Prediction and Interpretation Microglia Cytotoxicity by Machine Learning.

Ameliorating microglia-mediated neuroinflammation is a crucial strategy in developing new drugs for neurodegenerative diseases. Plant compounds are an important screening target for the discovery of drugs for the treatment of neurodegenerative diseases. However, due to the spatial complexity of phytochemicals, it becomes particularly important to evaluate the effectiveness of compounds while avoiding the mixing of cytotoxic substances in the early stages of compound screening. Traditional high-throughput screening methods suffer from high cost and low efficiency. A computational model based on machine learning provides a novel avenue for cytotoxicity determination. In this study, a microglia cytotoxicity classifier was developed using a machine learning approach. First, we proposed a data splitting strategy based on the molecule murcko generic scaffold, under this condition, three machine learning approaches were coupled with three kinds of molecular representation methods to construct microglia cytotoxicity classifier, which were then compared and assessed by the predictive accuracy, balanced accuracy, F1-score, and Matthews Correlation Coefficient. Then, the recursive feature elimination integrated with support vector machine (RFE-SVC) dimension reduction method was introduced to molecular fingerprints with high dimensions to further improve the model performance. Among all the microglial cytotoxicity classifiers, the SVM coupled with ECFP4 fingerprint after feature selection (ECFP4-RFE-SVM) obtained the most accurate classification for the test set (ACC of 0.99, BA of 0.99, F1-score of 0.99, MCC of 0.97). Finally, the Shapley additive explanations (SHAP) method was used in interpreting the microglia cytotoxicity classifier and key substructure smart identified as structural alerts. Experimental results show that ECFP4-RFE-SVM have reliable classification capability for microglia cytotoxicity, and SHAP can not only provide a rational explanation for microglia cytotoxicity predictions, but also offer a guideline for subsequent molecular cytotoxicity modifications.

MicroRNA-3061 downregulates the expression of PAX7/Wnt/Ca2+ signalling axis genes to induce premature ovarian failure in mice.

The in-depth mechanisms of microRNA regulation of premature ovarian failure (POF) remain unclear. Crispr-cas9 technology was used to construct transgenic mice. The qPCR and Western blot was used to detect the expression level of genes. H&E staining were used to detect ovarian pathological phenotypes. We found that the expression levels of microRNA-3061 were significantly higher in ovarian granulosa cells (OGCs) of POF mouse models than in controls. The miR-3061+/-/AMH-Cre+/- transgenic mice manifested symptoms of POF. RNA-Seq and luciferase reporter assay confirmed that the PAX7 was one of the target genes negatively regulated by microRNA-3061 (miR-3061-5p). Moreover, PAX7 mediated the expression of non-canonical Wnt/Ca2+ signalling pathway by binding to the motifs of promoters to stimulate the transcriptional activation of Wnt5a and CamK2a. In contrast, specific knock-in of microRNA-3061 in OGCs significantly downregulated the expression levels of PAX7 and inhibited the expression of downstream Wnt/Ca2+ signalling pathway. We also discerned a correlation between the expression levels of mRNAs of the Wnt/Ca2+ signalling pathway and the levels of E2 and FSH in POF patients by examining gene expression in the follicular fluid-derived exosomes of women. We confirmed that overexpression of microRNA-3061 induced proliferative inhibition of OGCs and ultimately induced POF in mice by suppressing the transcription factor PAX7 and downregulating expression levels of its downstream Wnt/Ca2+ signalling pathway genes.

DNMT1 driven by mouse amniotic fluid mesenchymal stem cell exosomes improved corneal cryoinjury via inducing microRNA-33 promoter DNA hypermethylation modification in corneal epithelium cells.

