Collagen I is a critical organizer of scarring and CNS regeneration failure.

Although axotomized neurons retain the ability to initiate the formation of growth cones and attempt to regenerate after spinal cord injury, the scar area formed as a result of the lesion in most adult mammals contains a variety of reactive cells that elaborate multiple extracellular matrix and enzyme components that are not suitable for regrowth 1,2 . Newly migrating axons in the vicinity of the scar utilize upregulated LAR family receptor protein tyrosine phosphatases, such as PTPσ, to associate with extracellular chondroitin sulphate proteoglycans (CSPGs), which have been discovered to tightly entrap the regrowing axon tip and transform it into a dystrophic non-growing endball. The scar is comprised of two compartments, one in the lesion penumbra, the glial scar, composed of reactive microglia, astrocytes and OPCs; and the other in the lesion epicenter, the fibrotic scar, which is made up of fibroblasts, pericytes, endothelial cells and inflammatory cells. While the fibrotic scar is known to be strongly inhibitory, even more so than the glial scar, the molecular determinants that curtail axon elongation through the injury core are largely uncharacterized. Here, we show that one sole member of the entire family of collagens, collagen I, creates an especially potent inducer of endball formation and regeneration failure. The inhibitory signaling is mediated by mechanosensitive ion channels and RhoA activation. Staggered systemic administration of two blood-brain barrier permeable-FDA approved drugs, aspirin and pirfenidone, reduced fibroblast incursion into the complete lesion and dramatically decreased collagen I, as well as CSPG deposition which were accompanied by axonal growth and considerable functional recovery. The anatomical substrate for robust axonal regeneration was provided by laminin producing GFAP + and NG2 + bridging cells that spanned the wound. Our results reveal a collagen I-mechanotransduction axis that regulates axonal regrowth in spinal cord injury and raise a promising strategy for rapid clinical application.

Red Emission Carbon Nanoparticles Which Can Simultaneously Responding to Hypochlorite and pH.

Multi-targets detection has obtained much attention because this sensing mode can realize the detection of multi-targets simultaneously, which is helpful for biomedical analysis. Carbon nanoparticles have attracted extensive attention due to their superior optical and chemical properties, but there are few reports about red emission carbon nanoparticles for simultaneous detection of multi-targets. In this paper, a red emission fluorescent carbon nanoparticles were prepared by 1, 2, 4-triaminobenzene dihydrochloride at room temperature. The as-prepared red emission fluorescent carbon nanoparticles exhibited strong emission peak located at 635 nm with an absolute quantum yield up to 24%. They showed excellent solubility, high photostability and good biocompatibility. Furthermore, it could sensitively and selectively response to hypochlorite and pH, thus simultaneous detection of hypochlorite and pH was achieved by combining the red emission fluorescent carbon nanoparticles with computational chemistry. The formation mechanisms of red emission fluorescent carbon nanoparticles and their response to hypochlorite and pH were investigated, respectively.

Compartmentalized Nano-MOFs as Co-delivery Systems for Enhanced Antitumor Therapy.

Therapeutic bioactive macromolecules hold great promise in cancer therapy, but challenges such as low encapsulation efficiency and susceptibility to inactivation during the targeted co-delivery hinder their widespread applications. Compartmentalized nano-metal-organic frameworks (nMOFs) can easily load macromolecules in the innermost layer, protect them from the outside environment, and selectively release them in the target location after stimulation, showing great potential in the co-delivery of biomacromolecules. Herein, the rationally designed (GOx + CAT)/ZIF-8@BSATPZ/ZIF-8 (named GCZ@BTZ) nMOFs with compartmentalized structures are employed to deliver cascaded enzymes and the chemotherapeutic drug tirapazamine (TPZ)-conjugated bovine serum albumin (BSATPZ). Benefiting from the compartmentalized structure and protective shell, the GCZ@BTZ system is stable during blood circulation and preferentially accumulates in the tumor. Furthermore, in response to the acidic tumor environment, GCZ@BTZ effectively released the loading enzymes and BSATPZ. Along with the tumor starvation caused by depletion of glucose, cascaded reactions could also contribute to the enhancement of tumor hypoxia, which further activated BSATPZ-based chemotherapy. Notably, in the mouse tumor models, GCZ@BTZ treatment significantly inhibits tumor survival and metastasis. Such a compartmentalized nMOF delivery system presents a promising avenue for the efficient delivery of bioactive macromolecules.

Effects of vibration training on motor and non-motor symptoms for patients with multiple sclerosis: A systematic review and meta-analysis.

