CD97 inhibits osteoclast differentiation via Rap1a/ERK pathway under compression

Acceleration of tooth movement during orthodontic treatment is challenging, with osteoclast-mediated bone resorption on the compressive side being the rate-limiting step. Recent studies have demonstrated that mechanoreceptors on the surface of monocytes/macrophages, especially adhesion G protein-coupled receptors (aGPCRs), play important roles in force sensing.However, its role in the regulation of osteoclast differentiation remains unclear. Herein, through single-cell analysis, we revealed that CD97, a novel mechanosensitive aGPCR, was expressed in macrophages. Compression upregulated CD97 expression and inhibited osteoclast differentiation;while knockdown of CD97 partially rescued osteoclast differentiation. It suggests that CD97 may be an important mechanosensitive receptor during osteoclast differentiation. RNA sequencing analysis showed that the Rap1a/ERK signalling pathway mediates the effects of CD97 on osteoclast differentiation under compression. Consistently, we clarified that administration of the Rap1a inhibitor GGTI298 increased osteoclast activity, thereby accelerating tooth movement. In conclusion,our results indicate that CD97 suppresses osteoclast differentiation through the Rap1a/ERK signalling pathway under orthodontic compressive force.

Nonlinear Flap-Wise Vibration Characteristics ofWind Turbine Blades Based onMulti-Scale AnalysisMethod

This work presents a novel approach to achieve nonlinear vibration response based on the Hamilton principle.We chose the 5-MW reference wind turbine which was established by the National Renewable Energy Laboratory(NREL),to research the effects of the nonlinear flap-wise vibration characteristics.The turbine wheel is simplified by treating the blade of a wind turbine as an Euler-Bernoulli beam,and the nonlinear flap-wise vibration characteristics of the wind turbine blades are discussed based on the simplification first.Then,the blade’s large-deflection flap-wise vibration governing equation is established by considering the nonlinear term involving the centrifugal force.Lastly,it is truncated by the Galerkin method and analyzed semi-analytically using the multi-scale analysis method,and numerical simulations are carried out to compare the simulation results of finite elements with the numerical simulation results using Campbell diagram analysis of blade vibration.The results indicated that the rotational speed of the impeller has a significant impact on blade vibration.When the wheel speed of 12.1 rpm and excitation amplitude of 1.23 the maximum displacement amplitude of the blade has increased from 0.72 to 3.16.From the amplitude-frequency curve,it can be seen that the multi-peak characteristic of blade amplitude frequency is under centrifugal nonlinearity.Closed phase trajectories in blade nonlinear vibration,exhibiting periodic motion characteristics,are found through phase diagrams and Poincare section diagrams.

Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts

Odontogenic keratocysts(OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome(NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations(at ～80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog(SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1^(R135 X/+) cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403 C>T(p.R135 X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated 9(Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1 R135 X/+heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.

A drone‑and feld‑based investigation of the land degradation and soil erosion at an opencast coal mine dump after 5 years’evolution of natural processes

Opencast coal mining has a large impact on the land surface,both at the mining pits themselves and at waste sites.After artifcial management is stopped,a reclaimed opencast coal mine dump is afected by wind and water erosion from natural processes,resulting in land degradation and even safety incidents.In this paper,the soil erosion and land degradation after 5 years of such natural processes,at the Xilinhot opencast coal mine dump in Inner Mongolia,were investigated.A multisource data acquisition method was applied:the vegetation fraction coverage(VFC)was extracted from GF-1 satellite imagery,high-precision terrain characteristics and the location and degree of soil erosion were obtained using a drone,and the physical properties of the topsoil were obtained by feld sampling.On this basis,the degree and spatial distribution of erosion cracks were identifed,and the causes of soil erosion and land degradation were analyzed using the geographical detector.The results show that(1)multi-source data acquisition method can provide efective basic data for the quantitative evaluation of the ecological environment at dumps,and(2)slope aspect and VFC are the main factors afecting the degree of degradation and soil erosion.Based on above analysis,several countermeasures are proposed to mitigate land degradation:(1)The windward slope be designed to imitate the natural landform.(2)Reasonable engineering measures should be applied at the slope to restrain soil erosion.(3)The Pioneer plants should be widely planted on the platform at the early stage of reclamation.

