Proton Magnetic Resonance Spectroscopy Study Research Articles

Glutamatergic neurotransmission in schizophrenia: A systematic review and quantitative synthesis of proton magnetic resonance spectroscopy studies across schizophrenia spectrum disorders.

Studies using proton magnetic resonance spectroscopy reveal substantial inconsistencies in the levels of brain glutamate, glutamine and glutamate + glutamine across schizophrenia spectrum disorders. This systematic review employs qualitative and quantitative methods to analyse the patterns and relationships between glutamatergic metabolites, schizophrenia spectrum disorders and brain regions. A literature search was conducted using various databases with keywords including glutamate, glutamine, schizophrenia, psychosis and proton magnetic resonance spectroscopy. Inclusion criteria were limited to case-control studies that reported glutamatergic metabolite levels in adult patients with a schizophrenia spectrum disorder diagnosis - i.e. first-episode psychosis, schizophrenia, treatment-resistant schizophrenia and/or ultra-treatment-resistant schizophrenia - using proton magnetic resonance spectroscopy at 3 T or above. Pooled study data were synthesized and analysed. A total of 92 studies met the inclusion criteria, including 2721 healthy controls and 2822 schizophrenia spectrum disorder participants. Glu levels were higher in the basal ganglia, frontal cortex and medial prefrontal of first-episode psychosis participants, contrasting overall lower levels in schizophrenia participants. For Gln, strong differences in metabolite levels were evident in the basal ganglia, dorsolateral prefrontal cortex and frontal cortex, with first-episode psychosis showing significantly higher levels in the basal ganglia. In glutamate + glutamine, higher metabolite levels were found across schizophrenia spectrum disorder groups, particularly in the basal ganglia and dorsolateral prefrontal cortex of treatment-resistant schizophrenia participants. Significant relationships were found between metabolite levels and medication status, clinical measures and methodological variables. The review highlights abnormal glutamatergic metabolite levels throughout schizophrenia spectrum disorders and in specific brain regions. The review underscores the importance of standardized future research assessing glutamatergic metabolites using proton magnetic resonance spectroscopy due to considerable literature heterogeneity.

Elevated circulating soluble interleukin-2 receptor (sCD25) level is associated with prefrontal excitatory-inhibitory imbalance in individuals with chronic pain: A proton MRS study

Aberrant neuronal excitability in the anterior cingulate cortex (ACC) is implicated in cognitive and affective pain processing. Such excitability may be amplified by activated circulating immune cells, including T lymphocytes, that interact with the central nervous system. Here, we conducted a study of individuals with chronic pain using magnetic resonance spectroscopy (MRS) to investigate the clinical evidence for the interaction between peripheral immune activation and prefrontal excitatory-inhibitory imbalance. In thirty individuals with chronic musculoskeletal pain, we assessed markers of peripheral immune activation, including soluble interleukin-2 receptor alpha chain (sCD25) levels, as well as brain metabolites, including Glx (glutamate + glutamine) to GABA+ (γ-aminobutyric acid + macromolecules/homocarnosine) ratio in the ACC. We found that the circulating level of sCD25 was associated with prefrontal Glx/GABA+. Greater prefrontal Glx/GABA+ was associated with higher pain catastrophizing, evaluative pain ratings, and anxiodepressive symptoms. Further, the interaction effect of sCD25 and prefrontal Glx/GABA+ on pain catastrophizing was significant, indicating the joint association of these two markers with pain catastrophizing. Our results provide the first evidence suggesting that peripheral T cellular activation, as reflected by elevated circulating sCD25 levels, may be linked to prefrontal excitatory-inhibitory imbalance in individuals with chronic pain. The interaction between these two systems may play a role as a potential mechanism underlying pain catastrophizing. Further prospective and treatment studies are needed to elucidate the specific role of the immune and brain interaction in pain catastrophizing.

