Mutual regulation between GDF11 and TET2 prevents senescence of mesenchymal stem cells.

Growth differentiation factor 11 (GDF11) is a putative systemic rejuvenation factor. In this study, we characterized the mechanism by which GDF11 reversed aging of mesenchymal stem cells (MSCs). In culture, aged MSCs proliferate slower and are positive for senescence markers senescence-associated ß-galactosidase and P16ink4a . They have shortened telomeres, decreased GDF11 expression, and reduced osteogenic potential. GDF11 can block MSC aging in vitro and reverse age-dependent bone loss in vivo. The antiaging effect of GDF11 is via activation of the Smad2/3-PI3K-AKT-mTOR pathway. Unexpectedly, GDF11 also upregulated a DNA demethylase Tet2, which served as a key mediator for GDF11 to autoregulate itself via demethylation of the GDF11 promoter. Mutation of Tet2 facilitates MSC aging by blocking GDF11 expression. Mutagenesis of Tet2-regulated CpG sites also blocks GDF11 expression, leading to MSC aging. Together, a novel mutual regulatory relationship between GDF11 and an epigenetic factor Tet2 unveiled their antiaging roles.

Development of a novel patient-reported outcome measure for orthognathic surgery.

OBJECTIVES: This study aimed to develop a new patient-reported outcome measure (PROM) to systematically and scientifically evaluate patients' subjective feelings after orthognathic surgery. METHODS: A literature review and semi-structured interviews were conducted to construct a conceptual framework and an item pool, followed by expert and patient surveys for measure construction. We conducted a clinical investigation to test the feasibility, reliability, and content validity of this measure. RESULTS: The conceptual framework included four domains: psychological health, physiological health, social function, and satisfaction, and 33 items were included in the survey. Following the expert analysis, 31 items remained in the draft. The clinical investigation showed a 100% recovery and completion rate and good reliability, with Cronman-Brown formula coefficients of 0.893 and 0.944, respectively. CONCLUSIONS: A new outcome measure to evaluate patients' subjective feelings after orthognathic surgery was successfully developed, and the clinical investigation demonstrated that the PROM had satisfactory feasibility, reliability, and validity. Further studies are possible based on our PROM, and data on a larger scale may reveal more information on patients' subjective feelings about orthognathic surgery. CLINICAL SIGNIFICANCE: The novel PROM provides a systematic and scientific way to evaluate the patient's subjective feelings to help surgeons obtain complete patient-reported information after orthognathic surgery. Additionally, standardised multicentre research on patients' subjective feelings using our PROM is possible and could improve the effectiveness of the evaluation and help maintain treatment quality.

Primary cilia support cartilage regeneration after injury.

In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.

The role of IFT140 in early bone healing of tooth extraction sockets.

OBJECTIVES: Primary cilium is a key organelle of regulating bone development and maintenance. The aim of this study is to investigate whether ciliary intraflagellar transporter protein 140 (IFT140) plays a positive role in extraction socket healing by promoting bone formation. MATERIALS AND METHODS: A left maxillary first molar extraction model was established using 6-week-old Ift140flox/flox (Ctrl group) and Ift140flox/flox , Osx-cre (cKO group) mice. The maxillary bone samples from 1, 2, and 3 weeks were postoperatively evaluated by micro-CT, molecular biology, and histomorphometry analysis. Alveolar bone marrow stromal cells (aBMSCs) from 4-week-old mice were cultured in vitro and tested for proliferation and osteogenic ability. RESULTS: Ciliated cells were predominantly observed in the early socket healing stage with highly expressed ciliary protein IFT140. Compared with the Ctrl group, the healing of extraction sockets in the cKO group was significantly delayed. The proliferation and osteogenic differentiation ability of aBMSCs were reduced in the cKO group. CONCLUSION: IFT140 has a facilitating role in the early osteogenesis of extraction socket healing and is involved in regulating the proliferation and osteogenic differentiation of aBMSCs.

Spatiotemporal analysis of land use pattern and stream water quality in southern Alberta, Canada.

