An Efficient Human Activity Recognition In-Memory Computing Architecture Development for Healthcare Monitoring.

Human activity recognition has played a crucial role in healthcare information systems due to the fast adoption of artificial intelligence (AI) and the internet of thing (IoT). Most of the existing methods are still limited by computational energy, transmission latency, and computing speed. To address these challenges, we develop an efficient human activity recognition in-memory computing architecture for healthcare monitoring. Specifically, a mechanism-oriented model of Ag/a-Carbon/Ag memristor is designed, serving as the core circuit component of the proposed in-memory computing system. Then, one-transistor-two-memristor (1T2M) crossbar array is proposed to perform high-efficiency multiply-accumulate (MAC) operation and high-density memory in the proposed scheme. To facilitate understanding of the proposed efficient human activity recognition in-memory computing design, self-attention ConvLSTM module, multi-head convolutional attention module, and recognition module are proposed. Furthermore, the proposed system is applied to perform human activity recognition, which contains eleven different human activities, including five different postural falls, and six basic daily activities. The experimental results show that the proposed system has advantages in recognition performance (≥ 0.20% accuracy, ≥ 1.10% F1-score) and time consumption (approximately 8∼10 times speed up) compared to existing methods, indicating an advancement in smart healthcare applications.

Enrichment of linoleic acid from yellow horn seed oil through low temperature crystallization followed by urea complexation method and hypoglycemic activities.

Yellow horn (Xanthoceras sorbifolia Bunge) contained abundant linoleic acid (LA), accounting for about 44% of its lipid. Here, LA was enriched by low temperature crystallization followed by urea complexation, and the optimal enrichment conditions were optimized with response surface methods (3:1 ratio of EtOH/FFA, crystallization at - 25 °C for 24.5 h; 2:1 ratio of urea/FFA1, 6.6:1 ratio of EtOH/urea, crystallization at - 10 °C for 22.4 h). Under these conditions, the final LA content and recovery were 97.10% and 62.09%, respectively. In vitro hypoglycemic studies suggested that the LA extract with stronger inhibition on α-glucosidase and lower one on α-amylase than acarbose exhibited a positive control for carbohydrate digestion with lower adverse effects. The enzyme kinetics and Lineweaver-Burk plots analyses revealed a reversible competitive inhibition on α-amylase and α-glucosidase. The findings of this research provided insights for the development of the LA extract as the functional component of health food. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01327-9.

Leflunomide alleviates obesity via activation of the TAK1-AMPK pathway and induction of lipophagy.

Lipophagy is a subset of selective autophagy that specifically degrades lipid droplets and plays an important role in obesity. Leflunomide treatment in rheumatoid arthritis (RA) patients has been associated with weight loss and decreased blood glucose levels, which cannot be attributed to its known side effects. Our prior studies showed that A77 1726, the active metabolite of leflunomide, acts as an inhibitor of S6K1 to sensitize the insulin receptor and control hyperglycemia. Whether the anti-obesity effect of leflunomide is mediated by targeting S6K1 and its underlying mechanisms remain unclear. Here, we report that A77 1726 induced LC3 lipidation and increased the formation of autophagosomes and lipoautolysosomes in 3T3-L1 adipocytes by activating TGF-ß-activated kinase 1 (TAK1), AMP-activated kinase (AMPK), and Unc-51 like autophagy-activated kinase 1 (ULK1). A77 1726 reduced the content of lipid droplets in 3T3-L1 adipocytes, which was blocked by bafilomycin or by beclin-1 knockdown. Similar observations were made in murine adipocytes differentiated from S6K1-/- embryonic fibroblasts (MEFs). Leflunomide treatment restricted bodyweight gains in ob/ob mice and reduced the visceral fat deposit and the size of adipocytes. Leflunomide treatment induced autophagy in adipose and liver tissues and reduced hepatic lipid contents. Consistently, S6K1 knockout increased the levels of LC3 lipidation in the liver, muscle, and fat of S6K-/- mice. Leflunomide treatment and S6K1 deficiency both induced TAK1, AMPK, and ULK1 phosphorylation in these tissues. These observations collectively suggest that leflunomide controls obesity in part by activating AMPK and inducing lipophagy. Our study provides insights into the mechanisms of leflunomide-mediated anti-obesity activity.

