Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant cancer, characterized by frequent mucin overexpression. MUC1 has been identified as a critical oncogene in the progression of CCA. However, the comprehensive understanding of how the mucin family influences CCA progression and prognosis is still incomplete. AIM: To investigate the functions of mucins on the progression of CCA and to establish a risk evaluation formula for stratifying CCA patients. METHODS: Single-cell RNA sequencing data from 14 CCA samples were employed for elucidating the roles of mucins, complemented by bioinformatic analyses. Subsequent validations were conducted through spatial transcriptomics and immunohistochemistry. The construction of a risk evaluation model utilized the least absolute shrinkage and selection operator regression algorithm, which was further confirmed by independent cohorts and diverse data types. RESULTS: CCA tumor cells with elevated levels of MUC1 and MUC4 showed activated nucleotide metabolic pathways and increased invasiveness. MUC5AC-high cells were found to promote CCA progression through WNT signaling. MUC5B-high cells exhibited robust cellular oxidation activities, leading to resistance against antitumoral treatments. MUC13-high cells were observed to secret chemokines, recruiting and transforming macrophages into the M2-polarized state, thereby suppressing antitumor immunity. MUC16-high cells were found to promote tumor progression through interleukin-1/nuclear factor kappa-light-chain-enhancer of activated B cells signaling upon interaction with neutrophils. Utilizing the expression levels of these mucins, a risk factor evaluation formula for CCA was developed and validated across multiple cohorts. CCA samples with higher risk factors exhibited stronger metastatic potential, chemotherapy resistance, and poorer prognosis. CONCLUSION: Our study elucidates the functional mechanisms through which mucins contribute to CCA development, and provides tools for risk stratification in CCA.

BF3 complexing phosphate/phosphonate ionic liquids: synthesis, characterization and thermophysical properties.

A new group of BF3 complexing phosphate/phosphonate ionic liquids (ILs) [Emim][X(BF3)2] (X = dimethyl phosphate, diethyl phosphate, methyl phosphonate, and ethyl phosphonate) were synthesized and characterized. Key thermophysical properties of the new complex ionic liquids, including density, viscosity, conductivity, surface tension, solid-liquid phase transition, and thermal stability were determined and compared with those of [Emim][X]. Some other important thermophysical properties such as isobaric thermal expansion coefficient, molecular volume, standard molar entropy, and lattice potential energy were obtained from measured density data, and the free volume was estimated by a linear equation presented in this article, while critical temperature, normal boiling temperature, and enthalpy of vaporization were estimated from measured surface tension and density data. Furthermore, Fragility study shows that [Emim][X(BF3)2] could be considered as metallic glass-forming liquids, while [Emim][X] could be considered as extremely fragile liquids. The ionicity of [Emim][X(BF3)2] was predicted by Walden rule, and the result shows that these ILs fit well with Walden law. The key features of these complex ILs are their extremely low glass transition (-95.33~-98.46 ℃) without melting, considerably low viscosities (33.876~58.117 mPa·s), and high values of free volume fraction (comparable to [Omim][BF4], [Emim][NTf2], and [Emim][TCB]).

[Source and Cause Analysis of High Concentration of Inorganic Aerosol During Two Typical Pollution Processes in Winter over Tianjin].

