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Liu Hu1,2 *, Jie Xu1 *, Wenli Zhang,1,2 Junrui Wang,1,2 Ni Fang,1,2 Ying Luo,1,2 Lian Xu,1,2 Jia Liu,1 Yu Zhang,1 Haitao Ran,3 Dajing Guo,1 Jun Zhou1 1Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Ultrasound Molecular Imaging & Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Ultrasound, Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Zhou, Tel +86 23 6288 7295, Email zhoujun@hospital.cqmu.edu.cnBackground and Objective: Thrombosis is a common disease that poses a great threat to life and health. Most thrombolytic effects of traditional treatments or nanomedicine are not efficient or safe enough. Therefore, we designed a nanoparticle (NP) with a combination of a phase transition material and thrombolytic drugs for efficient and safe thrombolysis.Methods: A thrombus fibrin-targeted and phase transition NP was designed and contained perfluorohexane (PFH) and the thrombolytic drug rtPA core, with CREKA polypeptides attached to the shell of the PLGA NPs. Characterization of the phase transition and ultrasound imaging of the NPs was carried out under low-intensity focused ultrasound (LIFU). LIFU-responsive drug release in vitro was also explored. Under the synergistic effect of PFH and rtPA, the efficient thrombolysis ability of the NPs was studied in vitro and in vivo. In vivo monitoring of thrombosis and biosafety were also verified.Results: The PPrC NPs had good ultrasound imaging ability under LIFU irradiation and were related to the phase transition characteristics of the NPs. CREKA polypeptides can effectively increase the aggregation of the NPs on thrombi. Under static and dynamic conditions in vitro, the “liquid to gas” transformation effect of PFH can perform the destruction function of the excavator at the thrombus site and promote the specific release of rtPA, and the subsequent rtPA drug thrombolysis can further fully dissolve the thrombus. In vivo experiments showed that the NPs can monitor the formation of thrombi and have good thrombolytic effects, with significantly reduced bleeding side effects. The biochemical indexes of the rats were within normal limits after treatment.Conclusion: PPrC NPs loaded with PFH and rtPA combining a mechanical way of blasting with thrombolytic drugs may be a promising new and reliable approach for thrombus monitoring and treatment.Keywords: low-intensity focused ultrasound, thrombolysis, PFH, rtPA, phase transition

Ni Fang,1,2,* Jia Liu,1,* Jingxin Hou,1,2 Yixin Zhong,1,2 Ying Luo,1,2 Liu Hu,1,2 Wenli Zhang,1,2 Junrui Wang,1,2 Jie Xu,1 Jun Zhou,1 Yu Zhang,1 Haitao Ran,2 Dajing Guo1 1Department of Radiology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China; 2Chongqing Key Laboratory of Ultrasound Molecular Imaging & Department of Ultrasound, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dajing Guo, Email guodaj@163.comBackground: Arterial thrombosis is a serious threat to human health. Recently, many thrombus-targeted nanoparticles (NPs) have been constructed for detecting thrombi or monitoring thrombolysis, but their thrombus-targeting performance is limited. Considering this drawback, we designed a specific bionic system with enhanced thrombus-targeting ability.Materials and Methods: In the bionic system, gelatin was chosen as a carrier, and Fe3O4 served as a magnetic navigation medium and a magnetic resonance (MR) imaging agent. The CREKA peptide, which targets fibrin, was conjugated to the surface of gelatin to prepare targeted NPs (TNPs), which were then engulfed by macrophages to construct the bionic system. At the targeted site, the bionic system released its interior TNPs under low-intensity focused ultrasound (LIFU) irradiation. Moreover, the targeting performance was further improved by the conjugated CREKA peptide.Results: In this study, we successfully constructed a bionic system and demonstrated its targeting ability in vitro and in vivo. The results indicated that most TNPs were released from macrophages under LIFU irradiation at 2 W/cm2 for 10 min in vitro. Additionally, the enhanced thrombus-targeting ability, based on the natural tropism of macrophages toward inflammatory thrombi, magnetic navigation and the CREKA peptide, was verified ex vivo and in vivo. Moreover, compared with the bionic system group, the group treated with TNPs had significantly decreased liver and spleen signals in MR images and significantly enhanced liver and spleen signals in fluorescence images, indicating that the bionic system is less likely to be cleared by the reticuloendothelial system (RES) than TNPs, which may promote the accumulation of the bionic system at the site of the thrombus.Conclusion: These results suggest that the magnet-guided bionic system with LIFU responsiveness is an excellent candidate for targeting thrombi and holds promise as an innovative drug delivery system for thrombolytic therapy.Keywords: bionic system, low-intensity focused ultrasound, thrombus, magnetic navigation, macrophage

