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Background & Aims: Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first months of life. Methods: We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis，and re-analyzed phenotype and WES data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. Results: Overall, we identified disease causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) were metabolic liver diseases, 9 (17%) were syndromic cholestasis, 9 (17%) were progressive familial intrahepatic cholestasis, 3 (6%) were bile acid synthesis defects, 3(6%) were infantile liver failure and 10 (19%) were phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G>A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By reanalyzing WES data, two patients were newly solved, which had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved trio families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice model. Conclusions: In a single center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Rigorous analysis of WES data of well-phenotyped patients with intrahepatic cholestasis leads to a broader understanding of gene-specific phenotypic spectra as well as monogenic candidate gene identification.

Background When a fetus was found has cleft lip palate (CL/P) by prenatal anatomical ultrasound assessment, it is difficult to determine the CL/P is isolated or companied with other animalities such as intellectual disability. We preformed comprehensive genetic test to support prenatal genetic counselling for CL/P fetus which is detected by ultrasound screening. Methods 105 unrelated fetuses with CL/P were enrolled. After excluding aneuploidy cases, SNP array and clinical exome sequencing (CES) were preformed simultaneously. All the fetuses were followed-up. Results Fetuses with CL/P were divided into two groups, cleft lip (CL)and cleft palate with or without cleft lip (CP/CLP). The detection rate was 12.4% (13/105) of the cases, in which SNP array contributed 3.8% (4/105) while CES added 8.6% yields. The positive rate of the CL group was lower than that of the CP/CLP group (0% (0/23) versus 15.9% (13/82), P = 0.067). CP/CLP with additional anomalies has higher positive rate than that of the apparently isolated CP/CLP (53.3% (8/15) versus 7.5% (5/67), P

The α-Ni(OH)2 coated with manganese (Mn) materials was synthesized by the chemical precipitation method, and the electrochemical properties were investigated. The results showed that the ingredient of the coating is a mixture of MnO2 and Mn2O3, and the coating can inhibit the intercalated anions escape and stabilize the α-Ni(OH)2 phase structure in KOH alkaline solution. The coated electrodes have higher discharge capacities and higher capacity retention rates than the uncoated α-Ni(OH)2 electrode, the discharge capacity of Mn-coated electrodes is over 350 mAh g−1, and the capacity retention rate exceeds 92%, separately. The reason may be that the Mn coatings can block or decelerate water molecule and the anion to escape from the interlayers, therefore prevent α phase structural collapse and maintain high discharge capacity during a long lifespan cycle. Therefore, the Mn coating α-Ni(OH)2 is a promising candidate for high-power Ni-MH batteries.

Insulin-like growth factor 1 (IGF-1) is considered to be a crucial gene in the animal development of bone and body size. In this study, a unique synonymous mutation (c.258 A > G) of the IGF-1 gene was modified with an adenine base editor to observe the growth and developmental situation of mutant mice. Significant expression differences and molecular mechanisms among vectors with different alanine synonymous codons were explored. Although modification of a single synonymous codon rarely interferes with animal phenotypes, we observed that the expression and secretion of IGF-1 were different between 8-week-old homozygous (Ho) and wild-type (WT) mice. In addition, the IGF-1 with optimal codon combinations showed a higher expression content than other codon combination modes at both transcription and translation levels and performed proliferation promotion. The gene stability and translation initiation efficiency also changed significantly. Our findings illustrated that the synonymous mutation altered the IGF-1 gene expression in individual mice and suggested that the synonymous mutation affected the IGF-1 expression and biological function through the transcription and translation processes.

