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Abstract Background Mandibular distraction osteogenesis (MDO) is a major part of the treatment for hemifacial microsomia patients. Due to the narrow surgical field of the intraoral approach, osteotomy accuracy is highly dependent on the surgeons’ experience. Electromagnetic (EM) tracking systems can achieve satisfying accuracy to provide helpful real-time surgical navigation. Our research team developed an EM navigation system based on artificial intelligence, which has been justified in improving the accuracy of osteotomy in the MDO in animal experiments. This study aims to clarify the effect of the EM navigation system in improving the MDO accuracy for hemifacial microsomia patients. Methods This study is designed as a single-centered and randomized controlled trial. Altogether, 22 hemifacial microsomia patients are randomly assigned to the experiment and control groups. All patients receive three-dimensional CT scans and preoperative surgical plans. The EM navigation system will be set up for those in the experiment group, and the control group will undergo traditional surgery. The primary outcome is the surgical precision by comparing the osteotomy position of pre- and postoperative CT scan images through the Geomagic Control software. The secondary outcomes include mandibular symmetry (occlusal plane deviation angle, mandibular ramus height, and body length), pain scale, and complications. Other indications, such as the adverse events of the system and the satisfactory score from patients and their families, will be recorded. Discussion This small sample randomized controlled trial intends to explore the application of an EM navigation system in MDO for patients, which has been adopted in other surgeries such as orthognathic procedures. Because of the delicate structures of children and the narrow surgical view, accurate osteotomy and protection of nearby tissue from injury are essential for successful treatment. The EM navigation system based on artificial intelligence adopted in this trial is hypothesized to provide precise real-time navigation for surgeons and optimally improve patient outcomes, including function and aesthetic results. The results of this trial will extend the application of new navigation technology in pediatric plastic surgery. Trial registration Chinese Clinical Trial Registry ChiCTR2200061565. Registered on 29 June 2022.

Abstract A representative class of kagome materials, AV3Sb5 (A = K, Rb, Cs), hosts several unconventional phases such as superconductivity, $${{\mathbb{Z}}}_{2}$$ Z 2 non-trivial topological states, and electronic nematic states. These can often coexist with intertwined charge-density wave states. Recently, the discovery of the isostructural titanium-based single-crystals, ATi3Bi5 (A = K, Rb, Cs), which exhibit similar multiple exotic states but without the concomitant charge-density wave, has opened an opportunity to disentangle these complex states in kagome lattices. Here, we combine high-resolution angle-resolved photoemission spectroscopy and first-principles calculations to investigate the low-lying electronic structure of RbTi3Bi5. We demonstrate the coexistence of flat bands and several non-trivial states, including type-II Dirac nodal lines and $${{\mathbb{Z}}}_{2}$$ Z 2 non-trivial topological surface states. Our findings also provide evidence for rotational symmetry breaking in RbTi3Bi5, suggesting a directionality to the electronic structure and the possible emergence of pure electronic nematicity in this family of kagome compounds.

Non-small cell lung cancer (NSCLC) is a common pathological type of lung cancer, which has a serious impact on human life, health, psychology and life. At present, chemotherapy, targeted therapy and other methods commonly used in clinic are prone to drug resistance and toxic side effects. Natural extracts of traditional Chinese medicine (TCM) have attracted wide attention in cancer treatment because of their small toxic and side effects. Kaempferol is a flavonoid from natural plants, which has been proved to have anticancer properties in many cancers such as lung cancer, but the exact molecular mechanism is still unclear. Therefore, on the basis of in vitro experiments, we used network pharmacology and molecular docking methods to study the potential mechanism of kaempferol in the treatment of non-small cell lung cancer. The target of kaempferol was obtained from the public database (PharmMapper, Swiss target prediction), and the target of non-small cell lung cancer was obtained from the disease database (Genecards and TTD). At the same time, we collected gene chips GSE32863 and GSE75037 in conjunction with GEO database to obtain differential genes. By drawing Venn diagram, we get the intersection target of kaempferol and NSCLC. Through enrichment analysis, PI3K/AKT is identified as the possible key signal pathway. PIK3R1, AKT1, EGFR and IGF1R were selected as key targets by topological analysis and molecular docking, and the four key genes were further verified by analyzing the gene and protein expression of key targets. These findings provide a direction for further research of kaempferol in the treatment of NSCLC.

