FDX1 as a novel biomarker and treatment target for stomach adenocarcinoma.

BACKGROUND: Stomach adenocarcinoma (STAD) is one of the main reasons for cancer-related deaths worldwide. This investigation aimed to define the connection between STAD and Cuproptosis-related genes (CRGs). Cuproptosis is a newly identified form of mitochondrial cell death triggered by copper. AIM: To explore the identification of potential biomarkers for STAD disease based on cuproptosis. METHODS: A predictive model using Gene Ontology (GO), Least Absolute Shrinkage and Selection Operator (LASSO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Variation Analysis (GSVA), and Gene Set Enrichment Analysis analyzed gene interconnections, focusing on 3 copper-related genes and their expression in The Cancer Genome Atlas-STAD. Networks for mRNA-miRNA and mRNA-transcription factor interactions were constructed. The prognostic significance of CRG scores was evaluated using time-receiver operating characteristic, Kaplan-Meier curves, and COX regression analysis. Validation was conducted with datasets GSE26942, GSE54129, and GSE66229. Expression of copper-related differentially expressed genes was also analyzed in various human tissues and gastric cancer subpopulations using the human protein atlas. RESULTS: Three significant genes (FDX1, LIAS, MTF1) were identified and selected via LASSO analysis to predict and classify individuals with STAD into high and low CRG score subgroups. These genes were down-regulated in both risk categories. GO and KEGG analyses highlighted their involvement mainly in the electron transport chain. After validating their differential expression, FDX1 emerged as the most accurate diagnostic marker for gastric cancer. Additionally, the RCircos package localized FDX1 on chromosome 11. CONCLUSION: Our study revealed that FDX1 could be a potential biomarker and treatment target for gastric malignancy, providing new ideas for further scientific research.

The toxic effects induced by benzethonium chloride on Daphnia carinata over two generations: Resistance and higher sublethal toxicity.

With the widespread utilization of the sanitizing product benzethonium chloride (BEC) throughout the coronavirus pandemic, concerns have emerged regarding its potential hazards. Nevertheless, the long-term and multigenerational toxic effects of BEC on aquatic organisms remains unexplored. This study investigates acute and chronic toxicity, oxidative stress, mitochondrial membrane potential, ATP concentrations, and gene expression using Daphnia carinata as the model organism. Meanwhile, hierarchical clustering analysis was utilized to investigate phenotypic effects among different treatment groups. The integrated biomarker response index version 2 (IBRv2) was employed to estimate the deviation in toxic effects over two generations. These results indicated that D. carinata in the second generation exhibited higher survival rate and lower levels of oxidative stress than the first generation. However, the higher sublethal effects were found in the second generation as follows, the weakened growth performance, mitochondrial membrane potential depolarization, reduced ATP concentrations, and down-regulated gene expression. The mitochondrial toxicity induced by BEC may account for the distinct toxic effects exhibited in two generations. The findings here can assist with the evaluation of potential risk for BEC on aquatic organisms, and provide new insight into the cross-generational toxicity mechanisms of pollutants in aquatic ecosystems.

Musical experience enhances time discrimination: Evidence from cortical responses.

Time discrimination, a critical aspect of auditory perception, is influenced by numerous factors. Previous research has suggested that musical experience can restructure the brain, thereby enhancing time discrimination. However, this phenomenon remains underexplored. In this study, we seek to elucidate the enhancing effect of musical experience on time discrimination, utilizing both behavioral and electroencephalogram methodologies. Additionally, we aim to explore, through brain connectivity analysis, the role of increased connectivity in brain regions associated with auditory perception as a potential contributory factor to time discrimination induced by musical experience. The results show that the music-experienced group demonstrated higher behavioral accuracy, shorter reaction time, and shorter P3 and mismatch response latencies as compared to the control group. Furthermore, the music-experienced group had higher connectivity in the left temporal lobe. In summary, our research underscores the positive impact of musical experience on time discrimination and suggests that enhanced connectivity in brain regions linked to auditory perception may be responsible for this enhancement.

