Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

Efficacy of Repetitive Transcranial Magnetic Stimulation over the Supplementary Motor Area on Motor Function in Parkinson's Disease: A Meta-Analysis.

OBJECTIVES: The objective of this study was to assess the effect of repetitive transcranial magnetic stimulation (rTMS) on the supplementary motor area (SMA) in motor function in Parkinson's disease (PD) patients. METHOD: Databases searched included 5 databases from October 7,2022 to January 4, 2023. The Cochrane Bias Risk Assessment Tool was used for quality assessment. Standardized mean differences (SMDs) were calculated using a random-effects model. Outcome measure is the motor function examination of the motor part of Unified Parkinson's Disease Rating Scale (UPDRS-III). RESULTS: Seven studies totaling 374 patients were included. Meta-analysis showed that stimulation of SMA significantly improved motor function in PD patients compared with sham stimulation (SMD = -1.24; 95% CI, -2.24 to -0.24; P = 0.02; I 2 = 93%). Stimulation of the same target (SMA), subgroup analysis showed that high-frequency rTMS (HF-rTMS) is more effective than low-frequency rTMS (LF-rTMS) in improving motor function in PD (SMD = -1.39; 95% CI, -2.21 to -0.57; P = 0.04; I 2 = 77.2%). CONCLUSIONS: Overall, rTMS over SMA had a statistically significant improvement in motor function in PD patients, and HF-rTMS is statistically significantly more effective than LF-rTMS.

Shikonin blocks CAF-induced TNBC metastasis by suppressing mitochondrial biogenesis through GSK-3ß/NEDD4-1 mediated phosphorylation-dependent degradation of PGC-1α.

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by its high metastatic potential, which results in poor patient survival. Cancer-associated fibroblasts (CAFs) are crucial in facilitating TNBC metastasis via induction of mitochondrial biogenesis. However, how to inhibit CAF-conferred mitochondrial biogenesis is still needed to explore. METHODS: We investigated metastasis using wound healing and cell invasion assays, 3D-culture, anoikis detection, and NOD/SCID mice. Mitochondrial biogenesis was detected by MitoTracker green FM staining, quantification of mitochondrial DNA levels, and blue-native polyacrylamide gel electrophoresis. The expression, transcription, and phosphorylation of peroxisome-proliferator activated receptor coactivator 1α (PGC-1α) were detected by western blotting, chromatin immunoprecipitation, dual-luciferase reporter assay, quantitative polymerase chain reaction, immunoprecipitation, and liquid chromatography-tandem mass spectrometry. The prognostic role of PGC-1α in TNBC was evaluated using the Kaplan-Meier plotter database and clinical breast cancer tissue samples. RESULTS: We demonstrated that PGC-1α indicated lymph node metastasis, tumor thrombus formation, and poor survival in TNBC patients, and it was induced by CAFs, which functioned as an inducer of mitochondrial biogenesis and metastasis in TNBC. Shikonin impeded the CAF-induced PGC-1α expression, nuclear localization, and interaction with estrogen-related receptor alpha (ERRα), thereby inhibiting PGC-1α/ERRα-targeted mitochondrial genes. Mechanistically, the downregulation of PGC-1α was mediated by synthase kinase 3ß-induced phosphorylation of PGC-1α at Thr295, which associated with neural precursor cell expressed developmentally downregulated 4e1 recognition and subsequent degradation by ubiquitin proteolysis. Mutation of PGC-1α at Thr295 negated the suppressive effects of shikonin on CAF-stimulated TNBC mitochondrial biogenesis and metastasis in vitro and in vivo. CONCLUSIONS: Our findings indicate that PGC-1α is a viable target for blocking TNBC metastasis by disrupting mitochondrial biogenesis, and that shikonin merits potential for treatment of TNBC metastasis as an inhibitor of mitochondrial biogenesis through targeting PGC-1α.

PredGCN: A Pruning-enabled Gene-Cell Net for Automatic Cell Annotation of Single Cell Transcriptome Data.