Shuyi Li, Yang Hui, Jiqiao Yuan, Ziqian Zhang, Xuyu Li, Nan Fang, Mingbao Lin, Qi Hou Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Mingbao Lin; Qi Hou Tel +86-10-63165192; +86-10-63165191Email mingbaolin@imm.cams.cn; houq@imm.ac.cnIntroduction: Asthma–chronic obstructive pulmonary (COPD) overlap (ACO) coexists with asthma and COPD syndrome characteristics, with more frequent exacerbations, heavier disease burden, higher medical utilization, and even lower quality of life. However, the ACO standard medications supported by evidence-based medicine have not yet appeared.Methods: By using an ACO mouse model established previously and LPS-stimulated RAW264.7 macrophages in vitro, a potential therapeutic candidate, EAPP-2, was screened from derivatives of 3-arylbenzofuran, and its effect and mechanism on ACO inflammation were evaluated.Results: EAPP-2 significantly alleviated airway inflammation in ACO mice and also inhibited the inflammatory reactions in LPS-induced RAW264.7 macrophages in vitro. Furthermore, EAPP-2 significantly inhibited the expression and phosphorylation of spleen tyrosine kinase (Syk), a common target regulating both eosinophils and neutrophils inflammation. In addition to this, EAPP-2 significantly down-regulates the expression of NF-κB, p-NF-κB, and NLRP3 in vivo and in vitro. Moreover, by using specific inhibitors in vitro, it was validated that EAPP-2 targeted on Syk and then regulated its downstream NF-κB and NLRP3.Conclusion: EAPP-2 is shown to be a potentially useful therapeutic candidate for ACO, and its mechanism is at least partially achieved by targeting on Syk and then inhibiting NF-κB or NLRP3. Moreover, this study suggests that Syk may be a potentially effective target for ACO therapy.Keywords: EAPP-2, asthma–COPD overlap, ACO, Syk, NF-κB, NLRP3

Yanjie Yang,1 Shuangyu Lv,1 Fengling Wang,1 Yang An,1 Na Fang,1 Weijuan Zhang,1 Wei Zhao,1 Xiangqian Guo,1 Shaoping Ji1,21School of Basic Medical Sciences, Henan University, Kaifeng 475004, People’s Republic of China; 2Henan Provincial Engineering Centre of Tumor Molecular Diagnosis and Therapy & Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng 475004, People’s Republic of ChinaPurpose: Mn-doped ZnS quantum dots (QDs) with special luminescent properties have been widely researched and applied in various fields. Thus, their release toxicity and security cannot be ignored.Methods: In the present study, the toxicity and non-targeted metabolomics of Mn-doped ZnS QDs were investigated after single intravenous injection. Serum metabolites were evaluated based on gas chromatography–mass spectrometry together with multivariate statistical analyses [principal component analysis, partial least squares discriminant analysis, and orthogonal PLS-DA].Results: The modified metabolites (variable importance in the projection (VIP) >1 and p

Abstract Precise calling of promiscuous adenosine-to-inosine RNA editing sites from transcriptomic datasets is hindered by DNA mutations and sequencing/mapping errors. Here, we present a stepwise computational framework, called DEMINING, to distinguish RNA editing and DNA mutations directly from RNA sequencing datasets, with an embedded deep learning model named DeepDDR. After transfer learning, DEMINING can also classify RNA editing sites and DNA mutations from non-primate sequencing samples. When applied in samples from acute myeloid leukemia patients, DEMINING uncovers previously underappreciated DNA mutation and RNA editing sites; some associated with the upregulated expression of host genes or the production of neoantigens.

Abstract The immunosuppressive tumor microenvironment (TME) significantly inhibits the effective anti-tumor immune response, greatly affecting the efficacy of immunotherapy. Most tumor-associated macrophages (TAMs) belong to the M2 phenotype, which contributes significantly to the immunosuppressive effects in non-small cell lung cancer (NSCLC) TME. The interaction between signal regulatory protein α (SIRPα) expressed on macrophages and CD47, a transmembrane protein overexpressed on cancer cells, activates the "eat-me-not" signaling pathway, inhibiting phagocytosis. In this study, a folic acid (FA)-modified ultrasound responsive gene/drugs delivery system, named FA@ PFP @ Fe3O4 @LNB-SIRPα siRNA (FA-PFNB-SIRPα siRNA), was developed using 1,2-dioleoacyl-3-trimethylammonium-propane (DOTAP), FA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol)2000] (DSPE-PEG2000-FA), cholesterol, and perfluoropentane (PFP), for the delivery of siRNA encoding SIRPα mRNA and immune adjuvant Fe3O4 nanoparticles. Under ultrasound conditions, the nanobubbles effectively transfected macrophages, inhibiting SIRPα mRNA and protein expression, promoting the phagocytosis of TAMs, and synergistically reversing M2 polarization. This system promotes the infiltration of T cells, enhances the proliferation and activation of cytotoxic T cells, and inhibits the infiltration of immunosuppressive cells in tumor tissues. Administration of FA-PFNB-SIRPα siRNA combined with ultrasound significantly inhibits NSCLC progression. The study highlights the potential of ultrasound nanotechnology-enabled delivery of SIRPα siRNA and Fe3O4 as an effective strategy for macrophage-based immunotherapy to reshape the immunosuppressive TME for cancer therapy. Graphical Abstract

