Traumatic life events may shape how individuals utilize health care, yet their impact on medical and dental service utilization is underexplored. This study investigates how such events influence subsequent health care use. We analyzed data from the Mexican Health and Aging Study, the first longitudinal cohort in Mexico of middle-aged and older adults. The analytic sample comprised 17,424 unique individuals across 39,875 total observations. Three traumatic events were examined in relation to their effects on medical and dental service use: (1) experience of a natural disaster, (2) experience of the death of a child, and (3) experience of a crime or accident. We combined propensity score weighting with multivariable mixed-effects logistic regression to account for both confounding and correlation arising from repeated measures. We estimated the effect of exposure to each traumatic event by parametric g-computation, calculating risk differences with 95% confidence intervals (CIs). Exposure to a natural disaster increased medical service use by 4.2% (95% CI, 2.2 to 6.2) while reducing utilization of dental care by 4.8% (95% CI, -7.0 to -2.5). The death of a child increased medical service use by 4.9% (95% CI, 2.7 to 7.2) while reducing utilization of dental care by 6.0% (95% CI, -8.6 to -3.4). Crime or accidents increased utilization of medical services by 12.7% (95% CI, 11.1 to 14.2) while having no clear effect on utilization of dental care. Traumatic events have substantial and differential impacts on health care utilization. In particular, among middle-aged and older adults in Mexico, natural disasters and the death of a child have divergent effects on the utilization of medical versus dental care, while crime and accidents only affect medical care. Future research into this underdeveloped area may help to develop a more precise understanding of the underlying mechanisms.
The entire vertebrate facial skeleton is derived from Hox-negative cranial neural crest cells (CNCCs) that populate the embryonic frontonasal prominence and the first pharyngeal arches. Previous studies have shown that the Edn1/Ednra-Dlx5/Dlx6-Hand2 regulatory network specifies the maxillomandibular identity of CNCCs in the first pharyngeal arches in mice and that the combined application of retinoic acid and noggin to the presumptive maxillary domain in avian embryos transformed maxillary tissues to frontonasal structures, but the molecular mechanisms regulating frontonasal CNCC identity remain unresolved. Biallelic loss of function of any of the aristaless-like homeobox genes, including ALX1, ALX3, and ALX4, which exhibit partly overlapping patterns of expression in the frontonasal CNCCs, causes frontonasal dysplasia. In this study, we show that mice with combined inactivation of Alx1 and Alx3 throughout CNCCs exhibit disruption of frontonasal CNCC identity with ectopic activation of maxillary CNCC developmental profiles. We show that transgenic Alx1 expression throughout the CNCCs, starting from when they were migrating toward the facial primordia, caused ectopic activation of frontonasal CNCC marker genes and suppression of the maxillomandibular marker genes in the developing maxillary and mandibular processes and resulted in the formation of duplicated premaxilla at the expense of maxillary structures. These data identify the ALX transcription factors as key regulators specifying frontonasal CNCC identity and fill a long-standing gap in the molecular mechanism patterning the regional identities of the CNCC-derived craniofacial mesenchyme.
Abnormal enamel mineralization has been reported in genetic conditions associated with hypocalcemia but never with hypercalcemia. In the present study, we report 10 patients from 2 unrelated families in whom hypomineralized enamel co-segregated with hypercalcemia due to a complete deletion or frameshifting premature truncation (p.(Ser18Argfs*2)) of the guanine nucleotide-binding protein (G-protein) subunit α11 (GNA11) gene. Both GNA11 variants were heterozygous and predicted to cause a loss of function of Gα11. Multiproxy imaging analyses of naturally exfoliated primary teeth and clinically extracted permanent teeth from 2 affected patients revealed abnormal enamel mineralization, with constitutive patches of hypomineralization following no set pattern. In parallel, the study of wild-type mouse tooth germs using combined molecular and protein analyses showed Gna11 and Gα11 protein expression in ameloblasts at the secretion and maturation stages, as well as in odontoblasts, suggesting a role for Gα11 in tooth formation. Furthermore, the analysis of a mouse model of Familial Hypocalciuric Hypercalcemia 2 (FHH2) revealed delayed onset of enamel mineralization in the continuously growing incisors and hypomineralized enamel in both incisor and molars of heterozygous (Gna11Tm1b+/-) mice, with defects that are very similar to those affecting human FHH2 teeth. In conclusion, our study reveals that abnormal enamel mineralization may occur in association with hypercalcemia due to loss-of-function GNA11 mutations, opening a new field of investigation and highlighting the need to include a dentist in the multidisciplinary team in charge of patients with monogenic calcium disorders.
