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Objective: This study aimed to investigate the mechanism that Lactobacillus murinus (L. murinus) alleviated lung inflammation induced by polycyclic aromatic hydrocarbons (PAHs) exposure based on metabolomics. Methods: Female mice were administrated with PAHs mix, L. murinus and indoleacrylic acid (IA) or indolealdehyde (IAId). Microbial diversity in feces was detected by 16 S rRNA gene sequencing. Non-targeted metabolomics analysis in urine samples and targeted analysis of tryptophan metabolites in serum by UPLC-Orbitrap-MS and short-chain fatty acids (SCFA) in feces by GC-MS were performed, respectively. Flow cytometry was used to determine T helper immune cell differentiation in gut and lung tissues. The levels of IgE, IL-4 and IL-17A in the bronchoalveolar lavage fluid (BALF) or serum were detected by ELISA. The expressions of aryl hydrocarbon receptor (Ahr), cytochrome P450 1A1 (Cyp1a1) and forkheadbox protein 3 (Foxp3) genes and the histone deacetylation activity were detected by qPCR and by ELISA in lung tissues, respectively. Results: PAHs exposure induced lung inflammation and microbial composition shifts and tryptophan metabolism disturbance in mice. L. murinus alleviated PAHs-induced lung inflammation and inhibited T helper cell 17 (Th17) cell differentiation and promoted regulatory T cells (Treg) cell differentiation. L. murinus increased the levels of IA and IAId in the serum and regulated Th17/Treg imbalance by activating AhR. Additionally, L. murinus restored PAHs-induced decrease of butyric acid and valeric acid which can reduce the histone deacetylase (HDAC) level in the lung tissues, enhancing the expression of the Foxp3 gene and promoting Treg cell differentiation. Conclusion: our study illustrated that L. murinus alleviated PAHs-induced lung inflammation and regulated Th17/Treg cell differentiation by regulating host tryptophan metabolism and SCFA levels. The study provided new insights into the reciprocal influence between gut microbiota, host metabolism and the immune system, suggesting that L. murinus might have the potential as a novel therapeutic strategy for lung diseases caused by environmental pollution in the future.

Background and objectivesThe oral and gut microbiota play significant roles in childhood asthma pathogenesis. However, the communication dynamics and pathogenic mechanisms by which oral microbiota influence gut microbiota and disease development remain incompletely understood. This study investigated potential mechanisms by which oral-originated gut microbiota, specifically Prevotella genus, may contribute to childhood asthma etiology.MethodsOral swab and fecal samples from 30 asthmatic children and 30 healthy controls were collected. Microbiome composition was characterized using 16S rRNA gene sequencing and metagenomics. Genetic distances identified potential oral-originated bacteria in asthmatic children. Functional validation assessed pro-inflammatory properties of in silico predicted microbial mimicry peptides from enriched asthma-associated species. Fecal metabolome profiling combined with metagenomic correlations explored links between gut microbiota and metabolism. HBE cells treated with Prevotella bivia culture supernatant were analyzed for lipid pathway impacts using UPLC-MS/MS.ResultsChildren with asthma exhibited distinct oral and gut microbiota structures. Prevotella bivia, P. disiens, P. oris and Bacteroides fragilis were enriched orally and intestinally in asthmatics, while Streptococcus thermophilus decreased. P. bivia, P. disiens and P. oris in asthmatic gut likely originated orally. Microbial peptides induced inflammatory cytokines from immune cells. Aberrant lipid pathways characterized asthmatic children. P. bivia increased pro-inflammatory and decreased anti-inflammatory lipid metabolites in HBE cells.ConclusionThis study provides evidence of Prevotella transfer from oral to gut microbiota in childhood asthma. Prevotella’s microbial mimicry peptides and effects on lipid metabolism contribute to disease pathogenesis by eliciting immune responses. Findings offer mechanistic insights into oral-gut connections in childhood asthma etiology.

