Microbial community characteristics and their influencing factors in Caragana korshinskii sand-fixing forests of different restoration years in the Mu Us Desert, China.

Soil microorganisms play a crucial role as a link between vegetation and soil nutrient cycling. However, it is unclear how vegetation and soil influence microbial community during the ecological restoration process of the Mu Us Desert. Using phospholipid fatty acid (PLFA) markers and integrating shrub, herbaceous plants, and soil factors, we explored the characteristics and regulations of soil microbial community changes. In this study, we used and took the soil after 10, 30, 50, and 70 years of Caragana korshinskii sand-fixing forest restoration, with moving dunes as a control (0 year). The results showed that the ecological restoration effect index increased significantly with the increase of recovery years. The total PLFA contents in 0, 10, 30, 50, and 70 years were 47.75, 55.89, 63.53, 67.23, and 82.29 nmol·g-1, respectively. With the increases of ecological restoration index, the biomass of fungi and bacteria, as well as the ratio of Gram-positive to Gram-negative bacteria, all showed significant increase, while the biomass of Gram-positive and Gram-negative bacterial communities, and the ratio of fungi to bacteria, demonstrated significant decrease. Shrub, herbaceous plants, and soil factors could explain 72.4% of the vari-ation of soil microbial community composition, with higher contribution of soil factors than vegetation factors. The total content of phospholipid fatty acids of soil microbial community in Mu Us Desert increased with the increases of restoration years. Soil water content, pH, total nitrogen, and soil organic carbon were the main driving factors affecting the characteristics of soil microbial community. With the increases of restoration years of C. korshinskii sand-fixation forests in the Mu Us Desert, there were significant changes in the structure of soil microbial communities, which were primarily driven by soil factors.

Influence of herbaceous litter thickness on bacterial community structure and physicochemical properties of aeolian sand.

The change and mechanism of soil and soil bacterial diversity during the change of herbaceous litter thickness in desert areas is crucial to understand. In the study, the dominant herbaceous litter mixture in Baijitan National Nature Reserve was selected as the research material, and an experiment was established by adjusting the litter depth. The results showed that the measured values of soil physicochemical factors (total nitrogen, total protein, total potassium, available phosphorus, available potassium, pH, and soil water content) increased with the increase of herbaceous litter mixture thickness in 0-5 cm soil layer. Actinobacteria, Proteobacteria, Acidobacteria, Chloroflexi, and Gemmatimonadetes were the dominant bacterial phyla under different thicknesses of herbaceous litter in 0-5 and 5-10 cm soil layers. Balneimonas, Rubrobacter, and Geodermatophilus were the dominant bacterial genera under different thicknesses of herbaceous litter in 0-5 and 5-10 cm soil layers. There was no obvious change in the α-diversity index of bacterial community the same soil layer, but the α-diversity index in the 0-5 cm soil layer was lower compared to the 5-10 cm soil layer. The results of this study revealed that the change of herbaceous litter thickness had no significant effect on soil bacterial community structure in desert areas.

Clinical Predictors of Medication Compliance in Patients With Acute Herpetic Neuralgia.

PURPOSE: Pain is one of the most common and harmful symptoms experienced by individuals with acute herpetic neuralgia (AHN). In this population, studies to determine the causes that affect patients taking medications compliance are rare. This study aimed to construct a predictive model for medication compliance of patients with AHN and to verify its performance. DESIGN AND METHODS: In this prospective study of 398 patients with AHN who were discharged from a tertiary hospital with medications from July 2020 to October 2022, we used logistic regression analysis to explore the predictive factors of medication compliance of patients with AHN and to construct a nomogram. The area under the curve was used to evaluate the predictive effect of the model. RESULTS: A predictive model of drug compliance of patients with AHN was constructed based on the following four factors: disease duration, pain severity before treatment, medication beliefs, and comorbidity of chronic diseases. The area under the curve of the model was 0.766 (95% confidence interval [0.713, 0.819]), with a maximum Youden's index of 0.431, sensitivity of 0.776, and specificity of 0.655. A linear calibration curve was found with a slope close to 1. CONCLUSIONS: The prediction model constructed in this study had good predictive performance and provided a reference for early clinical screening of independent factors that affected the medication compliance of patients with AHN.