Periodontitis is a chronic inflammatory disease characterized by dysregulated neutrophil responses that contribute to progressive periodontal tissue destruction. Here, we observed aberrant fibrin accumulation in inflamed periodontal tissues and hypothesized that fibrin acts as a pathogenic mediator that promotes neutrophil recruitment and activation, thereby triggering neutrophil extracellular traps (NETs) formation and reactive oxygen species (ROS) production. To therapeutically target fibrin deposition, we developed a ROS-responsive hydrogel (PVHA@tPA) that enables localized delivery of tissue plasminogen activator (tPA), activating plasminogen to mediate fibrin degradation. In vitro, tPA released from the hydrogel degraded fibrin matrices in the presence of plasminogen, which restrained fibrin-mediated neutrophil adhesion and migration while suppressing subsequent NETs formation and ROS overproduction. By attenuating this neutrophil overactivation, the treatment improved the osteogenic capacity of periodontal ligament stem cells (PDLSCs) and the angiogenic potential of human umbilical vein endothelial cells (HUVECs). In vivo, PVHA@tPA treatment in a mouse periodontitis model reduced gingival fibrin deposition, attenuated neutrophil-associated inflammation, downregulated proinflammatory factors, and alleviated alveolar bone loss. Together, these findings identify fibrin deposition as a key driver of neutrophil dysregulation in periodontitis and establish fibrin-targeted therapy as a promising strategy to rebalance neutrophil responses and ameliorate periodontitis.
The dental pulp resides within a rigid dentin chamber with a limited blood supply, creating a hypoxic environment that impedes tissue regeneration. While growth factor signaling in pulpal revascularization is well documented, the direct cellular mechanisms that protect endothelial cells (ECs) from hypoxia-induced apoptosis remain unclear. This study identifies intercellular mitochondrial transfer (MT) from dental pulp stem cells (DPSCs) to ECs as a critical survival and angiogenic mechanism under hypoxic stress. Using MitoTracker labeling and flow cytometry, we demonstrated that mitochondria are preferentially transferred from DPSCs to ECs, a process significantly upregulated by hypoxia. We found that contact-dependent mechanisms involving tunneling nanotube-like structures contribute to MT, as cytochalasin B treatment or Miro1 knockdown in DPSCs significantly reduced MT and impaired EC function. To assess the impact of this organelle exchange, we isolated mitochondria-recipient (Mito+) and nonrecipient (Mito-) ECs for analysis. Mito+ ECs exhibited enhanced mitochondrial membrane potential, improved energy metabolism, and yielded superior tube-forming capacity as compared with Mito- ECs. Furthermore, MT significantly reduced EC apoptosis under cobalt chloride-induced hypoxic stress. The in vivo Matrigel plug assay showed that inhibiting MT from DPSCs, genetically or by inhibiting mitochondrial respiration, markedly suppressed DPSC-supported angiogenesis and increased EC apoptosis. Mechanistically, RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that MT revives the EC transcriptome and activates the PI3K-AKT signaling pathway. Immunofluorescence confirmed upregulation of AKT signaling in recipient ECs and colocalization of P-AKT with transferred mitochondria. Furthermore, inhibition of AKT signaling with MK-2206 abolished the proangiogenic and prosurvival role associated with MT, suggesting a direct regulatory role. Collectively, these findings establish MT as a vital metabolic lifeline that prevents EC collapse and drives DPSC-supported angiogenesis in the hypoxic pulp during the vulnerable window of pulpal restoration, thereby emphasizing MT as a transformative regenerative endodontic target.