Abstract Background Genomic three-dimensional (3D) spatial organization plays a key role in shaping gene expression and associated chromatin modification, and it is highly sensitive to environmental stress conditions. In microalgae, exposure to nitrogen stress can drive lipid accumulation, yet the associated functional alterations in the spatial organization of the microalgal genome have yet to be effectively characterized. Results Accordingly, the present study employed RNA-seq, Hi-C, and ChIP-seq approaches to explore the relationship between 3D chromosomal architecture and gene expression during lipid accumulation in the marine microalga Nannochloropsis oceanica in response to nitrogen deprivation (ND). These analyses revealed that ND resulted in various changes in chromosomal organization, including A/B compartment transitions, topologically associating domain (TAD) shifts, and the disruption of short-range interactions. Significantly higher levels of gene expression were evident in A compartments and TAD boundary regions relative to B compartments and TAD interior regions, consistent with observed histone modification enrichment in these areas. ND-induced differentially expressed genes (DEGs) were notably enriched in altered TAD-associated regions and regions exhibiting differential genomic contact. These DEGs were subjected to Gene Ontology (GO) term analyses that indicated they were enriched in the ‘fatty acid metabolism’, ‘response to stress’, ‘carbon fixation’ and ‘photosynthesis’ functional categories, in line with the ND treatment conditions used to conduct this study. These data indicate that Nannochloropsis cells exhibit a clear association between chromatin organization and transcriptional activity under nitrogen stress conditions. Pronounced and extensive histone modifications were evident in response to ND. Observed changes in chromatin architecture were linked to shifts in histone modifications and gene expression. Conclusions Overall, the reprogramming of many lipid metabolism-associated genes was evident under nitrogen stress conditions with respect to both histone modifications and chromosomal organization. Together these results revealed that higher-order chromatin architecture represents a new layer that can guide efforts to understand the transcriptional regulation of lipid metabolism in nitrogen-deprived microalgae.

Polymethyl methacrylate (PMMA) frequently features in dental restorative materials due to its favorable properties. However, its surface exhibits a propensity for bacterial colonization, and the material can fracture under masticatory pressure. This study incorporated commercially available RHA-1F-II nano-silver loaded zirconium phosphate (Ag-ZrP) into room-temperature cured PMMA at varying mass fractions. Various methods were employed to characterize Ag-ZrP. Subsequently, an examination of the effects of Ag-ZrP on the antimicrobial properties, biosafety, and mechanical properties of PMMA materials was conducted. The results indicated that the antibacterial rate against Streptococcus mutans was enhanced at Ag-ZrP additions of 0%wt, 0.5%wt, 1.0%wt, 1.5%wt, 2.0%wt, 2.5%wt, and 3.0%wt, achieving respective rates of 53.53%, 67.08%, 83.23%, 93.38%, 95.85%, and 98.00%. Similarly, the antibacterial rate against Escherichia coli registered at 31.62%, 50.14%, 64.00%, 75.09%, 86.30%, 92.98%. When Ag-ZrP was introduced at amounts ranging from 1.0% to 1.5%, PMMA materials exhibited peak mechanical properties. However, mechanical strength diminished beyond additions of 2.5%wt to 3.0%wt, relative to the 0%wt group, while PMMA demonstrated no notable cytotoxicity below a 3.0%wt dosage. Thus, it is inferred that optimal antimicrobial and mechanical properties of PMMA materials are achieved with nano-Ag-ZrP (RHA-1F-II) additions of 1.5%wt to 2.0%wt, without eliciting cytotoxicity.

Machine degradation is a complex, dynamic and irreversible process and its modeling is a leading-edge technology in prognostics and health management (PHM). In recent years, machine learning algorithms have been widely used to model machine degradation. However, these degradation models are not physically interpreted so that their extended uses are reduced and weakened. Aiming at solving this problem and visualizing informative features learned from degradation data, in this paper, a generalized machine degradation modeling methodology is proposed by integrating multiple-source fusion with genetic programming (GP). A composite fitness function of GP tailored for machine degradation modeling is innovatively designed. Afterward, multiple process sensor data, such as temperature, pressure, currents, etc., and non-process sensor data, such as vibration and acoustic signals, can be respectively modeled and fused into structurally interpreted health indicators from the time domain and the frequency domain. Moreover, the proposed methodology can automatically select informative frequency components and sensors, and provide transparent modeling architecture for early fault detection and subsequent monotonic degradation assessment. Another benefit of the proposed methodology is that complicated data preprocessing and manual feature extraction are not required anymore. Hence, the proposed methodology would have many potential applications and it is easy to implement for online machine degradation modeling. A gearbox run-to-failure dataset (non-process data) and an aircraft engine degradation dataset (process data) are studied to verify the effectiveness of the proposed methodology. Comparisons show that structurally interpreted health indicators constructed from the proposed methodology are superior to state-of-the-art works.

The Li-ion battery is of paramount importance to electric vehicles (EVs). Propelled by the rapid growth of the EV industry, the performance of the battery is continuously improving. However, Li-ion batteries are susceptible to the working temperature and only obtain the optimal performance within an acceptable temperature range. Therefore, a battery thermal management system (BTMS) is required to ensure EVs’ safe operation. There are various basic methods for BTMS, including forced-air cooling, liquid cooling, phase change material (PCM), heat pipe (HP), thermoelectric cooling (TEC), etc. Every method has its unique application condition and characteristic. Furthermore, based on basic BTMS, more hybrid cooling methods adopting different basic methods are being designed to meet EVs’ requirements. In this work, the hybrid BTMS, as a more reliable and environmentally friendly method for the EVs, will be compared with basic BTMS to reveal its advantages and potential. By analyzing its cost, efficiency and other aspects, the evaluation criterion and design suggestions are put forward to guide the future development of BTMS.

