Translational informatics for human microbiota: data resources, models and applications.

With the rapid development of human intestinal microbiology and diverse microbiome-related studies and investigations, a large amount of data have been generated and accumulated. Meanwhile, different computational and bioinformatics models have been developed for pattern recognition and knowledge discovery using these data. Given the heterogeneity of these resources and models, we aimed to provide a landscape of the data resources, a comparison of the computational models and a summary of the translational informatics applied to microbiota data. We first review the existing databases, knowledge bases, knowledge graphs and standardizations of microbiome data. Then, the high-throughput sequencing techniques for the microbiome and the informatics tools for their analyses are compared. Finally, translational informatics for the microbiome, including biomarker discovery, personalized treatment and smart healthcare for complex diseases, are discussed.

In vitro characterization of alternative l-threonate and d-erythronate catabolic pathways.

l-threonate is the metabolite of vitamin C, while d-erythronate is the metabolite of N-acetyl-d-glucosamine, the nutritional supplement for joint health. They are widely distributed in the environment and human biofluids. Nevertheless, the catabolisms of l-threonate and d-erythronate are sparsely reported. Here we explored the functional diversity of an acid sugar kinase family (Pfam families PF07005-PF17042), and discovered a novel 2-oxo-tetronate kinase. The conserved genome neighborhood of the 2-oxo-tetronate kinase encodes members of class-II fructose-bisphosphate aldolase family (F_bP_aldolase, PF01116) and a dehydrogenase family (PF03446-PF14833). Instructed by this analysis, we experimentally verified that these enzymes are capable of degrading l-threonate into dihydroxyacetone phosphate (DHAP) in Arthrobacter sp. ZBG10, Clostridium scindens ATCC 35704, and Pseudonocardia dioxanivorans ATCC 55486. Meanwhile, a convergent catabolic pathway for d-erythronate was characterized in P. dioxanivorans ATCC 55486. Moreover, the phylogenetic distribution analysis indicates that the biological range of the identified l-threonate and d-erythronate catabolic pathways appears to extend mostly to members of the Actinomycetota, Cyanobacteriota, Bacillota, Pseudomonadota, and Bacteroidota phyla.

Unlatching the Additional Zinc Storage Ability of Vanadium Nitride Nanocrystallites.

Vanadium-based materials, due to their diverse valence states and open-framework lattice, are promising cathodes for aqueous zinc ion batteries (AZIBs), but encounters the major challenges of in situ electrochemical activation process, potent polarity of the aqueous electrolyte and periodic expansion/contraction for efficient Zn2+ storage. Herein, architecting vanadium nitride (VN) nanosheets over titanium-based hollow nanoarrays skeletal host (denoted VNTONC) can simultaneously modulate address those challenges by creating multiple interfaces and maintaining the (1 1 1) phase of VN, which optimizes the Zn2+ storage and the stability of VN. Benefiting from the modulated crystalline thermodynamics during the electrochemical activation of VN, two outcomes are achieved; I) the cathode transforms into a nanocrystalline structure with increased active sites and higher conductivity and; II) a significant portion of the (1 1 1) crystal facets is retained in the process leading to the additional Zn2+ storage capacity. As a result, the as-prepared VNTONC electrode demonstrates remarkable discharge capacities of 802.5 and 331.8 mAh g-1 @ 0.5 and 6.0 A g-1, respectively, due to the enhanced kinetics as validated by theoretical calculations. The assembled VNTONC||Zn flexible ZIB demonstrates excellent Zn storage properties up to 405.6 mAh g-1, and remarkable robustness against extreme operating conditions.

Melatonin, a potentially effective drug for the treatment of infected bone nonunion.

Osteomyelitis (OM), characterized by heterogeneity and complexity in treatment, has a high risk of infection recurrence which may cause limb disability. Management of chronic inactive osteomyelitis (CIOM) without typical inflammatory symptoms is a great challenge for orthopedic surgeons. On the basis of data analysis of 1091 OM cases, we reported that latent osteogenic decline in CIOM patients was the main cause of secondary surgery. Our research shows that impairment of osteoblasts capacity in CIOM patients is associated with ferroptosis of osteoblasts caused by internalization of Staphylococcus aureus. Further studies show that melatonin could alleviate ferroptosis of osteoblasts in infected states through Nox4/ROS/P38 axis and protect the osteogenic ability of CIOM patients. Knockout of NADPH oxidase 4 (Nox4) in vivo could effectively relieve ferroptosis of osteoblasts in the state of infection and promote osteogenesis. Through a large number of clinical data analyses combined with molecular experiments, this study clarified that occult osteogenic disorders in CIOM patients were related to ferroptosis of osteoblasts. We revealed that melatonin might be a potential therapeutic drug for CIOM patients and provided a new insight for the treatment of OM.