Background: Vibration therapy is one of the rehabilitation programs that may be effective in treating both motor and non-motor symptoms in Multiple Sclerosis patients. We conducted a comprehensive systematic review and meta-analysis to assess the effects of vibration therapy on motor and non-motor symptoms (functional mobility, balance, walking endurance, gait speed, fatigue, and quality of life) of this population. Methods: A systematic search of PubMed, Embase, the Cochrane Library, Web of Science, Physiotherapy Evidence Database, Scopus, Google Search Engine, and the China National Knowledge Infrastructure (CNKI). Two reviewers independently assessed the study quality. Results: Fourteen studies with 393 participants were finally included in the meta-analysis. The pooled results showed that vibration therapy had a significant advantage over the control intervention in improving balance function [mean difference (MD) = 2.04, 95% confidence interval (CI): 0.24-3.84, P = 0.03], and walking endurance (SMD = 0.34, 95% CI: 0.07-0.61, P = 0.01). Meanwhile, the degree of disability subgroup analysis revealed that the Expanded Disability Status Scale (EDSS) score (3.5-6) significantly improved functional mobility (MD: -1.18, 95% CI: -2.09 to 0.28, P = 0.01) and balance function (MD: 3.04, 95% CI: 0.49-5.59, P = 0.02) compared with the control group, and the EDSS (0-3.5) were more beneficial in walking endurance. The duration subgroup analysis indicated a significant difference in the effect of the duration (<4 weeks) on enhancing walking endurance (SMD: 0.46, 95% CI: 0.04-0.87, P = 0.03). However, no significant improvement was found in functional mobility, gait speed, fatigue, and quality of life. Conclusion: Vibration therapy may improve balance function and walking endurance, and the degree of disability and duration of intervention may affect outcomes. The evidence for the effects of vibration therapy on functional mobility, gait speed, fatigue, and quality of life remains unclear. More trials with rigorous study designs and a larger sample size are necessary to provide this evidence. Systematic Review Registration: PROSPERO, https://www.crd.york.ac.uk/prospero/#recordDetails, identifier: CRD42022326852.

CD3D, GZMK, and KLRB1 Are Potential Markers for Early Diagnosis of Rheumatoid Arthritis, Especially in Anti-Citrullinated Protein Antibody-Negative Patients.

Early diagnosis and monitoring of rheumatoid arthritis (RA) progress are critical for effective treatment. In clinic, the detection of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) are usually combined to diagnose early RA. However, the poor specificity of RF and high heterogeneity of ACPA make the early diagnosis of RA still challenging. Bioinformatics analysis based on high-throughput omics is an emerging method to identify novel and effective biomarkers, which has been widely used in many diseases. Herein, utilizing an integrated strategy based on expression correlation analysis and weighted gene coexpression network analysis (WGCNA), we identified 76 RA-trait different expression genes (DEGs). Combined with protein-protein interaction (PPI) network construction and clustering, new hub genes associated in RA synovia, CD3D, GZMK, and KLRB1, were identified. We verified the specificity of these genes in the synovium of RA patients through three external datasets. We also observed high sensitivity and specificity of them for ACPA-negative patients. CD3D, GZMK, and KLRB1 are potentially key mediators of RA pathogenesis and markers for RA diagnosis.

[Long-term Changes and Drivers of Ecological Security in Shahe Reservoir, China].

Monthly datasets of ecological indicators from 2010 to 2020 in Shahe Reservoir, Tianmuhu, China, were examined to reveal the long-term variations in water ecological security and its driving factors. The results of Secchi disk depth(SD) measurements revealed significantly spatial variation(P<0.05) within the reservoir. The highest SD was recorded in the downstream-linked reservoir, and the lowest SD was recorded in the upstream tributaries. In contrast, the values of other water ecological indicators were higher in the upstream tributaries than in the transition region and the downstream-linked reservoir area. In summer and autumn, the SD was low, while the concentrations of total phosphorous(TP), chlorophyll a(Chl-a), the permanganate index, and cyanobacterial biomass(BMc) were high. During the thermal stratification period from May to September, the concentrations of 2-methylisoborneol(MIB) and Chl-a were highest at a depth of 4 m, while diatom biomass(BMb) and BMc reached their maximum at depths of 2 m and 0.5 m, respectively. Therefore, spatial and temporal variations should be fully considered when evaluating aquatic ecological security. Focusing on spring and summer, when the risk of water ecological security was high, Chl-a combined with SD and MIB along with their correlation with other water quality indexes, was used to evaluate and optimize the ecological security of Shahe Reservoir. The evaluation results showed that the aquatic ecological security of the reservoir was excellent over the last 10 years; however, annual fluctuations have been large and the evaluation scores were spatially variable. While seasonal sampling strategies focusing on three layers depths are economical and reliable for lake regions with thermal stratification, our results indicate that tailored monitoring may be required to determine the aquatic ecological security of lakes and reservoirs. In Shahe Reservoir, the decrease in the SD and the increase in MIB caused by high TP and algal blooms were the most important drivers of ecological service function in the reservoir. Furthermore, hydrometeorological factors may also play important roles in the aquatic ecological security of reservoirs.

