Results of the 2023 ISBI challenge to reduce GABA-edited MRS acquisition time.

PURPOSE: Use a conference challenge format to compare machine learning-based gamma-aminobutyric acid (GABA)-edited magnetic resonance spectroscopy (MRS) reconstruction models using one-quarter of the transients typically acquired during a complete scan. METHODS: There were three tracks: Track 1: simulated data, Track 2: identical acquisition parameters with in vivo data, and Track 3: different acquisition parameters with in vivo data. The mean squared error, signal-to-noise ratio, linewidth, and a proposed shape score metric were used to quantify model performance. Challenge organizers provided open access to a baseline model, simulated noise-free data, guides for adding synthetic noise, and in vivo data. RESULTS: Three submissions were compared. A covariance matrix convolutional neural network model was most successful for Track 1. A vision transformer model operating on a spectrogram data representation was most successful for Tracks 2 and 3. Deep learning (DL) reconstructions with 80 transients achieved equivalent or better SNR, linewidth and fit error compared to conventional 320 transient reconstructions. However, some DL models optimized linewidth and SNR without actually improving overall spectral quality, indicating a need for more robust metrics. CONCLUSION: DL-based reconstruction pipelines have the promise to reduce the number of transients required for GABA-edited MRS.

Measurement of metabolite levels and treatment-induced changes in hepatic metastases of gastro-esophageal cancer using 7-T phosphorus magnetic resonance spectroscopic imaging.

Methods for early treatment response evaluation to systemic therapy of liver metastases are lacking. Tumor tissue often exhibits an increased ratio of phosphomonoesters to phosphodiesters (PME/PDE), which can be noninvasively measured by phosphorus magnetic resonance spectroscopy (31P MRS), and may be a marker for early therapy response assessment in liver metastases. However, with commonly used 31P surface coils for liver 31P MRS, the liver is not fully covered, and metastases may be missed. The objective of this study was to demonstrate the feasibility of 31P MRS imaging (31P MRSI) with full liver coverage to assess 31P metabolite levels and chemotherapy-induced changes in liver metastases of gastro-esophageal cancer, using a 31P whole-body birdcage transmit coil in combination with a 31P body receive array at 7 T. 3D 31P MRSI data were acquired in two patients with hepatic metastases of esophageal cancer, before the start of chemotherapy and after 2 (and 9 in patient 2) weeks of chemotherapy. 3D 31P MRSI acquisitions were performed using an integrated 31P whole-body transmit coil in combination with a 16-channel body receive array at 7 T, with a field of view covering the full abdomen and a nominal voxel size of 20-mm isotropic. From the 31P MRSI data, 12 31P metabolite signals were quantified. Prior to chemotherapy initiation, both PMEs, that is, phosphocholine (PC) and phosphoethanolamine (PE), were significantly higher in all metastases compared with the levels previously determined in the liver of healthy volunteers. After 2 weeks of chemotherapy, PC and PE levels remained high or even increased further, resulting in increased PME/PDE ratios compared with healthy liver tissue, in correspondence with the clinical assessment of progressive disease after 2 months of chemotherapy. The suggested approach may present a viable tool for early therapy (non)response assessment of tumor metabolism in patients with liver metastases.

Structural identification and antioxidant activity of trans-9, trans-11, cis-15-conjugated linolenic acid converted by probiotics.

The study aimed to determine the chemical structures of octadecatrienoic acid isomers produced by probiotics through the bioconversion of α-linolenic acid and to assess their antioxidant capacities. The chemical structures were identified using nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), while the antioxidant capacities were evaluated in vitro and in cellular. The NMR signals obtained allowed for definitive characterization, with the main ion fragments detected being m/z 58.0062, 59.0140, 71.0141, 113.0616, 127.0777, and 181.5833. Compounds at concentrations below 40 µM maintained the antioxidant capacity of HepG2 cells by protecting endogenous antioxidative enzymes and mitochondrial membrane potential. However, doses higher than 40 µM increase oxidative damage and mitochondrial dysfunction. These results confirmed the structure of the probiotic-derived compound as trans9, trans11, cis15-conjugated linolenic acid. Additionally, appropriate doses of CLNA can alleviate oxidative stress induced by AAPH, while high doses aggravate cellular damage. These findings provide foundational information for the further exploration of probiotic-derived edible lipids.