Micro- and Nano-Pollutants from Tires and Car Brakes Generated in the Winter Season in the Poznan City Urban Environment

This research, focusing on the environmental impact of tire and brake disc pad wear, constitutes a significant area of transport-related studies. These two key vehicle components are not only the most frequently worn but also generate micro- and nano-pollutants (i.e., rubber, metal oxides) that potentially harm the environment. Over half of the globally produced natural and synthetic rubbers, which amounted to about 30 million tons in 2022, are used for tire production. This work focuses on the study of roadside snow, sand, and standing water deposits from various locations in the urban agglomeration (Poznań, Poland) during the winter season, determining their qualitative composition and the quantitative content of pollutants originating from tire abrasion. In addition, the method of washing nano- and micro-rubber particles and their full characteristics was also presented. Fourier-transform infrared (FT-IR) and nuclear magnetic resonance (NMR) spectroscopic studies, optical and scanning electron microscopy (SEM-EDS), particle size studies using a dynamic light scattering (DLS) particle analyzer, and thermogravimetric analysis (TGA) were conducted for a detailed characterization of the pollutants in the environment. The conducted particle separation methods allowed for the extraction of a fraction mainly containing gum residues with particle sizes less than 2 µm. The results of these tests make it possible to estimate the level of contamination with rubber and metal residues during the abrasion of tires, pads, and brake discs while driving, which is crucial for understanding the impact of vehicle part exploitation on the environment.

Biophysical characterization and design of a minimal version of the Hoechst RNA aptamer

RNA aptamers are oligonucleotides, selected through Systematic Evolution of Ligands by EXponential Enrichment (SELEX), that can bind to specific target molecules with high affinity. One such molecule is the RNA aptamer that binds to a blue-fluorescent Hoechst dye that was modified with bulky t-Bu groups to prevent non-specific binding to DNA. This aptamer has potential for biosensor applications; however, limited information is available regarding its conformation, molecular interactions with the ligand, and binding mechanism. The study presented here aims to biophysically characterize the Hoechst RNA aptamer when complexed with the t-Bu Hoechst dye and to further optimize the RNA sequence by designing and synthesizing new sequence variants. Each variant aptamer-t-Bu Hoechst complex was evaluated through a combination of fluorescence emission, native polyacrylamide gel electrophoresis, fluorescence titration, and isothermal titration calorimetry experiments. The results were used to design a minimal version of the aptamer consisting of only 21 nucleotides. The performed study also describes a more efficient method for synthesizing the t-Bu Hoechst dye derivative. Understanding the biophysical properties of the t-Bu Hoechst dye-RNA complex lays the foundation for nuclear magnetic resonance spectroscopy studies and its potential development as a building block for an aptamer-based biosensor that can be used in medical, environmental or laboratory settings.

LC-HRMS and NMR studies for the characterization of degradation impurities of ubrogepant along with the in silico approaches for the prediction of degradation and toxicity

Ubrogepant is the first oral calcitonin gene-related peptide (CGRP) receptor antagonist which is used for the acute treatment of migraine in adults. The present study employs liquid chromatography-high resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance spectroscopy (NMR) techniques for the identification and characterization of degradation impurities of ubrogepant. The forced degradation study of ubrogepant was performed as per the International Council for Harmonisation (ICH) Q1A and Q1B guidelines. The in silico degradation profile of ubrogepant was predicted by Zeneth. It was observed that ubrogepant was labile to acidic hydrolysis, basic hydrolysis, and oxidative degradation conditions (H2O2), although it was stable in neutral hydrolysis and photolytic (UV light and visible light) conditions. Eight degradation impurities were formed, which were separated on reversed-phase HPLC with a gradient program on an InertSustain C8 column (4.6 × 250 mm, 5 µm) using 10 mM ammonium formate (pH unadjusted) and acetonitrile as the mobile phase. The structures of all the degradation impurities were characterized using the exact masses obtained from the HRMS/MS. Further, NMR studies were conducted on two major degradation impurities (UB-4 and UB-7). A plausible mechanism was proposed to support the structures of all the degradation impurities of UBR. In silico toxicity and mutagenicity assessment were done by DEREK Nexus, SARAH Nexus, and ProTox-II.

