The intra-individual reliability of 1 H-MRS measurement in the anterior cingulate cortex across 1 year.

Magnetic resonance spectroscopy (MRS) is the primary method that can measure the levels of metabolites in the brain in vivo. To achieve its potential in clinical usage, the reliability of the measurement requires further articulation. Although there are many studies that investigate the reliability of gamma-aminobutyric acid (GABA), comparatively few studies have investigated the reliability of other brain metabolites, such as glutamate (Glu), N-acetyl-aspartate (NAA), creatine (Cr), phosphocreatine (PCr), or myo-inositol (mI), which all play a significant role in brain development and functions. In addition, previous studies which predominately used only two measurements (two data points) failed to provide the details of the time effect (e.g., time-of-day) on MRS measurement within subjects. Therefore, in this study, MRS data located in the anterior cingulate cortex (ACC) were repeatedly recorded across 1 year leading to at least 25 sessions for each subject with the aim of exploring the variability of other metabolites by using the index coefficient of variability (CV); the smaller the CV, the more reliable the measurements. We found that the metabolites of NAA, tNAA, and tCr showed the smallest CVs (between 1.43% and 4.90%), and the metabolites of Glu, Glx, mI, and tCho showed modest CVs (between 4.26% and 7.89%). Furthermore, we found that the concentration reference of the ratio to water results in smaller CVs compared to the ratio to tCr. In addition, we did not find any time-of-day effect on the MRS measurements. Collectively, the results of this study indicate that the MRS measurement is reasonably reliable in quantifying the levels of metabolites.

Considerations on brain age predictions from repeatedly sampled data across time.

INTRODUCTION: Brain age, the estimation of a person's age from magnetic resonance imaging (MRI) parameters, has been used as a general indicator of health. The marker requires however further validation for application in clinical contexts. Here, we show how brain age predictions perform for the same individual at various time points and validate our findings with age-matched healthy controls. METHODS: We used densely sampled T1-weighted MRI data from four individuals (from two densely sampled datasets) to observe how brain age corresponds to age and is influenced by acquisition and quality parameters. For validation, we used two cross-sectional datasets. Brain age was predicted by a pretrained deep learning model. RESULTS: We found small within-subject correlations between age and brain age. We also found evidence for the influence of field strength on brain age which replicated in the cross-sectional validation data and inconclusive effects of scan quality. CONCLUSION: The absence of maturation effects for the age range in the presented sample, brain age model bias (including training age distribution and field strength), and model error are potential reasons for small relationships between age and brain age in densely sampled longitudinal data. Clinical applications of brain age models should consider of the possibility of apparent biases caused by variation in the data acquisition process.

Structure-based discovery of novel α-aminoketone derivatives as dual p53-MDM2/MDMX inhibitors for the treatment of cancer.

The function of the p53 protein is impaired by the overexpression of its negative regulator murine double minute 2 protein (MDM2) and homologous protein MDMX. Disruption of the p53-MDM2/MDMX interaction to restore the transcriptional function of p53 is considered a promising strategy for cancer therapy. To design dual MDM2/MDMX inhibitors, the binding modes of MDM2 or MDMX with their inhibitors are elucidated. Several hot-spot residues of MDM2 or MDMX are identified by molecular dynamics simulations, alanine scanning and MM-GBSA calculations. Then, focusing on the interaction with hot-spot residues, two series of derivatives bearing 1,3-diketone and α-aminoketone scaffolds are designed and synthesized. Among these compounds, C16 is identified as the most potent compound with low micromolar binding affinities with MDM2 and MDMX. C16 also displays moderate antiproliferative activities against MDM2-overexpressing and MDMX-overexpressing cells, with IC50 values of 0.68 µM in HCT116 cells and 0.54 µM in SH-SY5Y cells. Furthermore, C16 inhibits cell migration and invasion, reactivates the function of p53, arrests the cell cycle and induces cellular apoptosis in HCT116 and SH-SY5Y cells. Collectively, C16 can be developed as a dual MDM2 and MDMX inhibitor for cancer therapy.

Deep brain imaging of three participants across 1 year: The Bergen breakfast scanning club project.

Our understanding of the cognitive functions of the human brain has tremendously benefited from the population functional Magnetic Resonance Imaging (fMRI) studies in the last three decades. The reliability and replicability of the fMRI results, however, have been recently questioned, which has been named the replication crisis. Sufficient statistical power is fundamental to alleviate the crisis, by either "going big," leveraging big datasets, or by "going small," densely scanning several participants. Here we reported a "going small" project implemented in our department, the Bergen breakfast scanning club (BBSC) project, in which three participants were intensively scanned across a year. It is expected this kind of new data collection method can provide novel insights into the variability of brain networks, facilitate research designs and inference, and ultimately lead to the improvement of the reliability of the fMRI results.

