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Abstract Background and purpose Radiomics offers little explainability. This study aims to develop a radiomics model (Rad-Score) using diffusion-weighted imaging (DWI) to predict high-risk patients for nodal metastasis or recurrence in endometrial cancer (EC) and corroborate with choline metabolism. Materials and methods From August 2015 to July 2018, 356 EC patients were enrolled. Rad-Score was developed using LASSO regression in a training cohort (n = 287) and validated in an independent test cohort (n = 69). MR spectroscopy (MRS) was also used in 230 patients. Nuclear MRS measured choline metabolites in 70 tissue samples. The performance was compared against European Society for Medical Oncology (ESMO) risk groups. A P

Abstract The transition between yeast and hyphae is crucial for regulating the commensalism and pathogenicity in Candida albicans. The mechanisms that affect the invasion of hyphae in solid media, whose deficiency is more related to the pathogenicity of C. albicans, have not been elucidated. Here, we found that the disruption of VAM6 or VPS41 which are components of the homotypic vacuolar fusion and protein sorting (HOPS) complex, or the Rab GTPase YPT72, all responsible for vacuole fusion, led to defects in hyphal growth in both liquid and solid media, but more pronounced on solid agar. The phenotypes of vac8Δ/Δ and GTR1 OE-vam6Δ/Δ mutants indicated that these deficiencies are mainly caused by the reduced mechanical forces that drive agar and organs penetration, and confirmed that large vacuoles are required for hyphal mechanical penetration. In summary, our study revealed that large vacuoles generated by vacuolar fusion support hyphal penetration and provided a perspective to refocus attention on the role of solid agar in evaluating C. albicans invasion.

Abstract Chronic stress induces anxiety disorders via both neural pathways and circulating factors. Although many studies have elucidated the neural circuits involved in stress-coping behaviors, the origin and regulatory mechanism of peripheral cytokines in behavioural regulation under stress conditions are not fully understood. Here, we identified a serum cytokine, lipocalin 2 (LCN2), that was upregulated in participants with anxiety disorders. Using a mouse model of chronic restraint stress (CRS), circulating LCN2 was found to be related to stress-induced anxiety-like behaviour via modulation of neural activity in the medial prefrontal cortex (mPFC). These results suggest that stress increases hepatic LCN2 via a neural pathway, leading to disrupted cortical functions and behaviour.

Triptolide (TP), a diterpene from Tripterygium wilfordii, exhibits potent anti-inflammatory, immunomodulatory, and antitumor properties but is limited by severe hepatotoxicity. This study investigates sex differences in TP-induced liver injury and the protective role of estradiol (E2) in modulating macrophage-mediated inflammation and hepatocyte function. An acute liver injury model was established in male and female Balb/c mice using intraperitoneal TP injection. Liver function tests, histological analyses, and immunohistochemical staining were performed. THP-1 macrophage and various liver cell lines were used to study the effects of TP and E2 in vitro. Virtual screening, molecular docking, luciferase assays, and qPCR were employed to identify potential targets and elucidate underlying mechanisms. TP caused more severe liver injury in female mice, evidenced by increased liver indices, aspartate aminotransferase (AST) levels, and extensive hepatocyte damage. TP promoted M1 macrophage polarization, enhancing inflammation, particularly in female mice. E2 mitigated TP-induced inflammatory responses by downregulating pro-inflammatory cytokines and macrophage activation markers. Molecular docking and functional assays identified Nuclear receptor subfamily 1 group I member 2 (NR1I2) as a key target mediating the protective effects of E2. The study highlights significant sex differences in TP-induced hepatotoxicity, with females being more susceptible. E2 exerts protective effects against TP-induced liver injury by modulating immune responses, presenting a potential therapeutic approach to mitigate drug-induced liver injury (DILI). Further research on NR1I2 could lead to targeted therapies for reducing drug-induced liver damage.

BackgroundMaternal exposure to inflammation is one of the causes of autism spectrum disorder (ASD). Electrical stimulation of the vagus nerve exerts a neuroprotective effect via its anti-inflammatory action. We thus investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) can enhance social abilities in a mouse model of ASD induced by maternal immune activation (MIA).MethodsASD mouse model were constructed by intraperitoneal injection of polyinosinic:polycytidylic acid (poly (I:C)). TaVNS with different parameters were tested in ASD mouse model and in C57BL/6 mice, then various behavioral tests and biochemical analyses related to autism were conducted. ASD model mice were injected with an interleukin (IL)-17a antibody into the brain, followed by behavioral testing and biochemical analyses.ResultsTaVNS reduced anxiety, improved social function, decreased the number of microglia, and inhibited M1 polarization of microglia. Additionally, taVNS attenuated the expression of the IL-17a protein in the prefrontal cortex and blood of ASD model mice. To examine the possible involvement of IL-17a in taVNS-induced neuroprotection, we injected an IL-17a antibody into the prefrontal cortex of ASD model mice and found that neutralizing IL-17a decreased the number of microglia and inhibited M1 polarization. Furthermore, neutralizing IL-17a improved social function in autism model mice.ConclusionOur study revealed that reduced neuroinflammation is an important mechanism of taVNS-mediated social improvement and neuroprotection against autism. This effect of taVNS could be attributed to the inhibition of the IL-17a pathway.