Anatomical predispositions for silent cerebral infarction post carotid artery stenting: A retrospective cohort.

BACKGROUND: Silent cerebral infarction (SCI) that manifests following carotid artery stenting (CAS) has been postulated to correlate with cognitive decline, the onset of dementia, and an increased risk of subsequent cerebrovascular events. This investigation aimed to thoroughly examine the potential anatomical predispositions that are linked to the occurrence of SCI post-CAS, and further develop a predictive nomogram that could accurately forecast the risk of SCI post-CAS. METHODS: The present investigation conducted a retrospective examination of datasets from 250 individuals presenting with carotid artery stenosis who had been subjected to CAS within a tertiary healthcare institution from June 2020 to November 2021. Stratified by the procedural date, participants were allocated into a training cohort and a validation cohort. A nomogram was constructed predicated on salient prognostic determinants discerned via a multivariate logistic regression analysis. RESULTS: An aggregate of 184 patients were incorporated into the study, of which 60 (32.6%) manifested SCI, whereas 124 (67.4%) did not. Within the training cohort (n=123), age (OR 1.08, 95%CI 1.01-1.16; P=0.034), aortic arch type (Type III vs. I: OR 10.79, 95%CI 2.12-54.81; P=0.005), aortic arch variant (OR 47.71, 95%CI 6.05-376.09; P<0.001), common carotid artery (CCA) ostium lesions (OR 6.93, 95%CI 1.49-32.32; P=0.014), and proximal tortuosity index (TI) (OR 1.01, 95%CI 1.00-1.02; P=0.029) were demarcated as standalone risk predispositions for SCI subsequent to CAS. The concordance index (C-index) for the training cohort's nomogram stood at 0.89 (95% CI, 0.84-0.95). Moreover, the said nomogram exhibited commendable efficacy within the validation cohort (C-index=0.94) as well as the entire participant base (C-index=0.90). Furthermore, the decision curve analysis illustrated the exemplary clinical applicability of the nomogram. CONCLUSIONS: The findings of this inquiry underscore that age, aortic arch type, aortic arch variant, CCA ostium lesions, and proximal TI serve as independent determinants linked with SCI post-CAS. The formulated nomogram, predicated on these risk factors, possesses robust prognostic significance and might serve as a valuable adjunct to inform clinical decision-making.

Targeting macrophagic RasGRP1 with catechin hydrate ameliorates sepsis-induced multiorgan dysfunction.

BACKGROUND: The proinflammatory response induced by macrophages plays a crucial role in the development of sepsis and the resulting multiorgan dysfunction. Identifying new regulatory targets for macrophage homeostasis and devising effective treatment strategies remains a significant challenge in contemporary research. PURPOSE: This study aims to identify new regulatory targets for macrophage homeostasis and develop effective strategies for treating sepsis. STUDY DESIGN AND METHODS: Macrophage infiltration in septic patients and in lungs, kidneys, and brains of caecum ligation and puncture (CLP)-induced septic mice was observed using CIBERSORT and immunofluorescence (IF). Upon integrating the MSigDB database and GSE65682 dataset, differently expressed macrophage-associated genes (DEMAGs) were identified. Critical DEMAGs were confirmed through machine learning. The protein level of the critical DEMAG was detected in PBMCs of septic patients, RAW264.7 cells, and mice lungs, kidneys, and brains using ELISA, western blot, immunohistochemistry, and IF. siRNA was applied to investigate the effect of the critical DEMAG in RAW264.7 cells. A natural product library was screened to find a compound targeting the critical DEMAG protein. The binding of compounds and proteins was analyzed through molecular docking, molecular dynamics simulations, CETSA, and MST analysis. The therapeutic efficacy of the compounds against sepsis was then evaluated through in vitro and in vivo experiments. RESULTS: Macrophage infiltration was inversely correlated with survival in septic patients. The critical differentially expressed molecule RasGRP1 was frequently observed in the PBMCs of septic patients, LPS-induced RAW264.7 cells, and the lungs, kidneys, and brains of septic mice. Silencing RasGRP1 alleviated proinflammatory response and oxidative stress in LPS-treated RAW264.7 cells. Catechin Hydrate (CH) was identified as an inhibitor of RasGRP1, capable of maintaining macrophage homeostasis and mitigating lung, kidney, and brain damage during sepsis. CONCLUSION: This study demonstrates that RasGRP1, a novel activator of macrophage proinflammatory responses, plays a crucial role in the excessive inflammation and oxidative stress associated with sepsis. CH shows potential for treating sepsis by inhibiting RasGRP1.

