mTORC2 regulates hierarchical micro/nano topography-induced osteogenic differentiation via promoting cell adhesion and cytoskeletal polymerization.

Surface topography acts as an irreplaceable role in the long-term success of intraosseous implants. In this study, we prepared the hierarchical micro/nano topography using selective laser melting combined with alkali heat treatment (SLM-AHT) and explored the underlying mechanism of SLM-AHT surface-elicited osteogenesis. Our results show that cells cultured on SLM-AHT surface possess the largest number of mature FAs and exhibit a cytoskeleton reorganization compared with control groups. SLM-AHT surface could also significantly upregulate the expression of the cell adhesion-related molecule p-FAK, the osteogenic differentiation-related molecules RUNX2 and OCN as well as the mTORC2 signalling pathway key molecule Rictor. Notably, after the knocked-down of Rictor, there were no longer significant differences in the gene expression levels of the cell adhesion-related molecules and osteogenic differentiation-related molecules among the three titanium surfaces, and the cells on SLM-AHT surface failed to trigger cytoskeleton reorganization. In conclusion, the results suggest that mTORC2 can regulate the hierarchical micro/nano topography-mediated osteogenesis via cell adhesion and cytoskeletal reorganization.

Effects of immediate and delayed loading protocols on marginal bone loss around implants in unsplinted mandibular implant-retained overdentures: a systematic review and meta-analysis.

BACKGROUND: Immediate loading has recently been introduced into unsplinted mandibular implant-retained overdentures for the management of edentulous patients due to their increasing demand on immediate aesthetics and function. However, there is still a scarcity of meta-analytical evidence on the efficacy of immediate loading compared to delayed loading in unsplinted mandibular implant-retained overdentures. The purpose of this study was to compare the marginal bone loss (MBL) around implants between immediate and delayed loading of unsplinted mandibular implant-retained overdentures. METHODS: Randomized controlled trials (RCTs), controlled clinical trials (CCTs), and cohort studies quantitatively comparing the MBL around implants between immediate loading protocol (ILP) and delayed loading protocol (DLP) of unsplinted mandibular overdentures were included. A systematic search was carried out in PubMed, EMBASE, and CENTRAL databases on December 02, 2020. "Grey" literature was also searched. A meta-analysis was conducted to compare the pooled MBL of two different loading protocols of unsplinted mandibular overdentures through weighted mean differences (WMDs) with 95% confidence intervals (95% CIs). The subgroup analysis was performed between different attachment types (i.e. Locator attachment vs. ball anchor). The risk of bias within and across studies were assessed using the Cochrane Collaboration's tool, the Newcastle-Ottawa scale, and Egger's test. RESULTS: Of 328 records, five RCTs and two cohort studies were included and evaluated, which totally contained 191 participants with 400 implants. The MBL of ILP group showed no significant difference with that of DLP group (WMD 0.04, CI - 0.13 to 0.21, P > .05). The subgroup analysis revealed similar results with Locator attachments or ball anchors (P > .05). Apart from one RCT (20%) with a high risk of bias, four RCTs (80%) showed a moderate risk of bias. Two prospective cohort studies were proved with acceptable quality. Seven included studies have reported 5.03% implant failure rate (10 of 199 implants) in ILP group and 1.00% failure rate (2 of 201 implants) in DLP group in total. CONCLUSIONS: For unsplinted mandibular implant-retained overdentures, the MBL around implants after ILP seems comparable to that of implants after DLP. Immediate loading may be a promising alternative to delayed loading for the management of unsplinted mandibular implant-retained overdentures. PROSPERO registration number: CRD42020159124.

Down-Regulation of hspb9 and hspb11 Contributes to Wavy Notochord in Zebrafish Embryos Following Exposure to Polychlorinated Diphenylsulfides.