Feedback control of PLK1 by Apolo1 ensures accurate chromosome segregation.

Stable transmission of genetic material during cell division requires accurate chromosome segregation. PLK1 dynamics at kinetochores control establishment of correct kinetochore-microtubule attachments and subsequent silencing of the spindle checkpoint. However, the regulatory mechanism responsible for PLK1 activity in prometaphase has not yet been affirmatively identified. Here we identify Apolo1, which tunes PLK1 activity for accurate kinetochore-microtubule attachments. Apolo1 localizes to kinetochores during early mitosis, and suppression of Apolo1 results in misaligned chromosomes. Using the fluorescence resonance energy transfer (FRET)-based PLK1 activity reporter, we found that Apolo1 sustains PLK1 kinase activity at kinetochores for accurate attachment during prometaphase. Apolo1 is a cognate substrate of PLK1, and the phosphorylation enables PP1γ to inactivate PLK1 by dephosphorylation. Mechanistically, Apolo1 constitutes a bridge between kinase and phosphatase, which governs PLK1 activity in prometaphase. These findings define a previously uncharacterized feedback loop by which Apolo1 provides fine-tuning for PLK1 to guide chromosome segregation in mitosis.

Design, synthesis and cell imaging of a simple peptide-based probe for the selective detection of RNA.

Here we present a novel peptide-based fluorescent "turn-on" molecule P1 for detecting RNA, in a double or single strand, AU-rich or CG-rich. Both computational and experimental studies indicate that the detection efficiency depends on the binding affinity of P1 and conformational changes. P1 could be applied for cell imaging without any additional transfection vectors. Selective detection of RNA in cells was determined by RNase digestion. Successful application of P1 for RNA imaging in cell mitosis reveals that it may have broad applications in research, biotechnology and medical science.

Identification of the hot spot residues for pyridine derivative inhibitor CCT251455 and ATP substrate binding on monopolar spindle 1 (MPS1) kinase by molecular dynamic simulation.

Protein kinase monopolar spindle 1 plays an important role in spindle assembly checkpoint at the onset of mitosis. Over expression of MPS1 correlated with a wide range of human tumors makes it an attractive target for finding an effective and specific inhibitor. In this work, we performed molecular dynamics simulations of protein MPS1 itself as well as protein bound systems with the inhibitor and natural substrate based on crystal structures. The reported orally bioavailable 1 h-pyrrolo [3,2-c] pyridine inhibitors of MPS1 maintained stable binding in the catalytic site, while natural substrate ATP could not stay. Comparative study of stability and flexibility of three systems reveals position shifting of ß-sheet region within the catalytic site, which indicates inhibition mechanism was through stabilizing the ß-sheet region. Binding free energies calculated with MM-GB/PBSA method shows different binding affinity for inhibitor and ATP. Finally, interactions between protein and inhibitor during molecular dynamic simulations were measured and counted. Residue Gly605 and Leu654 were suggested as important hot spots for stable binding of inhibitor by molecular dynamic simulation. Our results reveal an important position shifting within catalytic site for non-inhibited proteins. Together with hot spots found by molecular dynamic simulation, the results provide important information of inhibition mechanism and will be referenced for designing novel inhibitors.

