Nonsyndromic cleft lip with or without a cleft palate (NSCL/P) is among the most common human congenital birth defects and imposes a substantial physical and financial burden on affected individuals. Here, we conduct a case–control-based GWAS followed by two rounds of replication; we include six independent cohorts from China to elucidate the genetic architecture of NSCL/P in Chinese populations. Using this combined analysis, we identify a new locus at 16p13.3 associated with NSCL/P: rs8049367 between CREBBP and ADCY9 (odds ratio=0.74, P=8.98 × 10⁻¹²). We confirm that the reported loci at 1q32.2, 10q25.3, 17p13.1 and 20q12 are also involved in NSCL/P development in Chinese populations. Our results provide additional evidence that the rs2235371-related haplotype at 1q32.2 could play a more important role than the previously identified causal variant rs642961 in Chinese populations. These findings provide information on the genetic basis and mechanisms of NSCL/P.

Objective: To construct a decision-making expert system (ES) for the orthodontic treatment of patients between 11 and 15 years old to determine whether extraction is needed by using artificial neural networks (ANN). Specifically, we will uncover the factors that affect this decision-making process. Methods: A total of 200 subjects were chosen; among them, 120 were accepted for extraction treatments, and 80 were chosen for nonextraction treatments. For each case, 23 indices were selected. A 23-13-1 Back Propagation (BP) ANN model was constructed, and the data for 180 patients were aggregated to constitute the training set. Data for the other 20 patients were used as the testing set. Results: When data from the 180 patients that had been trained were tested, the result was 100%, as expected. The untrained data from 20 patients in the testing set were 80% correct (ie, 16 cases were forecasted successfully). In the meantime, the relative contributions of the 23 input indices to the final output index (extraction/nonextraction) were calculated. “Anterior teeth uncovered by incompetent lips” and “IMPA (L1-MP)” were the two indices that gave the biggest contributions sequentially; the index of FMA (FH-MP) gave the smallest contribution. Conclusions: (1) The constructed artificial neural network in this study was effective, with 80% accuracy, in determining whether extraction or nonextraction treatment was best for malocclusion patients between 11 and 15 years old; (2) when the clinician is predicting whether an orthodontic treatment requires extraction, the indices “anterior teeth uncovered by incompetent lips” and “IMPA (L1-MP)” should be taken into consideration first.

Glial activation and neuroinflammation in the spinal trigeminal nucleus (STN) play a pivotal role in the genesis and maintenance of trigeminal neuralgia (TN). Resveratrol, a natural compound from grape and red wine, has a potential anti-inflammatory effect. We hypothesized that resveratrol could significantly suppress neuroinflammation in the STN mediated by glial activation and further relieve TN. In this study, we evaluated whether resveratrol could alleviate trigeminal allodynia and explore the mechanism underlying the antinociceptive effect of resveratrol. Animals were orally injected with resveratrol after chronic constriction injury (CCI) of the infraorbital nerve. Mechanical thresholds of the affected whisker pad were measured to assess nociceptive behaviors. The STN was harvested to quantify the changing levels of p-NR1, p-PKC, TNF-α, and IL1-β by western blotting and detect the expression of calcitonin gene-related peptide (CGRP) and c-Fos by immunofluorescence. Glial activation was observed by immunofluorescence and western blotting. Mitogen-activated protein kinase (MAPK) phosphorylation in vivo and in vitro was examined by western blotting. We found that resveratrol significantly attenuated trigeminal allodynia dose-dependently and decreased the increased expression of CGRP and c-Fos in the STN. Additionally, resveratrol showed an inhibitory effect on CCI-evoked astrocyte and microglia activation and reduced production of pro-inflammatory cytokines in the STN. Furthermore, the antinociceptive effect of resveratrol was partially mediated by reduced phosphorylation of MAP kinases via adenosine monophosphate-activated protein kinase (AMPK) activation. AMPK activation in the STN glia via resveratrol has utility in the treatment of CCI-induced neuroinflammation and further implicates AMPK as a novel target for the attenuation of trigeminal neuralgia.