A promising frontier: targeting NETs for stroke treatment breakthroughs.

Stroke is a prevalent global acute cerebrovascular condition, with ischaemic stroke being the most frequently occurring type. After a stroke, neutrophils accumulate in the brain and subsequently generate and release neutrophil extracellular traps (NETs). The accumulation of NETs exacerbates the impairment of the blood‒brain barrier (BBB), hampers neovascularization, induces notable neurological deficits, worsens the prognosis of stroke patients, and can facilitate the occurrence of t-PA-induced cerebral haemorrhage subsequent to ischaemic stroke. Alternative approaches to pharmacological thrombolysis or endovascular thrombectomy are being explored, and targeting NETs is a promising treatment that warrants further investigation.

Platelet factor 4 promotes deep venous thrombosis by regulating the formation of neutrophil extracellular traps.

The presence of neutrophil extracellular traps (NETs) in thrombotic diseases has been extensively studied. The exact mechanism of NET formation in deep venous thrombosis (DVT) has not been largely studied. This study is aimed to explore the role of NETs and their interaction with platelet factor 4 (PF4) in DVT. In plasma samples from 51 healthy volunteers and 52 DVT patients, NET markers and PF4 were measured using enzyme-linked immunosorbent assays (ELISA). NET generation in blood samples from healthy subjects and DVT patients was analyzed by confocal microscopy and flow cytometry. The plasma levels of NETs were significantly elevated in DVT patients, and neutrophils from patients showed a stronger ability to generate NETs after treatment. PF4 was upregulated in plasma samples from DVT patients and mediated NET formation. NETs enhanced procoagulant (PCA) via tissue factor and activating platelets to induce procoagulant activity. In addition, we established an inferior vena cava ligation (IVC) model to examine the role of NETs in thrombogenicity in DVT. In conclusion, NET formation was mediated by PF4 and enhance the procoagulant activity in DVT.

Targeting pyroptosis with nanoparticles to alleviate neuroinflammatory for preventing secondary damage following traumatic brain injury.

Posttraumatic neuroinflammation is a key driver of secondary injury after traumatic brain injury (TBI). Pyroptosis, a proinflammatory form of programmed cell death, considerably activates strong neuroinflammation and amplifies the inflammatory response by releasing inflammatory contents. Therefore, treatments targeting pyroptosis may have beneficial effects on the treatment of secondary brain damage after TBI. Here, a cysteine-alanine-glutamine-lysine peptide-modified ß-lactoglobulin (ß-LG) nanoparticle was constructed to deliver disulfiram (DSF), C-ß-LG/DSF, to inhibit pyroptosis and decrease neuroinflammation, thereby preventing TBI-induced secondary injury. In the post-TBI mice model, C-ß-LG/DSF selectively targets the injured brain, increases DSF accumulation, and extends the time of the systemic circulation of DSF. C-ß-LG/DSF can alleviate brain edema and inflammatory response, inhibit secondary brain injury, promote learning, and improve memory recovery in mice after trauma. Therefore, this study likely provided a potential approach for reducing the secondary spread of TBI.

Subgraph Propagation and Contrastive Calibration for Incomplete Multiview Data Clustering.

