Polarized M2 macrophages induced by glycosylated nano-hydroxyapatites activate bone regeneration in periodontitis therapy.

AIM: To investigate the association between periodontal macrophage polarization states and the alveolar bone levels, and to assess whether glycosylated nano-hydroxyapatites (GHANPs) could improve bone regeneration in periodontitis by inducing macrophage M2 polarization. MATERIALS AND METHODS: The change of macrophage polarization state in inflammatory periodontal tissues (with bone loss) was examined using clinical gingival samples. The relationship between macrophage phenotype and bone level in periodontal bone loss and repair was evaluated using a mouse periodontitis model. The effect of GHANPs on macrophage polarization was assessed by the in vitro model of lipopolysaccharide (LPS)-stimulated inflammation. The polarization-related markers were detected by immunofluorescence staining, real-time polymerase chain reaction and enzyme-linked immunosorbent assay analysis. The therapeutic effect of GHANPs on alveolar bone loss was explored in experimental periodontitis by histological staining and micro-CT analysis. RESULTS: A lower macrophage M2/M1 ratio was observed in periodontitis-affected human gingival tissues. The results of animal experiments demonstrated a positive correlation between a lower Arg-1/iNOS ratio and accelerated alveolar bone loss; also, the proportion of Arg-1-positive macrophages increased during bone repair and regeneration. The administration of GHANPs partially restored M2 macrophage polarization after LPS stimulation. GHANPs increased alveolar bone repair and regeneration in experimental periodontitis induced by ligation, potentially related to their macrophage M2 transition regulation. CONCLUSIONS: The findings of this study indicate that the induction of macrophage M2 polarization can be considered a viable approach for enhancing inflammatory bone repair. Additionally, GHANPs show potential in the clinical treatment of periodontitis.

Periodontitis salivary microbiota exacerbates colitis-induced anxiety-like behavior via gut microbiota.

The gut-brain axis is a bidirectional communication system between the gut and central nervous system. Many host-related factors can affect gut microbiota, including oral bacteria, making the brain a vulnerable target via the gut-brain axis. Saliva contains a large number of oral bacteria, and periodontitis, a common oral disease, can change the composition of salivary microbiota. However, the role and mechanism of periodontitis salivary microbiota (PSM) on the gut-brain axis remain unclear. Herein, we investigated the nature and mechanisms of this relationship using the mice with dextran sulfate sodium salt (DSS)-induced anxiety-like behavior. Compared with healthy salivary microbiota, PSM worsened anxiety-like behavior; it significantly reduced the number of normal neurons and activated microglia in DSS mice. Antibiotic treatment eliminated the effect of PSM on anxiety-like behavior, and transplantation of fecal microbiota from PSM-gavaged mice exacerbated anxiety-like behavior. These observations indicated that the anxiety-exacerbating effect of PSM was dependent on the gut microbiota. Moreover, the PSM effect on anxiety-like behavior was not present in non-DSS mice, indicating that DSS treatment was a prerequisite for PSM to exacerbate anxiety. Mechanistically, PSM altered the histidine metabolism in both gut and brain metabolomics. Supplementation of histidine-related metabolites had a similar anxiety-exacerbating effect as that of PSM, suggesting that histidine metabolism may be a critical pathway in this process. Our results demonstrate that PSM can exacerbate colitis-induced anxiety-like behavior by directly affecting the host gut microbiota, emphasizing the importance of oral diseases in the gut-brain axis.

Impact of COVID-19 Pandemic on Children's Fundamental Motor Skills: A Study for the Taiwanese Preschoolers Teachers.

