations. Unloaded B. mori silk fibres at different hydration levels (HL), the silk threads before and after tensile loading in water, and fibres after a stepped increase in temperature have been explored. NMR data discovered two components in T1 and T2 relaxations for both orientations of silk fibres (0° and 90°). For the slower T2 component, the results showed an obvious anisotropic effect with higher relaxation times for the silk fibres oriented at 90° to B0. The T1 component (water protons, HL = 0.11) was sequentially decreased over a range of fibres: 0° oriented, randomly oriented, silk B. mori cocoon, 90° oriented. The degree of anisotropy in T2 relaxation was decreasing with increasing HL. The T2 in silk threads oriented at 0° and 90° also showed anisotropy in increased HL (to 0.42 g H2O/g dry matter), at tensile loading, and at an increasing temperature towards 320 K. The changes in NMR parameters and different relaxation mechanisms affecting water molecular interactions and silk properties have been discussed. The findings provide new insights relating to the water anisotropy in hydrated Bombyx mori silk fibres at tensile loading and under a changing HL and temperature.

Design Strategies for Responsive Fluorine‐19 Magnetic Resonance Probes Using Paramagnetic Metal Complexes

AbstractMagnetic resonance imaging (MRI) is a powerful and widely used in vivo imaging technique that enables whole body imaging without ionizing radiation. In clinical practice, 1H MRI is employed for imaging anatomical and physiological states via monitoring of protons in water and lipids. In order to monitor biochemical processes at the molecular level, several research groups are exploring responsive MRI agents that alter their signal upon interaction with an analyte or biological environment of interest. Fluorine (19F) MRI agents are promising due to the 19F nucleus having similar magnetic resonance (MR) properties to proton and the absence of endogenous 19F in living systems, resulting in no background signal. In order to make responsive 19F MR agents for molecular imaging and analysis, fluorinated platforms must be developed in which their 19F MR signal changes after interacting with a target analyte. A promising strategy is to use paramagnetic metals to modulate the 19F MR signal by altering the relaxation rates and/or chemical shift of an appended 19F imaging tag. In this concept, we provide an overview of the theoretical principles and molecular design strategies that have been exploited in the design of responsive 19F MR agents, with a specific focus on agents based on small molecule paramagnetic metal ion chelates.

Optic compressive neuropathy secondary to anterior clinoid mucocele: diagnostic approach, a case report

Anterior clinoid process (ACP) mucoceles are an uncommon entity and an even rarer cause of visual impairment. We review the case of a 62-year-old female with a 2-year history of progressive right-sided monocular vision loss. Paranasal sinus computed tomography (CT) scan showed bilateral ACP pneumatization. A soft tissue density mass occupied the right ACP with bone expansion and compression of the right orbital canal. An endonasal approach was performed with total vision recovery. Dedicated images are necessary to diagnose ACP. On CT, the affected sinus will have bone erosions. On magnetic resonance imaging, the signal intensity is determined by its protein concentration and mobile water protons. ACP mucoceles’ accurate diagnosis determinates the treatment and surgical approach. Finally, the correct management selection will determine the retrieval of the visual ability.

MRI Detection of Hepatic N-Acetylcysteine Uptake in Mice.

This proof-of-concept study looked at the feasibility of using a thiol–water proton exchange (i.e., CEST) MRI contrast to detect in vivo hepatic N-acetylcysteine (NAC) uptake. The feasibility of detecting NAC-induced glutathione (GSH) biosynthesis using CEST MRI was also investigated. The detectability of the GSH amide and NAC thiol CEST effect at B0 = 7 T was determined in phantom experiments and simulations. C57BL/6 mice were injected intravenously (IV) with 50 g L−1 NAC in PBS (pH 7) during MRI acquisition. The dynamic magnetisation transfer ratio (MTR) and partial Z-spectral data were generated from the acquisition of measurements of the upfield NAC thiol and downfield GSH amide CEST effects in the liver. The 1H-NMR spectroscopy on aqueous mouse liver extracts, post-NAC-injection, was performed to verify hepatic NAC uptake. The dynamic MTR and partial Z-spectral data revealed a significant attenuation of the mouse liver MR signal when a saturation pulse was applied at −2.7 ppm (i.e., NAC thiol proton resonance) after the IV injection of the NAC solution. The 1H-NMR data revealed the presence of hepatic NAC, which coincided strongly with the increased upfield MTR in the dynamic CEST data, providing strong evidence that hepatic NAC uptake was detected. However, this MTR enhancement was attributed to a combination of NAC thiol CEST and some other upfield MT-generating mechanism(s) to be identified in future studies. The detection of hepatic GSH via its amide CEST MRI contrast was inconclusive based on the current results.

