Observation of a Novel Interligand Chiral Arrangement in Metal Nanoclusters and Its Implication in Resisting Racemization.

Given the scientifically significant importance of studying the chirality of clusters, the challenges of synthesizing chiral clusters are progressively surmounted. However, the racemization of clusters is unavoidable, and it limits the development of their follow-on chiral applications. To address this issue, chiral thiols are synthesized and used for the construction of high-stability optically pure nanoclusters in this work. As a result, a pair of chiral nanoclusters, Au24Cd2(SR)14, is obtained with excellent stability under thermal, acidic, alkaline, oxidizing, and reducing environments. Unexpectedly, it can also maintain its optical activity with the introduction of Cu2+ ions and chiral ligand with opposite configuration. Structural relationship analysis indicates that the excellent stability is mainly dependent on the hierarchical assembly of the nanoclusters, in which the chiral assembly of chiral ligands (a new pattern of chiral arrangement of intramolecular ligands on the surface of clusters) may be a key factor.

Effectiveness and safety of acupuncture as an adjunctive therapy for chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: The effectiveness and safety of acupuncture therapy to delay lung function decline in chronic obstructive pulmonary disease (COPD) remain unclear. This study aimed to determine whether acupuncture, as an adjunctive therapy to COPD-guided medication, could prevent lung function decline. METHODS: This randomised, two-centre study was conducted between February 2022 and July 2023. Men and women aged 40-80 years with COPD were recruited. Participants received active or sham acupuncture three times a week (36 sessions total). The primary outcome was the change in the percentage of forced expiratory volume for 1 s to the predicted value (FEV1%) between the baseline and after the intervention. RESULTS: Overall, 238 participants were screened, and 74 (58 men [78.4%]; mean [standard deviation] age, 69.6 [7.2] years) were randomised into the acupuncture and sham acupuncture groups (37 per group). After the intervention, the change in FEV1% was 1.35 (95% confidence interval [CI]: -0.47 to 3.17) and -2.44 (95% CI: -4.56 to -0.33) in the acupuncture and sham acupuncture groups, respectively. The difference was -3.97 (95% CI: -6.2 to -1.74), and the adjusted difference was -3.46 (95% CI: -5.69 to -1.24, P = 0.003) between the groups. A significantly less decline was found in forced expiratory volume for 1 s in the acupuncture group. All treatment-related adverse events (acupuncture = 11, sham = 2) were mild. CONCLUSIONS: Compared with sham acupuncture, acupuncture plus medication may delay lung function decline. However, further studies with a larger sample size and longer-term follow-up are needed to clarify the effects.

Full-length transcriptome sequencing of pepper fruit during development and construction of a transcript variation database.

Chili pepper is an important spice and a model plant for fruit development studies. Large-scale omics information on chili pepper plant development continues to be gathered for understanding development as well as capsaicin biosynthesis. In this study, a full-spectrum transcriptome data of eight chili pepper tissues at five growth stages using the Oxford Nanopore long-read sequencing approach was generated. Of the 485 351 transcripts, 35 336 were recorded as reference transcripts (genes), while 450 015 were novel including coding, lnc, and other non-coding RNAs. These novel transcripts belonged to unknown/intergenic (347703), those retained introns (26336), and had multi-exons with at least one junction match (20333). In terms of alternative splicing, retained intron had the highest proportion (14795). The number of tissue-specific expressed transcripts ranged from 22 925 (stem) to 40 289 (flower). The expression changes during fruit and placenta development are discussed in detail. Integration of gene expression and capsaicin content quantification throughout the placental development clarifies that capsaicin biosynthesis in pepper is mainly derived from valine, leucin, and isoleucine degradation as well as citrate cycle and/or pyrimidine metabolism pathways. Most importantly, a user-friendly Pepper Full-Length Transcriptome Variation Database (PFTVD 1.0) (http://pepper-database.cn/) has been developed. PFTVD 1.0 provides transcriptomics and genomics information and allows users to analyse the data using various tools implemented. This work highlights the potential of long-read sequencing to discover novel genes and transcripts and their diversity in plant developmental biology.