It is hypothesized that key genes, other than ahr2, are present and associated with the development of a unique type of notochord malformation known as wavy notochord in early life stages of zebrafish following exposure to polychlorinated diphenylsulfides (PCDPSs). To investigate the potential mechanism(s), time-dependent developmental morphologies of zebrafish embryos following exposure to 2500 nM 2,4,4',5-tetra-CDPS, 2,2',4-tri-CDPS or 4,4'-di-CDPS were observed to determine the developmental time point when notochord twists began to occur (i.e., 21 h-postfertilization (hpf)). Simultaneously, morphometric measurements suggested that PCDPS exposure did not affect notochord growth at 21 or 120 hpf; however, elongation of the body axis was significantly inhibited at 120 hpf. Transcriptome analysis revealed that the retardation of body growth was potentially related with dysregulation of transcripts predominantly associated with the insulin-associated Irs-Akt-FoxO cascade. Moreover, knockdown and gain-of-function experiments in vivo on codifferentially expressed genes demonstrated that reduced expression of hspb9 and hspb11 contributed to the occurrence of wavy notochord. The results of this study strongly support the hypothesis that the notochord kinks and twists are triggered by the down-regulation of hspb9 and hspb11, and intensified by body growth retardation along with normal notochord length in PCDPS-exposed zebrafish embryos.

Toxicogenomic Assessment of 6-OH-BDE47-Induced Developmental Toxicity in Chicken Embryos.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are analogs of PBDEs with hundreds of possible structures and are frequently detected in the environment. However, the in vivo evidence on the toxicity of OH-PBDEs is still very limited. Here, the developmental toxicity of 6-OH-BDE47, a predominant congener of OH-PBDEs detected in the environment, in chicken embryos was assessed using a toxicogenomic approach. Fertilized chicken eggs were dosed via in ovo administration of 0.006 to 0.474 nmol 6-OH-BDE47/g egg followed by 18 days of incubation. Significant embryo lethality (LD50 = 1.940 nmol/g egg) and increased hepatic somatic index (HSI) were caused by 6-OH-BDE47 exposure. The functional enrichment of differentially expressed genes (DEGs) was associated with oxidative phosphorylation, generation of precursor metabolites and energy, and electron transport chains, which suggest that 6-OH-BDE47 exposure may disrupt the embryo development by altering the function of energy production in mitochondria. Moreover, aryl hydrocarbon receptor (AhR)-mediated responses including up-regulation of CYP1A4 were observed in the livers of embryos exposed to 6-OH-BDE47. Overall, this study confirmed the embryo lethality by 6-OH-BDE47 and further improved the mechanistic understanding of OH-PBDEs-caused toxicity. Ecological risk assessment via application of both no-observed-effect level (NOEL) and the sensitive NOTEL (transcriptional NOEL) suggested that OH-PBDEs might cause ecological risk to wild birds.

In vitro dioxin-like potencies of HO- and MeO-PBDEs and inter-species sensitivity variation in birds.

Due to their bioaccumulative properties, hydroxylated and methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) may pose ecological risks to wild life, including birds. However, their toxicity potencies in avian species are largely unknown. In the present study, an avian AHR1 luciferase reporter gene (LRG) assay with luciferase probes from chicken, pheasant and quail was used to test activations of avian aryl hydrocarbon receptor (AHR)-mediated pathways by 19 HO- or MeO-PBDEs in different avian species. Species-specific relative potencies (RePs) of HO-/MeO-PBDEs to tetrachlorodibenzo-p-dioxin (TCDD) and relative sensitivities of various species to each chemical were estimated. The results indicated that the ReP of the most potent HO-/MeO-PBDEs, 5-Cl-6-HO-BDE-47, was 7.8×10(-4) for chicken, 1.1×10(-2) for pheasant, and 1.7×10(-1) for quail comparing to TCDD. In addition, it was found that avian species with the greatest sensitivity to TCDD did not always have the greatest sensitivity to HO-/MeO-PBDEs and vice versa. This study contributed to filling in the knowledge gap regarding the dioxin-like activity of HO-/MeO-PBDEs in birds, and provided beneficial information for the prioritization of HO-/MeO-PBDEs for further research. CAPSULE ABSTRACT: HO-/MeO-PBDEs activate avian AHR-mediated pathways in a congener- and species- specific manner. 5-Cl-6-HO-BDE-47 was the most potent among the nineteen HO-/MeO-PBDEs tested.

Two parabolic-hyperbolic oriented partial differential equations for denoising in electronic speckle pattern interferometry fringes.