Biomarkers of malignant transformation in oral leukoplakia:from bench to bedside

Oral leukoplakia is a common precursor lesion of oral squamous cell carcinoma,which indicates a high potential of malignancy.The malignant transformation of oral leukoplakia seriously affects patient survival and quality of life;however,it is difficult to identify oral leukoplakia patients who will develop carcinoma because no biomarker exists to predict malignant transformation for effective clinical management.As a major problem in the field of head and neck pathologies,it is imperative to identify biomarkers of malignant transformation in oral leukoplakia.In this review,we discuss the potential biomarkers of malignant transformation reported in the literature and explore the translational probabilities from bench to bedside.Although no single biomarker has yet been applied in the clinical setting,profiling for genomic instability might be a promising adjunct.

Digital pathology-based artificial intelligence models for differential diagnosis and prognosis of sporadic odontogenic keratocysts

Odontogenic keratocyst(OKC)is a common jaw cyst with a high recurrence rate.OKC combined with basal cell carcinoma as well as skeletal and other developmental abnormalities is thought to be associated with Gorlin syndrome.Moreover,OKC needs to be differentiated from orthokeratinized odontogenic cyst and other jaw cysts.Because of the different prognosis,differential diagnosis of several cysts can contribute to clinical management.We collected 519 cases,comprising a total of 2157 hematoxylin and eosinstained images,to develop digital pathology-based artificial intelligence(AI)models for the diagnosis and prognosis of OKC.The Inception_v3 neural network was utilized to train and test models developed from patch-level images.Finally,whole slide imagelevel AI models were developed by integrating deep learning-generated pathology features with several machine learning algorithms.The AI models showed great performance in the diagnosis(AUC=0.935,95%CI:0.898–0.973)and prognosis(AUC=0.840,95%CI:0.751–0.930)of OKC.The advantages of multiple slides model for integrating of histopathological information are demonstrated through a comparison with the single slide model.Furthermore,the study investigates the correlation between AI features generated by deep learning and pathological findings,highlighting the interpretative potential of AI models in the pathology.Here,we have developed the robust diagnostic and prognostic models for OKC.The AI model that is based on digital pathology shows promise potential for applications in odontogenic diseases of the jaw.

FAM19A4 is a novel cytokine ligand of formyl peptide receptor I （FPR 1） and is able to promote the migration and phagocytosis of macrophages

FAM 19A4 is an abbreviation for family with sequence similarity 19 （chemokine （C-C motif）-Iike） member A4, which is a secretory protein expressed in low levels in normal tissues. The biological functions of FAM19A4 remain to be determined, and its potential receptor（s） is unclarified. In this study, we demonstrated that FAM 19A4 was a classical secretory protein and we verified for the first time that its mature protein is composed of 95 amino acids. We found that the expression of this novel cytokine was upregulated in lipopolysaccharide （LPS）-stimulated monocytes and macrophages and was typically in polarized M 1. FAM 19A4 shows chemotactic activities on macrophages and enhances the macrophage phagocytosis of zymosan both in vitro and in vivo with noticeable increases of the phosphorylation of protein kinase B （Akt）. FAM 19A4 can also increase the release of reactive oxygen species （ROS） upon zymosan stimulation. Furthermore, based on receptor internalization, radio ligand binding assays and receptor blockage, we demonstrated for the first time that FAM19A4 is a novel ligand of formyl peptide receptor 1 （FPR1）. The above data indicate that upon inflammatory stimulation, monocyte/macrophage-derived FAM 19A4 may play a crucial role in the migration and activation of macrophages during pathogenic infections.

Improvement in the risk assessment of oral leukoplakia through morphology-related copy number analysis

Oral leukoplakia is the most common type of oral potentially malignant disorders and considered a precursor lesion to oral squamous cell carcinoma.However,a predictor of oral leukoplakia prognosis has not yet been identified.We investigated whether copy number alteration patterns may effectively predict the prognostic outcomes of oral leukoplakia using routinely processed paraffin sections.Comparison of copy number alteration patterns between oral leukoplakia with hyperplasia(HOL,n=22)and dysplasia(DOL,n=21)showed that oral leukoplakia with dysplasia had a higher copy number alteration rate(86%)than oral leukoplakia with hyperplasia(46%).Oral leukoplakia with dysplasia exhibited a wider range of genomic variations across all chromosomes compared with oral leukoplakia with hyperplasia.We also examined a retrospective cohort of 477 patients with oral leukoplakia with hyperplasia with detailed follow-up information.The malignant transformation(MT,n=19)and leukoplakia recurrence(LR,n=253)groups had higher frequencies of aneuploidy events and copy number loss rate than the free of disease(FD,n=205)group.Together,our results revealed the association between the degree of copy number alterations and the histological grade of oral leukoplakia and demonstrated that copy number alteration may be effective for prognosis prediction in oral leukoplakia patients with hyperplasia.