[Pulmonary PET /CT image instance segmentation based on dense interactive feature fusion Mask RCNN].

There are some problems in positron emission tomography/ computed tomography (PET/CT) lung images, such as little information of feature pixels in lesion regions, complex and diverse shapes, and blurred boundaries between lesions and surrounding tissues, which lead to inadequate extraction of tumor lesion features by the model. To solve the above problems, this paper proposes a dense interactive feature fusion Mask RCNN (DIF-Mask RCNN) model. Firstly, a feature extraction network with cross-scale backbone and auxiliary structures was designed to extract the features of lesions at different scales. Then, a dense interactive feature enhancement network was designed to enhance the lesion detail information in the deep feature map by interactively fusing the shallowest lesion features with neighboring features and current features in the form of dense connections. Finally, a dense interactive feature fusion feature pyramid network (FPN) network was constructed, and the shallow information was added to the deep features one by one in the bottom-up path with dense connections to further enhance the model's perception of weak features in the lesion region. The ablation and comparison experiments were conducted on the clinical PET/CT lung image dataset. The results showed that the APdet, APseg, APdet_s and APseg_s indexes of the proposed model were 67.16%, 68.12%, 34.97% and 37.68%, respectively. Compared with Mask RCNN (ResNet50), APdet and APseg indexes increased by 7.11% and 5.14%, respectively. DIF-Mask RCNN model can effectively detect and segment tumor lesions. It provides important reference value and evaluation basis for computer-aided diagnosis of lung cancer.

Impaired Cardiac AMPK (5'-Adenosine Monophosphate-Activated Protein Kinase) and Ca2+-Handling, and Action Potential Duration Heterogeneity in Ibrutinib-Induced Ventricular Arrhythmia Vulnerability.

BACKGROUND: We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear. METHODS AND RESULTS: The effects of ibrutinib on cardiac electrical activity and Ca2+ dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca2+-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P<0.002) and shorter action potential durations during pacing at various frequencies (P<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (P<0.05). Significant changes in myocardial Ca2+ transients included lower amplitude alternans ratios (P<0.05), longer times-to-peak (P<0.05), and greater spontaneous intracellular Ca2+ elevations (P<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside ameliorated abnormalities in action potential and Ca2+ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside, P<0.05) in hearts from ibrutinib-treated rats. CONCLUSIONS: VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.

High internal phase emulsions gel ink for direct-ink-writing 3D printing of liquid metal.

3D printing of liquid metal remains a big challenge due to its low viscosity and large surface tension. In this study, we use Carbopol hydrogel and liquid gallium-indium alloy to prepare a liquid metal high internal phase emulsion gel ink, which can be used for direct-ink-writing 3D printing. The high volume fraction (up to 82.5%) of the liquid metal dispersed phase gives the ink excellent elastic properties, while the Carbopol hydrogel, as the continuous phase, provides lubrication for the liquid metal droplets, ensuring smooth flow of the ink during shear extrusion. These enable high-resolution and shape-stable 3D printing of three-dimensional structures. Moreover, the liquid metal droplets exhibit an electrocapillary phenomenon in the Carbopol hydrogel, which allows for demulsification by an electric field and enables electrical connectivity between droplets. We have also achieved the printing of ink on flexible, non-planar structures, and demonstrated the potential for alternating printing with various materials.

Cuproptosis-related lncRNA signature as a prognostic tool and therapeutic target in diffuse large B cell lymphoma.

