KR4SL: knowledge graph reasoning for explainable prediction of synthetic lethality.

MOTIVATION: Synthetic lethality (SL) is a promising strategy for anticancer therapy, as inhibiting SL partners of genes with cancer-specific mutations can selectively kill the cancer cells without harming the normal cells. Wet-lab techniques for SL screening have issues like high cost and off-target effects. Computational methods can help address these issues. Previous machine learning methods leverage known SL pairs, and the use of knowledge graphs (KGs) can significantly enhance the prediction performance. However, the subgraph structures of KG have not been fully explored. Besides, most machine learning methods lack interpretability, which is an obstacle for wide applications of machine learning to SL identification. RESULTS: We present a model named KR4SL to predict SL partners for a given primary gene. It captures the structural semantics of a KG by efficiently constructing and learning from relational digraphs in the KG. To encode the semantic information of the relational digraphs, we fuse textual semantics of entities into propagated messages and enhance the sequential semantics of paths using a recurrent neural network. Moreover, we design an attentive aggregator to identify critical subgraph structures that contribute the most to the SL prediction as explanations. Extensive experiments under different settings show that KR4SL significantly outperforms all the baselines. The explanatory subgraphs for the predicted gene pairs can unveil prediction process and mechanisms underlying synthetic lethality. The improved predictive power and interpretability indicate that deep learning is practically useful for SL-based cancer drug target discovery. AVAILABILITY AND IMPLEMENTATION: The source code is freely available at https://github.com/JieZheng-ShanghaiTech/KR4SL.

NSF4SL: negative-sample-free contrastive learning for ranking synthetic lethal partner genes in human cancers.

MOTIVATION: Detecting synthetic lethality (SL) is a promising strategy for identifying anti-cancer drug targets. Targeting SL partners of a primary gene mutated in cancer is selectively lethal to cancer cells. Due to high cost of wet-lab experiments and availability of gold standard SL data, supervised machine learning for SL prediction has been popular. However, most of the methods are based on binary classification and thus limited by the lack of reliable negative data. Contrastive learning can train models without any negative sample and is thus promising for finding novel SLs. RESULTS: We propose NSF4SL, a negative-sample-free SL prediction model based on a contrastive learning framework. It captures the characteristics of positive SL samples by using two branches of neural networks that interact with each other to learn SL-related gene representations. Moreover, a feature-wise data augmentation strategy is used to mitigate the sparsity of SL data. NSF4SL significantly outperforms all baselines which require negative samples, even in challenging experimental settings. To the best of our knowledge, this is the first time that SL prediction is formulated as a gene ranking problem, which is more practical than the current formulation as binary classification. NSF4SL is the first contrastive learning method for SL prediction and its success points to a new direction of machine-learning methods for identifying novel SLs. AVAILABILITY AND IMPLEMENTATION: Our source code is available at https://github.com/JieZheng-ShanghaiTech/NSF4SL. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Taxifolin Protects Dental Pulp Stem Cells under Hypoxia and Inflammation Conditions.

BACKGROUND: Dental pulp stem cells (DPSCs) are a unique source for future clinical application in dentistry such as periodontology or endodontics. However, DPSCs are prone to apoptosis under abnormal conditions. Taxifolin is a natural flavonoid and possesses many pharmacological activities including anti-hypoxic and anti-inflammatory. We aimed to elucidate the mechanisms of taxifolin protects DPSC under hypoxia and inflammatory conditions. METHODS: DPSCs from human dental pulp tissue was purchased from Lonza (cat. no. PT-5025. Basel, Switzerland)) and identified by DPSC's biomarkers. DPSC differentiation in vitro following the manufacturers' instructions. ARS staining and Oil red staining verify the efficiency of differentiation in vitro after 2 weeks. The changes of various genes and proteins were identified by Q-PCR and western-blot, respectively. Cell viability was determined by the CCK-8 method, while apoptosis was determined by Annexin V/PI staining. RESULTS: DPSC differentiation in vitro shows that hypoxia and TNF-α synergistically inhibit the survival and osteogenesis of DPSCs. A final concentration of 10 µM Taxifolin can significantly reduce the apoptosis of DPSCs under inflammation and hypoxia conditions. Taxifolin substantially increases carbonic anhydrase IX (CA9) expression but not HIF1a, and inhibitions of CA9 expression nullify the protective role of taxifolin under hypoxia and inflammatory condition. CONCLUSION: Taxifolin significantly increased the expression of CA9 when it inhibits DPSC apoptosis and taxifolin synergistically to protect DPSCs against apoptosis with CA9 under hypoxia and inflammatory conditions. Taxifolin can be used as a potential drug for clinical treatment of DPSC-related diseases.

