CHIR-98014, a GSK 3ß Inhibitor, Protects Against Triptolide/Lipopolysaccharide-Induced Hepatotoxicity by Mitochondria-Dependent Apoptosis Inhibition.

Triptolide (TP) is a remarkable anti-inflammatory and immunosuppressive component separated from Tripterygium wilfordii Hook. F. However, its hepatotoxicity limits its application in the clinical. Our group has proposed a new perspective on TP-induced hepatotoxicity, in which TP enhances liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. Because the cause of the disease is unknown, there is currently no uniform treatment available. In this study, we attempted to determine whether the GSK-3ß-JNK pathway affects liver damage and its regulatory mechanism in response to TP/LPS costimulation. In addition, we investigated the effect of CsA or the GSK 3ß inhibitor CHIR-98014 on TP/LPS-induced hepatotoxicity. The results showed that the TP/LPS cotreatment mice exhibited obvious hepatotoxicity, as indicated by a remarkable increase in the serum ALT and AST levels, glycogen depletion, GSK 3ß-JNK upregulation, and increased apoptosis. Instead of the specific knockdown of JNK1, the specific knockdown of JNK2 had a protective effect. Additionally, 40 mg/kg of CsA and 30 mg/kg of CHIR-98014 might provide protection. In summary, CHIR-98014 could protect against TP/LPS- or TP/TNF-α-induced activation of the GSK 3ß-JNK pathway and mitochondria-dependent apoptosis, improving the indirect hepatotoxicity induced by TP.

Proteasome activity inhibition mediates endoplasmic reticulum stress-apoptosis in triptolide/lipopolysaccharide-induced hepatotoxicity.

Triptolide (TP) is a major active and toxic composition of the Chinese medicine Tripterygium wilfordii Hook. F. (TWHF), exhibiting various therapeutic bioactivities. Among the toxic effects, the hepatotoxicity of TP deserves serious attention. Previously, our research group proposed a new view of TP-related hepatotoxicity: hepatic hypersensitivity under lipopolysaccharide (LPS) stimulation. However, the mechanism of TP/LPS-induced hepatic hypersensitivity remains unclear. In this study, we investigated the mechanism underlying TP/LPS-induced hypersensitivity from the perspective of the inhibition of proteasome activity, activated endoplasmic reticulum stress (ERS)-related apoptosis, and the accumulation of reactive oxygen species (ROS). Our results showed that N-acetylcysteine (NAC), a common ROS inhibitor, decreased the expression of cleaved caspase-3 and cleaved PARP, which are associated with FLIP enhancement. Moreover, 4-phenylbutyric acid (4-PBA), an ERS inhibitor, was able to alleviate TP/LPS-induced hepatotoxicity by reducing ERS-related apoptosis protein expression (GRP78, p-eIF2α/eIF2α, ATF4, CHOP, cleaved caspase-3 and cleaved PARP) and ROS levels, with ATF4 being an indispensable mediator. In addition, the proteasome activity inhibitor MG-132 further aggravated ERS-related apoptosis, which indicated that the inhibition of proteasome activity also plays an important role in TP/LPS-related liver injuries. In summary, we propose that TP/LPS may upregulate the activation of ERS-associated apoptosis by inhibiting proteasome activity and enhancing ROS production through ATF4.

Association of cortical morphology, white matter hyperintensity, and glymphatic function in frontotemporal dementia variants.

INTRODUCTION: Frontotemporal dementia (FTD) can be phenotypically divided into behavioral variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). However, the neural underpinnings of this phenotypic heterogeneity remain elusive. METHODS: Cortical morphology, white matter hyperintensities (WMH), diffusion tensor image analysis along the perivascular space (DTI-ALPS), and their interrelationships were assessed in subtypes of FTD. Neuroimaging-transcriptional analyses on the regional cortical morphological deviances among subtypes were also performed. RESULTS: Changes in cortical thickness, surface area, gyrification, WMH, and DTI-ALPS were subtype-specific in FTD. The three morphologic indices are related to whole-brain WMH volume and cognitive performance, while cortical thickness is related to DTI-ALPS. Neuroimaging-transcriptional analyses identified key biological pathways linked to the formation and/or spread of TDP-43/tau pathologies. DISCUSSION: We found subtype-specific changes in cortical morphology, WMH, and glymphatic function in FTD. Our findings have the potential to contribute to the development of personalized predictions and treatment strategies for this disorder. HIGHLIGHTS: Cortical morphologic changes, white matter hyperintensities (WMH), and glymphatic dysfunction are subtype-specific. Cortical morphologic changes, WMH, and glymphatic dysfunction are inter-correlated. Cortical morphologic changes and WMH burden contribute to cognitive impairments.

Application of artificial neural network in daily prediction of bleeding in ICU patients treated with anti-thrombotic therapy.

