Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling ...in sensory innervation for OA pain. We show that osteoclasts secrete netrin-1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, dorsal root ganglion neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for netrin-1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase-positive (TRAP-positive) osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g., netrin-1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.
Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury. The exact pathogenesis of HO remains unknown. Here we show ...that TGF-β initiates and promotes HO in mice. We find that calcified cartilage and newly formed bone resorb osteoclasts after onset of HO, which leads to high levels of active TGF-β that recruit mesenchymal stromal/progenitor cells (MSPCs) in the HO microenvironment. Transgenic expression of active TGF-β in tendon induces spontaneous HO, whereas systemic injection of a TGF-β neutralizing antibody attenuates ectopic bone formation in traumatic and BMP-induced mouse HO models, and in a fibrodysplasia ossificans progressive mouse model. Moreover, inducible knockout of the TGF-β type II receptor in MSPCs inhibits HO progression in HO mouse models. Our study points toward elevated levels of active TGF-β as inducers and promoters of ectopic bone formation, and suggest that TGF-β might be a therapeutic target in HO.
Aging is a process associated with blood–brain barrier (BBB) damage and the reduction in neurogenesis, and is the greatest known risk factor for neurodegenerative disorders. However, the effects of ...Fe3O4 nanozymes on neurogenesis have rarely been studied. This study examined the effects of Fe3O4 nanozymes on neuronal differentiation in the dentate gyrus (DG) and BBB integrity of D-galactose-induced aged mice. Long-term treatment with Fe3O4 nanozymes (10 μg/mL diluted in ddH2O daily) markedly increased the doublecortin (DCX) immunoreactivity and decreased BBB injury induced by D-galactose treatment. In addition, the decreases in the levels of antioxidant proteins including superoxide dismutase (SOD) and catalase as well as autophagy-related proteins such as Becin-1, LC3II/I, and Atg7 induced by D-galactose treatment were significantly ameliorated by Fe3O4 nanozymes in the DG of the mouse hippocampus. Furthermore, Fe3O4 nanozyme treatment showed an inhibitory effect against apoptosis in the hippocampus. In conclusion, Fe3O4 nanozymes can relieve neuroblast damage and promote neuroblast differentiation in the hippocampal DG by regulating oxidative stress, apoptosis, and autophagy.
Ischemic stroke (IS) remains a major cause of disability and death. The changes in long non-coding RNA (lncRNA) RGD1566344 expression in the mouse cerebral cortex, including the infarct and penumbra ...regions after IS, are not clear. Less is known about the impact and underlying mechanisms of RGD1566344 in IS. In this study, we found that RGD1566344 levels were elevated in the ischemic infarct and penumbra regions 12 h after middle cerebral artery occlusion/reperfusion (MCAO/R) in male mice and in PC12 cells with oxygen glucose deprivation/reperfusion (OGD/R). The inhibition of RGD1566344 by small interference RNA (siRNA) significantly alleviated apoptosis in OGD/R PC12 cells. In cell transfection, quantitative real-time PCR, and Western blot experiments, we demonstrated the possible interaction of non-POU domain-containing octamer-binding protein (NONO) with RGD1566344. The NONO level in OGD/R PC12 cells was obviously increased after inhibiting the RGD1566344 treatment; subsequently the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was activated. This demonstrated the effect of the RGD1566344-NONO-AKT axis on neural protection after IS. These results revealed a new molecular mechanism of lncRNA RGD1566344 inhibitors through targeting NONO/AKT/mTOR signaling to protect against ischemic neuronal injury, providing strong evidence for the development of promising therapeutic strategies against IS.
In 2007, the Chinese government piloted the Free Teacher Education (FTE) program in the top normal universities with the aim to enlist high-quality young graduates to join the teaching profession and ...to improve education in underdeveloped rural regions. However, a conflict has arisen as FTE students enrolled in the program are reluctant to work in rural schools. Drawing on in-depth interviews with 19 FTE students, this study argues that the curriculum of the FTE program needs to be reformed to combat the social mobility discourse and to include social equity and justice as essential components.