The accuracy of the cutting simulation model greatly depends on the constitutive models, thermophysical models, and friction models. However, accurate modeling of physical and mechanical relationships is not enough. The physical and mechanical behavior of the machined surface from the last cut should be modelled in the FE model. In this study, the cutting simulation model of S316L stainless steel was established. The above model consists of two subsequent simulated cuts. The first simulated cut was used to obtain the machined surface with the residual stress, and the second simulated cut was subsequent with the first cut to obtain the actual simulated results. The constitutive model was obtained by the split Hopkinson pressure bar (SHPB) and high-temperature hardness experiments. The specific heat capacity and thermal conductivity models were developed by laser thermal conductivity experiments with various temperatures. The friction model between the workpiece and the tool was established by orthogonal cutting experiments. The simulated cutting forces of the first and second cut were extracted and compared with the experimental results to verify the accuracy of the simulation models. The results showed that the average error of cutting forces for the first cut is 28.33 %, but that for the second cut is 8.02 %, which verifies the accuracy of the two-subsequent cutting simulation model. Additionally, the significant differences in the simulated cutting forces between the first and second cutting depict that the residual stress cannot be ignored for the accuracy verification of cutting simulation models.

The failure mechanism and size effect during the quasi-static and dynamic shear tests of hat-shaped specimens were investigated in this study. Three types of specimens with different shear ring thicknesses (800, 400, and 50 μm) were designed. Quasi-static tests were carried out using an electronic universal testing machine, while dynamic impact tests were carried out using split Hopkinson pressure bar (SHPB) tests. The adiabatic temperature rises with different strain rates, and the shear ring thickness was calculated. We found that the adiabatic temperature rises of the specimens with shear ring thicknesses of 800 and 400 μm were much larger than those of the specimens with shear ring thicknesses of 50 μm. The failure surfaces after the SHPB test were investigated via scanning electron microscopy, and the failure surfaces after the SHPB test could be divided into three zones: tensile, shear, and impact zones. The effect of the shear ring thickness and impact speed on the failure surface morphology was discussed. The typical shear stress–strain curves could be divided into three sections: elastic, plastic rise, and plastic plateau sections. Subsequently, a modified Johnson–Cook constitutive model was employed to fit the shear stress–strain results, and the fitted curves showed good agreement with the tested curves.

Transforming growth factor-β (TGF-β) and programmed death ligand 1 (PD-L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF-β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial-to-mesenchymal transition, and angiogenesis. Meanwhile, PD-L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti-PD-L1 therapies have been approved for the treatment of various cancers, but TGF-β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF-β and PD-L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual-targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual-targeting agent is bintrafusp alfa. This drug is a first-in-class bifunctional fusion protein that consists of the extracellular domain of the TGF-βRII receptor (a TGF-β 'trap') fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD-L1. Given the immunosuppressive effects of the TGF-β and PD-L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.

Triptolide (TP) has various pharmacological activities, but its hepatotoxicity limits its therapeutic potential. Licorice has been evaluated to harmonize various medicines, and its active ingredient glycyrrhizic acid (GA) has been identified for its detoxification effect. In this study, we demonstrated that the combination of GA and TP (G&T) could mitigate TP-induced hepatotoxicity. To explore TP toxicity and G&T detoxification mechanisms, transcriptomics and proteomics have been utilized. TP was found to promote the expression of PKCα and FIS1, accompanied by an increase in mitochondrial fission. After pretreatment with GA, improvements were observed in TP-induced mitochondrial fission, as well as the expression of active-caspase3, and cytochrome c release. Silencing PKCα and FIS1 has a similar effect to GA on the regulation of mitochondria-dependent apoptosis and mitochondrial fission. In conclusion, PKCα and FIS1-involved mitochondrial dynamic regulation is associated with TP-induced hepatotoxicity. The G&T combination may be an effective strategy for ameliorating TP-induced toxicity.