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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.

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.

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.

Abstract Background Concurrent chemoradiotherapy (CCRT) is the standard of care for locally advanced cervical cancer. In this study, we analyzed the pretreatment clinical and 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) characteristics of patients with locally advanced cervical squamous cell carcinoma (SCC) to develop a scoring prototype for risk stratification. Methods Two cohorts were constructed in this study. Cohort 1 comprised patients with cervical SCC with 2009 FIGO stage III‐IVA or stage I–II with positive pelvic or para‐aortic lymph node (PALN) on PET/CT from AGOG09‐001 trial. Cohort 2 comprised patients with similar characteristics who had received adequate therapy in our hospital between 2016 and 2021. Pretreatment patient characteristics and PET/CT parameters including maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) of primary tumor and nodal SUVmax were assessed for cancer‐specific survival (CSS) using multivariate Cox regression. Results Analysis of combined data from cohorts 1 (n = 55) and 2 (n = 128) indicated age ≥ 66 years, primary tumor MTV ≥87 mL, and positive PALN on PET/CT to be independently significant adverse predictors for CSS (p

BackgroundAcute liver injury (ALI) is an important global health concern, primarily caused by widespread hepatocyte cell death, coupled with a complex immune response and a lack of effective remedies. This study explores the underlying mechanisms, immune infiltration patterns, and potential targets for intervention and treatment ALI.MethodsThe datasets of acetaminophen (APAP), carbon tetrachloride (CCl4), and lipopolysaccharide (LPS)-induced ALI were obtained from the GEO database. Differentially expressed genes (DEGs) were individually identified using the limma packages. Functional enrichment analysis was performed using KEGG, GO, and GSEA methods. The overlapping genes were extracted from the three datasets, and hub genes were identified using MCODE and CytoHubba algorithms. Additionally, PPI networks were constructed based on the String database. Immune cell infiltration analysis was conducted using ImmuCellAI, and the correlation between hub genes and immune cells was determined using the Spearman method. The relationship between hub genes, immune cells, and biochemical indicators of liver function (ALT, AST) was validated using APAP and triptolide (TP) -induced ALI mouse models.ResultsFunctional enrichment analysis indicated that all three ALI models were enriched in pathways linked to fatty acid metabolism, drug metabolism, inflammatory response, and immune regulation. Immune analysis revealed a significant rise in macrophage infiltration. A total of 79 overlapping genes were obtained, and 10 hub genes were identified that were consistent with the results of the biological information analysis after screening and validation. Among them, Clec4n, Ms4a6d, and Lilrb4 exhibited strong associations with macrophage infiltration and ALI.

DNMT1 (DNA methyltransferase 1) is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT and is involved in various diseases, including cancer and nervous system diseases. Programmed cell death (PCD) is a fundamental mechanism that regulates cell proliferation and maintains the development and homeostasis of multicellular organisms. DNMT1 plays a regulatory role in various types of PCD, including apoptosis, autophagy, necroptosis, ferroptosis, and others. DNMT1 is closely associated with the development of various diseases by regulating key genes and pathways involved in PCD, including caspase 3/7 activities in apoptosis, Beclin 1, LC3, and some autophagy-related proteins in autophagy, glutathione peroxidase 4 (GPX4) and nuclear receptor coactivator 4 (NCOA4) in ferroptosis, and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3-mixed lineage kinase domain-like protein (RIPK1-RIPK3-MLKL) in necroptosis. Our study summarizes the regulatory relationship between DNMT1 and different types of PCD in various diseases and discusses the potential of DNMT1 as a common regulatory hub in multiple types of PCD, offering a perspective for therapeutic approaches in disease.

AbstractA series of novel triazole derivatives containing aryl-propanamide side chains was designed and synthesised. In vitro antifungal activity studies demonstrated that most of the compounds inhibited the growth of six human pathogenic fungi. In particular, parts of phenyl-propionamide-containing compounds had excellent, broad-spectrum antifungal activity against Candida albicans SC5314, Cryptococcus neoformans 22-21, Candida glabrata 537 and Candida parapsilosis 22-20 with MIC values in the range of ≤0.125 µg/mL–4.0 µg/mL. In addition, compounds A1, A2, A6, A12 and A15 showed inhibitory activities against fluconazole-resistant Candida albicans and Candida auris. Preliminary structure-activity relationships (SARs) are also summarised. Moreover, GC-MS analysis demonstrated that A1, A3, and A9 interfered with the C. albicans ergosterol biosynthesis pathway by inhibiting Cyp51. Molecular docking studies elucidated the binding modes of A3 and A9 with Cyp51. These compounds with low haemolytic activity and favourable ADME/T properties are promising for the development of novel antifungal agents.