Background Anaplastic thyroid cancer (ATC) is the greatest lethal thyroid neoplasm with a low incidence and lacks an effective treatment strategy and standardized treatment protocol. PLX3397 (Pexidartinib) is an FDA-approved multitarget tyrosine kinase inhibitor. The research is designed to explore the possible anti-proliferative activity of pexidartinib on ATC, as well as its related molecular mechanisms. Methods The cell viability was assessed by CCK-8, LDH release, colony formation, and EdU detection assays. Apoptosis and the alteration on cell cycle arrest were characterized by flow cytometry (FCM). ER stress was evaluated by immunofluorescence (IF). ROS levels were determined by flow cytometry. Western blot assays were conducted to evaluate changes in key molecules related to apoptosis and ER stress. The ATC xenografts model was established, and immunohistochemistry was performed to validate the anti-ATC effects of pexidartinib in vivo. Results Pexidartinib significantly inhibited ATC cell proliferation and induced apoptosis and cell cycle arrest. Moreover, pexidartinib potently induced ER stress and elevated ROS in ATC cells, and the apoptotic cells and ER stress in ATC after administration of pexidartinib could be reversed by an ER stress inhibitor and ROS scavenger, respectively. Furthermore, pexidartinib treatment induced Nrf2 accumulation in nuclei and reduced the interaction of Nrf2 with Keap-1, and knockdown of Nrf2 enhanced the anti-ATC effects of pexidartinib in vitro. In addition, pexidartinib significantly inhibited ATC xenograft growth and proliferation in vivo, and the combination of ML385, an Nrf2 inhibitor, potently enhanced the anti-ATC effects of pexidartinib in vivo. Conclusion Our findings suggest pexidartinib is a potential agent for treating ATC. Co-administration with an Nrf2 inhibitor is an effective synergistic strategy.

van der Waals heterostructures (vdWHs), with their flexible combination of various two-dimensional (2D) materials, are continuously revealing new physics and functionalities. 2D magnetic materials have recently become a focus due to their fascinating electronic and spintronic properties. However, there has rarely been any investigation of the optical properties of 2D magnetic materials-based heterostructures. Herein, we construct a new WSe

The reduced chromite ore processing residue (rCOPR) deposited in environments is susceptible to surrounding factors and causes reoccurrence of Cr(VI). However, the impact of natural sunlight on the stability of rCOPR is still unexplored. Herein, we investigated the dissolution and transformation behaviors of Cr(III)-Fe(III) hydroxide, a typical Cr(III)-containing component in rCOPR, under visible light. At acidic conditions, the release rate of Cr(III) under illumination markedly increased, up to 7 times higher than that in the dark, yet no Cr(VI) was produced. While at basic conditions, only Cr(VI) was obtained by photo-oxidation, with an oxidation rate of ∼7 times higher than that by δ-MnO

While aqueous Zn-Na hybrid batteries have garnered widespread attention because of their low cost and high safety, it is still challenging to achieve long cycle-life and stable discharge-voltage due to sluggish reaction kinetics, zinc dendrite formation, and side reactions. Herein, we design a Zn2+/Na+ dual-salt battery, in which sodiation of the NVP cathode favors zinc intercalation under an energy threshold, leading to decoupled redox reactions on the cathode and anode. Systematic investigations of the electrolyte effects show that the ion intercalation mechanism and the kinetics in the mixture of triflate- and acetate-based electrolytes are superior to those in the common acetate-only electrolytes. As a result, we have achieved fast discharging capability, suppressed zinc dendrites, a stable discharge voltage at 1.45 V with small polarization, and nearly 100% Columbic efficiency in the dual-salt mixture electrolyte with optimized concentration of 1 M Zn(OAc)2 + 1 M NaCF3SO3. This work demonstrates the importance of electrolyte regulation in aqueous dual-salt hybrid batteries for the energy storage.