The gut-facial aging axis: A two-sample Mendelian randomization and mediation analysis of gut microbiota, gut microbiota metabolic pathways, and blood metabolites.

BACKGROUND: Facial aging (FA) is a complex process influenced by both genetic and environmental factors. Gut microbiota (GM), gut microbiota metabolic pathways (GMMPs), and blood metabolites (BMs) have been implicated in the regulation of FA, but the causal and mediating effects of these factors remain unclear. METHODS: We used summary-level data from genome-wide association studies (GWAS) of 16S rRNA gene sequencing data for GM (n = 18 340), GWAS of GMMPs (n = 7738), BMs (n = 24 925), and GWAS of FA (n = 423 999). We applied Mendelian randomization (MR) methods to estimate the causal effects of GM, GMMPs, and BMs on FA. We performed mediation analysis to quantify the proportion of the effects mediated by blood metabolites. RESULTS: We identified nine genus, two phylum, two families of GM, nine GM metabolic pathways, and 73 BMs that showed potential causal effects on FA. After Bonferroni correction, three BMs remained causally associated with FA, including average number of methylene groups per double bond (ß, -0.023; 95% CI, -0.032∼-0.014; p = 3.120×10-7) and average number of methylene groups in a fatty acid chain (ß, -0.031; 95% CI, -0.045∼-0.016; p = 2.062×10-5), which had strong negative causal effects on FA, and ratio of bisallylic groups to total fatty acids (ß, 0.023; 95% CI, 0.017∼-0.029; p = 8.441×10-15), which had a strong positive causal effect on FA. Mediation analysis revealed that histidine, average number of methylene groups in a fatty acid chain, and triglycerides in chylomicrons and largest VLDL particles mediated the effects of anaerofilum and/ or superpathway of Laspartate and Lasparagine biosynthesis on FA. CONCLUSION: Our study provides novel insights into the causal and mediating effects of GM, GMMPs, and BMs on FA. These findings may have implications for the development of new strategies for preventing or delaying FA.

A single-gold-atom addition regulates sharp redshift in the fluorescence of atomically precise nanoclusters.

The manipulation of emission peaks at the atomic level and the investigation of the fluorescent origin mechanism are important issues. In this study, a phosphine-mediated modification method was employed on Au36(TBBT)24 nanocluster to produce a new gold nanocluster Au37(TBBT)21(TPP)2. The structural comparison revealed that Au37(TBBT)21(TPP)2 has a structural framework similar to that of Au36(TBBT)24 except for the reconstruction of its surface motifs, the addition of one gold atom into the kernel, and local structural distortion. Interestingly, compared with Au36(TBBT)24, the emission peak of Au37(TBBT)21(TPP)2 is red-shifted into the NIR-II windows (972 nm vs. 1152 nm in CDCl3) with a quantum yield of 1.5%. Furthermore, the origin of the NIR-II fluorescence in Au37(TBBT)21(TPP)2 and the red-shift mechanism of the emission peak were explored by combining the crystal structure and DFT calculations. The results reveal that the insertion of the 37th gold atom into the core can increase the contribution of the gold atoms to the HOMO orbitals and change the origin of their fluorescence from local excitation (LE) to inter fragment charge transfer (IFCT).

Evaluation of Mac-2 binding protein glycosylation isomer (M2BPGi) as a diagnostic marker for staging liver fibrosis: a meta-analysis.

