Spatiotemporal cell landscape of human embryonic tooth development.

Understanding the cellular composition and trajectory of human tooth development is valuable for dentistry and stem cell engineering research. Previous single-cell studies have focused on mature human teeth and developing mouse teeth, but the cell landscape of human embryonic dental development is still unknown. In this study, tooth germ tissues were collected from aborted foetus (17-24 weeks) for single-cell RNA sequence and spatial transcriptome analysis. The cells were classified into seven subclusters of epithelium, and seven clusters of mesenchyme, as well as other cell types such as Schwann cell precursor and pericyte. For epithelium, the stratum intermedium branch and the ameloblast branch diverged from the same set of outer enamel-inner enamel-ALCAM+ epithelial cell lineage, but their spatial distribution of two branches was not clearly distinct. This trajectory received spatially adjacent regulation signals from mesenchyme and pericyte, including JAG1 and APP. The differentiation of pulp cell and pre-odontoblast showed four waves of temporally distinct gene expression, which involved regulation networks of LHX9, DLX5 and SP7, and these genes were regulated by upstream ligands such as the BMP family. This provides a reference landscape for the research on early human tooth development, covering different spatial structures and developmental periods.

The effect of cognitive ability on academic achievement: The mediating role of self-discipline and the moderating role of planning.

In this study, 572 secondary school students aged 15-18 years old stage were selected to study the effect of their cognitive ability and self-discipline and planning on academic achievement. Cognitive ability was classified into memory ability, representational ability, information processing ability, logical reasoning ability, and thinking conversion ability, and analyzed the effects of these five ability values on academic achievement. The mediating effect of self-discipline ability between cognitive ability and academic achievement was analyzed using structural equation modeling (SEM), and the moderating role of planning in the mediating effect was analyzed using planning as a moderating variable. The results showed that cognitive ability can have a significant positive effect on academic achievement, while self-discipline plays a partially mediating role between cognitive ability and academic achievement, and the moderating effect of Planning is significant in the second half of the mediating effect, i.e., the effect of self-discipline on academic achievement changes as the level of planning increases, and the mediating effect is stronger in the condition of higher planning, and the mediating model with moderating effect holds.

Analysis of the effect of cognitive ability on academic achievement: Moderating role of self-monitoring.

In this study, cognitive ability was classified into memory ability, representational ability, information processing ability, logical reasoning ability, and thinking conversion ability, and analyzed the effects of these five ability values on academic achievement. Structural equation modeling (SEM) was used to analyze the moderating effect of Self-monitoring between cognitive ability and Academic Achievement, using students' Self-monitoring as moderating variables. The results of the study showed that cognitive ability can significantly and positively affect academic achievement, while Self-monitoring can significantly moderate the effect of cognitive ability on academic performance, with a significant moderating effect on math subjects and English subjects among achievement subjects, and the higher the value of cognitive ability, the stronger the moderating effect.

Psychological factors as the risk factor of mouth ulcers: A two-sample Mendelian randomization study.

To examine whether psychological traits (PT) had causal effects on Mouth Ulcers (MU), we applied two-sample Mendelian randomization (MR) to genetics association summary statistics of eleven PT and MU. After the adjustment of outlier variants, genetic correlations and multiple testing, well-being (WB) spectrum PT like life satisfactory (odds ratio [OR] = 0.638 per one standard deviation increment of PT score) had protective effects on MU. Reverse WB traits like neuroticism (OR = 1.60) increased the risk of MU. The lack of well-being characteristics may increase the risk of MU, which highlighted the value of preventive oral care for people who have a reverse mental condition.