Abstract Background Augmented reality (AR) is a new technology that increases users’ perception of the real world. The purpose of this study is to evaluate the efficacy and safety of augmented reality navigation system in treatment with craniofacial fracture reduction. Methods This will be a single-center prospective randomized controlled trial. Twenty-two patients will be assigned to two groups of 11, and those with zygomaticomaxillary complex fractures will undergo preoperative three-dimensional CT modeling and have operational plans designed. The control team will use traditional optical navigation to perform the surgery, and the experimental team will use an AR navigation system. The primary outcome measures will be the accuracy of the key points of surgical area between the preoperational surgical plan and post-operation. The secondary outcome measures will be the blood loss, operation time, bone reduction time, hospital time, and complication rate. The findings obtained through this study are expected to evaluate efficacy and safety of the augmented reality navigation system in the treatment of zygomaticomaxillary complex fractures. Discussion This controlled trial of augmented reality navigation system in treatment with zygomaticomaxillary complex fracture reduction will clarify the efficacy and safety of this technology by measuring the accuracy of the key points of surgical area and blood loss, operation and bone reduction times, hospital stay duration, and complication rates. This is a single-center study, and the results are expected to promote the application of augmented reality in craniofacial fracture reduction to improve surgery accuracy and efficacy. Trial registration Chinese Clinical Trial Registry ChiCTR1900022626 . Registered on April 19, 2019.

Abstract The heterogeneity of exhausted T cells (Tex) is a critical determinant of immune checkpoint blockade therapy efficacy. However, few studies have explored exhausted T cell subpopulations in human cancers. In the present study, we examined samples from two cohorts of 175 patients with head and neck squamous cell cancer (HNSCC) by multiplex immunohistochemistry (mIHC) to investigate two subsets of Tex, CD8+PD1+TCF1+ progenitor exhausted T cells (TCF1+Texprog) and CD8+PD1+TCF1− terminally exhausted T cells (TCF1−Texterm). Moreover, fresh tumor samples from 34 patients with HNSCC were examined by flow cytometry and immunohistochemistry to further investigate their properties and cytotoxic capabilities and their correlation with regulatory T cells (Tregs) in the tumor immune microenvironment (TIME). mIHC and flow cytometry analysis showed that TCF1−Texterm represented a greater proportion of CD8+PD1+Tex than TCF1+Texprog in most patients. TCF1+Texprog produced abundant TNFα, while TCF1−Texterm expressed higher levels of CD103, TIM-3, CTLA-4, and TIGIT. TCF1−Texterm exhibited a polyfunctional TNFα+GZMB+IFNγ+ phenotype; and were associated with better overall survival and recurrence-free survival. The results also indicated that larger proportions of TCF1−Texterm were accompanied by an increase in the proportion of Tregs. Therefore, it was concluded that TCF1−Texterm was the major CD8+PD1+Tex subset in the HNSCC TIME and that these cells favor patient survival. A high proportion of TCF1−Texterm was associated with greater Treg abundance.

Abstract The promise of speech disorders as biomarkers in clinical examination has been identified in a broad spectrum of neurodegenerative diseases. However, to the best of our knowledge, a validated acoustic marker with established discriminative and evaluative properties has not yet been developed for oral tongue cancers. Here we cross‐sectionally collected a screening dataset that included acoustic parameters extracted from 3 sustained vowels /ɑ/, /i/, /u/ and binary perceptual outcomes from 12 consonant‐vowel syllables. We used a support vector machine with linear kernel function within this dataset to identify the formant centralization ratio (FCR) as a dominant predictor of different perceptual outcomes across gender and syllable. The Acoustic analysis, Perceptual evaluation and Quality of Life assessment (APeQoL) was used to validate the FCR in 33 patients with primary resectable oral tongue cancers. Measurements were taken before (pre‐op) and four to six weeks after (post‐op) surgery. The speech handicap index (SHI), a speech‐specific questionnaire, was also administrated at these time points. Pre‐op correlation analysis within the APeQoL revealed overall consistency and a strong correlation between FCR and SHI scores. FCRs also increased significantly with increasing T classification pre‐operatively, especially for women. Longitudinally, the main effects of T classification, the extent of resection, and their interaction effects with time (pre‐op vs. post‐op) on FCRs were all significant. For pre‐operative FCR, after merging the two datasets, a cut‐off value of 0.970 produced an AUC of 0.861 (95% confidence interval: 0.785–0.938) for T3‐4 patients. In sum, this study determined that FCR is an acoustic marker with the potential to detect disease and related speech function in oral tongue cancers. These are preliminary findings that need to be replicated in longitudinal studies and/or larger cohorts.