Objective: This study aimed to assess the accuracy of Mac-2 binding protein glycosylation isomer (M2BPGi) in predicting the stage of liver fibrosis. Methods: Articles published until October 10, 2023, were searched in the PubMed, Embase, Web of Science, and Cochrane Library databases. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver-operator curves (SROC), and Spearman's rank correlation coefficient were used to examine the accuracy of M2BPGi in predicting the stage of liver fibrosis. A 95% confidence interval (CI) was provided for each estimate. Results: Twenty-four studies were included in this meta-analysis, including 3,839 patients with liver fibrosis, 409 of whom progressed to stage 4 or above. The pooled sensitivity, specificity, and area under the ROC (AUC) for M2BPGi predicting liver fibrosis ≥F3 were 0.74 (95% CI [0.65-0.82]), 0.84 (95% CI [0.76-0.89]), and 14.99 (95% CI [9.28-24.21]), respectively. The pooled sensitivity, specificity, and AUC for ≥F4 were 0.80 (95% CI [0.70-0.88]), 0.80 (95% CI [0.73-0.86]), and 16.43 (95% CI [0.84-0.90]), respectively. Conclusion: Among different sample partitions, M2BPGi has the best diagnostic performance for liver fibrosis stage ≥4. Furthermore, the cutoff of 1-2 is more accurate than that of 0-1 or 2-3 for fibrosis ≥ F3 and ≥ F4. Registration: CRD42023483260.

Enhanced Whale optimization algorithms for parameter identification of solar photovoltaic cell models: a comparative study.

Parameter identification of solar photovoltaic (PV) cells is crucial for the PV system modeling. However, finding optimal parameters of PV models is an intractable problem due to the highly nonlinear characteristics between currents and voltages in different environments. To address this problem, whale optimization algorithm (WOA)-based meta-heuristic algorithm has turned out to be a feasible and effective approach. As a highly promising optimization algorithm, different enhanced WOA variants have been proposed. Nevertheless, there has been no comparative study of WOA and its variants for parameter identification of PV models so far. To further investigate and analyze the performance of WOA in the studied problem, this work applied and compared WOA and ten enhanced WOA variants for identifying five PV model parameters. Different evaluation indices including solution accuracy, search robustness, and convergence curve were employed to reveal their performance variation. Based on the simulation results, a multi-model statistical analysis with the Friedman test at a confidence level 0.05 was conducted to rank all algorithms. EWOA that hybridizes the sorting-based differential mutation operator and the Lévy flight strategy ranked first and its performance was further verified. Besides, according to the simulation results, possible effective improvement directions for WOA in tackling this intractable problem are concluded to guide future work.

Electroacupuncture pretreatment enhances the calcium efflux activity of Na+/Ca2+ exchanger to attenuate cerebral injury by PI3K/Akt-mediated NCX1 upregulation after focal cerebral ischaemia.

Electroacupuncture pretreatment is considered as an optimal strategy for inducing cerebral ischaemic tolerance. However, the underlying neuroprotective mechanism of this approach has never been explored from the perspective of calcium homeostasis. Intracellular calcium overload is a key inducer of cascade neuronal injury in the early stage after cerebral ischaemia attack and the Na+/Ca2+ exchanger (NCX) is the main plasma membrane calcium extrusion pathway maintaining post-ischaemic calcium homeostasis. This study aims to investigate whether the regulation of NCX-mediated calcium transport contributes to the cerebroprotective effect of electroacupuncture pretreatment against ischaemic injury and to elucidate the underlying mechanisms involved in this process. Following five days of repeated electroacupuncture stimulation on Baihui (GV20), Neiguan (PC6), and Sanyinjiao (SP6) acupoints in rats, in vivo and in vitro models of cerebral ischaemia were induced through middle cerebral artery occlusion and oxygen/glucose deprivation (OGD), respectively. Firstly, we verified the neuroprotective effect of electroacupuncture pretreatment from the perspective of neurological score, infarct volume and neuronal apoptosis. Our findings from brain slice patch-clamp indicated that electroacupuncture pretreatment enhanced the Ca2+ efflux capacity of NCX after OGD. NCX1 expression in the ischaemic penumbra exhibited a consistent decline from 1 to 24 h in MCAO rats. Electroacupuncture pretreatment upregulated the expression of NCX1, especially at 24 h, and silencing NCX1 by short hairpin RNA (shRNA) administration reversed the protective effect of electroacupuncture pretreatment against cerebral ischaemic injury. Furthermore, we administered LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, prior to inducing ischaemia to investigate the upstream regulatory mechanism of electroacupuncture pretreatment on NCX1 expression. Electroacupuncture pretreatment activates PI3K/Akt pathway, leading to an increase in the expression of NCX1, which facilitates calcium extrusion and exerts a neuroprotective effect against cerebral ischaemia. These findings provided a novel insight into the prevention of ischemic stroke and other similar conditions characterized by brain ischaemia or hypoperfusion.