MOTIVATION: The annotation of cell types from single-cell transcriptomics is essential for understanding the biological identity and functionality of cellular populations. Although manual annotation remains the gold standard, the advent of automatic pipelines has become crucial for scalable, unbiased, and cost-effective annotations. Nonetheless, the effectiveness of these automatic methods, particularly those employing deep learning, significantly depends on the architecture of the classifier and the quality and diversity of the training datasets. RESULTS: To address these limitations, we present a Pruning-enabled Gene-Cell Net (PredGCN) incorporating a Coupled Gene-Cell Net (CGCN) to enable representation learning and information storage. PredGCN integrates a Gene Splicing Net (GSN) and a Cell Stratification Net (CSN), employing a pruning operation (PrO) to dynamically tackle the complexity of heterogeneous cell identification. Among them, GSN leverages multiple statistical and hypothesis-driven feature extraction methods to selectively assemble genes with specificity for scRNA-seq data while CSN unifies elements based on diverse region demarcation principles, exploiting the representations from GSN and precise identification from different regional homogeneity perspectives. Furthermore, we develop a multi-objective Pareto pruning operation (Pareto PrO) to expand the dynamic capabilities of CGCN, optimizing the sub-network structure for accurate cell type annotation. Multiple comparison experiments on real scRNA-seq datasets from various species have demonstrated that PredGCN surpasses existing state-of-the-art methods, including its scalability to cross-species datasets. Moreover, PredGCN can uncover unknown cell types and provide functional genomic analysis by quantifying the influence of genes on cell clusters, bringing new insights into cell type identification and characterizing scRNA-seq data from different perspectives. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/IrisQi7/PredGCN and test data is available at https://figshare.com/articles/dataset/PredGCN/25251163. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Chromosome-level genome assembly of Cnidium monnieri, a highly demanded traditional Chinese medicine.

Cnidium monnieri, a medicinal herb of the Cnidium genus and the Apiaceae family, is among the most important traditional Chinese medicines and is widely distributed in China. However, to date, no C. monnieri-related genomic information has been described. In this study, we assembled the C. monnieri genome of approximately 1210.23 Mb with a contig N50 of 83.14 Mb. Using PacBio HiFi and Hi-C sequencing data, we successfully anchored 93.86% of the assembled sequences to 10 pseudochromosomes (2n = 20). We predicted a total of 37,460 protein-coding genes, with 97.02% of them being functionally annotated in Non-Redundant, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and other databases. In addition, we identified 2,778 tRNAs, 4,180 rRNAs, 258 miRNAs, and 1,700 snRNAs in the genome. This is the first reported C. monnieri genome. Hopefully, the availability of this chromosome-level reference genome provides a significant basis for upcoming natural product-related biosynthetic pathway assessment in C. monnieri.

[Clinical Features and Prognostic of Patients with Primary Central Nervous System Lymphoma].