To meet the “peak carbon and carbon neutrality” targets, the gradual reduction of coal-fired electricity generation through the co-firing of coal and NH3 has emerged as a new pathway to achieve carbon reduction. However, the co-firing characteristics of coal and NH3 are not yet clear. Therefore, the coal/NH3 co-firing experiments were conducted based on a flat-flame burner to investigate the influence of ammonia blending ratio (E(NH3), 0−100%) and coal/NH3 injection methods (pre-mixed, non-pre-mixed) on combustion characteristics. Camera, flue gas analyzer, and thermocouples were used to observe flame morphology, gas composition, temperature distribution along the centerline heights above the burner (HAB), and measure the unburned carbon content in fly ash. The results showed that during the initial stage of combustion, the competition for O2 between coal and NH3 was more pronounced. The NH3 combustion in the combustion zone created a rich water vapor atmosphere. Under low E(NH3) conditions in pre-mixed combustion, CO reacted with OH, resulting in a decrease in CO concentration. On the other hand, under high E(NH3) conditions, NH3 preferentially reacted with O2, leading to an incomplete combustion of a significant amount of carbon. Additionally, the rich water vapor atmosphere promoted coal gasification reactions, resulting in a significant increase in CO concentration in the combustion reduction zone, reaching a maximum of 19773.05 mg/Nm3. However, this process altered the pore structure of the coke, increased the specific surface area of the coke, accelerated the combustion process of coal powder, and reduced the residual carbon content in fly ash from 13.90% (pure coal combustion) to 13.44% (E(NH3)=80%) under pre-mixed conditions. An early injection of NH3 reduced the preheating effect of NH3 combustion on coal powder and decreased the combustion intensity in the flame reaction zone. The addition of NH3 significantly increased the NOx emissions, and with increasing E(NH3), there was an initial increase followed by a decrease in NOx, with the peak concentration of NO occurring earlier. The unburned NH3 content and oxygen content were the main factors influencing the formation of N2O and NO2. Increasing the residence time of coal/NH3 combustion, reducing the unburned NH3 content, and creating a reducing atmosphere were effective ways to reduce NOx emissions. Under high E(NH3) conditions in pre-mixed combustion (E(NH3)≥80%, HAB=100 mm) and non-pre-mixed conditions, the CO2 percentage showed a decreasing trend with increasing E(NH3). Pre-mixed conditions with an E(NH3) range of 40% to 60% were more favorable for achieving low nitrogen, low carbon, and high-efficiency combustion of coal/NH3. The co-firing of coal powder with NH3 exhibited mutual promotion and restriction effects, requiring some effective measures based on specific circumstances to harness the promotion effect of coal/NH3 co-firing.

The violent swinging motion of a payload imposes significant safety problems for the operation of offshore ship-mounted cranes (offshore cranes). We therefore propose a stable experimental hoisting platform for an offshore crane payload positioning system with a parallel cable-driven method (PP-PCDM), and an adaptive cable-drive anti-swing tension (ACAT) control method based on the PP-PCDM is developed to resolve the problem of swinging of the payload by limiting its spatial position. The PP-PCDM enables synchronous tracking of the movement of the payload when the crane is working. When the payload deviates from a stable state due to an external disturbance, the anti-swing cables are immediately retracted or released based on the feedback signal. The spatial position of the payload is then limited by adjusting the length and tension of the parallel cables until the payload appears stationary from the perspective of the ship’s deck. Operational safety and efficiency is substantially improved, and the proposed PP-PCDM structure and ACAT control method can be applied to a variety of different types of cranes. The results of simulations and physical experiments show that the anti-swing effect exceeds 89.86%. The PP-PCDM enables excellent performance of synchronous tracking and hoisting assistance, and ensures that the rated lifting weight of the offshore crane is not affected.