The outbreak of the COVID-19 pandemic has resulted in reduced opportunities for children to engage in fundamental motor skills [FMS]. This prolonged inactivity and restriction of play can have serious consequences for children's physical and mental health. The purpose of this study was to explore teaching strategies during the pandemic, whether there were differences in children's motor development, and the differences in the implementation of physical movement courses before and during the pandemic from the perspective of preschool teachers. This study was a retrospective study using an internet survey, and participants comprised 2337 preschool teachers. The statistical methodology of this study included descriptive statistics, the dependent t-test, and the independent t-test. The results showed that regardless of the time, frequency, activity intensity, and frequency of outdoor courses, the results from before the pandemic was better than those taken during the pandemic. Only the "frequency of implementing physical movement courses indoors every week" had not been affected by the pandemic. This study also obtained the performance of "children's fitness", "overall performance of physical movement ability", "stability movement skills", "locomotor movement skills", and "manipulative movement skills". All were better before the pandemic than during the pandemic. During the COVID-19 pandemic, mixed-age classes performed better than same-age classes in terms of frequency, time, intensity, outdoor course implementation, and physical fitness. Public schools performed better than private schools in terms of frequency, time, intensity, outdoor course implementation, and fundamental motor skills performance. Private schools implemented physical movement courses indoors every week, which was more than public schools. Excepting the frequency of implementing physical movement courses indoors every week, fewer than schools with five classes performed better than those who had more than schools with six classes. Finally, rural schools were better than urban schools in the implementation of outdoor courses and fundamental motor skills performance. Therefore, we suggest that in response to the pandemic, teachers should further improve their professionalism and use diversified teaching methods, and guide students to be willing to learn and improve their skill performance.

Epitaxial Kagome Thin Films as a Platform for Topological Flat Bands.

Systems with flat bands are ideal for studying strongly correlated electronic states and related phenomena. Among them, kagome-structured metals such as CoSn have been recognized as promising candidates due to the proximity between the flat bands and the Fermi level. A key next step will be to realize epitaxial kagome thin films with flat bands to enable tuning of the flat bands across the Fermi level via electrostatic gating or strain. Here, we report the band structures of epitaxial CoSn thin films grown directly on the insulating substrates. Flat bands are observed by using synchrotron-based angle-resolved photoemission spectroscopy (ARPES). The band structure is consistent with density functional theory (DFT) calculations, and the transport properties are quantitatively explained by the band structure and semiclassical transport theory. Our work paves the way to realize flat band-induced phenomena through fine-tuning of flat bands in kagome materials.

Acute inflammatory reaction during anti-angiogenesis therapy combined with immunotherapy as a possible indicator of the therapeutic effect: Three case reports and literature review.

The posterior line treatment of unresectable advanced or metastatic gastrointestinal (GI) tumors has always been a challenging point. In particular, for patients with microsatellite stable (MSS)/mismatch repair proficient (pMMR) 0GI tumors, the difficulty of treatment is exacerbated due to their insensitivity to immune drugs. Accordingly, finding a new comprehensive therapy to improve the treatment effect is urgent. In this study, we report the treatment histories of three patients with MSS/pMMR GI tumors who achieved satisfactory effects by using a comprehensive treatment regimen of apatinib combined with camrelizumab and TAS-102 after the failure of first- or second-line regimens. The specific contents of the treatment plan were as follows: apatinib (500 mg/d) was administered orally for 10 days, followed by camrelizumab (200 mg, ivgtt, day 1, 14 days/cycle) and TAS-102 (20 mg, oral, days 1-21, 28 days/cycle). Apatinib (500 mg/d) was maintained during treatment. Subsequently, we discuss the possible mechanism of this combination and review the relevant literature, and introduce clinical trials on anti-angiogenesis therapy combined with immunotherapy.

Research on Transportation Mode Recognition Based on Multi-Head Attention Temporal Convolutional Network.

Transportation mode recognition is of great importance in analyzing people's travel patterns and planning urban roads. To make more accurate judgments on the transportation mode of the user, we propose a deep learning fusion model based on multi-head attentional temporal convolution (TCMH). First, the time-domain features of a more extensive range of sensor data are mined through a temporal convolutional network. Second, multi-head attention mechanisms are introduced to learn the significance of different features and timesteps, which can improve the identification accuracy. Finally, the deep-learned features are fed into a fully connected layer to output the classification results of the transportation mode. The experimental results demonstrate that the TCMH model achieves an accuracy of 90.25% and 89.55% on the SHL and HTC datasets, respectively, which is 4.45% and 4.70% higher than the optimal value in the baseline algorithm. The model has a better recognition effect on transportation modes.

