A significant requirement for a bone implant is to let bone cells grow better. However, how to increase the cellular activity of the scaffold at a certain elastic modulus remains unclear. Here, we ...developed a method to derive the relationship between design parameters, porosity, and mechanical properties of uniform structures for pore functionally graded scaffolds (PFGS) design. PFGS is a combination of different uniform structures by matching design parameters. Ti6Al4V PFGS and uniform structures with sizes of 10 × 10 × 12 mm were designed and fabricated via selective laser melting (SLM). The mechanical properties and cell proliferation of these structures were investigated. Results indicated that the mathematical model of elastic modulus, yield strength and porosity can accurately predict the mechanical properties of structures. For PFGS, cell proliferation rate from day 4 to day 7 was 140%, while for the uniform structures were only 90%. The results demonstrated that PFGS is more suitable for bone tissue implantation.
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•Mathematical models were developed to calculate elastic modulus, yield strength and porosity of uniform structures.•A novel approach for the design of pore functionally graded scaffolds suitable for bone engineering application is proposed.•The strain-stress curves of pore functionally graded scaffold are as same as that of the uniform structures.•Cell proliferation rate is significantly higher for pore functionally graded scaffold, in comparison to the uniform scaffold.
The living environment of bone cells is a complex curved one. And based on the modeling method of triply periodic minimal surfaces (TPMS) can be used to design a variety of complex surface ...structures, so it has been more and more widely studied and applied. In this paper, the main research object is the Primitive structure of TPMS. As an artificial bone scaffold structure, it must possess good mechanical properties, permeability, and is conducive to cell adhesion and proliferation. In this study, several groups of Ti6Al4V Primitive models are designed and fabricated by selective laser melting (SLM). The mechanical properties of scaffold are evaluated by mechanical compression test. The morphology of the scaffold model is characterized. The permeability of the scaffold was predicted and evaluated by computational fluid dynamics (CFD) analyses. Finally, the evaluation of the effects of Ti6A14V scaffold on cell growth is conducted by cytotoxicity test. The results show that the mechanical properties and permeability of the designed Primitive surface scaffold are pretty good as bone tissue replacement. Among them, the Psy scaffold with pore size and porosity varying along the axisymmetric gradient has significant research and application potential in the field of artificial bone scaffold.
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•The relationship between pore size and porosity of Primitive surface structures is determined.•The three groups of Ti6Al4V Primitive scaffold models all meet the requirements of mechanical properties of bone scaffolds.•CFD analysis showed that the Primitive surface structure was beneficial to the adsorption of bone cells and nutrients.•The structure of Psy with symmetrical gradient variation of aperture proved to have better permeability.
Previous works have shown that coseismic ionospheric disturbances (CIDs) after the tsunamigenic 2011 Tohoku earthquake (Tohoku EQ, Mw9.1) covered a vast area and were observed thousands of kilometers ...away from the epicenter. For the purpose of making a comprehensive comparison between powerful oceanic and inland EQs, we conduct a retrospective investigation of CIDs and geomagnetic responses to the 2008 Wenchuan EQ (Mw7.9) using a combination of techniques, total electron content, HF Doppler, and ground magnetometer. It is the very first study to present CIDs recorded by different techniques at co‐located sites and profiled with regard to changes of both ionospheric plasma and current (geomagnetic field) simultaneously. The integrated observation also shows that (1) in the Wenchuan case, most of the ionospheric and geomagnetic disturbances were observed within 1000 km distance which is far less than the Tohoku case; (2) two groups of CIDs were found with maximum amplitudes in the direction of azimuth 150° and 135°, respectively; and (3) the geomagnetic changes were only registered by three magnetometers located to the east and southeast of the epicenter. All the facts indicate that the main directional lobe of Wenchuan EQ energy propagation is to southeast and perpendicular to the direction of the fault rupture, but this kind of directivity is not that distinct in the Tohoku case. We suggest that the different fault slip (inland or submarine) affecting the way of couplings of lithosphere with atmosphere may contribute to the discrepancies between the two events.