Severe corneal cryoinjury can cause permanent corneal swelling and bullous keratopathy, one of the main reason for loss of sight. Mouse amniotic fluid mesenchymal stem cells (mAF-MSCs) can repair corneal damage caused by freezing; however, whether the exosomes derived from mAF-MSCs have the same repair effect is unknown. In this study, the mAF-MSC-exosomes were transplanted into the eyeballs of corneal cryoinjured mice. Histopathological examination showed that the mAF-MSC-exosomes improved the corneal structure and status of corneal epithelial cells in corneal cryoinjured mice. RRBS-sequencing showed that compared with the control group, four genes (Rpl13-ps6, miR-33, Hymai, and Plagl1), underwent DNA hypermethylation modification after mAF-MSC-exosomes treatment. The result of FISH indicated that miR-33-3p hybridization signals were enhanced in corneal epithelial cells from mice treated with mAF-MSC-exosomes. Semi-quantitative PCR and western blotting indicated that mAF-MSC-exosomes contained high levels of DNMT1 mRNA and protein. Additionally, luciferase report assays indicated that miR-33-3p overexpression in NIH-3T3 mouse embryonic fibroblast cells inhibited the activity of luciferase carrying a sequence from the 3' untranslated region of Bcl6. Moreover, BCL6 mRNA and protein levels in corneal tissues from mice treated with mAF-MSC-exosomes were higher than those in the control group. Therefore, our results suggested that mAF-MSC-exosomes could repair corneal cryoinjury by releasing DNMT1, which induced hypermethylation of the miR-33 promoter in corneal epithelial cells. Consequent downregulated miR-33 transcription upregulated Bcl6 expression, ultimately achieving the repair of corneal cryoinjury in mice.

The Selective SIRT3 Inhibitor 3-TYP Represses Primary Myeloma Growth by Reducing c-Myc Stability.

Multiple myeloma is a hematological cancer that can be treated but remains incurable. With the advancement of science and technology, more drugs have been developed for myeloma chemotherapy that greatly improve the quality of life of patients. However, relapse remains a serious problem puzzling patients and doctors. Thus, developing more highly active and specific inhibitors is urgent for myeloma-targeted therapy. In this study, we identified the SIRT3 inhibitor 3-TYP (3-(1H-1,2,3-triazol-4-yl) pyridine) after screening a histone modification compound library, which showed high cytotoxicity and induced DNA damage in myeloma cells. Furthermore, the inhibitory effect of 3-TYP in our xenograft tumor studies also confirmed that compound 3-TYP could inhibit primary myeloma growth by reducing c-Myc protein stability by decreasing c-Myc Ser62 phosphorylation levels. Taken together, the results of our study identified 3-TYP as a novel c-Myc inhibitor, which could be a potential chemotherapeutic agent to target multiple myeloma.

Lentinan has a beneficial effect on cognitive deficits induced by chronic Toxoplasma gondii infection in mice.

BACKGROUND: Toxoplasma gondii (T. gondii) is increasingly considered a risk factor for neurodegenerative diseases. However, there is only limited information on the development of drugs for T. gondii infection. Lentinan from Lentinula edodes is a bioactive ingredient with the potential to enhance anti-infective immunity. The present study aimed to investigate the neuroprotective effect of lentinan on T. gondii-associated cognitive deficits in mice. METHODS: A chronic T. gondii infection mouse model was established by administering 10 cysts of T. gondii by gavage. Lentinan was intraperitoneally administered 2 weeks before infection. Behavioral tests, RNA sequencing, immunofluorescence, transmission electron microscopy and Golgi-Cox staining were performed to assess the effect of lentinan on cognitive deficits and neuropathology in vivo. In vitro, the direct and indirect effects of lentinan on the proliferation of T. gondii tachyzoites were evaluated in the absence and presence of BV-2 cells, respectively. RESULTS: Lentinan prevented T. gondii-induced cognitive deficits and altered the transcriptome profile of genes related to neuroinflammation, microglial activation, synaptic function, neural development and cognitive behavior in the hippocampus of infected mice. Moreover, lentinan reduced the infection-induced accumulation of microglia and downregulated the mRNA expression of proinflammatory cytokines. In addition, the neurite and synaptic ultrastructural damage in the hippocampal CA1 region due to infection was ameliorated by lentinan administration. Lentinan decreased the cyst burden in the brains of infected mice, which was correlated with behavioral performance. In line with this finding, lentinan could significantly inhibit the proliferation of T. gondii tachyzoites in the microglial cell line BV2, although lentinan had no direct inhibitory effect on parasite growth. CONCLUSIONS: Lentinan prevents cognitive deficits via the improvement of neurite impairment and synaptic loss induced by T. gondii infection, which may be associated with decreased cyst burden in the brain. Overall, our findings indicate that lentinan can ameliorate T. gondii-related neurodegenerative diseases.

Advances in high-performance MEMS pressure sensors: design, fabrication, and packaging.