Bio-inspired glycosylated nano-hydroxyapatites enhance endogenous bone regeneration by modulating macrophage M2 polarization.

A macrophage-associated immune response is vital in bone regeneration. Mannose receptor (MR), a macrophage pattern-recognition receptor, is crucial for the maintenance of immune homeostasis. Here, we designed MR-targeted glycosylated nano-hydroxyapatites (GHANPs) to reprogram macrophages into polarized M2s, promoting bone regeneration by improving the osteoimmune microenvironment. The prepared GHANPs induced macrophage M2 polarization, which then promoted osteoblastic differentiation of stem cells. Further, the mechanistic study showed that GHANPs might influence macrophage polarization by modulating cell metabolism, including enhancing mitochondrial oxidative phosphorylation and activating autophagy. Finally, a rat cranial defect model was used to verify the effect of GHANPs on endogenous bone regeneration in vivo, revealing that GHANPs promoted bone regeneration within the defect and increased the ratio of M2/M1 macrophages in early bone repair. Our results indicate that the MR-targeted macrophage M2 polarization strategy is promising in endogenous bone regeneration. STATEMENT OF SIGNIFICANCE: Macrophage is a pivotal immunity component for bone regeneration. A switch to M2 macrophage has been considered to contribute to osteogenesis. For inducing macrophage M2 polarization, an effective strategy to overcome off-target effects and insufficient specificity is a critical challenge. The mannose receptor on the surface of macrophages has been involved in regulating macrophage directional polarization. The glucomannan presented on the nano-hydroxyapatite rods acts as ligands targeting macrophage mannose receptors to promote their M2 polarization, improving the immunomicroenvironment and achieving bone regeneration. This approach has the advantage of easy preparation, specific regulation, and safety.

Momentum-Resolved Exciton Coupling and Valley Polarization Dynamics in Monolayer WS_{2}.

Using time- and angle-resolved photoemission, we present momentum- and energy-resolved measurements of exciton coupling in monolayer WS_{2}. We observe strong intravalley coupling between the B_{1s} exciton and A_{n>1} states. Our measurements indicate that the dominant valley depolarization mechanism conserves the exciton binding energy and momentum. While this conservation is consistent with Coulomb exchange-driven valley depolarization, we do not observe a momentum or energy dependence to the depolarization rate as would be expected for the exchange-based mechanism.

Modification of the swirling well cell culture model to alter shear stress metrics.

Effects of hemodynamic shear stress on endothelial cells have been extensively investigated using the "swirling well" method, in which cells are cultured in dishes or multiwell plates placed on an orbital shaker. A wave rotates around the well, producing complex patterns of shear. The method allows chronic exposure to flow with high throughput at low cost but has two disadvantages: a number of shear stress characteristics change in a broadly similar way from the center to the edge of the well, and cells at one location in the well may release mediators into the medium that affect the behavior of cells at other locations, exposed to different shears. These properties make it challenging to correlate cell properties with shear. The present study investigated simple alterations to ameliorate these issues. Flows were obtained by numerical simulation. Increasing the volume of fluid in the well-altered dimensional but not dimensionless shear metrics. Adding a central cylinder to the base of the well-forced fluid to flow in a square toroidal channel and reduced multidirectionality. Conversely, suspending a cylinder above the base of the well made the flow highly multidirectional. Increasing viscosity in the latter model increased the magnitude of dimensional but not dimensionless metrics. Finally, tilting the well changed the patterns of different wall shear stress metrics in different ways. Collectively, these methods allow similar flows over most of the cells cultured and/or allow the separation of different shear metrics. A combination of the methods overcomes the limitations of the baseline model.

Rapid capture and killing of bacteria by lyophilized nFeS-Hydrogel for improved healing of infected wounds.