The success of multiview raw data mining relies on the integrity of attributes. However, each view faces various noises and collection failures, which leads to a condition that attributes are only partially available. To make matters worse, the attributes in multiview raw data are composed of multiple forms, which makes it more difficult to explore the structure of the data especially in multiview clustering task. Due to the missing data in some views, the clustering task on incomplete multiview data confronts the following challenges, namely: 1) mining the topology of missing data in multiview is an urgent problem to be solved; 2) most approaches do not calibrate the complemented representations with common information of multiple views; and 3) we discover that the cluster distributions obtained from incomplete views have a cluster distribution unaligned problem (CDUP) in the latent space. To solve the above issues, we propose a deep clustering framework based on subgraph propagation and contrastive calibration (SPCC) for incomplete multiview raw data. First, the global structural graph is reconstructed by propagating the subgraphs generated by the complete data of each view. Then, the missing views are completed and calibrated under the guidance of the global structural graph and contrast learning between views. In the latent space, we assume that different views have a common cluster representation in the same dimension. However, in the unsupervised condition, the fact that the cluster distributions of different views do not correspond affects the information completion process to use information from other views. Finally, the complemented cluster distributions for different views are aligned by contrastive learning (CL), thus solving the CDUP in the latent space. Our method achieves advanced performance on six benchmarks, which validates the effectiveness and superiority of our SPCC.

Neutrophil extracellular traps mediated by platelet microvesicles promote thrombosis and brain injury in acute ischemic stroke.

AIMS: Neutrophil extracellular traps (NETs) have been implicated in thrombotic diseases. There is no definitive explanation for how NETs form during acute ischemic strokes (AIS). The purpose of our study was to investigate the potential mechanism and role of NETs formation in the AIS process. METHODS: As well as 45 healthy subjects, 45 patients with AIS had ELISA tests performed to detect NET markers. Expression of high-mobility group box 1 (HMGB1) on platelet microvesicles (PMVs) was analyzed by flow cytometry in healthy subjects and AIS patients' blood samples. We established middle cerebral artery occlusion (MCAO) mice model to elucidate the interaction between PMPs and NETs. RESULTS: A significant elevation in NET markers was found in patient plasma in AIS patients, and neutrophils generated more NETs from patients' neutrophils. HMGB1 expression was upregulated on PMVs from AIS patients and induced NET formation. NETs enhanced Procoagulant activity (PCA) through tissue factor and via platelet activation. Targeting lactadherin in genetical and in pharmacology could regulate the formation of NETs in MCAO model. CONCLUSIONS: NETs mediated by PMVs derived HMGB1 exacerbate thrombosis and brain injury in AIS. Video Abstract.

The marine Penicillium sp. GGF16-1-2 metabolite dicitrinone G inhibits pancreatic angiogenesis by regulating the activation of NLRP3 inflammasome.

Citrinin derivatives have been found to have various pharmacological activities, such as anti-inflammatory, anti-tumor, and antioxidant effects. Dicitrinone G (DG) was a new citrinin dimer isolated from marine-derived fungus Penicillium sp. GGF 16-1-2 which has potential activity. Here, we aim to investigate whether DG has anti-pancreatic cancer activity. In xenograft tumor model, 2 × 106 BXPC-3 cells were injected into the hind flank of NU/NU nude mice by subcutaneously for 2 weeks followed by treating with DG (0.25, 0.5, 1 mg/kg) and 5-FU (30 mg/kg) for 4 weeks. Tumor volume and weight were measured, and the expression of CD31, IL-18, NLRP3, and Caspase-1 in tumor tissue were detected. In vitro, HUVECs were treated with conditioned medium (CM) derived from BXPC-3 cells, the effects of DG on angiogenesis were detected by tube formation and western blot analysis. In vivo studies showed that the tumor growth and angiogenesis were greatly suppressed. The tumor weight inhibition rates of DG and 5-FU groups were about 42.36%, 38.94%, 43.80%, and 31.88%. Furthermore, the expression of CD31 and Caspase-1 were decreased. In vitro, CM derived from BXPC-3 cells which treated with DG could inhibit the tube formation and expression of pro-angiogenic NICD in HUVECs. Our study suggests that DG could suppress angiogenesis via the NLRP3/IL-18 pathway and may have the potential to inhibit tumor development.

