GPX4 allosteric activators inhibit ferroptosis and exert myocardial protection in doxorubicin-induced myocardial injury mouse model.

Ferroptosis is a unique type of non-apoptotic form of cell death characterized by increased lipid hydroperoxide levels. It has relevance for a number of pathological conditions including multiple organ injuries and degenerative diseases. GPX4 plays an important role in ferroptosis by repairing lipid hydroperoxides. Based on the reported allosteric sites, we obtained the GPX4 allosteric activator hit compound A9 through virtual screening. A9 can bind to GPX4 and prevent RSL3-induced lipid peroxidation production in HT-1080 cells. In addition, A9 can specifically rescue erastin-induced cell death. Further chemical modification and structure-activity relationship studies afforded the optimized compound C3. C3 showed the activity of alleviating myocardial injury in the doxorubicin-induced myocardial injury mouse model. This study demonstrated that inhibiting ferroptosis by activating GPX4 is expected to be a potential solution to treat myocardial injury.

Differential Signal-Amplitude-Modulated Multi-Beam Remote Optical Touch Based on Grating Antenna.

As screen sizes are becoming larger and larger, exceeding human physical limitations for direct interaction via touching, remote control is inevitable. However, among the current solutions, inertial gyroscopes are susceptible to positional inaccuracies, and gesture recognition is limited by cameras' focus depths and viewing angles. Provided that the issue of ghost points can be effectively addressed, grating antenna light-trapping technology is an ideal candidate for multipoint inputs. Therefore, we propose a differential amplitude modulation scheme for grating antenna-based multi-beam optical touch, which can recognize different incidence points. The amplitude of the incident beams was first coded with different pulse widths. Then, following the capture of incident beams by the grating antenna and their conversion into electrical currents by the aligned detector arrays, the incident points of the individual beams were recognized and differentiated. The scheme was successfully verified on an 18-inch screen, where two-point optical touch with a position accuracy error of under 3 mm and a response time of less than 7 ms under a modulation frequency of 10 kHz on both incident beams was achieved. This work demonstrates a practical method to achieve remote multi-point touch, which can make digital mice more accurately represent the users' pointing directions by obeying the natural three-point one-line aiming rule instantaneously.

Aberrant concordance among dynamics of spontaneous brain activity in patients with migraine without aura: A multivariate pattern analysis study.

Background: Alterations in the static and dynamic characteristics of spontaneous brain activity have been extensively studied to investigate functional brain changes in migraine without aura (MwoA). However, alterations in concordance among the dynamics of spontaneous brain activity in MwoA remain largely unknown. This study aimed to determine the possibilities of diagnosis based on the concordance indices. Methods: Resting-state functional MRI scans were performed on 32 patients with MwoA and 33 matched healthy controls (HCs) in the first cohort, as well as 36 patients with MwoA and 32 HCs in the validation cohort. The dynamic indices including fractional amplitude of low-frequency fluctuation, regional homogeneity, voxel-mirrored homotopic connectivity, degree centrality and global signal connectivity were analyzed. We calculated the concordance of grey matter volume-wise (across voxels) and voxel-wise (across time windows) to quantify the degree of integration among different functional levels represented by these dynamic indices. Subsequently, the voxel-wise concordance alterations were analyzed as features for multi-voxel pattern analysis (MVPA) utilizing the support vector machine. Results: Compared with that of HCs, patients with MwoA had lower whole-grey matter volume-wise concordance, and the mean value of volume-wise concordance was negatively correlated with the frequency of migraine attacks. The MVPA results revealed that the most discriminative brain regions were the right thalamus, right cerebellar Crus II, left insula, left precentral gyrus, right cuneus, and left inferior occipital gyrus. Conclusions: Concordance alterations in the dynamics of spontaneous brain activity in brain regions could be an important feature in the identification of patients with MwoA.

Modulation of temporal and occipital cortex by acupuncture in non-menstrual MWoA patients: a rest BOLD fMRI study.