Pressure sensors play a vital role in aerospace, automotive, medical, and consumer electronics. Although microelectromechanical system (MEMS)-based pressure sensors have been widely used for decades, new trends in pressure sensors, including higher sensitivity, higher accuracy, better multifunctionality, smaller chip size, and smaller package size, have recently emerged. The demand for performance upgradation has led to breakthroughs in sensor materials, design, fabrication, and packaging methods, which have emerged frequently in recent decades. This paper reviews common new trends in MEMS pressure sensors, including minute differential pressure sensors (MDPSs), resonant pressure sensors (RPSs), integrated pressure sensors, miniaturized pressure chips, and leadless pressure sensors. To realize an extremely sensitive MDPS with broad application potential, including in medical ventilators and fire residual pressure monitors, the "beam-membrane-island" sensor design exhibits the best performance of 66 µV/V/kPa with a natural frequency of 11.3 kHz. In high-accuracy applications, silicon and quartz RPS are analyzed, and both materials show ±0.01%FS accuracy with respect to varying temperature coefficient of frequency (TCF) control methods. To improve MEMS sensor integration, different integrated "pressure + x" sensor designs and fabrication methods are compared. In this realm, the intercoupling effect still requires further investigation. Typical fabrication methods for microsized pressure sensor chips are also reviewed. To date, the chip thickness size can be controlled to be <0.1 mm, which is advantageous for implant sensors. Furthermore, a leadless pressure sensor was analyzed, offering an extremely small package size and harsh environmental compatibility. This review is structured as follows. The background of pressure sensors is first presented. Then, an in-depth introduction to MEMS pressure sensors based on different application scenarios is provided. Additionally, their respective characteristics and significant advancements are analyzed and summarized. Finally, development trends of MEMS pressure sensors in different fields are analyzed.

Bio-Inspired Conductive Hydrogels with High Toughness and Ultra-Stability as Wearable Human-Machine Interfaces for all Climates.

Drawing inspiration from Salicornia, a plant with the remarkable ability to thrive in harsh environments, a conductive hydrogel with high toughness and ultra-stability is reported. Specifically, the strategy of pre-cross-linking followed by secondary soaking in saturated salt solutions is introduced to prepare the PAAM-alginate conductive hydrogel with dual cross-linked dual network structure. It allows the alginate network to achieve complete cross-linking, fully leveraging the structural advantages of the PAAM-alginate conductive hydrogel. The highest tensile strength of the obtained conductive hydrogel is 697.3 kPa and the fracture energy can reach 69.59 kJ m-2 , significantly higher than human cartilage and natural rubbers. Specially, by introducing saturated salt solutions within the hydrogel, the colligative properties endow the PAAM-alginate conductive hydrogel with excellent water retention and anti-freezing properties. The prepared conductive hydrogels can work stably in an ambient environment for more than 7 days and still maintain good mechanical behavior and ionic conductivity at -50 °C. Benefiting from the excellent comprehensive performance of conductive hydrogels, wearable human-machine interfaces that can withstand large joint movements and are adapted for extreme environments are prepared to achieve precise control of robots and prostheses, respectively.

ß-Glucan alleviates goal-directed behavioral deficits in mice infected with Toxoplasma gondii.

BACKGROUND: Toxoplasma gondii (T. gondii) is a neuroinvasive parasite causing neuroinflammation, which in turn is associated with a higher risk for several psycho-behavioral disorders. There is an urgent need to identify drugs capable of improving cognitive deficits induced by T. gondii infection. ß-Glucan, an active ingredient in mushrooms, could significantly enhance immunity. However, the effects of ß-glucan against neuroinflammation and cognitive decline induced by T. gondii infection remain unknown. The present study aimed to investigate the neuroprotective effect of ß-glucan on goal-directed behavior of mice chronically infected by T. gondii Wh6 strain. METHODS: A mice model of chronic T. gondii Wh6 infection was established by infecting mice by oral gavage with 10 cysts of T. gondii Wh6. Intraperitoneal injection of ß-glucan was manipulated 2 weeks before T. gondii infection. Performance of the infected mice on the Y-maze test and temporal order memory (TOM) test was used to assess the goal-directed behavior. Golgi-Cox staining, transmission electron microscopy, immunofluorescence, real-time PCR and western blot assays were used to detect prefrontal cortex-associated pathological change and neuroinflammation. RESULTS: The administration of ß-glucan significantly prevented T. gondii Wh6-induced goal-directed behavioral impairment as assessed behaviorally by the Y-maze test and TOM test. In the prefrontal cortex, ß-glucan was able to counter T. gondii Wh6-induced degeneration of neurites, impairment of synaptic ultrastructure and decrease of pre- and postsynaptic protein levels. Also, ß-glucan significantly prevented the hyperactivation of pro-inflammatory microglia and astrocytes, as well as the upregulation of proinflammatory cytokines caused by chronic T. gondii Wh6 infection. CONCLUSIONS: This study revealed that ß-glucan prevents goal-directed behavioral impairment induced by chronic T. gondii infection in mice. These findings suggest that ß-glucan may be an effective drug candidate to prevent T. gondii-associated psycho-behavioral disorders including goal-directed behavioral injury.