QiShenYiQi pills preserve endothelial barrier integrity to mitigate sepsis-induced acute lung injury by inhibiting ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: The QiShengYiQi pill (QSYQ) is a traditional Chinese medicinal formulation. The effectiveness and safety of QSYQ in treating respiratory system disorders have been confirmed. Its pharmacological actions include anti-inflammation, antioxidative stress, and improving energy metabolism. However, the mechanism of QSYQ in treating sepsis-induced acute lung injury (si-ALI) remains unclear. AIM OF THE STUDY: Si-ALI presents a clinical challenge with high incidence and mortality rates. This study aims to confirm the efficacy of QSYQ in si-ALI and to explore the potential mechanisms, providing a scientific foundation for its application and insights for optimizing treatment strategies and identifying potential active components. MATERIALS AND METHODS: The impact of QSYQ on si-ALI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of QSYQ on endothelial cells were observed through coculturing with LPS-stimulated macrophage-conditioned medium. Inflammatory cytokine levels, HE staining, Evans blue staining, lung wet/dry ratio, and cell count and protein content in bronchoalveolar lavage fluid were used to assess the degree of lung injury. Network pharmacology was utilized to investigate the potential mechanisms of QSYQ in treating si-ALI. Western blot and immunofluorescence analyses were used to evaluate barrier integrity and validate mechanistically relevant proteins. RESULTS: QSYQ reduced the inflammation and alleviated pulmonary vascular barrier damage in CLP mice (all P < 0.05). A total of 127 potential targets through which QSYQ regulates si-ALI were identified, predominantly enriched in the RAGE pathway. The results of protein-protein interaction analysis suggest that COX2, a well-established critical marker of ferroptosis, is among the key targets. In vitro and in vivo studies demonstrated that QSYQ mitigated ferroptosis and vascular barrier damage in sepsis (all P < 0.05), accompanied by a reduction in oxidative stress and the inhibition of the COX2 and RAGE (all P < 0.05). CONCLUSIONS: This study demonstrated that QSYQ maintains pulmonary vascular barrier integrity by inhibiting ferroptosis in CLP mice. These findings partially elucidate the mechanism of QSYQ in si-ALI and further clarify the active components of QSYQ, thereby providing a scientific theoretical basis for treating si-ALI with QSYQ.

Danlou tablet attenuates ischemic stroke injury and blood‒brain barrier damage by inhibiting ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Danlou tablet (DLT) is a traditional Chinese medicinal formulation known for replenishing Qi, promoting blood circulation, and resolving stasis. Its pharmacological actions primarily involve anti-inflammatory, antioxidant stress reduction, antiapoptotic, proangiogenic, and improved energy metabolism. DLT has been confirmed to have favorable therapeutic effects on ischemic stroke (IS). However, the underlying mechanism through which DLT affects IS-induced brain injury remains unknown. AIM OF THE STUDY: This study aims to investigate the effects and underlying mechanisms of danlou tablet on ischemic stroke based on network pharmacology and experimental verification. MATERIALS AND METHODS: Using a transient middle cerebral artery occlusion (tMCAO) mouse model, the impact of DLT on the blood‒brain barrier (BBB) and brain injury in mice was assessed. Network pharmacology and bioinformatics analyses were utilized to explore the potential mechanisms of DLT in treating IS. Endothelial cells were cultured to observe the effects of DLT on vascular endothelial cells after oxygen-glucose deprivation/reperfusion, and these findings were validated in the brains of tMCAO mice. RESULTS: DLT alleviated oxidative stress and brain damage in tMCAO mice, mitigating BBB damage. A total of 185 potential targets through which DLT regulates IS were identified, including COX2, a known critical marker of ferroptosis, which identified as a key target. In vitro and in vivo experiments demonstrated that DLT significantly (p < 0.05) improved cell death and vascular barrier damage in IS, reducing intracellular oxidative stress and COX2 protein levels while increasing SLC7A11 and GPX4 protein levels. CONCLUSIONS: This study demonstrated that DLT maintained BBB integrity and alleviated brain injury of tMCAO mice by inhibiting ferroptosis. The study partially unraveled the mechanism through which DLT functioned in treating IS and further clarified the pivotal active components of DLT, thereby providing a theoretical scientific basis for treating IS with DLT.