Abstract The incidence of autoimmune diseases has significantly increased over the past 20 years. Excessive host immunoreactions and disordered immunoregulation are at the core of the pathogenesis of autoimmune diseases. The traditional anti-tumor chemotherapy drug CPT-11 is associated with leukopenia. Considering that CPT-11 induces leukopenia, we believe that it is a promising drug for the control of autoimmune diseases. Here, we show that CPT-11 suppresses T cell proliferation and pro-inflammatory cytokine production in healthy C57BL/6 mice and in complete Freund’s adjuvant-challenged mice. We found that CPT-11 effectively inhibited T cell proliferation and Th1 and Th17 cell differentiation by inhibiting glycolysis in T cells. We also assessed CPT-11 efficacy in treating autoimmune diseases in models of experimental autoimmune encephalomyelitis and psoriasis. Finally, we proved that treatment of autoimmune diseases with CPT-11 did not suppress long-term immune surveillance for cancer. Taken together, these results show that CPT-11 is a promising immunosuppressive drug for autoimmune disease treatment.

[Objective] To explore the effects of degradable mulch film mulching on runoff and loss of dissolved nitrogen and phosphorus. [Methods] Polyethylene film mulching (PF) with a thickness of 0.003 mm, degradable film mulching with a thickness of 0.006 mm (BF1), 0.008 mm (BF2), 0.010 mm (BF3) and 0.012 mm (BF4), and no mulch (CK) were set up. In in-situ runoff plots, using mulching on ridge tillage peanut planting as the study object, the runoff and concentration of ammonium nitrogen (NH4+—N), nitrate nitrogen (NO3-—N), and available phosphorus (PO43-—P) in runoff under natural rainfall conditions were measured, and the runoff and nutrient loss characteristics under different thickness of degradable mulch film were analyzed. [Results] (1) The degradation time of degradable film increased with the increase of film thickness. (2) The order of cumulative runoff was BF1

Background: Colon cancer is one of the most prevalent digestive cancers worldwide. Results of epidemiological, experimental, and clinical studies suggest that aspirin inhibits the development of colon cancer. This study aimed to systematically elucidate the molecular mechanisms by which aspirin prevents colon carcinogenesis. Methods: We determined the global protein expression profiles of colorectal cancer and aspirin-treated cells using quantitative proteomic analysis. We analyzed the proteomic results using bioinformatics (including differential proteins, protein annotation, Kyoto Encyclopedia of Genes and Genomes [KEGG] pathways, and protein–protein interaction [PPI] network). The viability of the colon cancer cell line and HT29 ​cells treated with aspirin was determined using the cell counting kit-8 assay. The differentially expressed proteins, such as p53 and cyclin-dependent kinase 1 (CDK1), were quantified using real-time polymerase chain reaction (PCR) and Western blotting. We measured cell cycle distribution and apoptosis in HT29 ​cells exposed to aspirin using fluorescence-activated cell sorting (FACS). Results: We found that 552 proteins were significantly dysregulated, of which 208 and 334 were upregulated and downregulated, respectively, in colon cancer cells exposed to 10 ​mmol/L of aspirin (95% confidence interval [CI]: -1.269 to -0.106, P ​

Summary: The avidity between immune cells and target cells is crucial for effective immune responses. Here, we present a protocol to measure single-cell avidity between cord blood-derived natural killer (NK) cells and the human acute myelocytic leukemia cell line KG-1a. We describe the steps for isolating cord blood mononuclear cells, purifying NK cells, and culturing KG-1a cells. We then detail the procedures for detecting cell avidity between NK cells and KG-1a cells using the acoustic force-based z-Movi cell avidity analyzer.For complete details on the use and execution of this protocol, please refer to Wang et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Allelopathy is the main chemical means in the invasion process of exotic plants and one of the key factors in grassland degradation. In this experiment, we investigated the effects of ethyl acetate phase extract (EAE), n-butanol phase extract (BE) and aqueous phase extract (AE) from the aboveground (stems and leaves) and roots of Ligularia sagitta on seed germination and seedling growth of four Gramineae forages (Poa pratensis L. Festuca ovina L. Elymus nutans Griseb. Agropyron cristatum (L.) Gaertn.) in their sympatric domains and one Legosuminae forage (Medicago sativa L.). The chemical components in each phase extract of L. sagitta were determined with UHPLC-MS/MS non-targeted metabolomics, and the differential compounds were screened using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA). Within a set concentration range, EAE significantly inhibited seed germination and seedling growth of four Gramineae forages. BE and AE acted mainly in the seedling growth stage and did not significantly inhibit forage seed germination. P. pratensis was most sensitive to L. sagitta extracts; at 2.0 mg/mL of EAE from roots, germination energy and germination rate of P. pratensis seeds were 0. L. sagitta extracts inhibited the growth of M. sativa seedlings and did not inhibit its seed germination. A total of 904 compounds were identified with UHPLC-MS/MS, among which 31, 64, 81 and 66 metabolites displayed different accumulation patterns in the four comparison groups (R.EAE vs. R.BE, R.EAE vs. R.AE, SL.EAE vs. SL.BE, SL.EAE vs. SL.AE), respectively. In particular, 9 compounds were found to be common up-regulated differential metabolites in the four comparison groups and were enriched in EAE. Additionally, N,N-dimethylaniline, Caffeic acid, 4-Hydroxybenzoic acid, 4-Hydroxybenzaldehyde and cis-9-Octadecenoic acid as potential allelochemicals in L. sagitta. The results of this study support efforts at finding alternative control plants for the restoration of poisonous grass-type degraded grasslands.