DyGCN: Efficient Dynamic Graph Embedding With Graph Convolutional Network.

Graph embedding, aiming to learn low-dimensional representations (aka. embeddings) of nodes in graphs, has received significant attention. In recent years, there has been a surge of efforts, among which graph convolutional networks (GCNs) have emerged as an effective class of models. However, these methods mainly focus on the static graph embedding. In the present work, an efficient dynamic graph embedding approach is proposed, called dynamic GCN (DyGCN), which is an extension of the GCN-based methods. The embedding propagation scheme of GCN is naturally generalized to a dynamic setting in an efficient manner, which propagates the change in topological structure and neighborhood embeddings along the graph to update the node embeddings. The most affected nodes are updated first, and then their changes are propagated to further nodes, which in turn are updated. Extensive experiments on various dynamic graphs showed that the proposed model can update the node embeddings in a time-saving and performance-preserving way.

Wearable Sensors Adapted to Extreme Environments Based on the Robust Ionogel Electrolytes with Dual Hydrogen Networks.

Nonvolatile ionogels are promising soft electrolyte materials for flexible electronics, but it is challenging to fabricate stable electrolytes with mechanical robustness. Here, through rationally optimizing the chemical structure of polymer matrix and ionic liquids, the high-performance ionogel electrolytes with mechanical robustness and stability were fabricated. There are double hydrogen bonding networks in the as-prepared ionogel electrolytes, one of which exists between the polymer chains while the other one existing between the polymer chains and ionic liquid molecules. By adjusting the content of the ionic liquid and the ratio of the two hydrogen bonding networks, the prepared ionogel electrolytes exhibit tunable properties with an elasticity of 1.3-30 kPa, a stretchability of more than 1800%, a fracture energy of 125.8-548.3 KJ m-3, and a coordinated self-healing efficiency of 6.2-37.9% to satisfy the needs of different application scenarios. The assembled wearable sensors based on the high-performance ionogel electrolytes can be attached to a part of the human body, detecting various motions and body temperature. Benefiting from the nonvolatile and hydrophobic properties of the ionogel electrolytes, the wearable sensors can be operated under extreme environments including high/low temperature (-15-100 °C) and high humidity (100% relative humidity). It is believed that this work provides prospects for the application of wearable electronic devices.

Zwitterionic Hydrogel Electrolyte with Tunable Mechanical and Electrochemical Properties for a Wearable Motion and Thermal Sensor.

A high-performance zwitterionic hydrogel electrolyte was successfully fabricated, in which the polymer chains were cross-linked by multiple reversible non-covalent bonds. The mechanical and electrochemical properties of the synthesized zwitterionic hydrogel electrolyte can be facilely modulated by immersing the as-prepared zwitterionic hydrogel in saline solutions with different concentrations. The processed zwitterionic hydrogel electrolyte exhibits tunable mechanical and electrochemical properties (favorable elasticity of 3.2-202 kPa, high fracture energy of 0.34-1.15 MJ m-3, high stretchability of 1000-2880%, high self-healing efficiency of 30-70%, and coordinated ionic conductivity of 0.16-1.65 S m-1) to satisfy the needs of different application scenarios. A wearable sensor based on the zwitterionic hydrogel electrolyte is demonstrated. The wearable sensor can be attached to a part of the human body, and various human motions can be successfully monitored. Besides being functionalized as a motion monitor, the wearable sensor can also be used as a thermometer to monitor the body temperature instantaneously, showing an encouraging and strong practicability in wearable electronic device.