Long Noncoding RNA X-Inactive Specific Transcript (XIST) Promotes Osteogenic Differentiation of Periodontal Ligament Stem Cells by Sponging MicroRNA-214-3p.

BACKGROUND Osteogenic differentiation of periodontal ligament stem cells (PDLSCs) is associated with periodontitis. It has been reported that long noncoding RNA X-inactive specific transcript (lncRNA XIST) is upregulated and microRNA-214-3p (miR-214-3p) is downregulated in PDLSCs after osteogenic induction. However, whether XIST is involved in osteogenic differentiation of PDLSCs via miR-214-3p has not been reported. MATERIAL AND METHODS The protein expressions of osteogenic markers alkaline phosphatase (ALP), osteocalcin (OCN), and runt-related transcription factor 2 (RUNX2) were examined by Western blot. The levels of miR-214-3p and XIST were determined by qRT-PCR. The relationship between miR-214-3p and XIST was evaluated by luciferase reporter, RNA immunoprecipitation, and RNA pulldown assays. RESULTS We found that XIST was increased and miR-214-3p was decreased in PDLSCs after osteogenic stimulation. Silencing of XIST decreased the protein expressions of ALP, OCN, and RUNX2, and also decreased ALP activity. Higher miR-214-3p levels also inhibited osteogenic differentiation of PDLSCs. XIST interacted with miR-214-3p and depletion of miR-214-3p mitigated XIST absence-mediated suppression of osteogenic differentiation. CONCLUSIONS XIST participates in osteogenic differentiation of PDLSCs by sponging miR-214-3p.

The Inhibition of MicroRNA-139-5p Promoted Osteoporosis of Bone Marrow-Derived Mesenchymal Stem Cells by Targeting Wnt/Beta-Catenin Signaling Pathway by NOTCH1.

We investigated the therapeutic effects of microRNA-139-5p in relation to osteoporosis of bone marrow-derived mesenchymal stem cell (BMSCs) and its underlying mechanisms. In this study we used a dexamethasone-induced in vivo model of osteoporosis and BMSCs were used for the in vitro model. Real-time quantitative polymerase chain reaction (RT-PCR) and gene chip were used to analyze the expression of microRNA-139-5p. In an osteoporosis rat model, the expression of microRNA-139-5p was increased, compared with normal group. Downregulation of microRNA-139-5p promotes cell proliferation and osteogenic differentiation in BMSCs. Especially, up-regulation of microRNA-139-5p reduced cell proliferation and osteogenic differentiation in BMSCs. Overexpression of miR-139-5p induced Wnt/ß-catenin and down-regulated NOTCH1 signaling in BMSCs. Down-regulation of miR-139-5p suppressed Wnt/ß-catenin and induced NOTCH1 signaling in BMSCs. The inhibition of NOTCH1 reduced the effects of anti-miR-139-5p on cell proliferation and osteogenic differentiation in BMSCs. Activation of Wnt/ß-catenin also inhibited the effects of anti-miR-139-5p on cell proliferation and osteogenic differentiation in BMSCs. Taken together, our results suggested that the inhibition of microRNA-139-5p promotes osteogenic differentiation of BMSCs via targeting Wnt/ß-catenin signaling pathway by NOTCH1.

Notch pathway deactivation mediated by F-box/WD repeat domain-containing 7 ameliorates hydrogen peroxide-induced apoptosis in rat periodontal ligament stem cells.

