Directly Bound Deuterons Increase X-Nuclei Hyperpolarization using Dynamic Nuclear Polarization.

Deuterated C sites in sugars (D-glucose and 2-deoxy-D-glucose) showed 6.3-to-17.5-fold higher solid-state dynamic nuclear polarization (DNP) levels than their respective protonated sites at 3.

Clinical and functional efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis carrying the N1303K mutation.

Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations.

Signal enhancement of hyperpolarized N sites in solution-increase in solid-state polarization at 3.35 T and prolongation of relaxation in deuterated water mixtures.

Hyperpolarized N sites have been found to be promising for generating long-lived hyperpolarized states in solution, and present a promising approach for utilizing dissolution-dynamic nuclear polarization (dDNP)-driven hyperpolarized MRI for imaging in biology and medicine. Specifically, N sites with directly bound protons were shown to be useful when dissolved in D O. The purpose of the current study was to further characterize and increase the visibility of such N sites in solutions that mimic an intravenous injection during the first cardiac pass in terms of their H O:D O composition.

Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance.

Cardiovascular diseases account for more than 30% of all deaths worldwide and many could be ameliorated with early diagnosis. Current cardiac imaging modalities can assess blood flow, heart anatomy and mechanical function. However, for early diagnosis and improved treatment, further functional biomarkers are needed.

Observation of glucose-6-phosphate anomeric exchange in real-time using dDNP hyperpolarised NMR.

A hyperpolarised-NMR acquisition approach that is sensitive to the process of glucose-6-phosphate anomerization is presented. Using selective depolarisation of one of the anomer's signals, it is possible to observe the replenishing of this signal due to the fast anomeric exchange of this compound. The forward to reverse reaction rate constants ratio was 1.

The Effect of Gadolinium Doping in [ C , H ]Glucose Formulations on C Dynamic Nuclear Polarization at 3.35 T.

The promise of hyperpolarized glucose as a non-radioactive imaging agent capable of reporting on multiple metabolic routes has led to recent advances in its dissolution-DNP (dDNP) driven polarization using UV-light induced radicals and trityl radicals at high field (6.7 T) and 1.1 K.

Hyperpolarized product selective saturating-excitations for determination of changes in metabolic reaction rates in real-time.

Investigation of hyperpolarized substrate metabolism has been showing utility in real-time determination of in-cell and in vivo enzymatic activities. Intracellular reaction rates may vary during the course of a measurement, even on the very short time scales of visibility on hyperpolarized MR, due to many factors such as the availability of the substrate and co-factors in the intracellular space. Despite this potential variation, the kinetic analysis of hyperpolarized signals typically assumes that the same rate constant (and in many cases, the same rate) applies throughout the course of the reaction as observed via the build-up and decay of the hyperpolarized signals.

Hyperpolarized [N]nitrate as a potential long lived hyperpolarized contrast agent for MRI.

Reports on gadolinium deposits in the body and brains of adults and children who underwent contrast-enhanced MRI examinations warrant development of new, metal free, contrast agents for MRI. Nitrate is an abundant ion in mammalian biochemistry and sodium nitrate can be safely injected intravenously. We show that hyperpolarized [N]nitrate can potentially be used as an MR tracer.

Real-time ALT and LDH activities determined in viable precision-cut mouse liver slices using hyperpolarized [1- C]pyruvate-Implications for studies on biopsied liver tissues.

Precision-cut liver slices (PCLS) are widely used in liver research as they provide a liver model with all liver cell types in their natural architecture. The purpose of this study was to demonstrate the use of PCLS for hyperpolarized metabolic investigation in a mouse model, for potential future application in liver biopsy cores. Fresh normal liver was harvested from six mice.

Real-time ex-vivo measurement of brain metabolism using hyperpolarized [1-C]pyruvate.

The ability to directly monitor in vivo brain metabolism in real time in a matter of seconds using the dissolution dynamic nuclear polarization technology holds promise to aid the understanding of brain physiology in health and disease. However, translating the hyperpolarized signal observed in the brain to cerebral metabolic rates is not straightforward, as the observed in vivo signals reflect also the influx of metabolites produced in the body, the cerebral blood volume, and the rate of transport across the blood brain barrier. We introduce a method to study rapid metabolism of hyperpolarized substrates in the viable rat brain slices preparation, an established ex vivo model of the brain.

Author Correction: Biochemical phosphates observed using hyperpolarized P in physiological aqueous solutions.

The original version of the Supplementary Information associated with this Article contained an error in Supplementary Figure 2 and Supplementary Figure 5 in which the P NMR spectral lines were missing. The HTML has been updated to include a corrected version of the Supplementary Information.