Ultra-high-performance liquid chromatography-quadrupole-time of flight-mass spectrometry combined with network pharmacology for analysis of potential quality markers of three processed products of Qingpi.

Qingpi, a well-known traditional Chinese medicine for qi-regulating and commonly processed into three types of pieces, has been widely used in the clinical application of liver disease for thousands of years. In this study, an ultra-high-performance liquid chromatography-quadrupole-time of flight-mass spectrometry approach along with multivariate statistical analysis was developed to assess and characterize the differentiations of three processed products and confirm the potential quality markers of Qingpi. In addition, a systematic analysis combined with network pharmacology and molecular docking was performed to clarify the potential mechanism of Qingpi for the treatment of liver disease. As a result, 18 components were identified and an integrated network of Qingpi-Components-Target-Pathway-Liver Disease was constructed. Eight compounds were finally screened out as the potential quality markers acting on ten main targets and pathways of liver disease. Molecular docking analysis results indicated that the quality markers had a good binding activity with the targets. Overall, this work preliminarily identified the potential quality markers of three processed products of Qingpi, and predicted its targets in the prevention and treatment of liver disease, which can provide supporting information for further study of the pharmacodynamic substances and mechanisms of Qingpi.

Association between baseline hemoglobin level and early neurological deterioration after intravenous thrombolysis in patients with acute ischemic stroke. / åŸºçº¿è¡€çº¢è›‹ç™½æ°´å¹³å¯¹æ€¥æ€§ç¼ºè¡€æ€§è„‘å’ä¸­æ‚£è€ é™è„‰æº¶æ “åŽæ—©æœŸç¥žç»åŠŸèƒ½æ¶åŒ–çš„å½±å“.

OBJECTIVES: To investigate the association between baseline hemoglobin level and early neurologic deterioration (END) after intravenous thrombolysis in patients with acute ischemic stroke (AIS). METHODS: Data of AIS patients who received intravenous thrombolytic therapy at multiple hospitals across the country between January 2017 and July 2020 were collected from the online database Acute Stroke Patients for Stroke Management Quality Evaluation (CASE-Ⅱ, NCT04487340). Binary logistic regression analysis was used to study the factors affecting the occurrence of END after intravenous thrombolytic therapy, and the correlation between baseline hemoglobin level and END was investigated by limiting cubic spline curve analysis. RESULTS: A total of 8162 patients were included. Patients with END had lower baseline hemoglobin levels (136 and 140 g/L, P<0.01) and higher rates of anemia (24.2% and 16.9%, P<0.01) compared with non-END patients. Binary logistic regression analysis showed that baseline hemoglobin level (OR=0.995, 95%CI: 0.991-0.999, P<0.05) and anemia (OR=1.238, 95%CI: 1.055-1.454, P<0.01) were independently correlated with the occurrence of END after intravenous thrombolysis in AIS patients. Restricted cubic spline regression showed that there was a U-shaped relationship between hemoglobin level and the risk of END after intravenous thrombolysis in AIS patients (P<0.01), although this relationship was only significant in male patients (P<0.05) and not in female patients (P>0.05). CONCLUSIONS: There is a correlation between baseline hemoglobin level and the risk of END in AIS patients after intravenous thrombolysis, especially in male patients, in whom both lower and higher hemoglobin level may increase the risk of END.

Hydrogen Bond Organic Frameworks as Radical Reactors for Enhancement in ECL Efficiency and Their Ultrasensitive Biosensing.