Oriented partial differential equation (OPDE)-based filtering methods have been demonstrated to be a powerful tool for denoising while preserving all fringes. In this paper we propose new OPDE-filtering models, named parabolic-hyperbolic oriented partial differential equations (PH-OPDEs), based on variational methods. We test the proposed PH-OPDEs on two computer-simulated and two experimentally obtained ESPI fringe patterns with poor quality, and compare our models with related OPDE models. The experimental results have demonstrated that the new models have significantly better performance in numerical stability and computational efficiency as compared with the previous OPDE models.

Activation of avian aryl hydrocarbon receptor and inter-species sensitivity variations by polychlorinated diphenylsulfides.

It was hypothesized that polychlorinated diphenyl sulfides (PCDPSs) can potentially interact with an aryl hydrocarbon receptor (AHR) and thereby cause adverse effects in wildlife like birds. A recently developed avian AHR1-luciferase report gene (LRG) assay was used to assess the interaction between avian AHR1 and 18 PCDPSs and to compare the interspecies sensitivity among chicken, ring-necked pheasant, and Japanese quail by PCDPSs. Most of the tested PCDPSs could activate the AHR1-mediated pathways in avian species, and the relative potency (ReP) of the PCDPSs increased with the increasing number of substituted Cl atoms. The rank orders of PCDPSs potency were generally similar among birds, although the ReP varied. In addition, not all the sensitivity rank orders of avian AHR1 constructs for PCDPSs were consistent with that of TCDD. ReP values of PCDPSs suggested that some PCDPSs like 2,3,3',4,5,6-hexa-CDPS and 2,2',3,3',4,5,6-hepta-CDPS are higher than the avian WHO-TEFs of OctaCDD, OctaCDF, and most of the coplanar PCBs. Our results report for the first time the activation of an AHR1-mediated molecular toxicological mechanism by PCDPSs, and provide the ranking of ReP and relative sensitivity values of different congeners, which could guide the further toxicity test of this group of potential high priority environmental pollutants.

Research on energy-saving control of agricultural hybrid tractors integrating working condition prediction.

To address the issues of tractors using too much fuel and not being energy efficient, a predictive control strategy based on Pontryagin's minimum principle integrating working condition prediction is proposed for agricultural hybrid tractors. The Dongfanghong 1804 tractor is being used for research. Firstly, the main parameters of the hybrid drive system are determined and modeled. Secondly, based on the adaptive cubic exponential forecasting method, the working condition information for a period of time in the future is predicted through historical working condition information. Furthermore, combining the predicted working conditions information, the goal is to minimize the total energy consumption cost of the entire machine. Motor power and diesel engine power are control variables. The battery state of charge is a state variable. Subsequently, a predictive control strategy based on Pontryagin's minimum principle integrating working condition prediction is proposed. Finally, the simulation test is carried out based on the MATLAB simulation platform. Research indicates: under plowing conditions, compared with the power following control strategy, the proposed predictive control strategy can effectively manage the performance of the diesel engine and motor, ensuring they operate at their most efficient level. The total energy consumption costs of the power following control and predictive control strategies are 37.17 China Yuan (CNY) and 33.67 CNY, respectively. The cost of energy used is decreased by 9. 42%, which helps make tractor field plowing more efficient and economical.

Framework Nucleic Acids: A Promising Vehicle for Small Molecular Cargos.

Framework nucleic acids (FNAs), which are a series of self-assembled DNA nanostructures, are highly versatile tools for engineering intelligent molecular delivery vehicles. Owing to their precise and controllable design and construction, excellent programmability and functionality, as well as favorable intercalation between DNA and small molecules, FNAs provide a promising approach for small molecule delivery. This review discusses the advantages, applications, and current challenges of FNAs for the delivery of small molecular cargo. First, the physicochemical and biological properties that make FNAs favorable for the transport of small molecules are introduced. Thereafter, the classification of loaded cargos and the mechanism of combination between small molecules and FNAs are summarized in detail, and recent research on FNA-based delivery systems and their applications are highlighted. Finally, the challenges and prospects of FNA nanocarriers are discussed to advance their exploitation and clinical adoption.

Design of tractor virtual test system based on high-level architecture technology.