Due to their antibacterial activity, sulfur-containing nanomaterials are increasingly being developed into nanodrugs against bacterial infection. Nano iron sulfide (nFeS) is a new nanomaterial that can convert organic sulfur into inorganic sulfur, which has excellent antibacterial activity. However, the inorganic sulfur produced by nFeS can easily change its form or volatilize in aqueous solution, which may affect the efficacy of nFeS. We propose a new strategy to encapsulate nFeS in a hydrogel to preserve inorganic sulfides, and the macroporous structure of the hydrogel can capture bacteria to increase their interaction with nFeS. The in-depth characterization conducted in this study demonstrate that the water swelling characteristics of the lyophilized nFeS-Hydrogel and the ability to effectively maintain the antibacterial active ingredients in nFeS results in more effective killing of harmful bacteria than pure nFeS, while also prolonging the shelf life of antibacterial activity. We discovered that bacteria exhibit a unique mode of cell death when nFeS contained in hydrogels interacts with the cells by producing hydrogen polysulfanes, which increased intracellular ROS levels and reduced GSH levels. Furthermore, the nFeS-Hydrogel was found to reduce inflammation and exhibited excellent biocompatibility. Accordingly, the nFeS-Hydrogel has great application prospects as a fast excipient for clearing infection, reducing inflammation, and accelerating wound healing.

Stellettin B-Induced Oral Cancer Cell Death via Endoplasmic Reticulum Stress-Mitochondrial Apoptotic and Autophagic Signaling Pathway.

Oral squamous cell carcinoma (OSCC) affects tens of thousands of people worldwide. Despite advances in cancer treatment, the 5-year survival rate of patients with late-stage OSCC is low at 50-60%. Therefore, the development of anti-OSCC therapy is necessary. We evaluated the effects of marine-derived triterpene stellettin B in human OC2 and SCC4 cells. Stellettin B dose-dependently decreased the viability of both cell lines, with a significant reduction in OC2 cells at ≥0.1 µM at 24 and 48 h, and in SCC4 cells at ≥1 µM at 24 and 48 h. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells were significantly observed at 20 µM of stellettin B at 48 h, with the overexpression of cleaved caspase3 and cleaved poly(ADP-ribose) polymerase (PARP). Moreover, mitochondrial respiratory functions were ablated by stellettin B. Autophagy-related LC3-II/LC3-I ratio and Beclin-1 proteins were increased, whereas p62 was decreased. At 20 µM at 48 h, the expression levels of the endoplasmic reticulum (ER) stress biomarkers calnexin and BiP/GRP78 were significantly increased and mitogen-activated protein kinase (MAPK) signaling pathways were activated. Further investigation using the autophagy inhibitor 3-methyladenine (3-MA) demonstrated that it alleviated stellettin B-induced cell death and autophagy. Overall, our findings show that stellettin B induces the ER stress, mitochondrial stress, apoptosis, and autophagy, causing cell death of OSCC cells.

NPM1 promotes cell proliferation by targeting PRDX6 in colorectal cancer.

Colorectal cancer is a malignant tumor that begins in the colorectal mucosal epithelium. NPM1 is a nucleolar phosphoprotein that has been linked to tumor progression in humans. NPM1 is significantly overexpressed in a variety of tumors, including colorectal cancer, but its role and mechanism in colorectal cancer remain unknown. Therefore, the purpose of this study was to discover the role of NPM1 in promoting colorectal cancer proliferation via PRDX6 and its molecular mechanism. NPM1 knockdown or overexpression inhibited or promoted the proliferation and cell cycle progression of HCT-116 and HT-29 colorectal cancer cells, respectively, according to our findings. Furthermore, NPM1 knockdown or overexpression increased or decreased intracellular ROS levels. Animal experiments revealed that NPM1 knockdown or overexpression inhibited or promoted the growth of colorectal cancer cells transplanted subcutaneously. NPM1 knockdown or overexpression reduced or increased PRDX6 expression and related enzyme activities, respectively, according to our findings. NPM1 formed a complex with CBX3 as evidenced by immunoprecipitation, and the double luciferase reporter gene assay confirmed that the CBX3-NPM1 complex promoted PRDX6 transcription. Our data support the role of NPM1 in promoting the proliferation of colorectal cancer, which may be accomplished by CBX3 promoting the expression of the antioxidant protein PRDX6 and thus inhibiting intracellular ROS levels. NPM1 and PRDX6 are potential colorectal cancer therapeutic targets.