Inorganic aerosol is the main component of haze days in winter over Tianjin. In this study, two typical high concentrations of secondary inorganic aerosol (SIA) processes, defined as CASE1 and CASE2, were selected during polluted days in January 2020 over Tianjin, and the effects of meteorological factors, regional transport, and chemical processes were comprehensively investigated combined with observations and numerical models (WRF-NAQPMS). The average SIA concentrations in CASE1 and CASE2 were 76.8 µg·m-3 and 66.0 µg·m-3, respectively, and the nitrate concentration was higher than that of sulfate and ammonium, which were typical nitrate-dominated pollution processes. Meteorological conditions played a role in inorganic aerosol formation. The temperature of approximately -6-0℃ and 2-4℃ and the relative humidity of 50%-60% and 80%-100% would be suitable conditions for the high SIA concentration (>80 µg·m-3) in CASE1, whereas the temperature of approximately 2-4℃ and the relative humidity of 60%-70% would be suitable in CASE2. The average contribution rates of external sources to SIA in the CASE1 and CASE2 processes were 62.3% and 22.1%, which were regional transport-dominant processes and local emission-dominant processes, respectively. The contribution of the local emission of CASE1 to nitrate and sulfate was 16.2 µg·m-3 and 8.2 µg·m-3, respectively, higher than that of external sources (31.7 µg·m-3 and 8.8 µg·m-3). the local contribution of CASE2 to nitrate and sulfate was 29.3 µg·m-3 and 25.1 µg·m-3, respectively, whereas the contribution from external sources was 8.1 µg·m-3 and 9.4 µg·m-3, respectively. The quantitative result indicated that local formation and regional transport resulted in higher nitrate concentration than sulfate in CASE1, in contrast to only local sources in CASE2. The gas phase reaction was the main source of inorganic aerosol formation, contributing 48.9% and 57.8% in CASE1 and CASE2, respectively, whereas the heterogeneous reactions were also important processes, with contribution rates of 48.1% and 42.2% to SIA. The effect of aqueous phase reaction was negligible.

Diagnostic value of the creatine kinase-MB/creatine kinase and neutrophil/lymphocyte ratios in acute myocardial infarction.

OBJECTIVE: To investigate the clinical significance of the creatine kinase (CK)-MB/total CK ratio, neutrophil/lymphocyte ratio (NLR) and red blood cell distribution width in acute myocardial infarction (AMI). METHODS: A retrospective analysis was conducted of 196 AMI cases from our hospital's cardiology department; healthy people were selected over the same period as the control. The two groups' test indexes were compared through multivariate logistic regression analysis to screen for AMI risk factors; the receiver operating characteristic (ROC) curve was used to evaluate their AMI predictive values. RESULTS: The serum CK, CK-MB, CK index, neutrophils and NLR values in the AMI group were significantly higher compared with those in the control group (p < 0.05); however, the levels of serum lymphocytes were significantly lower compared with those in the control group (p < 0.05). Multivariate logistic regression analysis showed that elevated CK-MB and NLR levels were risk factors for AMI (p < 0.05). The ROC curve showed that the area under the curve of the NLR and CK levels were 0.917 and 0.594, respectively. CONCLUSION: The CK index and NLR have a clinical predicting value for AMI and could be used as a clinical auxiliary diagnostic index for the assessment of patients with AMI.

The transcription factor bmi1 increases hypoxic signaling in oral cavity epithelia.

The tongue epithelium is maintained by a proliferative basal layer. This layer contains long-lived stem cells (SCs), which produce progeny cells that move up to the surface as they differentiate. B-lymphoma Mo-MLV insertion region 1 (Bmi1), a protein in mammalian Polycomb Repressive Complex 1 (PRC1) and a biomarker of oral squamous cell carcinoma, is expressed in almost all basal epithelial SCs of the tongue, and single, Bmi1-labelled SCs give rise to cells in all epithelial layers. We previously developed a transgenic mouse model (KrTB) containing a doxycycline- (dox) controlled, Tet-responsive element system to selectively overexpress Bmi1 in the tongue basal epithelial SCs. Here, we used this model to assess Bmi1 actions in tongue epithelia. Genome-wide transcriptomics revealed increased levels of transcripts involved in the cellular response to hypoxia in Bmi1-overexpressing (KrTB + DOX) oral epithelia even though these mice were not subjected to hypoxia conditions. Ectopic Bmi1 expression in tongue epithelia increased the levels of hypoxia inducible factor-1 alpha (HIF1α) and HIF1α targets linked to metabolic reprogramming during hypoxia. We used chromatin immunoprecipitation (ChIP) to demonstrate that Bmi1 associates with the promoters of HIF1A and HIF1A-activator RELA (p65) in tongue epithelia. We also detected increased SC proliferation and oxidative stress in Bmi1-overexpressing tongue epithelia. Finally, using a human oral keratinocyte line (OKF6-TERT1R), we showed that ectopic Bmi1 overexpression decreases the oxygen consumption rate while increasing the extracellular acidification rate, indicative of elevated glycolysis. Thus, our data demonstrate that high Bmi1 expression drives hypoxic signaling, including metabolic reprogramming, in normal oral cavity epithelia.