MRI measurement of alanine uptake in a mouse xenograft model of U-87 MG glioblastoma

The potential use of alanine as an MRI contrast agent was investigated. The relaxation properties of alanine solutions were measured at 9.4 T. The T2 relaxivity caused by the chemical exchange (R2ex) between amine protons and water protons was 0.10 mM−1 s−1 at 37 °C. As a demonstration, alanine uptake in a mouse xenograft model of U-87 MG glioblastoma was measured using MRI, and was compared with immunohistochemistry staining of ASCT2, a transporter that imports amino acids into cancer cells. Statistically significant (p = 0.0079) differences in ASCT2 distribution were found between regions that show strong and weak alanine uptake in MRI. To better understand the influence of perfusion, the effect of ASCT2 inhibition on the alanine uptake in MRI was investigated, and dynamic contrast enhanced MRI was compared with alanine MRI.

An activatable Mn(II) MRI probe for detecting peroxidase activity in vitro and in vivo

Myeloperoxidase (MPO), a hallmark of the function and activation of innate immune cells, can act as a ‘double-edged sword’, contributing to clear infection as well as causing tissue oxidizing damage in various inflammatory diseases. In this study, an activatable Mn(II) chelate-based magnetic resonance imaging (MRI) contrast agent (CA), Mn-TyEDTA (TyEDTA = tyrosine derived ethylenediaminetetraacetic acid) structurally featuring a phenol group as the electron-donor, was developed to sense the activity of peroxidase in vitro and in vivo. Mn-TyEDTA demonstrated a peroxidase activity-dependent relaxivity in the presence of horseradish peroxidase (HRP)/H2O2 with more than a 2.6-fold increase in water proton relaxivity produced (HRP, 500 U; H2O2, 4.5 eq). A mechanism of peroxidase-mediated Mn(II) monomer radical polymerization was confirmed with those oligomers of Mn-TyEDTA such as dimer, trimer and tetramer were found in the LC-MS study. Dynamic MR imaging of normal mice revealed rapid blood clearance and mixed renal and hepatobiliary elimination of Mn-TyEDTA. Furthermore, compared to liver-specific and non-specific extracellular contrast agents (Mn-BnO-TyEDTA (BnO-TyEDTA = benzyl tyrosine-derived ethylenediaminetetraacetic acid) and Gd-DTPA (DTPA = diethylene triamine penta-acetic acid)), MRI on a monosodium urate (MSU) crystal-induced acute mice model of arthritis showed that inflamed tissues could be selectively enhanced by Mn-TyEDTA, suggesting that this peroxidase-activatable Mn(II) MRI probe could potentially be used for noninvasive detection of MPO activity in vivo.

Water proton NMR relaxation revisited: Ultrahighly diluted aqueous solutions beyond Avogadro’s limit prepared by iterative centesimal dilution under shaking cannot be considered as pure solvent

• Ultramolecular dilutions prepared according to homeopathic pharmacopoeia differ from solvent and from simply diluted samples. • Evidence for an unexpected gradual increase of correlation times of water with dilution in ultrahighly diluted solutions. • Evidence for solute-induced nanostructures in aqueous high dilutions growing with dilution. • Nanostructures result from nucleation between the solute, nanobubbles and elements coming from the medium during preparation. • Nanostructures in ultrahigh dilutions, even ultramolecular, enhance leaching processes in glass containers. The biological activity of ultrahigh dilutions (HDs) as used in homeopathy, especially those beyond Avogadro's limit, is still controversial and an intriguing problem for scientists. Homeopathic remedies are mostly prepared by iterative centesimal dilution under vigorous shaking, called dynamization. Cn corresponds to a dilution factor of 10 -2n , and C12 (10 -24 ) to the theoretical limit of molecular presence. Since the 1990 s, NMR relaxation of water protons has emerged as a potent tool for investigating HDs. This article reviews studies of high methodological quality by five independent teams over more than two decades. They demonstrate an increase in T1 and T1/T2, with a decrease in T2, although less constant, in dynamized aqueous HDs. No variation was observed in the similarly treated solvent controls. The phenomenon seems to be common, regardless of solute, dissolved oxygen, material used (glass or plastic), method of shaking, frequency from 0.02 to 600 MHz. Strikingly, the changes in relaxation times increased gradually with dilution, even in the C12-C30 ultramolecular range and they totally vanished after a heating–cooling cycle directly applied on the sealed NMR tubes. The results were interpreted in terms of increasing correlation times of water, greater than 10 −8 s, resulting from the formation of growing solute-induced nanostructures involving nanobubbles and various elements coming from the medium, the atmosphere and the container. Another unexpected result was that HDs were able to enhance some leaching processes in glass containers.

