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.

Vibration source analysis and structural optimization design of rotary table based on OTPA.

Due to the influence of coal rock shape, hardness, working environment and other factors in the cutting process of cantilever roadheader, the cutting head will produce irregular and violent vibration. As the rotary table of key stress components, its operation process stability, dynamic reliability and life affect the cutting efficiency and cutting stability of cantilever roadheader. In order to study the vibration characteristics of the rotary table in the cutting process, firstly, based on the theory of spatial force analysis and calculation, the spatial mechanical model of the rotary table of the cantilever roadheader is established. By solving the balance equation of the rotary table force system, the variation law of the load at the hinge ear of the rotary table with the cutting pitch angle and the horizontal angle is obtained. Secondly, based on the path transfer analysis method of working condition, the vibration data of cutting head, cutting cantilever, cutting lifting and rotary hydraulic cylinder under stable cutting condition are taken as input signals. By constructing the transfer path analysis model of rotary table working condition, the synthetic vibration of rotary table in cutting process is simulated, and the main vibration source of rotary table is determined. Then, the vibration contribution and contribution degree of each vibration excitation point to the hinge ear of rotary table are studied. By building a cutting test bench, the vibration response of rotary table in cutting process is tested to verify the correctness of the theoretical model.Thirdly, based on the frequency domain analysis method of random vibration fatigue life, combined with the S-N curve of the rotary table, the PSD curve at the maximum stress of the rotary table is obtained by modal excitation method, and the load data is imported into ANSYS nCode software to obtain the life cloud diagram and damage cloud diagram of the rotary table, and then the fatigue life of the rotary table under symmetrical cyclic load is solved. Finally, based on the response surface optimization analysis method, the maximum stress and maximum deformation of the rotary table are taken as the optimization objectives, and the aperture of each hinge ear of the rotary table is taken as the optimization variable. Based on Design Expert, a second-order regression model is established to realize the multi-objective optimization design of the key stress parts of the rotary table in the cutting process. The simulation results show that under the same cutting conditions, the maximum stress of the optimized rotary table is reduced by 15.82% year-on-year, and the maximum deformation is reduced by 24.70% year-on-year. The optimized rotary table structure can better adapt to the cutting process, which is beneficial to improve the service life of the rotary table and enhance its operation stability. The research results are beneficial to enrich the relevant research theory in the field of rotary table vibration of cantilever roadheader, and are beneficial to improve the service life of the rotary table and the efficiency of tunneling and mining.

Normalized lactate load as an independent prognostic indicator in patients with cardiogenic shock.

BACKGROUND: Early prognosis evaluation is crucial for decision-making in cardiogenic shock (CS) patients. Dynamic lactate assessment, for example, normalized lactate load, has been a better prognosis predictor than single lactate value in septic shock. Our objective was to investigate the correlation between normalized lactate load and in-hospital mortality in patients with CS. METHODS: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The calculation of lactate load involved the determination of the cumulative area under the lactate curve, while normalized lactate load was computed by dividing the lactate load by the corresponding period. Receiver Operating Characteristic (ROC) curves were constructed, and the evaluation of areas under the curves (AUC) for various parameters was performed using the DeLong test. RESULTS: Our study involved a cohort of 1932 CS patients, with 687 individuals (36.1%) experiencing mortality during their hospitalization. The AUC for normalized lactate load demonstrated significant superiority compared to the first lactate (0.675 vs. 0.646, P < 0.001), maximum lactate (0.675 vs. 0.651, P < 0.001), and mean lactate (0.675 vs. 0.669, P = 0.003). Notably, the AUC for normalized lactate load showed comparability to that of the Sequential Organ Failure Assessment (SOFA) score (0.675 vs. 0.695, P = 0.175). CONCLUSION: The normalized lactate load was an independently associated with the in-hospital mortality among CS patients.

Pharmacological Components and Mechanism Research on the Treatment of Myelosuppression after Chemotherapy with Danggui Jixueteng Decoction Based on Spectrum-Effect Relationships and Transcriptome Sequencing.