The epithelial mesenchymal transition (EMT) has roles in metastasis and invasion during fibrotic diseases and cancer progression. Some Traditional Chinese Medicines (TCMs) have shown inhibitory effects with respect to the EMT. The current study attempted to establish a multiparametric high-content method to screen for active monomeric compounds in TCM with the ability to target cellular EMT by assessing phenotypic changes. A total of 306 monomeric compounds from the MedChemExpress (MCE) compound library were screened by the high-content screening (HCS) system and 5 compounds with anti-EMT activity, including camptothecin (CPT), dimethyl curcumin (DMC), artesunate (ART), sinapine (SNP) and berberine (BER) were identified. To confirm anti-EMT activity, expression of EMT markers was assessed by qRT-PCR and Western blotting, and cell adhesion and migration measured by cell function assays. The results revealed that CPT, DMC, ART, SNP and BER inhibited transforming growth factor-β1 (TGF-β1)-induced expression of vimentin and α-SMA, upregulated expression of E-cadherin, increased cell adhesion and reduced cell migration. In summary, by quantifying the cell morphological changes during TGF-β1-induced EMT through multi-parametric analysis, TCM compounds with anti-EMT activity were successfully screened using the HCS system, a faster and more economical approach than conventional methods.

We present a data-driven or non-intrusive reduced-order model (NIROM) which is capable of making predictions for a significantly larger domain than the one used to generate the snapshots or training data. This development relies on the combination of a novel way of sampling the training data (which frees the NIROM from its dependency on the original problem domain) and a domain decomposition approach (which partitions unseen geometries in a manner consistent with the sub-sampling approach). The method extends current capabilities of reduced-order models to generalise, i.e., to make predictions for unseen scenarios. The method is applied to a 2D test case which simulates the chaotic time-dependent flow of air past buildings at a moderate Reynolds number using a computational fluid dynamics (CFD) code. The procedure for 3D problems is similar, however, a 2D test case is considered sufficient here, as a proof-of-concept. The reduced-order model consists of a sampling technique to obtain the snapshots; a convolutional autoencoder for dimensionality reduction; an adversarial network for prediction; all set within a domain decomposition framework. The autoencoder is chosen for dimensionality reduction as it has been demonstrated in the literature that these networks can compress information more efficiently than traditional (linear) approaches based on singular value decomposition. In order to keep the predictions realistic, properties of adversarial networks are exploited. To demonstrate its ability to generalise, once trained, the method is applied to a larger domain which has a different arrangement of buildings. Statistical properties of the flows from the reduced-order model are compared with those from the CFD model in order to establish how realistic the predictions are.

With the emergence of the remanufacturing industry, scheduling problems related to remanufacturing systems have drawn considerable interest from scholars. There are usually two execution modes of remanufacturing for reprocessing components, i.e., replacement mode and repair mode. However, few studies have focused on the job shop scheduling problem that considers the trade-off between the two execution modes. Thus, a new job shop scheduling method with job families (JSS-JF) is proposed, which can handle the selection of appropriate execution modes for reprocessing components with different damaged conditions. It decomposes the scheduling problem into three sub-problems: (1) execution mode selection; (2) replacement job assignment and sequencing; and (3) repair machine assignment and operation sequencing. The scheduling objective is to minimize the total completion time and total cost of job families. To solve the proposed JSS-JF model, an extended artificial bee colony algorithm with a new three-dimensional encoding scheme is presented to find a near-optimal solution of the proposed JSS-JF model. The crossover and mutation operators, local search, and elite replacement strategy are also integrated in the proposed algorithm. The experiments are conducted for verifying the practicality and effectiveness of the presented algorithm by comparing with six baseline algorithms.