Quantum Computation of Conical Intersections on a Programmable Superconducting Quantum Processor.

Conical intersections (CIs) are pivotal in many photochemical processes. Traditional quantum chemistry methods, such as the state-average multiconfigurational methods, face computational hurdles in solving the electronic Schrödinger equation within the active space on classical computers. While quantum computing offers a potential solution, its feasibility in studying CIs, particularly on real quantum hardware, remains largely unexplored. Here, we present the first successful realization of a hybrid quantum-classical state-average complete active space self-consistent field method based on the variational quantum eigensolver (VQE-SA-CASSCF) on a superconducting quantum processor. This approach is applied to investigate CIs in two prototypical systems─ethylene (C2H4) and triatomic hydrogen (H3). We illustrate that VQE-SA-CASSCF, coupled with ongoing hardware and algorithmic enhancements, can lead to a correct description of CIs on existing quantum devices. These results lay the groundwork for exploring the potential of quantum computing to study CIs in more complex systems in the future.

Diagnostic and Predictive Value of LncRNA MCM3AP-AS1 in Sepsis and Its Regulatory Role in Sepsis-Induced Myocardial Dysfunction.

The present study focused on exploring the clinical value and molecular mechanism of LncRNA MCM3AP antisense RNA 1 (MCM3AP-AS1) in sepsis and sepsis-induced myocardial dysfunction (SIMD). 122 sepsis patients and 90 healthy were included. Sepsis patients were categorized into SIMD and non-MD. The expression levels of MCM3AP-AS1 and miRNA were examined using RT-qPCR. Diagnostic value of MCM3AP-AS1 in sepsis assessed by ROC curves. Logistic regression to explore risk factors influencing the occurrence of SIMD. Cardiomyocytes were induced by LPS to construct cell models in vitro. CCK-8, flow cytometry, and ELISA to analyze cell viability, apoptosis, and inflammation levels. Serum MCM3AP-AS1 was upregulated in patients with sepsis. The sensitivity and specificity of MCM3AP-AS1 were 75.41% and 93.33%, for recognizing sepsis from healthy controls. Additionally, elevated MCM3AP-AS1 is a risk factor for SIMD and can predict SIMD development. Compared with the LPS-induced cardiomyocytes, inhibition of MCM3AP-AS1 significantly attenuated LPS-induced apoptosis and inflammation; however, this attenuation was partially reversed by lowered miR-28-5p, but this reversal was partially eliminated by CASP2. MCM3AP-AS1 may be a novel diagnostic biomarker for sepsis and can predict the development of SIMD. MCM3AP-AS1 probably participated in SIMD progression by regulating cardiomyocyte inflammation and apoptosis through the target miR-28-5p/CASP2 axis.

The Role of Endoscopic Ultrasound-guided Fine-needle Aspiration of Pelvic Lesions: A Meta-analysis.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a potentially valuable tool for the diagnosis of pelvic lesions. The aim of this meta­analysis was to evaluate the efficacy and feasibility of EUS-FNA in the diagnosis of pelvic lesions. METHODS: We performed a computerized search of PubMed, EMBASE, Cochrane Library, and Science Citation Index, through March 2023. The main outcome measures examined in the meta-analysis were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. RESULTS: We evaluated 22 trials that used surgical pathology or imaging follow-up results as the reference standard. The studies comprised 844 patients. The cumulative sensitivity, specificity, PPV, NPV, and accuracy were 94%, 100%, 100%, 89%, and 96%, respectively. In the subgroup analysis, the prospective studies revealed the cumulative sensitivity, specificity, PPV, NPV, and accuracy were 91%, 100%, 100%, 85%, and 93%, respectively. CONCLUSIONS: In conclusion, we provide evidence that EUS-FNA is a qualitative diagnostic technique with high sensitivity, specificity, PPV, and accuracy. However, its NPV is slightly low, which does not exclude the risk of a missed diagnosis, and more randomized controlled trials or prospective studies are still needed in the future. EUS-FNA is effective and feasible for pelvic space-occupying lesions. This technique has high clinical application value for pelvic lesions.

IFT80 promotes early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway.