Research and Evaluation of the Allosteric Protein-Specific Force Field Based on a Pre-Training Deep Learning Model.

Allosteric modulators are important regulation elements that bind the allosteric site beyond the active site, leading to the changes in dynamic and/or thermodynamic properties of the protein. Allosteric modulators have been a considerable interest as potential drugs with high selectivity and safety. However, current experimental methods have limitations to identify allosteric sites. Therefore, molecular dynamics simulation based on empirical force field becomes an important complement of experimental methods. Moreover, the precision and efficiency of current force fields need improvement. Deep learning and reweighting methods were used to train allosteric protein-specific precise force field (named APSF). Multiple allosteric proteins were used to evaluate the performance of APSF. The results indicate that APSF can capture different types of allosteric pockets and sample multiple energy-minimum reference conformations of allosteric proteins. At the same time, the efficiency of conformation sampling for APSF is higher than that for ff14SB. These findings confirm that the newly developed force field APSF can be effectively used to identify the allosteric pocket that can be further used to screen potential allosteric drugs based on these pockets.

Personal Precise Force Field for Intrinsically Disordered and Ordered Proteins Based on Deep Learning.

Intrinsically disordered proteins (IDPs) are proteins without a fixed three-dimensional (3D) structure under physiological conditions and are associated with Parkinson's disease, Alzheimer's disease, cancer, cardiovascular disease, amyloidosis, diabetes, and other diseases. Experimental methods can hardly capture the ensemble of diverse conformations for IDPs. Molecular dynamics (MD) simulations can sample continuous conformations that might provide a valuable complement to experimental data. However, the accuracy of MD simulations depends on the quality of force field. In particular, the evolutionary conservation and coevolution of IDPs introduce that current force fields could not precisely reproduce the conformation of IDPs. In order to improve the performance of force field, deep learning and reweighting methods were used to automatically generate personal force field parameters for intrinsically disordered and ordered proteins. At first, the deep learning method predicted more accuracy φ/ψ dihedral of residue than the previous method. Then, reweighting optimized the personal force field parameters for each residue. Finally, typical representative systems such as IDPs, structure protein, and fast-folding protein were used to evaluate this force field. The results indicate that two personal force field parameters (named PPFF1 and PPFF1_af2) could better reproduce the experimental observables than ff03CMAP force field. In summary, this strategy will provide feasibility for the development of precise personal force fields.

A Flexible Memristor Model With Electronic Resistive Switching Memory Behavior and Its Application in Spiking Neural Network.

Memristive technologies are attractive due to their non-volatility, high-density, low-power and compatibility with CMOS. For memristive devices, a model corresponding to practical behavioral characteristics is highly favorable for the realization of its neuromorphic system and applications. This paper presents a novel flexible memristor model with electronic resistive switching memory behavior. Firstly, the Ag-Au / MoSe2-doped Se / Au-Ag memristor is prepared using hydrothermal synthesis method and magnetron sputtering method, and its performance test is conducted on an electrochemical workstation. Then, the mathematical model and SPICE circuit model of the Ag-Au / MoSe2-doped Se / Au-Ag memristor are constructed. The model accuracy is verified by using the electrochemical data derived from the performance test. Furthermore, the proposed model is applied to the circuit implementation of spiking neural network with biological mechanism. Finally, computer simulations and analysis are carried out to verify the validity and effectiveness of the entire scheme.

Gallic Acid Ameliorates Aspergillus Fumigatus Keratitis Through Reducing Fungal Load and Suppressing the Inflammatory Response.