Context Berberine (Ber) can increase the survival rate of septic mice and inhibit inflammation, but whether it has a protective effect on septic cardiomyopathy (SCM) is unclear. Objective To investigate whether Ber ameliorates SCM in a rat model and its potential mechanism. Materials and methods Male SD rats were randomly divided into three groups: control (Con, n = 6) (DD H2O, 2 mL/100 g, ig, qd × 3 d, then saline, 10 mg/kg, ip); sepsis [LPS (lipopolysaccharide), n = 18] (LPS 10 mg/kg instead of saline, ip); and berberine intervention (Ber, n = 18) (Ber, 50 mg/kg instead of DD H2O, ig, qd × 3 d, LPS instead of saline, ip). Hemodynamics, HE staining, ELISA and western blot were performed at 6, 24, and 48 h after intraperitoneal injection of LPS to evaluate the effect of berberine in septic rats. Result Berberine could recover myocardial injury by partially increased ± dp/dt max (1151, 445 mmHg/s) and LVEDP levels (1.49 mmHg) with LPS-induced rats, as well as an ameliorated increase of cTnT (217.53 pg/mL) in the Ber group compared with that in the LPS group (at 24 h). In addition, HE staining results showed that berberine attenuated the myocardial cell swelling induced by LPS. In contrast to the LPS group, the up-regulation of TLR4, p65 TNF-α, and IL-1β were attenuated in the Ber group. Discussion and conclusions Berberine showed a protective effect on septic cardiomyopathy rats possibly through inhibiting the activation of TLR4/NF-κB signalling pathway. Whether it improves SCM through other mechanisms is our ongoing research.

A previous study on hepatoblastoma revealed novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex, including the tumor suppressor speckle-type BTB/POZ (SPOP). Moreover, the SPOP gene affected cell growth, and its S119N mutation was identified as a loss-of-function mutation in hepatoblastoma. This study aimed to explore more functions and the potential mechanism of SPOP and its S119N mutation. The in vitro effects of SPOP on cell proliferation, invasion, apoptosis, and in vivo tumor growth were investigated by western blot analysis, Cell Counting Kit-8, colony formation assay, flow cytometry, and xenograft animal experiments. The substrate of SPOP was discovered by a protein quantification assay and quantitative ubiquitination modification assay. The present study further proved that SPOP functioned as an anti-oncogene through the phosphatidylinositol 3-kinase/Akt signaling pathway to affect various malignant biological behaviors of hepatoblastoma both in vitro and in vivo. Furthermore, experimental results also suggested that solute carrier family 7 member 1 (SLC7A1) might be a substrate of SPOP and influence cell phenotype by regulating arginine metabolism. In conclusion, these findings demonstrated the function of SPOP and revealed a potential substrate related to hepatoblastoma tumorigenesis, which might thus provide a novel therapeutic target for hepatoblastoma.

Craniosynostosis is one of the most common craniofacial deformities demanding surgical treatment in infancy. LncRNA HOTAIR has verified its important role in osteogenesis and osteoarthritis. However, whether HOTAIR plays an essential role in the development of craniosynostosis is still unclear. In this study, we aimed to investigate the molecular role of HOTAIR in the osteoclast function and development of craniosynostosis.For osteoclast differentiation, RAW264.7 cells were induced by 50 ng/ml of RANKL and 10 ng/mL M-CSF, followed by TRAP staining. Cell proliferation and apoptosis were assayed by the CCK-8 kit and Annexin V-FITC apoptosis detection kit, respectively. The expression of HOTAIR was determined in PBMCs by qRT-PCR. Protein levels of all those involved genes were measured by Western blot assay. A luciferase reporter assay was used to determine the miRNA target validation. The HOTAIR expression in PBMCs from children with craniosynostosis was significantly downregulated. The results of cell proliferation and apoptosis assays indicated that silencing of HOTAIR could inhibit osteoclast differentiation and increase cell apoptosis. Moreover, the luciferase reporter assay revealed that the regulatory axis and HOTAIR-miR-152-CAMKIIα were the regulatory mechanisms of HOTAIR in the osteoclast function and development of craniosynostosis.In this study, our data showed that HOTAIR could promote osteoclast differentiation by binding miR-152. Furthermore, the HOTAIR/HOTAIR-miR-152-CAMKIIα axis was found to regulate osteoclast differentiation. These results indicate that the HOTAIR plays a crucial role in the development of osteoclasts.