Danggui Jixueteng decoction (DJD) has been used to treat anemia for many years and has been shown to be effective. However, the mechanism of action and effective components are yet unknown. We want to search for pharmacodynamic components in DJD with therapeutic effects on myelosuppression after chemotherapy (MAC), utilizing a spectrum-effect connection study based on gray relational analysis and partial least-squares regression analysis. Transcriptome sequencing (RNA-Seq) was used to investigate the mechanism by which DJD treats MAC. In this study, fingerprints of different batches of DJD (S1-S10) were established by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), after which the resulting shared peaks were screened and identified. A total of 21 common peaks were screened through the fingerprints of different batches of DJD, and the similarity of each profile was greater than 0.92. The 21 shared peaks were identified by comparison with the standard sample and searching on a MassLynx 4.1 workstation. The rat model of MAC was established by intraperitoneal injection of cyclophosphamide, and DJD treatment was carried out in parallel with the establishment of the model. White blood cell count, red blood cell count, platelet count, interleukin-3, hemoglobin concentration, granulocyte-macrophage colony-stimulating factor, and nucleated cell count were used as efficacy indicators. Pharmacodynamic results indicated that DJD could effectively improve the pharmacodynamic indices of MAC rats. The results of gray relational analysis demonstrated eight peaks with high correlation with efficacy, which were 2, 7, 10, 14, 15, 16, 18, and 21, and the partial least-squares regression analysis showed four peaks with variable importance in projection values greater than 1, which were 10, 12, 13, and 19. RNA-Seq was used to identify DEGs in rat bone marrow cells, Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs were performed. The genes related to the effects of DJD on MAC were mainly involved in the phosphatidylinositol 3-kinase/serine-threonine kinase (PI3K-Akt) signaling pathway, the mitogen-activated protein kinase signaling pathway, actin cytoskeleton regulation, focal adhesion, and Rap1 signaling pathways. The results of the RNA-Seq study were confirmed by a qPCR experiment. The effective compounds of DJD against MAC include albiflorin, paeoniflorin, gallopaeoniflorin, salvianolic acid H/I, albiflorin R1, salvianolic acid B, salvianolic acid E, benzoylpaeoniflorin, and C12H18N5O4. The mechanism by which DJD prevents and treats MAC might involve the control of the PI3K-Akt signaling pathway.

Safety, tolerability and pharmacokinetics of ASC10, a novel oral double prodrug of a broad-spectrum antiviral agent, ß-d-N4-hydroxycytidine: results from a randomized, double-blind, placebo-controlled phase 1 study in Chinese healthy subjects.

BACKGROUND: Considering the rise of new SARS-CoV-2 variants that have reduced the efficacy of COVID-19 vaccines, the development of new antiviral medications for the disease has become increasingly necessary. In this study, ASC10, a novel antiviral prodrug, was studied in a phase 1 trial in healthy Chinese participants. RESEARCH DESIGN AND METHODS: Part 1 involved 60 participants, receiving 50-800 mg ASC10 or placebo twice daily for 5.5 days. Part 2, with 12 participants, explored ASC10 dosing in the fed/fasting states. RESULTS: ASC10-A, the main pharmacologically active metabolite, rapidly appeared in plasma (Tmax: 1.00-2.00 h) and decreased (t1/2: 1.10-3.04 h) without accumulation. The Cmax and area under the plasma concentration - time curve (AUC) of ASC10-A increased dose-dependently (50-800 mg BID) over 5.5 days, with no accumulation. The Tmax was slightly delayed in the fed state; however, the Cmax and AUC were similar between the fed and fasting states. Adverse events (AEs) were comparable (ASC10/placebo, 66.7%) and mostly mild (95%). CONCLUSION: ASC10 was demonstrated to be safe and well tolerated and exhibited dose-proportional exposure and minimal food effects. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05523141.

Caregiver burden among parents of school-age children with asthma: a cross-sectional study.

