miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells.

JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Efficacy and Safety of Biosimilar SCT510 Compared with Bevacizumab for the First-Line Treatment of Advanced Non-Squamous Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study.

INTRODUCTION: SCT510 is a biosimilar to bevacizumab (Avastin) reference product (RP) that is approved for various metastatic cancers. In this study, we aimed to demonstrate the equivalence of SCT510 and bevacizumab in terms of efficacy, safety, immunogenicity and pharmacokinetics (PK) in patients with advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Patients with non-squamous NSCLC were randomized equally to the SCT510 group (comprising SCT510, paclitaxel, and carboplatin) and the bevacizumab group (comprising bevacizumab, paclitaxel, and carboplatin) for 4-6 cycles, followed by maintenance monotherapy with SCT510. The primary endpoint was the objective response rate (ORR) at week 12. Secondary endpoints included 18-week ORR, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and 1-year survival rate, as well as assessments of safety, immunogenicity, and multi-dose PK analysis. RESULTS: Between March 29, 2019, and April 27, 2021, 989 patients were screened and 567 eligible patients were randomly assigned to the SCT510 group (285 patients) and the bevacizumab group (282 patients). The ORR at week 12 was 52.6% [95% confidence interval (CI) 46.66-58.55%] in the SCT510 group and 52.5% (95% CI 46.47-58.47%) in the bevacizumab group. The ORR at week 18 was 55.4% (95% CI 49.46-61.30%) for SCT510 and 55.7% (95% CI 49.68-61.62%) for bevacizumab. The ORR risk ratio (RR) at weeks 12 and 18 was 0.99 (90% CI 0.873-1.133) and 0.99 (90% CI 0.872-1.114), respectively, both within the pre-specified equivalence margin of 0.75-1.33. There were no differences between the two groups in relation to other secondary endpoints, specifically DCR, DOR, PFS, OS, and 1-year survival rate. The overall safety findings were similar between the two treatment groups, and both SCT510 and bevacizumab RP exhibited low immunogenicity. CONCLUSIONS: SCT510 is similar to bevacizumab in clinical efficacy, safety, immunogenicity, and PK in patients with advanced non-squamous NSCLC. The totality of the evidence supports the clinical equivalence of SCT510 and bevacizumab. TRIAL REGISTRATION: NCT03792074.

Reactive capture of CO2 via amino acid.

Reactive capture of carbon dioxide (CO2) offers an electrified pathway to produce renewable carbon monoxide (CO), which can then be upgraded into long-chain hydrocarbons and fuels. Previous reactive capture systems relied on hydroxide- or amine-based capture solutions. However, selectivity for CO remains low (<50%) for hydroxide-based systems and conventional amines are prone to oxygen (O2) degradation. Here, we develop a reactive capture strategy using potassium glycinate (K-GLY), an amino acid salt (AAS) capture solution applicable to O2-rich CO2-lean conditions. By employing a single-atom catalyst, engineering the capture solution, and elevating the operating temperature and pressure, we increase the availability of dissolved in-situ CO2 and achieve CO production with 64% Faradaic efficiency (FE) at 50 mA cm-2. We report a measured CO energy efficiency (EE) of 31% and an energy intensity of 40 GJ tCO-1, exceeding the best hydroxide- and amine-based reactive capture reports. The feasibility of the full reactive capture process is demonstrated with both simulated flue gas and direct air input.

Association between serum 25-hydroxyvitamin D and asthma: Evidence from the National Health and Nutrition Examination Survey (NHANES) 2011-2018.