To reduce secondary caries-related restoration failure, ion-releasing fillers are being incorporated into resin-based composites (RBCs). However, a comprehensive investigation into the cytocompatibility of these materials, particularly concerning transcriptomic responses to monomer and ion release, has yet to be conducted. This study investigated model RBCs (80:20 UDMA:HEMA matrix, 62 vol% filler), including a fluorapatite (FA) containing composite (FA+, 9 vol%), to assess the effect of fluoride ion-releasing filler content on degree of conversion (DC%) and monomer release. Apparent water sorption and fluoride release were evaluated after 28 d of storage in artificial saliva (pH 7 and pH 4) and distilled deionized water. Cytocompatibility was assessed using an XTT assay on human gingival fibroblasts (HGFs), and the expression of genes encoding DNA-repair and stress-response markers following composite exposure was analyzed by quantitative reverse transcription polymerase chain reaction (RT-qPCR). RNA sequencing (RNA-seq) identified differentially expressed genes in response to FA+ and fluorapatite-free RBCs (FA-). Unfilled specimens exhibited lower DC% and higher monomer release compared to the RBCs. FA+ specimens had the highest apparent water sorption, particularly after pH 7 artificial saliva storage. Fluoride release was most significant in acidic environments. UDMA reduced HGF viability compared to HEMA at all concentrations up to 5 mM, but the polymerized RBCs caused no reduction compared to control HGFs. However, expression analysis by RT-qPCR of DNA-repair and stress-response markers following composite exposure revealed that UDMA reduced repair gene expression, whereas HEMA stimulated it. RNA-seq analysis revealed significant changes in gene expression profiles upon composite exposure, with enriched pathways related to ferroptosis and protein digestion. These findings highlight, for the first time, the potential for significant cellular responses even with limited composite component release from ion-releasing RBCs, underscoring the need for further research into the long-term biocompatibility of these materials.
Organs and tissues develop in close association with the vasculature, which transports blood and nutrients and helps to remove waste. The vasculature is composed primarily of endothelial cells, which provide structure, form barriers, and are a source of developmental signals. We recently found that Mediator, a multiprotein complex that regulates transcription, was essential for proper vascular development. Here, we investigated the specific role of the Mediator tail subunit Med23 in endothelial cells. Endothelial cell-specific knockout of Med23 in mouse embryos using Tek-Cre resulted in vascular anomalies, including edema, hemorrhage, and mispatterned vasculature, alongside craniofacial defects such as micrognathia and cleft palate. Spatial transcriptomics revealed the downregulated expression of key vascular and osteogenic genes in Med23 mutants, including Vegfr1 and Col1a1, with altered signaling dynamics between endothelial and osteoblast populations. Elevated hypoxia-inducible factor 1-alpha (HIF1α) expression and reduced vascular endothelial growth factor (VEGF) signaling were observed in Med23 mutants, suggesting a hypoxia-driven suppression of neural crest cell-derived osteoblast maturation. Consistent with this model, the pharmacologic inhibition of HIF1α, combined with VEGFA supplementation, rescued craniofacial ossification and extended embryonic viability. These findings reveal a critical role for Med23 in coordinating vascular patterning and intramembranous ossification and highlight distinct hypoxic and angiogenic requirements in craniofacial dermal bone versus axial and appendicular endochondral bone development. Thus, the cranial vasculature, and more specifically endothelial cells, plays an instructive role in neural crest cell and osteogenic differentiation during cranioskeletal development.