Objective: To investigate the caregiver burden of parents of school-age children with asthma and analyze the factors influencing their caregiver burden. Methods: A convenience sampling method was used to select 366 parents of school-age children with asthma who visited the outpatient departments of three tertiary hospitals in Sichuan Province, China, from January 2021 to July 2021. A general information questionnaire and the Caregiver Burden Inventory (CBI) were used to assess the current caregiver burden and analyze the influencing factors. Results: The caregiver burden score of parents of school-age children with asthma was 27 (17, 39), with 40.43% of parents experiencing moderate to high levels of burden. Detailed results of univariate analysis showed that there were significant differences in caregiver burden scores based on parents' gender, highest education level, number of children, occupation, family history of asthma, monthly family income, annual medical expenses for the child, child's gender, whether the child had undergone lung function tests, number of emergency visits due to asthma exacerbation in the past 3 months, and whether the child had missed school due to asthma exacerbation in the past 3 months (p < 0.1). Detailed results of multivariate analysis showed that parents' gender, occupation, family history of asthma, monthly family income, annual medical expenses for the child, number of emergency visits due to asthma exacerbation in the past 3 months, and whether the child had missed school due to asthma exacerbation in the past 3 months were independent risk factors for caregiver burden in parents of school-age children with asthma (p < 0.05). Conclusion: Parents of school-age children with asthma experience a certain level of caregiver burden, with over one-third of parents experiencing moderate to high levels of burden. Being a mother, being a worker, having no family history of asthma, having low monthly family income, having high annual medical expenses for the child, having frequent emergency visits due to asthma exacerbation in the past 3 months, and having missed school due to asthma exacerbation in the past 3 months are independent risk factors for caregiver burden in parents of school-age children with asthma, healthcare providers should develop feasible coping strategies, such as paying attention to caregivers' psychological condition to reduce the burden of caring for parents of school-age children with asthma. The entire society should also make efforts in improving social support and strengthening healthcare coverage in order to achieve the aforementioned goals.

Transcriptome analysis reveals the effect of cold storage time on the expression of genes related to oxidative metabolism in Chinese black truffle.

Chinese black truffle (Tuber indicum) is a hypogenous fungus of great value due to its distinctive aroma. In this study, both transcriptome and physicochemical analyses were performed to investigate the changes of nutrients and gene expression in truffle fruiting bodies during cold storage. The results of physicochemical analysis revealed the active metabolism of fruiting bodies in cold storage, showing the decreased contents of protein and soluble sugar, the variations in both polyphenol oxidase activity and total phenol content, and the detrimental effect of reactive oxygen species production caused by heavy metals (cadmium and lead) in truffles. Transcriptome analysis identified a total of 139,489 unigenes. Down-regulated expression of genes encoding the catalase-like domain-containing protein (katE), glutaredoxin protein (GRX), a copper/zinc superoxide dismutase (Sod_Cu), and aspartate aminotransferase (AAT) affected the degradation metabolism of intracellular oxides. Ribulose-5-phosphate-3-epimerase (RPE) was a key enzyme in response to oxidative stress in truffle cells through the pentose phosphate pathway (PPP). A total of 51,612 simple sequence repeats were identified, providing valuable resources for further genetic diversity analysis, molecular breeding, and genetic map-ping in T. indicum. Transcription factors GAL4 and SUF4-like protein were involved in glucose metabolism and histone methylation processes, respectively. Our study provided a fundamental characterization of the physicochemical and molecular variations in T. indicum during the cold storage at 4°C, providing strong experimental evidence to support the improvement of storage quality of T. indicum.

[Altitude Distribution Characteristics of Farmland Soil Bacteria in Loess Hilly Region of Ningxia].