Biophysical and nuclear magnetic resonance spectroscopic studies of the binding of baicalein to DNA sequence d(CACGTG)2 and its cytotoxicity evaluation

This paper reports the interaction of baicalein with a hexamer nucleic acid sequence d(CACGTG)2, present in the promoter region of various transcription factors, using biophysical techniques and nuclear magnetic resonance spectroscopy. UV–Visible absorption and fluorescence titration data implied partial intercalative binding of baicalein with a binding constant of 105 M−1. Continuous variation analysis using fluorescence data revealed a 1:1 stoichiometry of the baicalein and DNA in the solution. Circular dichroism data displayed a structural change of DNA upon baicalein binding. Thermal denaturing studied using circular dichroism showed that the melting temperature of the system does not significantly vary with the addition of baicalein. The spectral features suggest a partial intercalation of baicalein. Differential scanning calorimetric data exhibited two two-state transitions for alone DNA and its 1:1 complex with subtle changes in the melting temperatures supporting the non-intercalative binding of baicalein. Nuclear magnetic resonance data showed baicalein binding to the region near the C3pG4 base step, evidenced by the intermolecular nuclear overhauser effect cross peaks. Distance restrained molecular dynamics was employed to obtain the lowest energy structure. Biological evaluation of the effect of baicalein displayed excellent apoptotic effect on different cancer cell lines. IC50 values of 72.55, 79.9 and 96.7 µM were obtained in MCF-7, DU-145 and HCT-15 cell lines. The results uphold its chemotherapeutic potential.

Association of Age and Response to Methylphenidate HCL Treatment in Adult ADHD: A Proton Magnetic Resonance Spectroscopy Study.

This study investigated the age-dependent effects of methylphenidate (MPH) on brain metabolites including choline (Cho), N-acetyl aspartate (NAA) and creatine (Cr) levels in the dorsolateral prefrontal cortex (DLPFC), striatum, cerebellum, and anterior cingulate cortex (ACC) regions of the brain in adult patients with attention deficit hyperactivity disorder (ADHD). The study was included 60 patients with ADHD between the ages of 18 and 60 years. The patients were grouped with respect to their ages as follows: 18-24 years, 25-30 years, and 31 and over years. Levels of NAA, Cr and Cho in DLPFC, ACC, cerebellum and striatum were measured with magnetic resonance spectroscopy (MRS). Subjects were then given 10 mg of oral MPH and the same metabolite levels were measured 30 minutes apart. Twelve (20%) of the cases were female and 48 (80%) were male. The age distribution of the cases is as follows: 15 subjects between the ages of 18-24, 26 subjects between the ages of 25-30 and 19 subjects over the age of 30. NAA levels were higher after MPH in the DLPFC of the 18-24 age group (p = 0.016) and in the cerebellum of the 25-30 age group (p = 0.041). No increase in Cho and Cr levels was observed after treatment compared to before (p > 0.05). It is thought that treatment of MPH can be effective on metabolites in different brain regions and this effect can vary upon age adult ADHD patients. After MPH treatment, both the 18-24 age group (in the DLPFC) and the 25-30 age group (in the cerebellum) was detected significantly higher NAA levels compared to pre-treatment levels. This increase in NAA levels suggested that pharmacotherapy, especially at early ages, may be effective on neuronal damage.

Neurochemical differences in core regions of the autistic brain: a multivoxel 1H-MRS study in children

Autism spectrum disorder (ASD) is a neurodevelopmental condition which compromises various cognitive and behavioural domains. The understanding of the pathophysiology and molecular neurobiology of ASD is still an open critical research question. Here, we aimed to address ASD neurochemistry in the same time point at key regions that have been associated with its pathophysiology: the insula, hippocampus, putamen and thalamus. We conducted a multivoxel proton magnetic resonance spectroscopy (1H-MRS) study to non-invasively estimate the concentrations of total choline (GPC + PCh, tCho), total N-acetyl-aspartate (NAA + NAAG, tNAA) and Glx (Glu + Gln), presenting the results as ratios to total creatine while investigating replication for ratios to total choline as a secondary analysis. Twenty-two male children aged between 10 and 18 years diagnosed with ASD (none with intellectual disability, in spite of the expected lower IQ) and 22 age- and gender-matched typically developing (TD) controls were included. Aspartate ratios were significantly lower in the insula (tNAA/tCr: p = 0.010; tNAA/tCho: p = 0.012) and putamen (tNAA/tCr: p = 0.015) of ASD individuals in comparison with TD controls. The Glx ratios were significantly higher in the hippocampus of the ASD group (Glx/tCr: p = 0.027; Glx/tCho: p = 0.011). Differences in tNAA and Glx indices suggest that these metabolites might be neurochemical markers of region-specific atypical metabolism in ASD children, with a potential contribution for future advances in clinical monitoring and treatment.

A stable rhodium-coordinated carbene with a σ0π2 electronic configuration.