Nowadays, electrochemiluminescence (ECL) efficiency of an organic emitter is closely related with its potential applications in food safety and environmental monitoring fields. In this work, 2,4,6-tris(4-carboxyphenyl)-1,3,5-triazine (TATB) was self-assembled to form hydrogen bond organic frameworks (HOFs), which worked as ideal reactors to generate highly active oxygen-containing radicals, followed by linking with isoluminol (ILu) via amide bond (termed ILu-HOFs). After covalent assembly with aminated indium-tin oxide electrode (labeled NH2-ITO), the ECL efficiency of the ILu-HOFs NH2-ITO showed about a 23.4-time increase over that of ILu itself in the presence of H2O2. Meanwhile, the enhanced ECL mechanism was mainly studied by electron paramagnetic resonance, theoretical calculation, and electrochemistry. On the above foundation, an aptamer "sandwich" ECL biosensor was constructed for detecting isocarbophos (ICP) via in situ elimination of H2O2 with catalase-linked palladium nanocubes (CAT-Pd NCs). The as-built sensor showed a broad linear range (1 pM to 100 nM) and a low limit of detection (LOD) down to 0.4 pM, coupled with efficient assays of ICP in lake water and cucumber juice samples. This strategy provides an effective way for the synthesis of advanced ECL emitter, coupled by showing promising applications in environmental and food analysis.

Optimal weak measurement scheme for chiral molecular detection based on photonic spin Hall effect.

In this paper, we propose a precision method to measure the chiroptical signal of Artemisinin solutions using the photonic spin Hall effect (PSHE) on the Ce:YIG-YIG-SiO2 structure as a probe. The effects of transmission distance, incident angles, applied magnetic fields of different directions, and beam waist of light on the weak measurement system are analytically investigated through simulations. It is found that decreasing the beam waist of the incident spot, increasing the incident angle, increasing the transmission distance, and adding a longitudinal magnetic field is conducive to enhancing the amplification transverse shift of PSHE, thus the measurement sensitivity is greatly improved. Based on the optimal weak measurement scheme, the detection limit for concentration measurement of artemisinin based on optical rotatory (OR) was reduced to 0.05 mg/ml. The measurement precision of the OR angle has been improved to 10-7rad.

Observation of robust edge mode and in-gap corner mode in Kagome surface-wave photonic crystals.

Recent theory has demonstrated that Kagome photonic crystals (PCs) support first-order and second-order topological phenomena. Here, we extend the topological physics of the Kagome lattice to surface electromagnetic waves and experimentally show a Kagome surface-wave PC. Under the protection of first-order and second-order topologies, both robust edge modes and in-gap corner modes are observed. The robust transport of edge modes is demonstrated by high transmission through the waveguide with a sharp bend. The localized corner mode is found at the corner with one isolated rod when a triangle-shaped sample is constructed. Our work not only shows a platform to mimic the topological physics in classical wave systems, but also offers a potential application in designing high-performance photonic devices.

A Note on the Connection between Non-Additive Entropy and h-Derivative.

In order to study as a whole a wide part of entropy measures, we introduce a two-parameter non-extensive entropic form with respect to the h-derivative, which generalizes the conventional Newton-Leibniz calculus. This new entropy, Sh,h', is proved to describe the non-extensive systems and recover several types of well-known non-extensive entropic expressions, such as the Tsallis entropy, the Abe entropy, the Shafee entropy, the Kaniadakis entropy and even the classical Boltzmann-Gibbs one. As a generalized entropy, its corresponding properties are also analyzed.

[Chemical composition analysis and value evaluation of stems and leaves of Astragalus membranaceus var. mongholicus].

This study aimed to provide data support for resource utilization of the stems and leaves of Astragalus membranaceus var. mongholicus(SLAM) by analyzing and evaluating the chemical constituents. The crude protein, crude fiber, and soluble saccharide of SLAM were analyzed by Kjeldahl method, filtration method, and UV-Vis spectrophotometry, respectively. The nucleosides, amino acids, flavonoids, and saponins of SLAM were analyzed by ultraperformance liquid chromatography-triple quadrupole mass spectrometry(UPLC-TQ-MS). Combined with principal component analysis(PCA), the quality difference of resource components of SLAM was comprehensively evaluated. The results showed that the average content of crude protein, crude fiber, total polysaccharide, and redu-cing sugar in SLAM was 5.11%, 30.33%, 11.03 mg·g~(-1), and 31.90 mg·g~(-1), respectively. Six nucleosides, 15 amino acids, 22 flavonoids, and one saponin were detected, with an average content of 1.49 mg·g~(-1), 6.00 mg·g~(-1), 1.86 mg·g~(-1), and 35.67 µg·g~(-1), respectively. The content of various types of chemical components in SLAM differed greatly in different harvesting periods and growing years. The results of PCA showed that the quality of SLAM produced in Ningxia was superior. The results can provide references for the utilization of SLAM.

SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via p53/SLC7A11/GPX4 signaling.

SHARPIN is a tumor-associated gene involved in the growth and proliferation of many tumor types. A function of SHARPIN in cholangiocarcinoma (CCA) is so far unclear. Here, we studied the role and function of SHARPIN in CCA and revealed its relevant molecular mechanism. The expression of SHARPIN was analyzed in cholangiocarcinoma tissues from patients using immunohistochemistry, quantitative PCR, and western blot analysis. Expression of SHARPIN was suppressed/overexpressed by siRNA silencing or lentiviral overexpression vector, and the effect on cell proliferation was determined by the CCK-8 assay and flow cytometry. Accumulation of reactive oxygen species was measured with MitoTracker, and JC-1 staining showed mitochondrial fission/fusion and mitochondrial membrane potential changes as a result of the silencing or overexpression. The ferroptosis marker solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and the antioxidant enzymes superoxide dismutase 1 (SOD-1) and SOD-2 were analyzed by western blot. The results showed that SHARPIN expression was increased in CCA tissue, and this was involved in cell proliferation. SHARPIN silencing resulted in accumulated reactive oxygen species, reduced mitochondrial fission, and a reduced mitochondrial membrane potential. Silencing of SHARPIN inhibited the ubiquitination and degradation of p53, and downregulated levels of SLC7A11, GPX4, SOD-1, and SOD-2, all of which contributed to excessive oxidative stress that leads to ferroptosis. Overexpression of SHARPIN would reverse the above process. The collected data suggest that in CCA, SHARPIN-mediated cell ferroptosis via the p53/SLC7A11/GPX4 signaling pathway is inhibited. Targeting SHARPIN might be a promising approach for the treatment of CCA.

Near-infrared ITO-based photonic hypercrystals with large angle-insensitive bandgaps.

The angle-sensitive photonic bandgap (PBG) is one of the typical features of one-dimensional photonic crystals. Based on the phase-variation compensation effect between the dielectric and hyperbolic metamaterials (HMMs), angle-insensitive PBGs can be realized in photonic hypercrystals. However, since hypercrystals are usually constructed using metal components, these angle-insensitive PBGs are mostly limited to narrow bandwidths in visible range. Here, we replace metal with indium tin oxide (ITO) to construct HMMs in the near-infrared range. In these ITO-based HMMs, we experimentally demonstrate the negative refraction of light in transverse magnetic polarization. With this HMM component, we realize a photonic hypercrystal with an angle-insensitive PBG in the wavelength range of 1.15-2.02 µm. These ITO-based hypercrystals with large angle-insensitive PBGs can find applications in near-infrared reflectors or filters.

Dissipative Acousto-optic Interactions in Optical Microcavities.

We propose and demonstrate experimentally the strong dissipative acousto-optic interaction between a suspended vibrating microfiber and a whispering-gallery microcavity. On the one hand, the dissipative response driven by an external stimulus of acoustic waves is found to be stronger than the dispersive response by 2 orders of magnitude. On the other hand, dead points emerge with the zero dissipative response at certain parameters, promising the potentials in physical sensing such as precise measurements of magnetic field and temperature. The strong dissipative acousto-optic interaction is then explored for ultrasensitive detection of broadband acoustic waves. A noise equivalent pressure as low as 0.81 Pa at 140 kHz in air is demonstrated experimentally, insensitive to cavity Q factors and does not rely on mechanical resonances.

Knockout of interleukin-17A diminishes ventricular arrhythmia susceptibility in diabetic mice via inhibiting NF-κB-mediated electrical remodeling.