OBJECTIVES: Anti-thrombotic therapy is the basis of thrombosis prevention and treatment. Bleeding is the main adverse event of anti-thrombosis. Existing laboratory indicators cannot accurately reflect the real-time coagulation function. It is necessary to develop tools to dynamically evaluate the risk and benefits of anti-thrombosis to prescribe accurate anti-thrombotic therapy. METHODS: The prediction model,daily prediction of bleeding risk in ICU patients treated with anti-thrombotic therapy, was built using deep learning algorithm recurrent neural networks, and the model results and performance were compared with clinicians. RESULTS: There was no significant statistical discrepancy in the baseline. ROC curves of the four models in the validation and test set were drawn, respectively. One-layer GRU of the validation set had a larger AUC (0.9462; 95%CI, 0.9147-0.9778). Analysis was conducted in the test set, and the ROC curve showed the superiority of two layers LSTM over one-layer GRU, while the former AUC was 0.8391(95%CI, 0.7786-0.8997). One-layer GRU in the test set possessed a better specificity (sensitivity 0.5942; specificity 0.9300). The Fleiss' k of junior clinicians, senior clinicians, and machine learning classifiers is 0.0984, 0.4562, and 0.8012, respectively. CONCLUSIONS: Recurrent neural networks were first applied for daily prediction of bleeding risk in ICU patients treated with anti-thrombotic therapy. Deep learning classifiers are more reliable and consistent than human classifiers. The machine learning classifier suggested strong reliability. The deep learning algorithm significantly outperformed human classifiers in prediction time.

Transcranial brain atlas-based optimization for functional near-infrared spectroscopy optode arrangement: Theory, algorithm, and application.

The quality of optode arrangement is crucial for group imaging studies when using functional near-infrared spectroscopy (fNIRS). Previous studies have demonstrated the promising effectiveness of using transcranial brain atlases (TBAs), in a manual and intuition-based way, to guide optode arrangement when individual structural MRI data are unavailable. However, the theoretical basis of using TBA to optimize optode arrangement remains unclear, which leads to manual and subjective application. In this study, we first describe the theoretical basis of TBA-based optimization of optode arrangement using a mathematical framework. Second, based on the theoretical basis, an algorithm is proposed for automatically arranging optodes on a virtual scalp. The resultant montage is placed onto the head of each participant guided by a low-cost and portable navigation system. We compared our method with the widely used 10/20-system-assisted optode arrangement procedure, using finger-tapping and working memory tasks as examples of both low- and high-level cognitive systems. Performance, including optode montage designs, locations on each participant's scalp, brain activation, as well as ground truth indices derived from individual MRI data were evaluated. The results give convergent support for our method's ability to provide more accurate, consistent and efficient optode arrangements for fNIRS group imaging than the 10/20 method.

Targeting brain functions from the scalp: Transcranial brain atlas based on large-scale fMRI data synthesis.

Transcranial brain mapping techniques, such as functional near-infrared spectroscopy (fNIRS) and transcranial magnetic stimulation (TMS), have been playing an increasingly important role in studies of human brain functions. Given a brain function of interest, fNIRS probes and TMS coils should be properly placed on the scalp to ensure that the function is effectively measured or modulated. However, since brain activity is inside the skull and invisible to the researcher during placement, this blind targeting may cause the device to partially or completely miss the functional target, resulting in inconsistent experimental results and divergent clinical outcomes, especially when participants' structural MRI data are not available. To address this issue, we propose here a framework for targeting a designated function directly from the scalp. First, a functional brain atlas for the targeted brain function is constructed via a meta-analysis of large-scale functional magnetic resonance imaging datasets. Second, the functional brain atlas is presented on the scalp surface by using a transcranial mapping previously established from an structural MRI dataset (n â€‹= â€‹114), resulting in a novel functional transcranial brain atlas (fTBA). Finally, a low-cost, portable scalp-navigation system is used to localize the transcranial device on the individual's scalp with the guidance of the fTBA. To demonstrate the feasibility of the targeting framework, both fNIRS and TMS mapping experiments were conducted. The results show that fTBA-guided fNIRS positioning can detect functional activity with high sensitivity and specificity for working memory and motor systems; Moreover, compared with traditional TMS targeting approaches (e.g. the International 10-20 System and the conventional 5-cm rule), the fTBA suggested motor stimulation site is closesr to both the motor hotspot and the center of gravity of motor evoked potentials (MEP-COG). In summary, the proposed method unblinds the transcranial function targeting process using prior information, providing an effective and straightforward approach to transcranial brain mapping studies, especially those without participants' structural MRI data.

LRP4-related signalling pathways and their regulatory role in neurological diseases.