Isolable singlet carbenes have universally adopted a σ2π0 electronic state, making them σ-donors and π-acceptors. We present a rhodium-coordinated, cationic cyclic diphosphinocarbene with a σ0π2 ground state configuration. Nuclear magnetic resonance spectroscopy studies show a carbene carbon chemical shift below -30.0 parts per million. X-ray crystallography reveals a planar RhP2C configuration. Quantum chemical calculations rationalize how σ-electron delocalization/donation and π-electron negative hyperconjugation together stabilize the formally vacant σ orbital and the filled π orbital at the carbene center. In contrast to traditional carbene counterparts this carbene can undergo synthetic transformations with both a Lewis base and a silver salt, producing a Lewis acid/base adduct and a silver π-complex, respectively. Exhibiting ambiphilic reactivity, it can also form a ketenimine through reaction with an isocyanide.

Citric acid cross-linking of a hydrogel from Aloe vera (Aloe barbadensis M.) engenders a pH-responsive, superporous, and smart material for drug delivery.

The current research work is based on the evaluation of a citric acid (CA) cross-linked Aloe vera (Aloe barbadensis M.) leaf hydrogel (CL-ALH) for pH-dependent and sustained drug release application. The CA was used in different concentrations (1.25, 2.5, 5.0, and 10.0%) to cross-link the ALH using homogenous reaction conditions. The synthesis of CL-ALH was confirmed through Fourier transform and nuclear magnetic resonance spectroscopic studies. The thermal analysis indicated that the ALH and CL-ALH were stable and decomposed in two steps. The scanning electron microscopic images of CL-ALH confirmed its porous nature due to the presence of interconnected channeling. The swelling of CL-ALH was evaluated at pH 1.2, 6.8, and 7.4 as well as in deionized water (DW). High swelling of CL-ALH was observed in DW, and at pH 7.4 and 6.8 whereas, less swelling of CL-ALH was witnessed at pH 1.2. CL-ALH also exhibited swelling/deswelling behavior in DW and ethanol, DW and normal saline, and at pH 7.4 and 1.2. Tablets were prepared from CL-ALH as a release retarding agent demonstrating the sustained release of venlafaxine hydrochloride (VFX) for 8 h. Whereas, VFX was released within 4 h from the ALH-based tablet formulation (un-cross-linked material) indicating the prolonged and sustained release behavior of CL-ALH. The VFX was released from CL-ALH tablets and followed zero-order kinetics. The mechanism followed by VFX release from CL-ALH tablets was non-Fickian diffusion. The in vivo fate of the tablet formulation was observed through an X-ray study. The CL-ALH-based tablet safely passed through the stomach of a stray dog without any significant erosion and then disintegrated in the small intestine and colon. These findings confirmed that the CL-ALH is an effective excipient for designing a sustained-release drug delivery system for the small intestine and colon.

Resting state and activated brain glutamate-glutamine, brain lactate, cognition, and psychopathology among males with schizophrenia: A 3 Tesla proton magnetic resonance spectroscopic (1H-MRS) study.

Research on glutamate (Glu) in schizophrenia has so far been inconclusive. Based on preclinical studies on Glu lactate interaction, researchers have now focused on brain lactate level as a sign of major pathology, including cognitive dysfunctions in the brain. Our study aimed to examine changes at resting and activated states in brain lactate and Glu-glutamine (Glx) at the anterior cingulate cortex (ACC) in schizophrenia. A hospital-based prospective study was conducted with twenty-two male cases of schizophrenia and matched healthy controls (HCs). Positive and Negative Syndrome Scale (PANSS), Montreal Cognitive Assessment (MoCA), and Stroop tasks were administered among patients. Brain lactate and Glx at ACC were measured at resting state and during the Stroop test with proton magnetic resonance spectroscopy (1H-MRS) both at baseline and at remission and once among HC. Though MoCA scores improved significantly (P < 0.001) at remission from baseline among cases, repeated-measures analysis of variance (RM-ANOVA) did not find a significant time effect for Glx (P = 0.82) and lactate (P = 0.30) among cases from baseline to remission. Glx and lactate changed differently from baseline to remission. Our study did not find significant differences in Glx and lactate between schizophrenia patients and HC. No significant time effect on Glx and lactate was observed from baseline to remission among schizophrenia cases. Different changes observed in Glx and lactate from baseline to remission require replication in future studies with larger sample size, longer follow-up period, and multivoxel MR assessment.