How the brain encodes morphological constraints during Chinese word reading: An EEG-fNIRS study.

Although the role of morphology in alphabetic language processing has been extensively studied, it is still unclear how morphology is enabled and constrained in morpho-syllabic languages like Chinese. This study aims to inspect the time courses and patterns of brain activation associated with Chinese morphological constraint encoding. Chinese native speakers were recruited to perform visual lexical decisions on real Chinese compound words, pseudowords, and nonwords, whilst behavioral, electroencephalographic, and functional near infrared spectroscopy data were simultaneously recorded. For the first time, both morphological and semantic effects were examined to reveal the corresponding spatio-temporal brain activation patterns based on multimodal data. Brain activation differences between pseudowords and real words indexed morphological sensitivity, whereas differences between real words or pseudowords and nonwords characterized semantic effects. Electrophysiological data showed that semantic processing occurred earlier (N400, 300-450 msec) than morphological processing (450-570 msec), while brain activation patterns revealed a differentiation between morphological parsing (specified in the left inferior frontal gyrus) and semantic analysis (in a broader fronto-temporal network). These findings offer new evidence that morphological constraints are encoded at a late stage of compound word processing in Chinese and suggest that the left prefrontal cortex plays an essential role in this process.

The neural dynamics associated with lexicality effect in reading single Chinese words, pseudo-words and non-words.

In previous word reading studies, lexicality has been used as a variable to examine the impacts of word form and meaning information on the many stages of word recognition process. Yet the neural dynamics associated with lexicality effect of various information processing for Chinese visual word recognition has not been well elucidated. In this study, Chinese native speakers were instructed to read Chinese disyllabic compound words, morphological legal (pseudo-words) and illegal non-words with their brain potentials recorded. Event-related potentials (ERP) results showed that N200 was related to Chinese orthographic processing, where three lexical conditions elicited comparable patterns. A semantic discrimination was found for N400 between pseudo-words/non-words and real words, which is in favor of the lexical view of the N400 effect. Further, a later ERP component P600 exhibited the difference between the non-words and pseudo-words, reflecting a re-analysis of word meaning or grammatical operation on Chinese morphological legality. Therefore, we argue that Chinese morphological information might have an independent representation (the P600 effect) in mental lexicon.

Population Aging and Its Impact on Human Wellbeing in China.

Population aging is getting enlarged in the upcoming decades. Meanwhile, old-aged longevity and dependency are getting large due to improvement in life expectancy. In literature, it is claimed that old-aged dependency affects the wellbeing of society. Thus, the study intends to explore the impact of population aging on human wellbeing. The study adopts the Autoregressive Distributed Lag (ARDL) approach for empirical analysis by using time-series series data from 1990 to 2020. The study findings reveal that an increase in population aging reports a significant and decreasing impact on human wellbeing. However, an increase in health expenditure reports a significant and increasing impact on human wellbeing. Thus, China must pay attention to population aging to improve human health.

EEG Decoding of Dynamic Facial Expressions of Emotion: Evidence from SSVEP and Causal Cortical Network Dynamics.

The neural cognitive mechanism in processing static facial expressions (FEs) has been well documented, whereas the one underlying perceiving dynamic faces remains unclear. In this study, Fourier transformation and time-frequency analysis of Electroencephalography (EEG) data were carried out to detect the brain activation underlying dynamic or static FEs while twenty-one participants were viewing dynamic or static faces flicking at 10 Hz. In particular, steady-state visual evoked potentials (SSVEPs) were quantified through spectral power analysis of EEG recordings. Besides, Granger causality (GC) analysis (GCA) was also performed to capture the causal cortical network dynamics during dynamic or static FEs of emotion. It was discovered that the dynamic (from neural to happy (N2H) or vice versa (H2N)) FEs elicited larger SSVEPs than the static ones. Additionally, GCA demonstrated that the H2N case, in which happy FEs were being gradually changed into neutral ones, exhibited larger GC measure during the late processing stage than that from the early stage. Consequently, enhanced SSVEPs and effective brain connectivity for dynamic FEs illustrated that participants might need consume more attentional resources to process the dynamic faces, particularly for the change from happy to neutral faces. The new neural index might facilitate us to better understand the cognitive processing of dynamic and static FEs.

Heilaohuguosus A-S from the fruits of Kadsura coccinea and their hepatoprotective activity.