It is of great significance for the conservation of biodiversity in farmland ecosystems to study the diversity, structure, functions, and biogeographical distribution of soil microbes in farmland and their influencing factors. High-throughput sequencing technology was used to analyze the distribution characteristics of soil bacterial diversity, community structure, and metabolic function along elevation and their responses to soil physicochemical properties in farmland in the loess hilly areas of Ningxia. The results showed that:① The Alpha diversity index of soil bacterial was significantly negatively correlated with elevation (P < 0.05) and showed a trend of decreasing and then slightly increasing along the elevation. ② Seven phyla, including Proteobacteria, Actinobacteria, and Acidobacteria, were the dominant groups, and five of them showed highly significant differences between altitudes (P < 0.01). ③ At the secondary classification level, there were 36 metabolic functions of bacteria, including membrane transport, carbohydrate metabolism, and amino acid metabolism, of which 22 showed significant differences, and 12 showed extremely significant differences among different altitudes. ④ Pearson correlation analysis showed that soil water content, bulk density, pH, and carbon-nitrogen ratio had the most significant effects on bacterial Alpha diversity, whereas soil nutrients such as total organic carbon, total nitrogen, and total phosphorus had significant effects on bacterial Beta diversity. ⑤ Mantel test analysis showed that the soil water content, total organic carbon, and carbon-nitrogen ratio affected bacterial community structure at the phylum level, and soil pH, total organic carbon, total nitrogen, total phosphorus, and carbon-nitrogen ratio were significantly correlated with bacterial metabolic function. Variance partitioning analysis showed that soil water content had the highest explanation for the community structure of soil bacteria, whereas soil pH had the highest explanation for metabolic function. In conclusion, soil water content and pH were the main factors affecting the diversity, community composition, and metabolic function of soil bacteria in farmland in the loess hilly region of Ningxia.

Necessity for higher teicoplanin doses in older adults: a multicenter prospective observational study in China.

BACKGROUND: Many older adult patients receive low-dose teicoplanin with varied regimens, leading to a lack of clarity on its optimal regimens and toxicity profiles in China. This study aimed to clarify these aspects by analyzing teicoplanin treatment concentrations and toxicities. METHODS: We included older adult patients administered teicoplanin at four tertiary hospitals in Beijing from June 2021 to July 2023, targeting a trough concentration (Cmin) ≥ 10 mg/L. Teicoplanin concentrations and toxicities were monitored dynamically. RESULTS: From 204 patients, we obtained 632 teicoplanin concentrations. Most patients (83.3%) received low-dose regimens. Suboptimal concentrations were found in 66.4% of patients within 7 days of treatment and 17.0% after 15 days. Cmin gradually increased with treatment duration and was influenced initially by creatinine and by both body weight and creatinine from days 8 to 14. The target concentration was achieved in 53.1%, 33.9%, 15.6%, and 5.5% of patients at 3, ≤ 7, 8-14, and ≥ 15 days after withdrawal, respectively. Slow elimination was associated with average Cmin and eGFR. Nephrotoxicity, hepatotoxicity, and thrombocytopenia occurred in 12.5%, 4.1%, and 31.5% of patients, respectively, without significant differences between concentrations. CONCLUSIONS: Most older adult patients were underdosed, indicating a need for dose adjustment. Given the varied risk factors for suboptimal concentrations in different treatment stages, a one-size-fits-all regimen was ineffective. We recommend an initial dose of 400 mg at 12-h intervals for the first three days, with subsequent doses from days 4 to 14 adjusted based on creatinine and body weight; after day 14, a maintenance dose of 200 mg daily is advised. TRIAL REGISTRATION: ChiCTR2100046811; 28/05/2021.

The association of cumulative low-density lipoprotein cholesterol exposure and carotid intima-media thickness in a young adulthood population.