Role of vascular endothelial growth factor D in lung adenocarcinoma immunotherapy response.

OBJECTIVE: To identify key genes associated with tumor-associated macrophages (TAMs), tumor immunotherapy, in the prognosis of lung adenocarcinoma (LUAD). METHODS: The mRNA expression profiles of LUAD samples were obtained from The Cancer Genome Atlas (TCGA) database. The "CIBERSORT" R package was employed to calculate the proportion of innate immune cell infiltration in both tumor and adjacent normal tissues. TAM-associated genes in LUAD were identified to construct a prognostic risk model using weighted gene correlation network analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses (COX). The IMvigor210 cohort was utilized to validate the roles of these genes as predictors of immunotherapy response. Tissue microarrays, immunofluorescence staining, and mRNA level detection methods were used to determine the correlation of risk factors in LUAD tissues. RESULTS: CIBERSORT analysis revealed significant differences in innate immune cells between tumor and adjacent tissues. Seventy-four differential genes linked to these cells were identified from WGCNA. Four hub genes (endothelin receptor type B, vascular endothelial growth factor D (VEGFD), latent transforming growth factor beta binding protein 4 (LTBP4), and fibroblast growth factor receptor 4 (FGFR4)) in the TAM prognostic model were identified as independent prognostic risk factors (P < 0.05). VEGFD expression was identified as a low-risk factor for LUAD prognosis prediction (P < 0.05). Moreover, low-risk patients exhibited higher sensitivity to anti-PD-L1 therapy compared to high-risk patients (P < 0.05). VEGFD levels were negatively correlated with programmed cell death 1 (PD-1) levels (r = -0.363; P < 0.05), suggesting that VEGFD may serve as a predictor for anti-PD-1 treatment. CONCLUSIONS: VEGFD is associated with innate immunity in LUAD, it can predict LUAD prognosis, and therefor may be a potential predictor for anti-PD-1 treatment in patients with LUAD.

Identification of microtubule-associated biomarker using machine learning methods in osteonecrosis of the femoral head and osteosarcoma.

Background: This study aims to explore the microtubule-associated gene signatures and molecular processes shared by osteonecrosis of the femoral head (ONFH) and osteosarcoma (OS). Methods: Datasets from the TARGET and GEO databases were subjected to bioinformatics analysis, including the functional enrichment analysis of genes shared by ONFH and OS. Prognostic genes were identified using univariate and multivariate Cox regression analyses to develop a risk score model for predicting overall survival and immune characteristics. Furthermore, LASSO and SVM-RFE algorithms identified biomarkers for ONFH, which were validated in OS. Function prediction, ceRNA network analysis, and gene-drug interaction network construction were subsequently conducted. Biomarker expression was then validated on clinical samples by using qPCR. Results: A total of 14 microtubule-associated disease genes were detected in ONFH and OS. Subsequently, risk score model based on four genes was then created, revealing that patients with low-risk exhibited superior survival outcomes compared with those with high-risk. Notably, ONFH with low-risk profiles may manifest an antitumor immune microenvironment. Moreover, by utilizing LASSO and SVM-RFE algorithms, four diagnostic biomarkers were pinpointed, enabling effective discrimination between patients with ONFH and healthy individuals as well as between OS and normal tissues. Additionally, 21 drugs targeting these biomarkers were predicted, and a comprehensive ceRNA network comprising four mRNAs, 71 miRNAs, and 98 lncRNAs was established. The validation of biomarker expression in clinical samples through qPCR affirmed consistency with the results of bioinformatics analysis. Conclusion: Microtubule-associated genes may play pivotal roles in OS and ONFH. Additionally, a prognostic model was constructed, and four genes were identified as potential biomarkers and therapeutic targets for both diseases.