BACKGROUND AND OBJECTIVE: Asthma is a heterogeneous respiratory disease characterized by airway hyper-responsiveness and reversible airflow blockage. There is ongoing debate about the impact of vitamin D on asthma. This research is focused on investigating the correlation between serum levels of 25-hydroxyvitamin D and asthma. METHODS: This cross-sectional study comprised 22,708 eligible participants. Data on asthma and serum 25-hydroxyvitamin D levels from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 were analyzed. Serum 25-hydroxyvitamin D levels were the main factor, with the presence of asthma as the outcome variable. Weighted logistic regression was utilized to investigate the relationship between serum levels of 25-hydroxyvitamin D and asthma, while accounting for factors such as age, gender, race, length of time in US, annual family income, education level, high-density lipoprotein, low-density lipoprotein, triglycerides, and cholesterol. RESULTS: Upon adjusting all variables in model III, epi-25-hydroxyvitamin D3 displayed a negative correlation with current asthma at the lower quartile Q1 (0.784, [0.697 to 0.922]), Q2 (0.841, [0.729 to 0.946]), Q3 (0.396, [0.240 to 0.653]) when compared to the highest quartile Q4 level. However, no significant difference was observed between asthma and 25-hydroxyvitamin D2, as well as 25-hydroxyvitamin D3. CONCLUSIONS: In the U.S. population, elevated levels of epi-25-hydroxyvitamin D3 are correlated with an increased risk of developing existing asthma. However, it is important to interpret this finding carefully given the constraints of cross-sectional studies.

Visualizing Single V-ATPase Rotation Using Janus Nanoparticles.

Understanding the function of rotary molecular motors, such as the rotary ATPases, relies on our ability to visualize the single-molecule rotation. Traditional imaging methods often involve tagging those motors with nanoparticles (NPs) and inferring their rotation from translational motion of NPs. Here, we report an approach using ″two-faced″ Janus NPs to directly image the rotation of single V-ATPase from Enterococcus hirae , an ATP-driven rotary ion pump. By employing a 500-nm silica/gold Janus NP, we exploit its asymmetric optical contrast - silica core with a gold cap on one hemisphere - to achieve precise imaging of the unidirectional counter-clockwise rotation of single V-ATPase motors immobilized on surfaces. Despite the added viscous load from the relatively large Janus NP probe, our approach provides accurate torque measurements of single V-ATPase. This study underscores the advantages of Janus NPs over conventional probes, establishing them as powerful tools for single-molecule analysis of rotary molecular motors.

Phylogenomics analysis of Scutellaria (Lamiaceae) of the world.

BACKGROUND: Scutellaria, a sub-cosmopolitan genus, stands as one of the Lamiaceae family's largest genera, encompassing approximately 500 species found in both temperate and tropical montane regions. Recognized for its significant medicinal properties, this genus has garnered attention as a research focus, showcasing anti-cancer, anti-inflammatory, antioxidant, and hepatoprotective qualities. Additionally, it finds application in agriculture and horticulture. Comprehending Scutellaria's taxonomy is pivotal for its effective utilization and conservation. However, the current taxonomic frameworks, primarily based on morphological characteristics, are inadequate. Despite several phylogenetic studies, the species relationships and delimitations remain ambiguous, leaving the genus without a stable and reliable classification system. RESULTS: This study analyzed 234 complete chloroplast genomes, comprising 220 new and 14 previously published sequences across 206 species, subspecies, and varieties worldwide. Phylogenetic analysis was conducted using six data matrices through Maximum Likelihood and Bayesian Inference, resulting in a robustly supported phylogenetic framework for Scutellaria. We propose three subgenera, recommending the elevation of Section Anaspis to subgeneric rank and the merging of Sections Lupulinaria and Apeltanthus. The circumscription of Subgenus Apeltanthus and Section Perilomia needs to be reconsidered. Comparative analysis of chloroplast genomes highlighted the IR/SC boundary feature as a significant taxonomic indicator. We identified a total of 758 SSRs, 558 longer repetitive sequences, and ten highly variable regions, including trnK-rps16, trnC-petN, petN-psbM, accD-psaI, petA-psbJ, rpl32-trnL, ccsA-ndhD, rps15-ycf1, ndhF, and ycf1. These findings serve as valuable references for future research on species identification, phylogeny, and population genetics. CONCLUSIONS: The phylogeny of Scutellaria, based on the most comprehensive sample collection to date and complete chloroplast genome analysis, has significantly enhanced our understanding of its infrageneric relationships. The extensive examination of chloroplast genome characteristics establishes a solid foundation for the future development and utilization of Scutellaria, an important medicinal plant globally.

Sodium butyrate improves cognitive dysfunction in high-fat diet/ streptozotocin-induced type 2 diabetic mice by ameliorating hippocampal mitochondrial damage through regulating AMPK/PGC-1α pathway.

