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Dietary fructose, especially in the context of a high-fat western diet, has been linked to type 2 diabetes. Although the effect of fructose on liver metabolism has been extensively studied, a significant portion of the fructose is first metabolized in the small intestine. Here, we report that dietary fat enhances intestinal fructose metabolism, which releases glycerate into the blood. Chronic high systemic glycerate levels induce glucose intolerance by slowly damaging pancreatic islet cells and reducing islet sizes. Our findings provide a link between dietary fructose and diabetes that is modulated by dietary fat. [Display omitted] • High-fat diet increases fructose metabolism in the small intestine • Intestinal fructose metabolism releases glycerate into circulation • Circulating glycerate induces pancreatic islet cell damage • Circulating glycerate induces glucose intolerance Dietary fructose has been linked to metabolic syndromes such as diabetes. Wu et al. discovered that fructose metabolism in the small intestine releases glycerate into the blood circulation, which damages pancreatic islet cells and induces glucose intolerance. Dietary fat further elevates intestinal fructose metabolism and resulting circulating glycerate levels, supporting the long-term effect of western diet on exacerbating metabolic syndromes. [ABSTRACT FROM AUTHOR]

• This paper conducted the full-aeroelastic model test and segmental model test. • The effect of different factors on the vortex-induced responses are investigated. • This paper identifies the vortex-induced resonance based on response power spectrum. • An aerodynamic configuration is obtained to improve vortex-induced vibration. Cable-stayed bridges without backstays located in the abrupt valley are sensitive to wind-induced structural vibrations. The understanding of vortex-induced vibration for specific aerodynamic configuration with glass deck is of great importance for structure design. This paper thus aims to investigate the vortex-induced vibration of a cable-stayed bridges without backstays through the segmental model test and scaled full-aeroelastic model wind tunnel test. The results indicate that the bridge presents the vertical vortex-induced vibrations at the low wind speed whereas the maximum wind velocity causing the torsional vortex-induced vibrations increases to 41 m/s, which is much larger than that of the traditional bridge. The vertical and torsional vortex-induced vibrations in the smooth flow are observed at the positive wind angle of attack, owing to the responses for the bridge deck present a sharp single-frequency amplitude when the frequency of vortex-shedding is close to the flexural vibration frequency. The turbulence can effectively suppress the vortex-induced vibrations and only some small peaks are visible in the turbulent flow. The vortex-induced response of the bridge deck is significantly alleviated with increasing of damping ratio. Finally, the vortex-induced vibrations in the uniform flow disappear and the wind-induced responses are impaired with the ventilated railing in place of the airtight railing because the flow can go through the railing. It can provide a designing basis for engineering reference of cable-stayed bridges without backstays. [ABSTRACT FROM AUTHOR]

BiFeO 3 has promissing application in non-volatile ferroelectric memory, but the dominant mechanism has not been unified. Here, Pt/BiFeO 3 (100 nm)/La 0.5 Sr 0.5 CoO 3 (Pt/BFO/LSCO) heterostructures have been fabricated on (001) SrTiO 3 (STO) single crystal substrates by off-axis magnetron sputtering. Both XRD and TEM analyses confirm that the (001) oriented BFO/LSCO heterostructures have been epitaxially grown on STO. In addition, XRD, TEM along with XPS analyses further indicate that the BFO film (001) presents epitaxial perovskite structure. On the basis of electric field regulation of Pt/BFO and BFO/LSCO interface barrier, the switching interface state is controlled by charge filling and trapping in interface potential well, which is responsible for I–V resistance and G-V hysteretic curve. Based on the fitting results of the conduction mechanism of I–V characteristic curve, it proves that the space charges limiting current play a dominant role, and the filling and trapping of interface traps are considered as the main resistance mechanisms. Moreover, ultraviolet irradiation can modulate the I–V resistance curve but does not change its conduction mechanism. This work provides experimental data for the practical application of integrated BFO resistive memories. • Pt/BiFeO 3 /La 0.5 Sr 0.5 CoO 3 heterostructures have been fabricated. • The mechanism of resistive effect of BFO films was systemically investigated. • Ultraviolet irradiation can modulate the I–V resistance curve. [ABSTRACT FROM AUTHOR]