[Effect of Electroacupuncture Stimulation of Heart and Lung Meridians on Expression of Myocardial HCN 2 in Acute Myocardial Ischemia Rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of Heart and Lung meridians on the expression of hyperpolarization-activated cyclic nucleotide gated potassium channel 2 (HCN 2) mRNA and protein in the myocar-dium of the left ventricle in acute myocardial ischemia (AMI) rats, so as to underlying its mechanism in improving ischemic myocardial injury. METHODS: A total of 120 male SD rats were randomly divided into normal control, model, EA-Heart Meridian (HT) and EA-Lung Meridian (LU) groups (n＝30 rats in each group). The AMI model was established by occlusion of the anterior descending branch of coronary artery. EA (1 mA, 10 Hz) was applied to bilateral "Shenmen" (HT 7) or "Taiyuan" (LU 9) and the spot about 1 mm apart from the HT 7 or LU 9 on the axopetal end for 15 min on the second day after modeling, once a day for 7 days. The left ventricular myocardium tissue was sampled for determining the expression levels of HCN 2 mRNA and protein with qPCR and Western blot, separately. RESULTS: After AMI, both HCN 2 mRNA and protein expression levels in the model group were significantly decreased in comparison with the normal control group (P<0.01). Following EA intervention, the expression levels of HCN 2 mRNA and protein expressions were significantly up-regulated relevant to the model group (P<0.01)．The effects were more obvious in the EA-HT group than in the EA-LU group, and the expression levels were higher in the left ventricular myocardium tissue sampled on the next day after the treatment than those in the tissue sampled immediately after the treatment (P<0.01). CONCLUSION: Both EA stimulation of Heart Meridian and Lung Meridian can improve the expression of HCN 2 mRNA and protein in the myocardium in AMI rats, which existing a delayed effect and meridian specificity.

[Effect of Different Concentrations of Moxa-smoke on Lung Function and TNF-α and IL-1 ß Levels in Serum and Lung Tissues in Normal Rats].

OBJECTIVE: To study the effect of moxa-smoke inhaling on the respiratory system, so as to provide experimental data and theoretical basis for evaluating the safety of moxa-smoke inhaling during moxibustion treatment. METHODS: A total of 48 SD rats were randomized into control, low, medium and high moxa-smoke-concentration groups (n＝12 in each group). The low, medium and high concentrations of smoke were controlled in (0.11±0.05) mg/m3, (0.23±0.05) mg/m3 and (0.53±0.05) mg/m3 respectively in each of 3 glass boxes (with reference to the level of PM 2.5). The smoking was conducted 4 hours each time, twice a day for 100 days. The normal group did not receive any moxa-smoke inhaling. The histopathological changes of lung and bronchial tissues were detected by H．E. stainning, and the contents of TNF-α and IL-1 ß of plasma, bronchoalveolar la-vage fluid (BALF) and lung tissue detected by ELISA. The levels of forced vital capacity (FVC), forced expiratory volume (FEV), FEV 0.3/FVC (0.3＝ the 0.3rd second), maximal mid-expiratory flow rate(MMEF), peak expiratory flow(PEF) were detected by animal pulmonary function analysis system. RESULTS: After 100 days' moxa-smoke inhaling, the contents of TNF-α in the plasma, BALF and lung tissues and IL-1 ß in the lung tissue of the low, medium and high concentration moxa-smoke groups, and IL-1 ß in the plasma and BALF of the medium and high concentration groups were significantly increased relevant to the control group (P<0.05, P<0.01). H．E. stain showed various inflammatory changes in the lungs and trachea tissues, including obvious fusion of pulmonary alveoli, lymphocyte infiltration, increase of capillary permeability, red blood cell exudation, etc. in the high concentration group, these situations were milder in the medium concentration group and were not obvious in the low concentration group. Compared with the control group, there were no significant changes in the FVC, FEV, FEV 0.3/FVC, MMEF and PEF of lung function in the three concentration groups (P> 0.05)．. CONCLUSION: Long term inhalation of high concentration of moxa-smoke may lead to inflammatory injury in the lung and bronchial tissues but has no significant effect on the respiratory function in rats. Nevertheless, a good air-ventilation during moxibustion in a treatment room is necessary.

Ratiometric Detection of Intracellular Lysine and pH with One-Pot Synthesized Dual Emissive Carbon Dots.

Recently, the development of new fluorescent probes for the ratiometric detection of target objects inside living cells has received great attention. Normally, the preparation, modification as well as conjugation procedures of these probes are complicated. On this basis, great efforts have been paid to establish convenient method for the preparation of dual emissive nanosensor. In this work, a functional dual emissive carbon dots (dCDs) was prepared by a one-pot hydrothermal carbonization method. The dCDs exhibits two distinctive fluorescence emission peaks at 440 and 624 nm with the excitation at 380 nm. Different from the commonly reported dCDs, this probe exhibited an interesting wavelength dependent dual responsive functionality toward lysine (440 nm) and pH (624 nm), enabling the ratiometric detection of these two targets. The quantitative analysis displayed that a linear range of 0.5-260 µM with a detection limit of 94 nM toward lysine and the differentiation of pH variation from 1.5 to 5.0 could be readily realized in a ratiometric strategy, which was not reported before with other carbon dots (CDs) as the probe. Furthermore, because of the low cytotoxicity, good optical and colloidal stability, and excellent wavelength dependent sensitivity and selectivity toward lysine and pH, this probe was successfully applied to monitor the dynamic variation of lysine and pH in cellular systems, demonstrating the promising applicability for biosensing in the future.