Lonidamine Induced Selective Acidification and De-Energization of Prostate Cancer Xenografts: Enhanced Tumor Response to Radiation Therapy.

Prostate cancer is a multi-focal disease that can be treated using surgery, radiation, androgen deprivation, and chemotherapy, depending on its presentation. Standard dose-escalated radiation therapy (RT) in the range of 70-80 Gray (GY) is a standard treatment option for prostate cancer. It could be used at different phases of the disease (e.g., as the only primary treatment when the cancer is confined to the prostate gland, combined with other therapies, or as an adjuvant treatment after surgery). Unfortunately, RT for prostate cancer is associated with gastro-intestinal and genitourinary toxicity. We have previously reported that the metabolic modulator lonidamine (LND) produces cancer sensitization through tumor acidification and de-energization in diverse neoplasms. We hypothesized that LND could allow lower RT doses by producing the same effect in prostate cancer, thus reducing the detrimental side effects associated with RT. Using the Seahorse XFe96 and YSI 2300 Stat Plus analyzers, we corroborated the expected LND-induced intracellular acidification and de-energization of isolated human prostate cancer cells using the PC3 cell line. These results were substantiated by non-invasive 31P magnetic resonance spectroscopy (MRS), studying PC3 prostate cancer xenografts treated with LND (100 mg/kg, i.p.). In addition, we found that LND significantly increased tumor lactate levels in the xenografts using 1H MRS non-invasively. Subsequently, LND was combined with radiation therapy in a growth delay experiment, where we found that 150 µM LND followed by 4 GY RT produced a significant growth delay in PC3 prostate cancer xenografts, compared to either control, LND, or RT alone. We conclude that the metabolic modulator LND radio-sensitizes experimental prostate cancer models, allowing the use of lower radiation doses and diminishing the potential side effects of RT. These results suggest the possible clinical translation of LND as a radio-sensitizer in patients with prostate cancer.

Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study.

Introduction: Type C hepatic encephalopathy (HE) is a decompensating event of chronic liver disease leading to severe motor and cognitive impairment. The progression of type C HE is associated with changes in brain metabolite concentrations measured by 1H magnetic resonance spectroscopy (MRS), most noticeably a strong increase in glutamine to detoxify brain ammonia. In addition, alterations of brain cellular architecture have been measured ex vivo by histology in a rat model of type C HE. The aim of this study was to assess the potential of diffusion-weighted MRS (dMRS) for probing these cellular shape alterations in vivo by monitoring the diffusion properties of the major brain metabolites. Methods: The bile duct-ligated (BDL) rat model of type C HE was used. Five animals were scanned before surgery and 6- to 7-week post-BDL surgery, with each animal being used as its own control. 1H-MRS was performed in the hippocampus (SPECIAL, TE = 2.8 ms) and dMRS in a voxel encompassing the entire brain (DW-STEAM, TE = 15 ms, diffusion time = 120 ms, maximum b-value = 25 ms/µm2) on a 9.4 T scanner. The in vivo MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy). Results: The characteristic 1H-MRS pattern of type C HE, i.e., a gradual increase of brain glutamine and a decrease of the main organic osmolytes, was observed in the hippocampus of BDL rats. Overall increased metabolite diffusivities (apparent diffusion coefficient and intra-stick diffusivity-Callaghan's model, significant for glutamine, myo-inositol, and taurine) and decreased kurtosis coefficients were observed in BDL rats compared to control, highlighting the presence of osmotic stress and possibly of astrocytic and neuronal alterations. These results were consistent with the microstructure depicted by histology and represented by a decline in dendritic spines density in neurons, a shortening and decreased number of astrocytic processes, and extracellular edema. Discussion: dMRS enables non-invasive and longitudinal monitoring of the diffusion behavior of brain metabolites, reflecting in the present study the globally altered brain microstructure in BDL rats, as confirmed ex vivo by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.