Cuproptosis is a newly defined form of programmed cell death that relies on mitochondria respiration. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis and metastasis. However, whether cuproptosis-related lncRNAs are involved in the pathogenesis of diffuse large B cell lymphoma (DLBCL) remains unclear. This study aimed to identify the prognostic signatures of cuproptosis-related lncRNAs in DLBCL and investigate their potential molecular functions. RNA-Seq data and clinical information for DLBCL were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Cuproptosis-related lncRNAs were screened out through Pearson correlation analysis. Utilizing univariate Cox, least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analysis, we identified seven cuproptosis-related lncRNAs and developed a risk prediction model to evaluate its prognostic value across multiple groups. GO and KEGG functional analyses, single-sample GSEA (ssGSEA), and the ESTIMATE algorithm were used to analyze the mechanisms and immune status between the different risk groups. Additionally, drug sensitivity analysis identified drugs with potential efficacy in DLBCL. Finally, the protein-protein interaction (PPI) network were constructed based on the weighted gene co-expression network analysis (WGCNA). We identified a set of seven cuproptosis-related lncRNAs including LINC00294, RNF139-AS1, LINC00654, WWC2-AS2, LINC00661, LINC01165 and LINC01398, based on which we constructed a risk model for DLBCL. The high-risk group was associated with shorter survival time than the low-risk group, and the signature-based risk score demonstrated superior prognostic ability for DLBCL patients compared to traditional clinical features. By analyzing the immune landscapes between two groups, we found that immunosuppressive cell types were significantly increased in high-risk DLBCL group. Moreover, functional enrichment analysis highlighted the association of differentially expressed genes with metabolic, inflammatory and immune-related pathways in DLBCL patients. We also found that the high-risk group showed more sensitivity to vinorelbine and pyrimethamine. A cuproptosis-related lncRNA signature was established to predict the prognosis and provide insights into potential therapeutic strategies for DLBCL patients.

Zinc oxide/graphene oxide nanocomposites specifically remediated Cd-contaminated soil via reduction of bioavailability and ecotoxicity of Cd.

From both environment and health perspectives, sustainable management of ever-growing soil contamination by heavy metal is posing a serious global concern. The potential ecotoxicity of cadmium (Cd) to soil and ecosystem seriously threatens human health. Developing efficient, specific, and long-term remediation technology for Cd-contaminated soil is impending to synchronously minimize the bioavailability and ecotoxicity of Cd. In the present study, zinc oxide/graphene oxide nanocomposite (ZnO/GO) was developed as a novel amendment for remediating Cd-contaminated soil. Our results showed that ZnO/GO effectively decreased the available soil Cd content, and increased pH and cation exchange capacity (CEC) in both Cd-spiked standard soil and Cd-contaminated mine field soil through the interaction between ZnO/GO and soil organic acids. Using Caenorhabditis elegans (C. elegans) as a model organism for soil safety evaluation, ZnO/GO was further proved to decrease the ecotoxicity of Cd-contaminated soil. Specifically, ZnO/GO promoted Cd excretion and declined Cd storage in C. elegans by increasing the expression of gene ttm-1 and decreasing the level of gene cdf-2, which were responsible for Cd transportation and Cd accumulation, respectively. Moreover, the efficacy of ZnO/GO in remediating the properties and ecotoxicity of Cd-contaminated soil increased gradually with the time gradient, and could maintain a long-term effect after reaching the optimal remediation efficiency. Our findings established a specific and long-term strategy to simultaneously improve soil properties and reduce ecotoxicity of Cd-contaminated soil, which might provide new insights into the potential application of ZnO/GO in soil remediation for both ecosystem and human health.

Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton's Tyrosine Kinase Inhibitor Acalabrutinib.

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca2+ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca2+ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca2+ leak and Ca2+ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca2+ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.

The Key Role of Plant Hormone Signaling Transduction and Flavonoid Biosynthesis Pathways in the Response of Chinese Pine (Pinus tabuliformis) to Feeding Stimulation by Pine Caterpillar (Dendrolimus tabulaeformis).