Polymethyl methacrylate (PMMA) frequently features in dental restorative materials due to its favorable properties. However, its surface exhibits a propensity for bacterial colonization, and the material can fracture under masticatory pressure. This study incorporated commercially available RHA1F-II nano-silver loaded zirconium phosphate (Ag-ZrP) into roomtemperature cured PMMA at varying mass fractions. Various methods were employed to characterize Ag-ZrP. Subsequently, an examination of the effects of Ag-ZrP on the antimicrobial properties, biosafety, and mechanical properties of PMMA materials was conducted. The results indicated that the antibacterial rate against Streptococcus mutans was enhanced at Ag-ZrP additions of 0%wt, 0.5%wt, 1.0%wt, 1.5%wt, 2.0%wt, 2.5%wt, and 3.0%wt, achieving respective rates of 53.53%, 67.08%, 83.23%, 93.38%, 95.85%, and 98.00%. Similarly, the antibacterial rate against Escherichia coli registered at 31.62%, 50.14%, 64.00%, 75.09%, 86.30%, 92.98%. When Ag-ZrP was introduced at amounts ranging from 1.0% to 1.5%, PMMA materials exhibited peak mechanical properties. However, mechanical strength diminished beyond additions of 2.5%wt to 3.0%wt, relative to the 0%wt group, while PMMA demonstrated no notable cytotoxicity below a 3.0%wt dosage. Thus, it is inferred that optimal antimicrobial and mechanical properties of PMMA materials are achieved with nano-Ag-ZrP (RHA-1F-II) additions of 1.5%wt to 2.0%wt, without eliciting cytotoxicity. [ABSTRACT FROM AUTHOR]

ABSTRACT: Hematological parameters refer to the assessment of changes in the number and distribution of blood cells, including leukocytes (LES), erythrocytes (ERS), and platelets (PLS), which are essential for the early diagnosis of hematological system disorders and other systemic diseases in livestock. In this context, the primary objectives of this study were to investigate the genomic background of 19 hematological parameters in Holstein cattle, focusing on LES, ERS, and PLS blood components. Genetic and phenotypic (co)variances of hematological parameters were calculated based on the average information restricted maximum likelihood method and 1,610 genotyped individuals and 5,499 hematological parameter records from 4,543 cows. Furthermore, we assessed the genetic relationship between these hematological parameters and other economically important traits in dairy cattle breeding programs. We also carried out genome-wide association studies and candidate gene analyses. Blood samples from 21 primiparous cows were used to identify candidate genes further through RNA sequencing (RNA-seq) analyses. Hematological parameters generally exhibited low-to-moderate heritabilities ranging from 0.01 to 0.29, with genetic correlations between them ranging from −0.88 ± 0.09 (between mononuclear cell ratio and lymphocyte cell ratio) to 0.99 ± 0.01 (between white blood cell count and granulocyte cell count). Furthermore, low-to-moderate approximate genetic correlations between hematological parameters with one longevity, 4 fertility, and 5 health traits were observed. One hundred ninety-nine significant SNP located primarily on the Bos taurus autosomes (BTA) BTA4, BTA6, and BTA8 were associated with 16 hematological parameters. Based on the RNA-seq analyses, 6,687 genes were significantly downregulated and 4,119 genes were upregulated when comparing 2 groups of cows with high and low phenotypic values. By integrating genome-wide association studies (GWAS), RNA-seq, and previously published results, the main candidate genes associated with hematological parameters in Holstein cattle were ACRBP, ADAMTS3, CANT1, CCM2L, CNN3, CPLANE1, GPAT3, GRIP2, PLAGL2, RTL6, SOX4, WDFY3, and ZNF614. Hematological parameters are heritable and moderately to highly genetically correlated among themselves. The large number of candidate genes identified based on GWAS and RNA-seq indicate the polygenic nature and complex genetic determinism of hematological parameters in Holstein cattle.

