MARCH8 Mediates K27-Linked Polyubiquitination of IL-7 Receptor α to Negatively Regulate IL-7-Triggered T Cell Homeostasis.

IL-7 is a cytokine produced by stromal cells, which binds to IL-7Rα and plays an important role for homeostasis of T lymphocytes. Excessive activities of IL-7-triggered signaling pathways causes autoimmune diseases. How IL-7-triggered signaling and immune effects are regulated is not fully understood. In this study, we show that the membrane-associated RING-CH (MARCH) E3 ligase family member MARCH8 mediates K27-linked polyubiquitination of IL-7Rα, leading to its lysosomal degradation. Site-directed mutagenesis suggests that MARCH8 meditates polyubiquitination of IL-7Rα at K265/K266, and mutation of these residues renders IL-7Rα resistance to MARCH8-mediated polyubiquitination and degradation. MARCH8 deficiency increases IL-7-triggered activation of the downstream transcription factor STAT5 and transcriptional induction of the effector genes in human T lymphoma cells. MARCH8 deficiency also promotes IL-7-triggered T cell proliferation and splenic memory CD8+ T cell differentiation in mice. Our findings suggest that MARCH8 negatively regulates IL-7-triggered signaling by mediating K27-linked polyubiquitination and lysosomal degradation of IL-7Rα, which reveals a negative regulatory mechanism of IL-7-triggered T cell homeostasis.

Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood-brain barrier.

The human blood-brain barrier (BBB) comprises a single layer of brain microvascular endothelial cells (HBMECs) protecting the brain from bloodborne pathogens. Meningitis is among the most serious diseases, but the mechanisms by which major meningitis-causing bacterial pathogens cross the BBB to reach the brain remain poorly understood. We found that Streptococcus pneumoniae, group B Streptococcus, and neonatal meningitis Escherichia coli commonly exploit a unique vesicle fusion mechanism to hitchhike on transferrin receptor (TfR) transcytosis to cross the BBB and illustrated the details of this process in human BBB model in vitro and mouse model. Toll-like receptor signals emanating from bacteria-containing vesicles (BCVs) trigger K33-linked polyubiquitination at Lys168 and Lys181 of the innate immune regulator TRAF3 and then activate the formation of a protein complex containing the guanine nucleotide exchange factor RCC2, the small GTPase RalA and exocyst subcomplex I (SC I) on BCVs. The distinct function of SEC6 in SC I, interacting directly with RalA on BCVs and the SNARE protein SNAP23 on TfR vesicles, tethers these two vesicles and initiates the fusion. Our results reveal that innate immunity triggers a unique modification of TRAF3 and the formation of the HBMEC-specific protein complex on BCVs to authenticate the precise recognition and selection of TfR vesicles to fuse with and facilitate bacterial penetration of the BBB.

Protist ubiquitin ligase effector PbE3-2 targets cysteine protease RD21A to impede plant immunity.

Clubroot, caused by the soil-borne protist pathogen Plasmodiophora brassicae, is one of the most devastating diseases of Brassica oil and vegetable crops worldwide. Understanding the pathogen infection strategy is crucial for the development of disease control. However, because of its obligate biotrophic nature, the molecular mechanism by which this pathogen promotes infection remains largely unknown. P. brassicae E3 ubiquitin ligase 2 (PbE3-2) is a Really Interesting New Gene (RING)-type E3 ubiquitin ligase in P. brassicae with E3 ligase activity in vitro. Yeast (Saccharomyces cerevisiae) invertase assay and apoplast washing fluid extraction showed that PbE3-2 harbors a functional signal peptide. Overexpression of PbE3-2 in Arabidopsis (Arabidopsis thaliana) resulted in higher susceptibility to P. brassicae and decreases in chitin-triggered reactive oxygen species burst and expression of marker genes in salicylic acid signaling. PbE3-2 interacted with and ubiquitinated host cysteine protease RESPONSIVE TO DEHYDRATION 21A (RD21A) in vitro and in vivo. Mutant plants deficient in RD21A exhibited similar susceptibility and compromised immune responses as in PbE3-2 overexpression plants. We show that PbE3-2, which targets RD21A, is an important virulence factor for P. brassicae. Two other secretory RING-type E3 ubiquitin ligases in P. brassicae performed the same function as PbE3-2 and ubiquitinated RD21A. This study reveals a substantial virulence functional role of protist E3 ubiquitin ligases and demonstrates a mechanism by which protist E3 ubiquitin ligases degrade host immune-associated cysteine proteases to impede host immunity.