In nature, plants have developed a series of resistance mechanisms to face various external stresses. As understanding of the molecular mechanisms underlying plant resistance continues to deepen, exploring endogenous resistance in plants has become a hot topic in this field. Despite the multitude of studies on plant-induced resistance, how plants respond to stress under natural conditions remains relatively unclear. To address this gap, we investigated Chinese pine (Pinus tabuliformis) using pine caterpillar (Dendrolimus tabulaeformis) under natural conditions. Healthy Chinese pine trees, approximately 10 years old, were selected for studying induced resistance in Huangtuliangzi Forestry, Pingquan City, Chengde City, Hebei Province, China. Pine needles were collected at 2 h and 8 h after feeding stimulation (FS) via 10 pine caterpillars and leaf clipping control (LCC), to simulate mechanical damage caused by insect chewing for the quantification of plant hormones and transcriptome and metabolome assays. The results show that the different modes of treatments significantly influence the contents of JA and SA in time following treatment. Three types of differentially accumulated metabolites (DAMs) were found to be involved in the initial response, namely phenolic acids, lipids, and flavonoids. Weighted gene co-expression network analysis indicated that 722 differentially expressed genes (DEGs) are positively related to feeding stimulation and the specific enriched pathways are plant hormone signal transduction and flavonoid biosynthesis, among others. Two TIFY transcription factors (PtTIFY54 and PtTIFY22) and a MYB transcription factor (PtMYB26) were found to be involved in the interaction between plant hormones, mainly in the context of JA signal transduction and flavonoid biosynthesis. The results of this study provide an insight into how JA activates, serving as a reference for understanding the molecular mechanisms of resistance formation in conifers responding to mandibulate insects.

Efficacy and safety of anlotinib in combination with immune checkpoint inhibitors or not as advanced non-small cell lung cancer treatment: a systematic review and network meta-analysis.

Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality. Combined anlotinib and immune checkpoint inhibitors (ICIs) therapy may have synergistic antitumor effects in NSCLC. This study aimed to comparing the efficacy and safety of anlotinib and ICIs treatment, monotherapy and combination in NSCLC. Methods: We performed a systematic review and network meta-analysis of 14 studies involving 4,308 NSCLC patients across four regimens: anlotinib, ICIs, anlotinib plus ICIs, and placebo. Efficacy outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Safety outcomes included treatment-related adverse events (TRAEs), TRAE grade three or higher (TRAE ≥3). Analyses were performed in RevMan 5.3 and R 3.5.1 (gemtc package). P<0.05 or effect estimate with 95% confidence interval (CI) that did not include 1 indicated statistical significance. Results: Fourteen publications involving 4,308 patients across four treatment regimens (anlotinib, ICIs, anlotinib plus ICIs, placebo) were included. For PFS, network meta-analysis showed all three interventions significantly improved PFS versus placebo. Anlotinib plus ICIs demonstrated the greatest PFS improvement [hazard ratio (HR) =0.24; 95% CI: 0.14, 0.36], followed by anlotinib (HR =0.37; 95% CI: 0.23, 0.58), and ICIs (HR =0.43; 95% CI: 0.27, 0.67). For OS, compared to placebo, anlotinib plus ICIs showed the greatest OS improvement (HR =0.52; 95% CI: 0.33, 0.74), followed by anlotinib (HR =0.66; 95% CI: 0.47, 0.95), and ICIs (HR =0.72; 95% CI: 0.54, 0.97). For ORR, anlotinib plus ICIs demonstrated the greatest improvement versus placebo [odds ratio (OR) =5.29; 95% CI: 3.32, 8.58], followed by anlotinib (OR =4.38; 95% CI: 2.42, 8.19), and ICIs (OR =2.17; 95% CI: 1.65, 2.89). For DCR, anlotinib plus ICIs showed the greatest improvement versus placebo (OR =13.32; 95% CI: 4.99, 45.09), followed by anlotinib (OR =5.56; 95% CI: 2.17, 14.38), and ICIs (OR =3.46; 95% CI: 1.29, 10.85). Compared to placebo, anlotinib was associated with the highest risk of TRAEs (OR =3.67, 95% CI: 1.12, 15.77), followed by ICIs (OR =1.83; 95% CI: 1.26, 2.69). Due to lack of data on anlotinib plus ICIs, no comparison was conducted. For grade ≥3 TRAEs, compared to placebo, anlotinib increased the risk (OR =3.67; 95% CI: 1.12, 15.77), while anlotinib plus ICIs (OR =2.45; 95% CI: 0.51, 11.6) and ICIs (OR =1.29; 95% CI: 0.33, 4.38) did not increase the risk. Conclusions: Anlotinib combined with ICIs demonstrates improved efficacy over monotherapy for NSCLC treatment, without increased adverse events.