Long-term outcomes of survivors with influenza A H1N1 virus-induced severe pneumonia and ARDS: a single-center prospective cohort study.

Introduction: Systematic evaluation of long-term outcomes in survivors of H1N1 is still lacking. This study aimed to characterize long-term outcomes of severe H1N1-induced pneumonia and acute respiratory distress syndrome (ARDS). Method: This was a single-center, prospective, cohort study. Survivors were followed up for four times after discharge from intensive care unit (ICU) by lung high-resolution computed tomography (HRCT), pulmonary function assessment, 6-minute walk test (6MWT), and SF-36 instrument. Result: A total of 60 survivors of H1N1-induced pneumonia and ARDS were followed up for four times. The carbon monoxide at single breath (DLCO) of predicted values and the 6MWT results didn't continue improving after 3 months. Health-related quality of life didn't change during the 12 months after ICU discharge. Reticulation or interlobular septal thickening on HRCT did not begin to improve significantly until the 12-month follow-up. The DLCO of predicted values showed negative correlation with the severity degree of primary disease and reticulation or interlobular septal thickening, and a positive correlation with physical functioning. The DLCO of predicted values and reticulation or interlobular septal thickening both correlated with the highest tidal volume during mechanical ventilation. Levels of fibrogenic cytokines had a positive correlation with reticulation or interlobular septal thickening. Conclusion: The improvements in pulmonary function and exercise capacity, imaging, and health-related quality of life had different time phase and impact on each other during 12 months of follow-up. Long-term outcomes of pulmonary fibrosis might be related to the lung injury and excessive lung fibroproliferation at the early stage during ICU admission.

Trends and disparities in non-communicable diseases in the Western Pacific region.

The WHO Western Pacific region bears disproportionate deaths from non-communicable diseases (NCDs), with increased overall NCD proportional mortality over the past two decades. The disease burden of mental health increased, resulting from rapid ageing, enhanced stress, and the COVID-19 pandemic, but it was largely neglected. The highly diverse cultures, religions, political systems, socioeconomic contexts, lifestyles, and environmental factors probably have led to massive disparities across countries in NCD mortality, risk factors, and NCD management. Geographically, East Asia had the lowest NCD mortality whilst Pacific islands had the highest. Economic booms, ageing, nutrition transition, social stress, prevalent tobacco use, and fast-increasing obesity and hyperglycaemia are important drivers of NCDs. Men tended to have more adverse behavioural and metabolic risk factors. Rural residents are catching up with their urban counterparts in metabolic risk factors and conditions. Sustainable strategies tailored to NCD patterns are needed to fight the NCD epidemic and related disparities.

Preparation of functional oils rich in phytosterol esters and diacylglycerols by enzymatic transesterification.

Phytosterol esters (PEs) and diacylglycerols (DAGs) have various health benefits in humans. In this study, PEs and DAGs were synthesized by lipase-catalyzed transesterification between a natural oil and phytosterols. First, commercial lipases were screened for transesterification and were further verified using multiple-ligand molecular docking. AYS "Amano" (a lipase from Candida rugosa) was found to be the optimum lipase. Subsequently, the enzymatic transesterification conditions were optimized. The optimized conditions were determined to be a 1:2 M ratio of phytosterols to oil, 100 mmol/L phytosterols, and 9 % AYS "Amano", and 50 °C for 24 h in 20 mL n-hexane. Under these conditions, over 70 % of phytosterols were converted to PEs. In this study, an efficient enzymatic process was developed to produce value-added functional oils rich in PEs and DAGs, with PEs content ≥ 31.6 %, DAGs content ≥ 11.2 %, acid value ≤ 0.91 mg KOH/g, and peroxide value ≤ 2.38 mmol/kg.

Costunolide mitigates inflammation and promotes extracellualr matrix integrity of thoracic aortic dissection by inhibiting NF-κB signaling.