Cognitive dysfunction is an important comorbidity of type 2 diabetes mellitus (T2DM). Sodium butyrate (NaB) is a short-chain fatty acid and has an effect improving T2DM-associated cognitive dysfunction. Using a high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mouse model, the present study investigated the mechanism involved in the beneficial effect of butyrate on diabetic cognitive dysfunction, with a focus on ameliorating mitochondrial damage through regulating the adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1α (AMPK/PGC-1α) pathway considering the important role of mitochondrial impairments in the occurrence of T2DM-associated cognitive dysfunction. We found, based on reconfirmation of the improvement of NaB on cognitive impairment, that NaB treatment improved damaged synaptic structural plasticity including the decrease in dendritic spine density and downregulation in the expression of postsynaptic density protein 95 and synaptophysin in the hippocampus in the model mice. NaB treatment also ameliorated mitochondrial ultrastructural damage, increased mitochondrial membrane potential and adenosine 5'-triphosphate content, and improved mitochondrial biogenesis and dynamics in the model mice. Furthermore, the expression of phosphorylated AMPK and PGC-1α was upregulated after NaB treatment in the model mice. In particular, the above beneficial effects of NaB were blocked by the inhibition of either AMPK or PGC-1α. In conclusion, NaB treatment improved cognitive impairment and damaged synaptic structural plasticity in the hippocampus by ameliorating damage to mitochondrial morphology and function through regulating the AMPK/PGC-1α pathway in HFD/STZ-induced T2DM mice.

Molecular-level design of alternative media for energy-saving pilot-scale fibrillation of nanocellulose.

The outstanding mechanical properties, light weight, and biodegradability of cellulose nanofibrils (CNFs) make them promising components of renewable and sustainable next-generation reinforced composite biomaterials and bioplastics. Manufacturing CNFs at a pilot scale requires disc-refining fibrillation of dilute cellulose fibers in aqueous pulp suspensions to shear the fibers apart into their nanodimensional forms, which is, however, an energy-intensive process. Here, we used atomistic molecular dynamics (MD) simulation to examine media that might facilitate the reduction of interactions between cellulose fibers, thereby reducing energy consumption in fibrillation. The most suitable medium found by the simulations was an aqueous solution with 0.007:0.012 wt.% NaOH:urea, and indeed this was found in pilot-scale experiments to reduce the fibrillation energy by ~21% on average relative to water alone. The NaOH:urea-mediated CNFs have similar crystallinity, morphology, and mechanical strength to those formed in water. The NaOH and urea act synergistically on CNFs to aid fibrillation but at different length scales. NaOH deprotonates hydroxyl groups leading to mesoscale electrostatic repulsion between fibrils, whereas urea forms hydrogen bonds with protonated hydroxyl groups thus disrupting interfibril hydrogen bonds. This suggests a general mechanism in which an aqueous medium that contains a strong base and a small organic molecule acting as a hydrogen-bond acceptor and/or donor may be effectively employed in materials processes where dispersion of deprotonable polymers is required. The study demonstrates how atomic-detail computer simulation can be integrated with pilot-scale experiments in the rational design of materials processes for the circular bioeconomy.

Effect of salt substitution on fracture-a secondary analysis of the Salt Substitute and Stroke Study (SSaSS).

BACKGROUND: Associations of dietary sodium and potassium intake with fracture risk are inconsistent and the effects of salt substitute on fracture incidence are unknown. We assessed the effect of salt substitute compared to regular salt intake on fracture incidence using data from the Salt Substitute and Stroke Study (SSaSS). METHODS: SSaSS was a cluster-randomized controlled trial conducted in 600 villages in northern China. Villages were randomly allocated into intervention and control groups in a 1:1 ratio. Salt substitute was provided to intervention villages and control villages continued regular salt use for 5 years. The primary outcome for this secondary analysis was the incidence of all fractures. Secondary outcomes included incidence of vertebral fracture, non-vertebral fracture, and fracture of unknown or non-specific location. RESULTS: 20,995 participants were included in this study, and 821 fractures occurred during follow-up. Intention-to-treat analyses showed no differences between the salt substitute and regular salt groups in the incidence of all fractures (rate ratio (RR) 0.96; 95% CI 0.81 to 1.14), vertebral fracture (RR 0.82; 95% CI 0.53 to 1.26), non-vertebral fracture (RR 1.05; 95% CI 0.86 to 1.29), or fracture of unknown or non-specific location (RR 0.80; 95% CI 0.54 to 1.18). CONCLUSIONS: Use of salt substitute compared to regular salt had no detectable effect on the incidence of fracture in a population at high risk of cardiovascular disease and fracture. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02092090. Registered on March 12, 2014.