Key Points
Ionospheric and geomagnetic changes caused by a major inland earthquake
Strong directivity of CID distribution related to fault rupture direction
Different features in CIDs of inland case compared with oceanic case
Trimethylamine-N-oxide (TMAO), an important gut microbiota (GM)-derived metabolite, has been shown to be abnormally increased in osteoporosis. However, the role and underlying mechanism of TMAO in ...regulating bone loss during osteoporosis have not been fully investigated. In the current study, we found that 100–400 μM TMAO dose-dependently enhanced TRAP-positive osteoclasts, F-actin ring formation, and resorption area on bovine bone slices and up-regulated osteoclast-related gene expression (Calcr, Traf6, Dcstamp, Acp5, C-Fos, and NFATc1). Western blotting validated that TMAO not only activated NF-κB signaling pathway but also stimulated c-Fos and NFATc1 protein expression in a dose-dependent manner. Furthermore, BAY 11-7082, an NF-κB inhibitor, pretreatment markedly suppressed TRAP-positive osteoclast formation and osteoclast-related genes under TMAO treatment. BAY 11-7082 also inhibited p-p65/p65, c-Fos, and NFATc1 protein expression promoted by TMAO. Moreover, TMAO significantly increased ROS production, which was inhibited by N-acetylcysteine (NAC), an ROS antagonist. In addition, we proved that NAC pretreatment could inhibit TMAO-promoted NF-κB activation. NAC also suppressed TRAP-positive osteoclast formation, osteoclast-related gene expression, and protein expression of c-Fos and NFATc1 under TMAO treatment. In vivo studies showed significantly decreased bone mass and increased TRAP-positive osteoclasts in TMAO-treated C57BL/6 mice. Moreover, western-blotting and immunohistochemical staining showed that TMAO administration markedly stimulated NF-κB p65 expression. Additionally, TMAO administration significantly promoted the gene and protein expression of C-Fos and NFATc1. In conclusion, TMAO could promote osteoclast differentiation and induce bone loss in mice by activating the ROS-dependent NF-κB signaling pathway.
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•The honeycomb structures were prepared by selective laser melting.•A method for further optimizing elastic modulus was proposed (SC structure).•A method for increase the cell ...attachment area inside the scaffold was proposed.•The properties of the four groups of honeycomb structures were fully evaluated.
In this paper, the results of the study on the performance of four groups of different honeycomb structures show that the application of honeycomb structure in the design of biomimetic bone scaffold is feasible and promising. In terms of static properties, the elastic modulus (1.6–3 GPa) of the four scaffolds matched the elastic modulus of human cancellous bone (0.1–4.5 GPa), and the yield strength (88–146 MPa) was much higher than that of the femoral neck (0.56–3.71 MPa). In terms of permeability, except for the excessive permeability of SU scaffold, the permeability of the other three groups of scaffolds (1.5*10−8–4.8*10−8 m2) are all in the range of cancellous bone permeability (0.5*10−8–5.0*10−8 m2). In terms of the distribution of wall shear stress, the wall shear stress of the four groups of scaffolds ranged from 2.8 to 42.8 MPa, which could stimulate cells to deposit mineralized extracellular matrix (0.55–30 MPa) in the 3D scaffold, which was conducive to bone tissue regeneration.
Long-term survival is still low for high-risk patients with soft tissue sarcoma treated with standard management options, including surgery, radiation, and chemotherapy. Immunotherapy is a promising ...new potential treatment paradigm. However, the application of immune checkpoint inhibitors for the treatment of patients with sarcoma did not yield promising results in a clinical trial. Therefore, there is a considerable need to identify factors that may lead to immune checkpoint inhibitor resistance.
In this study, we performed a bioinformatic analysis of The Cancer Genome Atlas (TCGA) to detect key long noncoding RNAs (lncRNAs) that were correlated with immune checkpoint inhibitory molecules in sarcoma. The expression levels of these lncRNAs and their correlation with patient prognosis were explored. The upstream long noncoding RNAs were also examined
450K array data from the TCGA. The potential roles of these lncRNAs were further examined
KEGG and GO analysis using DAVID online software. Finally, the relationship between these lncRNAs and immune cell infiltration in tumors and their effect on immune checkpoint inhibitors were further explored.
We identified lncRNAs correlated with tumor cell immune evasion in sarcoma. The expression of these lncRNAs was upregulated and correlated with worse prognosis in sarcoma and other human cancer types. Moreover, low DNA methylation occupation of these lncRNA loci was detected. Negative correlations between DNA methylation and lncRNA expression were also found in sarcoma and other human cancer types. KEGG and GO analyses indicated that these lncRNAs correlated with immune evasion and negative regulation of the immune response in sarcoma. Finally, high expression of these lncRNAs correlated with more suppressive immune cell infiltration and reduced sensitivity to immune checkpoint inhibitors in sarcoma and other human cancer types.
Our results suggest that long noncoding RNAs confer immune checkpoint inhibitor resistance in human cancer. Further characterization of these lncRNAs may help to elucidate the mechanisms underlying immune checkpoint inhibitor resistance and uncover a novel therapeutic intervention point for immunotherapy.
Prospective studies that have examined the association between dietary magnesium intake and serum magnesium concentrations and the risk of cardiovascular disease (CVD) events have reported ...conflicting findings. We undertook a meta-analysis to evaluate the association between dietary magnesium intake and serum magnesium concentrations and the risk of total CVD events.
We performed systematic searches on MEDLINE, EMBASE, and OVID up to February 1, 2012 without limits. Categorical, linear, and nonlinear, dose-response, heterogeneity, publication bias, subgroup, and meta-regression analysis were performed. The analysis included 532,979 participants from 19 studies (11 studies on dietary magnesium intake, 6 studies on serum magnesium concentrations, and 2 studies on both) with 19,926 CVD events. The pooled relative risks of total CVD events for the highest vs. lowest category of dietary magnesium intake and serum magnesium concentrations were 0.85 (95% confidence interval 0.78 to 0.92) and 0.77 (0.66 to 0.87), respectively. In linear dose-response analysis, only serum magnesium concentrations ranging from 1.44 to 1.8 mEq/L were significantly associated with total CVD events risk (0.91, 0.85 to 0.97) per 0.1 mEq/L (P(nonlinearity)= 0.465). However, significant inverse associations emerged in nonlinear models for dietary magnesium intake (P(nonlinearity)= 0.024). The greatest risk reduction occurred when intake increased from 150 to 400 mg/d. There was no evidence of publication bias.