OBJECTIVE: To investigate the association between cumulative exposure to low-density lipoprotein cholesterol (LDL-C) and carotid intima-media thickness (IMT) in the young adulthood population. METHODS: Young adult subject (18-45 year old) from the Kailuan Study group who participated in the same period of follow-up and received carotid artery ultrasound were selected as the observation subjects. Among them, 3651 cases met the inclusion criteria, which required that carotid artery color ultrasound examinations be completed from 2010 to 2016, with complete IMT measurements, LDL-C data collected at least twice before carotid ultrasound, and participants' age to be ≤ 45 years at the time of carotid artery color ultrasound examination. Linear regression was used to analyze the correlation between time-weighted average (TWA) to LDL-C cumulative exposure and IMT the young population. Logistic regression was used to analyze the effects of different TWA groups on IMT thickening. Considering that the use of anti hypertensive drugs and lipid-lowering drugs may affect TWA LDL-C, this study excluded people taking antihypertensive drugs and lipid-lowering drugs, and conducted a repeat analysis of the main results. RESULTS: There was a positive correlation between TWA LDL-C and IMT, with IMT increasing by 0.017 mm when TWA LDL-C increased by 1 mmol/L * year. The TWA LDL-C in the highest group was identified as a risk factor for IMT thickening, with odds ratio (OR) values of 1.812(1.027 ~ 3.200) in the T3 group. After excluding patients taking antihypertensive drugs and lipid-lowering drugs, the results still showed that the T3 group with the highest TWA LDL-C was a risk factor for IMT thickening, with an OR value of 1.850(0.988-3.464), P for trend is 0.043. CONCLUSION: This cohort study revealed that TWA LDL-C is positively correlated with IMT in young adulthood for risk stratification, and control LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic disease. TRIAL REGISTRATION: ChiCTR-TNC-11001489.

Effects of Dietary Protein Level and Rumen-Protected Methionine and Lysine on Growth Performance, Rumen Fermentation and Serum Indexes for Yaks.

This study investigated the effects of the dietary protein level and rumen-protected methionine and lysine (RPML) on the growth performance, rumen fermentation, and serum indexes of yaks. Thirty-six male yaks were randomly assigned to a two by three factorial experiment with two protein levels, 15.05% and 16.51%, and three RPML levels: 0% RPML; 0.05% RPMet and 0.15% RPLys; and 0.1% RPMet and 0.3% RPLys. The trial lasted for sixty days. The results showed that the low-protein diet increased the DMI and feed conversion ratio of yaks. The diet supplemented with RPML increased the activities of IGF1 and INS and nutrient digestibility. The high-protein diet decreased the rumen butyrate concentration and increased the rumen isovalerate concentration. The low-protein diet supplemented with RPML increased the rumen pH and the concentrations of total volatile fatty acids, butyrate and NH3-N; the high-protein diet supplemented with a high level of RPML decreased the rumen pH and the concentrations of isobutyrate, isovalerate, propionate and NH3-N. The low-protein diet supplemented with RPML increased the total antioxidant capacity and glutathione peroxidase activity, along with the concentrations of malondialdehyde and amino acids such as aspartic acid, lysine, cysteine, etc. In conclusion, a low-protein diet supplemented with RPML is beneficial for rumen and body health, physiological response, and metabolic status in yaks.

D-MHGCN: An End-to-End Individual Behavioral Prediction Model Using Dual Multi-Hop Graph Convolutional Network.

Predicting individual behavior is a crucial area of research in neuroscience. Graph Neural Networks (GNNs), as powerful tools for extracting graph-structured features, are increasingly being utilized in various functional connectivity (FC) based behavioral prediction tasks. However, current predictive models primarily focus on enhancing GNNs' ability to extract features from FC networks while neglecting the importance of upstream individual network construction quality. This oversight results in constructed functional networks that fail to adequately represent individual behavioral capacity, thereby affecting the subsequent prediction accuracy. To address this issue, we proposed a new GNN-based behavioral prediction framework, named Dual Multi-Hop Graph Convolutional Network (D-MHGCN). Through the joint training of two GCNs, this framework integrates individual functional network construction and behavioral prediction into a unified optimization model. It allows the model to dynamically adjust the individual functional cortical parcellation according to the downstream tasks, thus creating task-aware, individual-specific FCNs that largely enhance its ability to predict behavior scores. Additionally, we employed multi-hop graph convolution layers instead of traditional single-hop methods in GCN to capture complex hierarchical connectivity patterns in brain networks. Our experimental evaluations, conducted on the large, public Human Connectome Project dataset, demonstrate that our proposed method outperforms existing methods in various behavioral prediction tasks. Moreover, it produces more functionally homogeneous cortical parcellation, showcasing its practical utility and effectiveness. Our work not only enhances the accuracy of individual behavioral prediction but also provides deeper insights into the neural mechanisms underlying individual differences in behavior.

Validation of the Chinese version of the Whooley questions for community screening of postpartum depression.