Molar root-incisor malformation (MRIM) is characterized by abnormalities in the root and pulpal floor, which may lead to dental complications. However, research on MRIM remains limited and is largely confined to case-based observations. Therefore, this study aimed to characterize the morphology and proteomic profile of the cervical mineralized diaphragm (CMD) in MRIM. Extracted MRIM-affected teeth (n = 11) from 6 patients and extracted third molars as controls (n = 11) were collected. Two MRIM-affected teeth and two control teeth were subjected to micro-computed tomography and scanning electron microscopy. CMD tissues adjacent to the pulpal floor and control pulpal-floor dentin were harvested for protein extraction and analyzed by liquid chromatography-tandem mass spectrometry. Label-free quantification and bioinformatics analyses (gene set enrichment and protein-protein interaction network analysis) were performed, and proteins with >2-fold change were considered differentially expressed. Micro-computed tomography demonstrated a highly radiopaque CMD at the pulpal floor that occluded pulp-root canal communication, with a radiodensity between that of the enamel and dentin and a dense/porous internal architecture. Scanning electron microscopy revealed columnar and crystal-like structures. Proteomic profiles differed between MRIM and controls, with reduced epithelial-mesenchymal transition signaling in MRIM (normalized enrichment score = 1.47, false discovery rate = 0.116; control vs. MRIM). A total of 116 proteins showed >2-fold change (62 upregulated and 54 downregulated). Upregulated proteins included keratinization-associated proteins (KRT75, KRT82, EVPL, and KRT6B) with enrichment of keratinization- and epidermis-related terms, whereas downregulated proteins included SPP1, AMBN, and ECM1, which were associated with biomineral tissue development. Within the limits of this study, the CMD in MRIM exhibits a distinctive mineralized microarchitecture and a proteomic signature implicating altered epithelial-associated and extracellular matrix/mineralization processes. These findings provide candidate targets for tissue-level validation and mechanistic studies of MRIM.
Additive manufacturing (AM) has expanded in dentistry, yet the color and translucency stability of 3-dimensional-printed resin-based materials remain insufficiently understood. This study investigated the main and interaction effects of printing orientation, specimen thickness, and surface treatments on the color and translucency stability of a 3-dimensional printed resin-ceramic hybrid material. Ninety AM specimens were fabricated using a factorial design combining 3 printing orientations, 3 specimen thicknesses, and 2 surface treatments (3 × 3 × 2, n = 5 per condition) and compared with 30 subtractively manufactured control specimens (Vita Enamic). Aging was simulated by thermocycling (5000 cycles, 5-55 °C). Color coordinates were measured via the Commission Internationale de l'Éclairage L*a*b* color system, and color change and translucency change were calculated. Degree of conversion, water sorption, and surface roughness were also evaluated. Printing orientation and specimen thickness significantly affected color change and translucency change (P < 0.05), with the 90° orientation showing lower changes than 0° and 45°. Surface treatment had a limited influence on color and translucency stability, although glazing resulted in higher water sorption as compared with polishing (P < 0.05). No significant effects of printing orientation were observed for degree of conversion or surface roughness, whereas surface treatment significantly influenced surface roughness (P < 0.05). Despite these variations, all groups remained within clinically acceptable thresholds for color and translucency changes. Overall, the findings suggest that AM resin-ceramic restorations have potential for use in definitive restorations. Optimizing printing orientation and material thickness may enhance the color and translucency stability of AM resin-ceramic restorations, supporting their clinical applicability.