(Invited) Advances in Photon-Harvesting Technologies for Perovskite Absorbers and Water Splitting Reactions

Hybrid halide perovskites have made significant progress in power conversion efficiencies (> 25 %) and high stability achieved through chemical engineering of the AMX3 composition. Compositional engineering of perovskite precursor inks minimizes batch-to-batch variations and fluctuation in PCE values, however the understanding of perovskite inks and solution behavior remains a key step towards the exploitation of solution-processed perovskite devices. Herein, a comprehensive 207Pb nuclear magnetic resonance spectroscopy (NMR) study performed on various lead perovskite precursor inks will be presented. The NMR data provide fresh insights in identifying molecular species that are invariably and predominantly formed in precursor mixtures to coexist with larger networks and colloids. The solution chemistry of PbI2+I- is dominated by the type of connectivity as edge- face- and corner-sharing (PbI6)-octahedra and their dimensionality. The trends in the 207Pb chemical shifts revealed dynamic equilibria in the inks that can be controlled by stoichiometry, nature of the solvents and temperature. Furthermore, perovskite precursor ink development can be applied to fabricate devices beyond the planar device structures, such as direct electrospinning of the three major perovskite solar cell components, namely, photo absorber, hole, and electron transport materials, as continuous single triaxial fibers of μm radial dimensions. These perovskite fibers lay the foundation of materials engineering for fabricating tiny solar cells, which can either be woven into fabrics or incorporated as single fibers to power wearables and a variety of devices or sensors, forming the internet of things. They are also suited for tandem PV-PEC set-up for solar-assisted photoelectrochemical production of hydrogen by water-splitting reactions.

NMR Spectroscopic Investigations of the Performance Limiting Mechanisms of Lithium-Sulfur Batteries

During the past decades, the development of alternative energy sources has become increasingly important as the growing consumption of non-regenerative fossil energy poses a threat to the environment. Hence, developing of next-generation batteries featuring high capacity, reduced costs and improved safety, such as in lithium-sulfur batteries, is of utmost importance. The benefits of lithium-sulfur batteries have led to widespread efforts to understand the fundamentals of the sulfur redox chemistry that drives their operation, as capacity fade has been observed in almost all Li-S batteries.[1] Therefore, the involved local structural changes that correlate with the (electro)chemical processes need to be unveiled during the operation of Li-S batteries, suitably by in situ and in operando methods. This presentation will demonstrate the development and application of one such (operando) technique: nuclear magnetic resonance (NMR) spectroscopy. NMR spectroscopic measurements allow the probing of the structural changes in a battery during electrochemical cycling. In particular, the application of a non-invasive experimental set-up, which can follow the reaction inside the battery in operando is highly desirable as it provides real-time structural information compared to ex situ analysis.[2] Lithium-sulfur batteries contain various NMR-active nuclear isotopes, like 7Li, 6Li and 33S, which allow the following of the chemical reactions during the charge-discharge process. This includes the transition between elemental sulfur and polysulfides on the cathode side, the formation of the solid-electrolyte interface (SEI) and the metal plating and stripping on the anode side. Herein, we use for the first time a combination of lithium and sulfur in operando NMR spectroscopy to reveal a fundamental understanding of the reaction pathway of lithium-sulfur batteries during the cycling process.Lithium NMR spectroscopy is a powerful technique to apply to batteries, as demonstrated by many previous investigations on different lithium battery systems, since it enables the detection of the chemical environments of lithium species during electrochemical cycling and parasitic reactions in the cell.[3] The great advantage of in operando 7Li NMR spectroscopy is that the 7Li signals of the lithium anode and the deposited metal differ due to the bulk magnetic susceptibility effects and the surface area, bringing the skin depth effect into play. Thus, this method enables a time-resolved and quantitative evaluation of the electrochemical metal deposition during electrochemical cycling. Therefore, it is possible to investigate a critical problem that reduces the cell performance – the formation of lithium dendrites. This lithium deposition is particularly problematic if it occurs uncontrolled and inhomogeneous and the exact mechanism of nucleation and propagation of dendrites is not yet fully understood.[4] The developed technique helps to understand this deposition to improve the safety during cycling. The interpretation of the electrolyte signal in the in operando 7Li spectra is much more difficult because of the overlapping signals. Therefore, in situ 33S and 6Li NMR spectroscopy supports the identification and quantification of (poly-)sulfides during the charge-discharge-process. 33S NMR experiments are rarely reported since 33S is a quadrupolar nucleus characterized by a low natural abundance and magnetogyric ratio, resulting in a very low receptivity. Nevertheless, the developed 33S NMR technique allows the detection of the formation Li2S under in operando conditions.[5] Additional in operando 6Li NMR experiments allow to follow the (poly-)sulfide formation as the spectra yield much sharper lines in asymmetric lithium environments in comparison to 7Li NMR experiments.[6] Thus, these techniques provide complementary results to the 7Li NMR spectroscopic studies and help to elucidate the sulfur redox mechanism in lithium-sulfur batteries.Our developed in situ NMR spectroscopic set-up is a powerful analytical method since real-time qualitative and quantitative detection of different sulfur and lithium species is crucial for understanding the electrochemical process in sulfur batteries. The first time, a combination of in operando lithium and sulfur NMR spectroscopy is presented, providing new insights at the molecular level that are essential for accelerating the development of lithium-sulfur battery technologies.[1] H. Wang, N. Sa, et al., The Journal of Physical Chemistry C 2017, 121, 6011–6017.[2] J. B. Richter, et al., Chemical Communications 2019, 55, 6042–6045.[3] R. Bhattacharyya, et al., Nat Mater 2010, 9, 504–510.[4] A. B. Gunnarsdóttir, et al., J Mater Chem A Mater 2020, 8, 14975–14992.[5] R. Musio, in Annu Rep NMR Spectrosc, 2006, pp. 1–88.[6] L. A. Huff, et al., Surf Sci 2015, 631, 295–300.