BACKGROUND: The study aims to validate the Whooley questions for screening postpartum depression in Chinese women in a community setting. METHODS: The Whooley questions was translated into Chinese following Beaton's intercultural debugging guidelines. From December 1, 2020 to June 30, 2021, primary maternal and child health workers in Kaifu District and Changsha County in Changsha City recruited women aged 18 years or older who had recently given birth during home visits within seven days of discharge from hospital. Participants women completed the Whooley questions online and underwent a diagnostic interview for DSM-IV within 7 days of the visit. We evaluated Cronbach's alpha, split-half reliability, area under the ROC curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and optimal cut-off value of the Whooley questions. RESULTS: Of the 3,004 eligible women, 1,862 completed the Whooley questions and diagnostic interviews. Sixty-two women (3.3%) were diagnosed with depressive disorders. The Cronbach's alpha coefficient was 0.64, the split-half reliability was 0.64. The optimal cut-off value was when at least one questions was answered "yes", with an AUC of 0.84 (SE=0.03, 95%CI 0.78-0.90, P<0.001), sensitivity of 0.77 (95%CI 0.65-0.87), specificity of 0.89 (95%CI 0.88-0.90), PPV of 0.20 (95%CI 0.15-0.25) and NPV of 0.99 (95%CI 0.98-1.00). CONCLUSION: This study shows that the Chinese version of the Whooley questions is a reliable tool for screening postpartum depression in the community, but it may lead to many false positive cases.

Advances in Drug Delivery Systems for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a common and catastrophic hematological neoplasm with high mortality rates. Conventional therapies, including chemotherapy, hematopoietic stem cell transplantation (HSCT), immune therapy, and targeted agents, have unsatisfactory outcomes for AML patients due to drug toxicity, off-target effects, drug resistance, drug side effects, and AML relapse and refractoriness. These intrinsic limitations of current treatments have promoted the development and application of nanomedicine for more effective and safer leukemia therapy. In this review, the classification of nanoparticles applied in AML therapy, including liposomes, polymersomes, micelles, dendrimers, and inorganic nanoparticles, is reviewed. In addition, various strategies for enhancing therapeutic targetability in nanomedicine, including the use of conjugating ligands, biomimetic-nanotechnology, and bone marrow targeting, which indicates the potential to reverse drug resistance, are discussed. The application of nanomedicine for assisting immunotherapy is also involved. Finally, the advantages and possible challenges of nanomedicine for the transition from the preclinical phase to the clinical phase are discussed.

Antioxidant effect of gallic acid on retinal ganglion cells in glaucoma model.

To evaluate the protective effect of gallic acid on the optic nerve by studying the inhibitory effect of gallic acid on oxidative stress in retinal ganglion cells. 100 male SD rats were randomly divided into four groups: normal control group, simple high IOP group, 0.5% gallic acid experimental group, and 1% gallic acid experimental group. HE staining, immunofluorescence, DHE staining, Western blot, and q-PCR were used to observe the antioxidant effect of gallic acid on the retina of acute ocular hypertension rats. HE staining of the retina of SD rats confirmed that the nucleus of RGCs was clear, the thickness of the RNFL was regular in the normal control group, and the nucleus of RGCs was ruptured and lysed in the simple high intraocular pressure (IOP) group and the gallic acid group, and the thickness of the RNFL was significantly thickened, but the thickness of the RNFL in the gallic acid group was significantly reduced compared with that in the simple high IOP group (p < 0.05). DHE staining showed that ROS content in the simple high IOP group was significantly increased compared with the normal control group, and ROS content was significantly decreased after the application of gallic acid (p < 0.05). Immunofluorescence staining with Brn-3a antibody confirmed that the number of RGCs was significantly reduced in the simple high IOP group compared with the normal control group, whereas after application of gallic acid, the number of RGCs was significantly more in the gallic acid group than in the simple high IOP group (p < 0.05). Western Blot and q-PCR confirmed that hypoxia-inducing factor 1α (HIF-1α) protein content and transcription level were significantly increased in the retinal tissue of the simple high IOP group, and gallic acid could inhibit HIF-1α protein content (p < 0.05) and reduce transcription factor level (p < 0.05). Gallic acid exerts a protective effect on RGC by inhibiting oxidative stress in rats with acute IOP elevation.