Outstanding Synergy of Sensitivity and Linear Range Enabled by Multigradient Architectures.

Flexible pressure sensors are devices that mimic the sensory capabilities of natural human skin and enable robots to perceive external stimuli. One of the main challenges is maintaining high sensitivity over a broad linear pressure range due to poor structural compressibility. Here, we report a flexible pressure sensor with an ultrahigh sensitivity of 153.3 kPa-1 and linear response over an unprecedentedly broad pressure range from 0.0005 to 1300 kPa based on interdigital-shaped, multigradient architectures, featuring modulus, conductivity, and microstructure gradients. Such multigradient architectures and interdigital-shaped configurations enable effective stress transfer and conductivity regulation, evading the pressure sensitivity-linear range trade-off dilemma. Together with high pressure resolution, high frequency response, and good reproducibility over the ultrabroad linear range, proof-of-concept applications such as acoustic wave detection, high-resolution pressure measurement, and healthcare monitoring in diverse scenarios are demonstrated.

Single-cell transcriptomics reveals zinc and copper ions homeostasis in epicardial adipose tissue of heart failure.

Epicardial adipose tissue (EAT) is a unique visceral fat reservoir that shares an immune microenvironment without a distinct boundary with myocardium. Increasingly, visceral fat has been studied as a secondary immune organ, and EAT is no exception in this regard. Cellular subsets of EAT are associated with disease development. In heart failure (HF) patients, however, the immune characteristics of EAT have rarely been studied, especially those non-immune cells related to the immune microenvironment. Herein, an analysis of seven EAT samples by single-cell RNA sequencing (scRNA-Seq) is presented here, including 1 neonate, 1 infant, 1 child, 2 adults with heart failure (Adults-HF) and 2 adult heart transplant donors as non-heart failure control (Adults-Non HF). Analysis of 51730 high-quality cells revealed eleven major cell types in EAT. For the first time, the pseudo-temporal reconstruction technique was employed to plot the cell trajectories of various major cell types (such as T lymphocytes, fibroblasts, endothelial cells, monocytes, and smooth muscle cells) in EAT across different developmental stages, achieving a single-cell resolution. The dynamic gene expression patterns of major cell types presented the immune characteristics of metabolism disorder of zinc and copper ions, and downregulated immune-related pathways in EAT of adult patients with HF. These data provide insights regarding HF immune dysregulation at the cellular level.

Polyester microplastic fibers induce mitochondrial damage, apoptosis and oxidative stress in Daphnia carinata, accompanied by changes in apoptotic and ferroptosis pathway.