The usage of cheap crude H2 in proton-exchange membrane fuel cells (PEMFCs) is still unrealistic to date, due to the suffering of the current Pt based nano-catalysts from impurities such as CO in anode. Recently, synergistic active sites between single atom (SA) and nanoparticle (NP) have been found to be promising for overcoming the poisoning problem. However, lengthening the nanoparticle-single atom (SA–NP) interface, i.e., constructing high density synergistic active sites, remains highly challenging. Herein, we present a new strategy based on molecular fusion strategy to create abundant SA–NP interfaces, with high density SA–NP interfaces created on a two dimensional nitrogen doped carbon nanosheets (Ir-SACs&NPs/NC). Owing to the abundance of SA–NP interface sites, the catalyst was empowered with a high tolerance towards up to 1000 ​ppm CO in H2 feed. These findings provide guidelines for the design and construction of active and anti-poisoning catalysts for PEMFC anode.

Listeria monocytogenes infection often leads to listeriosis in immunocompromised individuals, and screening for potential nutrients that improve immunity may be beneficial. Here, we found that pre-incubation with heptadecanoic acid (C17:0), an odd-chain saturated fatty acid, significantly inhibited L.monocytogenes replication in differentiated THP-1 and RAW264.7, as evidenced by comparison of listeriolysin expression and colony count. Mechanistically, the administration of C17:0 triggered the activation of the IFN and NF-κB signaling pathways. Furthermore, C17:0 upregulated ACOD1 expression and the generation of itaconate, an anti-bacterial metabolite in macrophages. Based on these results, our comparative analysis showed that sheep tail fat (STF), ruminant lipid rich in C17:0, had similar anti-L.monocytogenes effect. Collectively, our data highlighted the function of C17:0 in boosting the immune response, shedding light on the application of C17:0 and STF as potential candidates for strengthening anti-L.monocytogenes response.

Ulcerative Colitis(UC) is a chronic intestinal inflammation affecting the intestines, yet its underlying causes remain unclear. In recent decades, the global prevalence of UC has been on the rise, leading to an increasing demand for therapeutic drugs with minimal side effects. Huan Kui Le (HKL), a traditional Chinese medicine compound, has demonstrated promising efficacy when combined with Lactobacillus acidophilus (Lac.) for UC intervention. However, the precise therapeutic mechanism of this combination remains unknown. The study focused on understanding the mechanisms of UC by examining the effects of Lac. and HKL (LH) treatment. The outcomes discovered that the disruption of gut microbiota, triggered by the activation of the NLRP3 inflammasome, plays a crucial role in UC development. This disruption exacerbates UC symptoms by causing disturbances in inflammatory cytokines and mucosal permeability. We investigated the dynamic changes following the application of this treatment using 16S rRNA sequencing, HE, WB, IHC, and ELISA. Compared with the UC group, LH treatment reduced colon pathological injury, improved colon length, and decreased IL-1 β serum levels. Furthermore, it restored the expression of TJs and preserved mucosal barrier integrity. LH treatment also mitigated colon injury by attenuating the expression of pyroptosis-related genes and proteins, such as NLRP3 and Caspase-1. Additionally, LH treatment altered the gut microbiota's microecology, characterized by a reduction in pathogenic bacteria abundance like Escherichia-shigella and an increase in beneficial bacteria abundance like Akkermansia and Erysipelatoclostridium. Overall, our findings indicate that LH therapy may be associated with intestinal barrier repair, inflammasome inhibition, and gut microbiota regulation, suggesting its potential as a UC treatment.

Abstract. Background. Toxoplasmic encephalitis (TE) is the most frequent cause of expansive brain lesions among patients with acquired immunodeficiency syndrome (AIDS). However, the optimal timing of antiretroviral therapy (ART) initiation in these patients remains controversial. This study aims to investigate the differences in outcomes of ART initiation at different times, in order to help clarify the treatment timing of AIDS-associated TE. Methods. This multicenter prospective observational study included 87 patients recruited from 11 research centers in China (from March 2019 to December 2022). Of the patients, 38 were assigned to the early ART group (initiating ART within 2 weeks after anti-Toxoplasma treatment initiation), and the remaining 49 patients received deferred ART (initiating ART at least 2 weeks after anti-Toxoplasma treatment initiation). The main outcomes included mortality and emergence of immune reconstitution inflammatory syndrome (IRIS). Human immunodeficiency virus (HIV)-1 viral load and CD4+ T-cell counts at weeks 24 and 48 were observed. Results. The number of deaths (1 vs. 5, P = 0.225) and incidence of IRIS (2.6% vs. 0, P = 0.437) were not significantly different between the early and deferred ART groups at week 48. Early ART initiation did not contribute significantly to HIV-1 viral load control (