Alberta has over 70% of total irrigated land in Canada and 13 irrigation districts are mainly located along the rivers in southern Alberta. The runoff and irrigation return flow can carry excess nutrients, pesticides, and sediments, which adversely affect the river water quality. In the present study, the comprehensive spatiotemporal analysis of land use pattern and stream water quality in southern Alberta was conducted. The water quality monitoring on the South Saskatchewan River watershed within Alberta showed that most water quality indicators did not significantly change between 2003 and 2017. Land use maps demonstrated significant urban expansion and cropland decline in the study area from 2005 to 2015, while the irrigation area increased. Correlation analysis and redundancy analysis revealed that cropland, built-up land, and native grassland were three land use types that were positively correlated with water quality indicators. Stronger correlations between nitrogen concentration and built-up land were found in dry seasons compared with wet seasons. According to the results of cluster analysis, higher water quality indicator concentrations could be observed in groups with a higher proportion of cropland and built-up land. Significant relationships between land use patterns and water quality were found in this study, which demonstrated that further investigation is needed to identify the sources of water pollutants at a smaller scale.

LncRNA Nron regulates osteoclastogenesis during orthodontic bone resorption.

Activation of osteoclasts during orthodontic tooth treatment is a prerequisite for alveolar bone resorption and tooth movement. However, the key regulatory molecules involved in osteoclastogenesis during this process remain unclear. Long noncoding RNAs (lncRNAs) are a newly identified class of functional RNAs that regulate cellular processes, such as gene expression and translation regulation. Recently, lncRNAs have been reported to be involved in osteogenesis and bone formation. However, as the most abundant noncoding RNAs in vivo, the potential regulatory role of lncRNAs in osteoclast formation and bone resorption urgently needs to be clarified. We recently found that the lncRNA Nron (long noncoding RNA repressor of the nuclear factor of activated T cells) is highly expressed in osteoclast precursors. Nron is downregulated during osteoclastogenesis and bone ageing. To further determine whether Nron regulates osteoclast activity during orthodontic treatment, osteoclastic Nron transgenic (Nron cTG) and osteoclastic knockout (Nron CKO) mouse models were generated. When Nron was overexpressed, the orthodontic tooth movement rate was reduced. In addition, the number of osteoclasts decreased, and the activity of osteoclasts was inhibited. Mechanistically, Nron controlled the maturation of osteoclasts by regulating NFATc1 nuclear translocation. In contrast, by deleting Nron specifically in osteoclasts, tooth movement speed increased in Nron CKO mice. These results indicate that lncRNAs could be potential targets to regulate osteoclastogenesis and orthodontic tooth movement speed in the clinic in the future.

High-glucose-induced miR-214-3p inhibits BMSCs osteogenic differentiation in type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is an autoimmune insulin-dependent disease associated with destructive bone homeostasis. Accumulating evidence has proven that miRNAs are widely involved in the regulation of bone homeostasis. However, whether miRNAs also regulate osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in T1DM mice is under exploration. In this study, miRNA microarray was utilized to screen the differentially expressed miRNAs, which uncovered that miR-214-3p potentially inhibited BMSCs osteogenic differentiation in T1DM mice. We found that high glucose suppressed BMSCs osteogenic differentiation with significant elevation of the miR-214-3p expression. Further study found that the osteogenic differentiation of BMSCs was inhibited by AgomiR-214-3p while enhanced by AntagomiR-214-3p in BMSCs supplemented with high glucose. Moreover, we found that miR-214-3p knockout T1DM mice were resistant to high-glucose-induced bone loss. These results provide a novel insight into an inhibitory role of high-glucose-induced miR-214-3p in BMSCs osteogenic differentiation both in vitro and in vivo. Molecular studies revealed that miR-214-3p inhibits BMSCs osteogenic differentiation by targeting the 3'-UTR of ß-catenin, which was further corroborated in human bone specimens and BMSCs of T1DM patients. Taken together, our study discovered that miR-214-3p is a pivotal regulator of BMSCs osteogenic differentiation in T1DM mice. Our findings also suggest that miR-214-3p could be a potential target in the treatment of bone disorders in patients with T1DM.

The Role of IFT140 in Osteogenesis of Adult Mice Long Bone.

Primary cilia have a pivotal role in bone development and the dysfunctions of primary cilia cause skeletal ciliopathies. Intraflagellar transport (IFT) proteins are conserved mediators of cilium signaling. IFT sub-complex A is known to regulate retrograde IFT in the cilium. As a core protein of IFT complex A, IFT140 has been shown to have a relationship with serious skeletal ciliopathies caused in humans. However, the effects and mechanisms of IFT140 in bone formation have not been systematically disclosed. To further investigate the potential role of IFT140 in osteogenesis, we established a mouse model by conditional deletion of IFT140 in pre-osteoblasts. The adult knock-out mice exhibited dwarf phenotypes, such as short bone length, less bone mass, and decreased bone mineral apposition rate. In addition, by IFT140 deletion, the expressions of several osteoblastic markers were decreased and loss of bone became severe with aging. These results suggest that cilia gene Ift140 is essential in bone development.