With the widespread utilization of plastic products, microplastics (MPs) have merged as a newfound environmental contaminant in the United States, and the bulk of these MPs in the environment manifest as fibrous structures. Concerns have also been voiced regarding the potential hazards posed by microplastic fibers (MFs). However, research examining the toxicity of MFs, particularly in relation to planktonic organisms, remains severely limited. Meanwhile, polyester fiber materials find extensive applications across diverse industries. As a result, this investigation delved into the toxicology of polyester microplastic fibers (PET-MFs) with a focus on their impact on Daphnia carinata (D. carinata), a freshwater crustacean. Newly hatched D. carinata were subjected to varying concentrations of PET-MFs (0, 50, and 500 MFs/mL) to scrutinize the accumulation of PET-MFs within these organisms and their resultant toxicity. The outcomes revealed that D. carinata was capable of ingesting PET-MFs, leading to diminished rates of survival and reproduction. These effects were accompanied by mitochondrial impairment, heightened mitochondrial count, apoptosis, escalated generation of reactive oxygen species, augmented activity of antioxidant enzymes, and distinct patterns of gene expression. Interestingly, when comparing the group exposed to 50 MFs/mL with the one exposed to 500 MFs/mL, it was observed that the former triggered a more pronounced degree of mitochondrial damage, apoptosis, and oxidative stress. This phenomenon could be attributed to the fact that brief exposure to 500 MFs/mL resulted in greater mortality, eliminating individuals with lower adaptability. Those that survived managed to regulate elevated in vivo reactive oxygen species levels through an increase in glutathione S-transferase content, thereby establishing an adaptive mechanism. Low concentrations did not induce direct mortality, yet PET-MFs continued to inflict harm within the organism. RNA-seq analysis unveiled significant alterations in 279 and 55 genes in the 50 MFs/mL and 500 MFs/mL exposure groups, respectively. Functional enrichment analysis of the 50 MFs/mL group indicated involvement of the apoptosis pathway and ferroptosis pathway in the toxic effects exerted by PET-MFs on D. carinata. This study imparts valuable insights into the toxicological ramifications of PET-MFs on D. carinata, underscoring their potential risks within aquatic ecosystems.

Iterative Deep Structural Graph Contrast Clustering for Multiview Raw Data.

Multiview clustering has attracted increasing attention to automatically divide instances into various groups without manual annotations. Traditional shadow methods discover the internal structure of data, while deep multiview clustering (DMVC) utilizes neural networks with clustering-friendly data embeddings. Although both of them achieve impressive performance in practical applications, we find that the former heavily relies on the quality of raw features, while the latter ignores the structure information of data. To address the above issue, we propose a novel method termed iterative deep structural graph contrast clustering (IDSGCC) for multiview raw data consisting of topology learning (TL), representation learning (RL), and graph structure contrastive learning to achieve better performance. The TL module aims to obtain a structured global graph with constraint structural information and then guides the RL to preserve the structural information. In the RL module, graph convolutional network (GCN) takes the global structural graph and raw features as inputs to aggregate the samples of the same cluster and keep the samples of different clusters away. Unlike previous methods performing contrastive learning at the representation level of the samples, in the graph contrastive learning module, we conduct contrastive learning at the graph structure level by imposing a regularization term on the similarity matrix. The credible neighbors of the samples are constructed as positive pairs through the credible graph, and other samples are constructed as negative pairs. The three modules promote each other and finally obtain clustering-friendly embedding. Also, we set up an iterative update mechanism to update the topology to obtain a more credible topology. Impressive clustering results are obtained through the iterative mechanism. Comparative experiments on eight multiview datasets show that our model outperforms the state-of-the-art traditional and deep clustering competitors.

Newcastle disease virus nucleocapsid protein mediates the degradation of 14-3-3ε to antagonize the interferon response and promote viral replication.

Newcastle disease virus (NDV) is responsible for outbreaks that pose a threat to the global poultry industry. NDV triggers an interferon (IFN) response in the host upon infection. However, it also employs mechanisms that counteract this response. One important component in IFN-related signaling pathways is 14-3-3ε, which is known to interact with retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). The relationship between 14 and 3-3ε and NDV infection has not been previously explored; therefore, this study aimed to investigate this relationship in vivo and in vitro using overexpressed and knockdown 14-3-3ε experiments, along with co-immunoprecipitation analysis. We found that NDV infection led to the degradation of 14-3-3ε. Furthermore, 14-3-3ε inhibited the replication of NDV, suggesting that NDV may enhance its own replication by promoting the degradation of 14-3-3ε during infection. The study revealed that 14-3-3ε is degraded by lysosomes and the viral protein nucleocapsid protein (NP) of NDV induces this degradation. It was also observed that 14-3-3ε is involved in activating the IFN pathway during NDV infection and mediates the binding of MDA5 to MAVS. Our study reveals that NDV NP mediates the entry of 14-3-3ε into lysosomes and facilitates its degradation. These findings contribute to the existing knowledge on the molecular mechanisms employed by NDV to counteract the IFN response and enhance its own replication.

