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Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Erastin, the ferroptosis activator, binds to voltage-dependent anion channels VDAC2 and VDCA3, but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels. Depletion of Nedd4 limits the protein degradation of VDAC2/3, which increases the sensitivity of cancer cells to erastin. By understanding the molecular mechanism of erastin-induced cellular resistance, we can discover how cells adapt to new molecules to maintain homeostasis. Furthermore, erastin-induced resistance mediated by FOXM1-Nedd4-VDAC2/3 negative feedback loop provides an initial framework for creating avenues to overcome the drug resistance of ferroptosis activators. Erastin, the ferroptosis activator, binds to voltage gated ion channels CDAC2 and VDCA3 but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels.

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe acute respiratory failure and considerable extrapumonary organ dysfuction with substantial high mortality. For the limited number of autopsy reports, small animal models are urgently needed to study the mechanisms of MERS-CoV infection and pathogenesis of the disease and to evaluate the efficacy of therapeutics against MERS-CoV infection. In this study, we developed a transgenic mouse model globally expressing codon-optimized human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV. After intranasal inoculation with MERS-CoV, the mice rapidly developed severe pneumonia and multi-organ damage, with viral replication being detected in the lungs on day 5 and in the lungs, kidneys and brains on day 9 post-infection. In addition, the mice exhibited systemic inflammation with mild to severe pneumonia accompanied by the injury of liver, kidney and spleen with neutrophil and macrophage infiltration. Importantly, the mice exhibited symptoms of paralysis with high viral burden and viral positive neurons on day 9. Taken together, this study characterizes the tropism of MERS-CoV upon infection. Importantly, this hDPP4-expressing transgenic mouse model will be applicable for studying the pathogenesis of MERS-CoV infection and investigating the efficacy of vaccines and antiviral agents designed to combat MERS-CoV infection.

Background Pulmonary artery stenosis (PAS) is a major cause of pulmonary hypertension (PH). The advancement of non-invasive biomarkers to identify PAS in high-risk individuals has the potential to enhance the precision of clinical evaluations related to PH. This study aimed to present evidence that gene expression data within blood platelets could be valuable for detecting PAS in patients with PH. Methods Platelets were isolated from 241 PH patients and 98 healthy controls for RNA sequencing. Differentially expressed genes (DEGs) were identified between PAS and non-PAS, and between chronic thromboembolic pulmonary hypertension (CTEPH) and PH caused by fibrosing mediastinitis (FM-PH). Three machine learning algorithms—random forest (RF), extreme gradient boosting (XGBoost), and Boruta—were applied to select platelet genes of discriminative capability. Genes identified by all three algorithms were used for subsequent model construction. Fourteen predictive models were trained and validated using repeated fivefold cross-validation. Functional enrichment and gene set enrichment analyses (GSEA) were performed. Results Compared with the non-PAS group, PH patients with PAS exhibited 244 upregulated and 1,051 downregulated genes in platelets. GSEA revealed upregulation of pathways including platelet activation, fluid shear stress and atherosclerosis, and Rap1 signaling, alongside downregulation of PI3K-Akt and mTOR signaling in patients with PAS. Six platelet RNAs were identified by RF, XGBoost, and Boruta for differentiating PAS from non-PAS. The RF model, with NOTCH1 contributing most significantly (highest mean decrease in Gini index), achieved the highest area under the curves (AUCs) of 0.946, 0.862, and 0.749 in the training, internal, and external validation sets, respectively. Within PAS, 669 genes were upregulated and 697 downregulated in CTEPH versus FM-PH. Pathways including vascular smooth muscle contraction and blood vessel remodeling were positively enriched in platelets from patients with CTEPH compared to FM-PH. Two genes, PPP1CA and MAPRE1, were shared across all three feature selection algorithms for discriminating between CTEPH and FM-PH. The RF model based on these genes achieved the highest AUCs of 0.960, 0.925, and 0.961 across the training, internal, and external validation sets. Conclusions Platelet-derived biomarkers are potentially useful in identifying PAS and differentiating its subtypes in individuals with PH.