Interpreting the similarities and dissimilarities in spatiotemporal variations and various controls between surface and canopy urban heat islands (UHIs) is critical for a better understanding of their vertical structure. Preceding comparisons of the surface UHI (SUHI) and canopy UHI (CUHI), however, remain mostly restricted either in a single city or over a few cities within limited background climates; therefore, the associated similarities and dissimilarities between the SUHI and CUHI under different climates, especially at a global scale, remain largely unknown. Based on both satellite and in situ data, we simultaneously investigated the spatiotemporal patterns of the SUHI intensity (SUHII) and CUHI intensity (SUHII) of 366 global cities within various background climates. We further investigated the different impacts of several controls (e.g., vegetation coverage, population size, precipitation) on SUHII and CUHII. Our results indicate the following: (1) For the selected 366 cities, the annual mean SUHII is higher than CUHII by 1.1 ± 1.9 °C (mean ± Std) during the day and 0.3 ± 1.5 °C (mean ± Std) at night. The SUHII and CUHII in the equatorial, warm temperate, and snow climates are generally consistent with the above characteristics (i.e., SUHII > CUHII), however, in arid regions SUHII is lower than CUHII by 0.8 °C during the day. (2) The annual mean day–night difference in SUHII is positive (i.e., 0.6 ± 1.8 °C (mean ± Std)), while the difference in CUHII becomes negative (i.e., −0.2 ± 1.6 °C (mean ± Std)), indicating that urbanization increases the diurnal temperature range (DTR) based on land surface temperature, but it decreases the DTR based on surface air temperature. (3) Despite the high correlation between vegetation coverage and impervious surface percentage (ISP), their impacts on SUHII and CUHII were not consistent. The urban–rural difference in ISP exerts an insignificant impact on both SUHII and CUHII during the day and a greater impact on CUHII than on SUHII at night, whereas the urban–rural difference in vegetation coverage has a greater impact on SUHII than on CUHII during the day, while the opposite occurs at night. The impacts of population size on SUHII and CUHII are much greater during the night than on the day in which their impacts can be minimal. The relationship between annual mean precipitation and SUHII is positive during the day but negative at night, while for CUHII, their relationship is insignificantly negative both during the day and at night. These results can improve our understanding of the spatiotemporal patterns and controls of these two types of UHIs under various climates.

Bacillus cereus D2, a psychrotrophic strain, plays an essential role in the restoration of heavy metal-contaminated soils, especially at low temperatures. However, the cold shock response mechanisms of this strain are unclear. In this study, the cold shock response of B. cereus D2 was characterized; as per the Arrhenius curve, 10 °C was chosen as the cold shock temperature. Six cold shock-like proteins were found and temporarily named cold shock protein (Csp)1–6; the respective genes were cloned and identified. Quantitative real-time PCR results showed that csp1, csp2, csp3, and csp6 were overexpressed under cold shock conditions. Interestingly, after cloning the respective encoding genes into the pET-28a (+) vector and their subsequent transformation into E. coli BL21 (DE3), the strains expressing Csp2 and Csp6 grew faster at 10 °C, showing a large number of bacteria. These results suggest that Csp2 and Csp6 are the major cold shock proteins in B. cereus D2. Of note, the comparison of amino acid sequences and structures showed that Csp2 and Csp6 belong to the CspB and CspC families, respectively. Additionally, we show that the number of hydrophobic residues is not a determining feature of major Csps, while, on the other hand, the formation of an α-helix in the context of a leucine residue is the most dominant difference between major and other Bacillus and E. coli Csps.

Adhesion formation during tendon healing remains a severe problem in clinical practice. Multiple factors contribute to postoperative adhesion formation, and macrophage-driven inflammation is thought to be greatly involved in this process. We hypothesize that reducing macrophage-mediated inflammation in the injured tendon by regulating M1 to M2 macrophage polarization may effectively inhibit adhesion formation. Here, we developed an acellular immunomodulatory biomaterial consisting of an electrospun polycaprolactone/silk fibroin (PCL/SF) composite fibrous scaffold functionalized with mesenchymal stem cell (MSC)-derived extracellular matrix (ECM). To enhance the immunoregulatory potential of MSCs, we performed inflammatory licensing with IFN-γ to obtain immunomodulatory ECM (iECM). Proteomic analyses of MSCs and their secreted ECM components from different culture conditions revealed the MSC-ECM molecular signatures and the potential mechanism of ECM immunoregulation. Then, the immunoregulatory potential of the iECM-modified scaffold was evaluated in vitro and in vivo. Relative to the PCL/SF fibrous scaffold, the iECM-functionalized scaffold facilitated M2 macrophage polarization and inhibited the expression of multiple cytokines (IL-1β, IL-6, CXCL11, IL-10, IL-1R2, and TGF-β1) in vitro, strongly suggesting the immunosuppressive ability of iECM derived from inflammatory licensed MSCs. Consistent with the in vitro findings, the results of rat subcutaneous implantation indicated that a markedly lower foreign-body reaction (FBR) was obtained in the PCL/SF-iECM group than in the other groups, as evidenced by thinner fibrotic capsule formation, less type I collagen production and more M2-type macrophage polarization. In the rat Achilles tendon injury model, the PCL/SF-iECM scaffold greatly mitigated tendon adhesion with clear sheath space formation between the tendon and the scaffold. These data highlight the immunomodulatory potential of iECM-functionalized fibrous scaffolds to attenuate FBR by modulating M2 macrophage polarization, thereby preventing tendon adhesion. Statement of significance Electrospun PCL/SF fibrous scaffolds functionalized with ECM secreted by MSCs stimulated by inflammatory factor IFN-γ was developed that combined physical barrier and immunomodulatory functions to prevent tendon adhesion formation. PCL/SF micro-nanoscale bimodal fibrous scaffolds prepared by emulsion electrospinning possess high porosity and a large pore size beneficial for nutrient transport to promote intrinsic healing; moreover, surface modification with immunomodulatory ECM (iECM) mitigates the FBR of fibrous scaffolds to prevent tendon adhesion. The iECM-functionalized electrospun scaffolds exhibit powerful immunomodulatory potency in vitro and in vivo. Moreover, the iECM-modified scaffolds, as an anti-adhesion physical barrier with immunomodulatory ability, have an excellent performance in a rat Achilles tendon adhesion model. MSC secretome-based therapeutics, as an acellular regenerative medicine strategy, are expected to be applied to other inflammatory diseases due to its strong immunoregulatory potential.