OBJECTIVE: To investigate the changes in amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) values before and after acupuncture in young women with non-menstrual migraine without aura (MWoA) through rest blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI). METHODS: Patients with non-menstrual MWoA (Group 1, n = 50) and healthy controls (Group 2, n = 50) were recruited. fMRI was performed in Group 1 at 2 time points: before acupuncture (time point 1, TP1); and after the end of all acupuncture sessions (time point 2, TP2), and performed in Group 2 as a one-time scan. Patients in Group 1 were assessed with the Migraine Disability Assessment Questionnaire (MIDAS) and the Short-Form McGill Pain Questionnaire (SF-MPQ) at TP1 and TP2 after fMRI was performed. The ALFF and DC values were compared within Group 1 at two time points and between Group 1 and Group2. The correlation between ALFF and DC values with the statistical differences and the clinical scales scores were analyzed. RESULTS: Brain activities increased in the left fusiform gyrus and right angular gyrus, left middle occipital gyrus, and bilateral prefrontal cortex and decreased in left inferior parietal lobule in Group 1, which had different ALFF values compared with Group 2 at TP1. The bilateral fusiform gyrus, bilateral inferior temporal gyrus and right middle temporal gyrus increased and right angular gyrus, right superior marginal gyrus, right inferior parietal lobule, right middle occipital gyrus, right superior frontal gyrus, right middle frontal gyrus, right anterior central gyrus, and right supplementary motor area decreased in activity in Group 1 had different DC values compared with Group 2 at TP1. ALFF and DC values of right inferior temporal gyrus, right fusiform gyrus and right middle temporal gyrus were decreased in Group1 at TP1 compared with TP2. ALFF values in the left middle occipital area were positively correlated with the pain degree at TP1 in Group1 (correlation coefficient r, r = 0.827, r = 0.343; P < 0.01, P = 0.015). The DC values of the right inferior temporal area were positively correlated with the pain degree at TP1 in Group 1 (r = 0.371; P = 0.008). CONCLUSION: Spontaneous brain activity and network changes in young women with non-menstrual MwoA were altered by acupuncture. The right temporal area may be an important target for acupuncture modulated brain function in young women with non-menstrual MwoA.

Altered effective connectivity from cerebellum to motor cortex in chronic low back pain: A multivariate pattern analysis and spectral dynamic causal modeling study.

To explore the central processing mechanism of pain perception in chronic low back pain (cLBP) using multi-voxel pattern analysis (MVPA) based on the static and dynamic fractional amplitude of low-frequency fluctuations (fALFF) analysis, and spectral dynamic causal modeling (spDCM). Thirty-two patients with cLBP and 29 matched healthy controls (HCs) for the first cohort and 24 patients with cLBP and 22 HCs for the validation cohort underwent resting-state fMRI scan. The alterations in static and dynamic fALFF were as classification features to distinguish patients with cLBP from HCs. The brain regions gotten from the MVPA results were used for further spDCM analysis. We found that the most discriminative brain regions that contributed to the classification were the right supplementary motor area (SMA.R), left paracentral lobule (PCL.L), and bilateral cerebellar Crus II. The spDCM results displayed decreased excitatory influence from the bilateral cerebellar Crus II to PCL.L in patients with cLBP compared with HCs. Moreover, the conversion of effective connectivity from the bilateral cerebellar Crus II to SMA.R from excitatory influence to inhibitive influence, and the effective connectivity strength exhibited partially mediated effects on Chinese Short Form Oswestry Disability Index Questionnaire (C-SFODI) scores. Our findings suggest that the cerebellum and its weakened or inhibited connections to the motor cortex may be one of the underlying feedback pathways for pain perception in cLBP, and partially mediate the degree of dysfunction.

Paleo-Geomorphology Determines Spatial Variability of Geogenic Ammonium Concentration in Quaternary Aquifers.

Naturally occurring (i.e., geogenic) ammonium in groundwater has been widely detected globally, but the major controls on its regional distribution have been poorly characterized. Here, we identified the dominant role of paleo-geomorphology driven by paleo-climate in controlling the spatial variability of geogenic ammonium in groundwater using random forest algorithm and revealed the underlying mechanisms based on borehole sediment analysis of data obtained from the Dongting Lake Plain of the central Yangtze River basins in China. In the paleo-channel (PC) area, the aquifer depth-matched sediments were deposited during the last deglaciation when warm climate resulted in rapid filling into incised valleys, and terrestrial organic matter (OM) mainly as lignin experienced less degradation prior to sedimentation and had lower humification, higher N abundance, and nominal oxidation state of carbon (NOSC). In the paleo-interfluve (PI) area, the depth-matched sediments were deposited during the last glaciation, followed by intensive erosion in the surface during the last glacial maximum, and terrestrial OM mainly as lignin had been partly degraded into aliphatics prior to sedimentation and had higher humification, lower N abundance, and NOSC. As a result, under the present anaerobic conditions, less-humic and N-rich OM with more oxidized C tends to be more intensively mineralized into ammonium in the PC area than those in the PI area. These findings highlight the importance of paleo-geomorphology with paleo-climate in controlling the enrichment of geogenic ammonium in groundwater, which has a universal significance for understanding the genesis and distribution of high N loads in the aquatic environment worldwide.