Background Trigeminal neuralgia (TN) is a debilitating orofacial pain disorder characterized by paroxysmal, lancinating pain and prominent affective comorbidities. Increasing evidence suggests that chronic TN involves abnormal plasticity in supraspinal pain circuits. However, the lack of animal models that faithfully recapitulate key clinical features of TN has limited mechanistic investigations of these central processes. Here, building upon our previously established foramen lacerum impingement of the trigeminal nerve root (FLIT) model, we developed an improved glass bead-based version (FLIT-B) that enables reproducible and controlled compression of the trigeminal nerve root and facilitates investigation of supraspinal mechanisms in TN. Methods In the FLIT-B model, calibrated glass beads were implanted through the foramen lacerum to compress the trigeminal nerve root. Behavioral assays were used to assess sensory and affective phenotypes, while histological analyses evaluated trigeminal nerve pathology. To examine supraspinal circuit alterations, neuronal activation in the primary somatosensory barrel field (S1BF), anterior cingulate cortex (ACC), amygdala, and hippocampus was assessed using c-Fos immunostaining. Structural and functional changes in excitatory neurons, particularly in the ACC, were further analyzed using AAV-mediated labeling, in vivo fiber photometry, and two-photon calcium imaging in both sham and FLIT-B mice. Results FLIT-B mice exhibited spontaneous pain-like behaviors, including asymmetric facial grimacing and peri-orbital hair loss associated with excessive grooming, suggesting persistent orofacial discomfort. Histological analyses confirmed consistent trigeminal nerve root demyelination. c-Fos staining and calcium imaging revealed widespread activation of the S1BF, ACC, amygdala, and hippocampus, with the ACC showing the highest degree of activation, particularly in spontaneous activity patterns. Morphological analyses demonstrated significant dendritic remodeling in excitatory neurons of the ACC and S1BF. Chemogenetic inhibition of ACC excitatory neurons significantly alleviated both pain-like and anxiety-like behaviors. Conclusions The FLIT-B model provides a reproducible and clinically relevant rodent model of TN by compression of the trigeminal nerve root at an anatomically relevant site. Using this model, we identify ACC-centered structural and functional plasticity as a key supraspinal substrate linking chronic trigeminal pain to affective disturbances.

Coking coal was extracted with tetrahydrofuran solvent using ultrasonic and microwave-assisted method at 50°C and atmospheric pressure. Wettability of raw coal and its residue (residual coal) was tested with capillary penetration method. The raw and residual coals were studied by Fourier transform infrared spectroscopy (FTIR) with curve-fitting analysis. The variation of main surface functional groups of coking coal before and after extraction and its effect on wettability were analyzed. The results were obtained as the following: after extraction with tetrahydrofuran, hydroxyl, ether oxygen, and carbonyl in the coal structure were dissolved, the content of hydrophilic functional groups reduced, and then the hydrophobicity of coal enhanced. At the same time, part of aliphatic hydrocarbon dissolved, the length of aliphatic chains (I2) decreased from 3.961 of raw coal to 3.636 of residual coal, the length of aliphatic chains became shorter, aliphatic CH2 side-chains decreased and aliphatic CH3 side-chains increased, and hydrophobic functional groups content increased. In the aromatic structure, four hydrogens per ring increased and two, three, and five hydrogens per ring decreased. Reduction of substitution functional groups and aliphatic hydrocarbon decreased with the side-chains breakage produce more active sites, which increases the degree of condensation of the aromatic ring (I3). The combined action of the decrease of the hydrophilic functional groups and the increase of the hydrophobic functional groups made the wettability of the coking coal become weak.

Expansive soil is widely distributed and often needs to be improved for engineering and construction needs. Using blast furnace slag and fly ash as precursors and NaOH as an alkali activator, a geopolymer was prepared to solidify expansive soil, and the effect of nano-SiO2 on the compressive strength and water stability of the geopolymer-solidified expansive soil was further studied. The effects of alkali addition ratio, nano-SiO2 addition ratio, and curing agent addition ratio on the unconfined compressive strength and water stability of the cured soil were studied through unconfined compressive strength tests, and the curing mechanism was analyzed by electron microscopy scanning. The experimental results showed that the unconfined compressive strength and water stability of geopolymer-stabilized soil first increased and then decreased with an increase in alkali activator dosage. The optimal dosage of alkali activator was found to be 12.5%. Furthermore, it was found that adding nano-SiO2 can further enhance the strength and water stability of solidified soil. When the content of nano-SiO2 was 3%, the unconfined compressive strength was increased by 15%. With an increase in the content of nano-SiO2 doped polymer (GFNS), the unconfined compressive strength and water stability of the solidified soil showed a trend of first increasing and then decreasing, reaching a peak at a content of 20%. The cementitious materials, such as hydrated calcium silicate and hydrated calcium silicate aluminate, generated by the reaction between nano-SiO2 and geopolymer played a role in bonding and filling in the solidified soil. Under the joint action of the two, the structural arrangement between the solidified soil particles became more compact, which improved the strength of the solidified soil.

