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To perform in vitro high-resolution 900 MHz magnetic resonance spectroscopy (NMR) analysis of human brain tumor tissue extracts and analyze for the oncometabolite 2-hydroxyglutarate (2HG) and other brain metabolites, not only for 1H but also for 13C with indirect detection by heteronuclear single quantum correlation (HSQC). Four surgically removed human brain tumor tissue samples were used for extraction and preparation of NMR samples. These tissue samples were extracted with 4% perchloric acid and chloroform, freeze-dried, then dissolved into 0.28 mL of deuterium oxide (D2O, 99.9 atom % deuterium) containing 0.025 wt % sodium 3-(trimethylsilyl)propionate-2,2,3,3-d4 (TSP). All samples were adjusted to pH range of 6.9-7.1 before finally transferred to 5 mm Shigemi™ NMR microtube. NMR experiments were performed on Bruker DRX 900 MHz spectrometer with 1H/13C/15N Cryo-probe™ with Z-gradient, without further temperature control for the samples. All chemical shift values were presented relative to TSP at 0.00 ppm for both 1H and 13C. 1H 1D, 1H-13C HSQC, 1H-1H correlation spectroscopy (COSY) and 1H-13C heteronuclear multiple bond correlation (HMBC) spectra were acquired and analyzed. 2-hydroxyglutarate, an oncometabolite associated with gliomas with IDH mutations, was successfully detected and assigned by both 1H-13C HSQC and 1H-1H COSY experiments as well as 1H 1D experiments in two of the tissue samples. In particular, to our knowledge this work shows the first example of detecting 900 MHz 13C-NMR spectral lines of 2-hydroxyglutarate in human brain tumor tissue samples. In addition to the oncometabolite 2-hydroxyglutarate, at least 42 more metabolites were identified from our series of NMR experiment. The detection of 2-hydroxyglutarate and other metabolites can be facilitated by homonuclear and heteronuclear two-dimensional 900 MHz NMR spectroscopy even in case of real tumor tissue sample extracts without physical separation of metabolites.

A dual-nuclei radiofrequency coil array was constructed for phosphorus and proton magnetic resonance imaging and spectroscopy of the human brain at 7T. An eight-channel transceive degenerate birdcage phosphorus module was implemented to provide whole-brain coverage and significant sensitivity improvement over a standard dual-tuned loop coil. A nested eight-channel proton module provided adequate sensitivity for anatomical localization without substantially sacrificing performance on the phosphorus module. The developed array enabled phosphorus spectroscopy, a saturation transfer technique to calculate the global creatine kinase forward reaction rate, and single-metabolite whole-brain imaging with 1.4cm nominal isotropic resolution in 15min (2.3cm actual resolution), while additionally enabling 1mm isotropic proton imaging. This study demonstrates that a multi-channel array can be utilized for phosphorus and proton applications with improved coverage and/or sensitivity over traditional single-channel coils. The efficient multi-channel coil array, time-efficient pulse sequences, and the enhanced signal strength available at ultra-high fields can be combined to allow volumetric assessment of the brain and could provide new insights into the underlying energy metabolism impairment in several neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, as well as mental disorders such as schizophrenia. •A degenerate birdcage array provided high SNR and a uniform B1+ field for 31P MRI.•Single metabolite imaging was demonstrated with a 3D non-Cartesian acquisition.•γ-ATP was saturated with non-adiabatic pulses to estimate the CK forward reaction rate.•A nested 1H array enabled straightforward image co-registration.