Adipose-derived stem cells (ADSCs) are an attractive cell source for bone tissue engineering and have great potential for bone regeneration and defect repair. The transcriptional coactivator with PDZ-binding motif (TAZ) has been demonstrated to modulate osteogenic and adipogenic differentiation of mesenchymal stem cells. However, its roles during ADSC differentiation and therapeutic potentials for bone regeneration have as yet not been well established. TAZ expression was measured during osteogenic differentiation of ADSCs in vitro. Both loss-of-function and gain-of-function approaches by TAZ knockdown or enforced overexpression were utilized to determine its functions during osteogenic differentiation of ADSCs. TM-25659, a chemical activator of TAZ, was used to determine whether pharmacological activation of TAZ in ADSCs enhanced osteogenic differentiation in vitro and bone formation in animal models. The molecular mechanisms underlying TAZ in promoting osteogenesis of ADSCs were also explored. Increased TAZ expression was observed during osteogenic differentiation of human ADSCs. TAZ knockdown resulted in compromised osteogenic differentiation and enhanced adipogenic differentiation of ADSCs. In contrast, enforced TAZ overexpression yielded increased osteogenic differentiation and bone regeneration in vivo, and impaired adipogenic differentiation of ADSCs. Pharmacological activation of TAZ by its chemical activator TM-25659 facilitated osteogenic differentiation of ADSCs. Noticeably, transient treatment of ADSCs with TM-25659 or intraperitoneal injection of TM-25659 significantly enhanced bone regeneration of ADSCs loaded with porous β-TCP in vivo. Mechanistically, TM-25659 exposure significantly promoted TAZ phosphorylation and nuclear translocation, and potentiated the assembly of the TAZ-Runx2 complex. Subsequently, the TAZ-Runx2 complex was further recruited to the promoter of osteocalcin and in turn enhanced its transcription. Our findings indicate that TAZ is a key mediator that promotes ADSC commitment to the osteoblast lineage. Pharmacological activation of TAZ in ADSCs might become a feasible and promising approach to enhance bone regeneration and repair.

Physiological occlusal force constitutively exists in the oral environment and is important for periodontal homeostasis and remodeling. Cyclic tensile stress (CTS) triggers the biological response of periodontal ligament (PDL). However, a few reports have studied the correlation between CTS during physiological occlusal force and PDL cell activities such as osteogenic differentiation. In the present study, human PDL cells (hPDLCs) were subjected to 10% elongation CTS loading at 0.5 Hz for 24 h, which represents the physiological conditions of occlusal force. Gene expression microarray was used to investigate the mechano-induced differential gene profile and pathway analysis in vitro. The osteogenic relative factors, that is, SPP1, RUNX2, and SP7, were assessed by real-time PCR and Western blot. The involvement of mitogen-activated protein kinase (MAPK) signaling pathways was investigated by Western blot with a specific inhibitor. The expressions of SPP1, RUNX2, SP7, p-ERK1/2, and p-Elk1 were up-regulated after 10% CTS exposure. However, these up-regulated expressions were prevented by ERK1/2 inhibitor U0126 in the physiological occlusal force-applied hPDLCs. These results showed that 10% CTS could enhance osteogenic differentiation of hPDLCs via ERK1/2-Elk1 MAPK pathway, indicating that CTS during physiological occlusal force is a potent agent for PDL remodeling.

Objective: : To investigate cranial base characteristics in malocclusions with sagittal discrepancies. Materials and Methods: : An electronic search was performed in PubMed, Embase, Web of Science, and the Cochrane Library. A fixed- or random-effect model was applied to calculate weighted mean difference with 95% confidence intervals (CIs) according to statistical heterogeneity. Outcome measures were anterior, posterior, and total cranial base length and cranial base angle. Sensitivity analysis and publication bias were conducted. Results: : Twenty studies that together included 1121 Class I, 1051 Class II, and 730 Class III cases qualified for the final analysis. Class III malocclusion demonstrated significantly reduced anterior (95% CI: −1.74, −0.53; P < .001 vs Class I; 95% CI: −3.30, −2.09; P < .001 vs Class II) and total cranial base length (95% CI: −3.33, −1.36; P < .001 vs Class I; 95% CI: −7.38, −4.05; P < .001 vs Class II). Further, Class II patients showed significantly greater anterior and total cranial base length than did Class I patients (95% CI: 0.51, 1.87; P < .001 for SN; 95% CI: 2.20, 3.30; P < .001 for NBa). Cranial base angle was significantly smaller in Class III than in Class I (95% CI: −3.14, −0.93; P < .001 for NSBa; 95% CI: −2.73, −0.68; P = .001 for NSAr) and Class II malocclusions (95% CI: −5.73, −1.06; P = .004 for NSBa; 95% CI: −6.11, −1.92; P < .001 for NSAr) and greater in Class II than in Class I malocclusions (95% CI: 1.38, 2.38; P < .001 for NSBa). Conclusions: : This meta-analysis showed that anterior and total cranial base length and cranial base angle were significantly smaller in Class III malocclusion than in Class I and Class II malocclusions, and that they were greater in Class II subjects compared to controls.