Endurance training and hydroxyurea have synergistic effects on muscle function and energetics in sickle cell disease mice.

Sickle cell disease (SCD) is an hemoglobinopathy resulting in the production of an abnormal Hb (HbS) which can polymerize in deoxygenated conditions, leading to the sickling of red blood cells (RBC). These alterations can decrease the oxygen-carrying capacity leading to impaired function and energetics of skeletal muscle. Any strategy which could reverse the corresponding defects could be of interest. In SCD, endurance training is known to improve multiples muscle properties which restores patient's exercise capacity but present reduced effects in anemic patients. Hydroxyurea (HU) can increase fetal hemoglobin production which can reduce anemia in patients. The present study was conducted to determine whether HU can improve the effects of endurance training to improve muscle function and energetics. Twenty SCD Townes mice have been trained for 8 weeks with (n = 11) or without (n = 9) HU. SCD mice muscle function and energetics were analyzed during a standardized rest-exercise-recovery protocol, using Phosphorus-31 Magnetic resonance spectroscopy (31P-MRS) and transcutaneous stimulation. The combination of training and HU specifically decreased fatigue index and PCr consumption while muscle oxidative capacity was improved. These results illustrate the potential synergistic effects of endurance training and HU on muscle function and energetics in sickle cell disease.

GABA and Glx predict EEG responses of visual sensitivity in autism.

The mechanisms underlying atypical sensory processing in autism remain to be elucidated, but research points toward a role of the glutamatergic/GABAergic balance. To investigate the potential relationships between visual sensitivity and its molecular correlates in autism, we combined data from electroencephalography (EEG) and magnetic resonance spectroscopy (MRS) studies. Twenty autistic adults and sixteen neurotypical adults (NT) participated in both an EEG study assessing visual sensitivity (Sapey-Triomphe et al., Autism Research, 2023) and in an MRS study measuring Glx and GABA+ concentrations in the occipital cortex (Sapey-Triomphe et al., Molecular Autism, 2021). These studies revealed no group differences in neural detection thresholds or in Glx/GABA levels in the occipital cortex. Neural detection thresholds for contrast and spatial frequency (SF) were determined using fast periodic visual stimulations and neural frequency tagging. In the present study, Glx/GABA+ concentrations in the occipital cortex and neural detection thresholds did not differ between groups. Interestingly, lower Glx/GABA+ ratios were associated with lower contrast detection thresholds and higher SF detection thresholds. These correlations were also significant within the neurotypical and autistic groups. This report suggests that the Glx/GABA balance regulates visual detection thresholds across individuals. In both autistic and NTs, lower Glx/GABA ratios in the occipital cortex allow for better detection of visual inputs at the neural level. This study sheds light on the neurochemical underpinnings of visual sensitivity in autism and warrants further investigation.

Clinical Assessment of Magnetic Resonance Spectroscopy and Diffusion-Weighted Imaging in Diffuse Glioma: Insights Into Histological Grading and IDH Classification.

PURPOSE: To assess the diagnostic utility of clinical magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) in distinguishing between histological grading and isocitrate dehydrogenase (IDH) classification in adult diffuse gliomas. METHODS: A retrospective analysis was conducted on 247 patients diagnosed with adult diffuse glioma. Experienced radiologists evaluated DWI and MRS images. The Kruskal-Wallis test examined differences in DWI and MRS-related parameters across histological grades, while the Mann-Whitney U test assessed molecular classification. Receiver Operating Characteristic (ROC) curves evaluated parameter effectiveness. Survival curves, stratified by histological grade and IDH classification, were constructed using the Kaplan-Meier test. RESULTS: The cohort comprised 141 males and 106 females, with ages ranging from 19 to 85 years. The Kruskal-Wallis test revealed significant differences in ADC mean, Cho/NAA, and Cho/Cr concerning glioma histological grade (P < .01). Subsequent application of Dunn's test showed significant differences in ADC mean among each histological grade (P < .01). Notably, Cho/NAA exhibited a marked distinction between grade 2 and grade 3/4 gliomas (P < .01). The Mann-Whitney U test indicated that only ADC mean showed statistical significance for IDH molecular classification (P < .01). ROC curves were constructed to demonstrate the effectiveness of the specified parameters. Survival curves were also delineated to portray survival outcomes categorized by histological grade and IDH classification. Conclusions: Clinical MRS demonstrates efficacy in glioma histological grading but faces challenges in IDH classification. Clinical DWI's ADC mean parameter shows significant distinctions in both histological grade and IDH classification.