OBJECTIVE: To explore the clinical features and prognosis of patients with primary central nervous system lymphoma（PCNSL）. METHODS: A retrospective analysis was performed on the relationship between clinical features, treatment regimen and prognosis in 46 newly diagnosed patients with primary central nervous system lymphoma who were diagnosed and treated in The Second Hospital of Lanzhou University from January 2015 to September 2022. Fisher's exact probability method was used to analyze the differences in clinical data of different subgroups. Kaplan-Meier survival curve was used to analyze the overall survival rate and progression-free survival rate of patients with different treatments, and the factors influencing survival were analyzed. RESULTS: Among 46 patients with PCNSL, which pathological type were diffuse large B-cell lymphoma（DLBCL）. There were 26(56.5%) cases of male and 20(43.5%) of female, with a median age of 54(17-71) years. In Hans subtypes, 14 cases (30.4%) of GCB subtype, 32 cases (69.6%) of non-GCB subtype. 32 cases (69.6%) of Ki-67≥80%. Among 36 patients who completed at least 2 cycles of treatment with follow-up data, the efficacy evaluation was as follows: overall response rate(ORR) was 63.9%, complete response(CR) rate was 47.2%, 17 cases of CR, 6 cases of PR. The 1-year progression-free survival rate and 1-year overall survival rate was 73.6% and 84.9%, respectively. The 2-year progression-free survival rate and 2-year overall survival rate was 52.2% and 68.9%, respectively. The ORR and CR rate of 17 patients treated with RMT regimen was 76.5% and 52.9% (9 cases CR and 4 cases PR), respectively. Univariate analysis of 3 groups of patients treated with RMT regimen, RM-BTKi regimen, and RM-TT regimen as first-line treament showed that deep brain infiltration was associated with adverse PFS(P =0.032), and treatment regimen was associated with adverse OS in PCNSL patients（P =0.025）. CONCLUSION: Different treatment modalities were independent prognosis predictors for OS, the deep brain infiltration of PCNSL is a poor predictive factor for PFS. Patients with relapse/refractory (R/R) PCNSL have a longer overall survival time because to the novel medication BTKi. They have strong toleration and therapeutic potential as a first-line therapy for high-risk patients.

[Whole Exome Sequencing Reveals Gene Mutation Characteristics of Primary Central Nervous System Lymphoma].

OBJECTIVE: To investigate gene mutation characteristics of primary central nervous system lymphoma (PCNSL) through whole exome sequencing (WES) to 18 patients with PCNSL. METHODS: Tumor tissues from 18 patients with diffuse large B-cell lymphoma who were diagnosed with PCNSL in Department of Hematology, Lanzhou University Second Hospital from September 2018 to December 2020 and had normal immune function, no history of HIV or immunosuppressant therapy were collected. High-throughput-based WES was performed on the tumor tissues, with an average sequencing depth of >100×. After data processing and bioinformatics analysis of sequencing results, the mutation maps and mutation characteristics of 18 PCNSL patients were obtained. RESULTS: Obvious somatic mutations were detected in all 18 patients. The median number of somatic mutations was 321. Missense mutations were most prominent (accounting for about 90%), and the mutation type was dominated by C>T (50.2%), reflecting the age-related mutation pattern. Among the top 15 frequently mutated genes, PSD3, DUSP5, MAGEB16, TELO2, FMO2, TRMT13, AOC1, PIGZ, SVEP1, IP6K3, and TIAM1 were the driver genes. The enrichment results of driver gene pathways showed that RTK-RAS, Wnt, NOTCH, Hippo and Cell-Cycle pathways were significantly enriched. The tumor mutation burden was between 3.558 48/Mb and 8.780 89/Mb, and the average was 4.953 32/Mb, which was significantly higher than other cancer research cohorts in the TCGA database. CONCLUSIONS: PCNSL occurs somatic missense mutations frequently, mainly point mutations, and the mutation type is mainly C>T. The driver genes are mainly involved in RTK-RAS, Wnt, NOTCH and Hippo pathways, indicating that the above pathways may be related to the pathogenesis of PCNSL. PCNSL has a significantly high tumor mutation burden, which may explain the efficacy of PD-1 inhibitors in PCNSL.

What Is the Real Origin of Single-Walled Carbon Nanotubes for the Performance Enhancement of Si-Based Anodes?

A large amount of lithium-ion storage in Si-based anodes promises high energy density yet also results in large volume expansion, causing impaired cyclability and conductivity. Instead of restricting pulverization of Si-based particles, herein, we disclose that single-walled carbon nanotubes (SWNTs) can take advantage of volume expansion and induce interfacial reactions that stabilize the pulverized Si-based clusters in situ. Operando Raman spectroscopy and density functional theory calculations reveal that the volume expansion by the lithiation of Si-based particles generates ∼14% tensile strains in SWNTs, which, in turn, strengthens the chemical interaction between Li and C. This chemomechanical coupling effect facilitates the transformation of sp2-C at the defect of SWNTs to Li-C bonds with sp3 hybridization, which also initiates the formation of new Si-C chemical bonds at the interface. Along with this process, SWNTs can also induce in situ reconstruction of the 3D architecture of the anode, forming mechanically strengthened networks with high electrical and ionic conductivities. As such, with the addition of only 1 wt % of SWNTs, graphite/SiOx composite anodes can deliver practical performance well surpassing that of commercial graphite anodes. These findings enrich our understanding of strain-induced interfacial reactions, providing a general principle for mitigating the degradation of alloying or conversion-reaction-based electrodes.