Unraveling the genetic and molecular landscape of sepsis and acute kidney injury: A comprehensive GWAS and machine learning approach.

OBJECTIVES: This study aimed to explore the underlying mechanisms of sepsis and acute kidney injury (AKI), including sepsis-associated AKI (SA-AKI), a frequent complication in critically ill sepsis patients. METHODS: GWAS data was analyzed for genetic association between AKI and sepsis. Then, we systematically applied three distinct machine learning algorithms (LASSO, SVM-RFE, RF) to rigorously identify and validate signature genes of SA-AKI, assessing their diagnostic and prognostic value through ROC curves and survival analysis. The study also examined the functional and immunological aspects of these genes, potential drug targets, and ceRNA networks. A mouse model of sepsis was created to test the reliability of these signature genes. RESULTS: LDSC confirmed a positive genetic correlation between AKI and sepsis, although no significant shared loci were found. Bidirectional MR analysis indicated mutual increased risks of AKI and sepsis. Then, 311 key genes common to sepsis and AKI were identified, with 42 significantly linked to sepsis prognosis. Six genes, selected through LASSO, SVM-RFE, and RF algorithms, showed excellent predictive performance for sepsis, AKI, and SA-AKI. The models demonstrated near-perfect AUCs in both training and testing datasets, and a perfect AUC in a sepsis mouse model. Significant differences in immune cells, immune-related pathways, HLA, and checkpoint genes were found between high- and low-risk groups. The study identified 62 potential drug treatments for sepsis and AKI and constructed a ceRNA network. CONCLUSIONS: The identified signature genes hold potential clinical applications, including prognostic evaluation and targeted therapeutic strategies for sepsis and AKI. However, further research is needed to confirm these findings.

Lysosome-Targeted and pH-Activatable Phototheranostics for NIR-II Fluorescence Imaging-Guided Nasopharyngeal Carcinoma Phototherapy.

Currently, clinical therapeutic strategies for nasopharyngeal carcinoma (NPC) confront insurmountable dilemmas in which surgical resection is incomplete and chemotherapy/radiotherapy has significant side effects. Phototherapy offers a maneuverable, effective, and noninvasive pattern for NPC therapy. Herein, we developed a lysosome-targeted and pH-responsive nanophototheranostic for near-infrared II (NIR-II) fluorescence imaging-guided photodynamic therapy (PDT) and photothermal therapy (PTT) of NPC. A lysosome-targeted S-D-A-D-S-type NIR-II phototheranostic molecule (IRFEM) is encapsulated within the acid-sensitive amphiphilic DSPE-Hyd-PEG2k to form IRFEM@DHP nanoparticles (NPs). The prepared IRFEM@DHP exhibits a good accumulation in the acidic lysosomes for facilitating the release of IRFEM, which could disrupt lysosomal function by generating an amount of heat and ROS under laser irradiation. Moreover, the guidelines of NIR-II fluorescence enhance the accuracy of PTT/PDT for NPC and avoid damage to normal tissues. Remarkably, IRFEM@DHP enable efficient antitumor effects both in vitro and in vivo, opening up a new avenue for precise NPC theranostics.

Lysine 2-hydroxyisobutyrylation proteomics analyses reveal the regulatory mechanism of CaMYB61-CaAFR1 module in regulating stem development in Capsicum annuum L.

