Simulation-Guided Rational Design of DNA Walker-Based Theranostic Platform.

Biomolecule-functionalized nanoparticles represent a type of promising biomaterials in biomedical applications owing to their excellent biocompatibility and versatility. DNA-based reactions on nanoparticles have enabled emerging applications including intelligent biosensors, drug delivery, and biomimetic devices. Among the reactions, strand hybridization is the critical step to control the sensitivity and specificity of biosensing, and the efficiency of drug delivery. However, a comprehensive understanding of DNA hybridization on nanoparticles is still lacking, which may differ from the process in homogeneous solutions. To address this limitation, coarse-grained model-based molecular dynamic simulation is harnessed to disclose the critical factors involved in intermolecular hybridization. Based on simulation guidance, DNA walker-based smart theranostic platform (DWTP) based on "on-particle" hybridization is developed, showing excellent consistency with simulation. DWTP is successfully applied for highly sensitive miRNA 21 detection and tumor-specific miRNA 21 imaging, driven by tumor-endogenous APE 1 enzyme. It enables the precise release of antisense oligonucleotide triggered by tumor-endogenous dual-switch miRNA 21 and APE 1, facilitating effective gene silencing therapy with high biosafety. The simulation of "on-particle" DNA hybridization has improved the corresponding biosensing performance and the release efficiency of therapeutic agents, representing a conceptually new approach for DNA-based device design.

Effects of decompressive operation on cardiac autonomic regulation in patients with cervical spondylotic myelopathy: analysis of blood pressure, heart rate, and heart rate variability.

PURPOSE: To investigate the effects of cervical decompression operation on cardiac autonomic regulation and its relationship to recovery of somatic neurological function in cervical spondylotic myelopathy (CSM) patients. METHODS: One hundred and thirty-two consecutive patients were enrolled in this study, in which 73 patients received decompression operation and the remaining 59 were treated non-operatively. The follow-up period was 6 months. Baseline and follow-up evaluation included Japanese Orthopaedic Association (JOA) score, office-based blood pressure (BP) measurement, heart rate (HR), and 24-h heart rate variability (HRV) assessment. Relationship between achieved JOA score (final JOA score-baseline score) and changes of BP, HR, and HRV parameters in both operative and non-operative groups was analyzed. RESULTS: In operative group, patients' JOA score and markers of parasympathetic activity in HRV assessment were significantly higher than baseline level 6 months later. Blood pressure, especially systolic blood pressure (SBP), was significantly downregulated in both hypertension and non-hypertension patients. Mean heart rate was also significantly decreased. Furthermore, achieved JOA score was significantly negatively correlated with changes of SBP, minimal HR, mean HR, maximum HR, but significantly positively correlated with changes of HRV parameters reflecting parasympathetic activity. However, changes of JOA score, BP, HR, and HRV parameters in non-operative group were not significant. CONCLUSIONS: Cervical decompression operation could improve both somatic neurological function and cardiac autonomic regulation in CSM patients, and achieved JOA score was significantly positively correlated with improvement in HRV and cardiac parasympathetic activity. These slides can be retrieved under Electronic Supplementary Material.

ZIP4 upregulation aggravates nucleus pulposus cell degradation by promoting inflammation and oxidative stress by mediating the HDAC4-FoxO3a axis.