Interleukin-17A (IL-17), a potent proinflammatory cytokine, has been shown to participate in cardiac electrical disorders. Diabetes mellitus is an independent risk factor for ventricular arrhythmia. In this study, we investigated the role of IL-17 in ventricular arrhythmia of diabetic mice. Diabetes was induced in both wild-type and IL-17 knockout mice by intraperitoneal injection of streptozotocin (STZ). High-frequency electrical stimuli were delivered into the right ventricle to induce ventricular arrhythmias. We showed that the occurrence rate of ventricular tachycardia was significantly increased in diabetic mice, which was attenuated by IL-17 knockout. We conducted optical mapping on perfused mouse hearts and found that cardiac conduction velocity (CV) was significantly decreased, and action potential duration (APD) was prolonged in diabetic mice, which were mitigated by IL-17 knockout. We performed whole-cell patch clamp recordings from isolated ventricular myocytes, and found that the densities of Ito, INa and ICa,L were reduced, the APDs at 50% and 90% repolarization were increased, and early afterdepolarization (EAD) was markedly increased in diabetic mice. These alterations were alleviated by the knockout of IL-17. Moreover, knockout of IL-17 alleviated the downregulation of Nav1.5 (the pore forming subunit of INa), Cav1.2 (the main component subunit of ICa,L) and KChIP2 (potassium voltage-gated channel interacting protein 2, the regulatory subunit of Ito) in the hearts of diabetic mice. The expression of NF-κB was significantly upregulated in the hearts of diabetic mice, which was suppressed by IL-17 knockout. In neonatal mouse ventricular myocytes, knockdown of NF-κB significantly increased the expression of Nav1.5, Cav1.2 and KChIP2. These results imply that IL-17 may represent a potential target for the development of agents against diabetes-related ventricular arrhythmias.

Strain Response and Buckling Behavior of Composite Cylindrical Shells Subjected to External Pressure with One End Fixed and the Other under Free Boundary Conditions.

This study aims to reveal the buckling behavior of filament-wound composite cylindrical shells subjected to external pressure. The boundary conditions of the cylindrical shells were one end fixed and the other free. The carbon fiber stacking sequences were [±90]2/([±20]/[±90]/[±40]/[±90]/[±60]/[±90])2/[±90]. Finite element software ANSYS 16.2 was used for the numerical simulation to predict the critical buckling pressure and buckling behavior of composite cylindrical shell. External hydrostatic pressure tests were conducted, where the buckling behavior and strain response were observed. Numerical simulation accurately predicted the critical buckling pressure of carbon fiber/epoxy filament composite cylindrical shells under external pressure with 3.5% deviation from the experimental results. The buckling modes simulated by the finite element method agreed well with the deformed shape observed in the experiment, which was characterized by the uniform distribution of the three hoop waves. Comparing the axial compressive strain and hoop compressive strain of the composite shell, it was found that the circumferential stiffness of the shell was weaker than the axial stiffness. In addition, a comparative study of the strains of the fixed-end and free-end metal control sleeves was carried out. The results show that the boundary conditions have a significant influence on the strain response of control sleeves.

The dark triad and depressive symptoms among chinese adolescents: moderated mediation models of age and emotion regulation strategies.

Dark Triad has been found to relate with depressive symptoms, but the underlying mechanism was rarely investigated. In the present study, we examined the mediating effect of two emotion regulation strategies (cognitive reappraisal and expressive suppression) and the moderating effect of gender and age. 709 Chinese adolescents aged 12-18 years (M = 14.54, SD = 1.70;55.3% girls) filled out the Dirty Dozen, Emotion Regulation Questionnaire and the 10-item of Center for Epidemiological Studies Depression Scale. As expected, Dark Triad was related with increased levels of depression and emotion regulation strategies acted as mediators in these associations. Suppression mediated the relationship between Machiavellianism and depression. Reappraisal and suppression mediated the link between psychopathy and depression. Reappraisal mediated the association between narcissism and depression. Besides, age moderated the effect of Machiavellianism on reappraisal, suggesting Machiavellianism had a negative impact on reappraisal for younger adolescents, but not for older adolescents. Age also moderated the effect of reappraisal on depression, indicating the negative effect of reappraisal on depression was stronger for younger adolescents than for older adolescents. These results address how Dark Triad traits affect depression via emotion regulation strategies and indicate the effectiveness of Dark Triad and emotion regulation strategies may change across age groups.

Quasiperiodic metamaterials empowered non-metallic broadband optical absorbers.