BACKGROUND: Thoracic aortic dissection (TAD) is one of the most fatal cardiovascular diseases. One of its important pathological characteristics is the local inflammatory response. Many studies have found that Macrophage polarization plays an extremely critical role in the inflammatory progression and tissue remodeling of TAD. Costunolide (CTD) has an improving effect on oxidative stress and inflammation in the body. However, whether it can promote the integrity of extracellular matrix in Aortic dissection and its mechanism are still unclear. METHODS: The male C57BL/6J mice were used to construct an animal model of TAD with ß-aminopropionitrile (BAPN) (100 mg/kg/day, lasting for 28 days), and then CTD (10 mg/kg or 100 mg/kg) was injected intraperitoneally for 28 days to check the survival rate, TAD incidence, aortic morphology and other indicators of the mice. Using hematoxylin-eosin (HE), Masson, Elastin van Gieson (EVG) staining, immunofluorescence (IF), and immunohistochemical staining, the study aimed to determine the therapeutic effects of CTD on an animal model with BAPN-induced TAD. To enhance the examination of the regulatory mechanism of CTD, we conducted transcriptome sequencing on arterial tissues of mice in both the BAPN group and the BAPN + CTD100 group. Next, ANG II were used to construct TAD model in vascular smooth muscle cells (VMSCs). The effects of CTD on the proliferation, migration, invasion, and apoptosis of ANG II-induced cells are to be detected. The expression of MMP2, MMP9, P65, and p-P65 in each group will be examined using Western blot. Finally, the overexpression of IκB kinaseß (IKKß) will be established in VMSCs cells to further explore the protective function of CTD. RESULTS: The result showed that CTD significantly inhibited BAPN induced mortality and TAD incidence in the animal model, improved aortic vascular morphology, promoted the integrity of extracellular matrix in TAD, reduced tissue inflammation, reduced the accumulation of M1 macrophage, promoted M2 macrophage polarization, and reduced the expression of NF-κB pathway related proteins. Mechanistically, CTD significantly weakened the proliferation, migration, invasion, and apoptosis. p-P65 protein expression of TAD cells were induced by ANG II and IKK-ß. CONCLUSION: CTD has the potential to alleviate inflammation, VSMC apoptosis, MMP2/9 levels, and enhance extracellular matrix integrity in TAD by inhibiting the NF-κB signaling pathway.

A GC×GC-MS method based on solid-state modulator for non-targeted metabolomics: Comparison with traditional GC-MS method.

The formidable challenge posed by the presence of extremely high amounts of compounds and large differences in concentrations in plasma significantly complicates non-targeted metabolomics analyses. In this study, a comprehensive two-dimensional gas chromatography-quadrupole mass spectrometry (GC×GC-qMS) method with a solid-state modulator (SSM) for non-targeted metabolomics in beagle plasma was first established based on a GC-MS method, and the qualitative and quantitative performance of the two platforms were compared. Identification of detected compounds was accomplished utilizing NIST database match scores, retention indices (RIs) and standards. Semi-quantification involved the calculation of peak area ratios to internal standards. Metabolite identification sheets were generated for plasma samples on both analytical platforms, featuring 22 representative metabolites chosen for validating qualitative accuracy, and for conducting comparisons of linearity, accuracy, precision, and sensitivity. The outcomes revealed a threefold increase in the number of identifiable metabolites on the GC×GC-MS platform, with lower limits of quantitation (LLOQs) reduced to 0.5-0.05 times those achieved on the GC-MS platform. Accuracy in quantification for both GC×GC-MS and GC-MS fell within the range of 85-115%, and the vast majority of intra- and inter-day precisions were within the range of 20%. These findings underscore that relative to the conventional GC-MS method, the GC×GC-MS method developed in this study, combined with SSM, exhibits enhanced qualitative capabilities, heightened sensitivity, and comparable accuracy and precision, rendering it more suitable for non-targeted metabolomics analyses.

FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression.