Extracellular matrix protein DMP1 suppresses osteogenic differentiation of Mesenchymal Stem Cells.

Mesenchymal Stem Cells (MSCs) are self-renewing and multipotent stem cells which was investigated for diverse clinical applications. However, complex mechanism of MSCs fate determination is still not fully disclosed. Extracellular matrix (ECM) proteins contribute to maintain MSCs stemness by providing extracellular microenvironment. Increasing evidences show that ECM proteins could also regulate the fate of MSCs directly. Dentin matrix protein 1 (DMP1) is an ECM protein enrich in bone tissue and terminal cells, which well-known in promoting osteoblasts and osteocytes maturation, and facilitate mineralization. Recently, our experiment indicated that DMP1 was also expressed in MSCs of long bone. In present study, it is found that DMP1 expressed in Prx1 positive MSCs. And, DMP1 is down-regulated in early osteoblasts and up-regulated again in mature osteoblasts. DMP1 conditional knockout mice model under Prx1cre was generated to explore whether DMP1 regulates MSCs osteogenic differentiation. Specific ablation of DMP1 in Prx1 positive MSCs increased bone mass in vivo and promoted osteoblasts activity in vitro. This study provides a new understanding of DMP1's function in regulation of osteogenesis: not only an enhancer of bone formation, but also a negative regulator of MSCs differentiation in bone.

Waste management under multiple complexities: inexact piecewise-linearization-based fuzzy flexible programming.

To tackle nonlinear economies-of-scale (EOS) effects in interval-parameter constraints for a representative waste management problem, an inexact piecewise-linearization-based fuzzy flexible programming (IPFP) model is developed. In IPFP, interval parameters for waste amounts and transportation/operation costs can be quantified; aspiration levels for net system costs, as well as tolerance intervals for both capacities of waste treatment facilities and waste generation rates can be reflected; and the nonlinear EOS effects transformed from objective function to constraints can be approximated. An interactive algorithm is proposed for solving the IPFP model, which in nature is an interval-parameter mixed-integer quadratically constrained programming model. To demonstrate the IPFP's advantages, two alternative models are developed to compare their performances. One is a conventional linear-regression-based inexact fuzzy programming model (IPFP2) and the other is an IPFP model with all right-hand-sides of fussy constraints being the corresponding interval numbers (IPFP3). The comparison results between IPFP and IPFP2 indicate that the optimized waste amounts would have the similar patterns in both models. However, when dealing with EOS effects in constraints, the IPFP2 may underestimate the net system costs while the IPFP can estimate the costs more accurately. The comparison results between IPFP and IPFP3 indicate that their solutions would be significantly different. The decreased system uncertainties in IPFP's solutions demonstrate its effectiveness for providing more satisfactory interval solutions than IPFP3. Following its first application to waste management, the IPFP can be potentially applied to other environmental problems under multiple complexities.

An integrated multi-level watershed-reservoir modeling system for examining hydrological and biogeochemical processes in small prairie watersheds.

Eutrophication of small prairie reservoirs presents a major challenge in water quality management and has led to a need for predictive water quality modeling. Studies are lacking in effectively integrating watershed models and reservoir models to explore nutrient dynamics and eutrophication pattern. A water quality model specific to small prairie water bodies is also desired in order to highlight key biogeochemical processes with an acceptable degree of parameterization. This study presents a Multi-level Watershed-Reservoir Modeling System (MWRMS) to simulate hydrological and biogeochemical processes in small prairie watersheds. It integrated a watershed model, a hydrodynamic model and an eutrophication model into a flexible modeling framework. It can comprehensively describe hydrological and biogeochemical processes across different spatial scales and effectively deal with the special drainage structure of small prairie watersheds. As a key component of MWRMS, a three-dimensional Willows Reservoir Eutrophication Model (WREM) is developed to addresses essential biogeochemical processes in prairie reservoirs and to generate 3D distributions of various water quality constituents; with a modest degree of parameterization, WREM is able to meet the limit of data availability that often confronts the modeling practices in small watersheds. MWRMS was applied to the Assiniboia Watershed in southern Saskatchewan, Canada. Extensive efforts of field work and lab analysis were undertaken to support model calibration and validation. MWRMS demonstrated its ability to reproduce the observed watershed water yield, reservoir water levels and temperatures, and concentrations of several water constituents. Results showed that the aquatic systems in the Assiniboia Watershed were nitrogen-limited and sediment flux played a crucial role in reservoir nutrient budget and dynamics. MWRMS can provide a broad context of decision support for water resources management and water quality protection in the prairie region.