Breast cancer anti-estrogen resistance protein 3 (BCAR3) is involved in anti-estrogen resistance and other important aspects of breast cancer. However, the role of BCAR3 in other solid tumors remains unclear. The relationship between the clinicopathologic characteristics of head and neck squamous cell carcinoma (HNSCC) patients and BCAR3 was analyzed using the Wilcoxon’s signed-rank test and logistic regression. The association between BCAR3 expression and clinicopathologic features and survival was analyzed using Cox regression and the Kaplan–Meier method. In vivo and in vitro assays were performed to validate the effect of BCAR3 on HNSCC growth. BCAR3-related mRNAs were determined by calculating the Pearson’s correlation coefficient based on The Cancer Genome Atlas (TCGA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and gene set enrichment analysis (GSEA) were used to predict the potential functions of BCAR3. BCAR3 expression is overexpressed in HNSCC and was shown to be associated with perineural invasion (PNI) and poor survival. BCAR3 silencing significantly attenuated the proliferation of HNSCC cells, whereas BCAR3 depletion inhibited tumor growth in vitro. GO and KEGG functional enrichment analyses, and GSEA showed that BCAR3 expression in HNSCC was associated with biological processes, such as cell adhesion, actin binding, cadherin binding, and angiogenesis. BCAR3, which promotes HNSCC growth, is associated with perineural invasion and may be a potential molecular prognostic marker of poor survival in HNSCC.

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

To explore the perspectives of stroke survivors, caregivers and nurse coaches on a health coaching program during hospital-to-home transitional care.Stroke is a major public health problem that seriously affects the health and safety of people in China. Nurse-led health coaching is a promising support option in enabling smooth hospital-to-home transition for stroke survivors and family caregivers. A qualitative study is valuable for gaining insight into their perspectives on using this program.An exploratory, descriptive qualitative process evaluation was conducted parallel with a former randomised controlled trial. Data were obtained from 26 stroke survivors, 33 caregivers and four nurse coaches with semi-structured interviews. The inductive reflexive thematic analysis approach was used for data analysis. The COREQ checklist was followed in reporting this study.Seven themes were generated from the data: (1) the applicability of individualised health coaching sessions, (2) driving self-efficacy to establish self-care skills, (3) the key role of nurse coaches, (4) coordination among healthcare teams during the transition, (5) adequate community and social support, (6) insufficient rehabilitative services after discharge and (7) perceived extra workload for nurse coaches.The study captured perspectives on a nurse-led health coaching program towards hospital-to-home transition care from stroke survivors, caregivers and nurse coaches. Individualised health coaching sessions and driving self-efficacy were perceived as facilitators for empowering the self-care skills of stroke survivors and caregivers. The key role of nurse coaches in coordinating healthcare teams and adequate community and social support were detected as the power frame of the program's implementation. However, health system obstacles, such as insufficient rehabilitative services and the high workload of nurses, still need to be addressed to ensure the sustainability of health coaching intervention in transitional care.The study suggested the feasibility of implementing nurse-led health coaching to smooth post-stroke hospital-to-home transitional care. The findings also highlighted the importance of qualitative process evaluation when implementing evidence-based interventions in health care.The trial was registered with the Australia New Zealand Clinical Trials Registry (ID: ACTRN12619000321145).