The limitations of the tractor virtual test system are evident in various aspects, including model reuse, system expansion, offsite interconnection, and virtual reality verification. To address these challenges, a distributed virtual test system for tractors based on the high-level architecture (HLA) is proposed. Involve analyzing the hardware structure and the tractor virtual test system, constructing the system federation and its members, and designing the federated object model (FOM) and simulation object model (SOM) tables. The system integrates multi-domain commercial software and enables real-time virtual testing through TCP/IP interconnection of multiple machines. To evaluate the system's performance, a virtual test of the tractor's reversing clutch engagement performance is conducted. The system's simulation performance and data transmission delay are thoroughly tested and analyzed. The results indicate that when the system's data volume reaches 5000KB, the data delay is 9.7ms, which satisfies the requirement of not exceeding 10ms for tractor virtual testing delay. The virtual test of the reversing clutch power reversal process demonstrates that it lasts 0.7s, with the vehicle speed changing from -3.5km/h to 3.5km/h, the forward gear piston oil pressure increasing from 0MPa to 5MPa, and the peak impact degree reaching 17m/s3. The slip work during the reversing process is measured to be 21kJ. Furthermore, the gray correlation method is employed to compare the virtual test results with the bench test results, confirming their consistency. The power reversal process exhibits relatively smooth speed changes overall. Therefore, the tractor power shift transmission (PST) reversing clutch virtual test model operates effectively within the HLA-based tractor virtual test system.

Design and optimization of dual-motor electric tractor drive system based on driving cycles.

Aiming at the unreasonable determination of the power coupling device speed ratio and the power battery capacity in the initial design stage of the dual-motor electric tractor, a dual-motor drive system is designed, and a parameter optimization method based on driving cycles (POMBDC) is proposed. By analyzing the driving characteristics requirements and actual working conditions of the tractor, the dynamic model of the dual-motor drive system under different working modes is established, and the parameters of the dual-motor, transmission and maximum service mass are designed. On this basis, based on the driving cycles and aiming at the lowest power consumption, the POMBDC is formed, this method can collaboratively optimize the power coupling device speed ratio and the power battery capacity. In order to verify the rationality of the POMBDC, the instantaneous optimization-constant speed ratio design method (IO-CSRDM), rule-optimization speed ratio design method (R-OSRDM) and rule-constant speed ratio design method (R-CSRDM) are developed as comparison methods, and simulation experiments are carried out. Under plowing conditions, the power battery capacity of the POMBDC is 3.08%, 5.71%, and 8.73% lower than those of the IO-CSRDM, R-OSRDM, and R-CSRDM, respectively. The power consumption resulting from the POMBDC is reduced by 3.11%, 5.74%, and 8.8%, compared with those of the IO-CSRDM, R-OSRDM and R-CSRDM, respectively. Under rotary tillage conditions, the power battery capacity of the POMBDC is 6%, 8.64%, and 11.11% lower than those of the IO-CSRDM, R-OSRDM, and R-CSRDM, respectively. The power consumption resulting from the POMBDC is reduced by 6.05%, 8.66%, and 11.13%, compared with those of the IO-CSRDM, R-OSRDM and R-CSRDM, respectively. The POMBDC can effectively increase the operating mileage of pure electric tractors and reduce costs.

Tetrahedral Framework Nucleic Acids Ameliorate Insulin Resistance in Type 2 Diabetes Mellitus via the PI3K/Akt Pathway.

Insulin resistance (IR) is one of the essential conditions in the development of type 2 diabetes mellitus (T2DM). IR occurs in hepatic cells when the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway is downregulated; thus, activating this pathway can significantly improve insulin sensitivity and ameliorate T2DM. Tetrahedral framework nucleic acids (tFNAs), a DNA nanomaterial, are synthesized from four single-stranded DNA molecules. tFNAs possess excellent biocompatibility and good water solubility and stability. tFNAs can promote cell proliferation, cell autophagy, wound healing, and nerve regeneration by activating the PI3K/Akt pathway. Herein, we explore the effects and underlying mechanisms of tFNAs on IR. The results displayed that tFNAs could increase glucose uptake and ameliorate IR by activating the IRS-1/PI3K/Akt pathway in glucosamine (GlcN)-stimulated HepG2 cells. By employing a PI3K inhibitor, we confirmed that tFNAs reduce IR through the PI3K/Akt pathway. Moreover, tFNAs can promote hepatic cell proliferation and inhibit GlcN-induced cell apoptosis. In a T2DM mouse model, tFNAs reduce blood glucose levels and ameliorate hepatic IR via the PI3K/Akt pathway. Taken together, tFNAs can improve hepatic IR and alleviate T2DM through the PI3K/Akt pathway, making contribution to the potential application of tFNAs in T2DM.