Purpose: The purpose of this study was to explore the antifungal and anti-inflammatory effects of gallic acid (GA) on Aspergillus fumigatus (A. fumigatus) keratitis. Methods: CCK-8 assay and Draize eye test were used to determine the non-cytotoxic concentration of GA in RAW264.7 cells and an A. fumigatus keratitis mouse model. The antifungal effects of GA were analyzed using minimal inhibitory concentration (MIC), biofilm formation test, fungal adherence assay, calcofluor white staining, and propidium iodide staining. The therapeutic effects of GA were estimated by slit lamp photographs, clinical score, hematoxylin and eosin (H&E) staining, and Periodic acid-Schiff staining in vivo. Immunofluorescence staining and myeloperoxidase assay were conducted to identify neutrophil infiltration and activity. RT-PCR, ELISA, and Western blot were performed to detect the expression of pro-inflammatory cytokines and Nrf2/HO-1. Results: In HCECs and A. fumigatus keratitis mouse model, GA at 100 µg/mL did not affect cell viability, thus this concentration was applied to subsequent experiments. In vitro, GA significantly inhibited A. fumigatus growth, biofilm formation, and adhesion. In vivo, 100 µg/mL GA alleviated the severity of fungal keratitis (FK) by repressing fungal load, reducing neutrophil infiltration, and lowering MPO activity. Besides, the expression of IL-1ß, TNF-α, LOX-1, and COX-2 was inhibited, whereas Nrf2 and HO-1 expression was enhanced at both mRNA and protein levels in the 100 µg/mL GA treated group in comparison to PBS control. Conclusions: GA ameliorates FK severity through inhibiting A. fumigatus load, reducing neutrophils infiltration, downregulating the expression of pro-inflammatory cytokines, and enhancing the Nrf2/HO-1 pathway, which provides new insight into A. fumigatus keratitis treatment.

Laccase-mediated functionalization of natamycin by gallic acids for the therapeutic effect on Aspergillus fumigatus keratitis.

To improve the therapeutic effect of natamycin on fungal keratitis (FK), the grafted derivatives of natamycin and gallic acid were obtained, and the effects of the grafted derivatives on Aspergillus fumigatus (A. fumigatus) keratitis were investigated. The structure of natamycin grafted with gallic acid was identified by FT-IR and UV-Vis, and the successful synthesis of Gallic-Natamycin (GA-NAT) was proved. CCK-8 and the Draize eye test showed that GA-NAT had less cytotoxicity. Then, through in vitro antibacterial experiments such as minimum inhibitory concentration (MIC), adhesion, biofilm formation, and calcium fluorescence staining and in vivo experiments such as clinical score and plate counting, the results showed that GA-NAT had similar antifungal activity to natamycin, but had a better therapeutic effect than natamycin. Myeloperoxidase assay and immunofluorescence staining also showed that GA-NAT significantly inhibited neutrophil recruitment and activity. Moreover, It was further found that GA-NAT could inhibit the mRNA and protein expressions of LOX-1, TNF-α, and IL-1ß. These results indicated that GA-NAT inhibited the fungal growth, reduced the neutrophil infiltration into cornea, and down-regulated the expression of inflammatory factors in lesions, which provides a new choice for FK treatment.

Comparative Analysis of Volatile Terpenes and Terpenoids in the Leaves of Pinus Species-A Potentially Abundant Renewable Resource.

Pinaceae plants are widely distributed in the world, and the resources of pine leaves are abundant. In the extensive literature concerning Pinus species, there is much data on the composition and the content of essential oil of leaves. Still, a detailed comparative analysis of volatile terpenes and terpenoids between different species is missing. In this paper, headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry was used to determine the volatile terpenes and terpenoids of typical Pinus species in China. A total of 46 volatile terpenes and terpenoids were identified, and 12 common compounds were found, which exhibited a great diversity in the leaves of Pinus species. According to the structures and properties of the compounds, all those compounds can be classified into four categories, namely monoterpenes, oxygenated terpenes, terpene esters, and sesquiterpenes. The results of principal component analysis and cluster analysis showed that the leaves of the six Pinus species could be divided into two groups. The species and contents of volatile terpenes and terpenoids in the leaves were quite different. The results not only provide a reference for the utilization of pine leaves resource, but also bring a broader vision on the biodiversity.

Comprehensive Analysis of Gene Expression Changes and Validation in Hepatocellular Carcinoma.