Background: We investigated whether mutations in plasma circulating tumor DNA (ctDNA) can provide prognostic insight in patients with different histological types of ovarian carcinoma. We also examined the concordance of mutations detected in ctDNA samples with those identified in the corresponding formalin-fixed paraffin-embedded (FFPE) tumor specimens. Methods: Between July 2016 and December 2017, 29 patients with ovarian carcinoma were prospectively enrolled. FFPE tumor specimens were obtained from all participants. A total of 187 blood samples for ctDNA analysis were collected before surgery (C0), immediate after surgery before adjuvant chemotherapy (C1), and at six-month intervals. Progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. Results: The study cohort consisted of 13 (44.8%) patients with high-grade serous carcinomas (HGSC), 9 (31.0%) with clear cell carcinoma, 2 (6.9%) with mucinous carcinomas, 4 (13.8%) with low-grade serous carcinomas, and 1 (3.4%) with endometrioid carcinoma. Twenty-four (82.8%) patients had at least one detectable ctDNA variant. The concordance rate between mutations identified in pretreatment ctDNA and corresponding FFPE tumor specimens was 92.3% for patients with HGSC and 58.6% for the entire cohort. The median follow-up time was 33.15 months (range: 0.79–46.13 months). Patients with an advanced stage disease more likely had detectable ctDNA mutations before surgery (C0) and after surgery at C1, while those with HGSC more likely had ctDNA mutations detected before surgery. The presence of ctDNA mutations at C1 was an independent predictor of worse OS with a hazard ratio of 6.56 (95% confidence interval, (1.07–40.17) for detectable versus undetectable C1 ctDNA variants, p = 0.042). Conclusions: ctDNA mutations are common in patients with ovarian carcinoma. The presence of ctDNA mutations after surgery was an independent predictor of less favorable PFS and OS.

Abstract Aerobic exercise effectively relieves anxiety disorders via modulating neurogenesis and neural activity. The molecular mechanism of exercise-mediated anxiolysis, however, remains incomplete. On a chronic restrain stress (CRS) model in adolescent mice, we showed that 14-day treadmill exercise profoundly maintained normal neural activity and axonal myelination in the medial prefrontal cortex (mPFC), in association with the prevention of anxiety-like behaviors. Further interrogation of molecular mechanisms revealed the activation of the mechanistic target of the rapamycin (mTOR) pathway within mPFC under exercise training. At the upstream of mTOR, exercise-mediated brain RNA methylation inhibited the expression of Fragile X mental retardation protein (FMRP) to activate the mTOR pathway. In summary, treadmill exercise modulates an FMRP–mTOR pathway to maintain cortical neural activity and axonal myelination, contributing to improved stress resilience. These results extended our understanding of the molecular substrate of exercise-mediated anxiolytic effect during adolescent period.

As a typical multiphase alloy, FGH4097 has good lasting strength (thermal stability and thermal fatigue properties), excellent wear resistance and heat resistance. It has been widely used in aerospace and other hot-end parts manufacturing fields. Most of the existing researches on the mechanical properties of FGH4097 alloy are carried out at low strain rate. There is no effective research on high temperature dynamic mechanical properties of FGH4097. Through the impact compression test of FGH4097 under different strain rates and different temperature conditions by the split Hopkinson compression bar equipment, the corresponding true stress-true strain curve was obtained, the strain rate sensitivity and temperature sensitivity of the material were analyzed. The specific heat capacity of FGH4097 alloy at different temperatures was measured by a laser thermal conductivity meter, and the adiabatic temperature rise of the alloy at different temperatures and strain rates was studied. The isothermal true stress-strain curve of the alloy was obtained by calculating the thermal softening coefficient. Two constitutive equations, Johnson-Cook and Power-Law, were introduced to fit and characterize the dynamic mechanical properties of FGH4097 alloy at different strain rates and temperatures, and the corresponding material constitutive models were obtained. Comparing the fitting accuracy of the two models, it is found that the fitting accuracy of the Power-Law model is higher, with an average error of less than 8%. The cutting simulation of FGH4097 alloy was carried out by AdvantEdge software, and the effects of strain and strain rate on the machinability of FGH4097 alloy were investigated.

Abstract Nauclea officinalis (N. officinalis), a medicinal plant of the genus Nauclea in the family Rubiaceae, is used in the treatment of fever, pneumonia, pharyngolaryngitis, and enteritis in China. Extracts of N. officinalis include alkaloids, phenolic acids, pentacyclic triterpenoids, and flavonoids, which exert all kinds of pharmacological effects, for instance anti-inflammatory, anti-tumor, antibacterial, and antiviral and therefore show good effectiveness. To gain a comprehensive and deep understanding, the medicinal chemistry and chemical biology of N. officinalis are summarized in this review to provide a theoretical basis. The pharmacological effects were reviewed to provide evidence or insights into potential opportunities for further studies and medicinal exploitation of N. officinalis.

Background: We aimed to develop and validate a preoperative CT-based radiomics signature for differentiating lymphoma versus benign splenomegaly. Methods: We retrospectively analyzed CT studies from 139 patients (age range 26–93 years, 43% female) between 2011 and 2019 with histopathological diagnosis of the spleen (19 lymphoma, 120 benign) and divided them into developing (n = 79) and testing (n = 60) datasets. The volumetric radiomic features were extracted from manual segmentation of the whole spleen on venous-phase CT imaging using PyRadiomics package. LASSO regression was applied for feature selection and development of the radiomic signature, which was interrogated with the complete blood cell count and differential count. All p values < 0.05 were considered to be significant. Results: Seven features were selected for constructing the radiomic signature after feature selection, including first-order statistics (10th percentile and Robust Mean Absolute Deviation), shape-based (Surface Area), and texture features (Correlation, MCC, Small Area Low Gray-level Emphasis and Low Gray-level Zone Emphasis). The radiomic signature achieved an excellent diagnostic accuracy of 97%, sensitivity of 89%, and specificity of 98%, distinguishing lymphoma versus benign splenomegaly in the testing dataset. The radiomic signature significantly correlated with the platelet and segmented neutrophil percentage. Conclusions: CT-based radiomics signature can be useful in distinguishing lymphoma versus benign splenomegaly and can reflect the changes in underlying blood profiles.