Enrichment of geogenic phosphorus in a coastal groundwater system: New insights from dissolved organic matter characterization.

High concentrations of geogenic phosphorus (P) in coastal aquifer systems pose a serious and continuous threat to the health of marine ecosystems. A major source for geogenic P enrichment in aquifer systems is the mineralization of P-containing organic matter. However, the mechanisms that drive the enrichment remain unclear. Therefore, our study sought to characterize the occurrence, sources, and enrichment mechanisms of geogenic P in a coastal confined aquifer system of the Pearl River Delta, southern China. To achieve this, we conducted Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and fluorescence excitation-emission-matrix spectra (EEMs) as well as hydrochemistry and stable carbon isotope analyses. Our findings indicated that intense degradation of P-containing organic matter produced up to 8.07 mg/L of geogenic P in a reducing environment with abundant organic matter. The dissolved organic matter (DOM) of high-P groundwater (P > 1 mg/L) contained more humic-like fluorophores and exhibited higher humification. Groundwater with high P concentrations contained more aliphatic compounds and highly unsaturated-low O compounds, and the enrichment of P was mostly associated with CHOP compounds in the region of aliphatic compounds and CHON2P compounds in the region of highly unsaturated-low O compounds. Different types of dissolved organic phosphorus (DOP) can be mineralized into P, and even the mineralization of phosphonates takes precedence over the more unstable phosphate esters. P produced by the metabolism of different types of DOP was assimilated by marine microorganisms (e.g., heterotrophic bacteria and archaea), and the newly synthesized organic P compounds by chemosynthesis were subsequently released into the groundwater. Over time, P continues to be enriched in the aquifer system. This study provides new insights into subsurface P cycling in coastal aquatic systems.

A true response of the brain network during electroacupuncture stimulation at scalp acupoints: An fMRI with simultaneous EAS study.

OBJECTIVES: The aim of this study was to explore simultaneous brain network responses to electroacupuncture stimulation (EAS) at scalp acupoints by accounting for placebo effects. MATERIALS AND METHODS: Sixty healthy subjects were recruited and randomly divided into two groups: Group 1 and Group 2. Functional magnetic resonance imaging (fMRI) was performed in Group 1 with sham acupuncture stimulation at acupoints Shenting (GV24) and Touwei (ST8) without EAS. Group 2 underwent verum EAS at the same acupoints during fMRI. Independent component analysis was used to analyze the fMRI data. Full-factor statistical analysis was used to compare the differences in fMRI data between the two groups and evaluate the changes in functional connectivity in brain networks after verum electrical stimulation (Group 1 [after sham electrical current stimulation - before sham electrical current stimulation] - Group 2 [after verum electrical current stimulation - before verum electrical current stimulation]) (p <.001, extent threshold k = 20 voxels). RESULTS: Six brain networks were identified. Significant increased functional connectivity was observed in the right and left executive control networks, sensorimotor network, and attention network, while decreased functional connectivity was mainly found in the default mode network. There were no statistically significant differences in the salience network. CONCLUSIONS: fMRI with simultaneous EAS provides a method to explore brain network responses due to EAS at scalp acupoints. The networks responsible for cognition are differentially activated by EAS in a coordinated manner.

Comparison of contrast-enhanced fat-suppressed T1-3D-VIBE and T1-TSE MRI in evaluating anal fistula.