Long-lived N Hyperpolarization and Rapid Relaxation as a Potential Basis for Repeated First Pass Perfusion Imaging - Marked Effects of Deuteration and Temperature.

Deuteration of the exchangeable hydrogens of [ N ]urea was found to prolong the T of the N sites to more than 3 min at physiological temperatures. This significant increase in the lifetime of the hyperpolarized state of [ N ]urea, compared to [ C]urea - a pre-clinically proven perfusion agent, makes [ N ]urea a promising perfusion agent. The molecular parameters that may lead to this profound effect were assessed by investigating small molecules with different molecular structures containing N sites bound to labile protons and determining the hyperpolarized N T in H O and D O.

Biochemical phosphates observed using hyperpolarized P in physiological aqueous solutions.

The dissolution-dynamic nuclear polarization technology had previously enabled nuclear magnetic resonance detection of various nuclei in a hyperpolarized state. Here, we show the hyperpolarization of P nuclei in important biological phosphates (inorganic phosphate and phosphocreatine) in aqueous solutions. The hyperpolarized inorganic phosphate showed an enhancement factor >11,000 (at 5.

Defective ATP breakdown activity related to an ENTPD1 gene mutation demonstrated using P NMR spectroscopy.

The ecto-nucleoside triphosphate diphosphohydrolase-1 (E-NTPDase-1, CD39) enzyme is responsible for the breakdown of extracellular ATP to ADP and then to AMP by a two-step process. Defective CD39 activity has been described in a variety of medical conditions including malignancy and rheumatic diseases and has been proved to be of major diagnostic and clinical importance. Here we show for the first time that a P NMR spectroscopy methodology enables the quantification of these two steps in a single blood sample.

Higher levels of myelin phospholipids in brains of neuronal α-Synuclein transgenic mice precede myelin loss.

α-Synuclein is a protein involved in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We investigated the role of neuronal α-Syn in myelin composition and abnormalities. The phospholipid content of purified myelin was determined by P NMR in two mouse lines modeling PD, PrP-A53T α-Syn and Thy-1 wt-α-Syn.

Application of the Steady-State Variable Nutation Angle Method for Faster Determinations of Long T 1s-An Approach Useful for the Design of Hyperpolarized MR Molecular Probes.

In the dissolution-dynamic nuclear polarization technique, molecular probes with long T 1s are preferred. 13C nuclei of small molecules with no directly bonded protons or sp(3 13)C nuclei with proton positions substituted by deuterons may fulfill this requirement. The T 1 determination of such new molecular probes is crucial for the success of the hyperpolarized observation.

Transaldolase Deficiency: A New Case Expands the Phenotypic Spectrum.

Transaldolase (TALDO) deficiency has various clinical manifestations including liver dysfunction, hepatosplenomegaly, anemia, thrombocytopenia, and dysmorphic features. We report a case presenting prenatally with hyperechogenic bowel and intrauterine growth restriction. The infant was born small for gestational age, with cutis laxa and hypertrichosis.

In vitro visualization of betaine aldehyde synthesis and oxidation using hyperpolarized magnetic resonance spectroscopy.

Real-time monitoring of betaine aldehyde metabolism at high temporal resolution was accomplished using a hyperpolarized choline analog and (13)C-NMR. This represents the first observation of an aldehyde intermediate on hyperpolarized MR and opens the way for kinetic studies of oxidase/dehydrogenase enzymes in vitro and in vivo.

A hyperpolarized choline molecular probe for monitoring acetylcholine synthesis.

Choline as a reporter molecule has been investigated by in vivo magnetic resonance for almost three decades. Accumulation of choline metabolites (mainly the phosphorylated forms) had been observed in malignancy in preclinical models, ex-vivo, in vivo and in patients. The combined choline metabolite signal appears in (1) H-MRS of the brain and its relative intensity had been used as a diagnostic factor in various conditions.

Determining radical penetration of lipid bilayers with new lipophilic spin traps.

Predicting the susceptibility of lipid moieties to radical attack requires a determination of the depth of radical penetration into a lipid membrane. We thus synthesized three homologous series of lipophilic spin traps--DMPO analogs 2-alkanoyl-2-methyl-1-pyrroline N-oxides (11) and PBN derivatives 4-alkoxyphenyl N-tert-butylnitrones (18) and 4-alkoxyphenyl N-admantylnitrones (20). The intercalation depth of these spin traps within the liposomal bilayer was determined via the previously reported NMR technique, which correlates the chemical shift and the micropolarity (measured in ET(30) units) experienced by the pivotal nitronyl carbon.