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression. Aberrant glycosylation has been intricately linked with immune escape and tumor growth. SEMA7A is a highly glycosylated protein with five glycosylated sites. The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear. Here, we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma, and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides (Asn 105, 157, 258, 330, and 602) via a direct protein‒protein interaction. A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane. Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8, whereas TGF-ß1 promotes abnormal glycosylation of SEMA7A via induction of epithelial-mesenchymal transition. Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8+ T cells along a trajectory toward an exhausted state, thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death. Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy. Finally, we also define RBM4, a splice regulator, as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing. These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

Rack1-mediated ferroptosis affects hindgut development in rats with anorectal malformations: Spatial transcriptome insights.

Anorectal malformation (ARM), a common congenital anomaly of the digestive tract, is a result of insufficient elongation of the urorectal septum. The cytoplasmic protein Receptor of Activated C-Kinase 1 (Rack1) is involved in embryonic neural development; however, its role in embryonic digestive tract development and ARM formation is unexplored. Our study explored the hindgut development and cell death mechanisms in ARM-affected rats using spatial transcriptome analysis. We induced ARM in rats by administering ethylenethiourea via gavage on gestational day (GD) 10. On GDs 14-16, embryos from both normal and ARM groups underwent spatial transcriptome sequencing, which identified key genes and signalling pathways. Rack1 exhibited significant interactions among differentially expressed genes on GDs 15 and 16. Reduced Rack1 expression in the ARM-affected hindgut, verified by Rack1 silencing in intestinal epithelial cells, led to increased P38 phosphorylation and activation of the MAPK signalling pathway. The suppression of this pathway downregulated Nqo1 and Gpx4 expression, resulting in elevated intracellular levels of ferrous ions, reactive oxygen species (ROS) and lipid peroxides. Downregulation of Gpx4 expression in the ARM hindgut, coupled with Rack1 co-localisation and consistent mitochondrial morphology, indicated ferroptosis. In summary, Rack1, acting as a hub gene, modulates ferrous ions, lipid peroxides, and ROS via the P38-MAPK/Nqo1/Gpx4 axis. This modulation induces ferroptosis in intestinal epithelial cells, potentially influencing hindgut development during ARM onset.

Resting state functional connectome in breast cancer patients with fear of cancer recurrence.

This study aimed to investigate network-level brain functional changes in breast cancer patients and their relationship with fear of cancer recurrence (FCR). Resting-state functional MRI was collected from 43 patients with breast cancer and 40 healthy controls (HCs). Graph theory analyses, whole-brain voxel-wise functional connectivity strength (FCS) analyses and seed-based functional connectivity (FC) analyses were performed to identify connection alterations in breast cancer patients. Correlations between brain functional connections (i.e. FCS and FC) and FCR level were assessed to further reveal the neural mechanisms of FCR in breast cancer patients. Graph theory analyses indicated a decreased clustering coefficient in breast cancer patients compared to HCs (P = 0.04). Patients with breast cancer exhibited significantly higher FCS in both higher-order function networks (frontoparietal, default mode, and dorsal attention systems) and primary somatomotor networks. Among the hyperconnected regions in breast cancer, the left inferior frontal operculum demonstrated a significant positive correlation with FCR. Our findings suggest that breast cancer patients exhibit less segregation of brain function, and the left inferior frontal operculum is a key region associated with FCR. This study offers insights into the neural mechanisms of FCR in breast cancer patients at the level of brain connectome.

Mortality of children and adolescents co-infected with tuberculosis and HIV: a systematic review and meta-analysis.

OBJECTIVE: Children and adolescents with HIV infection are well-known to face a heightened risk of tuberculosis. However, the exact mortality rates and temporal trends of those with HIV-TB co-infection remain unclear. We aimed to identify the overall mortality and temporal trends within this population. METHODS: PubMed, Web of Science, and Embase were employed to search for publications reporting on the mortality rates of children and adolescents with HIV-TB co-infection from inception to March 2, 2024. The outcome is the mortality rate for children and adolescents with HIV-TB co-infection during the follow-up period. In addition, we evaluate the temporal trends of mortality. RESULTS: During the follow-up period, the pooled mortality was 16% (95% CI 13-20). Single infection of either HIV or TB exhibit lower mortality rates (6% and 4%, respectively). We observed elevated mortality risks among individuals aged less than 12 months, those with EPTB, poor adherence to ART, and severe immunosuppression. In addition, we observed a decreasing trend in mortality before 2008 and an increasing trend after 2008, although the trends were not statistically significant (P = 0.08 and 0.2 respectively). CONCLUSIONS: Children and adolescents with HIV-TB co-infection bear a significant burden of mortality. Timely screening, effective treatment, and a comprehensive follow-up system contribute to reducing the mortality burden in this population.