Phytochemical investigations on the fresh fruits of Kadsura coccinea (Lem.) A. C. Sm. have led to the isolation of fourteen undescribed 2,2'-cyclolignans named heilaohuguosus A-N, four undescribed aryltetrahydronaphthalene lignans, heilaohuguosus O-R and one tetrahydrofuran lignan, heilaohuguosu S, with twenty-seven previously described lignan analogues. Their structures and absolute configurations of heilaohuguosus A-S were established by spectroscopic methods including 1D and 2D-NMR techniques and CD experiments. All isolated compounds were evaluated for their hepatoprotective activity against APAP-induced toxicity in HepG-2 cells, four 2,2'-cyclolignans, heilaohuguosus A and L, tiegusanin I and kadsuphilol I showed good hepatoprotective activities against APAP toxicity in HepG-2 cells with cell survival rates of 53.5 ± 1.7%, 55.2 ± 1.2%, 52.5 ± 2.4%, and 54.0 ± 2.2% (positive control bicyclol, 52.1 ± 1.3%) at 10 µM, respectively.

Functional near-infrared spectroscopy can detect low-frequency hemodynamic oscillations in the prefrontal cortex during steady-state visual evoked potential-inducing periodic facial expression stimuli presentation.

Brain oscillations are vital to cognitive functions, while disrupted oscillatory activity is linked to various brain disorders. Although high-frequency neural oscillations (> 1 Hz) have been extensively studied in cognition, the neural mechanisms underlying low-frequency hemodynamic oscillations (LFHO) < 1 Hz have not yet been fully explored. One way to examine oscillatory neural dynamics is to use a facial expression (FE) paradigm to induce steady-state visual evoked potentials (SSVEPs), which has been used in electroencephalography studies of high-frequency brain oscillation activity. In this study, LFHO during SSVEP-inducing periodic flickering stimuli presentation were inspected using functional near-infrared spectroscopy (fNIRS), in which hemodynamic responses in the prefrontal cortex were recorded while participants were passively viewing dynamic FEs flickering at 0.2 Hz. The fast Fourier analysis results demonstrated that the power exhibited monochronic peaks at 0.2 Hz across all channels, indicating that the periodic events successfully elicited LFHO in the prefrontal cortex. More importantly, measurement of LFHO can effectively distinguish the brain activation difference between different cognitive conditions, with happy FE presentation showing greater LFHO power than neutral FE presentation. These results demonstrate that stimuli flashing at a given frequency can induce LFHO in the prefrontal cortex, which provides new insights into the cognitive mechanisms involved in slow oscillation.

Effective Connectivity Study Guiding the Neuromodulation Intervention in Figurative Language Comprehension Using Optical Neuroimaging.

The current study is aimed at establishing links between brain network examination and neural plasticity studies measured by optical neuroimaging. Sixteen healthy subjects were recruited from the University of Macau to test the Granger Prediction Estimation (GPE) method to investigate brain network connectivity during figurative language comprehension. The method is aimed at mapping significant causal relationships across language brain networks, captured by functional near-infrared spectroscopy measurements (fNIRS): (i) definition of regions of interest (ROIs) based on significant channels extracted from spatial activation maps; (ii) inspection of significant causal relationships in temporal resolution, exploring the experimental task agreement; and (iii) early identification of stronger causal relationships that guide neuromodulation intervention, targeting impaired connectivity pathways. Our results propose top-down mechanisms responsible for perceptive-attention engagement in the left anterior frontal cortex and bottom-up mechanism in the right hemispheres during the semantic integration of figurative language. Moreover, the interhemispheric directional flow suggests a right hemisphere engagement in decoding unfamiliar literal sentences and fine-grained integration guided by the left hemisphere to reduce ambiguity in meaningless words. Finally, bottom-up mechanisms seem activated by logographic-semantic processing in literal meanings and memory storage centres in meaningless comprehension. To sum up, our main findings reveal that the Granger Prediction Estimation (GPE) integrated strategy proposes an effective link between assessment and intervention, capable of enhancing the efficiency of the treatment in language disorders and reducing the neuromodulation side effects.

Altered Functional Connectivity in the Motor and Prefrontal Cortex for Children With Down's Syndrome: An fNIRS Study.