Intraflagellar transport (IFT) proteins have been reported to regulate cell growth and differentiation as the essential functional component of primary cilia. The effects of IFT80 on early bone healing of extraction sockets have not been well studied. To investigate whether deletion of Ift80 in alveolar bone-derived mesenchymal stem cells (aBMSCs) affected socket bone healing, we generated a mouse model of specific knockout of Ift80 in Prx1 mesenchymal lineage cells (Prx1Cre ;IFT80f/f ). Our results demonstrated that deletion of IFT80 in Prx1 lineage cells decreased the trabecular bone volume, ALP-positive osteoblastic activity, TRAP-positive osteoclastic activity, and OSX-/COL I-/OCN-positive areas in tooth extraction sockets of Prx1Cre ; IFT80f/f mice compared with IFT80f/f littermates. Furthermore, aBMSCs from Prx1Cre ; IFT80f/f mice showed significantly decreased osteogenic markers and downregulated migration and proliferation capacity. Importantly, the overexpression of TAZ recovered significantly the expressions of osteogenic markers and migration capacity of aBMSCs. Lastly, the local administration of lentivirus for TAZ enhanced the expression of RUNX2 and OSX and promoted early bone healing of extraction sockets from Prx1Cre ; IFT80f/f mice. Thus, IFT80 promotes osteogenesis and early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway.

Single-Cell RNA Sequencing Reveals Roles of Fibroblasts During Intestinal Injury and Repair in Rats with Severe Acute Pancreatitis.

Purpose: To explore the molecular mechanisms of intestinal injury and treatment by analyzing changes in cellular heterogeneity and composition in rat ileal tissue during injury and treatment processes. Methods: We constructed a rat model of SAP and evaluated treatment with an injected of monoacylglycerol lipase (MAGL) inhibitor (JZL184) solution using three experimental groups: healthy male Sprague-Dawley (SD) rats injected with vehicle (CON), male SD SAP model rats injected with vehicle (SAP), and male SAP rats injected with JZL184. We obtained and prepared a single-cell suspension of ileal tissue of each rat for single-cell transcriptome sequencing. Results: This project classified changes in cellular heterogeneity and composition in rat ileal tissue during SAP-induced intestinal injury and MAGL treatment. We found that the number of fibroblast clusters was decreased in the SAP group relative to the CON group, and increased after JZL184 treatment. Further analysis of differences in gene expression between cell clusters in each group reveals that fibroblasts had the greatest number of differentially expressed genes. Most notably, expression of genes involved in communication between cells was found to vary during SAP-induced intestinal injury and JZL184 treatment. Among these changes, the degree of difference in expression of genes involved in communication between fibroblasts and other cells was the highest, indicating that fibroblasts in rat ileal tissue affect intestinal injury and repair through cell-to-cell communication. In addition, our results reveal that differentially expressed RNA-binding proteins in fibroblasts may affect their functions in intestinal injury and treatment by affecting the expression of genes regulating communication between cells. Conclusion: These findings emphasize the importance of understanding the interactions between fibroblasts and other cells in the context of intestinal injury, providing valuable insights for further exploring molecular mechanisms and insight for discovering new treatment targets and strategies.

Integration of transcriptomics and metabolomics analysis for unveiling the toxicological profile in the liver of mice exposed to uranium in drinking water.

Uranium is a contaminate in the underground water in many regions of the world, which poses health risks to the local populations through drinking water. Although the health hazards of natural uranium have been concerned for decades, the controversies about its detrimental effects continue at present since it is still unclear how uranium interacts with molecular regulatory networks to generate toxicity. Here, we integrate transcriptomic and metabolomic methods to unveil the molecular mechanism of lipid metabolism disorder induced by uranium. Following exposure to uranium in drinking water for twenty-eight days, aberrant lipid metabolism and lipogenesis were found in the liver, accompanied with aggravated lipid peroxidation and an increase in dead cells. Multi-omics analysis reveals that uranium can promote the biosynthesis of unsaturated fatty acids through dysregulating the metabolism of arachidonic acid (AA), linoleic acid, and glycerophospholipid. Most notably, the disordered metabolism of polyunsaturated fatty acids (PUFAs) like AA may contribute to lipid peroxidation induced by uranium, which in turn triggers ferroptosis in hepatocytes. Our findings highlight disorder of lipid metabolism as an essential toxicological mechanism of uranium in the liver, offering insight into the health risks of uranium in drinking water.