Metabolic heterogeneity in different subtypes of malformations of cortical development causing epilepsy: a proton magnetic resonance spectroscopy study.

The most common subtypes of malformations of cortical development (MCDs) are gray matter heterotopia (GMH), focal cortical dysplasia (FCD), and polymicrogyria (PMG). This study aimed to characterize the possible neurometabolic abnormalities and heterogeneity in different MCDs subtypes using proton magnetic resonance spectroscopy (1H-MRS). In this prospective cross-sectional study, we recruited 29 patients with MCDs and epilepsy, including ten with GMH, ten with FCD, and nine with PMG, as well as 25 age- and sex-matched healthy controls (HC) from the Epilepsy Center of West China Hospital of Sichuan University between August 2018 and November 2021. Inclusion criteria for the patients were based upon typical magnetic resonance imaging (MRI) findings of MCDs and full clinical assessment for epilepsy. Single-voxel point-resolved spectroscopy was used to acquire data from both the lesion and the normal-appearing contralateral side (NACS) in patients and from the frontal lobe in HC. Metabolite measures, including N-acetyl aspartate (NAA), myoinositol (Ins), choline (Cho), creatine (Cr), and glutamate + glutamine (Glx) concentrations, were quantitatively estimated with linear combination model (LCModel) software and corrected for the partial volume effect of cerebrospinal fluid (CSF). The NAA concentration was lower and the Ins concentration was higher in the MCDs lesions than in the NACS and in HC (P=0.002-0.007), and the Cho and Cr concentrations were higher in MCDs lesions than in HC (P=0.001-0.016). Moreover, the Cho concentration was higher in NACS than in HC (P=0.015). In the GMH lesions, the only metabolic alteration was an NAA reduction (GMH_lesion vs. HC: P=0.001). In the FCD lesions, there were more metabolite abnormalities than in the other two subtypes, particularly a lower NAA and a higher Ins than in HC and NACS (P=0.012-0.042). In the PMG lesions, Cr (lesion vs. HC or NACS: P=0.017-0.021) and Glx (lesion vs. NACS: P=0.043) were increased, while NAA was normal. Correlation analysis revealed that the Cr concentration in MCDs lesions was positively correlated with seizure frequency (r=0.411; P=0.027). Based upon 1H-MRS, our study demonstrated that different MCDs subtypes exhibited variable metabolic features, which may be associated with distinct functional and cytoarchitectural properties.

Carbon-Nitrogen Bond Formation Using Sodium Hexamethyldisilazide: Solvent-Dependent Reactivities and Mechanisms.