Using mixed reality technique combines multimodal imaging signatures to adjuvant glioma photodynamic therapy.

Background: Photodynamic therapy (PDT) promotes significant tumor regression and extends the lifetime of patients. The actual operation of PDT often relies on the subjective judgment of experienced neurosurgeons. Patients can benefit more from precisely targeting PDT's key operating zones. Methods: We used magnetic resonance imaging scans and created 3D digital models of patient anatomy. Multiple images are aligned and merged in STL format. Neurosurgeons use HoloLens to import reconstructions and assist in PDT execution. Also, immunohistochemistry was used to explore the association of hyperperfusion sites in PDT of glioma with patient survival. Results: We constructed satisfactory 3D visualization of glioma models and accurately localized the hyperperfused areas of the tumor. Tumor tissue taken in these areas was rich in CD31, VEGFA and EGFR that were associated with poor prognosis in glioma patients. We report the first study using MR technology combined with PDT in the treatment of glioma. Based on this model, neurosurgeons can focus PDT on the hyperperfused area of the glioma. A direct benefit was expected for the patients in this treatment. Conclusion: Using the Mixed Reality technique combines multimodal imaging signatures to adjuvant glioma PDT can better exploit the vascular sealing effect of PDT on glioma.

Neutrophil extracellular traps induced by the hypoxic microenvironment in gastric cancer augment tumour growth.

BACKGROUND: Inflammation-related predisposition to cancer plays an essential role in cancer progression and is associated with poor prognosis. A hypoxic microenvironment and neutrophil infiltration are commonly present in solid tumours, including gastric cancer (GC). Neutrophil extracellular traps (NETs) have also been demonstrated in the tumour immune microenvironment (TIME), but how NETs affect GC progression remains unknown. Here, we investigated the role of NET formation in the TIME and further explored the underlying mechanism of NETs in GC tumour growth. METHODS: Hypoxia-induced factor-1α (HIF-1α), citrulline histone 3 (citH3) and CD66b expression in tumour and adjacent nontumor tissue samples was evaluated by western blotting, immunofluorescence and immunohistochemical staining. The expression of neutrophil-attracting chemokines in GC cells and their hypoxic-CM was measured by qRT‒PCR and ELISA. Neutrophil migration under hypoxic conditions was evaluated by a Transwell assay. Pathway activation in neutrophils in a hypoxic microenvironment were analysed by western blotting. NET formation was measured in vitro by immunofluorescence staining. The protumour effect of NETs on GC cells was identified by Transwell, wound healing and cell proliferation assays. In vivo, an lipopolysaccharide (LPS)-induced NET model and subcutaneous tumour model were established in BALB/c nude mice to explore the mechanism of NETs in tumour growth. RESULTS: GC generates a hypoxic microenvironment that recruits neutrophils and induces NET formation. High mobility group box 1 (HMGB1) was translocated to the cytoplasm from the nucleus of GC cells in the hypoxic microenvironment and mediated the formation of NETs via the toll-like receptor 4 (TLR4)/p38 MAPK signalling pathway in neutrophils. HMGB1/TLR4/p38 MAPK pathway inhibition abrogated hypoxia-induced neutrophil activation and NET formation. NETs directly induced GC cell invasion and migration but not proliferation and accelerated the augmentation of GC growth by increasing angiogenesis. This rapid tumour growth was abolished by treatment with the NET inhibitor deoxyribonuclease I (DNase I) or a p38 MAPK signalling pathway inhibitor. CONCLUSIONS: Hypoxia triggers an inflammatory response and NET formation in the GC TIME to augment tumour growth. Targeting NETs with DNase I or HMGB1/TLR4/p38 MAPK pathway inhibitors is a potential therapeutic strategy to inhibit GC progression. Video Abstract.