Effects of cluster nursing interventions on the prevention of pressure ulcers in intensive care units patients: A meta-analysis.

A meta-analysis was conducted to comprehensively evaluate the impact of cluster nursing interventions on the prevention of pressure ulcers (PUs) in intensive care unit (ICU) patients. Computer searches were performed in databases including Embase, Google Scholar, Cochrane Library, PubMed, Wanfang and China National Knowledge Infrastructure for randomized controlled trials (RCTs) implementing cluster nursing interventions for PUs prevention in ICU patients, with the search period covering the database inception to November 2023. Two researchers independently screened the literature, extracted data and conducted quality assessments. Stata 17.0 software was employed for data analysis. Overall, 17 RCTs involving 1463 ICU patients were included. The analysis showed that compared with conventional nursing, cluster nursing interventions significantly reduced the incidence of PUs (odds ratio: 0.24, 95% confidence intervals [CI]: 0.17-0.34, p < 0.001) and also significantly improved the levels of anxiety (standardized mean difference [SMD]: -1.39, 95% CI: -1.57 to 1.22, p < 0.001) and depression (SMD: -1.64, 95% CI: -2.02 to 1.26, p < 0.001) in ICU patients. This study indicates that the application of cluster nursing interventions in ICU patients can effectively reduce the incidence of PUs, as well as improve patients' anxiety and depression levels, thereby enhancing their quality of life, which is worth clinical promotion and application.

Antibacterial Activity of Plants in Cirsium: A Comprehensive Review.

As ethnic medicine, the whole grass of plants in Cirsium was used as antimicrobial. This review focuses on the antimicrobial activity of plants in Cirsium, including antimicrobial components, against different types of microbes and bacteriostatic mechanism. The results showed that the main antimicrobial activity components in Cirsium plants were flavonoids, triterpenoids and phenolic acids, and the antimicrobial ability varied according to the species and the content of chemicals. Among them, phenolic acids showed a strong antibacterial ability against Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecium. The antibacterial mechanisms include: (1) damaging the cell membrane, cell walls, mitochondria and nucleus of bacteria; (2) inhibiting the synthesis of proteins and nucleic acids; (3) suppressing the synthesis of enzymes for tricarboxylic acid cycle pathways and glycolysis, and then killing the bacteria via inhibition of energy production. Totally, most research results on antimicrobial activity of Cirsium plants are reported based on in vitro assays. The evidence from clinical data and comprehensive evaluation are needed.

The plant-like protein phosphatase PPKL regulates parasite replication and morphology in Toxoplasma gondii.