Abstract Severe air pollution poses a significant threat to public safety and human health. Predicting future air quality conditions is crucial for implementing pollution control measures and guiding residents' activity choices. However, traditional single-module machine learning models suffer from long training times and low prediction accuracy. To improve the accuracy of air quality forecasting, this paper proposes a ISSA–LSTM model-based approach for predicting the air quality index (AQI). The model consists of three main components: random forest (RF) and mRMR, improved sparrow search algorithm (ISSA), and long short-term memory network (LSTM). Firstly, RF–mRMR is used to select the influential variables affecting AQI, thereby enhancing the model's performance. Next, ISSA algorithm is employed to optimize the hyperparameters of LSTM, further improving the model’s performance. Finally, LSTM model is utilized to predict AQI concentrations. Through comparative experiments, it is demonstrated that the ISSA–LSTM model outperforms other models in terms of RMSE and R2, exhibiting higher prediction accuracy. The model's predictive performance is validated across different time steps, demonstrating minimal prediction errors. Therefore, the ISSA–LSTM model is a viable and effective approach for accurately predicting AQI.

Abstract Costimulatory molecules can promote the activation and proliferation of T cells and play an essential role in immunotherapy. However, their role in the prognosis of colon adenocarcinoma remains elusive. In this study, the expression data of costimulatory molecules and clinicopathological information of 429 patients with colon adenocarcinoma were obtained from The Cancer Genome Atlas database. The patients were divided into training and verification cohorts. Correlation, Cox regression, and Lasso regression analyses were performed to identify costimulatory molecules related to prognosis. After mentioning the construction of the risk mode, a nomogram integrating the clinical characteristics and risk scores of patients was constructed to predict prognosis. Eventually, three prognostic costimulatory molecules were identified and used for constructing a risk model. High expression of these three molecules indicated a poor prognosis. The predictive accuracy of the risk model was verified in the GSE17536 dataset. Subsequently, multivariate regression analysis showed that the signature based on the three costimulatory molecules was an independent risk factor in the training cohort (HR = 2.12; 95% CI = 1.26, 3.56). Based on the risk model and clinicopathological data, the AUC values for predicting the 1-, 3-, and 5-year survival probability of patients with colon adenocarcinoma were 0.77, 0.77, and 0.71, respectively. To the best of our knowledge, this study is the first to report a risk signature constructed based on the costimulatory molecules TNFRSF10c, TNFRSF13c, and TNFRSF11a. This risk signature can serve as a prognostic biomarker for colon adenocarcinoma and is related to the immunotherapeutic response of patients.

Abstract Aim of the study We aimed to elucidate the synergistic effect and potential mechanism of New Baitouweng Decoction (NBD) combined with fecal microbiota transplantation (FMT) in rats with DSS-induced ulcerative colitis (UC). Materials and methods Colitis was induced by 5% (w/v) dextran sulfate sodium (DSS) in drinking water for 7 days. NBD or NBD combined with FMT were administered to the colitis rats. Body weight and disease activity index were measured, and the colon histological change was imaged to further examine the efficacy of NBD and FMT. The specific effects of NBD on STAT3/NF-κB signaling pathway and gut microbiota in rats with UC were also investigated. Results The efficacy of NBD in combination with FMT was demonstrated by the lower disease activity index scores; increased tight junction proteins expression; and a lower expression of macrophage marker (F4/80) in colon tissues. NBD combined with FMT elevated the concentrations of short-chain fatty acids and inhibited activation of the JAK2/STAT3/NF-κB related proteins. Furthermore, 16SrDNA sequencing indicated that the gut microbiota in rats with UC was perturbed, in contrast to that in healthy rats. After treatment with NBD and FMT, the diversity and abundance of intestinal flora showed clear improvements. Spearman correlation analysis indicated a strong correlation between specific microbiota and fecal concentrations of acetate, propionate and butyrate. Conclusions The protective mechanism of NBD combined with FMT may be linked to regulation NF-κB/STAT3 and restoration of the intestinal flora.

Abstract Background The most appropriate alternative to induction therapy for HIV-associated cryptococcal meningitis (CM) remains unclear when standard treatment is unavailable, inaccessible, intolerable, or ineffective. Methods A prospective, multi-centre cohort study was conducted to analyze the data of 156 HIV-infected patients with CM who were treated with amphotericin B deoxycholate (AmB-D) + flucytosine (5FC), voriconazole (VCZ) + 5FC, or AmB-D + Fluconazole (Flu) as induction regimens. Clinical efficacy, cumulative mortality, and adverse effects were compared among the three treatment groups. Results Fewer deaths occurred by week 4 and week 10 among patients receiving AmB-D + 5FC than among those receiving AmB-D + Flu [4 (5.1%) vs. 8 (16.0%) deaths by week 4; hazard ratio, 1.8; 95% confidence interval [CI], 1.0 to 3.3; p = 0.039; and 8 (10.3%) vs. 14 (28.0%) deaths by week 10; hazard ratio, 1.8; 95% CI, 1.1 to 2.7; p = 0.008, respectively]. AmB-D plus 5FC was found to result in significantly higher rates of cerebrospinal fluid (CSF) culture sterility (57.6% vs. 34% by week 2; 87.9% vs. 70% by week 10; p