Network Pharmacology Analysis of Huangqi Jianzhong Tang Targets in Gastric Cancer.

Background: The Chinese medicine, Huangqi Jianzhong Tang (HJT), is widely used to treat gastric cancer (GC). In this study, network pharmacological methods were used to analyze the potential therapeutic targets and pharmacological mechanisms of HJT in GC. Methods: Bioactive components and targets of HJT and GC-related targets were identified using public databases. The protein-protein interaction network of potential targets of HJT in GC was constructed using the Cytoscape plug-in (v3.8.0), CytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, in addition to molecular docking and animal experiments to verify the results of network pharmacology analysis. Results: A total of 538 GC-related targets were identified. The bioactive components of HJT were selected for drug-likeness evaluation and binomial statistical model screening, which revealed 63 bioactive components and 72 targets. Based on GO enrichment analysis, all targets in the protein-protein interaction network were mainly involved in the response to oxidative stress and neuronal death. Further, KEGG enrichment analysis suggested that the treatment of GC with HJT mainly involved the Wnt signaling pathway, PI3K-Akt signaling pathway, TGF-ß signaling pathway, and MAPK signaling pathway, thereby providing insights into the mechanism of the effects of HJT on GC. Conclusion: This study revealed the potential bioactive components and molecular mechanisms of HJT, which may be useful for the treatment of GC, and provided insights into the development of new drugs for GC.

Identification of Novel Genes and Associated Drugs in Cervical Cancer by Bioinformatics Methods.

BACKGROUND Cervical cancer is one of the common gynecological tumors that seriously harm women's health, so it is particularly important to accurately explore the underlying mechanism of its occurrence and clinical prognosis. MATERIAL AND METHODS In the GEO database, GEO2R was used to analyze the differentially expressed genes from the 4 databases: GSE6791, GSE9750, GSE63514, and GSE67522. Then, the DAVID website was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. These protein-protein interaction (PPI) networks of DEGS were visualized and analyzed using the STRING website and the hub genes were further screened using the Cytohubba plugin. Lastly, the functions of the hub genes were further analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) online tools, Human Protein Atlas (HPA) databases, and the QuartataWeb database. RESULTS In the 4 Profile datasets, 101 cancer tissues and 67 normal tissues were collected. Among the 78 differentially expressed genes in the 4 datasets, 51 genes were upregulated and 27 genes were downregulated. The PPIs of these differentially expressed genes were visualized using Cytoscape and the Interaction Gene Search Tool (STRING). Then, further analysis of hub genes using the GEPIA tool and Kaplan-Meier curves that showed upregulation of CDK1 and PRC1 is associated with better survival, while AURKA is associated with worse survival. Among these hub genes, only AURKA was closely related to the prognosis of cervical cancer, and 21 potential drugs were found. CONCLUSIONS These results suggest that AURKA and its drug candidates can improve the individualized diagnosis and treatment of cervical cancer in the future.

Mutational characteristics of young and elderly gastric cancer: a comparative study.

Background: Young gastric cancer (YGC) has been indicated as having a worse prognosis than in elderly gastric cancer (EGC). It has been reported that YGC and EGC patients show different genomic profiles; however, there has been no comparative study conducted to reveal their mutational characteristics. Methods: Firstly, we divided and analyzed the mutational landscape and 50 cancer-related genes characters of YGC (n=18) and EGC (n=18) patients from The Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD). A total of 8 gastric cancer samples including 4 YGC and 4 EGC patients were collected to detect 50 cancer-related genes by multiplex polymerase chain reaction (PCR) next generation sequencing. The R/maftools package was used to describe the mutational characteristics. Results: Our results showed that the EGC group harbored more mutations than the YGC group. In 50 cancer-related genes in our cohort, the YGC group tended to be different from the EGC group using multiplex PCR next generation sequencing. In the YGC group, candidate mutations were identified within the following genes: IDH2, PDGFRA, KRAS, FLT3, FGFR2, and FGFR3. The YGC group showed less tumor mutational burden (TMB) level then EGC. Conclusions: The YGC group tended to be more sensitive to molecularly targeted therapy because of it having more somatic mutations in 50 cancer-related genes using targeted next-generation sequencing.