Escherichia coli O157:H7 senses microbiota-produced riboflavin to increase its virulence in the gut.

Riboflavin is produced by most commensal bacteria in the human colon, where enterohemorrhagic Escherichia coli (EHEC) colonizes and causes diseases. Sensing environmental signals to site-specifically express the type-III secretion system (T3SS), which injects effectors into host cells leading to intestinal colonization and disease, is key to the pathogenesis of EHEC. Here, we reveal that EHEC O157:H7, a dominant EHEC serotype frequently associated with severe diseases, acquired a previously uncharacterized two-component regulatory system rbfSR, which senses microbiota-produced riboflavin to directly activate the expression of LEE genes encoding the T3SS in the colon. rbfSR is present in O157:H7 and O145:H28 but absent from other EHEC serotypes. The binding site of RbfR through which it regulates LEE gene expression was identified and is conserved in all EHEC serotypes and Citrobacter rodentium, a surrogate for EHEC in mice. Introducing rbfSR into C. rodentium enabled bacteria to sense microbiota-produced riboflavin in the mouse colon to increase the expression of LEE genes, causing increased disease severity in mice. Phylogenic analysis showed that the O55:H7 ancestor of O157:H7 obtained rbfSR which has been kept in O157:H7 since then. Thus, acquiring rbfSR represents an essential step in the evolution of the highly pathogenic O157:H7. The expression of LEE genes and cell attachment ability of other EHEC serotypes in the presence of riboflavin significantly increased when rbfSR was introduced into them, indicating that those serotypes are ready to use RbfSR to increase their pathogenicity. This may present a potential public health issue as horizontal gene transfer is frequent in enteric bacteria.

Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2.

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key enzyme, which extensively digests CoV replicase polyproteins essential for viral replication and transcription, making it an attractive target for antiviral drug development. However, the molecular mechanism of how Mpro of SARS-CoV-2 digests replicase polyproteins, releasing the nonstructural proteins (nsps), and its substrate specificity remain largely unknown. Here, we determine the high-resolution structures of SARS-CoV-2 Mpro in its resting state, precleavage state, and postcleavage state, constituting a full cycle of substrate cleavage. The structures show the delicate conformational changes that occur during polyprotein processing. Further, we solve the structures of the SARS-CoV-2 Mpro mutant (H41A) in complex with six native cleavage substrates from replicase polyproteins, and demonstrate that SARS-CoV-2 Mpro can recognize sequences as long as 10 residues but only have special selectivity for four subsites. These structural data provide a basis to develop potent new inhibitors against SARS-CoV-2.

Characterizing advanced heart failure risk and hemodynamic phenotypes using interpretable machine learning.