Realizing a polarization-insensitive broadband optical absorber plays a key role in the implementation of microstructure optoelectrical devices with on-demand functionalities. However, the challenge is that most of these devices involve the constituent metals, thus suffering from poor chemical and thermal stability and a complicated manufacturing process. In addition, the extreme contrast between the negative (metallic) and positive (dielectric) real parts of the constituent permittivities can cause additional problems in the design of structural devices. Based on these facts, this work proposes a design of planar broadband one-dimensional structure based on Fibonacci geometry. Experimental results show that the proposed planar structure exhibits high absorptivity behavior independent of polarization and angle in the wavelength range of 300-1000 nm. The absorptivity remains more than 80% when the incident angle is 60°. This proof-of-concept represents a new strategy for realizing non-metallic broadband optical absorbers with advantages of polarization-independence, low-cost, and wide-field-of-view and paves the way for light manipulation under harsh conditions.

Nonreciprocal Tamm plasmon absorber based on lossy epsilon-near-zero materials.

Contrary to conventional Tamm plasmon (TP) absorbers of which narrow absorptance peaks will shift toward short wavelengths (blueshift) as the incident angle increases for both transverse magnetic (TM) and transverse electric (TE) polarizations, here we theoretically and experimentally achieve nonreciprocal absorption in a planar photonic heterostructure composed of an isotropic epsilon-near-zero (ENZ) slab and a truncated photonic crystal for TM polarization. This exotic phenomenon results from the interplay between ENZ and material loss. And the boundary condition across the ENZ interface and the confinement effect provided by the TP can enhance the absorption in the ENZ slab greatly. As a result, a strong and nonreciprocal absorptance peak is observed experimentally with a maximum absorptance value of 93% in an angle range of 60∼70°. Moreover, this TP absorber shows strong angle-independence and polarization-dependence. As the characteristics above are not at a cost of extra nanopatterning, this structure is promising to offer a practical design in narrowband thermal emitter, highly sensitive biosensing, and nonreciprocal nonlinear optical devices.

HA-g-CS Implant and Moderate-intensity Exercise Stimulate Subchondral Bone Remodeling and Promote Repair of Osteochondral Defects in Mice.

Background: Substantial evidence shows that crosstalk between cartilage and subchondral bone may play an important role in cartilage repair. Animal models have shown that hydroxyapatite-grafted-chitosan implant (HA-g-CS) and moderate-intensity exercise promote regeneration of osteochondral defects. However, no in vivo studies have demonstrated that these two factors may have a synergistic activity to facilitate subchondral bone remodeling in mice, thus supporting bone-cartilage repair. Questions: This study was to clarify whether HA-g-CS and moderate-intensity exercise might have a synergistic effect on facilitating (1) regeneration of osteochondral defects and (2) subchondral bone remodeling in a mouse model of osteochondral defects. Methods: Mouse models of osteochondral defects were created and divided into four groups. BC Group was subjected to no treatment, HC Group to HA-g-CS implantation into osteochondral defects, ME group to moderate-intensity treadmill running exercise, and HC+ME group to both HA-g-CS implantation and moderate-intensity exercise until sacrifice. Extent of subchondral bone remodeling at the injury site and subsequent cartilage repair were assessed at 4 weeks after surgery. Results: Compared with BC group, HC, ME and HC+ME groups showed more cartilage repair and thicker articular cartilage layers and HC+ME group acquired the best results. The extent of cartilage repair was correlated positively to bone formation activity at the injured site as verified by microCT and correlation analysis. Histology and immunofluorescence staining confirmed that bone remodeling activity was increased in HC and ME groups, and especially in HC+ME group. This bone formation process was accompanied by an increase in osteogenesis and chondrogenesis factors at the injury site which promoted cartilage repair. Conclusions: In a mouse model of osteochondral repair, HA-g-CS implant and moderate-intensity exercise may have a synergistic effect on improving osteochondral repair potentially through promotion of subchondral bone remodeling and generation of osteogenesis and chondrogenesis factors. Clinical Relevance: Combination of HA-g-CS implantation and moderate-intensity exercise may be considered potentially in clinic to promote osteochondral defect repair. Also, cartilage and subchondral bone forms a functional unit in an articular joint and subchondral bone may regulate cartilage repair by secreting growth factors in its remodeling process. However, a deeper insight into the exact role of HA-g-CS implantation and moderate-intensity exercise in promoting osteochondral repair in other animal models should be explored before they can be applied in clinic in the future.