YAP1 (Yes-associated protein 1) transcriptional coactivator is a downstream gene of the Hippo signaling pathway, which controls cell proliferation and differentiation. YAP1 plays a significant role in the regulation of cartilage and bone development. However, the molecular mechanism by which YAP1 regulates chondrocyte differentiation remains to be elucidated. Immunofluorescent staining was used to visualize the localization of YAP1 expression in the mouse chondroprogenitor ATDC5 cell line. ATDC5 cells with lentivirus-vector-mediated YAP1 overexpression and knockdown were established. The differentiation abilities were examined by real-time quantitative PCR and two staining methods The expression levels of sex-determining region Y-type high mobility group box protein (SOX9) and key proteins in the Wnt/β-catenin pathway were analyzed by Western blot. The Dickkopf-1 (Dkk1) and small interfering RNA (siRNA) of β-catenin were used for further study. The YAP1 protein was mainly expressed in the nucleus of ATDC5 cells. YAP1 overexpression enhanced chondrocyte proliferation but inhibited chondrocyte differentiation, which were contrary to the findings of the YAP1-knockdown group. Moreover, YAP1 overexpression activated Wnt/β-catenin signaling pathway. Treatment with exogenous DKK1 and β-catenin siRNA partially recaptured the effects of YAP1 overexpression on ATDC5 cell differentiation. Taken together, our study suggested that YAP1 attenuated ATDC5 cell chondrogenic and hypertrophic differentiation. We also demonstrated that YAP1 exerted its effect on the chondrocyte differentiation by activating the Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) methylation is one of the most common internal modifications in eukaryotic messenger RNA occurring on N6 nitrogen of adenosine. However, the roles of m6A in temporomandibular joint osteoarthritis (TMJ OA) are still elusive. Here, we investigate the function and mechanism of methyltransferase-like 3 (Mettl3) in chondrocytes in inflammation. We found that the expression of Mettl3 decreased both in vivo TMJ OA mice and in vitro inflammatory stimulation. Functionally, loss and gain studies illustrated that Mettl3 inhibited the apoptosis and autophagy of chondrocytes induced by TNF-α stimulation in vitro. Mettl3 inhibitor, S-adenosylhomocysteine (SAH) promoted the apoptosis and autophagy of chondrocytes with inflammation in vitro and aggravated the degeneration of chondrocytes and subchondral bone in monosodium iodoacetate (MIA) induced TMJ OA mice in vivo. Mechanistically, the bioinformatics analysis, m6A-RNA immunoprecipitation (MeRIP) and RNA immunoprecipitation (RIP) were used to identify that Bcl2 mRNA was the downstream target of Mettl3 for m6A modification. Furthermore, the results revealed that Yth m6A RNA binding protein 1 (Ythdf1) mediated the stability of Bcl2 mRNA catalyzed by Mettl3. Co-immunoprecipitation (Co-IP) showed that Bcl2 protein interacted with Beclin1 protein in chondrocytes induced by TNF-α stimulation. In conclusion, our findings identify that Mettl3 inhibits the apoptosis and autophagy of chondrocytes in inflammation through m6A/Ythdf1/Bcl2 signal axis which provides promising therapeutic strategy for TMJ OA. • Mettl3 positively regulates Bcl2 to inhibit the apoptosis and autophagy of chondrocytes induced by TNF-α. • Ythdf1 mediates Bcl2 mRNA stability by an m6A-dependent manner in chondrocytes induced by TNF-α. • SAH restrains Mettl3 to play a role in chondrocytes with inflammation both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