Discovery of an unconventional lamprey lymphocyte lineage highlights divergent features in vertebrate adaptive immune system evolution.

Lymphocyte receptors independently evolved in both jawed and jawless vertebrates with similar adaptive immune responses. However, the diversity of functional subtypes and molecular architecture in jawless vertebrate lymphocytes, comparable to jawed species, is not well defined. Here, we profile the gills, intestines, and blood of the lamprey, Lampetra morii, with single-cell RNA sequencing, using a full-length transcriptome as a reference. Our findings reveal higher tissue-specific heterogeneity among T-like cells in contrast to B-like cells. Notably, we identify a unique T-like cell subtype expressing a homolog of the nonlymphoid hematopoietic growth factor receptor, MPL-like (MPL-L). These MPL-L+ T-like cells exhibit features distinct from T cells of jawed vertebrates, particularly in their elevated expression of hematopoietic genes. We further discovered that MPL-L+ VLRA+ T-like cells are widely present in the typhlosole, gill, liver, kidney, and skin of lamprey and they proliferate in response to both a T cell mitogen and recombinant human thrombopoietin. These findings provide new insights into the adaptive immune response in jawless vertebrates, shedding new light on the evolution of adaptive immunity.

Apolipoprotein A-I: Potential Protection Against Intestinal Injury Induced by Dietary Lipid.

The intestinal barrier system protects the human body from harmful factors, by continuously renewing the intestinal epithelium, tight junctions and enteric microbes. However, dietary fat can harm the intestinal epithelial barrier enhancing gut permeability. In recent years, Apolipoprotein A-I has attracted much attention because of its anti-inflammatory properties. Numerous studies have demonstrated that Apolipoprotein A-I can regulate mucosal immune cells, inhibit the progression of inflammation, promote epithelial proliferation and repair, and maintain physical barrier function; it can also regulate angiogenesis, thereby improving local circulation. This article is intended to elucidate the mechanism by which Apolipoprotein A-I improves intestinal barrier damage caused by dietary fat and to review the role of Apolipoprotein A-I in maintaining intestinal homeostasis.

Identifying and Validating Extracellular Matrix-Related Gene CTSH in Diabetic Foot Ulcer Using Bioinformatics and Machine Learning.

Background: Diabetic foot ulcer (DFU) is a serious clinical problem with high amputation and mortality rates, yet there is a lack of desirable therapy. While the extracellular matrix (ECM) contributes significantly to wound healing, ECM-related biomarker for DFU is still unknown. The study was designed to identify ECM-related biomarker in DFU using bioinformatics and machine learning and validate it in STZ-induced mice models. Methods: GSE80178 and GSE134431 microarray datasets were fetched from the GEO database, and differentially expressed genes (DEGs) analysis was performed, respectively. By analyzing DEGs and ECM genes, we identified ECM-related DEGs, and functional enrichment analysis was conducted. Subsequently, three machine learning algorithms (LASSO, RF and SVM-RFE) were applied to filter ECM-related DEGs to identify key ECM-related biomarkers. Next, we conducted immune infiltration analysis, GSEA, and correlation analysis to explore the hub gene underlying mechanism. A lncRNA-miRNA-mRNA and drug regulatory network were constructed. Finally, we validated the key ECM-related biomarker in STZ-induced mice models. Results: One hundred and forty-five common DEGs in adult DFU between the two datasets were identified. Taking the intersection of 145 common DEGs and 964 ECM genes, we identified 13 ECM-related DEGs. Thirteen ECM-related DEGs were mainly enriched in pathways associated with tissue remodeling, inflammation and defense against infectious agents. Ultimately, CTSH was identified as the key ECM-related biomarker. CTSH was associated with difference immune cells during the occurrence and development of DFU, and it influenced hedgehog, IL-17 and TNF signaling pathway. Additionally, CTSH expression is correlated with many ECM- and immune-related genes. A lncRNA-miRNA-mRNA and drug regulatory network were constructed with 10 lncRNAs, 2 miRNAs, CTSH and 1 drug. Finally, CTSH was validated as a key biomarker for DFU in animal models. Conclusion: Our study found that CTSH can be used for both diagnostic and prognostic purposes and might be a potential therapeutic target.