Effect of short-chain organic acids and pH on the behaviors of pyrene in soil-water system.

The effects of five short-chain organic acids (SCOAs) on the behaviors of pyrene in soil-water system were investigated. The influences of the quantity and species of organic acids, pH, and soil dissolved organic matter were considered. The results showed the presence of SCOAs inhibited the adsorption and promoted the desorption of pyrene in the following order: citric acid>oxalic acid>tartaric acid>lactic acid>acetic acid. The decreased extents of pyrene adsorption performance enhanced with increasing SCOA concentrations, while the decreasing rate became less pronounced at high SCOA concentrations. In the presence of organic acids, the adsorption ability of pyrene decreased with increasing pH. However, there was a slight increase of pyrene adsorption with the addition of oxalic acid, tartaric acid and citric acid above pH 8. The capacity for pyrene retention differentiated significantly between the soils with and without dissolved organic matter. The presence of SCOAs was also favorable for the decrease of pyrene adsorption on soil without dissolved organic matter. The results of this study have important implications for the remediation of persistent organic pollutants in soil and groundwater.

Effects of fulvic acid concentration and origin on photodegradation of polycyclic aromatic hydrocarbons in aqueous solution: importance of active oxygen.

With an Xe arc lamp house as simulated sunlight, the influences of fulvic acid (FA) concentration and origins on photodegradation of acenaphthene, fluorine, phenanthrene, fluoranthene and pyrene in aqueous solution have been studied. Similar effects of FAs, collected from five places around China, on polycyclic aromatic hydrocarbon (PAH) photodegradation have been observed. Active oxygen was of significance in PAH photodegradation with the presence of FAs. For systems with 1.25 mg L(-1) FAs, the contributions of 8*OH to PAH photodegradation rates were from 33% to 69%. FAs had two opposite effects, i.e., stimulating the generation of active oxygen and advancing PAH photodegradation; competing with PAHs for energy and photons and restraining PAH photodegradation. Generally, photodegradation rates of the 5 PAHs decreased with the increase of FAs concentration; except fluoranthene and pyrene were advanced in solutions with low FA concentration. The influences of FA concentration on PAH photodegradation were more significant than FA origin.

[Pollution of polycyclic aromatic hydrocarbons (PAHS) in middle and lower reaches of the Yellow River].

Samples of water, suspended particulate matter (SPM) and sediment in the Yellow River was analyzed. The total concentration of PAHs in the main river varies from 179 ng/L to 369 ng/L (sigma 15PAHs) in water, from 54 microg/kg to 155 microg/kg (sigma 13PAHs) in SPM dry weight, and from 31 microg/kg to 133 microg/kg (sigma 13PAHs) dry weight in sediment. The levels of PAHs in water of tributaries are higher than those in the corresponding sites in the main river, and concentrations of benzo(a)pyrene in most of the stations sampled are above drinking water standard. In SPM, PAHs of 3 to 6 benzene rings are mainly correlated to the content of total organic carbon (TOC) in different sites of the main river, while only 4 to 6 rings PAHs in sediment of main river are correlated to TOC for the influence of Mengzhou Canal, whose concentration of 3-ring PAHs are quite high. The distribution of PAHs in all media sampled in the main river indicates that PAHs are mainly transported from water into SPM between Mengzhou and Jiaogong Bridge, while in the reach between Jiaogong bridge and Huayuankou a great reduce of PAHs in SPM is mainly due to the diluting effect in the interchanging process between sediment and SPM. Source analysis also reveals that PAHs are mainly originating from coal burning, although in some tributaries PAH inputs could come from combustion of petroleum.

Distribution and sources of polycyclic aromatic hydrocarbons in the middle and lower reaches of the Yellow River, China.

In this study, concentrations, distribution between different phases, transition along the Middle and Lower reaches of the Yellow River and possible sources of PAHs were assessed. Results demonstrated that the relative proportions of 15 PAHs in all stations of the main River were similar, with concentrations of benzo[a]pyrene all above drinking water standards in most of the stations sampled. PAHs concentrations in tributaries were higher than those in the corresponding sites in the main River. PAHs concentrations of suspended particles were mainly correlated with contents of total organic carbon. However, PAHs concentrations in sediments were mainly correlated to the volume of particles with size smaller than 0.01 mm. The distribution of PAHs in all media sampled indicated that sediments could act as a sink/source for PAHs in different sections and source analysis revealed that PAHs mainly originated from coal burning, although in some tributaries PAH inputs could come from combustion of petroleum.