Children with Down's syndrome (DS) might exhibit disrupted brain functional connectivity in the motor and prefrontal cortex. To inspect the alterations in brain activation and functional connectivity for children with DS, the functional near-infrared spectroscopy (fNIRS) method was applied to examine the brain activation difference in the motor and prefrontal cortex between the DS and typically developing (TD) groups during a fine motor task. In addition, small-world analysis based on graph theory was also carried out to characterize the topological organization of functional brain networks. Interestingly, behavior data demonstrated that the DS group showed significantly long reaction time and low accuracy as compared to the TD group (p < 0.05). More importantly, significantly reduced brain activations in the frontopolar area, the pre-motor, and the supplementary motor cortex (p < 0.05) were identified in the DS group compared with the TD group. Meanwhile, significantly high global efficiency (E g ) and short average path length (L p ) were also detected for the DS group. This pilot study illustrated that the disrupted connectivity of frontopolar area, pre-motor, and supplementary motor cortex might be one of the core mechanisms associated with motor and cognitive impairments for children with DS. Therefore, the combination of the fNIRS technique with functional network analysis may pave a new avenue for improving our understanding of the neural mechanisms of DS.

Global discovery the PstP interactions using Mtb proteome microarray and revealing novel connections with EthR.

Mycobacterium tuberculosis (Mtb) serine/threonine protein phosphatase PstP plays an important role in regulating Mtb cell division and growth by reversible phosphorylation signaling. However, the substrates of Mtb with which the PstP interacts, and the underlying molecular mechanisms are still largely unknown. In this study, we performed an Mtb proteome microarray to globally identify the PstP bindings. In this way, we discovered 78 interactors between PstP and Mtb proteins, and found a novel connections with EthR. The interaction between PstP and EthR has been validated by Bio-Layer interferometry and Yeast-two-hybrid. And functional studies showed that PstP significantly enhances the binding between EthR and related DNA domain through its interaction with EthR. Phenotypically, overexpression of PstP promoted the resistance of Mycobacterium smegmatis with the antibiotic of ethionamide. Overall, we hopefully wish that the PstP interactors identified in this study will serve as a useful resource for further systematic studies of the roles that PstP plays in the regulation of Mtb dephosphorylation. SIGNIFICANCE: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which is responsible of ~1.5 million death per year. Understanding the knowledge about the basic biological regulation pathways in Mtb is an effective approach to discover the novel drug targets for cure TB. PstP is a serine/threonine protein phosphatase in Mtb, and plays important roles in regulating Mtb cell division and growth by reversible phosphorylation signaling. In this study, we identified 78 PstP interacting Mtb proteins using Mtb proteome microarray, which could preliminarily explain the roles of PstP played in Mtb. Moreover, functional analysis showed that a novel transcription factor EthR had been found regulated by PstP through binding, which could enhance the resistance to the antibiotic ETH. Overall, this network constructed with PstP-Mtb proteins could serve as a valuable resource for studying Mtb growth.

Antibacterial stilbenes from the tubers of Bletilla striata.

Three new bibenzyl derivatives (bletstrins A-C, 1-3), including two bibenzyls that have hydroxyl-substituted chiral centers on the aliphatic bibenzyl bridge, along with eighteen known stilbenoids (4-21) were isolated from the tubers of Bletilla striata. The structures of new compounds were elucidated by the use of 1D/2D NMR spectroscopic data. The absolute configurations of bletitrins A and B were determined by optical rotation value. Compounds 13-16 were isolated from the Orchidaceae for the first time. Most of the isolated compounds were evaluated for their antibacterial activities against three gram-positive bacterial strains and one gram-negative bacterial strain. Compounds 4, 10, 12, 14, 15, 16 and 18 showed potent inhibitory activities, with MICs of (6-52 µg/mL) against S. aureus ATCC 6538.

A novel phase analysis method for examining fNIRS neuroimaging data associated with Chinese/English sight translation.

In this study, a phase method for analyzing functional near-infrared spectroscopy (fNIRS) signals was developed, which can extract the phase information of fNIRS data by using Hilbert transform. More importantly, the phase analysis method can be further performed to generate the brain phase activation and to construct the brain networks. Meanwhile, the study of translation between Chinese and English has been exciting and interesting from both the language and neuroscience standpoints due to their drastically different linguistic features. In particular, inspecting the brain phase activation and functional connectivity based on the phase data and phase analysis method will enable us to better understand the neural mechanism associated with Chinese/English translation. Our phase analysis results showed that the left prefrontal cortex, including the dorsolateral prefrontal cortex (DLPFC) and frontopolar area, was involved in the translation process of the language pair. In addition, we also discovered that the most significant brain phase activation difference between translating into non-native (English) vs. native (Chinese) language was identified in the Broca's area. As a result, the proposed phase analysis approach can provide us an additional tool to reveal the complex cognitive mechanism associated with Chinese/English sight translation.

Concurrent mapping of brain activation from multiple subjects during social interaction by hyperscanning: a mini-review.