Unique microbial landscape in the human oropharynx during different types of acute respiratory tract infections.

BACKGROUND: Secondary bacterial infections and pneumonia are major mortality causes of respiratory viruses, and the disruption of the upper respiratory tract (URT) microbiota is a crucial component of this process. However, whether this URT dysbiosis associates with the viral species (in other words, is viral type-specific) is unclear. RESULTS: Here, we recruited 735 outpatients with upper respiratory symptoms, identified the infectious virus types in 349 participants using multiplex RT-PCR, and profiled their upper respiratory microbiome using the 16S ribosomal RNA gene and metagenomic gene sequencing. Microbial and viral data were subsequently used as inputs for multivariate analysis aimed at revealing viral type-specific disruption of the upper respiratory microbiota. We found that the oropharyngeal microbiota shaped by influenza A virus (FluA), influenza B virus (FluB), respiratory syncytial virus (RSV), and human rhinovirus (HRV) infections exhibited three distinct patterns of dysbiosis, and Veillonella was identified as a prominent biomarker for any type of respiratory viral infections. Influenza virus infections are significantly correlated with increased oropharynx microbiota diversity and enrichment of functional metabolic pathways such as L-arginine biosynthesis and tetracycline resistance gene tetW. We used the GRiD algorithm and found the predicted growth rate of common respiratory pathogens was increased upon influenza virus infection, while commensal bacteria, such as Streptococcus infantis and Streptococcus mitis, may act as a colonization resistance to the overgrowth of these pathogens. CONCLUSIONS: We found that respiratory viral infections are linked with viral type-specific disruption of the upper respiratory microbiota, particularly, influenza infections uniquely associated with increased microbial diversity and growth rates of specific pathogens in URT. These findings are essential for clarifying the differences and dynamics of respiratory microbiota in healthy participants and acute respiratory viral infections, which contribute to elucidating the pathogenesis of viral-host-bacterial interactions to provide insights into future studies on effective prevention and treatment of respiratory tract infections. Video Abstract.

Antimicrobial and Antibiofilm Efficacy and Mechanism of Oregano Essential Oil Against Shigella flexneri.

The aim of this study was to assess the antimicrobial activity of oregano essential oil (OEO) against Shigella flexneri and eradication efficacy of OEO on biofilm. The results showed that the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of OEO against S. flexneri were 0.02% (v/v) and 0.04% (v/v), respectively. OEO effectively killed S. flexneri in Luria-Bertani (LB) broth and contaminated minced pork (the initial population of S. flexneri was about 7.0 log CFU/mL or 7.2 log CFU/g), and after treatment with OEO at 2 MIC in LB broth or at 15 MIC in minced pork, the population of S. flexneri decreased to an undetectable level after 2 or 9 h, respectively. OEO increased intracellular reactive oxygen species concentration, destroyed cell membrane, changed cell morphology, decreased intracellular ATP concentration, caused cell membrane depolarization, and destroyed proteins or inhibited proteins synthesis of S. flexneri. In addition, OEO effectively eradicated the biofilm of S. flexneri by effectively inactivating S. flexneri in mature biofilm, destroying the three-dimensional structure, and reducing exopolysaccharide biomass of S. flexneri. In conclusion, OEO exerts its antimicrobial action effectively and also has a valid scavenging effect on the biofilm of S. flexneri. These findings suggest that OEO has the potential to be used as a natural antibacterial and antibiofilm material in the control of S. flexneri in meat product supply chain, thereby preventing meat-associated infections.

Endoscopic-Directed Trans-Gastric Retrograde Cholangiopancreatography in Patients With Roux-en-Y gastric Bypasses: A Meta-Analysis.