► Unequal distribution of quality teachers influences educational equity. ► The FTE Program in China aims to channel quality teachers to poor schools. ► The FTE students are driven by the incentive for upward social mobility. ► FTE students are resistant to long-term service in rural schools. ► Teacher education programs should emphasize social commitment in curriculum.
Unreasonable irrigation and nitrogen application reduce tomato yield and waste resources. This study explored the effects of water conservation and nitrogen reduction on tomato yield, dry matter, ...quality, water productivity and nitrogen use efficiency in Northeast China. Experiments were conducted during 2020 and 2021 at three irrigation levels (85–95 %, 75–85 %, and 65–75 % θFC) and three nitrogen application levels (120, 180, and 240 kg hm−2). The optimal water and nitrogen supply patterns were obtained by establishing a newly evaluated Entropy Weight Method−Technique for Order Preference by Similarity to Ideal Solution−Adversarial Interpretive Structure Model (EWM−TOPSIS−AISM). The results showed that the amount of irrigation and nitrogen application significantly affected tomato quality (P ≤ 0.5). Proper deficit irrigation improved tomato quality. Reducing the nitrogen application rate improved nitrogen use efficiency but decreased the tomato yield. Increasing the amount of irrigation increased tomato yield and nitrogen use efficiency. Tomato yield was negatively correlated with water productivity (R= −0.25 in 2020 and R= −0.37 in 2021) and nitrogen use efficiency (R= −0.30 in 2020 and R= −0.20 in 2021). The evaluation results showed that the best water and nitrogen supply mode for our experiment was irrigation at 75–85 % θFC and nitrogen application rate of 180 kg hm−2. The study could promote the sustainable production of greenhouse tomatoes in Northeast China.
The aroma characteristics of Pu-erh tea were studied in this work. A total of 117 volatile compounds were identified by HS-SPME combined with GC–TOF/MS, of which 29 active aroma compounds were ...identified by olfactometry. The active aroma compounds of Pu-erh tea were analyzed by intensity aroma (IA), aroma extraction dilution (AEDA), sensory quantification value (MF), detection frequency (DFA) and odor activity value (OAV). 24, 21 and 23 active aroma components were identified by DFA, AEDA and OAV, while 20 by IA and MF. Recombination of the obtained active aroma components indicated that OAV method was best for determining the active aroma compounds as the aroma profile of OAV recombination model was the most similar to that of Pu-erh tea sample. Omission test of the OAV recombination model furtherly identified 19 characteristic active aroma compounds of Pu-erh tea, and linalool, 1,2,3-trimenthoxybenzebe, 1,2,4-trimethoxybenzene and ɑ-ionone were the key characteristic active aromatic compounds.
Objective
This study aimed to explore decision‐making impulsivity and its neural mechanisms in patients with episodic migraine without aura (EMoA).
Background
Previous evidence indicates increased ...impulsivity and altered reward processing in patients with chronic migraine and medication overuse; however, whether the same holds true for those with EMoA is unclear.
Methods
Patients newly diagnosed with EMoA (n = 51) and healthy controls (HC, n = 45) were recruited. All participants completed delay discounting task, cognitive assessments, a questionnaire for headache profile, and resting‐state function magnetic resonance imaging scans. Resting‐state functional connectivity (RSFC) between the regions of interest and the entire brain was explored.
Results
Patients with EMoA showed a steeper subjective discount rate than HCs (F = 4.74, p = .032), which was positively related to a history of migraines (r = .742, p < .001). RSFC among the ventral striatum (vSTR), ventromedial prefrontal cortex, and occipital cortex was lower in patients with EMoA than in control groups, which was correlated with history (r′ = .294, p = .036) and subjective discount rate (r′ = .380, p = .006). Additionally, discounting rates and RSFC between the vSTR and occipital regions were significantly abnormal in the triptan group than the non‐triptan group. Mediating effect analysis indicated a significant mediating effect in the change in RSFC between the vSTR and occipital status, history of triptan use, and subjective discount rate.