Salivary gland (SG) fibrosis represents a critical pathological feature of exocrine hypofunction driven by the persistent activation of myofibroblasts (MFs). However, the translational gap between the convoluted in vivo regulatory networks governing these cells and the deployment of precise, disease-modifying interventions remains a formidable challenge. This review systematically examines current mechanistic evidence undergirding MF activation, survival, and its phenotypic reversal, focusing on restoring glandular function. We synthesize recent literature mapping in vivo canonical profibrotic signaling cascades, noncanonical crosstalks, and cellular heterogeneity within the injured exocrine stroma. Evidence underscores that the pathological tilt between profibrotic Smad3 and inhibitory Smad7 acts as a critical rheostat for MF differentiation across diverse etiologies. Beyond classical pathways, emerging mechanisms-such as mitochondrial metabolic reprogramming, store-operated calcium entry (SOCE) collapse, and persistent cGAS-STING innate immune sensing-are mechanically reinforced by extracellular matrix rigidity via a YAP/TAZ mechanotransduction loop. These events, coupled with aberrant epigenetic imprinting, structurally lock the persistent MF phenotype and restrict cellular plasticity. Consequently, we evaluate targetable interventions-ranging from small-molecule inhibitors (SB431542, decitabine) and biologics (rituximab) to traditional botanical formulations (Shengmai San) and stem cell-derived extracellular vesicles-that effectively attenuate scar formation and improve salivary flow rates in preclinical or clinical models. Ultimately, this review establishes a novel, etiology-driven "etiology-origin-pathway-target" matrix that shifts the paradigm from empirical anti-inflammatory management toward origin-specific precision therapeutics capable of reversing established salivary gland fibrosis.
Molar incisor hypomineralisation (MIH) is a common developmental dental defect of unknown etiology and considerable morbidity. Observational and experimental studies suggest systemic inflammation as a key mechanism, but there are no prospective human data. This study aimed to describe how the prevalence and severity of MIH vary with early childhood inflammation. It also aimed to investigate the extent to which early childhood inflammation affects the risk of MIH. Data were from the Barwon Infant Study, a population-based prebirth cohort. Glycoprotein acetyls (GlycA), measured by nuclear magnetic resonance, and high-sensitivity C-reactive protein (hsCRP), measured by immunoassay, were quantified from prenatal maternal serum and infant plasma from birth, 6 mo, 12 mo, and 4 y. Cytokine/chemokine responses were also measured from samples collected at 4 y of age. MIH was diagnosed by standardized clinical dental examination at 9 to 13 y of age via the modified European Association of Paediatric Dentistry index. In total, 1,074 mother–infant dyads consented to participate; 481 participants had dental examinations at a mean of 11.9 y (standard deviation = 0.96), and the prevalence of MIH was 27% (n = 129). The unadjusted odds ratio for standardized hsCRP and GlycA showed no difference in the odds of MIH and when comparing the mild and severe MIH subgroups to the non-MIH group at any time point. The estimated average causal effect after adjusting for confounding showed that a 1-unit increase of GlycA measured at 12 mo of age led to a decrease of 0.03 in the risk of MIH (95% confidence interval = −0.07, 0.02, P = 0.24). In this present study, there was no clear evidence of an association between systemic inflammation in early childhood and the risk of MIH.
Hypohidrotic ectodermal dysplasia (HED), primarily caused by mutations in EDA and EDAR, is characterized by tooth agenesis and other dental anomalies, including smaller teeth, conical or peg-shaped teeth, and taurodontism. However, the specific role of EDAR in this process remains unclear, and suitable animal models for functional studies are lacking. In this study, we generated both global and epithelium-specific Edar knockout mice, demonstrating that epithelial Edar is essential for ectodermal organ development. Loss of Edar in the epithelium led to multiple developmental dental anomalies, including third molar agenesis, reduced tooth size, fused roots, decreased cusp number, taurodontism-like molars, and enamel hypoplasia, which could mimic most of the phenotypes seen in global Edar deletion and HED. Single-cell RNA sequencing further revealed that Edar deletion alters the normal developmental progression of preameloblast lineage cells toward later ameloblast states. This alteration may underlie the enamel defects observed upon Edar loss and is further supported by the finding that Edar knockdown impaired mineralization of ameloblast lineage cells in vitro. Notably, Dlx3 was downregulated in ameloblasts at various stages in Edar-deficient mice, and Dlx3 overexpression in Edar-knockdown ameloblast lineage cells could rescue the mineralization function. Chromatin immunoprecipitation-quantitative polymerase chain reaction revealed that p65 binds to the Dlx3 promoter, linking Edar to Dlx3 transcriptional activation via NF-κB signaling. Collectively, these findings reveal a critical role of epithelial EDAR in tooth development and, for the first time, provide evidence that its downregulated expression can lead to enamel formation defects, offering new insights into the pathogenic mechanisms of EDAR-related HED.