Neuronal repair after spinal cord injury by in vivo astrocyte reprogramming mediated by the overexpression of NeuroD1 and Neurogenin-2.

BACKGROUND: As a common disabling disease, irreversible neuronal death due to spinal cord injury (SCI) is the root cause of functional impairment; however, the capacity for neuronal regeneration in the developing spinal cord tissue is limited. Therefore, there is an urgent need to investigate how defective neurons can be replenished and functionally integrated by neural regeneration; the reprogramming of intrinsic cells into functional neurons may represent an ideal solution. METHODS: A mouse model of transection SCI was prepared by forceps clamping, and an adeno-associated virus (AAV) carrying the transcription factors NeuroD1 and Neurogenin-2(Ngn2) was injected in situ into the spinal cord to specifically overexpress these transcription factors in astrocytes close to the injury site. 5-bromo-2´-deoxyuridine (BrdU) was subsequently injected intraperitoneally to continuously track cell regeneration, neuroblasts and immature neurons marker expression, neuronal regeneration, and glial scar regeneration. In addition, immunoprotein blotting was used to measure the levels of transforming growth factor-ß (TGF-ß) pathway-related protein expression. We also evaluated motor function, sensory function, and the integrity of the blood-spinal cord barrier(BSCB). RESULTS: The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord was achieved by specific AAV vectors. This intervention led to a significant increase in cell regeneration and the proportion of cells with neuroblasts and immature neurons cell properties at the injury site(p < 0.0001). Immunofluorescence staining identified astrocytes with neuroblasts and immature neurons cell properties at the site of injury while neuronal marker-specific staining revealed an increased number of mature astrocytes at the injury site. Behavioral assessments showed that the intervention did not improve The BMS (Basso mouse scale) score (p = 0.0726) and gait (p > 0.05), although the treated mice had more sensory sensitivity and greater voluntary motor ability in open field than the non-intervention mice. We observed significant repair of the BSCB at the center of the injury site (p < 0.0001) and a significant improvement in glial scar proliferation. Electrophysiological assessments revealed a significant improvement in spinal nerve conduction (p < 0.0001) while immunostaining revealed that the levels of TGF-ß protein at the site of injury in the intervention group were lower than control group (p = 0.0034); in addition, P70 s6 and PP2A related to the TGF-ß pathway showed ascending trend (p = 0.0036, p = 0.0152 respectively). CONCLUSIONS: The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord after spinal cord injury can reprogram astrocytes into neurons and significantly enhance cell regeneration at the injury site. The reprogramming of astrocytes can lead to tissue repair, thus improving the reduced threshold and increasing voluntary movements. This strategy can also improve the integrity of the blood-spinal cord barrier and enhance nerve conduction function. However, the simple reprogramming of astrocytes cannot lead to significant improvements in the striding function of the lower limbs.

Computational identification of novel potential genetic pathogenesis and otherwise biomarkers in acute liver allograft rejection.

Acute cellular rejection (ACR) is a prevalent postoperative complication following liver transplantation (LT), exhibiting an increasing incidence of morbidity and mortality. However, the molecular mechanisms of ACR following LT remain unclear. To explore the genetic pathogenesis and identify biomarkers of ACR following LT, three relevant Gene Expression Omnibus (GEO) datasets consisting of data on ACR or non-ACR patients after LT were comprehensively investigated by computational analysis. A total of 349 upregulated and 260 downregulated differentially expressed genes (DEGs) and eight hub genes (ISG15, HELZ2, HNRNPK, TIAL1, SKIV2L2, PABPC1, SIRT1, and PPARA) were identified. Notably, HNRNPK, TIAL1, and PABPC1 exhibited the highest predictive potential for ACR with AUCs of 0.706, 0.798, and 0.801, respectively. KEGG analysis of hub genes revealed that ACR following LT was predominately associated with ferroptosis, protein processing in the endoplasmic reticulum, complement and coagulation pathways, and RIG-I/NOD/Toll-like receptor signaling pathway. According to the immune cell infiltration analysis, γδT cells, NK cells, Tregs, and M1/M2-like macrophages had the highest levels of infiltration. Compared to SIRT1, ISG15 was positively correlated with γδT cells and M1-like macrophages but negatively correlated with NK cells, CD4+ memory T cells, and Tregs. In conclusion, this study identified eight hub genes and their potential pathways, as well as the immune cells involved in ACR following LT with the greatest levels of infiltration. These findings provide a new direction for future research on the underlying mechanism of ACR following LT.