【Objective】The study was carried out to develop new molecular markers and analyze the molecular phylogeny of Magnolia officinalis in Longshan Tree Farm, Lechang, Guangdong, with a view to facilitating subsequent researches on the selection of excellent plants and breeding of superior varieties.【Method】Fourteen Magnolia officinalis (provenances from Jiangxi Province) individual plants collected from Longshan Tree Farm were used as tested materials. By using Primer BLAST on NCBI (https://www.ncbi.nlm.nih.gov), fixed primers of TRAP molecular markers were designed based on the sequences of M. officinalis cDNA in the GenBank. The fixed primers were matched with random primers (sequence related amplified polymorphism) to amplify genomic DNA and develop TRAP molecular markers. The electrophoretogram of TRAP markers and amplified products of M. officinalis SSR (Simple Sequence Repeat) were counted. Then, NTSYSpc2.10e was used for cluster analysis to discover the genetic diversity and phylogeny of fourteen M. officinalis resources.【Result】Seven TRAP molecular markers showing good polymorphism and clear electrophoresis bands were successfully developed from seventy primer pairs formed by fourteen fixed primers and five random primers. The phylogenetic tree of M. officinalis plants was constructed. The genetic similarity coefficient of these M.officinalis plants was 0.75-0.88 and it was not the highest between mother plant and its offspring.【Conclusion】M. officinalis was rich in genetic diversity and gene exchange was frequent in M. officinalis population. The newly developed TRAP molecular markers will facilitate identification of superior plants, breeding of excellent varieties and marker-assisted selection of M. officinalis in the future.

Research on the regenerative capacity of the neonatal heart could open new avenues for the treatment of myocardial infarction (MI). However, the mechanism of cardiac regeneration remains unclear. In the present study, we constructed a mouse model of heart regeneration and then performed transcriptomic and proteomic analyses on them. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and Gene Set Enrichment Analysis (GSEA) of differentially expressed genes (DEGs) were conducted. Western blot (WB) and qPCR analyses were used to validate the hub genes expression. As a result, gene expression at the mRNA level and protein level is not the same. We identified 3186 DEGs and 42 differentially expressed proteins (DEPs). Through functional analysis of DEGs and DEPs, we speculate that biological processes such as ubiquitination, cell cycle, and oxygen metabolism are involved in heart regeneration. Integrated transcriptomic and proteomic analysis identified 19 hub genes and Ankrd1, Gpx3, and Trim72 were screened out as potential regulators of cardiac regeneration through further expression verification. In conclusion, we combined transcriptomic and proteomic analyses to characterize the molecular features during heart regeneration in neonatal mice. Finally, Ankrd1, Gpx3, and Trim72 were identified as potential targets for heart regeneration therapy.

Objectives: Acute myeloid leukemia (AML) is a malignant disease characterized by clonal proliferation of myeloid cells, and its treatment continues to be a challenge due to high morbidity and mortality. Ginsenoside compound K, a major active metabolite of the protopanaxadiol-type ginsenosides, exhibits biological activities in various cancer cells and animal models. Here, we investigated the role of CK in anticancer potential in AML both in vitro and in vivo. Materials and methods: To investigate the inhibitory effects of CK in AML cells, in vitro experiments, including cell viability assays, colony forming assays, and cell cycle and apoptosis assays were performed. AML animal experiment was established and quantitative analysis of lung tumor growth nodules and spleen weight and H&E staining were carried out to further determine the effects of CK on AML. In addition, the potential key genes induced and influenced by CK during treatment was identification by RNA-seq and qRT-PCR. Results: CK suppressed AML cell activity and induced apoptosis and G1 cell cycle arrest based on the experiment results. Moreover, significantly down-regulated expression genes of BCL2, KIT, DNMT3A, MYC and CSF-1 and up-regulated expression gene of TET2 in CK treatment AML cells were discovered. Conclusion: Our results demonstrated that CK could be used as an anti-AML drug with significant therapeutic efficacy and good biosafety.