Post mortem analysis of hepatic volume and lipid content by magnetic resonance imaging and spectroscopy in fixed murine neonates.

Maternal obesity and hyperglycemia are linked to an elevated risk for obesity, diabetes, and steatotic liver disease in the adult offspring. To establish and validate a noninvasive workflow for perinatal metabolic phenotyping, fixed neonates of common mouse strains were analyzed postmortem via magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) to assess liver volume and hepatic lipid (HL) content. The key advantage of nondestructive MRI/MRS analysis is the possibility of further tissue analyses, such as immunohistochemistry, RNA extraction, and even proteomics, maximizing the data that can be gained per individual and therefore facilitating comprehensive correlation analyses. This study employed an MRI and 1H-MRS workflow to measure liver volume and HL content in 65 paraformaldehyde-fixed murine neonates at 11.7 T. Liver volume was obtained using semiautomatic segmentation of MRI acquired by a RARE sequence with 0.5-mm slice thickness. HL content was measured by a STEAM sequence, applied with and without water suppression. T1 and T2 relaxation times of lipids and water were measured for respective correction of signal intensity. The HL content, given as CH2/(CH2 + H2O), was calculated, and the intrasession repeatability of the method was tested. The established workflow yielded robust results with a variation of ~3% in repeated measurements for HL content determination. HL content measurements were further validated by correlation analysis with biochemically assessed triglyceride contents (R2 = 0.795) that were measured in littermates. In addition, image quality also allowed quantification of subcutaneous adipose tissue and stomach diameter. The highest HL content was measured in C57Bl/6N (4.2%) and the largest liver volume and stomach diameter in CBA (53.1 mm3 and 6.73 mm) and NMRI (51.4 mm3 and 5.96 mm) neonates, which also had the most subcutaneous adipose tissue. The observed effects were independent of sex and litter size. In conclusion, we have successfully tested and validated a robust MRI/MRS workflow that allows assessment of morphology and HL content and further enables paraformaldehyde-fixed tissue-compatible subsequent analyses in murine neonates.

Metabolite T1 relaxation times decrease across the adult lifespan.

Relaxation correction is an integral step in quantifying brain metabolite concentrations measured by in vivo magnetic resonance spectroscopy (MRS). While most quantification routines assume constant T1 relaxation across age, it is possible that aging alters T1 relaxation rates, as is seen for T2 relaxation. Here, we investigate the age dependence of metabolite T1 relaxation times at 3 T in both gray- and white-matter-rich voxels using publicly available metabolite and metabolite-nulled (single inversion recovery TI = 600 ms) spectra acquired at 3 T using Point RESolved Spectroscopy (PRESS) localization. Data were acquired from voxels in the posterior cingulate cortex (PCC) and centrum semiovale (CSO) in 102 healthy volunteers across 5 decades of life (aged 20-69 years). All spectra were analyzed in Osprey v.2.4.0. To estimate T1 relaxation times for total N-acetyl aspartate at 2.0 ppm (tNAA2.0) and total creatine at 3.0 ppm (tCr3.0), the ratio of modeled metabolite residual amplitudes in the metabolite-nulled spectrum to the full metabolite signal was calculated using the single-inversion-recovery signal equation. Correlations between T1 and subject age were evaluated. Spearman correlations revealed that estimated T1 relaxation times of tNAA2.0 (rs = -0.27; p < 0.006) and tCr3.0 (rs = -0.40; p < 0.001) decreased significantly with age in white-matter-rich CSO, and less steeply for tNAA2.0 (rs = -0.228; p = 0.005) and (not significantly for) tCr3.0 (rs = -0.13; p = 0.196) in graymatter-rich PCC. The analysis harnessed a large publicly available cross-sectional dataset to test an important hypothesis, that metabolite T1 relaxation times change with age. This preliminary study stresses the importance of further work to measure age-normed metabolite T1 relaxation times for accurate quantification of metabolite levels in studies of aging.