Transcranial ultrasound with electrical stimulation of the cerebello-parietal nucleus on cerebral blood flow and limb function in patients with stroke.

OBJECTIVE: To investigate the efficacy of transcranial ultrasound stimulation (TUS) combined with Fastigial nucleus stimulation (FNS) on cerebral blood flow and limb function in patients in the acute phase of ischemic stroke. METHODS: A total of 90 patients in the acute phase of ischemic stroke were randomly divided into an FNS, TUS, and TUS + FNS group (30 patients each), and all patients also received conventional treatment. The FNS group was treated with FNS alone. The TUS group was treated with TUS alone. The TUS + FNS group was treated with both TUS and FNS. The three groups were treated once a day for 6 days a week. RESULTS: The simplified Fugl-Meyer Assessment (FMA) and Barthel index scores (BI), and the peak systolic blood flow velocity (Vs) and the mean blood flow velocity (Vm) of the anterior cerebral artery, middle cerebral artery, and posterior cerebral artery, were significantly higher in all three groups compared with before treatment (P < 0.05). The scores for the TUS group were higher than for the FNS group (P < 0.05), and the scores of the TUS + FNS group were higher than the TUS and FNS groups, respectively (P < 0.05). The total effective rate was 63.3%, 70.0%, and 90.0% in the FNS, TUS, and TUS + FNS groups, respectively, and the difference between the three groups was statistically significant (P < 0.05). CONCLUSION: The FNS and TUS treatments improved the function of and accelerated cerebral blood flow in patients with acute ischemic stroke to different degrees, and the combined use of both treatment types was overall more effective.

Effect of information-motivation-behavioral skills model based perioperative nursing on pain in patients with gallstones.

BACKGROUND: The incidence of cholecystolithiasis is on the rise. Use of information, motivation, and behavioral skills can play a positive role in promoting changes in individual health behaviors. However, reports on the effects of information-motivation-behavioral (IMB) skills model based high-quality nursing as a perioperative nursing intervention for patients with gallstones are nonexistent. AIM: To explore the application of IMB skills model based high-quality nursing in patients with gallstones. METHODS: Two hundred and sixteen patients with cholecystolithiasis treated at our hospital from January 2022 to January 2023 were enrolled and divided into a control, high-quality, and combined nursing groups, with 72 patients in each group. The control, high-quality, and combination groups received conventional, high-quality, and IMB skills model based perioperative nursing services, respectively. Differences in clinical indicators, stress levels, degree of pain, emotional state, and quality of life were observed, and complications and nursing satisfaction among the three groups were evaluated. RESULTS: After nursing, the time to recovery of gastrointestinal function in the high-quality and combined nursing groups was significantly shorter than that of the control group, with the recovery of gastrointestinal function being the fastest in the combined nursing group (P < 0.05). After nursing intervention, cortisol and norepinephrine levels in the high-quality and combined nursing groups were closer to normal than those of the control group 24 h after surgery, with the combined nursing group having the closest to normal levels (P < 0.05). After 3 and 7 d of intervention, the patients' pain significantly improved, which was more prominent in the high-quality and combination groups. Meanwhile, the pain score in the combination group was significantly lower than those of the control and high-quality nursing groups (P < 0.05). After nursing intervention, the emotional states of all patients improved, and the scores of patients in the combination group were significantly lower than those of the control and high-quality nursing groups. The quality of life of patients in the high-quality and combined nursing groups significantly improved after nursing intervention compared to that of the control group, with the combined nursing group having the highest quality of life score. After intervention, the incidence of complications in the high-quality and combination groups was significantly lower than that of the control group (P < 0.05), but the difference between the combination and high-quality nursing groups was not significant. Nursing satisfaction of patients in the high-quality and combination groups was significantly higher than that of the control group, with the nursing satisfaction being the highest in the combination group (P < 0.05). CONCLUSION: IMB skills model based nursing can improve surgical stress levels, degrees of pain, emotional state, quality of life, and nursing satisfaction of patients with gallstones and reduce the incidence of complications.