Characterization of Mesenchymal Stem Cells Derived from Bisphosphonate-Related Osteonecrosis of the Jaw Patients' Gingiva.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition that specifically occurs in the oral cavity, characterized by retarded wound healing in oral mucosa accelerating the exposure of bone. Moreover, the pathological mechanism remains poorly understood. Gingival mesenchymal stem cells (GMSCs) play a critical role in gingival healing and soft tissue regeneration. Although previous studies have showed that bisphosphonates (BPs) are highly toxic to healthy GMSC, there is overall lack of direct evidence demonstrating the characterization of GMSCs derived from BRONJ patients. In present study, we isolated GMSCs for the first time from the central area of BRONJ patients' gingiva (center-BRONJ GMSCs) and the peripheral area (peri-BRONJ GMSCs), and found that they exhibited decreased proliferation, adhesion, migration capacities and underwent early apoptosis in vitro compared control GMSCs. Notably, the central and peripheral BRONJ GMSCs transplantation in a mice excisional skin model also displayed lower cell survival rate and poor healing effects than that of controls. Mechanistically, TGF-ß1 signaling pathway was suppressed not only in BRONJ patients' gingival lesions but also in BRONJ GMSCs transplantation animal model. The results above suggested that under the microenvironment of BRONJ patients, the dysfunction of GMSCs and the suppressed TGF-ß1 signaling pathway may be the vital factors in impaired gingival healing, thus contributing to persistent exposure of underlying bone and development of BRONJ. This study provides new insights into the prevention for BRONJ by improving the functions of GMSCs and upregulating TGF-ß1 in accelerating gingival wound healing. Schematic illustration of the dysfunction of BRONJ GMSCs in vitro and BRONJ GMSCs transplantation in a mice skin model delaying cutaneous wound healing mainly via suppressing TGF-ß1 signaling pathway.

Cognition and Academic Performance: Mediating Role of Personality Characteristics and Psychology Health.

This study uses personality and psychology health characteristics of high school students as intermediary variables to study how cognitive ability affects academic performance, and analyzes memory, information processing, presentation, logical reasoning, and thinking transformation ability in high school students. In this study, the structural equation model (SEM) was used to analyze the mediating effect, and the bootstrap method was used to test the significance of the mediating effect. The participants were 572 high school students from Beijing, China. They completed a survey that included questions on cognitive ability, personality characteristics, and psychology health. This study uses structural equation modeling for mediation analysis. Through the analysis of four models of comprehensive academic performance, Chinese academic performance, mathematics academic performance, and English academic performance, the results of the study showed that cognitive ability has a significant effect on academic performance, and personality characteristics and psychology health play a partially mediating role between cognitive ability and English academic performance. The mediation effect is about 40%.

Cognitive Ability and Self-Control's Influence on High School Students' Comprehensive Academic Performance.

This study uses a hierarchical linear model (HLM) to examine the effects of cognitive ability and self-control on comprehensive academic performance among students in a high school in Beijing. The study included 572 participating students, including 291 boys and 281 girls, ranging in age from 16 to 18 years old. In this study, the individual level of students' cognitive abilities are used as the first-level variables, including memory ability (MA), information processing ability (IPA), representation ability (RA), logical reasoning ability (LRA), and thinking transformation ability (TCA). Consider self-control at the class level as the second-level variable. The research results show that the five cognitive abilities have a significant positive impact on comprehensive academic performance. Self-control plays an active role in regulating the relationship between RA, LRA, TCA, and comprehensive academic performance.

A selection pressure landscape for 870 human polygenic traits.

Characterizing the natural selection of complex traits is important for understanding human evolution and both biological and pathological mechanisms. We leveraged genome-wide summary statistics for 870 polygenic traits and attempted to quantify signals of selection on traits of different forms in European ancestry across four periods in human history and evolution. We found that 88% of these traits underwent polygenic change in the past 2,000-3,000 years. Recent selection was associated with ancient selection signals in the same trait. Traits related to pigmentation, body measurement and nutritional intake exhibited strong selection signals across different time scales. Our findings are limited by our use of exclusively European data and the use of genome-wide association study data, which identify associations between genetic variants and phenotypes that may not be causal. In sum, we provide an overview of signals of selection on human polygenic traits and their characteristics across human evolution, based on a European subset of human genetic diversity. These findings could serve as a foundation for further populational and medical genetic studies.

A single-cell interactome of human tooth germ from growing third molar elucidates signaling networks regulating dental development.