The Role and Activation Mechanism of TAZ in Hierarchical Microgroove/Nanopore Topography-Mediated Regulation of Stem Cell Differentiation.

PURPOSE: To investigate the role and activation mechanism of TAZ in periodontal ligament stem cells (PDLSCs) perceiving hierarchical microgroove/nanopore topography. MATERIALS AND METHODS: Titanium surface with hierarchical microgroove/nanopore topography fabricated by selective laser melting combined with alkali heat treatment (SLM-AHT) was used as experimental group, smooth titanium surface (Ti) and sandblasted, large-grit, acid-etched (SLA) titanium surface were employed as control groups. Alkaline phosphatase (ALP) activity assays, qRT-PCR, Western blotting, and immunofluorescence were carried out to evaluate the effect of SLM-AHT surface on PDLSC differentiation. Moreover, TAZ activation was investigated from the perspective of nuclear localization to transcriptional activity. TAZ knockdown PDLSCs were seeded on three titanium surfaces to detect osteogenesis- and adipogenesis-related gene expression levels. Immunofluorescence and Western blotting were employed to investigate the effect of the SLM-AHT surface on actin cytoskeletal polymerization and MAPK signaling pathway. Cytochalasin D and MAPK signaling pathway inhibitors were used to determine whether actin cytoskeletal polymerization and the MAPK signaling pathway were indispensable for TAZ activation. RESULTS: Our results showed that SLM-AHT surface had a greater potential to promote PDLSC osteogenic differentiation while inhibiting adipogenic differentiation than the other two groups. The nuclear localization and transcriptional activity of TAZ were strongly enhanced on the SLM-AHT surface. Moreover, after TAZ knockdown, the enhanced osteogenesis and decreased adipogenesis in SLM-AHT group could not be observed. In addition, SLM-AHT surface could promote actin cytoskeletal polymerization and upregulate p-ERK and p-p38 protein levels. After treatment with cytochalasin D and MAPK signaling pathway inhibitors, differences in the TAZ subcellular localization and transcriptional activity were no longer observed among the different titanium surfaces. CONCLUSION: Our results demonstrated that actin cytoskeletal polymerization and MAPK signaling pathway activation triggered by SLM-AHT surface were essential for TAZ activation, which played a dominant role in SLM-AHT surface-induced stem cell fate decision.

Polymeric non-spherical coarse microparticles fabricated by double emulsion-solvent evaporation for simvastatin delivery.

Polymeric particles with non-spherical shape or coarse surface have distinct advantages for drug delivery, tissue regeneration and immunomodulation respectively, but it is not easy to control polymeric microparticles in required geometry and surface texture simultaneously. In this study, polymeric non-spherical microparticles with coarse surface were successfully prepared by double emulsion-solvent evaporation technique in the presence of ammonium bicarbonate and the formation mechanism was proposed. In addition, simvastatin was encapsulated in poly[lactic-co-(glycolic acid)] (PLGA) non-spherical microparticles with coarse surface by the same technique and the release kinetics in vitro was fitted as well, which not only enrich the encapsulation techniques of liposoluble drugs in polymeric non-spherical carriers but also envision the potential application for alveolar ridge preservation with local delivery of simvastatin.

Sulphur doped carbon dots enhance photodynamic therapy via PI3K/Akt signalling pathway.