Intraoral ultrasonography (iUS) has emerged as a noninvasive, radiation-free imaging modality capable of real-time visualization of both soft and hard tissues, yet its clinical accuracy and reliability remain incompletely characterized. This study aims to evaluate the accuracy and reliability of periodontal parameters measured on intraoral ultrasonograms. An in-house customized 20-MHz ultrasound imaging system with a rotational head was used to image the periodontium. Ex vivo accuracy was assessed in 58 teeth from 3 cadaver specimens with high-resolution micro-computed tomography (µCT) as the gold standard. Two raters independently performed repeated measurements of alveolar bone level (ABL) and alveolar bone thickness (ABT) on 50 iUS images using a standardized anatomy-guided protocol. Intermethod agreement was quantified using intraclass correlation coefficients (ICCs), mean absolute differences (MADs), paired t tests, and Bland-Altman analysis. In vivo clinical reliability was evaluated in 19 adolescents undergoing orthodontic treatment, with 3 raters measuring the ABL, ABT, attached gingival thickness, and free gingival thickness on 134 iUS images. Ex vivo analysis demonstrated excellent iUS accuracy and consistency for ABL (MAD 0.18-0.31 mm, ICCs 0.94-0.96) and excellent accuracy and good agreement for ABT (MAD 0.05 mm; ICCs 0.87). Paired t tests revealed no significant differences between iUS and µCT measurements for either parameter (all P > 0.05). Bland-Altman analysis demonstrated excellent agreement with near-zero bias for both ABL and ABT, with narrow 95% limits of agreement across raters. In vivo measurements exhibited outstanding intrarater reliability (ICCs ≥ 0.84; MAD ≤ 0.10 mm) and good-to-excellent interrater reliability (ICCs ≥ 0.82; MAD ≤ 0.18 mm) for all parameters. The standardized, anatomy-guided protocol minimized operator dependency, enabling reproducible assessments across raters. These results demonstrate that iUS provides highly reproducible and reliable periodontal measurements in cadavers and healthy adolescents. Further studies in patients with moderate-to-severe periodontal disease are required to fully validate iUS for longitudinal monitoring.
Panoramic radiography (PR) is the one of the most widely prescribed diagnostic imaging modalities in dentistry. Achieving clinical-level automated interpretation of PR is critical for improving diagnostic efficiency, reducing radiologist workload, and ensuring interpretive consistency. Artificial intelligence (AI) has demonstrated significant utility and promise in PR interpretation, improving diagnostic efficiency, reducing radiologists' workload, and enhancing interpretive consistency. However, developing AI-based PR interpretation methods remains hindered by persistent challenges of data scarcity, privacy constraints, and annotation imbalance. Facing these limitations, the aim of this study is to develop a disease-guided, anatomy-controllable generative model, named PRGen (for "panoramic radiograph generation"), designed to mitigate challenges related to data scarcity, privacy constraints, and annotation imbalance. PRGen is developed using 50,127 paired text-image samples and overcomes the uncontrollability of existing generative models, synthesizing both realistic PRs and paired masks from textual disease descriptions, enabling precise control of dental anatomy through simple or detailed sketches, and effectively mitigating barriers to large-scale, well-annotated dataset construction. We comprehensively evaluated the quality and clinical utility of PRGen-generated PRs across held-out internal test sets, publicly available datasets, and assessments by 10 radiologists. Incorporating PRGen-synthesized images into training led to a 47.59% improvement in Dice score for segmentation and a 11.53% increase in the area under the curve. Upon expert review, more than 82% of synthesized PRs were judged to faithfully reflect the described diseases while maintaining clinically realistic anatomical structures and radiographic appearances. External multicenter validation confirmed robust generalizability, with an average Dice improvement of 25.58% for segmentation and consistent gains in diagnostic tasks. Collectively, these results demonstrate that PRGen enables the generation of high-quality, mask-annotated PRs, thereby reducing the reliance on manual annotations and supporting more reliable and automated analysis of PRs, ultimately facilitating both model development and clinical translation.