Hyperpolarized [1-13C]-pyruvate MRS evaluates immune potential and predicts response to radiotherapy in cervical cancer.

BACKGROUND: Monitoring pyruvate metabolism in the spleen is important for assessing immune activity and achieving successful radiotherapy for cervical cancer due to the significance of the abscopal effect. We aimed to explore the feasibility of utilizing hyperpolarized (HP) [1-13C]-pyruvate magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to evaluate pyruvate metabolism in the human spleen, with the aim of identifying potential candidates for radiotherapy in cervical cancer. METHODS: This prospective study recruited six female patients with cervical cancer (median age 55 years; range 39-60) evaluated using HP [1-13C]-pyruvate MRI/MRS at baseline and 2 weeks after radiotherapy. Proton (1H) diffusion-weighted MRI was performed in parallel to estimate splenic cellularity. The primary outcome was defined as tumor response to radiotherapy. The Student t-test was used for comparing 13C data between the groups. RESULTS: The splenic HP [1-13C]-lactate-to-total carbon (tC) ratio was 5.6-fold lower in the responders than in the non-responders at baseline (p = 0.009). The splenic [1-13C]-lactate-to-tC ratio revealed a 1.7-fold increase (p = 0.415) and the splenic [1-13C]-alanine-to-tC ratio revealed a 1.8-fold increase after radiotherapy (p = 0.482). The blood leukocyte differential count revealed an increased proportion of neutrophils two weeks following treatment, indicating enhanced immune activity (p = 0.013). The splenic apparent diffusion coefficient values between the groups were not significantly different. CONCLUSIONS: This exploratory study revealed the feasibility of HP [1-13C]-pyruvate MRS of the spleen for evaluating baseline immune potential, which was associated with clinical outcomes of cervical cancer after radiotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04951921 , registered 7 July 2021. RELEVANCE STATEMENT: This prospective study revealed the feasibility of using HP 13C MRI/MRS for assessing pyruvate metabolism of the spleen to evaluate the patients' immune potential that is associated with radiotherapeutic clinical outcomes in cervical cancer. KEY POINTS: • Effective radiotherapy induces abscopal effect via altering immune metabolism. • Hyperpolarized 13C MRS evaluates patients' immune potential non-invasively. • Pyruvate-to-lactate conversion in the spleen is elevated following radiotherapy.

Model-based frequency-and-phase correction of 1H MRS data with 2D linear-combination modeling.

Purpose: Retrospective frequency-and-phase correction (FPC) methods attempt to remove frequency-and-phase variations between transients to improve the quality of the averaged MR spectrum. However, traditional FPC methods like spectral registration struggle at low SNR. Here, we propose a method that directly integrates FPC into a two-dimensional linear-combination model (2D-LCM) of individual transients ('model-based FPC'). We investigated how model-based FPC performs compared to the traditional approach, i.e., spectral registration followed by 1D-LCM in estimating frequency-and-phase drifts and, consequentially, metabolite level estimates. Methods: We created synthetic in-vivo-like 64-transient short-TE sLASER datasets with 100 noise realizations at 5 SNR levels and added randomly sampled frequency and phase variations. We then used this synthetic dataset to compare the performance of 2D-LCM with the traditional approach (spectral registration, averaging, then 1D-LCM). Outcome measures were the frequency/phase/amplitude errors, the standard deviation of those ground-truth errors, and amplitude Cramér Rao Lower Bounds (CRLBs). We further tested the proposed method on publicly available in-vivo short-TE PRESS data. Results: 2D-LCM estimates (and accounts for) frequency-and-phase variations directly from uncorrected data with equivalent or better fidelity than the conventional approach. Furthermore, 2D-LCM metabolite amplitude estimates were at least as accurate, precise, and certain as the conventionally derived estimates. 2D-LCM estimation of frequency and phase correction and amplitudes performed substantially better at low-to-very-low SNR. Conclusion: Model-based FPC with 2D linear-combination modeling is feasible and has great potential to improve metabolite level estimation for conventional and dynamic MRS data, especially for low-SNR conditions, e.g., long TEs or strong diffusion weighting.

Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database.

BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) due to an X-linked OTC mutation, is responsible for moderate to severe hyperammonemia (HA) with substantial morbidity and mortality. About 80% of females with OTCD remain apparently "asymptomatic" with limited studies of their clinical characteristics and long-term health vulnerabilities. Multimodal neuroimaging studies and executive function testing have shown that asymptomatic females exhibit limitations when stressed to perform at higher cognitive load and had reduced activation of the prefrontal cortex. This retrospective study aims to improve understanding of factors that might predict development of defined complications and serious illness in apparent asymptomatic females. A proband and her daughter are presented to highlight the utility of multimodal neuroimaging studies and to underscore that asymptomatic females with OTCD are not always asymptomatic. METHODS: We review data from 302 heterozygote females with OTCD enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history database. We apply multiple neuroimaging modalities in the workup of a proband and her daughter. RESULTS: Among the females in the database, 143 were noted as symptomatic at baseline (Sym). We focused on females who were asymptomatic (Asx, n = 111) and those who were asymptomatic initially upon enrollment in study but who later became symptomatic sometime during follow-up (Asx/Sym, n = 22). The majority of Asx (86%) and Asx/Sym (75%) subjects did not restrict protein at baseline, and ~38% of Asx and 33% of Asx/Sym subjects suffered from mild to severe neuropsychiatric conditions such as mood disorder and sleep problems. The risk of mild to severe HA sometime later in life for the Asx and Asx/Sym subjects as a combined group was ~4% (5/133), with ammonia ranging from 77 to 470 µM and at least half (2/4) of subjects requiring hospital admission and nitrogen scavenger therapy. For this combined group, the median age of first HA crisis was 50 years, whereas the median age of first symptom which included neuropsychiatric and/or behavioral symptoms was 17 years. The multimodal neuroimaging studies in female heterozygotes with OTCD also underscore that asymptomatic female heterozygotes with OTCD (e.g., proband) are not always asymptomatic. CONCLUSIONS: Analysis of Asx and Asx/Sym females with OTCD in this study suggests that future evidence-based management guidelines and/or a clinical risk score calculator for this cohort could be useful management tools to reduce morbidity and improve long-term quality of life.

Applications of chromatographic methods in metabolomics: A review.

Chromatography is a robust and reliable separation method that can use various stationary phases to separate complex mixtures commonly seen in metabolomics. This review examines the types of chromatography and stationary phases that have been used in targeted or untargeted metabolomics with methods such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. General considerations for sample pretreatment and separations in metabolomics are considered, along with the various supports and separation formats for chromatography that have been used in such work. The types of liquid chromatography (LC) that have been most extensively used in metabolomics will be examined, such as reversed-phase liquid chromatography and hydrophilic liquid interaction chromatography. In addition, other forms of LC that have been used in more limited applications for metabolomics (e.g., ion-exchange, size-exclusion, and affinity methods) will be discussed to illustrate how these techniques may be utilized for new and future research in this field. Multidimensional LC methods are also discussed, as well as the use of gas chromatography and supercritical fluid chromatography in metabolomics. In addition, the roles of chromatography in NMR- vs. MS-based metabolomics are considered. Applications are given within the field of metabolomics for each type of chromatography, along with potential advantages or limitations of these separation methods.