There is a statistically significant nonlinear inverse association between dietary magnesium intake and total CVD events risk. Serum magnesium concentrations are linearly and inversely associated with the risk of total CVD events.
Osteosarcoma (OS) is a primary malignant bone tumour. However, the genetic basis for the pathogenesis of OS remains elusive. In this study, we uncovered the role of the histone methyltransferase NSD2 ...in regulating tumourigenesis and chemosensitivity in OS. We show that NSD2 knockdown leads to increased apoptosis in OS cells in vitro and in vivo. Additionally, NSD2 knockdown significantly enhances the efficacy of cisplatin against OS cells and accordingly inhibits properties associated with cancer stem cells (CSCs). Furthermore, RNA sequencing (RNAseq) and Gene Ontology (GO) analysis revealed that NSD2 promotes transcription of genes associated with negative regulation of apoptotic signalling pathways and CSC properties. The results of chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) assays indicated that NSD2 knockdown leads to decreased H3K36me2 modification at BCL2 and SOX2 loci, thus inhibiting the transcription of these two genes that are closely correlated with apoptosis, CSC properties and chemosensitivity in OS cells. Pathway analysis demonstrated that the ERK and AKT pathways mediate the regulation of OS progression and chemosensitivity by NSD2. Overall, our study is the first to uncover the function of NSD2 in OS chemosensitivity. NSD2 regulates the expression of the apoptosis regulatory proteins BCL2 and SOX2 through the ERK and AKT pathways. Our results suggest that NSD2 is a new target for combined chemotherapy and is a prognostic factor for OS.
Osteosarcoma (OS) is the primary malignant bone tumor. Despite therapeutic strategies including surgery, chemotherapy, and radiotherapy have been introduced into the war of fighting OS, the 5‐year ...survival rate for patients still remains unchangeable for decades. Besides, the critical bone defects after surgery, drug‐resistance and side effects also attenuate the therapeutic effects and predict poor prognosis. Recently, photothermal therapy (PTT) has attracted extensive attention featuring minimal invasiveness and high spatial‐temporal precision characteristics. Herein, an ultrathin 2D inorganic ancient pigment Egyptian blue decorated 3D‐printing scaffold (CaPCu) with profound PTT efficacy at the second near‐infrared (NIR‐II) biowindow against OS and enhanced osteogenesis performance is successfully constructed. Importantly, this work uncovers the underlying biological mechanisms that genes associated with cell death, proliferation, and bone development are regulated by CaPCu‐scaffold‐based therapy. This work not only elucidates the fascinating clinical translation prospects of CaPCu‐scaffold‐based PTT against OS in NIR‐II biowindow, but also demonstrates the potential mechanisms and offers a novel strategy to develop the next‐generation, multifunctional tissue‐engineering biomaterials.
Herein, the authors develope an ultrathin 2D ancient pigment Egyptian blue decorated 3D‐printing scaffold with profound PTT efficacy at the second biological window of light against OS and enhanced osteogenesis performance. This work also unveils the underlying biological mechanisms through RNA‐seq that genes related to cell death, proliferation, and bone development are regulated by CaPCu‐scaffold‐based therapy.
The ionosphere exhibits some characteristic perturbations during sudden stratospheric warming (SSW) events, of which the mechanism is not thoroughly understood. This study focuses on the latitudinal ...and interhemispheric differences of the enhanced semi-diurnal lunitidal (M2) perturbations related to SSW using total electron content calculated from the network of Global Navigation Satellite System and ionosonde data in the eastern Asia–Australia sector during the January 2009 SSW. Our results show that the most distinct M2 perturbations in the northern and southern hemispheres occur near the Equatorial Ionization Anomaly crest regions around ± 15° geomagnetic latitudes, but corresponds to different moon phases, respectively. Clear M2 perturbations extend to middle latitudes only in the southern hemisphere and have another local maximum in the southern middle latitude. Such latitudinal and interhemispheric features of ionospheric M2 perturbations in the low latitude in the eastern Asia–Australia sector are similar as those in the American sector during the same SSW event. This supports previous suggestion that such latitudinal and interhemispheric differences in the low latitude can be primarily explained by the summer–winter thermospheric wind modulation on equatorial plasma fountain and thus emphasize its role in the vertical coupling process of M2 perturbation. The clear differences of M2 perturbations in the southern middle latitude between the eastern Asia–Australia and American sectors indicate that the thermospheric circulation related to the Weddell Sea Anomaly may have influence on the lower atmosphere–ionosphere coupling.
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