In order to meet the energy and power requirements of large-scale battery applications, lithium-ion batteries have to be connected in series and parallel to form various battery packs. However, unavoidable connector resistances cause the inconsistency of the cell current and state of charge (SoC) within packs. Meanwhile, different assembly methods and module collector positions (MCPs) may result in different connector resistance arrangements, thereby leading to different cell current distributions. Therefore, the correlation of connector resistance to battery pack performance is worth investigating. Based on the simplified equivalent circuit model (ECM), the mathematical models of cell current distribution within packs under different assembly methods are obtained in this paper. Then, we use COMSOL Multiphysics simulation to analyze the guidelines of series assembly for parallel modules and then study the influences of connector resistance and MCP on series–parallel battery packs. The results show that the assembly method with an equal distance between each cell and the assembly contact surface for series assembly can effectively reduce the inhomogeneous current. However, the cell current and SoC distribution within the series–parallel battery pack is completely independent of the Z-configuration and ladder configuration. In addition, for series–parallel battery packs, the non-edge parallel module part of the series–parallel battery pack can be replaced with a series cell module (SCM) structure. Finally, the influences of the value of the connector resistance and current rate on the cell current distribution are discussed.

Detecting circulating tumor cells (CTCs) has proven valuable for evaluating the prognosis of cancer patients and for studying the mechanisms of treatment resistance. Owing to the lack of universal and specific tumor markers for neuroblastoma (NB), in this prospective study, we adopted an EpCAM-independent method to detect CTCs in the peripheral blood of NB patients.We used an EpCAM-independent assay to delete leukocytes and to enrich the CTCs. CTCs were identified by immunostaining of CD45, DAPI and DNA fluorescence in situ hybridization (FISH) of the centromere of chromosome 8 probe (CEP8). Cells that were DAPI+/CD45-/CEP8 ≥ 3 were considered CTCs. We collected peripheral blood from 28 NB patients as well as clinical and follow-up data.The number of CTCs among the different risk groups were significantly different (p = .0208, Kruskal–Wallis test). Patients with metastasis had more CTCs than those without metastasis (p

Abstract Background Prognostic factors aid in the stratification and treatment of cancer. This study evaluated prognostic importance of tumor infiltrating immune cell in patients with oral squamous cell carcinoma. Methods Profiles of infiltrating immune cells and clinicopathological data were available for 78 OSCC patients with a median follow-up of 48 months. The infiltrating intensity of CD8, CD4, T-bet, CD68 and CD57 positive cells were assessed by immunohistochemistry. Chi-square test was used to compare immune markers expression and clinicopathological parameters. Univariate and multivariate COX proportional hazard models were used to assess the prognostic discriminator power of immune cells. The predictive potential of immune cells for survival of OSCC patients was determined using ROC and AUC. Results The mean value of CD8, CD4, T-bet, CD68 and CD57 expression were 28.99, 62.06, 8.97, 21.25 and 15.75 cells per high-power field respectively. The patient cohort was separated into low and high expression groups by the mean value. Higher CD8 expression was associated with no regional lymph node metastasis (p = 0.033). Patients with more abundant stroma CD57+ cells showed no metastasis into regional lymph node (p = 0.005), and early clinical stage (p = 0.016). The univariate COX regression analyses showed that no lymph node involvement (p