Correlation between abnormal cellular immune and changes of magnetic resonance spectroscopy in patients with Alzheimer's disease.

BACKGROUND: Evidence from previous studies indicates that neuroinflammation contributes to the onset of Alzheimer's Disease (AD). Moreover, cellular dysfunction is induced by impaired signaling of neurotransmitters. This study aimed to explore the correlation between cellular immune dysfunction and neurotransmitter changes through cranial Magnetic Resonance Spectroscopy (MRS) in AD patients. METHODS: Here, 32 AD, 40 Vascular Dementia (VD), and 35 Non-Dementia Elderly Control (NDE) cases were enrolled. Flow cytometry was performed to characterize lymphocyte subsets in plasma samples. The IL-1ß and Caspase-1 levels were detected by ELISA. The NLRP3 expression level was measured by Western Blot (WB). The equivalence of N-acetylaspartate (NAA), Creatine (Cr), Choline (Cho), and Inositol (MI) in bilateral hippocampi of patients was examined by MRS. The association of NAA/Cr or MI/Cr ratios with the proportion of T lymphocyte subsets or NK cell subsets was determined through single-factor correlation analysis. RESULTS: The proportion of T lymphocyte subsets was significantly lower in the AD group than in the NDE group (P < 0.01). On the other hand, the Caspase-1, NLRP3, and IL-1ß protein expression levels were significantly higher in the AD group than in the other groups. Further analysis showed that the NAA/Cr ratio was lower in the AD group than in the NDE group. Additionally, a significant positive correlation was found between the NAA/Cr ratio and the MMSE score (r = 0.81, P < 0.01). Moreover, a significant positive correlation was observed between the NAA/Cr and T lymphocyte ratios. The NAA/Cr ratio was significantly negatively correlated with the proportion of NK cells in the blood (r = ï¼0.83, P < 0.01). A significant negative correlation was also recorded between the MI/Cr and T cell ratios in blood samples. CONCLUSIONS: Impaired cellular immune dysfunction in AD patients was significantly correlated with abnormal MRS. Neuroimmune dysfunction may contribute to the pathogenesis of AD and alter the metabolism of neurotransmitters such as aspartic acid and MI in the brains of AD patients. TRIAL REGISTRATION: Not applicable.

1H, 13C, and 15N backbone and methyl group resonance assignments of ricin toxin A subunit.

Ricin is a potent plant toxin that targets the eukaryotic ribosome by depurinating an adenine from the sarcin-ricin loop (SRL), a highly conserved stem-loop of the rRNA. As a category-B agent for bioterrorism it is a prime target for therapeutic intervention with antibodies and enzyme blocking inhibitors since no effective therapy exists for ricin. Ricin toxin A subunit (RTA) depurinates the SRL by binding to the P-stalk proteins at a remote site. Stimulation of the N-glycosidase activity of RTA by the P-stalk proteins has been studied extensively by biochemical methods and by X-ray crystallography. The current understanding of RTA's depurination mechanism relies exclusively on X-ray structures of the enzyme in the free state and complexed with transition state analogues. To date we have sparse evidence of conformational dynamics and allosteric regulation of RTA activity that can be exploited in the rational design of inhibitors. Thus, our primary goal here is to apply solution NMR techniques to probe the residue specific structural and dynamic coupling active in RTA as a prerequisite to understand the functional implications of an allosteric network. In this report we present de novo sequence specific amide and sidechain methyl chemical shift assignments of the 267 residue RTA in the free state and in complex with an 11-residue peptide (P11) representing the identical C-terminal sequence of the ribosomal P-stalk proteins. These assignments will facilitate future studies detailing the propagation of binding induced conformational changes in RTA complexed with inhibitors, antibodies, and biologically relevant targets.

The influence of anterior cingulate GABA+ and glutamate on emotion regulation and reactivity in adolescents and adults.