Nanoparticles targeting OPN loaded with BY1 inhibits vascular restenosis by inducing FTH1-dependent ferroptosis in vascular smooth muscle cells.

Vascular restenosis following angioplasty continues to pose a significant challenge. The heterocyclic trioxirane compound [1, 3, 5-tris((oxiran-2-yl)methyl)-1, 3, 5-triazinane-2, 4, 6-trione (TGIC)], known for its anticancer activity, was utilized as the parent ring to conjugate with a non-steroidal anti-inflammatory drug, resulting in the creation of the spliced conjugated compound BY1. We found that BY1 induced ferroptosis in VSMCs as well as in neointima hyperplasia. Furthermore, ferroptosis inducers amplified BY1-induced cell death, while inhibitors mitigated it, indicating the contribution of ferroptosis to BY1-induced cell death. Additionally, we established that ferritin heavy chain1 (FTH1) played a pivotal role in BY1-induced ferroptosis, as evidenced by the fact that FTH1 overexpression abrogated BY1-induced ferroptosis, while FTH1 knockdown exacerbated it. Further study found that BY1 induced ferroptosis by enhancing the NCOA4-FTH1 interaction and increasing the amount of intracellular ferrous. We compared the effectiveness of various administration routes for BY1, including BY1-coated balloons, hydrogel-based BY1 delivery, and nanoparticles targeting OPN loaded with BY1 (TOP@MPDA@BY1) for targeting proliferated VSMCs, for prevention and treatment of the restenosis. Our results indicated that TOP@MPDA@BY1 was the most effective among the three administration routes, positioning BY1 as a highly promising candidate for the development of drug-eluting stents or treatments for restenosis.

Components analysis of San-Bai decoction, and its pharmacodynamics and mechanism on preventing and treating melasma.

ETHNOPHARMACOLOGICAL RELEVANCE: San-Bai Decoction (SBD) is a classic whitening prescription originally recorded in the 'Introduction to Medicine' of the Ming Dynasty. SBD has been known for invigorating Qi and blood, promoting spleen and stomach, whitening skin, and fading melasma. However, its pharmacodynamic material basis and specific mechanism remain unclear. AIM OF THE STUDY: The aim of this study is to clarify the pharmacodynamic material basis of SBD and its mechanism of removing melasma. MATERIALS AND METHODS: The positive and negative ion mass spectrum data of SBD extract were collected by UHPLC-Q-Exactive Orbitrap MS/MS, imported into Compound Discoverer (CD) 3.1 software, matched through the online database, and manually checked. Finally, the in vitro chemical components of SBD were classified. Similarly, the mass spectrum data of SBD in the serum of normal rats and melasma model rats were also analyzed by CD 3.1 software. The in vitro identified Compound file of SBD was imported into the Expected Compounds and the Generate Expected Compounds project was selected. The SBD compounds were then chosen under the Compound Section. All phase I and II reaction types related to SBD components were selected, and the metabolic platform of CD 3.1 software was utilized to process the results and obtain possible metabolites. The metabolites were scored and products with high scores were subsequently screened. According to literature comparison, the final metabolites of SBD in both normal rats and melasma model rats were determined and comprehensively analyzed. The Melasma model rats were constructed through intramuscular injection of progesterone and ultraviolet radiation B (UVB) irradiation. The preventing and treating effect of SBD on melasma were evaluated by regulating inflammation, epidermal collagen content, and oxidative stress. Additionally, the effect of SBD on the Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (Akt)/Glycogen synthase kinase 3ß (GSK3ß) pathway was investigated through Western blot (WB) to explore its underlying mechanism on whitening and removing melasma efficacy. RESULTS: Ultimately, 94 components were identified in SBD, including 41 flavonoids, 27 organic acids, and 9 glycosides, 3 terpenoids, 2 amides, 2 aldehydes, 1 phenylpropanoid and 9 other compounds. In the blood of normal rat group, a total of 24 prototype components and 61 metabolites were identified. Similarly, there were19 prototype components and 44 metabolites identified from the blood of melasma model rats. Pharmacodynamic experiment results indicated that SBD effectively reduced the incidence of melasma, prevent the loss of epidermal collagen, and elevate the activity of superoxide dismutase and decrease the malondialdehyde content in both liver and skin. Interestingly, the WB results demonstrated that SBD effectively activated PI3K/Akt/GSK3ß pathway, and down-regulated the expression of melanin-related proteins. CONCLUSIONS: For the first time, the components of SBD extracts, and its prototype components and metabolites in the blood of normal rats and melasma model rats were successfully identified by high-resolution liquid chromatography-mass spectrometry with CD software. Additionally, the differences of in vivo components of SBD between normal rats and melasma model rats were analyzed. The preventive and therapeutic effect of SBD on melasma was verified in the melasma model rats induced by progesterone and UVB irradiation, and its mechanism was related to activating PI3K/Akt/GSK3ß pathway and downregulating the expression of melanin-related proteins. These results provide an experimental foundation for further research on the pharmacodynamic substance basis and pharmacodynamic mechanism of SBD, as well as developing new anti-melasma formula with SBD.