BACKGROUND: The protozoan parasite Toxoplasma gondii encodes dozens of phosphatases, among which a plant-like phosphatase absent from mammalian genomes named PPKL, which is involved in regulating brassinosteroid signaling in Arabidopsis, was identified in the genome. Among the Apicomplexa parasites, T. gondii is an important and representative pathogen in humans and animals. PPKL was previously identified to modulate the apical integrity and morphology of the ookinetes and parasite motility and transmission in another important parasite, Plasmodium falciparum. However, the exact function of PPKL in the asexual stages of T. gondii remains unknown. METHODS: The plant auxin-inducible degron (AID) system was applied to dissect the phenotypes of PPKL in T. gondii. We first analyzed the phenotypes of the AID parasites at an induction time of 24 h, by staining of different organelles using their corresponding markers. These analyses were further conducted for the parasites grown in auxin for 6 and 12 h using a quantitative approach and for the type II strain ME49 of AID parasites. To further understand the phenotypes, the potential protein interactions were analyzed using a proximity biotin labeling approach. The essential role of PPKL in parasite replication was revealed. RESULTS: PPKL is localized in the apical region and nucleus and partially distributed in the cytoplasm of the parasite. The phenotyping of PPKL showed its essentiality for parasite replication and morphology. Further dissections demonstrate that PPKL is required for the maturation of daughter parasites in the mother cells, resulting in multiple nuclei in a single parasite. The phenotype of the daughter parasites and parasite morphology were observed in another type of T. gondii strain ME49. The substantial defect in parasite replication and morphology could be rescued by genetic complementation, thus supporting its essential function for PPKL in the formation of parasites. The protein interaction analysis showed the potential interaction of PPKL with diverse proteins, thus explaining the importance of PPKL in the parasite. CONCLUSIONS: PPKL plays an important role in the formation of daughter parasites, revealing its subtle involvement in the proper maturation of the daughter parasites during division. Our detailed analysis also demonstrated that depletion of PPKL resulted in elongated tubulin fibers in the parasites. The important roles in the parasites are potentially attributed to the protein interaction mediated by kelch domains on the protein. Taken together, these findings contribute to our understanding of a key phosphatase involved in parasite replication, suggesting the potential of this phosphatase as a pharmaceutic target.

Itaconate inhibits corticosterone-induced necroptosis and neuroinflammation via up-regulating menin in HT22 cells.

Corticosterone (CORT) damages hippocampal neurons as well as induces neuroinflammation. The tricarboxylic acid cycle metabolite itaconate has an anti-inflammatory role. Necroptosis is a form of programmed cell death, also known as inflammatory cell death. Menin is a multifunctional scaffold protein, which deficiency aggravates neuroinflammation. In this study, we explored whether itaconate inhibits CORT-induced neuroinflammation as well as necroptosis and further investigated the mediatory role of Menin in this protective effect of itaconate by using an exposure of CORT to HT22 cells (a hippocampal neuronal cell line). The viability of HT22 cells was examined by the cell counting kit 8 (CCK-8). The morphology of HT22 cells was observed by transmission electron microscope (TEM). The expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) were evaluated by western blotting. The contents of inflammatory factors were detected by an enzyme-linked immunosorbent assay (ELISA) kit. Our results showed that CORT increases the contents of pro-inflammatory factors (IL-1ß, TNF-α) as well as decreases the contents of anti-inflammatory factors (IL-4, IL-10) in HT22 cells. We also found that CORT increases the expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) and decreases the cell viability in HT22 cells, indicating that CORT induces necroptosis in HT22 cells. Itaconate improves CORT-induced neuroinflammation and necroptosis. Furthermore, itaconate upregulates the expression of Menin in CORT-exposed HT22 cells. Importantly, silencing Menin abolishes the antagonistic effect of itaconate on CORT-induced necroptosis and neuroinflammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroinflammation and necroptosis via upregulating Menin.

Robust Magnetoelectric Coupling in FeTiO3/Ga2O3 Non-van der Waals Heterostructures.

Magnetoelectric coupling represents a significant breakthrough for next-generation electronics, offering the ability to achieve nonvolatile magnetic control via electrical means. In this comprehensive investigation, leveraging first-principles calculations, we unveil a robust magnetoelectric coupling within multiferroic heterostructures (HSs) by ingeniously integrating a non-van der Waals (non-vdW) magnetic FeTiO3 monolayer with the ferroelectric (FE) Ga2O3. Diverging from conventional van der Waals (vdW) multiferroic HSs, the magnetic states of the FeTiO3 monolayer can be efficiently toggled between ferromagnetic (FM) and antiferromagnetic (AFM) configurations by reversing the polarization of the Ga2O3 monolayer. This intriguing phenomenon arises from polarization-dependent substantial interlayer electron transfers and the interplay between superexchange and direct-exchange magnetic couplings of the iron atoms. The carrier-mediated interfacial interactions induce crucial shifts in Fermi level positions, decisively imparting distinct electronic characteristics near the Fermi level of composite systems. These novel findings offer exciting prospects for the future of magnetoelectric technology.