Effect of vascular senescence on the efficacy and safety of warfarin: insights from rat models and a prospective cohort study.

Warfarin, with its narrow therapeutic range, requires the understanding of various influencing factors for personalized medication. Vascular senescence, marked by vascular stiffening and endothelial dysfunction, has an unclear effect on the efficacy and safety of warfarin. Based on previous studies, we hypothesized that vascular senescence increases the risk of bleeding during warfarin therapy. This study aimed to explore these effects using animal models and clinical cohorts. We established rat models of vascular senescence and calcification using d-galactose (D-Gal), vitamin D and nicotine (VDN). After validating the models, we examined changes in the International Normalized Ratio (INR) at fixed warfarin doses (0.20 and 0.35 mg/kg). We found that vascular senescence caused significantly elevated INR values and increasd bleeding risk. In the prospective clinical cohort study(NCT06428110), hospitalized warfarin patients with standard dose adjustments were divided into vascular senescence and control groups based on ultrasound and Computed Tomography (CT) diagnosis. Using propensity score matching (PSM) to exclude the influence of confounding factors, we found that the vascular senescence group had lower steady-state warfarin doses and larger dose adjustments, with a higher probability of INR exceeding the therapeutic range. The vascular senescence group tended to experience more bleeding or thromboembolic/ischemic events during one year of follow-up, while there was no statistical difference. In conclusion, vascular senescence leads to unstable INR values and increases higher bleeding risk during warfarin therapy, highlighting the importance of considering vascular senescence in future precision warfarin therapies. Significance Statement Many factors influence warfarin efficacy, however, the effect of vascular senescence remains unclear. This study aimed to investigate the effects of vascular senescence on the efficacy and safety of warfarin. Through both rat models and clinical cohort studies, our findings indicated that vascular senescence may compromise the stability of warfarin, presenting challenges in maintaining its efficacy and safety.

Astragalus polysaccharides sensitize ovarian cancer stem cells to PARPi by inhibiting mitophagy via PINK1/Parkin signaling.

Ovarian cancer (OC) remains the most lethal gynecological malignant tumor. PARP inhibitors (PARPi) have significantly improved survival, particularly in patients with OC with BRCA1/2 mutations. However, the majority of patients eventually develop resistance to PARPi. Cancer stem cells (CSCs) are considered the source of drug resistance in cancer. Our study found that the synergistic effect of astragalus polysaccharides (APSs) and PARPi was observed in ovarian cancer stem cells (OCSCs) by decreasing cell viability and self-renewal potential while inducing apoptosis. The present study also demonstrated that OCSCs had increased mitophagy. Furthermore, it was observed that APS in combination with PARPi inhibits mitophagy and downregulates the PINK1 protein level in OCSCs. The overexpression of PINK1 via the pEGFP(+)-PINK1 plasmid resulted in a partial reversal of the increased susceptibility of OCSCs when PARPi were administrated concurrently with APS. In conclusion, APS increases OCSC sensitivity to PARPi by inhibiting mitophagy via the PINK1/Parkin pathway regulation.

Diagnostic value of procalcitonin in infections in patients with malignant hematologic diseases. / é™é’™ç´ åŽŸåœ¨æ¶æ€§è¡€æ¶²ç— æ‚£è€ æ„ŸæŸ“ä¸­çš„è¯Šæ–­ä»·å€¼.