All-in-one strategy to develop a near-infrared triggered multifunctional bioactive magnesium phosphate bone cement for bone repair.

Bone cement is widely used in clinical with optimistic filling and mechanical properties. However, the setting time of bone cement is difficult to accurately control, and the existing bone cements exhibit limited therapeutic functionalities. In response to these challenges, we designed and synthesized Nd-doped whitlockite (Nd-WH), endowing bone cement with photothermal-responsive and fluorescence imaging capabilities. The doping amount and photothermal properties of Nd-doped whitlockite were studied, and the composite bone cement was prepared. The results showed that the setting time of bone cement could be regulated by near infrared irradiation, and the multiple functions of promoting osteogenic differentiation, antibacterial and anti-tumor could be realized by adjusting the power and irradiation time of near infrared. By incorporating Nd-doped whitlockite and bone cement, we developed an all-in-one strategy to achieve setting time control, enhanced osteogenic ability, tumor cell clearance, bacterial clearance, and bone tissue regeneration. The optimized physical and mechanical properties of composite bone cement ensure adaptability and plasticity. In vitro and in vivo experiments validated the effectiveness of this bone cement platform for bone repair, tumor cell clearance and bacterial clearance. The universal methods to regulate the setting time and function of bone cement by photothermal effect has potential in orthopedic surgery and is expected to be a breakthrough in the field of bone defect repair. Further research and clinical validation are needed to ensure its safety, efficacy and sustainability. STATEMENT OF SIGNIFICANCE: Bone cement is a valuable clinical material. However, the setting time of bone cement is difficult to control, and the therapeutic function of existing bone cement is limited. Various studies have shown that the bone repair capacity of bone cements can be enhanced by synergistic stimulatory effects in vivo and ex vivo. Unfortunately, most of the existing photothermal conversion materials are non-degradable and poorly biocompatible. This study provides a bone-like photothermal conversion material with photothermal response and fluorescence imaging properties, and constructed a platform for integrated regulation of the setting time of bone cement and diversification of its functions. Therefore, it helps to design multi-functional bone repair materials that are more convenient and effective in clinical operation.

Corrigendum to "Design and fabrication of high-performance self-setting trimagnesium phosphate" [Bioact. Mater. 28 (2023) 348-357].

[This corrects the article DOI: 10.1016/j.bioactmat.2023.05.019.].

IL-17A Aggravated Blood-Brain Barrier Disruption via Activating Src Signaling in Epilepsy Mice.