BACKGROUND: Development of dental tissue is regulated by extensive cell crosstalk based on various signaling molecules, such as bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) pathways. However, an intact network of the intercellular regulation is still lacking. RESULT: To gain an unbiased and comprehensive view of this dental cell interactome, we applied single-cell RNA-seq on immature human tooth germ of the growing third molar, discovered refined cell subtypes, and applied multiple network analysis to identify the central signaling pathways. We found that immune cells made up over 80% of all tooth germ cells, which exhibited profound regulation on dental cells via Transforming growth factor-ß, Tumor necrosis factor (TNF) and Interleukin-1. During osteoblast differentiation, expression of genes related to extracellular matrix and mineralization was continuously elevated by signals from BMP and FGF family. As for the self-renewal of apical papilla stem cell, BMP-FGFR1-MSX1 pathway directly regulated the G0-to-S cell cycle transition. We also confirmed that Colony Stimulating Factor 1 secreted from pericyte and TNF Superfamily Member 11 secreted from osteoblast regulated a large proportion of genes related to osteoclast transformation from macrophage and monocyte. CONCLUSIONS: We constructed the intercellular signaling networks that regulated the essential developmental process of human tooth, which served as a foundation for future dental regeneration engineering and the understanding of oral pathology.

Quantitative Segmentation Analysis of the Radiological Changes by Using ITK-SNAP: Risk Assessment of the Severity and Recurrence of Medication-related Osteonecrosis of the Jaw.

Background and purpose: Medication-related osteonecrosis of the jaw (MRONJ) severely impairs patients' quality of life and is remarkably refractory to treatment. There are lots of studies about identification of the radiographic features of MRONJ, yet reports about quantitative radiographic analysis for the risk assessment of the severity and recurrence of MRONJ are rarely heard. The aim of this study was to investigate the volumes of osteolytic lesions and radiodensity values of osteosclerotic lesions in MRONJ patients by using ITK-SNAP for severity prediction and prognosis evaluation. Materials and methods: Of 78 MRONJ patients (78 lesions) involved in this retrospective study, 53 were presented as osteolytic lesions and 25 were presented as osteosclerotic changes alone. Comprehensive CBCT images, demographics and clinical data of patients were investigated. The volumetric analysis and radiodensity measurement were performed by ITK-SNAP. SPSS 25.0 were used for statistical analysis. Results: The osteolytic lesion volumes in MRONJ patients receiving intravenous bisphosphonates (P=0.004) and patients without osteoporosis (P=0.027) were significantly large. No significant correlation between the volumes and bisphosphonates duration was found (P=0.094). The radiodensity values of osteosclerotic lesions was significantly correlated with bisphosphonates duration (P=0.040). The surrounding area of post-surgical lesions in MRONJ patients with recurrence showed significantly great radiodensity values (P=0.025). No significant correlation between the radiodensity values and the transformation from osteosclerotic lesions to osteolytic lesions was observed (P=0.507). Conclusion: MRONJ patients receiving intravenous bisphosphonates develop into large volumes of osteolytic lesions more easily. Long-term bisphosphonates duration is possibly related with higher bone density of osteosclerotic lesions, while higher density is not associated with the transformation from osteosclerotic lesions to osteolytic lesions. A rise of bone mineral density nearby post-surgical lesions is probably a predictor for MRONJ recurrence.

Activation of mesenchymal stem cells promotes new bone formation within dentigerous cyst.