OBJECTIVE: To investigate the protective role of F-box/WD repeat domain-containing 7 in rat periodontal ligament stem cells under oxidative stress. MATERIALS AND METHODS: The apoptosis of rat periodontal ligament stem cells was induced by exposure to various concentrations of hydrogen peroxide for 24 h, after which cell viability and the cleaved caspase-3 and -9 levels were determined. The levels of proteins in the Notch signaling pathway were determined by western blotting. RESULTS: The overexpression of F-box/WD repeat domain-containing 7 increased cell viability following hydrogen peroxide administration and suppressed the activation of caspases-3 and -9. The overexpression of F-box/WD repeat domain-containing 7 inhibited Notch signaling. Furthermore, the protective effect of F-box/WD repeat domain-containing 7 could be resumed by PF-03084014, a Notch-specific inhibitor. CONCLUSIONS: These observations suggest a protective role of F-box/WD repeat domain-containing 7 against hydrogen peroxide-induced oxidative stress in rat periodontal ligament stem cells. These findings will facilitate the in vitro culturing of periodontal ligament stem cell for clinical usage and promote stem cell-based therapy for periodontal tissue regeneration.

Activation of the ERK/Creb/Bcl­2 pathway protects periodontal ligament stem cells against hydrogen peroxide­induced oxidative stress.

Periodontal ligament stem cells (PDLSCs) are promising stem cells sources for regenerative medicine, particularly clinical periodontal ligament repair. It is critical to maintain high quality and a large quantity of PDLSCs for clinical usage. However, how PDLSCs respond to environmental stimuli, including reactive oxygen species (ROS), is poorly understood. The aim of the present study was to investigate how PDLSCs react to oxidative stress and the underlying mechanisms. Hydrogen peroxide­induced oxidative stress was used to mimic a ROS increase in rat PDLSCs. The expression levels of Creb were detected under oxidative stress to examine the role that Creb serves in PDLSCs under oxidative stress. The present results demonstrated that the expression of Creb was reduced in a dose­dependent manner in response to the H2O2 stimulus. Overexpressing Creb significantly reduced the ROS levels and protein expression levels of apoptotic genes in PDLSCs. The phosphorylation of the ERK pathway is indispensable in the activation of Creb­induced protection. Our results revealed a protective role of Creb in ROS­induced apoptosis, and validated the ERK/Creb/apoptosis regulator Bcl­2 pathway works as an anti­apoptotic signaling in PDLSCs. These findings will facilitate the in vitro culturing of PDLSCs for clinical usage and promote stem cell based therapy for periodontal tissue regeneration.

Stromal cell-derived factor 1 protects human periodontal ligament stem cells against hydrogen peroxide-induced apoptosis.

Periodontal ligament stem cells (PDLSCs) are considered a promising cell source for dental tissue regeneration. Stromal cell-derived factor 1 [SDF­1, also known as chemokine (C­X­C motif) ligand 12] is regarded as a critical cytokine involved in stem/progenitor cell chemotaxis and homing during tissue regeneration. The present study described a previously unsuspected role for SDF­1 in the protection of PDLSCs against oxidative stress­induced apoptosis. In the present study, apoptosis was induced by exposure of PDLSCs to various concentrations of H2O2 for 12 h, following which cell viability was assessed, and cleaved caspase­3 and ­9 expression levels were evaluated. To investigate the potential mechanism underlying this protection, the protein expression levels of total and phosphorylated extracellular signal­regulated kinase (ERK), a key protein of the mitogen­activated protein kinase (MAPK) signaling pathway, were examined. The results of the present study revealed that SDF­1 pretreatment increased cell viability following H2O2 administration, and downregulated protein expression levels of activated caspase­3 and ­9. Furthermore, treatment with SDF­1 increased the phosphorylation of ERK. The protective effect of SDF­1 was partially inhibited by treatment with PD98059, a MAPK/ERK inhibitor, which decreased cell viability. The results of the present study suggested that SDF­1 treatment is a potential strategy to improve the survival of PDLSCs, which may be beneficial for dental tissue regeneration.

Three-D imaging of dental alveolar bone change after fixed orthodontic treatment in patients with periodontitis.