AIM: This study aimed to analyze the involvement of hub genes in hepatocellular carcinoma. METHODS: Four series were used in this study: GSE45267, GSE84402, and GSE101685 from GPL570 platform in the Gene Expression Omnibus and the other from The Cancer Genome Atlas. The gene audition was completed using R software and Venn diagrams. The outcome, Gene Ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes preliminary analyses of differentially expressed genes were performed using the R software. A string image was obtained using the Search Tool for the Retrieval of Interacting Genes. The protein-protein interaction network was examined using Cytoscape software. The corrplot package was used to analyze the correlation of genes. Human Protein Atlas was used to confirm the protein levels. Univariate Cox regression was used to analyze whether these genes were related to survival. UALCAN was used to confirm the effect of these genes on patient survival. RESULTS: A total of 107 differentially expressed genes from 491 patients with hepatocellular carcinoma and 119 normal individuals were selected in this study. Cytoscape revealed 25 central nodes from the 107 genes. CCNB1, CDK1, CCNA2, PTTG1, and CDC20 were selected based on the cell cycle pathway. A significant correlation was found among the 6 DEGs. The transcription levels and protein levels of these genes were verified in cells and human tissue samples. The overall survival for these genes was analyzed using univariate Cox regression and UALCAN. CONCLUSION: CCNB1, CDK1, CDC20, PTTG1, CCNA2, and TTK were overexpressed and correlated in hepatocellular carcinoma cells and tumors. The results might help explore the prognosis and diagnostic markers of HCC.

Restriction of intracellular Salmonella typhimurium growth by the small-molecule autophagy inducer A77 1726 through the activation of the AMPK-ULK1 axis.

Autophagy plays an important role in restricting the growth of invading intracellular microbes. Salmonella (S) Typhimurium, an intracellular pathogen that causes gastroenteritis and food poisoning in humans, evades autophagic detection by multiple mechanisms. There has been growing interest in developing autophagy inducers as novel antimicrobial agents for treating intracellular bacterial infections. We recently reported that A77 1726, the active metabolite of the anti-inflammatory drug leflunomide, induces autophagy by activating AMP-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase 1 (ULK1). Our present study aims to determine if A77 1726 was able to restrict intracellular Salmonella growth by inducing autophagy. We first confirmed the ability of A77 1726 to induce autophagy by activating the AMPK-ULK1 axis in uninfected RAW264.7 (a murine macrophage cell line) and HeLa cells (a human cervical carcinoma cell line). A77 1726 enhanced autophagy in S. Typhimurium-infected cells, as evidenced by increased levels of LC3 lipidation and increased numbers of autophagosomes and autolysosomes. Confocal microscopy revealed that A77 1726 induced xenophagy in macrophages, as evidenced by an increased number of LC3-coated bacteria in the cytoplasm. A77 1726 significantly decreased the number of intracellular S. Typhimurium in macrophages. Taken together, our study has demonstrated the ability of A77 1726 to restrict intracellular S. Typhimurium growth in vitro by enhancing xenophagy.

Hydroxypropyl-ß-Cyclodextrin Complexes of Styryllactones Enhance the Anti-Tumor Effect in SW1116 Cell Line.

Styryllactones, a class of compounds obtained from the genus Goniothalamus (Annonaceae), have demonstrated in vitro antitumor activity. However, the aqueous solubility of these compounds is poor. In this study, we identified the absolute configurations of the previously isolated compounds, which were first isolated in our laboratory, by single-crystal X-ray diffraction analysis using Cu Kα radiation. Subsequently, the antitumor activities of the compounds were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide staining in four tumor cell lines. The induced apoptosis activity of leiocarpin E-7'-Monoacetate was studied by an annexin V fluorescein isothiocyanate/propidium iodide double-staining experiment, and the caspase activity was tested in the SW1116 cell line. The results demonstrated that the antitumor activities of cheliensisin A and goniodiol-7-monoacetate were limited by their poor water solubility. To address this issue, hydroxypropyl-ß-cyclodextrin (HP-ß-CD) complexes of the compounds were synthesized by the saturated aqueous method. The complexes were then analyzed using a differential scanning calorimeter. The IC50 of cheliensisin A was reduced by 45% and 58% against SW1116 and SMMC-7721 cell lines, respectively. Similarly, the IC50 of goniodiol-7-monoacetate was reduced by 55% and 34% against the two tumor cell lines, respectively. To further evaluate whether the styryllactones and complexes possessed selectivity against cancer cell lines and normal cell lines, toxicity against human normal cell line (HEK293T) was evaluated. The results demonstrated that the HP-ß-CD complexes displayed more cytotoxicity than the respective pristine compounds against the HEK293T cell line. However, there existed a therapeutic window when the complexes were applied against cancer cell lines. In summary, the synthesis of several styryllactone compounds complexed with HP-ß-CD was reported for the first time. These complexes could significantly enhance the cytotoxic effects of styryllactone compounds.