Discovery and characterization of panaxatriol as a novel thrombin inhibitor from Panax notoginseng using combination of computational and experimental approach.

Thrombin is a crucial enzyme in the coagulation cascade, and inhibitors of thrombin have been extensively studied as potential antithrombotic agents. The objective of this study was to identify natural inhibitors of thrombin from Panax notoginseng and evaluate their biological activity in vitro and binding characteristics. A combined approach involving molecular docking, thrombin inhibition assay, surface plasmon resonance (SPR) and molecular dynamics simulation was utilized to identify natural thrombin inhibitors. The results demonstrated that that panaxatriol directly inhibits thrombin with an IC50 of 10.3 µM. Binding studies using SPR revealed that panaxatriol interacts with thrombin with a KD value of 7.8 µM. Molecular dynamics analysis indicated that the thrombin-panaxatriol system reached equilibrium rapidly with minimal fluctuations, and the calculated binding free energy was -23.8 kcal/mol. The interaction between panaxatriol and thrombin involves the amino acid residues Glu146, Glu192, Gly216, Gly219, Tyr60A, and Trp60D. This interaction provides a mechanistic basis for further optimizing panaxatriol as a thrombin inhibitor. Our study has shown that panaxatriol serves as a direct thrombin inhibitor, laying the groundwork for further research and development of novel thrombin inhibitor.

A remaining useful life prediction algorithm incorporating real-time and integrated model for hidden actuator degradation.

This paper proposed a prediction algorithm for the degraded actuator taking into account the impact of estimation error of hidden index in the closed-loop system. To this end, a unified prediction framework is established to evaluate the hidden degradation information and recursively update the degradation model parameters simultaneously. The advantage is that the prediction framework can comprehensively compensate the estimation error of hidden degradation index caused by system uncertainty. To jointly estimate the degradation information in avoidance of the impact of system uncertainty, a modified adaptive Kalman filter is designed, and the proof of stability is provided. With the priori estimate from the filter, the degradation model parameters are updated by the inverse filtering probability based on Bayes' theorem. It is followed by the computation of the remaining useful life (RUL) prediction utilizing aforementioned hidden degradation information and the latest degradation model. The effectiveness of the proposed RUL prediction algorithm is demonstrated by the degraded actuator in the continuous casting process.

A multi-omic single-cell landscape of cellular diversification in the developing human cerebral cortex.

The vast neuronal diversity in the human neocortex is vital for high-order brain functions, necessitating elucidation of the regulatory mechanisms underlying such unparalleled diversity. However, recent studies have yet to comprehensively reveal the diversity of neurons and the molecular logic of neocortical origin in humans at single-cell resolution through profiling transcriptomic or epigenomic landscapes, owing to the application of unimodal data alone to depict exceedingly heterogeneous populations of neurons. In this study, we generated a comprehensive compendium of the developing human neocortex by simultaneously profiling gene expression and open chromatin from the same cell. We computationally reconstructed the differentiation trajectories of excitatory projection neurons of cortical origin and inferred the regulatory logic governing lineage bifurcation decisions for neuronal diversification. We demonstrated that neuronal diversity arises from progenitor cell lineage specificity and postmitotic differentiation at distinct stages. Our data paves the way for understanding the primarily coordinated regulatory logic for neuronal diversification in the neocortex.

Extracellular vesicles activated cancer-associated fibroblasts promote lung cancer metastasis through mitophagy and mtDNA transfer.