Abstract Parkinson’s disease (PD) is a common neurodegenerative disorder that primarily affects the elderly. While the etiology of PD is likely multifactorial with the involvement of genetic, environmental, aging and other factors, α-synuclein (α-syn) pathology is a pivotal mechanism underlying the development of PD. In recent years, astrocytes have attracted considerable attention in the field. Although astrocytes perform a variety of physiological functions in the brain, they are pivotal mediators of α-syn toxicity since they internalize α-syn released from damaged neurons, and this triggers an inflammatory response, protein degradation dysfunction, mitochondrial dysfunction and endoplasmic reticulum stress. Astrocytes are indispensable coordinators in the background of several genetic mutations, including PARK7, GBA1, LRRK2, ATP13A2, PINK1, PRKN and PLA2G6. As the most abundant glial cells in the brain, functional astrocytes can be replenished and even converted to functional neurons. In this review, we discuss astrocyte dysfunction in PD with an emphasis on α-syn toxicity and genetic modulation and conclude that astrocyte replenishment is a valuable therapeutic approach in PD.

The mammalian heart possesses entire regeneration capacity after birth, which is lost in adulthood. The role of the kinase network in myocardial regeneration remains largely elusive. SGK3 (threonine-protein kinase 3) is a functional kinase we identified previously with the capacity to promote cardiomyocyte proliferation and cardiac repair after myocardial infarction. However, the upstream signals regulating SGK3 are still unknown. Based on the quantitative phosphoproteomics data and pulldown assay, we identified cyclin-dependent kinase 9 (CDK9) as a novel therapeutic target in regeneration therapy. The direct combination between CDK9 and SGK3 was further confirmed by co-immunoprecipitation (Co-IP). CDK9 is highly expressed in the newborn period and rarely detected in the adult myocardium. In vitro, the proliferation ratio of primary cardiomyocytes was significantly elevated by CDK9 overexpression while inhibited by CDK9 knockdown. In vivo, inhibition of CDK9 shortened the time window of cardiac regeneration after apical resection (AR) in neonatal mice, while overexpression of CDK9 significantly promoted mature cardiomyocytes (CMs) to re-enter the cell cycle and cardiac repair after myocardial infarction (MI) in adult mice. Mechanistically, CDK9 promoted cardiac repair by directly activating SGK3 and downstream GSK-3β/β-catenin pathway. Consequently, our study indicated that CDK9 might be a novel target for MI therapy by stimulating myocardial regeneration.

Early neurologic deterioration (END) is a common and feared complication for acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT). This study aimed to develop an interpretable machine learning (ML) model for individualized prediction to predict END in AIS patients treated with MT. The retrospective cohort of AIS patients who underwent MT was from two hospitals. ML methods applied include logistic regression (LR), random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBoost). The area under the receiver operating characteristic curve (AUC) was the main evaluation metric used. We also used Shapley Additive Explanation (SHAP) and Local Interpretable Model-Agnostic Explanations (LIME) to interpret the result of the prediction model. A total of 985 patients were enrolled in this study, and the development of END was noted in 157 patients (15.9%). Among the used models, XGBoost had the highest prediction power (AUC = 0.826, 95% CI 0.781–0.871). The Delong test and calibration curve indicated that XGBoost significantly surpassed those of the other models in prediction. In addition, the AUC in the validating set was 0.846, which showed a good performance of the XGBoost. The SHAP method revealed that blood glucose was the most important predictor variable. The constructed interpretable ML model can be used to predict the risk probability of END after MT in AIS patients. It may help clinical decision making in the perioperative period of AIS patients treated with MT.

BackgroundRenal cell carcinoma (RCC) is a disease of genomic alterations, of which the complete panorama helps in facilitating molecular-guided therapy. Germline mutation profiles and associated somatic and clinical characteristics remains unexplored in Chinese RCC patients.MethodsWe retrospectively profiled the germline and somatic mutations of 322 unselected RCC patients using a panel consisting of 808 cancer-related genes. We categorized patients into three groups based on germline mutation status and compared the somatic mutation spectrum among different groups.ResultsApproximately one out of ten (9.9%) RCC patients were identified to carry pathogenic/likely pathogenic (P/LP) germline variants (PGVs), of which 3.7% were variants in syndromic RCC-associated genes and 6.2% were other cancer-predisposition genes. The most common PGV was found in VHL (2.2%), followed by FH, TSC2, ATM, BRCA1, NBN, and BLM (0.6% each). Young patients (≤46 years) were more likely to harbor PGVs. Variants in syndromic RCC-associated genes were predominant identified in young patients, while variants in other cancer-predisposition genes were found in patients >46 years more frequently. Furthermore, 39.3% (11/28) of patients carrying PGVs were detected to have somatic “second hit” events. Germline and somatic sequencing, including microsatellite instability (MSI) status analysis, provided potentially actionable therapeutic targets in 17.1% of patients in the whole cohort.ConclusionsOur results revealed that approximately 10% of RCC patients carried clinically significant germline mutations. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing in RCC population.