BACKGROUND AND AIM: Endoscopic ultrasound-directed trans-gastric retrograde cholangiopancreatography (EDGE) is a new procedure for treating pancreaticobiliary diseases in patients with Roux-en-Y gastric bypass (RYGB). The aim of this meta­analysis was to determine the overall outcomes and safety of EDGE. MATERIALS AND METHODS: We performed a computerized search of the main databases, including PubMed, EMBASE, Cochrane Library, and Science Citation Index, through October 2022. The main outcome measures examined in the meta-analysis were technical and clinical success rates and overall adverse event (AE) rate, especially the lumen-apposing metal stent (LAMS) dislodgement rate. AE rates were assessed according to LAMS size (15 vs. 20 mm), number of stages (single vs. two) and access route (gastrogastric vs. jejuno-gastric). RESULTS: Fourteen trials with a total of 574 patients who had undergone 585 EDGE procedures were included in this study. The cumulative technical and clinical success and AE rates were 98%, 94%, and 14%, respectively. The commonest AE was LAMS dislodgement (rate 4%). The overall AE rate was lower in the 20-mm LAMS than in the 15-mm LAMS group (odds ratio [OR]=5.79; 95% confidence interval [CI]: 2.35 to 14.29). There were no significant differences in AE rate between number of stages (OR=1.36; 95% CI: 0.51 to 3.64) or differing access routes (OR=1.03; 95% CI 0.48 to 2.22). CONCLUSION: We here provide evidence that EDGE for endoscopic retrograde cholangiopancreatography yields good treatment outcomes in patients with RYGBs. The AE rate is significantly lower with 20-mm versus 15-mm LAMS; thus, the former is likely preferable.

Influencing factors of early dramatic recovery of neurological function after intravenous thrombolysis in patients with branch atheromatous disease.

BACKGROUND: Intravenous thrombolysis can significantly improve the neurological function of patients with acute ischemic stroke. However, the expected early dramatic recovery (EDR) of neurological function after thrombolysis is not achieved in some patients with branch atheromatous disease (BAD). Here we evaluated the factors associated with EDR after thrombolysis in BAD patients. METHODS: We conducted a retrospective study on 580 consecutive BAD patients. All patients met the diagnostic criteria of BAD and received intravenous recombinant tissue-type plasminogen activator (rt-PA). EDR was defined when the improvement of National Institutes of Health Stroke Scale (NIHSS) score was >8 points within 2 or 24 hours after rt-PA, or the total NIHSS score was 0 or 1. The factors associated with EDR were analyzed with multivariate logistic regression analysis. RESULTS: Among 580 patients, the incidence of EDR was 35.2% (204 cases). Compared with patients without EDR, patients with EDR had lower incidence of diabetes (15.7% vs 29.3%, P < .001), lower NIHSS scores at 2 and 24 hours after rt-PA (P < .001), less cerebral hemorrhage (0% vs 5.3%, P = .001), and shorter onset to treatment time (OTT) (P < .001). Multivariate logistic regression analysis in propensity score-matched cohort showed that EDR was associated with OTT (adjusted OR = 0.994; 95% CI, 0.989-0.999) and NIHSS score after rt-PA (adjusted OR = 0.768; 95% CI, 0.663-0.890). Notably, diabetes (adjusted OR = 0.477, 95% CI, 0.234-0.972) was an independent factor related to EDR of neurological function in BAD patients. In the subgroup analysis, a lower incidence of diabetes (adjusted OR = 0.205, 95% CI: 0.059-0.714, P = .013) and a lower NIHSS score after thrombolysis in patients with paramedian pontine infarction (adjusted OR = 0.809, 95% CI: 0.656-0.997, P = .047) were significantly associated with EDR. CONCLUSION: Diabetes is not conducive to EDR of neurological function in patients with BAD, especially in patients with paramedian pontine infraction. Low NIHSS score and short OTT after thrombolysis may be closely related to EDR after intravenous thrombolysis.

Efficient encapsulation of fat-soluble food-derived biofunctional substances (curcumin as an example) in dual-modified starch-based nanoparticles containing large conjugated systems.