During adolescence, emotion regulation and reactivity are still developing and are in many ways qualitatively different from adulthood. However, the neurobiological processes underpinning these differences remain poorly understood, including the role of maturing neurotransmitter systems. We combined magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (dACC) and self-reported emotion regulation and reactivity in a sample of typically developed adolescents (n = 37; 13-16 years) and adults (n = 39; 30-40 years), and found that adolescents had higher levels of glutamate to total creatine (tCr) ratio in the dACC than adults. A glutamate Í age group interaction indicated a differential relation between dACC glutamate levels and emotion regulation in adolescents and adults, and within-group follow-up analyses showed that higher levels of glutamate/tCr were related to worse emotion regulation skills in adolescents. We found no age-group differences in gamma-aminobutyric acid+macromolecules (GABA+) levels; however, emotion reactivity was positively related to GABA+/tCr in the adult group, but not in the adolescent group. The results demonstrate that there are developmental changes in the concentration of glutamate, but not GABA+, within the dACC from adolescence to adulthood, in accordance with previous findings indicating earlier maturation of the GABA-ergic than the glutamatergic system. Functionally, glutamate and GABA+ are positively related to emotion regulation and reactivity, respectively, in the mature brain. In the adolescent brain, however, glutamate is negatively related to emotion regulation, and GABA+ is not related to emotion reactivity. The findings are consistent with synaptic pruning of glutamatergic synapses from adolescence to adulthood and highlight the importance of brain maturational processes underlying age-related differences in emotion processing.

Metabolic coupling between glutamate and N-acetylaspartate in the human brain.

A metabolic coupling between glutamate and N-acetylaspartate measured by in vivo magnetic resonance spectroscopy has been recently reported in the literature with inconsistent findings. In this study, confounders originating from Pearson's spurious correlation of ratios and spectral correlation due to overlapping magnetic resonance spectroscopy signals of glutamate and N-acetylaspartate were practically eliminated to facilitate the determination of any metabolic link between glutamate and N-acetylaspartate in the human brain using in vivo magnetic resonance spectroscopy. In both occipital and medial prefrontal cortices of healthy individuals, correlations between glutamate and N-acetylaspartate were found to be insignificant. Our results do not lend support to a recent hypothesis that N-acetylaspartate serves as a significant reservoir for the rapid replenishment of glutamate during signaling or stress.

Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a serious disease causing human dementia and social problems. The quality of life and prognosis of AD patients have attracted much attention. The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important. AIM: To study the relationship among cognitive dysfunction, abnormal cellular immune function, neuroimaging results and poor prognostic factors in patients. METHODS: A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020. Collect cognitive dysfunction performance characteristics, laboratory test data and neuroimaging data from medical records within 24 h of admission, including Mini Mental State Examination Scale score, drawing clock test, blood T lymphocyte subsets, and neutrophils and lymphocyte ratio (NLR), disturbance of consciousness, extrapyramidal symptoms, electroencephalogram (EEG) and head nucleus magnetic spectroscopy (MRS) and other data. Multivariate logistic regression analysis was used to determine independent prognostic factors. the modified Rankin scale (mRS) was used to determine whether the prognosis was good. The correlation between drug treatment and prognostic mRS score was tested by the rank sum test. RESULTS: Univariate analysis showed that abnormal cellular immune function, extrapyramidal symptoms, obvious disturbance of consciousness, abnormal EEG, increased NLR, abnormal MRS, and complicated pneumonia were related to the poor prognosis of AD patients. Multivariate logistic regression analysis showed that the decrease in the proportion of T lymphocytes in the blood after abnormal cellular immune function (odd ratio: 2.078, 95% confidence interval: 1.156-3.986, P < 0.05) was an independent risk factor for predicting the poor prognosis of AD. The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score (r = 0.578, P < 0.05). CONCLUSION: The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD. It is recommended that the proportion of T lymphocytes < 55% is used as the cut-off threshold for predicting the poor prognosis of AD. The early and continuous drug treatment is associated with a good prognosis.