OBJECTIVES: Photodynamic therapy (PDT) is a promising approach for cancer treatment, and the underlying signalling pathway changes has been carried out for studying the PDT mechanisms, but is majorly limited to organic photosensitizers (PSs). For the emerging nano-PSs typically possessing higher 1 O2 quantum yield, few mechanistic studies were carried out, which limited their further applications in clinical therapeutics. PI3K/Akt signalling pathway, a most frequently activated signalling network in cancers, could promote cancer cell survival, but was seldom reported in previous PDT studies mediated by nano-PSs. MATERIALS AND METHODS: Sulphur doped carbon dots (S-CDs) was prepared via a hydrothermal synthetic route and was characterized by transmission electron microscopy, X-ray photoelectron spectroscopy and so on. CCK-8 assay and Annexin V/PI staining were performed to demonstrate the death of cancer cells, Western blot, RT-PCR and immunofluorescence were employed to explore the underlying mechanism, and variation of PI3K/Akt and other signalling pathways was detected by Western blot. RESULTS: S-CDs was successfully synthesized, and it was much more efficient compared with classic organic PSs. S-CDs could induce cancer cell death through mitochondria mediated cell apoptosis with the imbalance of Bcl-2 family proteins and caspase cascade via several signalling pathways. Low concentration of S-CDs could effectively inhibit PI3K/Akt pathway and promote p38/JNK pathway, on one way inhibiting cancer cell survival and on the other way promoting cell apoptosis. CONCLUSIONS: Herein, we found that S-CDs acted as an inhibitor of the PI3K/Akt pathway for efficient cancer cell killing, thus yielding in a higher PDT performance over the existing photosensitizers.

High-throughput transcriptomics: An insight on the pathways affected in HepG2 cells exposed to nickel oxide nanoparticles.

Nickel oxide nanoparticles (NiO-NPs) have been used in several consumer goods, reported to demonstrate the hepatotoxic effects in vitro and in vivo test models. Nonetheless the molecular mechanism of hepatotoxicity is still missing. Hence, a toxicogenomic approach integrating microscopic techniques and high-throughput RNA sequencing (RNA-Seq) was applied to reveal hepatotoxicity in human hepatocellular carcinoma cells (HepG2). NiO-NPs induced a concentration dependent (5-100 µg/ml) cytotoxicity, with a No observed effect level (NOEL) of 5 µg/ml. Hypoxia-inducible transcription factor-1α (HIF-1α) and miR-210 microRNA were upregulated at 25 and 100 µg/ml, while significant alteration on transcriptome at mRNA and pathway level was observed at non-toxic level of NiO-NPs treatment. The treated cells also showed activation of glycolysis, glutathione, lysosomes and autophagy pathways by a pathway-driven analysis. Flow cytometric analysis affirmed the elevation in nitric oxide (NO), Ca++ influx, esterase, and disruption of mitochondrial membrane potential (ΔΨm). Cell cycle dysregulation was affirmed by the appearance of 30.5% subG1 apoptotic peak in NiO-NPs (100 µg/ml) treated cells. The molecular responses were consistent with the microscopic observation that NiO-NPs induced subcellular alterations in HepG2 cells. We conclude that hypoxia stress played a pivotal role in NiO-NPs induced hepatoxicity in HepG2 cells. Concentration dependent effects on transcriptomics specify a powerful tool to evaluate the molecular mechanisms of nanoparticle induced cytotoxicity. Overall our study unequivocally affirmed the transcriptomic alterations in human cells, consequently the prevalent usage of NiO-NPs should be given subtle consideration owing to its effects on biological processes.

KDM6A promotes chondrogenic differentiation of periodontal ligament stem cells by demethylation of SOX9.

OBJECTIVES: KDM6A has been demonstrated critical in the regulation of cell fates. However, whether KDM6A is involved in cartilage formation remains unclear. In this study, we investigated the role of KDM6A in chondrogenic differentiation of PDLSCs, as well as the underlying epigenetic mechanisms. METHODS: KDM6A shRNA was transfected into PDLSCs by lentivirus. The chondrogenic differentiation potential of PDLSCs was assessed by Alcian blue staining. Immunofluorescence was performed to demonstrate H3K27me3 and H3K4me3 levels during chondrogenesis. SOX9, Col2a1, ACAN and miRNAs (miR-29a, miR-204, miR-211) were detected by real-time RT-PCR. Western blot was performed to evaluate SOX9, H3K27me3 and H3K4me3. RESULTS: The production of proteoglycans in PDLSCs was decreased after knockdown of KDM6A. Depletion of KDM6A inhibited the expression of SOX9, Col2a1, ACAN and resulted in increased H3K27me3 and decreased H3K4me3 levels. EZH2 inhibitor rescued the chondrogenic potential of PDLSCs after knockdown of KDM6A by regulating H3K27me3. Additionally, miR-29a, miR-204 and miR-211 were also involved in the process of PDLSCs chondrogenesis. CONCLUSIONS: KDM6A is required in chondrogenic differentiation of PDLSCs by demethylation of H3K27me3, and EZH2 inhibitor could rescue chondrogenesis of PDLSCs after knockdown of KDM6A. It could be inferred that upregulation of KDM6A or application of EZH2 inhibitor might improve mesenchymal stem cell mediated cartilage regeneration in inflammatory tissue destruction such as osteoarthritis.