Red Emission B, N, S-co-Doped Carbon Dots for Colorimetric and Fluorescent Dual Mode Detection of Fe3+ Ions in Complex Biological Fluids and Living Cells.

Colorimetric and fluorescent dual mode detection methods have gained much attention in recent years; however, it is still desirable to develop new colorimetric and fluorescent dual mode nanosensors with more simple preparation procedures, low cost, and excellent biocompatibility. Herein, a colorimetric and fluorescent nanosensor based on B, N, S-co-doped carbon dots (BNS-CDs) was synthesized by one-step hydrothermal treatment of 2,5-diaminobenzenesulfonic acid and 4-aminophenylboronic acid hydrochloride. Using this nanosensor, a highly sensitive assay of Fe3+ in the range of 0.3-546 µM with a detection limit of 90 nM was provided by quenching the red emission fluorescence. It is more attractive that Fe3+ can also be visualized by this nanosensor via evident color changes of the solution (from red to blue) under sunlight without the aid of an ultraviolet (UV) lamp. Furthermore, the designed nanosensor can be applied for efficient detection of intracellular Fe3+ with excellent biocompatibility and cellular imaging capability, and it holds great promise in biomedical applications.

Discovery of Cdc25A Lead Inhibitors with a Novel Chemotype by Virtual Screening: Application of Pharmacophore Modeling Based on a Training Set with a Limited Number of Unique Components.

Cdc25 phosphatase was studied as an attractive target for cancer therapy. Multiple pharmacophore models with the unique core features of classic quinone inhibitors and those of novel inhibitors were used to discover a novel lead inhibitor. A total of 21 compounds with qualified physical properties were screened from the Maybridge HitFinder database containing 14 400 compounds by pharmacophore models. Four compounds were found to inhibit Cdc25A activity by more than 50 % at a concentration of 100 µm. Among these compounds, KM10389 (N-{2-[(furan-2-ylmethyl)thio]ethyl}-2-[(4-hydroxy-6-propylpyrimidin-2-yl)thio]acetamide) showed high inhibitory activity with an IC50 value of 7.9 µm. Selective cytotoxicity toward HeLa cells was observed with an IC50 value of 66.3 µm, whereas the IC50 value for HEK293 cells was higher than 100 µm. Blocking of the G1/S transition was also observed for HeLa cells in the presence of the compound by increasing the G1 phase by 16.15 %. Together with compounds HTS02435 and HTS01205, a novel lead inhibitor structure was identified and analyzed by a molecular docking study. The implication of virtual screening by using different pharmacophore models representing the different features is fully discussed.

[Safety test of air quality in simulated moxibustion clinic].

The air quality of simulated moxibustion clinic was tested, which could provide references for the evaluation on air pollution in moxibustion clinic. After the clinical environment of moxibustion was established,the contents of CO,NO2, PM 10 and PM 2.5 in the air at 5 different time points (0.5 h, 1 h and 2 h after 10 moxa sticks were ignited as well as 5 min ventilation after 0.5 h moxibustion burning and 5 min ventilation after 1 h moxibustion burning) were measured by testing organizations.0.5 h, 1 h and 2 h after 10 moxa sticks were ignited, the content ranges of CO,NO2, PM 10 and PM 2.5 in the air were 15.9 to 37.0 mg/m3,0.012 6 to 0.022 4 mg/m3,0.22 to 1.28 mg/m3 and 0.13 to 0.53 mg/m3, respectively; the contents of CO, PM 10 and PM 2.5 were higher than national standard. With 5 min ventilation after 0.5 h moxibustion burning and 5 min ventilation after 1 h moxibustion burning, the content ranges of CO,NO2,PM 10 and PM 2.5 were 0.3 to 0.4 mg/m3,0.015 5 to 0.018 0 mg/m3,0.11 to 0.13 mg/m3 and 0.04 mg/m3, respectively; the contents of CO, PM 10 and PM 2.5 were lower than national standard. It is concluded that long-time moxibustion could cause relatively high concentration of moxa smoke, and the contents of CO, PM 10 and PM 2.5 in the air will exceed the national standard. However, by keeping good ventilation, the contents of CO,NO2,PM 10 and PM 2.5 in the air can be controlled within safe ranges.