DNA damage-inducible transcript 3 (DDIT3), a member of the CCAAT/enhancer-binding protein (C/EBP) family, is involved in cellular apoptosis and differentiation. DDIT3 participates in the regulation of adipogenesis and osteogenesis in vitro and in vivo. However, the role of DDIT3 in osteoclastogenesis is not yet known. In this study, the involvement of DDIT3 in osteoclast differentiation and function was reported for the first time. CRISPR/Cas9-mediated DDIT3 knockout (KO) mice were generated for functional assessment. Tartrate-resistant acid phosphatase (TRAP) staining of distal femurs showed increased positive cells in DDIT3 KO mice. DDIT3 expression was downregulated during the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation of bone marrow-derived macrophages (BMMs). The loss of DDIT3 increased the expression of osteoclast-specific markers, including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), TRAP, cathepsin K (CTSK), and dendritic cell-specific transmembrane protein (DC-STAMP) and promoted the formation of TRAP-positive multinucleated osteoclasts. The actin ring number and resorption area of bone slices were also increased in DDIT3 KO BMMs. Lentivirus-mediated DDIT3 overexpression significantly inhibited the osteoclast differentiation of RAW264.7 cells. In the tumor necrosis factor-α-induced osteolysis model, DDIT3 deficiency enhanced osteoclast formation and aggravated bone resorption. DDIT3 inhibited osteoclast differentiation by regulating the C/EBPα-CTSK axis. Furthermore, DDIT3 KO intensified the RANKL-triggered activation of the MAPKs and Akt signaling pathways. Taken together, the results revealed the essential role of DDIT3 in osteoclastogenesis in vitro and in vivo and its close relationship with osteoclast-associated transcription factors and pathways. • DDIT3 deficiency enhanced osteoclastogenesis in vitro and in vivo. • DDIT3 regulated C/EBPα-CTSK axis and MAPKs and Akt pathways. • DDIT3 influenced bone mass by regulating osteoclast-mediated bone resorption. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress can initiate autophagy via unfolded protein response (UPR). As a key downstream gene of UPR, DDIT3/CHOP is expressed in chondrocytes. However, the regulation mechanism of DDIT3/CHOP on autophagy in chondrocytes remains unclear. In this study, the expression levels of autophagic markers Beclin1 and LC3B were found to decrease while p62 increase in the tibial growth plate and costal primary chondrocytes from DDIT3/CHOP KO mice. In vitro, overexpressing DDIT3/CHOP induced autophagy in ATDC5 chondrocytes, displaying an elevated immunofluorescence signal of LC3B and elevated numbers of autophagosomes and autolysosomes. Analysis of the gain- and loss-of-function indicated that the protein level of Beclin1 and the ratio of LC3BII/I increased in DDIT3/CHOP overexpression cells, whereas decreased in DDIT3/CHOP knockdown cells. The decreased level of p62 and additional accumulation of LC3BII caused by chloroquine (CQ) further indicated that DDIT3/CHOP enhanced autophagic flux. Mechanistically, we found that DDIT3/CHOP binds directly to the promoter of SIRT1 to promote its expression by CHIP, qRT-PCR, and Western blot analysis. In addition, SIRT1 enhanced autophagic activity in ATDC5 cells, and inhibition or activation of SIRT1 partially reversed the effect of overexpressing or downregulating DDIT3/CHOP on autophagy. Furthermore, AKT signaling was found to be responsible for DDIT3/CHOP-regulated autophagy in ATDC5 cells. SIRT1 knockdown reversed the effect of DDIT3/CHOP overexpression on AKT signaling. In conclusion, our data clarifies that DDIT3/CHOP promotes autophagy in ATDC5 chondrocytes through the SIRT1-AKT pathway. These results were also confirmed in the primary chondrocytes. • Knockout of DDIT3/CHOP suppressed autophagy in the growth plate and costal primary chondrocytes. • DDIT3/CHOP interacts directly with SIRT1 in ATDC5 chondrocytes. • DDIT3/CHOP promoted autophagy in chondrocytes via SIRT1-AKT pathway. [ABSTRACT FROM AUTHOR]

This study aimed to examine the effect of ubiquitin-specific peptidase 7 (USP7) on the proliferation and differentiation of ATDC5 cells and explore the underlying mechanisms. PCR, western blot, and immunofluorescence staining were used to observe the expression of USP7 after chondrogenic induction. The expressions of markers of chondrogenic and hypertrophic differentiation, and parathyroid hormone-related protein (PTHrP)/parathyroid hormone 1 receptor (PTH1R) signalling, were assessed by PCR, western blot, and histological staining under USP7 knockdown or its inhibitor. Cell proliferation was assessed by the CCK-8 assay and crystal violet staining. An in vivo experiment was performed to verify the functions of USP7 through histological and immunohistochemistry staining. Cyclopamine and abaloparatide were used to verify the signalling pathway. The interactions between USP7 and both PTHrP and sex-determining region Y-box 9 (Sox9) were tested by co-immunoprecipitation. The relationship between Sox9 and PTHrP was tested by chromatin immunoprecipitation and siRNA. USP7 knockdown or its inhibitor suppressed cell proliferation and chondrogenic differentiation but improved hypertrophic differentiation. The in vivo study obtained the same results. USP7 knockdown or its inhibitor inhibited PTHrP/PTH1R signalling to exert its function. Supplementation with cyclopamine suppressed PTHrP/PTH1R signalling and inhibited ATDC5 cell proliferation and differentiation. Supplementation with abaloparatide activated PTH1R to upregulate proliferation and chondrogenic differentiation but downregulated hypertrophic differentiation. Furthermore, USP7 interacted with Sox9 and Sox9 bound to PTTHrP to promote its expression. In conclusion, USP7 modulates the proliferation and differentiation of ATDC5 cells via the Sox9-PTHrP-PTH1R axis. • USP7 promoted proliferation and chondrogenic differentiation, but inhibited hypertrophic differentiation of ATDC5 cells. • USP7 activated PTHrP/PTH1R signalling to exert these effects. • USP7 reacted with the Sox9 protein and the Sox9 protein bound to the PTTHrP gene promoter to upregulate its expression. [ABSTRACT FROM AUTHOR]