Association between drinking water sources and cognitive functioning in Chinese older adults residing in rural areas.

OBJECTIVES: To explore the association between drinking water sources and cognitive functioning among older adults residing in rural China. METHODS: Data were extracted from the 2008-2018 Chinese Longitudinal Healthy Longevity Survey. Drinking water sources were categorized according to whether purification measures were employed. The Chinese version of the Mini-Mental State Examination was used for cognitive functioning assessment, and the score of <24 was considered as having cognitive dysfunction. Cox regression analyses were conducted to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the effects of various drinking water sources, changes in such sources, and its interaction with exercise on cognition dysfunction. RESULTS: We included 2304 respondents aged 79.67 ± 10.02 years; of them, 1084 (44.49%) were men. Our adjusted model revealed that respondents consistently drinking tap water were 21% less likely to experience cognitive dysfunction compared with those drinking untreated water (HR = 0.79, 95% CI: 0.70-0.90). Respondents transitioning from natural to tap water showed were 33% less likely to experience cognitive dysfunction (HR = 0.67, 95% CI: 0.58-0.78). Moreover, the HR (95% CI) for the interaction between drinking tap water and exercising was 0.86 (0.75-1.00) when compared with that between drinking untreated water and not exercising. All results adjusted for age, occupation, exercise, and body mass index. CONCLUSIONS: Prolonged tap water consumption and switching from untreated water to tap water were associated with a decreased risk of cognitive dysfunction in older individuals. Additionally, exercising and drinking tap water was synergistically associated with the low incidence of cognitive dysfunction. These findings demonstrate the importance of prioritizing drinking water health in rural areas, indicating that purified tap water can enhance cognitive function among older adults.

The Difference between Stress Deformation and Adsorption Deformation of Coal Reservoirs and Its Role in Permeability Prediction.

The key to the variation in permeability within coal reservoirs lies in the stress-induced deformation and desorption-induced deformation during the coalbed methane (CBM) production. The differences in sample scale and measurement methods between stress-induced deformation and desorption-induced deformation significantly affect the accuracy of permeability measurements. Therefore, in order to elucidate the relationship between stress-induced deformation and adsorption-induced deformation, as well as the influencing factors, and to assess the accuracy of permeability evolution prediction, this study conducted a series of parallel experiments, including compression deformation experiments under stress loading (stress-induced deformation), methane adsorption-induced deformation experiments (adsorption-induced deformation), µCT scanning, and overburden permeability measurements.The results of the study indicate that stress-induced deformation and adsorption-induced deformation are negatively correlated but exhibit a relatively weak correlation. Stress-induced deformation encompasses deformation of coal matrix, minerals, and fractures, whereas adsorption-induced deformation primarily reflects coal matrix deformation. While there is some overlap between the two, they are not entirely identical. The main influencing factor of stress-induced deformation is the mechanical strength of coal, with minerals in coal increasing the Young's modulus of coal reservoirs. Among them, minerals that are more dispersed and have smaller particles have a more significant impact on stress-induced deformation. The primary influencing factor of adsorption-induced deformation is the deformation capability of the coal matrix, with minerals and fractures having less significant effects. Permeability changes are controlled by fracture deformation, but stress-induced deformation measurements weakly reflect this aspect, leading to an inability to accurately predict the scale of the impact of effective stress changes on permeability during CBM production and CO2-ECBM processes. In contrast, adsorption-induced deformation relatively accurately reflects the deformation capability of the coal matrix and provides a more accurate prediction of permeability rebound under the condition of almost unchanged effective stress in the late stages of mining. Therefore, deformation parameters under stress loading are challenging to directly apply to the prediction of permeability evolution, while adsorption-induced deformation parameters can be effectively utilized.