The mechanism of action of low-density lipoprotein receptor related protein 4 (LRP4) is mediated largely via the Agrin-LRP4-MuSK signalling pathway in the nervous system. LRP4 contributes to the development of synapses in the peripheral nervous system (PNS). It interacts with signalling molecules such as the amyloid beta-protein precursor (APP) and the wingless type protein (Wnt). Its mechanisms of action are complex and mediated via interaction between the pre-synaptic motor neuron and post-synaptic muscle cell in the PNS, which enhances the development of the neuromuscular junction (NMJ). LRP4 may function differently in the central nervous system (CNS) than in the PNS, where it regulates ATP and glutamate release via astrocytes. It mayaffect the growth and development of the CNS by controlling the energy metabolism. LRP4 interacts with Agrin to maintain dendrite growth and density in the CNS. The goal of this article is to review the current studies involving relevant LRP4 signaling pathways in the nervous system. The review also discusses the clinical and etiological roles of LRP4 in neurological illnesses, such as myasthenia gravis, Alzheimer's disease and epilepsy. In this review, we provide a theoretical foundation for the pathogenesis and therapeutic application of LRP4 in neurologic diseases.

Simple fluorescence "turn-off" assay for Congo red using commercial 2-aminophthalic acid.

In this work, the fluorescence properties of 2-aminophthalic acid (NH2-BDC) were studied. NH2-BDC possessed excellent optical properties including bright blue emission with maximum emission at 425 nm, a high quantum yield of 38.49% and excellent photostability. And the fluorescence of NH2-BDC could be selectively quenched by Congo red, which was ascribed to the inner filter effect. Accordingly, NH2-BDC was further employed for fluorescence "turn-off" assay of Congo red with a linear range of 0.05-50 µM and a limit of detection of 1.72 µM. And the sensor was used for the detection of Congo red in real water samples with acceptable results.

A brief real-time fNIRS-informed neurofeedback training of the prefrontal cortex changes brain activity and connectivity during subsequent working memory challenge.

Working memory (WM) represents a building-block of higher cognitive functions and a wide range of mental disorders are associated with WM impairments. Initial studies have shown that several sessions of functional near-infrared spectroscopy (fNIRS) informed real-time neurofeedback (NF) allow healthy individuals to volitionally increase activity in the dorsolateral prefrontal cortex (DLPFC), a region critically involved in WM. For the translation to therapeutic or neuroenhancement applications, however, it is critical to assess whether fNIRS-NF success transfers into neural and behavioral WM enhancement in the absence of feedback. We therefore combined single-session fNIRS-NF of the left DLPFC with a randomized sham-controlled design (N = 62 participants) and a subsequent WM challenge with concomitant functional MRI. Over four runs of fNIRS-NF, the left DLPFC NF training group demonstrated enhanced neural activity in this region, reflecting successful acquisition of neural self-regulation. During the subsequent WM challenge, we observed no evidence for performance differences between the training and the sham group. Importantly, however, examination of the fMRI data revealed that - compared to the sham group - the training group exhibited significantly increased regional activity in the bilateral DLPFC and decreased left DLPFC - left anterior insula functional connectivity during the WM challenge. Exploratory analyses revealed a negative association between DLPFC activity and WM reaction times in the NF group. Together, these findings indicate that healthy individuals can learn to volitionally increase left DLPFC activity in a single training session and that the training success translates into WM-related neural activation and connectivity changes in the absence of feedback. This renders fNIRS-NF as a promising and scalable WM intervention approach that could be applied to various mental disorders.

Transcranial magnetic stimulation mapping of the motor cortex: comparison of five estimation algorithms.

Background: There are currently five different kinds of transcranial magnetic stimulation (TMS) motor mapping algorithms available, from ordinary point-based algorithms to advanced field-based algorithms. However, there have been only a limited number of comparison studies conducted, and they have not yet examined all of the currently available algorithms. This deficiency impedes the judicious selection of algorithms for application in both clinical and basic neuroscience, and hinders the potential promotion of a potential superior algorithm. Considering the influence of algorithm complexity, further investigation is needed to examine the differences between fMRI peaks and TMS cortical hotspots that were identified previously. Methods: Twelve healthy participants underwent TMS motor mapping and a finger-tapping task during fMRI. The motor cortex TMS mapping results were estimated by five algorithms, and fMRI activation results were obtained. For each algorithm, the prediction error was defined as the distance between the measured scalp hotspot and optimized coil position, which was determined by the maximum electric field strength in the estimated motor cortex. Additionally, the study identified the minimum number of stimuli required for stable mapping. Finally, the location difference between the TMS mapping cortical hotspot and the fMRI activation peak was analyzed. Results: The projection yielded the lowest prediction error (5.27 ± 4.24 mm) among the point-based algorithms and the association algorithm yielded the lowest (6.66 ± 3.48 mm) among field-based estimation algorithms. The projection algorithm required fewer stimuli, possibly resulting from its suitability for the grid-based mapping data collection method. The TMS cortical hotspots from all algorithms consistently deviated from the fMRI activation peak (20.52 ± 8.46 mm for five algorithms). Conclusion: The association algorithm might be a superior choice for clinical applications and basic neuroscience research, due to its lower prediction error and higher estimation sensitivity in the deep cortical structure, especially for the sulcus. It also has potential applicability in various other TMS domains, including language area mapping and more. Otherwise, our results provide further evidence that TMS motor mapping intrinsically differs from fMRI motor mapping.