OBJECTIVES: The objective of this study was to radiographically quantify bone height and bone density in patients with periodontitis after fixed orthodontic treatment using cone beam computed tomography (CBCT). MATERIALS AND METHODS: A total of 81 patients including 40 patients with chronic periodontitis (group 1) and 41 patients with normal periodontal tissues (group 2) were selected. CBCT scanning for anterior teeth were taken before and after orthodontic treatment. Measurements of bone height and bone density were performed using CBCT software. RESULTS: The group 1 presented a statistically lesser bone density and bone height when compared to group 2 before treatment. There was a significant loss of bone density for both groups after orthodontic treatment, but bone density loss was significantly greater in the group 1. There was no statistically significant bone height change in two groups after treatment. CONCLUSIONS: This study demonstrated that orthodontic treatment can preserve bone height but not capable of maintaining bone density, especially for patients with periodontitis. It is indicated that the change of bone density may be more susceptible than that of bone height when radiographically evaluating bone status under this combined periodontal and orthodontic therapy.

[Inter-relationship between mandibular rotation center and maxillary Le Fort I impaction osteotomies].

PURPOSE: The purpose of the present investigation was to locate the instantaneous rotation center of the mandible during maxillary surgical impaction, and explore the relationship between automatic rotation center of the mandible and maxillary elevation amount, the length of the mandible and mandibular plane angle. METHODS: Twenty-five patients who underwent maxillary Le Fort I impaction without concomitant major mandibular ramus split osteotomies were included. The preoperative and postoperative lateral cephalograms were used to evaluate the surgical changes and locate the mandibular autorotation center with Reuleaux method. The automatic rotation center of the mandible was compared to the maxillary elevation amount, the length of the mandible and mandibular plane angle with Pearson correlation and linear regression analysis. The data was analyzed by SPSS 13.0 software package. RESULTS: The mandibular automatic rotation center was located in average 15.64 mm below and 0.82 mm behind the center of the condylar head in these 25 patients. The correlation analysis demonstrated a positive correlation between maxillary elevation amount, the length of the mandible and the position of the rotation center of the mandible. Similar positive correlation was presented between the mandibular plane angle and the vertical position of the rotation center of the mandible. CONCLUSIONS: The rotation center in 25 cases were located outside the condylar head. The maxillary elevation amount, the length of the mandible and the mandibular plane angle was positively correlated to the position of the rotation center of the mandible.

[Research on periodontal changes on the compression side during rapid tooth movement into newly distracted bone].

PURPOSE: To investigate periodontal remodeling mechanism on the compression side during early tooth movement into newly distracted bone. METHODS: Ten male Beagle dogs were selected. Distraction osteogenesis was performed on randomized side as experimental group, while the fourth premolars were extracted on the other side as control group. Then the third premolars were distalized with 30g orthodontic force instantly after the cessation of distraction or extraction. The distance of the tooth movement was measured with a sliding caliper every week. Each distance was measured 3 times and the mean value was recorded. The measurement data were analysed with paired t test by SPSS 18.0 software package. Beagle dogs were killed in the first, second, fourth week after tooth movement. Slices were obtained for HE staining and TRAP staining to observe the periodontal tissue on the compression side. RESULTS: The average moving velocity of the teeth in the distracted bone was (1.055±0.054)mm per week, which was significantly faster than that in the control group(P<0.05).There was no apparent lag period in the experimental group. In addition, there was no hyalinization observed on the compression side of the periodontal tissue in the experimental group, while the amount and area of distribution of the TRAP-positive cells on the compression side was significantly larger and strongly expressed. CONCLUSIONS: The moving velocity of the teeth in the newly distracted bone was significantly faster, and no apparent lag period, which may be related to no hyalinization and more early-appeared, vigorous and wide-distributed osteoclasts on the compression side of the periodontal tissue.

Reconstruction of partial maxillary defect with intraoral distraction osteogenesis assisted by miniscrew implant anchorages.

OBJECTIVE: The paper reports a custom-made trifocal transport distractor assisted by miniscrew implant anchorages (MIAs) used to reconstruct maxillary defects and evaluates the clinical results of function and esthetics. STUDY DESIGN: Eight patients aged 19-43 years who suffered regional maxillary defects were involved. Each one underwent segmental bone excision of the maxilla and distraction osteogenesis (DO) in the defect region by a custom-made interoral 3-dimensional distractor which was activated by orthodontic elastic force assisted by MIAs at the rate of

Mia-assisted orthodontic treatment for dental malocclusion secondary to periodontal disease.