Inflammation is an important pathogenic driving force in the genesis and development of epilepsy. The latest researches demonstrated that IL-17A mediated blood-brain barrier (BBB) dysfunction through disruption of tight junction protein expression. To investigate whether IL-17A is involved in BBB disruption after acute seizure attack, the pilocarpine model was established with C57BL/6 J (wild type, WT) and IL-17R-deficient mice in vivo and with primary cultured rat brain microvascular endothelial cells in vitro. The mortality rate and brain water content were evaluated at 24 h after status epilepticus, and IL-17A concentration, endothelial tight junction, adherens junction proteins, and albumin leakage were assessed at 0 h, 4 h, 12 h, and 24 h after status epilepticus (SE). IL-17R-deficient mice showed lessen severity of epilepsy than WT mice, accompanied by less albumin leakage, reduced brain water content, decreased IL-17A, and upregulated expression of target proteins (ZO-1, Occludin and VE-cadherin). IL-17R knockout abrogated abnormal upregulation of Src kinase and phosphorylated Src kinase in the setting of SE, and Src kinase inhibitor PP1 abrogated IL-17A-induced SE related endothelial injury in vitro. In conclusion, IL-17A inhibition might be a promising therapeutic option to attenuate endothelial cell injury and further BBB disruption by reducing Src kinase activation.

SpaNCMG: improving spatial domains identification of spatial transcriptomics using neighborhood-complementary mixed-view graph convolutional network.

The advancement of spatial transcriptomics (ST) technology contributes to a more profound comprehension of the spatial properties of gene expression within tissues. However, due to challenges of high dimensionality, pronounced noise and dynamic limitations in ST data, the integration of gene expression and spatial information to accurately identify spatial domains remains challenging. This paper proposes a SpaNCMG algorithm for the purpose of achieving precise spatial domain description and localization based on a neighborhood-complementary mixed-view graph convolutional network. The algorithm enables better adaptation to ST data at different resolutions by integrating the local information from KNN and the global structure from r-radius into a complementary neighborhood graph. It also introduces an attention mechanism to achieve adaptive fusion of different reconstructed expressions, and utilizes KPCA method for dimensionality reduction. The application of SpaNCMG on five datasets from four sequencing platforms demonstrates superior performance to eight existing advanced methods. Specifically, the algorithm achieved highest ARI accuracies of 0.63 and 0.52 on the datasets of the human dorsolateral prefrontal cortex and mouse somatosensory cortex, respectively. It accurately identified the spatial locations of marker genes in the mouse olfactory bulb tissue and inferred the biological functions of different regions. When handling larger datasets such as mouse embryos, the SpaNCMG not only identified the main tissue structures but also explored unlabeled domains. Overall, the good generalization ability and scalability of SpaNCMG make it an outstanding tool for understanding tissue structure and disease mechanisms. Our codes are available at https://github.com/ZhihaoSi/SpaNCMG.

Protective effect of short-chain fructo-oligosaccharides from chicory on alcohol-induced injury in GES-1 cells via Keap1/Nrf2 and NLRP3 inflammasome signaling pathways.

Numerous studies have demonstrated that polysaccharides derived from chicory possess the ability to regulate host signaling and modify mucosal damage. Yet, the effect and mechanism of short-chain fructo-oligosaccharides (scFOS) on gastric mucosa remain unclear. Hence, the protective effect of three scFOS (1-Kestose, Nystose, and 1F-Fructofuranosylnystose) against ethanol-induced injury in gastric epithelial (GES-1) cells, and the underlying molecular mechanism involved was investigated in this study. Treatment with 7% ethanol decreased the cell viability of GES-1 cells, resulting in oxidative stress and inflammation. However, pretreatment with scFOS exhibited significant improvements in cell viability, and mitigated oxidative stress and inflammation. scFOS markedly elevated the protein expression of Nrf2, HO-1, SOD1 and SOD2, while suppressing the expression of Keap1. scFOS pretreatment could also maintain mitochondrial membrane potential balance and reduce apoptosis. In addition, scFOS was observed to reduce the protein level of NLRP3, Caspase-1 and ASC. In conclusion, scFOS served a preventive function in mitigating oxidative stress and inflammation in ethanol-exposed GES-1 cells through modulation of the Keap1/Nrf2 and NLRP3 inflammasome signaling pathways. Collectively, the results indicated that scFOS could significantly mitigate ethanol-induced gastric cell damage, suggesting its potential for safeguarding gastrointestinal health.