Autonomous laboratories can accelerate discoveries in chemical synthesis, but this requires automated measurements coupled with reliable decision-making 1 , 2 . Most autonomous laboratories involve bespoke automated equipment 3 – 6 , and reaction outcomes are often assessed using a single, hard-wired characterization technique 7 . Any decision-making algorithms 8 must then operate using this narrow range of characterization data 9 , 10 . By contrast, manual experiments tend to draw on a wider range of instruments to characterize reaction products, and decisions are rarely taken based on one measurement alone. Here we show that a synthesis laboratory can be integrated into an autonomous laboratory by using mobile robots 11 – 13 that operate equipment and make decisions in a human-like way. Our modular workflow combines mobile robots, an automated synthesis platform, a liquid chromatography–mass spectrometer and a benchtop nuclear magnetic resonance spectrometer. This allows robots to share existing laboratory equipment with human researchers without monopolizing it or requiring extensive redesign. A heuristic decision-maker processes the orthogonal measurement data, selecting successful reactions to take forward and automatically checking the reproducibility of any screening hits. We exemplify this approach in the three areas of structural diversification chemistry, supramolecular host–guest chemistry and photochemical synthesis. This strategy is particularly suited to exploratory chemistry that can yield multiple potential products, as for supramolecular assemblies, where we also extend the method to an autonomous function assay by evaluating host–guest binding properties. A modular autonomous platform for general exploratory synthetic chemistry uses mobile robots to integrate an automated synthesis platform and two analysis platforms.

Magnetic Resonance Spectroscopy (MRS) allows for a non-invasive and non-ionizing determination of in vivo tissue concentrations and metabolic turn-over rates of more than 20 metabolites and compounds in the central nervous system of humans. The aim of this review is to give a comprehensive overview about the advantages, challenges and advances of ultra-high field MRS with regard to methodological development, discoveries and applications from its beginnings around 15 years ago up to the current state. The review is limited to human brain and spinal cord application at field strength of 7T and 9.4T and includes all relevant nuclei (1H, 31P, 13C).

Spectral editing allows direct measurement of low-concentration metabolites, such as GABA, glutathione (GSH) and lactate (Lac), relevant for understanding brain (patho)physiology. The most widely used spectral editing technique is MEGA-PRESS, which has been diversely implemented across research sites and vendors, resulting in variations in the final resolved edited signal. In this paper, we describe an effort to develop a new universal MEGA-PRESS sequence with HERMES functionality for the major MR vendor platforms with standardized RF pulse shapes, durations, amplitudes and timings. New RF pulses were generated for the universal sequence. Phantom experiments were conducted on Philips, Siemens, GE and Canon 3 T MRI scanners using 32-channel head coils. In vivo experiments were performed on the same six subjects on Philips and Siemens scanners, and on two additional subjects, one on GE and one on Canon scanners. On each platform, edited MRS experiments were conducted with the vendor-native and universal MEGA-PRESS sequences for GABA (TE = 68 ms) and Lac editing (TE = 140 ms). Additionally, HERMES for GABA and GSH was performed using the universal sequence at TE = 80 ms. The universal sequence improves inter-vendor similarity of GABA-edited and Lac-edited MEGA-PRESS spectra. The universal HERMES sequence yields both GABA- and GSH-edited spectra with negligible levels of crosstalk on all four platforms, and with strong agreement among vendors for both edited spectra. In vivo GABA+/Cr, Lac/Cr and GSH/Cr ratios showed relatively low variation between scanners using the universal sequence. In conclusion, phantom and in vivo experiments demonstrate successful implementation of the universal sequence across all four major vendors, allowing editing of several metabolites across a range of TEs.

MRSI in the brain at ≥7 T is a technique of great promise, but has been limited mainly by low B0/B1+-homogeneity, specific absorption rate restrictions, long measurement times, and low spatial resolution. To overcome these limitations, we propose an ultra-high resolution (UHR) MRSI sequence that provides a 128×128 matrix with a nominal voxel volume of 1.7×1.7×8mm3 in a comparatively short measurement time. A clinically feasible scan time of 10–20min is reached via a short TR of 200 ms due to an optimised free induction decay-based acquisition with shortened water suppression as well as parallel imaging (PI) using Controlled Aliasing In Parallel Imaging Results IN Higher Acceleration (CAIPIRINHA). This approach is not limited to a rectangular region of interest in the centre of the brain, but also covers cortical brain regions. Transversal pulse-cascaded Hadamard encoding was able to further extend the coverage to 3D-UHR-MRSI of four slices (100×100×4 matrix size), with a measurement time of 17min. Lipid contamination was removed during post-processing using L2-regularisation. Simulations, phantom and volunteer measurements were performed. The obtained single-slice and 3D-metabolite maps show the brain in unprecedented detail (e.g., hemispheres, ventricles, gyri, and the contrast between grey and white matter). This facilitates the use of UHR-MRSI for clinical applications, such as measurements of the small structures and metabolic pathologic deviations found in small Multiple Sclerosis lesions. [Display omitted] •Ultra-high resolution MRSI (128×128 in-plane matrix) at 7 T.•Parallel imaging and short TR of 200ms make UHR-MRSI clinically feasible (10–20min).•Pulse-cascaded Hadamard encoding provides 3D-MRSI coverage.