TRANSPARENT TESTA GLABRA1 Regulates High-Intensity Blue Light-Induced Phototropism by Reducing CRYPTOCHROME1 Levels.

The asymmetrical distribution of auxin supports high intensity blue light (HBL)-mediated phototropism. Flavonoids, secondary metabolites induced by blue light and TRANSPARENT TESTA GLABRA1 (TTG1), alter auxin transport. However, the role of TTG1 in HBL-induced phototropism in Arabidopsis (Arabidopsis thaliana) remains unclear. We found that TTG1 regulates HBL-mediated phototropism. HBL-induced degradation of CRYPTOCHROME 1 (CRY1) was repressed in ttg1-1, and depletion of CRY1 rescued the phototropic defects of the ttg1-1 mutant. Moreover, overexpression of CRY1 in a cry1 mutant background led to phototropic defects in response to HBL. These results indicated that CRY1 is involved in the regulation of TTG1-mediated phototropism in response to HBL. Further investigation showed that TTG1 physically interacts with CRY1 via its N-terminus and that the added TTG1 promotes the dimerization of CRY1. The interaction between TTG1 and CRY1 may promote HBL-mediated degradation of CRY1. TTG1 also physically interacted with blue light inhibitor of cryptochrome 1 (BIC1) and Light-Response Bric-a-Brack/Tramtrack/Broad 2 (LRB2), and these interactions either inhibited or promoted their interaction with CRY1. Exogenous gibberellins (GA) and auxins, two key plant hormones that crosstalk with CRY1, may confer the recovery of phototropic defects in the ttg1-1 mutant and CRY1-overexpressing plants. Our results revealed that TTG1 participates in the regulation of HBL-induced phototropism by modulating CRY1 levels, which are coordinated with GA or IAA signaling.

Determinants of the interaction between the 5'-leader of HIV-1 genome and human lysyl-tRNA synthetase in reverse transcription primer release process.

Reverse transcription of human immunodeficiency virus type 1 (HIV-1) initiates from the 3' end of human tRNALys3. The primer tRNALys3 is selectively packaged into the virus in the form of a complex with human lysyl-tRNA synthetase (LysRS). To facilitate reverse transcription initiation, part of the 5' leader (5'L) of HIV-1 genomic RNA (gRNA) evolves a tRNA anticodon-like element (TLE), which binds LysRS and releases tRNALys3 for primer annealing and reverse transcription initiation. Although TLE has been identified as a key element in 5'L responsible for LysRS binding, how the conformations and various hairpin structures of 5'L regulate 5'L-LysRS interaction is not fully understood. Here, these factors have been individually investigated using direct and competitive fluorescence anisotropy binding experiments. Our data showed that the conformation of 5'L significantly influences its binding affinity with LysRS. The 5'L conformation favoring gRNA dimerization and packaging exhibits much weaker binding affinity with LysRS compared to the alternative 5'L conformation that is not selected for packaging. Additionally, dimerization of 5'L impairs LysRS-5'L interaction. Furthermore, among various regions of 5'L, both the primer binding site/TLE domain and the stem-loop 3 are important for LysRS interaction, whereas the dimerization initiation site and the splicing donor plays a minor role. In contrast, the presence of the transacting responsive and the polyadenylation signal hairpins slightly inhibit LysRS binding. These findings reveal that the conformation and various regions of the 5'L of HIV-1 genome regulate its interaction with human LysRS and the reverse transcription primer release process.

Overexpression of a nuclear receptor HR96 contributes to spirodiclofen susceptibility in Panonychus citri (McGregor).