HDAC6 inhibitor promotes reactive oxygen species-meditated clearance of Staphylococcus aureus in macrophage.

Staphylococcus aureus (S. aureus) pneumonia has become an increasingly important public health problem. Recent evidence suggests that epigenetic modifications are critical in the host immune defence against pathogen infection. In this study, we found that S. aureus infection induces the expression of histone deacetylase 6 (HDAC6) in a dose-dependent manner. Furthermore, by using a S. aureus pneumonia mouse model, we showed that the HDAC6 inhibitor, tubastatin A, demonstrates a protective effect in S. aureus pneumonia, decreasing the mortality and destruction of lung architecture, reducing the bacterial burden in the lungs and inhibiting inflammatory responses. Mechanistic studies in primary bone marrow-derived macrophages demonstrated that the HDAC6 inhibitors, tubastatin A and tubacin, reduced the intracellular bacterial load by promoting bacterial clearance rather than regulating phagocytosis. Finally, N-acetyl-L- cysteine, a widely used reactive oxygen species (ROS) scavenger, antagonized ROS production and significantly inhibited tubastatin A-induced S. aureus clearance. These findings demonstrate that HDAC6 inhibitors promote the bactericidal activity of macrophages by inducing ROS, an important host factor for S. aureus clearance and production. Our study identified HDAC6 as a suitable epigenetic modification target for preventing S. aureus infection, and tubastatin A as a useful compound in treating S. aureus pneumonia.

Impact evaluation of invisible intimate partner violence on maternal healthcare utilization in Pakistan.

INTRODUCTION: Existing research has shown that intimate partner violence (IPV) may hinder maternal access to healthcare services, thereby affecting maternal and child health. However, current studies have ignored whether emotional intimate partner violence (EV) could negatively affect maternal healthcare use. This study aims to evaluate the impact of invisible IPV on maternal healthcare utilization in Pakistan. METHODS: We analyzed nationally representative data from the Pakistan Demographic and Health Survey database from 2012-2013 and 2017-2018. Exposure to physical intimate partner violence (PV) and EV was the primary predictor. Based on women's last birth records, outcomes included three binary variables indicating whether women had inadequate antenatal care (ANC) visits, non-institutional delivery, and lack of postnatal health check-ups. A logistic regression model was established on weighted samples. RESULTS: Exposure to EV during pregnancy was significantly associated with having inadequate ANC visits (aOR = 2.16, 95% CI: 1.06 to 4.38, p = 0.033) and non-institutional delivery (aOR = 2.24, 95% CI: 1.41 to 3.57, p = 0.001). Lifetime exposure to EV was associated with increased risks of inadequate ANC visits (aOR = 1.48, 95% CI: 1.00 to 2.19, p = 0.049). Lifetime exposure to low-scale physical intimate partner violence (LSPV) (adjusted OR (aOR) = 1.73, 95% CI: 1.29 to 2.31, p < 0.001) was associated with increased risks of having no postnatal health check-ups. CONCLUSIONS: Pregnant women who experienced EV and LSPV are at greater risk of missing maternal healthcare, even if the violence occurred before pregnancy. Therefore, in countries with high levels of IPV, early screening for invisible violence needs to be integrated into policy development, and healthcare providers need to be trained to identify EV and LSPV.

Remarkable flexibility in freestanding single-crystalline antiferroelectric PbZrO3 membranes.