Plant stems constitute the most abundant renewable resource on earth. The function of lysine (K)-2-hydroxyisobutyrylation (Khib), a novel post-translational modification (PTM), has not yet been elucidated in plant stem development. Here, by assessing typical pepper genotypes with straight stem (SS) and prostrate stem (PS), we report the first large-scale proteomics analysis for protein Khib to date. Khib-modifications influenced central metabolic processes involved in stem development, such as glycolysis/gluconeogenesis and protein translation. The high Khib level regulated gene expression and protein accumulation associated with cell wall formation in the pepper stem. Specially, we found that CaMYB61 knockdown lines that exhibited prostrate stem phenotypes had high Khib levels. Most histone deacetylases (HDACs, e.g., switch-independent 3 associated polypeptide function related 1, AFR1) potentially function as the "erasing enzymes" involved in reversing Khib level. CaMYB61 positively regulated CaAFR1 expression to erase Khib and promote cellulose and hemicellulose accumulation in the stem. Therefore, we propose a bidirectional regulation hypothesis of "Khib modifications" and "Khib erasing" in stem development, and reveal a novel epigenetic regulatory network in which the CaMYB61-CaAFR1 molecular module participating in the regulation of Khib levels and biosynthesis of cellulose and hemicellulose for the first time.

Efficacy and safety of therapies related to acupuncture for acute herpes zoster: A PRISMA systematic review and network meta-analysis.

BACKGROUND: Herpes zoster (HZ) is mainly characterized by intense pain and severe skin lesions, particularly during the acute phase, which seriously affects the patient's quality of life. Acupuncture is a widely used and effective treatment for HZ. However, there are many types of acupuncture, which have different curative efficacy. This study employed a network meta-analysis (NMA) to assess and rank the clinical efficacy of different acupuncture therapies. METHODS: The database of Cochrane Library, Web of Science, PubMed, MEDLINE, Embase, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Database, VIP Database, and Wanfang Database were searched from inception to December 31, 2022 to identify eligible randomized controlled trials (RCTs) of acupuncture related therapies in the treatment of acute HZ. The outcome indicators measured were visual analogue scale (VAS), date of cessation of herpes increase (DCHI), effective rate (ER), postherpetic neuralgia (PHN), and adverse events (AEs). Bayesian network meta-analyses were performed using the GeMTC package (version 1.0-1) and R software (version 4.2.3). RESULTS: A total of 59 RCTs with 3930 patients were included. The results of this NMA were as follows: compared with pharmacotherapy, electroacupuncture (EA) + pricking and cupping (PC) shown the best efficacy to improve VAS score and reduce DCHI. In terms of ER, EA + fire needle (FN) had the highest results of probability ranking. PC was more effective in reducing the incidence of PHN. Furthermore, this study shown that the incidence of AEs associated with acupuncture-related therapies was acceptable. CONCLUSIONS: This study indicated that therapies related to acupuncture were both effective and safe in treating acute HZ, and could significantly reduce patients' symptoms such as pain and skin lesions with fewer adverse events. Clinically, the selection of the appropriate therapy should be based on practical considerations. However, due to the limitations of this study, more high-quality trials are required to evaluate the efficacy and safety of acupuncture-related therapy for the treatment of acute HZ.

Efficacy and safety of different immunotherapies combined with chemotherapy as first-line therapy in patients with small cell lung cancer: a network meta-analysis.