The aims of this study were 1) to determine how ligature-induced periodontitis (LIP) disrupts barrier functions of the junctional epithelium (JE); 2) to determine, using a genetic approach, the necessity of Wnt signaling for JE barrier functions; and 3) to test, using a biochemical strategy, whether a WNT therapeutic is sufficient to improve barrier functions of a pocket epithelium. In a murine model of LIP, quantitative analyses performed at multiple time points assessed epithelial apoptosis; expression of attachment proteins laminin 5 and β4 integrin, inflammation, and bone resorption. Axin2CreERT2/+; R26RmTmG/+ mice were used to evaluate how LIP impacted Wnt-responsive cells and their progeny, and K14CreERT2/+;Wlsfl/fl mice were used to determine whether Wnt signaling was required for JE barrier functions. In some cases, LIP was followed by a recovery period to assess molecular changes in pocket epithelium, and in a subset of these mice, a liposomal formulation of human WNT3A protein (L-WNT3A) was tested for its effects on early repair dynamics in pocket epithelium. LIP triggered apoptosis, significantly reduced expression of laminin 5 and β4 integrin in the JE, and disrupted the Wnt-responsive compartment; these epithelial changes were accompanied by inflammation and alveolar bone resorption. Reepithelialization occurred even with a ligature present, but this pocket epithelium had compromised barrier functions. Wntless (Wls) deletion was sufficient to convert a JE into pocket epithelium, while topical L-WNT3A treatment was sufficient to increase hemidesmosomal protein expression in pocket epithelium and reduce inflammation at early time points. LIP destroys barrier functions and thus converts a JE into pocket epithelium. Deletion of epithelial Wls demonstrates that this conversion is a Wnt-dependent event. L-WNT3A restores some early barrier features to pocket epithelium; future studies will focus on the durability of these effects.
Mandibular incisors are the most frequently congenitally absent teeth in Asian populations, affecting mastication, speech, aesthetics, and oral and maxillofacial functions over the long term. However, the genetic etiology of mandibular incisor agenesis (MIA) remains obscure. In this study, we conducted the first genome-wide association study on MIA in a Chinese population and identified an enhancer variant, rs71514987, associated with an increased risk of MIA (odds ratio, 2.18; 95% CI, 1.83 to 2.58; P = 3.62 × 10-19). Functional characterization indicated that the rs71514987 C allele reduced the binding affinity of GATA4 to the OSR2 promoter, leading to increased OSR2 expression via remote regulation. Notably, elevated OSR2 levels promoted cell proliferation but diminished cell differentiation, migration, and apoptosis capabilities in stem cells from human exfoliated deciduous teeth, as well as abnormal development of pharyngeal teeth in zebrafish models. Mechanistic experiments further revealed that OSR2 bound to the promoter region of CXCR4, promoting its transcription level in the GPCR pathway, thereby influencing odontogenic differentiation during tooth development. Our findings provide novel insights into the molecular etiology of MIA.