The Gli1-Snail axis contributes to Salmonella Typhimurium-induced disruption of intercellular junctions of intestinal epithelial cells.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular pathogen that damages gastrointestinal tissue and causes severe diarrhoea. The mechanisms by which Salmonella disrupts epithelial barrier and increases the paracellular permeability are incompletely understood. Our present study aims to determine the role of Gli1, a transcription factor activated in the sonic hedgehog (Shh) pathway, in decreasing the levels of apical junction proteins in a Salmonella-infected human colonic epithelial cancer cell line, Caco-2, and in the intestinal tissue of Salmonella-infected mice. Here, we report that S. Typhimurium increased the mRNA and protein levels of Gli1 and Snail, a downstream transcription factor that plays an important role in the epithelial-to-mesenchymal transition (EMT). S. Typhimurium also decreased the levels of E-cadherin and three tight junction proteins (ZO-1, claudin-1, and occludin). Gli1 siRNA and GANT61, a Gli1-specific inhibitor, blocked S. Typhimurium-induced Snail expression, restored the levels of E-cadherin and tight junction proteins, and prevented S. Typhimurium-increased paracellular permeability. Further study showed that Gli1 was cross-activated by the MAP and PI-3 kinase pathways. S. Typhimurium devoid of sopB, an effector of the Type 3 secretion system (T3SS) responsible for AKT activation, was unable to induce Snail expression and to decrease the expression of apical junction proteins. Our study uncovered a novel role of Gli1 in mediating the Salmonella-induced disruption of the intestinal epithelial barrier.

In silico screening and surface plasma resonance-based verification of programmed death 1-targeted peptides.

Programmed death 1 (PD-1) is a key immune checkpoint molecule. When it binds to programmed death-ligand 1 (PD-L1), it can negatively regulate the immune response. Therefore, blockade of the PD-1/PD-L1 interaction could unleash the power of immune system. Though successes achieved by anti-PD-1/PD-L1 antibody drugs in clinical for various cancers, many intrinsic limitations of the high molecular weight drugs require alternatives such as peptide drugs and chemical compounds. In this study, we described a novel in silico approach which was used to screen peptides from PDB database and aimed to identify peptides that have potential to bind the PD-L1 binding area of PD-1 molecule. Based on the docking poses, eight peptides were synthesized and measured for their binding abilities by surface plasma resonance technique. The KD values of the synthesized peptides ranged from 10.0 to 133.0 µM. Furthermore, the binding mechanism between PD-1 and the peptides was studied. In conclusion, we established a fast and reliable screening method for peptide discovery, which could be applied for identifying peptide inhibitors of various targets. The synthesized peptides could be served as starting points for designing PD-1 drug for cancer immunotherapy.

TLC-bioautography directed isolation of antibacterial compounds from active fractionation of Ferula ferulioides.

A novel optimised isolation method, TLC-bioautography, was evaluated and utilised in this research. Antibacterial compounds which were isolated from the dichloromethane extract of Ferula ferulioides (Steud.) Korovin were detected by means of the method. Their structures were elucidated by extensive spectral and chemical methods. Their antibacterial activities against drug-resistant Staphylococcus aureus (S. aureus) strains were evaluated with broth microdilution method, and the results proved that TLC-bioautography was an effective and highly efficient way to screen natural compounds from plant extracts against drug-resistant strains.