Background: The efficacy and safety of different immunosuppressants combined with chemotherapy in treating patients with small-cell lung cancer (extensive-disease small-cell lung cancer, limited-disease small-cell lung cancer and relapsed small-cell lung cancer) are still unknown, and there are no reports directly comparing the efficacy and safety of other immunotherapies. Objective: This study aimed to compare the efficacy and safety of first-line immunotherapy combined with chemotherapy in patients with small-cell lung cancer. Method: We searched Pubmed, Embase, Cochrane Library, CNKI, and Wanfang databases for relevant articles published from inception to November 11, 2020. The risk of bias of the included studies was conducted using the Cochrane risk-of-bias (RoB) tool. Multiple Bayesian network meta-analyses were performed. They conducted data analysis using R Studio and STATA version 15.1. The outcomes comprised overall survival (OS), progression-free survival (PFS), stability of response (SOR), duration of response (DOR) and adverse events of grade 3 or higher (AE grade≥3). A 95% confidence interval (CI) was provided for each estimate. Results: This meta-analysis included 16 RCT studies with 5898 patients. For OS, relative to chemotherapy (MD=-4.49; 95%CI [-7.97, -1.03]), durvalumab plus tremelimumab (MD=-4.62; 95%CI [-9.08, -0.11]), ipilimumab (MD=-4.26; 95%CI [-8.01, -0.3]) and nivolumab(MD=-5.66; 95%CI [-10.44, -1.11]) and nivolumab plus ipilimumab (MD=-4.56; 95%CI [-8.7, -0.1]), serplulimab can significantly increase the OS of SCLC patients. There was no significant difference between PFS, SOR and DOR. Analysis of AE showed that different immunotherapy combined chemotherapy regimens were similar to single chemotherapy regarding the overall incidence of AE grade≥3. However, after the cumulative ranking of the common symptoms of different adverse reactions, it was found that nivolumab ranked first in the occurrence probability of anemia (99.08%), fatigue (84.78%), and decreased appetite (89.66%). durvalumab was the most likely in nausea (75.4%). Pembrolizumab (76.24%) was most likely to cause pruritus. Chemotherapy combined with immunotherapy caused less diarrhea than chemotherapy alone (80.16%). Conclusions: According to our analysis, serplulimab combined with chemotherapy is more likely to show better efficacy with a manageable safety profile for small-cell lung cancer. However, the evidence for this comparison shows some limitations due to the number of literature. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023486053.

Machine learning and deep learning to identifying subarachnoid haemorrhage macrophage-associated biomarkers by bulk and single-cell sequencing.

We investigated subarachnoid haemorrhage (SAH) macrophage subpopulations and identified relevant key genes for improving diagnostic and therapeutic strategies. SAH rat models were established, and brain tissue samples underwent single-cell transcriptome sequencing and bulk RNA-seq. Using single-cell data, distinct macrophage subpopulations, including a unique SAH subset, were identified. The hdWGCNA method revealed 160 key macrophage-related genes. Univariate analysis and lasso regression selected 10 genes for constructing a diagnostic model. Machine learning algorithms facilitated model development. Cellular infiltration was assessed using the MCPcounter algorithm, and a heatmap integrated cell abundance and gene expression. A 3 × 3 convolutional neural network created an additional diagnostic model, while molecular docking identified potential drugs. The diagnostic model based on the 10 selected genes achieved excellent performance, with an AUC of 1 in both training and validation datasets. The heatmap, combining cell abundance and gene expression, provided insights into SAH cellular composition. The convolutional neural network model exhibited a sensitivity and specificity of 1 in both datasets. Additionally, CD14, GPNMB, SPP1 and PRDX5 were specifically expressed in SAH-associated macrophages, highlighting its potential as a therapeutic target. Network pharmacology analysis identified some targeting drugs for SAH treatment. Our study characterised SAH macrophage subpopulations and identified key associated genes. We developed a robust diagnostic model and recognised CD14, GPNMB, SPP1 and PRDX5 as potential therapeutic targets. Further experiments and clinical investigations are needed to validate these findings and explore the clinical implications of targets in SAH treatment.

Therapeutic effects of orexin-A in sepsis-associated encephalopathy in mice.