Query-Efficient Black-Box Adversarial Attacks Guided by a Transfer-Based Prior.

Adversarial attacks have been extensively studied in recent years since they can identify the vulnerability of deep learning models before deployed. In this paper, we consider the black-box adversarial setting, where the adversary needs to craft adversarial examples without access to the gradients of a target model. Previous methods attempted to approximate the true gradient either by using the transfer gradient of a surrogate white-box model or based on the feedback of model queries. However, the existing methods inevitably suffer from low attack success rates or poor query efficiency since it is difficult to estimate the gradient in a high-dimensional input space with limited information. To address these problems and improve black-box attacks, we propose two prior-guided random gradient-free (PRGF) algorithms based on biased sampling and gradient averaging, respectively. Our methods can take the advantage of a transfer-based prior given by the gradient of a surrogate model and the query information simultaneously. Through theoretical analyses, the transfer-based prior is appropriately integrated with model queries by an optimal coefficient in each method. Extensive experiments demonstrate that, in comparison with the alternative state-of-the-arts, both of our methods require much fewer queries to attack black-box models with higher success rates.

Atomic-scale visualization of topological spin textures in the chiral magnet MnGe.

Topological spin textures in chiral magnets such as manganese germanide (MnGe) are of fundamental interest and may enable magnetic storage and computing technologies. Our spin-polarized scanning tunneling microscopy images of MnGe thin films reveal a variety of textures that are correlated to the atomic-scale structure. Our images indicate helical stripe domains, in contrast to bulk, and associated helimagnetic domain walls. In combination with micromagnetic modeling, we can deduce the three-dimensional (3D) orientation of the helical wave vectors, and we find that three helical domains can meet in two distinct ways to produce either a "target-like" or a "π-like" topological spin texture. The target-like texture can be reversibly manipulated through either current/voltage pulsing or applied magnetic field, which represents a promising step toward future applications.

Spin-Orbit Torque in Bilayers of Kagome Ferromagnet Fe3Sn2 and Pt.

Spin-orbit torque phenomena enable efficient manipulation of the magnetization in ferromagnet/heavy metal bilayer systems for prospective magnetic memory and logic applications. Kagome magnets are of particular interest for spin-orbit torque due to the interplay of magnetic order and the nontrivial band topology (e.g., flat bands and Dirac and Weyl points). Here we demonstrate spin-orbit torque and quantify its efficiency in a bilayer system of topological kagome ferromagnet Fe3Sn2 and platinum. We use two different techniques, one based on the quasistatic magneto-optic Kerr effect (MOKE) and another based on time-resolved MOKE, to quantify spin-orbit torque. Both techniques give a consistent value of the effective spin Hall angle of the Fe3Sn2/Pt system. Our work may lead to further advances in spintronics based on topological kagome magnets.

Natural Anti-Inflammatory Compounds as Drug Candidates for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) represents chronic recurrent intestinal inflammation resulting from various factors. Crohn's disease (CD) and ulcerative colitis (UC) have been identified as the two major types of IBD. Currently, most of the drugs for IBD used commonly in the clinic have adverse reactions, and only a few drugs present long-lasting treatment effects. Moreover, issues of drug resistance and disease recurrence are frequent and difficult to resolve. Together, these issues cause difficulties in treating patients with IBD. Therefore, the development of novel therapeutic agents for the prevention and treatment of IBD is of significance. In this context, research on natural compounds exhibiting anti-inflammatory activity could be a novel approach to developing effective therapeutic strategies for IBD. Phytochemicals such as astragalus polysaccharide (APS), quercetin, limonin, ginsenoside Rd, luteolin, kaempferol, and icariin are reported to be effective in IBD treatment. In brief, natural compounds with anti-inflammatory activities are considered important candidate drugs for IBD treatment. The present review discusses the potential of certain natural compounds and their synthetic derivatives in the prevention and treatment of IBD.