OBJECTIVE: To evaluate the accuracy of contrast-enhanced (CE) fat-suppressed three-dimensional (3D) T1-weighted imaging with volumetric interpolated breath-hold examination (FS-T1-3D-VIBE) and fat-suppressed T1-weighted turbo spin echo (FS-T1-TSE) sequence in characteristics of anal fistula. METHODS: One hundred and two patients underwent perianal CE-MRI examination on a 3T scanner including FS-T1-3D-VIBE and FS-T1-TSE sequences before surgery. The performance of each sequence was evaluated in terms of fistula classification, clarity of internal opening, number and position of internal openings including the distance between internal opening and anal verge, presence of secondary tracts and blind-ending sinus tracts. MRI findings were compared with surgical findings. Signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) of fistula, gluteus maximus, and subcutaneous fat were compared between CE FS-T1-TSE and CE FS-T1-3D-VIBE. RESULTS: Compared with CE FS-T1-TSE, CE FS-T1-3D-VIBE displayed more accurate in secondary tract, lithotomy position of the internal opening and the distance between internal opening and anal verge (P < 0.05). CE FS-T1-3D-VIBE was found superior to CE FS-T1-TSE in the clarity of the internal openings and in the diagnostic accuracy of blind-ending sinus tracts and complex fistulas in Standard Practice Task Force classification (P < 0.05). CE FS-T1-3D-VIBE achieved higher SNRs and CNRs in fistula and gluteus maximus than CE FS-T1-TSE (P ≤ 0.001). CONCLUSION: CE-MRI of FS-T1-3D-VIBE might be a more valuable noninvasive technique than FS-T1-TSE to evaluate the anal fistula on evaluating the lithotomy position of internal opening, distance between internal opening and anal verge, clarity of internal opening, secondary tract, blind-ending sinus tract and classification of the complex fistula. The trial registration number for this prospective trial was Chi-TR1800020206 and the trial registration date was December 20, 2018.

The cumulative therapeutic effect of acupuncture in patients with migraine without aura: Evidence from dynamic alterations of intrinsic brain activity and effective connectivity.

We explored the dynamic alterations of intrinsic brain activity and effective connectivity after acupuncture treatment to investigate the underlying neurological mechanism of acupuncture treatment in patients with migraine without aura (MwoA). The Functional Magnetic Resonance Imaging (fMRI) scans were separately obtained at baseline, after the first and 12th acupuncture sessions in 40 patients with MwoA. Compared with the healthy controls (HCs), patients with MwoA mostly showed a decreased dynamic amplitude of low-frequency fluctuation (dALFF) variability in the rostral ventromedial medulla (RVM), superior lobe of left cerebellum (Cerebellum_Crus1_L), right precuneus (PCUN.R), and so on. The decreased dALFF variability of RVM, Cerebellum_Crus1_L, and PCUN.R progressively recovered after the first and 12th acupuncture treatment sessions as compared to the baseline. There was gradually increased dynamic effective connectivity (DEC) variability in RVM outflow to the right middle frontal gyrus, left insula, right precentral gyrus, and right supramarginal gyrus, and gradually enhanced DEC variability from the right fusiform gyrus inflow to RVM. Furthermore, the gradually increased DEC variability was found from Cerebellum_Crus1_L outflow to the left middle occipital gyrus and the left precentral gyrus, from PCUN.R outflow to the right thalamus. These dALFF variabilities were positively correlated with the frequency of migraine attacks and negatively correlated with disease duration at baseline. The dynamic Granger causality analysis (GCA) coefficients of this DEC variability were positively correlated with Migraine-Specific Quality of Life Questionnaire scores and negatively correlated with the frequency of migraine attacks and visual analog scale (VAS) scores after 12th acupuncture sessions. Our results were analyzed by a longitudinal fMRI in the absence of a sham acupuncture control group and provided insight into the dynamic alterations of brain activity and effective connectivity in patients with MwoA after acupuncture intervention. Acupuncture might relieve MwoA by increasing the effective connectivity of RVM, Cerebellum_Crus1_L, and PCUN.R to make up for the decreased dALFF variability in these brain areas.

Ultrafast liquid chromatography-tandem mass spectrometry determination of donepezil in human plasma: application to a bioequivalence study.

A liquid chromatography equipped with tandem mass spectrometric method using multi-stage flow rates was developed for the determination of donepezil in human plasma to support a randomized, crossover bioequivalence (BE) study in which healthy volunteers each received a single oral dose of the reference and test formulations of 10 mg donepezil hydrochloride. This integrated liquid chromatography with tandem mass spectrometry (LC-MS/MS) system with electrospray ionization and a deuterium-labeled internal standard (IS) were employed for the positive multiple-reaction-monitoring (MRM) analyses. The baseline separation using a high-resolution monolithic column under gradient and flexible flowrate conditions between donepezil and multiple interfering peaks from the extracted quality control, calibration standard and study plasma samples following simple protein precipitation extraction procedures was accomplished within 1.5 minutes. The ultrafast monolithic column performance in terms of chromatographic separation efficiency, peak asymmetry and resolution and retention time reproducibility was found to be sustainable. The linear dynamic range was detected over a concentration range of 0.2-50 ng/mL. The intra- and inter-day assay accuracy and precision were within 15% for the analyte in individual biological fluids. A positive correlation coefficient (r) greater than 0.995 for donepezil concentrations in study plasma samplers measured by the proposed and the other validated LC-MS/MS methods in support of a bioequivalence study was observed.