BACKGROUND: Extracellular matrix metabolism dysregulation in nucleus pulposus (NP) cells represents a crucial pathophysiological feature of intervertebral disc degeneration (IDD). Our study elucidates the role and mechanism of Testis expressed 11 (TEX11, also called ZIP4) extracellular matrix degradation in the NP. MATERIALS AND METHODS: Interleukin-1ß (IL-1ß) and H2O2 were used to treat NP cells to establish an IDD cell model. Normal NP tissues and NP tissues from IDD patients were harvested. ZIP4 mRNA and protein profiles in NP cells and tissues were examined. Enzyme-linked immunosorbent assay (ELISA) confirmed the profiles of TNF-α, IL-6, MDA, and SOD in NP cells. The alterations of reactive oxygen species (ROS), lactate dehydrogenase (LDH), COX2, iNOS, MMP-3, MMP-13, collagen II, aggrecan, FoxO3a, histone deacetylase 4 (HDAC4), Sirt1 and NF-κB levels in NP cells were determined using different assays. RESULTS: The ZIP4 profile increased in the NP tissues of IDD patients and IL-1ß- or H2O2-treated NP cells. ZIP4 upregulation bolstered inflammation and oxidative stress in NP cells undergoing IL-1ß treatment and exacerbated their extracellular matrix degradation, whereas ZIP4 knockdown produced the opposite outcome. Mechanistically, ZIP4 upregulated HDAC4 and enhanced NF-κB phosphorylation while repressing Sirt1 and FoxO3a phosphorylation levels. HDAC4 knockdown or Sirt1 promotion attenuated the effects mediated by ZIP4 overexpression in NP cells. CONCLUSIONS: ZIP4 upregulation aggravates the extracellular matrix (ECM) degradation of NP cells by mediating inflammation and oxidative stress through the HDAC4-FoxO3a axis.

Weak correlations among leaf thermal metrics, economic traits and damages under natural heatwaves.

The frequency and intensity of heatwaves are increasing around the world, causing severe damages to plants, but whether leaf thermal metrics is in line with leaf economic spectrum is still controversial. Here, we measured leaf damage ratio, leaf thermal metrics (tolerance and sensitivity) and economic traits of 131 woody species across five cities along the Yangtze River after a two-month natural extreme temperature event. We found that leaf thermal sensitivity but not thermal tolerance was correlated with leaf damage ratio, and the relationships between leaf thermal metrics and economic traits were weak, indicating that leaf thermal adaptation may be independent from leaf carbon construction. This study suggests a potential indicator for predicting plant survival under heatwaves, urging future research to explore more physiological traits to comprehensively understand plant heat responses and adaptations.

Circular RNA circVRK1 suppresses the proliferation, migration and invasion of osteosarcoma cells by regulating zinc finger protein ZNF652 expression via microRNA miR-337-3p.

Circular RNA is an innovative kind of endogenous non-coding RNA, which could take part in tumorigenesis. Nonetheless, the potential molecular mechanisms of circVRK1 in the progression of osteosarcoma remain unresolved. In the current study, we initially investigated circVRK1 levels in osteosarcoma clinical samples and cell lines by qRT-PCR analysis and northern blot assay. RNase R treatments, RNA stability assay and nucleoplasmic separation assay were conducted to identify the characteristics of circVRK1. We adopted CCK-8, colony formation, wound-healing, and transwell assays to assess the biological effects of circVRK1 on the proliferation, migration, and invasiveness of osteosarcoma cells in vitro. We then constructed a xenograft model in nude mice to confirm the suppressive role of circVRK1 in vivo. Moreover, dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays were utilized to elucidate the underlying molecular mechanisms mediated by circVRK1. We demonstrated that circVRK1 was a stable circular transcript localized in the cytoplasm of osteosarcoma cells, and the down-regulation of circVRK1 in osteosarcoma tissues was related to poor outcome of patients. Meanwhile, over-expressed circVRK1 obviously restrained the growth, migration, and invasion of osteosarcoma in vitro and in vivo. Mechanistically, circVRK1 was assumed to be a microRNA sponge for miR-337-3p, and ZNF652 was the downstream gene of miR-337-3p. CircVRK1 overexpression or miR-337-3p knockdown accelerated ZNF652 expression, and up-regulated miR-337-3p efficiently abolished the promotion of ZNF652 induced by circVRK1. Moreover, rescue experiments have proved that circVRK1 inhibits the progression of osteosarcoma by modulating the miR-337-3p/ZNF652 axis. Therefore, we conclude that circVRK1 promotes ZNF652 expression by sponging miR-337-3p. CircVRK1 serves as a molecule sponge for miR-337-3p and mediates the ceRNA network to promote the expression of ZNF652, thus suppresses osteosarcoma proliferation, migration and invasion.

METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6.