Acid-ethanol hydrolysis and subsequent cinnamic acid (CA) esterification were employed to prepare a series of dual-modified starches efficiently loaded with curcumin (Cur) utilizing large conjugation systems provided by CA. Structures of the dual-modified starches were confirmed by IR and NMR, and their physicochemical properties were characterized by SEM, XRD and TGA. The nanoparticles fabricated from the dual-modified starch have perfect spherical shape (250.7-448.5 nm, polydispersity index <0.3), excellent biosafety (no hematotoxicity, no cytotoxicity, no mutagenicity) and high loading of Cur (up to 26.7 % loading). By XPS analysis, this high loading was believed to be supported by the synergistic effect of hydrogen bonding (provided by hydroxyl groups) and π-π interactions (provided by large conjugation system). In addition, the encapsulation of dual-modified starch nanoparticles effectively enhanced the water solubility (18-fold) and physical stability (6-8-fold) of free Cur. In vitro gastrointestinal release showed that Cur-encapsulated dual-modified starch nanoparticles were released more preferably than free Cur and that the Korsmeyer-Peppas model was the most suitable release model. These studies suggest that dual-modified starches containing large conjugation systems would be a better alternative for encapsulating fat-soluble food-derived biofunctional substances in functional food and pharmaceutical applications.

Isoliquiritigenin regulates microglial M1/M2 polarisation by mediating the P38/MAPK pathway in cerebral stroke.

OBJECTIVES: Regulation of microglia polarisation may be a new way to treat ischaemic stroke based on its effects on brain injury. Isoliquiritigenin (ILG) is a flavonoid with neuroprotective function. The study investigated whether ILG regulated microglial polarisation and affects brain injury. METHODS: Here, a transient middle cerebral artery occlusion (tMCAO) model in vivo and lipopolysaccharide (LPS)-induced BV2 cells in vitro were established. Brain damage was assessed using a 2,3,5-triphenyl-tetrazolium-chloride staining assay. Microglial polarisation was analysed using enzyme linked immunosorbent assay, quantitative real-time polymerase chain reaction, and immunofluorescence assay. The levels of p38/MAPK pathway-related factors were measured by western blot. KEY FINDINGS: ILG suppressed infarct volume and neurological function of tMCAO rats. Moreover, ILG facilitated M2 microglia polarisation and suppressed M1 polarisation in the tMCAO model and LPS-induced BV2 cells. Moreover, ILG reduced the phosphorylation of p38, MAPK activated protein kinase 2, and heat shock protein 27 induced by LPS. Rescue study showed that activating the p38/MAPK pathway reversed the microglia polarisation induced by ILG and inactivating the p38/MAPK pathway enchanced the microglia polarisation. CONCLUSION: ILG promoted microglia M2 polarisation by inactivating the p38/MAPK pathway, suggesting that ILG has the potential for the treatment of ischaemic stroke.

Roles of glutathione peroxidase 4 on the mercury-triggered ferroptosis in renal cells: implications for the antagonism between selenium and mercury.

Understanding of how mercury species cause cellular impairments at the molecular level is critical for explaining the detrimental effects of mercury exposure on the human body. Previous studies have reported that inorganic and organic mercury compounds can induce apoptosis and necrosis in a variety of cell types, but more recent advances reveal that mercuric mercury (Hg2+) and methylmercury (CH3Hg+) may result in ferroptosis, a distinct form of programmed cell death. However, it is still unclear which protein targets are responsible for ferroptosis induced by Hg2+ and CH3Hg+. In this study, human embryonic kidney 293T cells were used to investigate how Hg2+ and CH3Hg+ trigger ferroptosis, given their nephrotoxicity. Our results demonstrate that glutathione peroxidase 4 (GPx4) plays a key role in lipid peroxidation and ferroptosis in renal cells induced by Hg2+ and CH3Hg+. The expression of GPx4, the only lipid repair enzyme in mammal cells, was downregulated in response to Hg2+ and CH3Hg+ stress. More importantly, the activity of GPx4 could be markedly inhibited by CH3Hg+, owing to the direct binding of the selenol group (-SeH) in GPx4 to CH3Hg+. Selenite supplementation was demonstrated to enhance the expression and activity of GPx4 in renal cells, and consequently relieve the cytotoxicity of CH3Hg+, suggesting that GPx4 is a crucial modulator implicated in the Hg-Se antagonism. These findings highlight the importance of GPx4 in mercury-induced ferroptosis, and provide an alternative explanation for how Hg2+ and CH3Hg+ induce cell death.

Clinical Significance of NKD Inhibitor of WNT Signaling Pathway 1 (NKD1) in Glioblastoma.