This article presents an intelligent algorithm based on extreme learning machine and sequential mutation genetic algorithm to determine the inverse kinematics solutions of a robotic manipulator with six degrees of freedom. This algorithm is developed to minimize the computational time without compromising the accuracy of the end effector. In the proposed algorithm, the preliminary inverse kinematics solution is first computed by extreme learning machine and the solution is then optimized by an improved genetic algorithm based on sequential mutation. Extreme learning machine randomly initializes the weights of the input layer and biases of the hidden layer, which greatly improves the training speed. Unlike classical genetic algorithms, sequential mutation genetic algorithm changes the order of the genetic codes from high to low, which reduces the randomness of mutation operation and improves the local search capability. Consequently, the convergence speed at the end of evolution is improved. The performance of the extreme learning machine and sequential mutation genetic algorithm is also compared with that of a hybrid intelligent algorithm, and the results showed that there is significant reduction in the training time and computational time while the solution accuracy is retained. Based on the experimental results, the proposed extreme learning machine and sequential mutation genetic algorithm can greatly improve the time efficiency while ensuring high accuracy of the end effector.

Curbing PD-1 immunosuppressive signaling represents an effective immune awakening or immune-reactivation approach for tumor eradication for many cancers. Yet, the potential involvement of this critical PD-1 immunosuppressive signaling in de novo malignant transformation of epithelial cells to pre-cancerous or cancerous lesions is largely unknown. In this study, we demonstrate that PD-1 signaling is critically involved in de novo malignant transformation of oral mucosa upon carcinogen exposure in vivo. Our findings revealed that 4NQO-treated mice had almost double the numbers of PD-1-positive CD4+ cells and PD-1-positive CD8+ cells in peripheral blood lymphocytes as well as elevated PD-1 expression in tumor infiltrating lymphocytes (when compared to that of control-treated mice), strongly supportive of a general immune-suppression induced by carcinogen challenges in vivo. Importantly, inhibition of PD-1 signaling during the carcinogenesis process (immediately after 4NQO challenge) significantly reduced and delayed de novo formation of both pre-cancerous and cancerous lesions in vivo, in conjunction with effective PD-1 down-modulation in the tumor infiltrating leukocyte and peripheral lymph organs. Lastly, reduction of carcinogen-induced lesions upon PD-1 mAb treatment in vivo was accompanied by reduction of potent immunosuppressive myeloid-derived suppressor cells (MDSCs), and increase in “activated” T cell accumulations in the lesion-microenvironment (127% increase) and peripheral lymph nodes (25% increase). These data support PD-1 blockade as a new approach to enhance the efficacy of T-cell immunotherapy and reduce canceration rate in premalignant lesions.

Caffeine (1, 3, 7-trimethylxanthine) and theobromine (3, 7-dimethylxanthine) are the major purine alkaloids in plants, e.g., tea (Camellia sinensis) and coffee (Coffea arabica). Caffeine is a major component of coffee and is used widely in food and beverage industries. Most of the enzymes involved in the caffeine biosynthetic pathway have been reported previously. Here, we demonstrated the biosynthesis of caffeine (0.38 mg/L) by co-expression of Coffea arabica xanthosine methyltransferase (CaXMT) and Camellia sinensis caffeine synthase (TCS) in Saccharomyces cerevisiae. Furthermore, we endeavored to develop this production platform for making other purine-based alkaloids. To increase the catalytic activity of TCS in an effort to increase theobromine production, we identified four amino acid residues based on structural analyses of 3D-model of TCS. Two TCS1 mutants (Val317Met and Phe217Trp) slightly increased in theobromine accumulation and simultaneously decreased in caffeine production. The application and further optimization of this biosynthetic platform are discussed.

Giving farmers more rights and interests on land property is the basis of achieving balanced and coordinated economic development between urban and rural areas as well as building a sharing economy during the period of economic transition in China. Based on the survey data of suburban households of Tianjin, in this paper, measurement method was adopted to study factors influencing farmer's willingness on land management right mortgage. The results shows that the willingness of individual farmer on mortgage is not strong, however, their willingness on mortgage is bound to have a significant relationship with farmland right confirmation and land transfer and other factors. Finally, it is concluded that it is necessary to promote land transfer on the basis of land right of confirmation while carrying out farmland mortgage under the premise of large-scale operation in China. [ABSTRACT FROM AUTHOR]