This study examines the differential association between sex and depression, and the possible mediating pathways.We analysed survey data from 296 (age 7-17.1 years) cancer survivors from three centres affiliated with Beijing Children's Hospital. Linear regression analysis was used to assess the association between sex and depression. Quantile regression analysis was used to estimate the regression coefficients (β) and 95% confidence intervals for sex in depression at different quantiles. Mediation analysis with multiple mediators was used to explore the effects of sex on depression.Using linear regression, we found that the age ranged from 8.7 to 10.4 years and the regression coefficient of sex on depression was significant (β = -2.75, p = 0.03). Quantile regression results showed a significant negative association between sex and depression in the 0.30-0.75 quantiles. Mediation analysis revealed that boys were 1.545 times more depressed than girls, with family resilience, self-perceived burden, and behavioural problems explaining approximately 16.79%, 21.57%, and 43.94% of the sex difference, respectively. The combined effect of family functioning, resilience, social support, self-perceived burden, and behavioural problems might explain the 89.17% sex difference.Clinicians should consider sex effects when assessing depression in childhood cancer survivors and target sex-specific interventions for further treatment.

SummaryPhylogenetically distant coronaviruses have evolved to use ACE2 as their common receptors, including NL63 and many Severe acute respiratory syndrome (SARS) coronavirus-related viruses. We recently reported two Middle East respiratory syndrome coronavirus (MERS-CoV) closely related bat merbecoviruses, NeoCoV and PDF-2180, use Angiotensin-converting enzyme 2 (ACE2) for entry. However, their host range and cross-species transmissibility remain unknown. Here, we characterized their species-specific receptor preference by testing ACE2 orthologs from 49 bats and 53 non-bat mammals. Both viruses exhibited broad receptor recognition spectra and are unable to use ACE2 orthologs from 24 species, mainly Yinpterochiropteran bats. Comparative analyses of bat ACE2 orthologs underscored four crucial host range determinants, all confirmed by subsequent functional assays in human and bat cells. Among them, residue 305, participating in a critical interaction, plays a crucial role in host tropism determination. NeoCoV-T510F, a mutation that enhances human ACE2 recognition, further expanded the potential host range via tighter interaction with an evolutionary conserved hydrophobic pocket. Our results elucidated the molecular basis for the species-specific ACE2 usage of MERS-related viruses across mammals and shed light on their zoonotic risks.

In this work, the photoelectrochemical (PEC) properties of TiO2 nanotube arrays (NTAs) were enhanced by forming heterostructures with non-substituted covalent organic frameworks (H-COFs) and fluoro...

The pivotal steps for the practical application of dehydrogenation of aluminum hydride (AlH3) have been to decrease the temperature and increase the content of AlH3. Herein, the initial dehydrogenation temperature of AlH3 decreased to 43 °C with the amount of released hydrogen of 8.3 wt % via introducing TiO2 and Pr6O11 with synergistic catalysis effects, and its apparent activation energy of the dehydrogenation reaction decreased to 56.1 kJ mol-1, which is 52% lower than that of pure AlH3. These differences in performances of the samples are further evaluated by determining the electron density of Al-H bonds during dehydrogenation. The multiple valence state conversions of TiO2 and Pr6O11 promoted the electron transfer of H in AlH3, and a novel dehydrogenation pathway of PrH2.37 formed simultaneously, which could accelerate the breakage of Al-H bonds. The density functional theory calculations further exhibit that there are fewer electrons around H in AlH3 and the Al-H bond energy is weaker at the atomic levels, which is more conducive to the release of hydrogen. A higher hydrogen storage capacity and a lower dehydrogenation temperature make AlH3 one of the most promising hydrogen source media for mobile applications.