CMOS electrochemical pH localizer-imager.

pH controls a large repertoire of chemical and biochemical processes in water. Densely arrayed pH microenvironments would parallelize these processes, enabling their high-throughput studies and applications. However, pH localization, let alone its arrayed realization, remains challenging because of fast diffusion of protons in water. Here, we demonstrate arrayed localizations of picoliter-scale aqueous acids, using a 256-electrochemical cell array defined on and operated by a complementary metal oxide semiconductor (CMOS)–integrated circuit. Each cell, comprising a concentric pair of cathode and anode with their current injections controlled with a sub-nanoampere resolution by the CMOS electronics, creates a local pH environment, or a pH “voxel,” via confined electrochemistry. The system also monitors the spatiotemporal pH profile across the array in real time for precision pH control. We highlight the utility of this CMOS pH localizer-imager for high-throughput tasks by parallelizing pH-gated molecular state encoding and pH-regulated enzymatic DNA elongation at any selected set of cells.

Theory of chemical exchange saturation transfer MRI in the context of different magnetic fields.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is a versatile MRI method that provides contrast based on the level of molecular and metabolic activity. This contrast arises from indirect measurement of protons in low concentration molecules that are exchanging with the abundant water proton pool. The indirect measurement is based on magnetization transfer of radio frequency (rf)-prepared magnetization from the small pool to the water pool. The signal can be modeled by the Bloch-McConnell equations combining standard magnetization dynamics and chemical exchange processes. In this article, we review analytical solutions of the Bloch-McConnell equations and especially the derived CEST signal equations and their implications. The analytical solutions give direct insight into the dependency of measurable CEST effects on underlying parameters such as the exchange rate and concentration of the solute pools, but also on the system parameters such as the rf irradiation field B1 , as well as the static magnetic field B0 . These theoretical field-strength dependencies and their influence on sequence design are highlighted herein. In vivo results of different groups making use of these field-strength benefits/dependencies are reviewed and discussed.

Friend or Foe: How to Suppress and Measure Fat During Abdominal Resonance Imaging?

The suppression of fat signals in abdominal magnetic resonance imaging has become a basic and routine practice in the diagnosis of pathologic conditions of abdominal organs in clinical settings. Many fat-suppression techniques have been developed in the past several decades, with fat-quantification methods introduced in response in more recent years. Fat-suppression techniques can be divided into two categories. Chemical shift–based techniques include chemical shift selective (CHESS), water excitation, and the Dixon method. CHESS is the most commonly used fat-suppression method, nulling the fat signal using a fat-selective radiofrequency pulse with a spoiler gradient. Water excitation employs a binomial pulse that excites only the water protons. Finally, the Dixon method involves using the in-phase/out-of-phase cycling of fat and water. An inversionbased technique, known as short tau inversion recovery (STIR), uses a pre-excitation inversion pulse that inverts the spin of all tissues. By selecting the appropriate MRI inversion time such that the longitudinal magnetization of fat is zero, fat protons will not contribute to the MRI signal. Also, spectral attenuated inversion recovery (SPAIR) is a hybrid technique that combines the characteristics of both CHESS and STIR. The most precise fat-quantification technique known to date is a complex-based multipoint Dixon method, with which the protondensity fat fraction (PDFF) can be obtained. Multiple confounding factors must be well-corrected for accurate fat quantification. Radiologists should be familiar with the various fat suppression and measurement methods during MRI and be able to apply them to enhance patient care.