BACKGROUND: Dentigerous cyst (DC) is a bone destructive disease and remains a challenge for clinicians. Marsupialization enables the bone to regenerate with capsule maintaining, making it a preferred therapeutic means for DC adjacent to vital anatomical structures. Given that capsules of DC are derived from odontogenic epithelium remnants at the embryonic stage, we investigated whether there were mesenchymal stem cells (MSCs) located in DC capsules and the role that they played in the bone regeneration after marsupialization. METHODS: Samples obtained before and after marsupialization were used for histological detection and cell culture. The stemness of cells isolated from fresh tissues was analyzed by morphology, surface marker, and multi-differentiation assays. Comparison of proliferation ability between MSCs isolated from DC capsules before (Bm-DCSCs) and after (Am-DCSCs) marsupialization was evaluated by Cell Counting Kit-8 (CCK-8), fibroblast colony-forming units (CFU-F), and 5'-ethynyl-2'-deoxyuridine (EdU) assay. Their osteogenic capacity in vitro was detected by alkaline phosphatase (ALP) and Alizarin Red staining (ARS), combined with real-time polymerase chain reaction (RT-PCR) and immunofluorescence (IF) staining. Subcutaneous ectopic osteogenesis as well as cranial bone defect model in nude mice was performed to detect their bone regeneration and bone defect repairability. RESULTS: Bone tissue and strong ALP activity were detected in the capsule of DC after marsupialization. Two types of MSCs were isolated from fibrous capsules of DC both before (Bm-DCSCs) and after (Am-DCSCs) marsupialization. These fibroblast-like, colony-forming cells expressed MSC markers (CD44+, CD90+, CD31-, CD34-, CD45-), and they could differentiate into osteoblast-, adipocyte-, and chondrocyte-like cells under induction. Notably, Am-DCSCs performed better in cell proliferation and self-renewal. Moreover, Am-DCSCs showed a greater osteogenic capacity both in vitro and in vivo compared with Bm-DCSCs. CONCLUSIONS: There are MSCs residing in capsules of DC, and the cell viability as well as the osteogenic capacity of them is largely enhanced after marsupialization. Our findings suggested that MSCs might play a crucial role in the healing process of DC after marsupialization, thus providing new insight into the treatment for DC by promoting the osteogenic differentiation of MSCs inside capsules.

Combined Administration of Bisphosphonates, Chemotherapeutic Agents, and/or Targeted Drugs Increases the Risk for Stage 3 Medication-Related Osteonecrosis of the Jaw: A 4-Year Retrospective Study.

OBJECTIVES: Patients with stage 3 medication-related osteonecrosis of the jaw (MRONJ) suffer from severe complications. Chemotherapeutic agents and targeted drugs are considered to be associated with the development of MRONJ. However, little is known regarding the association of those agents with stage 3 MRONJ. The purpose of this study is to analyze the comprehensive medication history of patients with advanced-stage MRONJ (stage 2 and stage 3) and evaluate the possible risk factors for stage 3 MRONJ. Patients and Methods. Sixty patients with advanced-stage MRONJ were involved in this retrospective study. Patients with developmental maxillofacial anomalies, previous radiation in the head and neck areas, and jaw bone tumors were excluded from the study. All patients were divided into two groups by their MRONJ stage (stage 2 or stage 3). Demographic and clinical characteristics, comprehensive medication data (bisphosphonates, chemotherapeutic agents, targeted drugs, and immunosuppressive agents), and results of serological biomarkers were recorded and compared between two groups. Univariate and multivariate logistic regressions were performed by SPSS 25.0 for evaluating risk factors of stage 3 MRONJ. RESULTS: Our results indicate that chemotherapy (adjusted OR = 3.43; 95% CI: 1.03 to 11.38), targeted drugs (adjusted OR = 3.69; 95% CI: 1.06 to 12.80), and maxillary lesions (adjusted OR = 4.26; 95% CI: 1.19 to 15.23) increase the risk of stage 3 MRONJ. CONCLUSION: The outcome of this study justifies that chemotherapeutic agents and targeted drugs are probably risk factors for stage 3 MRONJ. In addition, the osteonecrosis in maxilla is more easily to develop into stage 3 MRONJ. Intense clinical observation is recommended in MRONJ patients with maxillary osteonecrosis and in those who concurrently administered bisphosphonates, chemotherapeutic agents, and/or targeted drugs. This trial is registered with ChiCTR2000032428.

Stress response in periodontal ligament stem cells may contribute to bisphosphonate­associated osteonecrosis of the jaw: A gene expression array analysis.