2-µm fused-core column ultra-high-performance liquid chromatography/tandem mass spectrometric determination of donepezil in human plasma: Application to a bioequivalence study.

Ultra-high-performance liquid chromatography (UHPLC) hyphenated to tandem mass spectrometric methods using the dimethylpentafluorophenylpropyl stationary phase with polar and nonpolar characteristics of a 2-µm fused-core silica particle packing were evaluated to perform efficient separation for the analysis of donepezil in human plasma. The fused-core silica particle design providing the shorter diffusional mass transfer path for the analytes is less affected in resolving power by increasing mobile-phase velocity for faster chromatographic resolution between the administered compound and multiple interfering peaks from the extracted quality control, calibration standard and study samples following simple protein precipitation extraction procedures. In this work, two UHPLC-MS/MS approaches requiring 1.2 min per sample run time and neither expensive ultra-high-pressure instrumentation nor new laboratory protocols were applied and compared for determination of donepezil in human plasma at sub-nanograms per milliliter region to support a randomized, crossover bioequivalence (BE) study in which healthy volunteers each received a single oral dose of the test and reference formulations of 10 mg donepezil hydrochloride. The column performance in terms of chromatographic separation efficiency, peak asymmetry and resolution and retention time reproducibility was found to be sustainable over a thousand extracted plasma injections. The linear dynamic range was detected over a concentration range of 0.2-50 ng/mL. The intra- and inter-day assay accuracy and precision were within 15% for the analyte in individual biological fluids. Positive correlation coefficients (r) greater than 0.98 and 0.99 for donepezil concentrations in study plasma samplers measured by the proposed UHPLC-MS/MS approaches and another validated HPLC-MS/MS method were observed.

The Changes of Brain Function After Spinal Manipulation Therapy in Patients with Chronic Low Back Pain: A Rest BOLD fMRI Study.

OBJECTIVE: To investigate the changes of regional homogeneity (Reho) values before and after spinal manipulative therapy (SMT) in patients with chronic low back pain (CLBP) through rest blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI). METHODS: Patients with CLBP (Group 1, n = 20) and healthy control subjects (Group 2, n = 20) were recruited. The fMRI was performed three times in Group 1 before SMT (time point 1, TP1), after the first SMT (time point 2, TP2), after the sixth SMT (time point 3, TP3), and for one time in Group 2, which received no intervention. The clinical scales were finished in Group 1 every time before fMRI was performed. The Reho values were compared among Group 1 at different time points, and between Group 1 and Group 2. The correlation between Reho values with the statistical differences and the clinical scale scores were calculated. RESULTS: The bilateral precuneus and right mid-frontal gyrus in Group 1 had different Reho values compared with Group 2 at TP1. The Reho values were increased in the left precuneus and decreased in the left superior frontal gyrus in Group 1 at TP2 compared with TP1. The Reho values were increased in the left postcentral gyrus and decreased in the left posterior cingulate cortex and the superior frontal gyrus in Group 1 at TP3 compared with TP1. The ReHo values of the left precuneus in Group 1 at TP1 were negatively correlated with the pain degree at TP1 and TP2 (r = -0.549, -0.453; p = 0.012, 0.045). The Reho values of the middle temporal gyrus in Group 1 at TP3 were negatively correlated with the changes of clinical scale scores between TP3 and TP1 (r = 0.454, 0.559; p = 0.044, 0.01). CONCLUSION: Patients with CLBP showed abnormal brain function activity, which was altered after SMT. The Reho values of the left precuneus could predict the immediate analgesic effect of SMT.

Performance of a Flexible 12-Channel Head Coil in Comparison to Commercial 16- And 24-Channel Rigid Head Coils.