Silk fibroin-coated PLGA dimpled microspheres for retarded release of simvastatin.

The surface physical features and chemical components of polymeric particles play an important role in drug delivery systems. In this study, PLGA blank microspheres and simvastatin-loaded PLGA microspheres with dimpled surface structure were prepared by single emulsion-solvent evaporation method in the absence of any additives. Subsequently, glutaraldehyde cross-linking was optimized for silk fibroin coating on simvastatin-loaded PLGA dimpled microspheres due to good solubility of simvastatin in alcohol. Furthermore, simvastatin release kinetics was investigated for silk-coated or plain PLGA dimpled microspheres. These drug carriers may have potential applications for alveolar ridge preservation with local delivery of simvastatin.

A high-throughput, computational system to predict if environmental contaminants can bind to human nuclear receptors.

Some pollutants can bind to nuclear receptors (NRs) and modulate their activities. Predicting interactions of NRs with chemicals is required by various jurisdictions because these molecular initiating events can result in adverse, apical outcomes, such as survival, growth or reproduction. The goal of this study was to develop a high-throughput, computational method to predict potential agonists of NRs, especially for contaminants in the environment or to which people or wildlife are expected to be exposed, including both persistent and pseudo-persistent chemicals. A 3D-structure database containing 39 human NRs was developed. The database was then combined with AutoDock Vina to develop a System for Predicting Potential Effective Nuclear Receptors (SPEN), based on inverse docking of chemicals. The SPEN was further validated and evaluated by experimental results for a subset of 10 chemicals. Finally, to assess the robustness of SPEN, its ability to predict potentials of 40 chemicals to bind to some of the most studied receptors was evaluated. SPEN is rapid, cost effective and powerful for predicting binding of chemicals to NRs. SPEN was determined to be useful for screening chemicals so that pollutants in the environment can be prioritized for regulators or when considering alternative compounds to replace known or suspected contaminants with poor environmental profiles.

Activation of AhR-mediated toxicity pathway by emerging pollutants polychlorinated diphenyl sulfides.

Polychlorinated diphenyl sulfides (PCDPSs) are a group of environmental pollutants for which limited toxicological information is available. This study tested the hypothesis that PCDPSs could activate the mammalian aryl hydrocarbon receptor (AhR) mediated toxicity pathways. Eighteen PCDPSs were tested in the H4IIE-luc transactivation assay, with 13/18 causing concentration-dependent AhR activation. Potencies of several congeners were similar to those of mono-ortho substituted polychlorinated biphenyls. A RNA sequencing (RNA-seq)-based transcriptomic analysis was performed on H4IIE cells treated with two PCDPS congeners, 2,2',3,3',4,5,6-hepta-CDPS, and 2,4,4',5-tetra-CDPS. Results of RNA-seq revealed a remarkable modulation on a relatively short gene list by exposure to the tested concentrations of PCDPSs, among which, Cyp1 responded with the greatest fold up-regulation. Both the identities of the modulated transcripts and the associated pathways were consistent with targets and pathways known to be modulated by other types of AhR agonists and there was little evidence for significant off-target effects within the cellular context of the H4IIE bioassay. The results suggest AhR activation as a toxicologically relevant mode of action for PCDPSs suggests the utility of AhR-related toxicity pathways for predicting potential hazards associated with PCDPS exposure in mammals and potentially other vertebrates.