The citrus red mite, Panonychus citri, is one of the most notorious and devastating citrus pests around the world that has developed resistance to multiple chemical acaricides. In previous research, we found that spirodiclofen-resistant is related to overexpression of P450, CCE, and ABC transporter genes in P. citri. However, the regulatory mechanisms of these detoxification genes are still elusive. This study identified all hormone receptor 96 genes of P. citri. 8 PcHR96 genes contained highly conserved domains. The expression profiles showed that PcHR96h was significantly upregulated in spirodiclofen resistant strain and after exposure to spirodiclofen. RNA interference of PcHR96h decreased expression of detoxification genes and increased spirodiclofen susceptibility in P. citri. Furthermore, molecular docking, heterologous expression, and drug affinity responsive target stability demonstrated that PcHR96h can interact with spirodiclofen in vitro. Our research results indicate that PcHR96h plays an important role in regulating spirodiclofen susceptibility and provides theoretical support for the resistance management of P. citri.

Structural, physicochemical and digestive properties of non-covalent and covalent complexes of ultrasound treated soybean protein isolate with soybean isoflavone.

The non-covalent and covalent complexes of ultrasound treated soybean protein isolate (SPI) and soybean isoflavone (SI) were prepared, and the structure, physicochemical properties and in vitro digestion characteristics of SPI-SI complexes were investigated. Ultrasonic treatment increased the non-covalent and covalent binding degree of SPI with SI, and the 240 W ultrasonic covalent complexes had higher binding efficiency. Appropriate ultrasonic treatment caused more uniform particle size distribution, lower average particle size and higher surface charge, which enhanced the free sulfhydryl groups and surface hydrophobicity, thus improving the stability, solubility and emulsifying properties of complexes. Ultrasonic treatment resulted in more disordered secondary structure, tighter tertiary conformation, higher thermal stability and stronger SPI-SI covalent interactions of complexes. These structural modifications of particles had important effects on the chemical stability and gastrointestinal digestion fate of SI. The ultrasonic covalent complexation had a greater resistance to heat-induced chemical degradation of SI and improved its chemical stability. Furthermore, the 240 W ultrasonic covalent complexes showed lower protein digestibility during digestion, and provided stronger protection for SI, which improved the digestion stability and antioxidant activity. Therefore, appropriate ultrasound promoted SPI-SI interactions to improve the stability and functional properties of complexes, which provided a theoretical basis for the development of new complexes and their applications in functional foods.

The Effect of Peer Relationships on Adolescent Loneliness: The Role of Psychological Resilience and the OXTR Gene.

Background: Based on the gene-environment interaction paradigm, this study explored the effect of peer relationships on adolescent loneliness and the role of psychological resilience and the oxytocin receptor gene (OXTR). Methods: A survey was conducted in a sample of 619 adolescents, and their oral cells were collected for DNA extraction and genotyping. Results: The results showed that (1) both peer relationships and psychological resilience significantly affected adolescent loneliness; (2) psychological resilience partially mediated the relationship between peer relationships and loneliness in adolescents; (3) OXTR gene rs53576 polymorphism moderated both the first and second half of the indirect pathway of the mediation model. Specifically, carriers of the rs53576 polymorphism A/A genotype showed a significantly enhanced effect of peer relationships on adolescent psychological resilience, while carriers of the rs53576 polymorphism G/G genotype showed a significantly enhanced effect of psychological resilience on adolescent loneliness. Conclusion: These findings helped elucidate the developmental mechanisms of adolescent loneliness in terms of peer relationships, psychological resilience, and OXTR gene polymorphisms.

A moderated mediation effects analysis was conducted to investigate the effect of peer relationships on adolescent loneliness and the role of psychological resilience and the oxytocin receptor gene (OXTR). The results revealed psychological resilience partially mediated the relationship between peer relationships and loneliness in adolescents; OXTR gene rs53576 polymorphism moderated both the first and second half of the indirect pathway of the mediation model. These findings helped elucidate the developmental mechanisms of adolescent loneliness in terms of peer relationships, psychological resilience, and OXTR gene polymorphisms.