OBJECTIVES: The incidence of infections in patients with malignant hematologic diseases is extremely high and significantly affects their prognosis. Identifying early and precise biomarkers for infection is crucial for guiding the treatment of infections in these patients. Previous studies have shown that procalcitonin (PCT) can serve as an early diagnostic marker for bloodstream infections in patients with malignant hematologic diseases. This study aims to compare serum PCT levels in these patients with different pathogens, disease types, infection sites, and severity levels. METHODS: Clinical data and laboratory results of infected patients with malignant hematologic diseases treated at the Department of Hematology, the Third Xiangya Hospital of Central South University from January 2018 to August 2023 were collected. General patient information was retrospectively analyzed. Serum PCT levels were compared among patients with different pathogens, types of malignant hematologic diseases, infection sites, and infection severity; Receiver operator characteristic (ROC) curves were used to determine the cut-off values and diagnostic value of serum PCT levels in diagnosing bloodstream infections versus local infections and severe infections versus non-severe infections. Mortality rates after 4-7 days of anti-infective treatment were compared among groups with rising, falling, and unchanged PCT levels. RESULTS: A total of 526 patients with malignant hematologic diseases were included. The main pathogens were Gram-negative bacteria (272 cases, 51.7%), followed by Gram-positive bacteria (120 cases, 22.8%), fungi (65 cases, 12.4%), viruses (23 cases, 4.4%), and mixed pathogens (46 cases, 8.7%). The main types of malignant hematologic diseases were acute myeloid leukemia (216 cases, 41.1%), acute lymphoblastic leukemia (107 cases, 20.3%), and lymphoma (93 cases, 17.7%). Granulocyte deficiency was present in 68.3% (359 cases) of the patients during infection, with severe infection in 24.1% (127 cases). Significant differences in serum PCT levels were found among patients with different types of pathogens (P<0.001), with the highest levels in Gram-negative bacterial infections. Significant differences in serum PCT levels were also found among patients with different types of malignant hematologic diseases (P<0.05), with the highest levels in lymphoma patients. Serum PCT levels were significantly higher in systemic infections and severe infections compared to local infections and non-severe infections (both P<0.001). ROC curve analysis showed that the cut-off values for diagnosing bloodstream infections and severe infections were 0.22 and 0.28 ng/mL, with areas under the curve of 0.670 and 0.673, respectively. After 4-7 days of anti-infective treatment, the mortality rates of the PCT declining, PCT unchanged, and PCT rising groups were 11.9%, 21.2%, and 35.7%, respectively, and pairwise comparisons were statistically significant (all P<0.05). CONCLUSIONS: PCT can be used as an auxiliary indicator for early identification of different pathogens, infection sites, and severity levels in patients with malignant hematologic diseases combined with infections. Dynamic monitoring of PCT levels after empirical antibiotic treatment provides important guidance for assessing patient's prognosis.

Regional citrate anticoagulation versus LMWH anticoagulation for CRRT in liver failure patients without increased bleeding risk.

BACKGROUND: The optimal anticoagulation regimen for continuous renal replacement therapy (CRRT) in liver failure (LF) patients without increased bleeding risk remains controversial. Therefore, we conducted a monocentric retrospective study to evaluate the efficacy and safety of the regional citrate anticoagulation (RCA) versus low molecular weight heparin (LMWH) anticoagulation for CRRT in LF without increased bleeding risk. METHOD: According to the anticoagulation strategy for CRRT, patients were divided into the RCA and LMWH-anticoagulation groups. The evaluated endpoints were patient survival, filter lifespan, bleeding, citrate accumulation, and totCa/ionCa ratio. RESULT: Totally 167 and 164 filters were used in the RCA and LMWH group, respectively. The median filter lifespan was significantly longer in the RCA group (34 h (IQR = 24-54) versus 24 h (IQR = 18-45.5) [95%CI, 24.5-33]; p < 0.001). The 4-week mortality rate was significantly higher in the LMWH-anticoagulation group (71 (57.72%) vs 53 (40.46%); p = 0.006). After adjusted the important parameters in the multivariate COX regression model, the mortality risk was significantly reduced in the RCA group (HR = 0.668 [95%CI, 0.468-0.955]; p = 0.027). In the LMWH group, 30 bleeding episodes (24,19%) were observed, whereas only 7 (5.34%) occurred in the RCA group (p < 0.001). Two patients (1.5%) in the RCA group occurred citrate accumulation. CONCLUSIONS: In LF patients without increased bleeding risk who underwent CRRT, RCA significantly extended the filter lifespan and improved patient survival rate. There was no significant difference in the rate of adverse events between the two groups.