The ultrahigh flexibility and elasticity achieved in freestanding single-crystalline ferroelectric oxide membranes have attracted much attention recently. However, for antiferroelectric oxides, the flexibility limit and fundamental mechanism in their freestanding membranes are still not explored clearly. Here, we successfully fabricate freestanding single-crystalline PbZrO3 membranes by a water-soluble sacrificial layer technique. They exhibit good antiferroelectricity and have a commensurate/incommensurate modulated microstructure. Moreover, they also have good shape recoverability when bending with a small radius of curvature (about 2.4 µm for the thickness of 120 nm), corresponding to a bending strain of 2.5%. They could tolerate a maximum bending strain as large as 3.5%, far beyond their bulk counterpart. Our atomistic simulations reveal that this remarkable flexibility originates from the antiferroelectric-ferroelectric phase transition with the aid of polarization rotation. This study not only suggests the mechanism of antiferroelectric oxides to achieve high flexibility but also paves the way for potential applications in flexible electronics.

Metabolic Control During Macrophage Polarization by a Citrate-Functionalized Scaffold for Maintaining Bone Homeostasis.

Metabolites, as markers of phenotype at the molecular level, can regulate the function of DNA, RNA, and proteins through chemical modifications or interactions with large molecules. Citrate is an important metabolite that affects macrophage polarization and osteoporotic bone function. Therefore, a better understanding of the precise effect of citrate on macrophage polarization may provide an effective alternative strategy to reverse osteoporotic bone metabolism. In this study, a citrate functional scaffold to control the metabolic pathway during macrophage polarization based on the metabolic differences between pro-inflammatory and anti-inflammatory phenotypes for maintaining bone homeostasis, is fabricated. Mechanistically, only outside M1 macrophages are accumulated high concentrations of citrate, in contrast, M2 macrophages consume massive citrate. Therefore, citrate-functionalized scaffolds exert more sensitive inhibitory effects on metabolic enzyme activity during M1 macrophage polarization than M2 macrophage polarization. Citrate can block glycolysis-related enzymes by occupying the binding-site and ensure sufficient metabolic flux in the TCA cycle, so as to turn the metabolism of macrophages to oxidative phosphorylation of M2 macrophage, largely maintaining bone homeostasis. These studies indicate that exogenous citrate can realize metabolic control of macrophage polarization for maintaining bone homeostasis in osteoporosis.

Exercise-induced improvement of glycemic fluctuation and its relationship with fat and muscle distribution in type 2 diabetes.

AIMS: Management of blood glucose fluctuation is essential for diabetes. Exercise is a key therapeutic strategy for diabetes patients, although little is known about determinants of glycemic response to exercise training. We aimed to investigate the effect of combined aerobic and resistance exercise training on blood glucose fluctuation in type 2 diabetes patients and explore the predictors of exercise-induced glycemic response. MATERIALS AND METHODS: Fifty sedentary diabetes patients were randomly assigned to control or exercise group. Participants in the control group maintained sedentary lifestyle for 2 weeks, and those in the exercise group specifically performed combined exercise training for 1 week. All participants received dietary guidance based on a recommended diet chart. Glycemic fluctuation was measured by flash continuous glucose monitoring. Baseline fat and muscle distribution were accurately quantified through magnetic resonance imaging (MRI). RESULTS: Combined exercise training decreased SD of sensor glucose (SDSG, exercise-pre vs exercise-post, mean 1.35 vs 1.10 mmol/L, p = .006) and coefficient of variation (CV, mean 20.25 vs 17.20%, p = .027). No significant change was observed in the control group. Stepwise multiple linear regression showed that baseline MRI-quantified fat and muscle distribution, including visceral fat area (ß = -0.761, p = .001) and mid-thigh muscle area (ß = 0.450, p = .027), were significantly independent predictors of SDSG change in the exercise group, as well as CV change. CONCLUSIONS: Combined exercise training improved blood glucose fluctuation in diabetes patients. Baseline fat and muscle distribution were significant factors that influence glycemic response to exercise, providing new insights into personalized exercise intervention for diabetes.