Electronic nicotine delivery systems (ENDS), including e-cigarettes, are increasingly marketed as safer alternatives to combustible tobacco, yet their effects on oral health remain underexplored. Although the role of ENDS in creating dysbiotic oral bacterial communities is documented, effects on the oral mycobiome remain underexplored. This study compared the subgingival fungal communities of 123 periodontally and systemically healthy e-cigarette-only users, smokers, dual users, former smokers, and never-smokers using whole-genome shotgun sequencing for functional profiling. Taxonomic assignment using Kraken 2 and the PlusPF database identified 98 fungal taxa, and functional annotation with the Kyoto Encyclopedia of Genes and Genomes identified 2,960 fungal genes. Cross-domain bacterial-fungal interactions were interrogated using a correlation threshold of |r| ≥ 0.7 and P ≤ 0.001. E-cigarette users demonstrated a significantly higher α-diversity than smokers and never-smokers did (P < 0.001; P < 0.005) and a mycobiome enriched with Candida albicans, Aspergillus oryzae, and Schizosaccharomyces pombe. Functional profiling revealed enrichment of genes encoding or DNA repair, xenobiotic degradation, membrane transport, and stress response. The mycobiome of dual users and former smokers using e-cigarettes did not differ from that of e-cigarette users. Cross-kingdom networks identified 5- to 10-fold higher bacterial-fungal connectivity in e-cigarette users, with fungi capable of enhanced stress tolerance, DNA repair capacity, and metabolic adaptability acting as network anchors. Our data support an association between e-cigarette use and remodeling of the oral mycobiome and microbiome, driven by enhanced polymicrobial interactions and increased functional complexity, suggesting that assumptions regarding the biological neutrality of e-cigarette aerosols warrant further investigation.
Dental caries is a highly prevalent chronic condition requiring accurate tools to identify at-risk patients and guide preventive care. Most existing caries risk models provide only binary predictions and overlook time-to-event information. Considering that modern caries management relies on risk assessment during routine dental examinations, we developed RT2C, a survival model based on a recurrent neural network (RNN). This model supports caries risk management by assessing the likelihood (Caries Management by Risk Assessment [CAMBRA]) that a patient will be diagnosed with new caries by the next visit. It also estimates the time until this event occurs, using structured longitudinal dental data. Data were extracted from 4 dental organizations, comprising 466,782 patients and 1,062,553 examination visits (D0120, D0150, D0145) between 2019 and 2023. Structured electronic dental record (EDR) data included demographics, dental care history, clinical findings, and the CAMBRA-caries risk assessment (CRA). Patients were split into development (326,748 patients; 744,624 visits), validation (46,678; 106,616), and test (93,356; 211,313) sets, with similar event rates (~20%). The RT2C model used a bidirectional gated recurrent unit network to capture temporal dependencies across visits and estimate individualized survival probabilities. Model performance was compared against a Cox proportional hazards model and a random survival forest using the concordance index (C-index), integrated Brier score, and calibration analysis. Subgroup analyses evaluated generalizability across insurance types, age groups, racial groups, and CRA-based risk groups. The RT2C model achieved the highest concordance index on the held-out test set (0.883 ± 0.08), outperforming the CRA-only and traditional survival baselines. Performance remained consistent across demographic and clinical subgroups, demonstrating robustness and fairness across diverse populations. RT2C models visit-indexed risk trajectories and predicted new caries occurrence by the subsequent visit, aligning with the preventive framework of CAMBRA. By integrating longitudinal EDR data, it adds value to existing CRA tools and supports proactive, personalized caries management.
Enamel remineralization holds considerable promise for dental caries, yet clinical translation remains hampered by the spontaneous deposition of acquired salivary pellicle (ASP), which passivates enamel surfaces and suppresses mineralization kinetics. Here, we present an ASP-repelling mineralization strategy based on a phase-transitioned bovine serum albumin (PTB) nanocoating fabricated via amyloid-like protein self-assembly. The PTB nanocoating confers robust antifouling properties that effectively inhibit ASP adsorption while simultaneously providing exceptional biomineralization activity. Under simulated physiological oral conditions, PTB drives heterogeneous nucleation and crystallization of calcium phosphate, generating a dense, well-integrated remineralized layer for enamel restoration. Both in vitro and in vivo evaluations demonstrate that ASP-coated enamel exhibits markedly attenuated remineralization capacity, whereas PTB treatment reverses this inhibition by efficiently repelling ASP and leveraging its abundant amino acid residues alongside amyloid-like architectures to direct mineral deposition. This work elucidates the interaction between ASP and remineralizing interfaces, providing a conceptually novel and clinically promising avenue to overcome remineralization barriers for caries prevention and enamel restoration.