Gene expression alterations in periodontal ligament stem cells (PDLSCs) during bisphosphonate (BP) usage and the transcriptomic mechanism underlying BP­related osteonecrosis of the jaw have not been fully elucidated. In the present study, human PDLSCs were isolated from adults with no history of periodontal disease, and subsequently incubated and treated with zoledronate on days 3 and 5. Subsequently, PDLSCs from all timepoints were screened using an Affymetrix Gene Expression Array. Limma differential expression analysis was performed on a normalized gene expression matrix, followed by cluster analysis, pathway and network analyses. Overall, 906 genes (352 upregulated and 554 downregulated) exhibited differential expression levels between days 0 and 5, and these were termed slow­response genes. These slow­response genes were enriched in cellular stress response signaling pathways (upregulated genes), as well as proliferation­ and ossification­associated signaling pathways (downregulated genes). Furthermore, 168 (day 3 vs. 0) and 105 (day 5 vs. 3) genes were differentially expressed between adjacent timepoints. These genes were also enriched in stress response­ and proliferation­associated signaling pathways, but not in ossification­associated signaling pathways. Poly(ADP­ribose) polymerase 1 (PARP1) and CYLD lysine 63 deubiquitinase (CYLD) had the most protein­protein interaction partners among the slow­response genes and were connected with both stress­ (e.g. caspase­1) and ossification­associated genes [e.g. secreted phosphoprotein 1 and collagen type I α1 chain (COL1A1)]. BP treatment induced stress response­like transcriptional alterations in PDLSCs, followed by inhibition of proliferation and ossification. These alterations may contribute to the onset of jaw osteonecrosis. PARP1 and CYLD may be two key genes involved in this pathological procedure.

Study of the Microstructure Characteristics of Three Different Fine-grained Tailings Sand Samples during Penetration.

This paper explores the microstructural evolution characteristics of tailings sand samples of different types of infiltration failure during the infiltration failure process. The homemade small infiltration deformation instrument is used to test the infiltration failure characteristics of the tailings sand during the infiltration failure process. Evolutionary characteristics of the internal microstructure pores and particle distribution were also studied. Using CT (computerized tomography) technology to establish digital image information, the distribution of the microscopic characteristics of the particle distribution and pore structure after tailing sand infiltration were studied. Microscopic analysis was also performed to analyze the microscopic process of infiltration and destruction, as well as to see the microscopic structural characteristics of the infiltration and destruction of the total tailings. The test results show that there are obvious differences in the microstructure characterization of fluid soil and piping-type infiltration failures. Microstructure parameters have a certain functional relationship with macrofactors. Combining the relationship between macrophysical and mechanical parameters and microstructural parameters, new ideas for future research and the prevention of tailings sand infiltration and failure mechanisms is provided.

Decreased Osteogenic Ability of Periodontal Ligament Stem Cells Leading to Impaired Periodontal Tissue Repair in BRONJ Patients.

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a severe adverse reaction, which results in progressive bone destruction in the maxillofacial region of patients. To date, the pathological mechanisms remain largely unclear. Recently, we found that BRONJ patient had significantly deep periodontal pockets and severe periodontal bone defects before the exposed necrotic bone. Human periodontal ligament stem cells (hPDLSCs) play key roles in physiological maintenance and regeneration of periodontal tissues. However, the activities of hPDLSCs derived from BRONJ lesions and the role of hPDLSCs in BRONJ periodontal defect repair remain poorly understood. The aim of the present study was to elucidate the role of hPDLSCs in BRONJ. In this study, we found that the capacities of cell proliferation, adhesion, and migration of hPDLSCs derived from BRONJ lesions (BRONJ-hPDLSCs) were significantly decreased compared with control-hPDLSCs. BRONJ-hPDLSCs underwent early apoptosis compared with control-hPDLSCs. Importantly, we first demonstrated that BRONJ-hPDLSCs exhibited impaired osteogenic differentiation abilities in ectopic osteogenesis of nude mice. The above results suggested that the impaired BRONJ-hPDLSCs may be an important factor in deficient periodontal repair of BRONJ lesions and provide new insight into the underlying mechanism of BRONJ.