Imbalanced osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is considered the core pathological characteristic of steroid-associated osteonecrosis of the femoral head (SONFH). N6-Methyladenosine (m6A) is the most common type of RNA modification in eukaryotic cells and participates in various physiological and pathological processes. However, the relationship between m6A modification and SONFH has not been reported. In the present study, we aimed to explore the roles of m6A modifications and methyltransferase METTL14 in SONFH. Our results showed that the m6A levels were down-regulated in femoral head tissues and BMSCs from SONFH patients, and this effect was attributed to the reduction of METTL14. Furthermore, METTL14 overexpression in BMSCs from SONFH patients enhanced cell proliferation and osteogenic differentiation. We further identified PTPN6 as the downstream target of METTL14 by mRNA sequencing. Mechanistically, METTL14 regulated PTPN6 expression by increasing PTPN6 mRNA stability in an m6A-dependent manner. Moreover, PTPN6 knockdown abrogated the beneficial effects of METTL14 overexpression on BMSCs. Additionally, we found that METTL14 activated the Wnt signaling pathway, and this effect was caused by the interaction of PTPN6 and GSK-3ß. In conclusion, we elucidated the functional roles of METTL14 and m6A methylation in SONFH BMSCs and identified a novel RNA regulatory mechanism, providing a potential therapeutic target for SONFH.

Recovery Process After Anterior Cervical Decompression in Patients With Cervical Spondylotic Myelopathy With Different Natural History.

STUDY DESIGN: An observational prospective cohort study. OBJECTIVE: To investigate the influence of natural history on the recovery of patients with cervical spondylotic myelopathy (CSM) after anterior cervical decompression. SUMMARY OF BACKGROUND DATA: The natural history of CSM has not been clearly elucidated, it remains unclear whether the natural history of CSM is associated with the recovery process after surgical treatment. MATERIALS AND METHODS: Patients with CSM (n=117) after anterior cervical decompression were stratified variously on the basis of natural history features. Baseline and postoperative neurological functions were rated using the Japanese Orthopaedic Association (JOA) and patient-based self-evaluation (PBSE) scores. The minimum and maximum recovery times for sensory function, and motor functions of the upper and lower extremities were analyzed separately at time points 1-60 months after surgery. RESULTS: In all patients, the postoperative JOA and PBSE scores were significantly improved relative to baseline, in which sensory function recovered most quickly, followed by upper-extremity and lower-extremity motor functions. However, when compared with patients whose first symptom onset at the lower extremity, patients with the first onset at the upper extremity required less time to recover lower-extremity motor function, but more time to recover upper-extremity motor function. Patients with rapid progression had significantly lower preoperative and final JOA and PBSE scores compared with patients whose progression was steady or stepwise. Patients with preoperative symptoms ≥1 year had longer recovery time and poorer functional outcomes compared with those symptoms <1 year. CONCLUSIONS: In patients with CSM, the location of first symptom onset, progressive velocity of symptom, and duration of preoperative symptoms significantly influenced the recovery process after anterior cervical decompression. LEVEL OF EVIDENCE: Level 2-observational prospective study.

Important evidence of constant low CO2 windows and impacts on the non-closure of the greenhouse effect.

The CO2 distribution in the atmosphere remains unclear for the complexity of the long-range vertical transport process and other influencing factors. In this work, regression analysis was used to verify the accuracy of CO2 concentrations datasets. Geostatistical analyses were used to investigate the spatiotemporal distributions of CO2 at 7 levels from near the surface to the mid-troposphere (0~5 km). Spatial correlation and time series analyses were used to further determine the diffusion characteristics of the CO2 concentration based on the horizontal wind (NCEP R2), which is one of the main driving factors. The results showed that the horizontal, not vertical, diffusion of CO2 becomes increasingly more prominent with the decrease in atmospheric pressure to the mid-troposphere, whereas many regions, such as the Rocky Mountains and Qinghai-Tibet Plateau, have constant low values throughout the year due to the influence of high topography (up to 10.756 ppmv lower than that near the surface). These areas form low CO2 concentration 'windows' keeping letting thermal infrared energy out into space. This study is the first to question the existing view of the closure of the 'greenhouse effect'. Future research studies should more precisely determine the closure threshold and the uncertainties about the surface fluxes.