Social interaction plays an essential role in acquiring knowledge and developing our own personalities in our daily life. Meanwhile, functional magnetic resonance imaging (fMRI)-, electroencephalograph (EEG)-, and functional near inferred spectroscopy (fNIRS)-hyperscanning, enables us to concurrently map brain activation from two or more participants who are engaged in social interaction simultaneously. In this review, we first highlight the recent technologies advances and the most significant findings towards social interaction by using the hyperscanning method. In addition, we also illustrate several well-designed hyperscanning tasks that have been extensively adopted for the study of social interaction. Basically, hyperscanning contains six categories of experimental paradigms that can track the interactive neural process of interest. Furthermore, it contains two main elucidated neural systems which are involved in social interaction, including the mirror neuron system (MNS) and mentalizing system (MS). Finally, future research directions and clinical implications that are associated with hyperscanning are also highlighted and discussed.

Neuroticism and conscientiousness respectively positively and negatively correlated with the network characteristic path length in dorsal lateral prefrontal cortex: A resting-state fNIRS study.

BACKGROUND: Accumulating evidence shows that the dorsal lateral prefrontal cortex (dlPFC) is implicated in personality traits. In this study, resting-state functional near infrared spectroscopy (fNIRS) combined with small-world analysis was utilized to examine the relationship between the network properties of dlPFC and personality traits. METHODS: Thirty college students (aged between 20 and 29) were recruited from the University of Macau campus, whose personality scores were accessed with the NEO-FFT questionnaire. Graph theory combined with resting-state fNIRS data was used to quantify the network properties of dlPFC, whereas Pearson correlation analysis was performed to generate the relationship between the small-world indicators and personality scores. RESULTS: Compared to matched random networks, the resting-state brain networks exhibited a larger clustering coefficient (Cp , 0.1-0.66), shorter characteristic path length (Lp , 0.1-0.66), and higher global (Eg , 0.1-0.66) and local efficiency (Eloc , 0.1-0.65). In particular, conscientiousness (r = -0.63) and neuroticism (r = 0.40) respectively showed negative and positive correlation with the Lp . CONCLUSIONS: The resting-state functional brain networks in dlPFC exhibited the small-world properties. In addition, participants with higher conscientiousness scores showed a shorter Lp .

Optical mapping of prefrontal brain connectivity and activation during emotion anticipation.

Accumulated neuroimaging evidence shows that the dorsal lateral prefrontal cortex (dlPFC) is activated during emotion anticipation. The aim of this work is to examine the brain connectivity and activation differences in dlPFC between the positive, neutral and negative emotion anticipation by using functional near-infrared spectroscopy (fNIRS). The hemodynamic responses were first assessed for all subjects during the performance of various emotion anticipation tasks. And then small-world analysis was performed, in which the small-world network indicators including the clustering coefficient, average path length, average node degree, and measure of small-world index were calculated for the functional brain networks associated with the positive, neutral and negative emotion anticipation, respectively. We discovered that compared to negative and neutral emotion anticipation, the positive one exhibited enhanced brain activation in the left dlPFC. Although the functional brain networks for the three emotion anticipation cases manifested the small-world properties regarding the clustering coefficient, average path length, average node degree, and measure of small-world index, the positive one showed significantly higher clustering coefficient and shorter average path length than those from the neutral and negative cases. Consequently, the small-world network indicators and brain activation in dlPPC were able to distinguish well between the positive, neutral and negative emotion anticipation.

An efficient scheme for purification of a novel recombinant immunotoxin, rCCK8PE38, for anti-tumour experiments.

rCCK8PE38 is a novel immunotoxin that targets choleystokinin B receptor, which is over-expressed in some tumor tissues. Although we constructed a prokaryotic expression vector to express rCCK8PE38 in our laboratory, thorough purification was necessary to quantitatively assess its anti-tumor effect. In this study, we established a purification protocol to obtain rCCK8PE38 with high purity from E. coli. Three different types of chromatography, hydrophobic chromatography, ion exchange chromatography and size exclusion chromatography, were used in combination. The purification technological parameters of each chromatography type were optimized. The whole process of purification was arranged to minimize the purification steps and achieve purity and bioactivity. Finally, through this optimized scheme, we obtained a recombinant protein with a purity of >95%; then, the protein was stored at -80°C after lyophilization. The purified protein was used in a tumor inhibition experiment and was effective in killing tumor cells that over-expressed choleystokinin B receptor. The results of this study may provide some valuable information about protein purification and lay the foundation for further clinical experiments with rCCK8PE38.