Conclusion
This study further elucidated that an increase in delayed discounting rate exists in patients with EMoA and is related to the abnormality of the value processing network.
Blood always shows some immune changes after spinal cord injury (SCI), and detection of such changes in blood may be helpful for diagnosis and treatment of SCI. However, studies to date on blood ...immune changes after SCI in humans are not comprehensive. Therefore, to obtain the characteristics of blood immune changes and immunodiagnostic blood biomarkers of SCI and its different grades, a human blood transcriptome sequencing dataset was downloaded and analyzed to obtain differentially expressed immune-related genes (DEIGs), related functions and signaling pathways related to SCI and its various grades. Characteristic biomarkers of SCI and its different grades were identified by using weighted gene coexpression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) logistic regression. Expression of biomarkers was verified through experiments. The area under the curve (AUC) of biomarkers was calculated to evaluate their diagnostic value, and differences in immune cell content were examined. In this study, 17 kinds of immune cells with different contents between the SCI group and healthy control (HC) group were identified, with 7 immune cell types being significantly increased. Differences in the content of immune cells between different grades of SCI and the HC group were also discovered. DEIGs were identified, with alteration in some immune-related signaling pathways, vascular endothelial growth factor signaling pathways, and axon guidance signaling pathways. The SCI biomarkers identified and those of American Spinal Injury Society Impairment Scale (AIS) A and AIS D of SCI have certain diagnostic sensitivity. Analysis of the correlation of immune cells and biomarkers showed that biomarkers of SCI, AIS A grade and AIS D grade correlated positively or negatively with some immune cells. CKLF, EDNRB, FCER1G, SORT1, and TNFSF13B can be used as immune biomarkers for SCI. Additionally, GDF11and HSPA1L can be used as biomarkers of SCI AIS A grade; PRKCA and CMTM2 can be used as biomarkers of the SCI AIS D grade. Detecting expression of these putative biomarkers and changes in related immune cells may be helpful for predicting the severity of SCI.
The difference between MRI (Magnetic resonance imaging)-R2* and T2 mapping sequences regarding their superiority in the detection of microstructural cartilage changes in knees with limited ROM (range ...of motion) was unknown.
Twenty male cynomolgus monkeys (mean age: 10.65 ± 0.97 years) underwent knee ROM evaluations and were divided into three groups: Group A (n = 10), with similar left and right knee ROM; Group B (n = 5), with left knee ROM superior to right; and Group C (n = 5), with left knee ROM inferior to right. Twenty-eight ROIs (regions of interest) in the cartilage of the lateral (L) and medial (M) femoral trochlea (FT), anterior (A)/central (C)/posterior (P) femoral condyle (FC) and tibial plateau (TP) of both knees were identified in each monkey. The corresponding ROI values in R2* and T2 mapping sequences were recorded for analysis. One-way ANOVA, Chi-square tests and Pearson's correlation analysis were used for statistical analyses.
Among the total 1120 ROIs, significant differences in R2* values among the three groups existed in two ROIs: cartilage of the right MPTP (F = 5.216, P = 0.017) and left MAFC (F = 4.919, P = 0.021). However, the T2 mapping values of all ROIs were similar among the three groups. Microstructural cartilage changes occurred more frequently in the medial (40 ROIs) than in the lateral (0 ROIs) knee compartment (χ
= 43.077, P < 0.001). The Group B cartilage R2* value of the right MPTP increased with the difference in bilateral knee ROM (r = 0.913, P = 0.030).
In knees with limited ROM, MRI-R2* sequence is superior to T2 mapping in the detection of microstructural cartilage changes, which the medial knee compartment was more susceptible to. Cartilage R2* values tend to increase with the amount of knee ROM loss.
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