Ion Current Rectification Activity Induced by Boron Hydride Nanosheets to Enhance Magnesium Analgesia.

The low analgesic efficiency has limited magnesium used in analgesia. Here, we report boron hydride (BH) with ion current rectification activity can significantly improve the analgesic efficiency of magnesium, even higher than morphine. The synthesized injectable MgB2 composes of hexagonal boron sheets alternating with Mg2+. In pathological environment, while the intercalated Mg2+ will be exchanged by H+, the 2-dimensional borophene-analogue BH sheets will be formed to interact with the charged cations via the cation-pi interaction, synergistically leading to a sort of two-way dynamic modulation of sodium and potassium ion currents in neurons. By coordinating with the released Mg2+ to compete Ca2+, the threshold potential remarkably increases from the normal -35.9 mV to -5.9 mV, which significantly suppresses neuronal excitability, providing a potent analgesic effect. In three typical pain models , including CFA-induced inflammatory pain, PINP- or CCI-induced neuropathic pain, MgB2 demonstrates its analgesic efficiency approximately 2.23, 3.20, and 2.0 times higher than the clinical MgSO4, respectively. The development of MgB2 as analgesic drugs addresses the unmet medical need of pain relief without the risks of drug tolerance or addiction to opioids.

Human umbilical cord-derived mesenchymal stem cells attenuate hepatic stellate cells activation and liver fibrosis.

BACKGROUND: Liver cirrhosis, a prevalent chronic liver disease, is characterized by liver fibrosis as its central pathological process. Recent advancements highlight the clinical efficacy of umbilical cord mesenchymal stem cell (UC-MSC) therapy in the treatment of liver cirrhosis. METHODS AND RESULTS: We investigated the pharmacodynamic effects of UC-MSCs and MSC conditional medium (MSC-CM) in vivo, utilizing a carbon tetrachloride (CCl4)-induced fibrotic rat model. Concurrently, we assessed the in vitro impact of MSCs and MSC-CM on various cellular process of hepatic stellate cells (HSCs), including proliferation, apoptosis, activation, immunomodulatory capabilities, and inflammatory factor secretion. Our results indicate that both MSCs and MSC-CM significantly ameliorate the pathological extent of fibrosis in animal tissues, reducing the collagen content, serum biochemical indices and fibrosis biomarkers. In vitro, MSC-CM significantly inhibited the activation of the HSC line LX-2. Notably, MSC-CM modulated the expression of type I procollagen and TGFß-1 while increasing MMP1 expression. This modulation restored the MMP1/TIMP1 ratio imbalance and extracellular matrix deposition in TGFß-1 induced fibrosis. Both MSCs and MSC-CM not only induced apoptosis in HSCs but also suppressed proliferation and inflammatory cytokine release from activated HSCs. Furthermore, MSCs and MSC-CM exerted a suppressive effect on total lymphocyte activation. CONCLUSIONS: UC-MSCs and MSC-CM primarily modulate liver fibrosis severity by regulating HSC activation. This study provides both in vivo and in vitro pharmacodynamic evidence supporting the use of MSCs in liver fibrosis treatment.

The anti-non-small cell lung cancer effect of Diosbulbin B: Targeting YY1 induced cell cycle arrest and apoptosis.