Abstract Background Microcirculatory perfusion disorder and inflammatory response are critical links in acute kidney injury (AKI). We aim to construct anti‐vascular cell adhesion molecule‐1(VCAM‐1) targeted microbubbles (TM) to monitor renal microcirculatory perfusion and inflammatory response. Methods TM carrying VCAM‐1 polypeptide was constructed by biological coupling. The binding ability of TM to human umbilical vein endothelial cells (HUVECs) was detected. Bilateral renal ischemia–reperfusion injury (IRI) models of mice were established to evaluate microcirculatory perfusion and inflammatory response using TM. Thirty‐six mice were randomly divided into six groups according to the different reperfusion time (0.5, 2, 6, 12, and 24 h) and sham‐operated group (Sham group). The correlation of TM imaging with serum and histopathological biomarkers was investigated. Results TM has advantages such as uniform distribution, regular shape, high stability, and good biosafety. TM could bind specifically to VCAM‐1 molecule expressed by tumor necrosis factor‐alpha (TNF‐α)‐treated HUVECs. In the renal IRI‐AKI model, the area under the curve (AUC) of TM significantly decreased both in the renal cortical and medullary after 2 h of reperfusion compared with the Sham group (p

Abstract The engineering of ferroic orders, which involves the evolution of atomic structure and local ferroic configuration in the development of next‐generation electronic devices. Until now, diverse polarization structures and topological domains are obtained in ferroelectric thin films or heterostructures, and the polarization switching and subsequent domain nucleation are found to be more conducive to building energy‐efficient and multifunctional polarization structures. In this work, a continuous and periodic strain in a flexible freestanding BaTiO3 membrane to achieve a zigzag morphology is introduced. The polar head/tail boundaries and vortex/anti‐vortex domains are constructed by a compressive strain as low as ≈0.5%, which is extremely lower than that used in epitaxial rigid ferroelectrics. Overall, this study c efficient polarization structures, which is of both theoretical value and practical significance for the development of next‐generation flexible multifunctional devices.

For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered at ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7–T11 injuries than in T2–T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.

Objective: To investigate the effect of pelvic floor electromyography Biofeedback and “four sacral needles” on pelvic floor muscle strength and quality of life in mild to moderate female stress Urinary incontinence (UI) patients. Methods: A total of 96 patients with mild to moderate female stress UI who were treated in Qingpu District Hospital of Traditional Chinese Medicine from June 2021 to May 2023 were randomly divided into a control group and a test group, with 48 cases in each group. The control group was given pelvic floor myoelectric stimulation combined with Biofeedback, and the treatment group was given “four sacral needles” on the basis of the control group. Record the Glazer electromyography assessment and 1-hour urine pad test leakage at weeks 0, 4, and 8 of treatment, and compare the therapeutic differences between the two groups. Result: Compared with before treatment, after 4 and 8 weeks of treatment, the Glazer evaluation and 1 h urine pad test leakage in both groups were significantly reduced ([Formula: see text]), and the experimental group had better indicators than the control group at 4 and 8 weeks of treatment ([Formula: see text]). The total effective rate of the experimental group was 97.7%, significantly higher than the control group’s 90.9% ([Formula: see text]). Conclusion: Pelvic floor electromyography Biofeedback combined with “four sacral needles” and simple pelvic floor electromyography Biofeedback is effective for women with mild to moderate stress UI. Pelvic floor electromyography Biofeedback combined with “four sacral needles” is superior to simple pelvic floor Biofeedback in the treatment of mild to moderate stress UI.