In contemporary dental care, an increasing number of adult patients with periodontal disease are seeking orthodontic treatment. Achieving optimal results in such adult patients is difficult because decreased posterior tooth anchorage is risky. This case report demonstrates the use of miniscrew implant anchorage (MIA) in a Chinese male 21 years 5 months of age with maxillary and mandibular anterior dental spacing, bimaxillary protrusion, and severe bone loss caused by periodontal disease. Prior to orthodontic treatment, the patient underwent treatment to control his periodontitis. The patient was treated with 0.022-in straight-wire orthodontic appliances. After 17 months of active orthodontic treatment, the patient had healthier periodontal tissue with increased bone support, as well as improved facial esthetics and a functional occlusion. The results demonstrate that MIA is useful in enhancing anchorage in patients with bone loss associated with severe periodontal disease.

[Cephalometric analysis of implant anchorage-assisted retraction of anterior teeth].

PURPOSE: The purpose of this study is to compare the different effects of alveolar bone remolding due to retraction of anterior teeth by two types of anchorage mini-screw implant or regular maximum anchorage. METHODS: The sample comprised 26 orthodontic patients with upper dental alveolar bone protrusion and mild crowding. The treatment plan was to remove the four first bicuspids. 14 patients,3 males,11 females, aged 20-54 years old (mean: 25 years) were treated with implant anchorage to retract the maxillary anterior teeth. 12 patients, 1 male,11 females, aged 18-30 years old (mean: 21 years) were treated with regular maximum anchorage to retract maxillary anterior teeth. Lateral cephalograms of all patients were evaluated at two stages: pretreatment, post-treatment.The changes of the long axis of the anterior teeth and dental alveolar were measured.SPSS11.0 software package was used for statistical analysis. RESULTS: The cephalometric findings showed that the anterior teeth were retracted with implant anchorage significantly more than the maximum anchorage, there was no significant difference in the dental alveolar bone remolding between two groups. The first molars moved anteriorly slightly (less than 1mm) with implant anchorage, but significantly (3.08 mm) with regular maximum anchorage. CONCLUSIONS: The maxillary anterior teeth are significantly retraced with the implant anchorage; the molars move mesially significantly less in the implant group than the maximum group. There are no significant differences in dental alveolar bone remolding between both groups. Support by Shanghai Leading Academic Discipline Project (Grant No.Y0203) and Research Fund of Science and Technology Committee of Shanghai Municipality (Grant No. 05B224).

[Clinical evaluation of implant anchorage for molar intrusion: report of the short-term results].

PURPOSE: The purpose of this study is to evaluate the efficiency and security of self-drilling mini-screw implant anchorage for molar intrusion, to achieve the right position of the mini-screw implant. METHODS: Ten patients with overerupted maxillary molars were selected, aging from 25 to 53 years old, the average age was 33 years old. There were 2 men and 8 women. All the overerupted molars were intruded in gingival direction with mini-screw implants anchorage. RESULTS: The mean intrusive movement of the overerupted maxillary molars was 3 mm, the mean treatment time were 3.5 months.All of the missing teeth were treated by prosthetic treatment. No obvious root resorption, pulp necrosis and tooth loosen were found. CONCLUSIONS: Significant true intrusion of maxillary molars could be obtained by mini-screw implant as bony anchorage.Supported by Shanghai Leading Academic Discipline Project (Grant No.Y0203) and Research Fund of Science and Technology Committee of Shanghai Municipality (Grant No.05B224).

[Current gene study in etiological analysis of congenital craniofacial abnormalities].

The cause of congenital craniofacial abnormalities are very complicated. Understanding of the gene mechanisms of abnormalities taking place are very important for prevention and therapy.DNA sequence analysis provides the fundaments of gene study of the congenital craniofacial abnormalities. Human genome project (HGP) paved the confirmation of candidate gene of the congenital craniofacial abnormalities.Transgenic animal models and gene knockout techniques are effective methods in study of gene function. This paper reviews current gene study in etiopathogenisis analysis of the congenital craniofacial abnormalities.