Introduction: As the most malignant type of gliomas, glioblastoma is characterized with disappointing prognosis. Here, we aimed to investigate expression and function of NKD inhibitor of Wnt signaling pathway 1 (NKD1), an antagonist of Wnt-beta-catenin signaling pathways, in glioblastoma. Methods: The mRNA level of NKD1 was firstly retrieved from TCGA glioma dataset to evaluate its correlation with clinical characteristics and its value in prognosis prediction. Then, its protein expression level in glioblastoma was tested by immunohistochemistry staining in a retrospectively cohort collected from our medical center (n = 66). Univariate and multivariate survival analyses were conducted to assess its effect on glioma prognosis. Two glioblastoma cell lines, U87 and U251, were used to further investigate the tumor-related role of NKD1 through overexpression strategy in combination with cell proliferation assays. Immune cell enrichment in glioblastoma and its correlation with NKD1 level was finally assessed using bioinformatics analyses. Results: NKD1 shows a lower expression level in glioblastoma compared to that in the normal brain or other glioma subtypes, which is independently correlated to a worse prognosis in both the TCGA cohort and our retrospective cohort. Overexpressing NKD1 in glioblastoma cell lines can significantly attenuate cell proliferation. In addition, expression of NKD1 in glioblastoma is negatively correlated to the T cell infiltration, indicating it may have crosstalk with the tumor immune microenvironment. Conclusions: NKD1 inhibits glioblastoma progression and its downregulated expression indicates a poor prognosis.

Thorium(IV) triggers ferroptosis through disrupting iron homeostasis and heme metabolism in the liver following oral ingestion.

Thorium is a byproduct of the rare earth mining industry and can be utilized as fuel for the next-generation nuclear power facilities, which may pose health risks to the population. Although published literature has shown that the toxicity of thorium possibly originates from its interactions with iron/heme-containing proteins, the underlying mechanisms are still largely unclear. Since the liver plays an irreplaceable role in iron and heme metabolism in the body, it is essential to investigate how thorium affects iron and heme homeostasis in hepatocytes. In this study, we first assessed the liver injury in mice exposed to tetravalent thorium (Th(IV)) in the form of thorium nitrite via the oral route. After a two-week oral exposure, thorium accumulation and iron overload were observed in the liver, which are both closely associated with lipid peroxidation and cell death. Transcriptomics analysis revealed that ferroptosis, which has not previously been documented in cells for actinides, is the main mechanism of programmed cell death induced by Th(IV). Further mechanistic studies suggested that Th(IV) could activate the ferroptotic pathway through disrupting iron homeostasis and generating lipid peroxides. More significantly, the disorder of heme metabolism, which is crucial for maintaining intracellular iron and redox homeostasis, was found to contribute to ferroptosis in hepatocytes exposed to Th(IV). Our findings may shed light on a key mechanism of hepatoxicity in response to Th(IV) stress and provide in-depth understanding of the health risk of thorium.

NLRP3 Regulates Mandibular Healing through Interaction with UCHL5 in MSCs.

NLRP3 has been involved in several physiological and pathological processes. However, the role and mechanism of NLRP3 activation in mandibular healing remain unclear. Here, a full-thickness mandibular defect model by osteotomy was established in wild-type (WT) and Prx1-Cre/ROSAnTnG mice to demonstrate the NLRP3 inflammasome activation in mandibular healing. We found that NLRP3 was activated in mesenchymal stem cells (MSCs)-mediated mandibular healing and was prominent in Prx1+ cells. Inhibition of NLRP3 exerted a positive effect on bone formation without changing the number of Prx1-cre+ cells in the defect areas. In addition, NLRP3 deficiency promoted osteoblast differentiation. We next screened for the deubiquitinating enzymes that were previously reported to be associated with NLRP3, and identified UCHL5 as a regulator of NLRP3 activation in mandibular healing. Mechanistically, NLRP3 directly bound to UCHL5 and maintained its stability through reducing ubiquitin-proteasome pathway degradation in mandibular MSCs. At last, UCHL5 inhibition enhanced osteoblast differentiation by promoting NLRP3 ubiquitination and degradation. Thus, our results provided the proof that NLRP3 acted as a negative modulator in mandibular healing and extended the current knowledge regarding posttranslational modification of NLRP3 by UCHL5.