Atractylodin (ATL) has been reported to exert anti-inflammatory effects. Osteogenic changes induced by inflammation in valve interstitial cells (VICs) play a key role in the development of calcified aortic valve disease (CAVD). This study aimed to investigate the anti-calcification effects of ATL on aortic valves. Human VICs (hVICs) were exposed to osteogenic induction medium (OM) containing ATL to investigate cell viability, osteogenic gene and protein expression, and anti-calcification effects. Gas chromatography-mass spectroscopy (GC-MS) metabolomics analysis was used to detect changes in the metabolites of hVICs stimulated with OM before and after ATL administration. The compound-reaction-enzyme-gene network was used to identify drug targets. Gene interference was used to verify the targets. ApoE-/- mice fed a high-fat (HF) diet were used to evaluate the inhibition of aortic valve calcification by ATL. Treatment with 20 μM ATL in OM prevented calcified nodule accumulation and decreases in the gene and protein expression levels of ALP, RUNX2, and IL-1β. Differential metabolite analysis showed that D-mannose was highly associated with the anti-calcification effect of ATL. The addition of D-mannose prevented calcified nodule accumulation and inhibited succinate-mediated HIF-1α activation and IL-1β production. The target of ATL was identified as GLA. Silencing of the GLA gene (si-GLA) reversed the anti-osteogenic differentiation of ATL. In vivo, ATL ameliorated aortic valve calcification by preventing decreases in GLA expression and the up-regulation of IL-1β expression synchronously. In conclusion, ATL is a potential drug for the treatment of CAVD by targeting GLA to regulate D-mannose metabolism, thereby inhibiting succinate-mediated HIF-1α activation and IL-1β production.

A wound dressing based on a thermosensitive hydrogel shows advantages over performed traditional dressings, such as rapid reversible sol-gel-sol transition properties and the capacity to fill an irregular-shaped wound area. Herein, RA-Amps was fabricated by coupling a self-assembled peptide RADA16 with an antibacterial peptide (Amps) and incorporated into a PNIPAM hydrogel containing an MGF E peptide to develop a multi-functional composite hydrogel with thermo-response properties, good biocompatibility, good mechanical properties, and antibacterial and carrier functions for wound healing. PNI/RA-Amps is an injectable thermo-reversible system with a phase transition temperature of ∼32 °C, and exhibits a rapid reversible sol-gel-sol transition of ∼23 s, which makes it conducive to sealing the wound area and avoiding sol diffusion caused by a lengthy gel time. MGF E peptide was loaded into a hydrogel and released continuously to promote fibroblast proliferation. Rat full-thickness skin experiments revealed that the PNI/RA-Amps/E hydrogel accelerates wound healing significantly by accelerating epithelialization, the generation of new blood vessels and promoting the generation of collagen fiber compared with commercial dressing. Thus, our findings establish a new candidate for use as an injectable wound dressing for the clinical treatment of wounds.

Cartilage injury affects numerous individuals, but the efficient repair of damaged cartilage is still a problem in clinic. Hydrogel is a potent scaffold candidate for tissue regeneration, but it remains a big challenge to improve its mechanical property and figure out the interaction of chondrocytes and stiffness. Herein, a novel hybrid hydrogel with tunable stiffness was fabricated based on methacrylated gelatin (GelMA) and iron oxide nanoparticles (Fe(2)O(3)) through chemical bonding. The stiffness of Fe(2)O(3)/GelMA hybrid hydrogel was controlled by adjusting the concentration of magnetic nanoparticles. The hydrogel platform with tunable stiffness modulated its cellular properties including cell morphology, microfilaments and Young's modulus of chondrocytes. Interestingly, Fe(2)O(3)/GelMA hybrid hydrogel promoted oxidative phosphorylation of mitochondria and facilitated catabolism of lipids in chondrocytes. As a result, more ATP and metabolic materials generated for cellular physiological activities and organelle component replacements in hybrid hydrogel group compared to pure GelMA hydrogel. Furthermore, implantation of Fe(2)O(3)/GelMA hybrid hydrogel in the cartilage defect rat model verified its remodeling potential. This study provides a deep understanding of the bio-mechanism of Fe(2)O(3)/GelMA hybrid hydrogel interaction with chondrocytes and indicates the hydrogel platform for further application in tissue engineering.