PURPOSE: To compare the performance of a 12-channel flexible head coil (HFC12) with commercial 16-channel (HRC16) and 24-channel (HRC24) rigid coils. METHODS: The phantom study was performed on a 1.5 T MR scanner with HFC12, HRC16, and HRC24. The SNR and noise correlation matrix of T1WI, T2WI, and diffusion weighted imaging (DWI) were measured. The SNR profiles were created according to the SNR. In addition, 1/g-factors were calculated in different acceleration directions. In the in vivo study, T1WI, T2WI, and DWI were performed in one healthy volunteer with three different coils. The SNR and noise correlation matrix were measured. RESULTS: In the phantom study and in vivo study, the SNR of HFC12 in the transverse, sagittal, and coronal planes was the highest, followed by HRC24, and that of HRC16 was the lowest. The SNR profiles showed that the SNR at the edge of HFC12 was the highest. The mean value of the noise correlation matrix of HFC12 was the highest. The 1/g-factor results showed that HFC12 obtained the best acceleration ability in the head-foot acceleration direction when the reduction factor was set to two. The SNR of HFC12 in most cortices was significantly higher than that of HRC16 and HRC24, except in the occipital cortex. The SNR of HRC24 in the occipital cortex was higher than that of HFC12. CONCLUSION: The SNR of HFC12 in T1WI, T2WI, and DWI was better than that of the HRC24 and HFC16. The SNR of HFC12 in the cortex was significantly higher than that of the commercial rigid head coil, except in the occipital cortex.

Electroacupuncture Synergistically Inhibits Proinflammatory Cytokine Production and Improves Cognitive Function in Rats with Cognitive Impairment due to Hepatic Encephalopathy through p38MAPK/STAT3 and TLR4/NF-κB Signaling Pathways.

OBJECTIVE: To investigate the effect of electroacupuncture (EA) on cognitive dysfunction in rats with hepatic encephalopathy and its underlying mechanism. METHODS: Fifty Wistar rats were randomly divided into a normal group (n = 10) and model group (n = 40). Rat models of hepatic encephalopathy were established by administration of carbon tetrachloride and thioacetamide for a total of 12 weeks. At the 9th week after modeling, rats with cognitive impairment in the model group were identified by conducting the Morris water maze test, which were then randomly divided into a control group (CCl4) and treatment groups including EA group (CCl4 + EA), lactulose group (CCl4 + Lac), and EA plus lactulose group (CCl4 + CM), with 9 rats in each group. At the end of the 9th week, rats in CCl4 + Lac and CCl4 + CM groups had lactulose gavage at a dose of 10 mL/kg body weight, while normal control and CCl4 groups had gavage with the same volume of normal saline once a day for 21 days until the end of the experiment. Rats in CCl4 + EA and CCl4 + CM groups underwent acupuncture at Baihui (GV[DU]20), Shenting (GV[DU]24), and Zusanli (ST36) acupoints, among which EA at Baihui and Shenting acupoints were given once daily for 30 min lasting for 21 consecutive days. The effect of the treatment was measured by the Morris water maze test for learning and memory ability and magnetic resonance spectroscopy (MRS) for neuronal metabolism in the hippocampus of rats with hepatic encephalopathy. Pathological change in the rat hippocampus was observed by HE staining, while serum ammonia and liver function markers were detected. Western blot and real-time fluorescent quantitative PCR were used to detect the expressions of specific genes and proteins in the brain tissue. RESULTS: Compared with those in the control group, rats undergoing EA had significantly shortened escape latency and increased number of platform crossing. H&E staining confirmed that EA improved brain tissue necrosis and ameliorated nuclear pyknosis in rats with hepatic encephalopathy. Significantly decreased levels of serum ammonia, alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), and total bile acid (TBA) were observed in rats undergoing EA, as well as improved levels of total protein (TP) and albumin (ALB). In addition, EA inhibited the brain expressions of TNF-α, IL-1ß, IL-6, iNOS, TLR4, MyD88, NF-κB, p38MAPK, phosphorylated (p)-p38MAPK, STAT3, and p-STAT3 genes, as well as protein expressions of TNF-α, IL-6, TLR4, MyD88, NF-κB, p38MAPK, p-p38MAPK, STAT3, and p-STAT3. MRS showed increased Glx/Cr and decreased NAA/Cr, Cho/Cr and mI/Cr in the control group, and EA significantly reversed such changes in Glx/Cr and mI/Cr values. CONCLUSION: EA ameliorated the production of excessive proinflammatory cytokines in the hippocampus of rats with cognitive dysfunction secondary to hepatic encephalopathy, which also gave rise to subsequent changes such as reduced blood ammonia level, brain-protective activated astrocytes, and lower degree of brain tissue injury. The p38MAPK/STAT3 and TLR4/MyD88/NF-κB signaling pathways may be involved. EA can also improve the metabolism of NAA and Cho in the rat hippocampus and thereby improve learning and memory abilities.

Novel Insights into Dissolved Organic Matter Processing Pathways in a Coastal Confined Aquifer System with the Highest Known Concentration of Geogenic Ammonium.