State-of-the-art NMR spectrometers using superconducting magnets have enabled, with their ultrafine spectral resolution, the determination of the structure of large molecules such as proteins, which is one of the most profound applications of modern NMR spectroscopy. Many chemical and biotechnological applications, however, involve only small-to-medium size molecules, for which the ultrafine resolution of the bulky, expensive, and high-maintenance NMR spectrometers is not required. For these applications, there is a critical need for portable, affordable, and low-maintenance NMR spectrometers to enable in-field, on-demand, or online applications (e.g., quality control, chemical reaction monitoring) and co-use of NMR with other analytical methods (e.g., chromatography, electrophoresis). As a critical step toward NMR spectrometer miniaturization, small permanent magnets with high field homogeneity have been developed. In contrast, NMR spectrometer electronics capable of modern multidimensional spectroscopy have thus far remained bulky. Complementing the magnet miniaturization, here we integrate the NMR spectrometer electronics into 4-mm ² silicon chips. Furthermore, we perform various multidimensional NMR spectroscopies by operating these spectrometer electronics chips together with a compact permanent magnet. This combination of the spectrometer-electronics-on-a-chip with a permanent magnet represents a useful step toward miniaturization of the overall NMR spectrometer into a portable platform.

Detection of glycogen in vivo would have utility in the study of normal physiology and many disorders. Presently, the only magnetic resonance (MR) method available to study glycogen metabolism in vivo is ¹³C MR spectroscopy, but this technology is not routinely available on standard clinical scanners. Here, we show that glycogen can be detected indirectly through the water signal by using selective radio frequency (RF) saturation of the hydroxyl protons in the 0.5- to 1.5-ppm frequency range downfield from water. The resulting saturated spins are rapidly transferred to water protons via chemical exchange, leading to partial saturation of the water signal, a process now known as chemical exchange saturation transfer. This effect is demonstrated in glycogen phantoms at magnetic field strengths of 4.7 and 9.4 T, showing improved detection at higher field in adherence with MR exchange theory. Difference images obtained during RF irradiation at 1.0 ppm upfield and downfield of the water signal showed that glycogen metabolism could be followed in isolated, perfused mouse livers at 4.7 T before and after administration of glucagon. Glycogen breakdown was confirmed by measuring effluent glucose and, in separate experiments, by ¹³C NMR spectroscopy. This approach opens the way to image the distribution of tissue glycogen in vivo and to monitor its metabolism rapidly and noninvasively with MRI.

Magnetic resonance imaging and spectroscopy are versatile methods for probing brain physiology, but their intrinsically low sensitivity limits the achievable spatial and temporal resolution. Here, we introduce a monolithically integrated NMR-on-a-chip needle that combines an ultra-sensitive 300 µm NMR coil with a complete NMR transceiver, enabling in vivo measurements of blood oxygenation and flow in nanoliter volumes at a sampling rate of 200 Hz. A miniaturized NMR-on-a-chip needle can be implanted into rodent brains and can measure blood flow and oxygenation changes in vivo in a small volume at an unprecedentedly high temporal resolution of a few milliseconds.

We develop magnetic resonance (MR) methods for real-time measurement of tissue microstructure and membrane permeability of live and fixed excised neonatal mouse spinal cords. Diffusion and exchange MR measurements are performed using the strong static gradient produced by a single-sided permanent magnet. Using tissue delipidation methods, we show that water diffusion is restricted solely by lipid membranes. Most of the diffusion signal can be assigned to water in tissue which is far from membranes. The remaining 25% can be assigned to water restricted on length scales of roughly a micron or less, near or within membrane structures at the cellular, organelle, and vesicle levels. Diffusion exchange spectroscopy measures water exchanging between membrane structures and free environments at 100 s-1.