BACKGROUND: Toxic components frequently exhibit unique characteristics and activities, offering ample opportunities for the advancement of anti-cancer medications. As the main hepatotoxic component of Dioscorea bulbifera L. (DB), Diosbulbin B (DIOB) has been widely studied for its anti-tumor activity at nontoxic doses. However, the effectiveness and mechanism of DIOB against non-small cell lung cancer (NSCLC) remains unclear. PURPOSE: To evaluate the anti-NSCLC activity of DIOB and to elucidate the specific mechanism of action. METHOD: The effect of DIOB on NSCLCL in vitro was evaluated through CCK8, colony formation, and flow cytometry. The in vivo efficacy and safety of DIOB in treating NSCLC were assessed using various techniques, including HE staining, tunel staining, immunohistochemistry, and biochemical index detection. To understand the underlying mechanism, cell transfection, western blotting, molecular docking, cellular thermal shift assay (CESTA), and surface plasmon resonance (SPR) were employed for investigation. RESULTS: DIOB effectively hindered the progression of NSCLC both in vitro and in vivo settings at a no-observed-adverse-effect concentration (NOAEC) and a safe dosage. Specifically, DIOB induced significant G0/G1 phase arrest and apoptosis in A549, PC-9, and H1299 cells, while also notably inhibiting the growth of subcutaneous tumors in nude mice. Mechanistically, DIOB could directly interact with oncogene Yin Yang 1 (YY1) and inhibit its expression. The reduction in YY1 resulted in the triggering of the tumor suppressor P53, which induced cell cycle arrest and apoptosis in NSCLC cells by inhibiting the expression of Cyclin A2, B2, CDK1, CDK2, CDK4, BCL-2, and inducing the expression of BAX. In NSCLC cells, the induction of G0/G1 phase arrest and apoptosis by DIOB was effectively reversed when YY1 was overexpressed or P53 was knocked down. Importantly, we observed that DIOB exerted the same effect by directly influencing the expression of YY1-regulated c-Myc and BIM, particularly in the absence of P53. CONCLUSION: For the inaugural investigation, this research unveiled the anti-NSCLC impact of DIOB, alongside its fundamental mechanism. DIOB has demonstrated potential as a treatment agent for NSCLC due to its impressive efficacy in countering NSCLC.

Responsive Organic Fluorescent Aggregates Based on Ion-π Interactions Away from Fluorescent Conjugated Groups.

Responsive organic luminescent aggregates have a wide range of application fields, but currently there is still a lack of reasonable molecular design strategies. Introducing ion-π interactions into molecules can effectively alter their luminescent properties. However, current research typically focuses on ion localization at luminescent conjugated groups with the strong interaction forces. In this work, we introduce the flexible alkoxy chain spacers between fluorescent conjugated groups and ion-π interaction sites, and then adjust the fluorescence performance of the molecule by changing the strength of ion-π interactions. Bromine ion-based molecules with strong ion-π interactions exhibit high and stable fluorescence quantum yields in crystals and amorphous powders under the external stimuli. Hexafluorophosphate ion-based molecules with weak ion-π interactions have the high fluorescence quantum yield in crystals and very low fluorescence quantum yield in amorphous powders, showing variable fluorescence intensities under external stimuli. This demonstrates a new class of responsive organic luminescent solid-state materials.

Deciphering the pathogenic risks of microplastics as emerging particulate organic matter in aquatic ecosystem.

Microplastics are accumulating rapidly in aquatic ecosystems, providing habitats for pathogens and vectors for antibiotic resistance genes (ARGs), potentially increasing pathogenic risks. However, few studies have considered microplastics as particulate organic matter (POM) to elucidate their pathogenic risks and underlying mechanisms. Here, we performed microcosm experiments with microplastics and natural POM (leaves, algae, soil), thoroughly investigating their distinct effects on the community compositions, functional profiles, opportunistic pathogens, and ARGs in Particle-Associated (PA) and Free-Living (FL) bacterial communities. We found that both microplastics and leaves have comparable impacts on microbial community structures and functions, enriching opportunistic pathogens and ARGs, which may pose potential environmental risks. These effects are likely driven by their influences on water properties, including dissolved organic carbon, nitrate, DO, and pH. However, microplastics uniquely promoted pathogens as keystone species and further amplified their capacity as hosts for ARGs, potentially posing a higher pathogenic risk than natural POM. Our research also emphasized the importance of considering both PA and FL bacteria when assessing microplastic impacts, as they exhibited different responses. Overall, our study elucidates the role and underlying mechanism of microplastics as an emerging POM in intensifying pathogenic risks of aquatic ecosystems in comparison with conventional natural POM.