The solvent-dependent reactivity of sodium hexamethyldisilazide (NaHMDS) toward carbon-centered electrophiles reveals reactions that are poorly represented or unrepresented in the literature, including direct aminolysis of aromatic methyl esters to give carboxamides, nitriles, or amidines, depending on the choice of solvent. SNAr substitutions of aryl halides and opening of terminal epoxides are also examined. A combination of 1H and 29Si nuclear magnetic resonance (NMR) spectroscopic studies using [15N]NaHMDS, kinetic studies, and computational studies reveals the complex mechanistic basis of the preferences for simple aryl carboxamides in toluene and dimethylethylamine and arylnitriles or amidines in tetrahydrofuran (THF). A prevalence of dimer- and mixed dimer-based chemistry even starting from the observable NaHMDS monomer in THF solution is notable.

Stratification of hypertension and SARS-CoV-2 infection by quantitative NMR spectroscopy of human blood serum

BackgroundDiagnostic approaches like the nuclear magnetic resonance spectroscopy (NMR) based quantification of metabolites, lipoproteins, and inflammation markers has helped to identify typical alterations in the blood serum of COVID-19 patients. However, confounders such as sex, and comorbidities, which strongly influence the metabolome, were often not considered. Therefore, the aim of this NMR study was to consider sex, as well as arterial hypertension (AHT), when investigating COVID-19-positive serum samples in a large age-and sex matched cohort.MethodsNMR serum data from 329 COVID-19 patients were compared with 305 healthy controls. 134 COVID-19 patients were affected by AHT. These were analyzed together with NMR data from 58 hypertensives without COVID-19. In addition to metabolite, lipoprotein, and glycoprotein data from NMR, common laboratory parameters were considered. Sex was considered in detail for all comparisons.ResultsHere, we show that several differences emerge from previous NMR COVID-19 studies when AHT is considered. Especially, the previously described triglyceride-rich lipoprotein profile is no longer observed in COVID-19 patients, nor an increase in ketone bodies. Further alterations are a decrease in glutamine, leucine, isoleucine, and lysine, citric acid, HDL-4 particles, and total cholesterol. Additionally, hypertensive COVID-19 patients show higher inflammatory NMR parameters than normotensive patients.ConclusionsWe present a more precise picture of COVID-19 blood serum parameters. Accordingly, considering sex and comorbidities should be included in future metabolomics studies for improved and refined patient stratification. Due to metabolic similarities with other viral infections, these results can be applied to other respiratory diseases in the future.

NMR characterization of the structure of the intrinsically disordered region of human origin recognition complex subunit 1, hORC1, and of its interaction with G-quadruplex DNAs

Human origin recognition complex (hORC) binds to the DNA replication origin and then initiates DNA replication. However, hORC does not exhibit DNA sequence-specificity and how hORC recognizes the replication origin on genomic DNA remains elusive. Previously, we found that hORC recognizes G-quadruplex structures potentially formed near the replication origin. Then, we showed that hORC subunit 1 (hORC1) preferentially binds to G-quadruplex DNAs using a hORC1 construct comprising residues 413 to 511 (hORC1413−511). Here, we investigate the structural characteristics of hORC1413−511 in its free and complex forms with G-quadruplex DNAs. Circular dichroism and nuclear magnetic resonance (NMR) spectroscopic studies indicated that hORC1413−511 is disordered except for a short α-helical region in both the free and complex forms. NMR chemical shift perturbation (CSP) analysis suggested that basic residues, arginines and lysines, and polar residues, serines and threonines, are involved in the G-quadruplex DNA binding. Then, this was confirmed by mutation analysis. Interestingly, CSP analysis indicated that hORC1413−511 binds to both parallel- and (3 + 1)-type G-quadruplex DNAs using the same residues, and thereby in the same manner. Our study suggests that hORC1 uses its intrinsically disordered G-quadruplex binding region to recognize parallel-type and (3 + 1)-type G-quadruplex structures at replication origin.

Brain MRI Biomarkers in Isolated Rapid Eye Movement Sleep Behavior Disorder: Where Are We? A Systematic Review.