Avian influenza A/H7N9 virus infection causes pneumonia in humans with a high case fatality rate. However, virus-induced modulation of immune responses is being recognized increasingly as a factor in the pathogenesis of this disease. In this study, we compared the pathogenicity of A/H7N9 infection in BALB/c and C57BL/6 mouse models, and investigated the putative involvement of proinflammatory cytokines in lung injury and viral clearance. In both mouse strains, A/Anhui/1/2013(H7N9) infection with 10(6) TCID50 resulted in viral replication in lung, severe body weight loss and acute lung injury. During the early infection stage, infected C57BL/6 mice exhibited more severe lung injury, slower recovery from lung damage, less effective viral clearance, higher levels of interlukine (IL)-6, monocyte chemotactic protein (MCP)-1, and IL-1β, and lower levels of tumor necrosis factor (TNF)-α and interferon (IFN)-γ than infected BALB/c mice. These results suggest that TNF-α and IFN-γ may help suppress viral gene expression and increase viral clearance, and that IL-6 and MCP-1 may contribute to lung injury in A/H7N9-infected individuals. In addition, lung damage and the distribution of virus antigen in tissues were similar in young and middle-aged mice. These results suggest that the more serious lung injury in middle-aged or older H7N9 cases is not mainly caused by differences in viral replication in the lung but probably by a dysregulated immune response induced by underlying comorbidities. These results indicate that the extent of dysregulation of the host immune response after H7N9 virus infection most probably determines the outcome of H7N9 virus infection.

With the epidemic of betacoronavirus increasing frequently, it poses a great threat to human public health. Therefore, the research on the pathogenic mechanism of betacoronavirus is becoming greatly important. Murine hepatitis virus strain-3 (MHV-3) is a strain of betacoronavirus which cause tissue damage especially fulminant hepatic failure (FHF) in mice, and is commonly used to establish models of acute liver injury. Recently, MHV-3-infected mice have also been introduced to a mouse model of COVID-19 that does not require a Biosafety Level 3 (BSL-3) facility. FHF induced by MHV-3 is a type of severe liver damage imbalanced by regenerative hepatocellular activity, which is related to numerous factors. The complement system plays an important role in host defense and inflammation and is involved in first-line immunity and/or pathogenesis of severe organ disorders. In this study, we investigated the role of aberrant complement activation in MHV-3 infection-induced FHF by strategies that use C3-deficient mice and intervene in the complement system. Our results showed that mice deficient in C3 had more severe liver damage, a higher viral load in the liver and higher serum concentrations of inflammatory cytokines than wild-type controls. Treatment of C57BL/6 mice with C3aR antagonist or anti-C5aR antibody reduced liver damage, viral load, and serum IFN-γ concentration compared with the control group. These findings indicated that complement system acts as a double-edged sword during acute MHV-3 infection. However, its dysregulated activation leads to sustained inflammatory responses and induces extensive liver damage. Collectively, by investigating the role of complement activation in MHV-3 infection, we can further understand the pathogenic mechanism of betacoronavirus, and appropriate regulation of immune responses by fine-tuning complement activation may be an intervention for the treatment of diseases induced by betacoronavirus infection.

Ferroptosis is a regulated form of cell death driven by small molecules or conditions that induce lipid-based reactive oxygen species (ROS) accumulation. This form of iron-dependent cell death is morphologically and genetically distinct from apoptosis, necroptosis, and autophagy. miRNAs are known to play crucial roles in diverse fundamental biological processes. However, to date no study has reported miRNA-mediated regulation of ferroptosis. Here we show that miR-137 negatively regulates ferroptosis by directly targeting glutamine transporter SLC1A5 in melanoma cells. Ectopic expression of miR-137 suppressed SLC1A5, resulting in decreased glutamine uptake and malondialdehyde (MDA) accumulation. Meanwhile, antagomir-mediated inactivation of endogenous miR-137 increased the sensitivity of melanoma cells to erastin- and RSL3-induced ferroptosis. Importantly, knockdown of miR-137 increased the antitumor activity of erastin by enhancing ferroptosis both in vitro and in vivo. Collectively, these data indicate that miR-137 plays a novel and indispensable role in ferroptosis by inhibiting glutaminolysis and suggest a potential therapeutic approach for melanoma.