High levels of geogenic ammonium in groundwater is a highly neglected nitrogen pool in coastal aquatic systems. Although organic matter (OM) mineralization is known to significantly influence geogenic ammonium enrichment, the detailed mechanism underlying ammonium enrichment based on dissolved organic matter (DOM) characterization in coastal aquifer systems remains unclear. In this study, we characterized the optical and molecular signatures of DOM coupled with hydrogeochemistry and multiple isotopes (H/O/C/N) to elucidate in detail the mechanisms underlying the anomalously high ammonium in the coastal confined aquifer system of the Pearl River Delta, which exhibits the highest reported geogenic ammonium concentration in groundwater on the Earth. We identified three DOM fluorescent components, a marine humic-like component (C1) and two other humic-like components (C2 and C3). The autochthonous OM was first processed to the C1 component, which was further transformed to C2 and C3 components. In terms of molecular classes, the processing pathway from bacterial- or algal-derived OM to aliphatic compounds and highly unsaturated-low O compounds was identified, and highly unsaturated-low O compounds were accumulated as the main products. Compounds containing two or three N atoms were processed, and compounds with one N atom gradually accumulated, which was further degraded into CHO compounds. The ammonium (up to 179 mg/L as N) was gradually enriched due to the decomposition of CHO+3N to CHO+2N, CHO+1N, and CHO compounds. Owing to the longer residence time and less frequent fresh water flushing, the produced ammonium was retained in the aquifer as a "long-term result". The contrasting DOM characteristics, together with the differing depositional and hydrogeological conditions, give rise to the higher levels of geogenic ammonium in coastal confined aquifer systems compared with inland alluvial-lacustrine confined aquifer systems. To our knowledge, this is the first study to characterize DOM and its relationship with geogenic ammonium in coastal aquifer systems.

Dissolved organic matter characterization in high and low ammonium groundwater of Dongting Plain, central China.

High levels of ammonium in groundwater is a potential threat to drinking water security and ecological status. The role of dissolved organic matter (DOM) in mobilization of natural ammonium in groundwater is crucial but the intrinsic link between them has still been poorly understood. This study used high-pressure size exclusion chromatography (HPSEC) and fluorescence excitataion-emission-matrix spectra (EEMs) with parallel factor analysis (PARAFAC) to elucidate the influence of DOM characteristics in groundwater systems having contrastive ammonium levels in Dongting Plain, central Yangtze River. The results indicate that NH4+-N concentration in groundwater of western plain (0-16.75 mg/L) are much higher compared with southern plain (0-1.5 mg/L). The groundwater in western plain is in a more reductive environment and characterized by larger molecular weight (MW) of DOM and lower polydispersity (ρ), whereas DOM with relatively small molecular weight and high polydispersity is detected in the south with a more oxidative condition. The groundwater in western plain is characterized by lower fluorescence index (f450/500) and biological index (BIX), and dominated by the high molecular weight terrestrial humic-like component and larger amounts of microbial humic-like components. Protein-like is the main component in groundwater of southern plain with higher f450/500 and BIX. The ammonium concentration in groundwater correlates well with molecular weight and increases significantly with the content of high molecular weight terrestrial humic-like component, indicating that mobilization of ammonium is more closely associated with the terrestrial organic matter of high molecular weight. This study further enriches the theory on mobilization of ammonium in Quaternary alluvial-lacustrine aquifer systems and provides theoretical basis for the local water supply security.

Spinal Manipulative Therapy Alters Brain Activity in Patients With Chronic Low Back Pain: A Longitudinal Brain fMRI Study.