BACKGROUND: Studies have shown that oxidative stress and its resistance plays important roles in the process of tumor metastasis, and mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) damage is an important molecular event in oxidative stress. In lung cancer, the normal fibroblasts (NFs) are activated as cancer-associated fibroblasts (CAFs), and act in the realms of the tumor microenvironment (TME) with consequences for tumor growth and metastasis. However, its activation mechanism and whether it participates in tumor metastasis through antioxidative stress remain unclear. METHODS: The role and signaling pathways of tumor cell derived extracellular vesicles (EVs) activating NFs and the characteristic of induced CAFs (iCAFs) were measured by the transmission electron microscopy, nanoparticle tracking analysis, immunofluorescence, collagen contraction assay, quantitative PCR, immunoblotting, luciferase reporter assay and mitochondrial membrane potential detection. Mitochondrial genome and single nucleotide polymorphism sequencing were used to investigate the transport of mtDNA from iCAFs to ρ0 cells, which were tumor cells with mitochondrial dysfunction caused by depletion of mtDNA. Further, the effects of iCAFs on mitochondrial function, growth and metastasis of tumor cells were analysed in co-culture models both in vitro and in vivo, using succinate dehydrogenase, glutathione and oxygen consumption rate measurements, CCK-8 assay, transwell assay, xenotransplantation and metastasis experiments as well as in situ hybridization and immunohistochemistry. RESULTS: Our findings revealed that EVs derived from high-metastatic lung cancer cells packaged miR-1290 that directly targets MT1G, leading to activation of AKT signaling in NFs and inducing NFs conversion to CAFs. The iCAFs exhibit higher levels of autophagy and mitophagy and more mtDNA release, and reactive oxygen species (ROS) could further promote this process. After cocultured with the conditioned medium (CM) of iCAFs, the ρ0 cells may restore its mitochondrial function by acquisition of mtDNA from CAFs, and further promotes tumor metastasis. CONCLUSIONS: These results elucidate a novel mechanism that CAFs activated by tumor-derived EVs can promote metastasis by transferring mtDNA and restoring mitochondrial function of tumor cells which result in resistance of oxidative stress, and provide a new therapeutic target for lung cancer metastasis.

Promotive effect of skin precursor-derived Schwann cells on brachial plexus neurotomy and motor neuron damage repair through milieu-regulating secretome.

Brachial plexus injury (BPI) with motor neurons (MNs) damage still remain poor recovery in preclinical research and clinical therapy, while cell-based therapy approaches emerged as novel strategies. Previous work of rat skin precursor-derived Schwann cells (SKP-SCs) provided substantial foundation for repairing peripheral nerve injury (PNI). Given that, our present work focused on exploring the repair efficacy and possible mechanisms of SKP-SCs implantation on rat BPI combined with neurorrhaphy post-neurotomy. Results indicated the significant locomotive and sensory function recovery, with improved morphological remodeling of regenerated nerves and angiogenesis, as well as amelioration of target muscles atrophy and motor endplate degeneration. Besides, MNs could restore from oxygen-glucose-deprivation (OGD) injury upon SKP-SCs-sourced secretome treatment, implying the underlying paracrine mechanisms. Moreover, rat cytokine array assay detected 67 cytokines from SKP-SC-secretome, and bioinformatic analyses of screened 32 cytokines presented multiple functional clusters covering diverse cell types, including inflammatory cells, Schwann cells, vascular endothelial cells (VECs), neurons, and SKP-SCs themselves, relating distinct biological processes to nerve regeneration. Especially, a panel of hypoxia-responsive cytokines (HRCK), can participate into multicellular biological process regulation for permissive regeneration milieu, which underscored the benefits of SKP-SCs and sourced secretome, facilitating the chorus of nerve regenerative microenvironment. Furthermore, platelet-derived growth factor-AA (PDGF-AA) and vascular endothelial growth factor-A (VEGF-A) were outstanding cytokines involved with nerve regenerative microenvironment regulating, with significantly elevated mRNA expression level in hypoxia-responsive SKP-SCs. Altogether, through recapitulating the implanted SKP-SCs and derived secretome as niche sensor and paracrine transmitters respectively, HRCK would be further excavated as molecular underpinning of the neural recuperative mechanizations for efficient cell therapy; meanwhile, the analysis paradigm in this study validated and anticipated the actions and mechanisms of SKP-SCs on traumatic BPI repair, and was beneficial to identify promising bioactive molecule cocktail and signaling targets for cell-free therapy strategy on neural repair and regeneration.