BACKGROUND: Sepsis-associated encephalopathy (SAE) causes acute and long-term cognitive deficits. However, information on the prevention and treatment of cognitive dysfunction after sepsis is limited. The neuropeptide orexin-A (OXA) has been shown to play a protective role against neurological diseases by modulating the inflammatory response through the activation of OXR1 and OXR2 receptors. However, the role of OXA in mediating the neuroprotective effects of SAE has not yet been reported. METHODS: A mouse model of SAE was induced using cecal ligation perforation (CLP) and treated via intranasal administration of exogenous OXA after surgery. Mouse survival, in addition to cognitive and anxiety behaviors, were assessed. Changes in neurons, cerebral edema, blood-brain barrier (BBB) permeability, and brain ultrastructure were monitored. Levels of pro-inflammatory factors (IL-1ß, TNF-α) and microglial activation were also measured. The underlying molecular mechanisms were investigated by proteomics analysis and western blotting. RESULTS: Intranasal OXA treatment reduced mortality, ameliorated cognitive and emotional deficits, and attenuated cerebral edema, BBB disruption, and ultrastructural brain damage in mice. In addition, OXA significantly reduced the expression of the pro-inflammatory factors IL-1ß and TNF-α, and inhibited microglial activation. In addition, OXA downregulated the expression of the Rras and RAS proteins, and reduced the phosphorylation of P-38 and JNK, thus inhibiting activation of the MAPK pathway. JNJ-10,397,049 (an OXR2 blocker) reversed the effect of OXA, whereas SB-334,867 (an OXR1 blocker) did not. CONCLUSION: This study demonstrated that the intranasal administration of moderate amounts of OXA protects the BBB and inhibits the activation of the OXR2/RAS/MAPK pathway to attenuate the outcome of SAE, suggesting that OXA may be a promising therapeutic approach for the management of SAE.

Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges.

Resistance to targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) is a significant challenge in the treatment of this disease. The mechanisms of resistance are multifactorial and include molecular target alterations and activation of alternative pathways, tumor heterogeneity and tumor microenvironment change, immune evasion, and immunosuppression. Promising strategies for overcoming resistance include the development of combination therapies, understanding the resistance mechanisms to better use novel drug targets, the identification of biomarkers, the modulation of the tumor microenvironment and so on. Ongoing research into the mechanisms of resistance and the development of new therapeutic approaches hold great promise for improving outcomes for patients with NSCLC. Here, we summarize diverse mechanisms driving resistance to targeted therapy and immunotherapy in NSCLC and the latest potential and promising strategies to overcome the resistance to help patients who suffer from NSCLC.

Orexin-A mediates glioblastoma proliferation inhibition by increasing ferroptosis triggered by unstable iron pools and GPX4 depletion.

Glioblastoma (GBM) represents a prevalent form of primary malignant tumours in the central nervous system, but the options for effective treatment are extremely limited. Ferroptosis, as the most enriched programmed cell death process in glioma, makes a critical difference in glioma progression. Consequently, inducing ferroptosis has become an appealing strategy for tackling gliomas. Through the utilization of multi-omics sequencing data analysis, flow cytometry, MDA detection and transmission electron microscopy, the impact of orexin-A on ferroptosis in GBM was assessed. In this report, we provide the first evidence that orexin-A exerts inhibitory effects on GBM proliferation via the induction of ferroptosis. This induction is achieved by instigating an unsustainable increase in iron levels and depletion of GPX4. Moreover, the regulation of TFRC, FTH1 and GPX4 expression through the targeting of NFE2L2 appears to be one of the potential mechanisms underlying orexin-A-induced ferroptosis.

Electrode-Supported Endohedral Metallofullerenes: Insights into the Confined Internal Dynamics.

Endohedral metallofullerenes show great promise as molecular-scale memory units due to their robust architecture and protective capability for encapsulated atoms. However, the flat potential-energy surface within the cage often results in a severe disorder of encapsulated atoms. Here, we focused on prototypical systems involving Li@C60 on metallic surfaces, emphasizing the electrode's confinement effect on caged dynamics. We demonstrated that the varying interfacial stabilities induced by Li motion predominantly depend on the synergetic effect of van der Waals forces and covalent bonds rather than the previously assumed electrostatic interactions. We unveiled that the repulsion effect between encapsulated atom and the metal electrode primarily arises from the antibonding states between the metal states below the Fermi level and the degenerated frontier orbitals from HOMO-4 to HOMO. By manipulating orbital interactions, we observed an ordered arrangement of the encapsulated atom on Rec-Pt(111) at room temperature. Furthermore, our findings underscore the disruptive influence of electric fields on the stability of distinct Li positions, a phenomenon closely tied to the dipole moment induced by Li motion. This research provides a new perspective on the confined internal dynamics of endohedral metallofullerenes by manipulating cage-electrode interactions, contributing to precisely controlled molecular electronics.