Background: Spinal manipulative therapy (SMT) helps to reduce chronic low back pain (cLBP). However, the underlying mechanism of pain relief and the neurological response to SMT remains unclear. We utilized brain functional magnetic resonance imaging (fMRI) upon the application of a real-time spot pressure mechanical stimulus to assess the effects of SMT on patients with cLBP. Methods: Patients with cLBP (Group 1, n = 14) and age-matched healthy controls without cLBP (Group 2, n = 20) were prospectively enrolled. Brain fMRI was performed for Group 1 at three time points: before SMT (TP1), after the first SMT session (TP2), and after the sixth SMT session (TP3). The healthy controls (Group 2) did not receive SMT and underwent only one fMRI scan. During fMRI scanning, a real-time spot pressure mechanical stimulus was applied to the low back area of all participants. Participants in Group 1 completed clinical questionnaires assessing pain and quality of life using a visual analog scale (VAS) and the Chinese Short Form Oswestry Disability Index (C-SFODI), respectively. Results: Before SMT (TP1), there were no significant differences in brain activity between Group 1 and Group 2. After the first SMT session (TP2), Group 1 showed significantly greater brain activity in the right parahippocampal gyrus, right dorsolateral prefrontal cortex, and left precuneus compared to Group 2 (P < 0.05). After the sixth SMT session (TP3), Group 1 showed significantly greater brain activity in the posterior cingulate gyrus and right inferior frontal gyrus compared to Group 2 (P < 0.05). After both the first and sixth SMT sessions (TP2 and TP3), Group 1 had significantly lower VAS pain scores and C-SFODI scores than at TP1 (P < 0.001). Conclusion: We observed alterations in brain activity in regions of the default mode network in patients with cLBP after SMT. These findings suggest the potential utility of the default mode network as a neuroimaging biomarker for pain management in patients with cLBP. Clinical Trial Registration: Chinese Clinical Trial Registry, identifier ChiCTR1800015620.

Enrichment of Geogenic Ammonium in Quaternary Alluvial-Lacustrine Aquifer Systems: Evidence from Carbon Isotopes and DOM Characteristics.

Geogenic ammonium in groundwater owing to mineralization of natural organic matter (NOM) has been reported in different geologic settings, but detailed mechanisms responsible for high ammonium concentration levels are poorly understood. To this end, we chose Quaternary high ammonium aquifer systems in central Yangtze River basins and used carbon isotopes in both dissolved organic carbon and inorganic carbon together with characterization of dissolved organic matter (DOM) and groundwater chemistry to reveal mechanisms related to the genesis of ammonium. The results indicate that high levels of geogenic ammonium (up to 33.50 mg/L as N) occur due to long-term water-rock interactions in a relatively sluggish hydrogeological environment with abundant organic matter that is rich in both C and N. The stable carbon isotope data suggest that ammonium in the groundwater is released from intensive degradation of organic matter with higher contents of ammonium associated with methanogenesis. The optical signatures of DOM indicate ammonium in the groundwater is mostly associated with terrestrial humic-like components rather than protein-like components. Molecular characterization of DOM by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) shows that, compared to low ammonium groundwater, high ammonium groundwater has larger mass weights, greater abundance of CHO+N compounds, higher percentages of lignin- and condensed-hydrocarbon-like components, lower H/C ratios, higher nominal oxidation state of carbon (NOSC) values and more double bonds, rings, and aromatic structures. Strong degradation of NOM and preferential utilization of energetically more favorable, terrestrial humic-like components (lignin-like as the main class) with high NOSC values facilitates the formation of high ammonium groundwater. To the best of our knowledge, this is the first effort to use carbon isotopes and DOM characteristics to identify enrichment mechanisms for geogenic ammonium in alluvial-lacustrine aquifer systems.

Prediction of nodal involvement in primary rectal carcinoma without invasion to pelvic structures: accuracy of preoperative CT, MR, and DWIBS assessments relative to histopathologic findings.

OBJECTIVE: To investigate the accuracy of preoperative computed tomography (CT), magnetic resonance (MR) imaging and diffusion-weighted imaging with background body signal suppression (DWIBS) in the prediction of nodal involvement in primary rectal carcinoma patients in the absence of tumor invasion into pelvic structures. METHODS AND MATERIALS: Fifty-two subjects with primary rectal cancer were preoperatively assessed by CT and MRI at 1.5 T with a phased-array coil. Preoperative lymph node staging with imaging modalities (CT, MRI, and DWIBS) were compared with the final histological findings. RESULTS: The accuracy of CT, MRI, and DWIBS were 57.7%, 63.5%, and 40.4%. The accuracy of DWIBS with higher sensitivity and negative predictive value for evaluating primary rectal cancer patients was lower than that of CT and MRI. Nodal staging agreement between imaging and pathology was fairly strong for CT and MRI (Kappa value = 0.331 and 0.348, P<0.01) but was relatively weaker for DWIBS (Kappa value = 0.174, P<0.05). The accuracy was 57.7% and 59.6%, respectively, for CT and MRI when the lymph node border information was used as the criteria, and was 57.7% and 61.5%, respectively, for enhanced CT and MRI when the lymph node enhancement pattern was used as the criteria. CONCLUSION: MRI is more accurate than CT in predicting nodal involvement in primary rectal carcinoma patients in the absence of tumor invasion into pelvic structures. DWIBS has a great diagnostic value in differentiating small malignant from benign lymph nodes.