Abnormalities in programmed cell death (PCD) signaling cascades can be observed in the development and progression of various cardiovascular diseases, such as apoptosis, necrosis, pyroptosis, ferroptosis, and cell death associated with autophagy. Aberrant activation of PCD pathways is a common feature leading to excessive cardiac remodeling and heart failure, involved in the pathogenesis of various cardiovascular diseases. Conversely, timely activation of PCD remodels cardiac structure and function after injury in a spatially or temporally restricted manner and corrects cardiac development similarly. As many cardiovascular diseases exhibit abnormalities in PCD pathways, drugs that can inhibit or modulate PCD may be critical in future therapeutic strategies. In this review, we briefly describe the process of various types of PCD and their roles in the occurrence and development of cardiovascular diseases. We also discuss the interplay between different cell death signaling cascades and summarize pharmaceutical agents targeting key players in cell death signaling pathways that have progressed to clinical trials. Ultimately a better understanding of PCD involved in cardiovascular diseases may lead to new avenues for therapy.

The unfavorable outcome of acute ischemic stroke (AIS) with large vessel occlusion (LVO) is related to clinical factors at multiple time points. However, predictive models used for dynamically predicting unfavorable outcomes using clinically relevant preoperative and postoperative time point variables have not been developed. Our goal was to develop a machine learning (ML) model for the dynamic prediction of unfavorable outcomes. We retrospectively reviewed patients with AIS who underwent a consecutive mechanical thrombectomy (MT) from three centers in China between January 2014 and December 2018. Based on the eXtreme gradient boosting (XGBoost) algorithm, we used clinical characteristics on admission (“Admission” Model) and additional variables regarding intraoperative management and the postoperative National Institute of Health stroke scale (NIHSS) score (“24-Hour” Model, “3-Day” Model and “Discharge” Model). The outcome was an unfavorable outcome at the three-month mark (modified Rankin scale, mRS 3–6: unfavorable). The area under the receiver operating characteristic curve and Brier scores were the main evaluating indexes. The unfavorable outcome at the three-month mark was observed in 156 (62.0%) of 238 patients. These four models had a high accuracy in the range of 75.0% to 87.5% and had a good discrimination with AUC in the range of 0.824 to 0.945 on the testing set. The Brier scores of the four models ranged from 0.122 to 0.083 and showed a good predictive ability on the testing set. This is the first dynamic, preoperative and postoperative predictive model constructed for AIS patients who underwent MT, which is more accurate than the previous prediction model. The preoperative model could be used to predict the clinical outcome before MT and support the decision to perform MT, and the postoperative models would further improve the predictive accuracy of the clinical outcome after MT and timely adjust therapeutic strategies.

In this work, cold-rolling was utilized to induce a high density of crystal defects in Al0.3CoCrFeNi high-entropy alloys. The effects of annealing temperature on static recrystallization, precipitation behavior and mechanical properties were investigated. With increasing annealing temperature from 590 °C to 800 °C, the area fraction of recrystallized region increases from 26.9% to 93.9%. Cold-rolling deformation largely promotes the precipitation of B2 phases during annealing, and the characteristics of the precipitates are linked to recrystallization level. The coarse and equiaxed B2 phases exist in the recrystallized region and the fine and elongated B2 phases occupy the non-recrystallized region. Combined use of cold-rolling and annealing can remarkably enhance the strength and toughness. A partially recrystallized microstructure in a cold-rolled sample annealed at 700 °C exhibits a better combination of strength and toughness than a fully recrystallized microstructure in a cold-rolled sample annealed at 800 °C. Finally, related mechanisms are discussed.

The structure of cucurbit[6]uril (CB[6]), as a fascinating supramolecular receptor, is regarded as ‘indestructible’. Herein, we investigated the hydrolysis of CB[6] catalysed by alkali. Our results showed that CB[6] was easily hydrolysed in 30% NaOH at 160°C within 3 h. Separation and purification of hydrolytic products demonstrated the presence of NH3, CO2, HCOONa, glycine and hydantoic acid. Based on the studies of the hydrolysis of substances similar to CB[6] including 4,5-dihydroxyethyleneurea, glycoluril and glycoluril dimer, we proposed that a plausible reaction mechanism involved a Cannizzaro reaction, which is supported by HPLC, mass spectrometry data and previous reports. Further studies are dedicated towards a controlled hydrolysis of CB[6], which will provide a new route for direct functionalization of CB[6].