The increasing number of MRI studies focused on prodromal Parkinson's Disease (PD) demonstrates a strong interest in identifying early biomarkers capable of monitoring neurodegeneration. In this systematic review, we present the latest information regarding the most promising MRI markers of neurodegeneration in relation to the most specific prodromal symptoms of PD, namely isolated rapid eye movement (REM) sleep behavior disorder (iRBD). We reviewed structural, diffusion, functional, iron-sensitive, neuro-melanin-sensitive MRI, and proton magnetic resonance spectroscopy studies conducted between 2000 and 2023, which yielded a total of 77 relevant papers. Among these markers, iron and neuromelanin emerged as the most robust and promising indicators for early neurodegenerative processes in iRBD. Atrophy was observed in several regions, including the frontal and temporal cortices, limbic cortices, and basal ganglia, suggesting that neurodegenerative processes had been underway for some time. Diffusion and functional MRI produced heterogeneous yet intriguing results. Additionally, reduced glymphatic clearance function was reported. Technological advancements, such as the development of ultra-high field MRI, have enabled the exploration of minute anatomical structures and the detection of previously undetectable anomalies. The race to achieve early detection of neurodegeneration is well underway.

Association Between Taurine Level in the Hippocampus and Major Depressive Disorder in Young Women: A Proton Magnetic Resonance Spectroscopy Study at 7T

BackgroundMajor depressive disorder (MDD) is characterized by depressed mood or loss of interest or pleasure. Generally, women are twice as likely as men to have depression. Taurine, a type of amino acid, plays critical roles in neuronal generation, differentiation, arborization, and formation of synaptic connections. Importantly, it enhances proliferation and synaptogenesis in the hippocampus. When injected into animals, taurine has an antidepressant effect. However, there is no in vivo evidence to show an association between taurine concentration in the human brain and the development of MDD. MethodsForty-one unmedicated young women with MDD (ages 18–29) and 43 healthy control participants matched for gender and age were recruited in South Korea. Taurine concentration was measured in the hippocampus, anterior cingulate cortex, and occipital cortex of the MDD and healthy control groups using proton magnetic resonance spectroscopy at 7T. Analysis of covariance was used to examine differences in taurine concentration, adjusting for age as a covariate. ResultsTaurine concentration in the hippocampus was lower (F1,75 = 5.729, p = .019, Δη2 = 0.073) for the MDD group (mean [SEM] = 0.91 [0.06] mM) than for the healthy control group (1.13 [0.06] mM). There was no significant difference in taurine concentration in the anterior cingulate cortex or occipital cortex between the two groups. ConclusionsThis study demonstrates that a lower level of taurine concentration in the hippocampus may be a novel characteristic of MDD.

Assessment of neurotransmitter imbalances within the anterior cingulate cortex in women with primary dysmenorrhea: An initial proton magnetic resonance spectroscopy study

PurposeThe neural pathophysiology underlying primary dysmenorrhea (PDM), which leads to poor mode and changes in central pain modulatory systems, remains largely unknown. The objective of this study was to investigate the changes in glutamate/glutamine (Glx) and gamma-aminobutyric acid (GABA+) levels within anterior cingulate cortex (ACC), and their associations with clinical indicators in PDM women. MethodsUsing 3 T proton magnetic resonance spectroscopy (1H-MRS), we acquired and compared ACC-Glx and ACC-GABA+ levels in PDMs (N = 41) and age- and education-matched healthy controls (HCs) (N = 39) during both the menstrual and periovulatory phases, and between menstrual and periovulatory phases within each group. Total creatine (Cr referencing) level was used as an endogenous reference. The correlations of ACC-neurotransmitter levels with clinical characteristics and the correlations of ACC-Glx with ACC-GABA+ levels in the two groups were analyzed. ResultsCompared to HCs or the periovulatory phase, PDMs exhibited significantly increased ACC-Glx levels (p < 0.05) during the menstrual phase. Positive correlations between GABA+ and Glx levels (r = 0.385, p = 0.025) were found in PDMs during the menstrual phase. ACC-GABA+ levels were associated with self-rating distress scale (SDS) scores (GABA+/Cr: r = 0.369, p = 0.045) and pain catastrophizing scale (PCS) scores (GABA+/Cr: r = 0.373, p = 0.042) in PDM group in only the menstrual phase. ConclusionOur study represents the first report of ACC-GABA+/Glx imbalances in PDMs during the menstrual phase, which may underlie the mechanisms mediating depression and painful catastrophic symptoms.