BACKGROUND: Although previous risk models exist for advanced heart failure with reduced ejection fraction (HFrEF), few integrate invasive hemodynamics or support missing data. This study developed and validated a heart failure (HF) hemodynamic risk and phenotyping score for HFrEF, using Machine Learning (ML). METHODS: Prior to modeling, patients in training and validation HF cohorts were assigned to 1 of 5 risk categories based on the composite endpoint of death, left ventricular assist device (LVAD) implantation or transplantation (DeLvTx), and rehospitalization in 6 months of follow-up using unsupervised clustering. The goal of our novel interpretable ML modeling approach, which is robust to missing data, was to predict this risk category (1, 2, 3, 4, or 5) using either invasive hemodynamics alone or a rich and inclusive feature set that included noninvasive hemodynamics (all features). The models were trained using the ESCAPE trial and validated using 4 advanced HF patient cohorts collected from previous trials, then compared with traditional ML models. Prediction accuracy for each of these 5 categories was determined separately for each risk category to generate 5 areas under the curve (AUCs, or C-statistics) for belonging to risk category 1, 2, 3, 4, or 5, respectively. RESULTS: Across all outcomes, our models performed well for predicting the risk category for each patient. Accuracies of 5 separate models predicting a patient's risk category ranged from 0.896 +/- 0.074 to 0.969 +/- 0.081 for the invasive hemodynamics feature set and 0.858 +/- 0.067 to 0.997 +/- 0.070 for the all features feature set. CONCLUSION: Novel interpretable ML models predicted risk categories with a high degree of accuracy. This approach offers a new paradigm for risk stratification that differs from prediction of a binary outcome. Prospective clinical evaluation of this approach is indicated to determine utility for selecting the best treatment approach for patients based on risk and prognosis.

SETDB1: Progress and prospects in cancer treatment potential and inhibitor research.

SET domain bifurcated methyltransferase 1 (SETDB1) serves as a histone lysine methyltransferase, catalyzing the di- and tri-methylation of histone H3K9. Mounting evidence indicates that the abnormal expression or activity of SETDB1, either through amplification or mutation, plays a crucial role in tumorigenesis and progression. This is particularly evident in the context of tumor immune evasion and resistance to immune checkpoint blockade therapy. Furthermore, there is a robust association between SETDB1 dysregulation and an unfavorable prognosis across various types of tumors. The oncogenic role of SETDB1 primarily arises from its methyltransferase function, which contributes to the establishment of a condensed and transcriptionally inactive heterochromatin state. This results in the inactivation of genes that typically hinder cancer development and silencing of retrotransposons that could potentially trigger an immune response. These findings underscore the substantial potential for SETDB1 as an anti-tumor therapeutic target. Nevertheless, despite significant strides in recent years in tumor biology research, challenges persist in SETDB1-targeted therapy. To better facilitate the development of anti-tumor therapy targeting SETDB1, we have conducted a comprehensive review of SETDB1 in this account. We present the structure and function of SETDB1, its role in various tumors and immune regulation, as well as the advancements made in SETDB1 antagonists. Furthermore, we discuss the challenges encountered and provide perspectives for the development of SETDB1-targeted anti-tumor therapy.

Epitope mapping and establishment of a blocking ELISA for mAb targeting the p72 protein of African swine fever virus.

The African swine fever virus (ASFV) has the ability to infect pigs and cause a highly contagious acute fever that can result in a mortality rate as high as 100%. Due to the viral epidemic, the pig industry worldwide has suffered significant financial setbacks. The absence of a proven vaccine for ASFV necessitates the development of a sensitive and reliable serological diagnostic method, enabling laboratories to effectively and expeditiously detect ASFV infection. In this study, four strains of monoclonal antibodies (mAbs) against p72, namely, 5A1, 4C4, 8A9, and 5E10, were generated through recombinant expression of p72, the main capsid protein of ASFV, and immunized mice with it. Epitope localization was performed by truncated overlapping polypeptides. The results indicate that 5A1 and 4C4 recognized the amino acid 20-39 aa, 8A9 and 5E10 are recognized at 263-282 aa, which is consistent with the reported 265-280 aa epitopes. Conserved analysis revealed 20-39 aa is a high conservation of the epitopes in the ASFV genotypes. Moreover, a blocking ELISA assay for detection ASFV antibody based on 4C4 monoclonal antibody was developed and assessed. The receiver-operating characteristic (ROC) was performed to identify the best threshold value using 87 negative and 67 positive samples. The established test exhibited an area under the curve (AUC) of 0.9997, with a 95% confidence interval ranging from 99.87 to 100%. Furthermore, the test achieved a diagnostic sensitivity of 100% (with a 95% confidence interval of 95.72 to 100%) and a specificity of 98.51% (with a 95% confidence interval of 92.02 to 99.92%) when the threshold was set at 41.97%. The inter- and intra-batch coefficient of variation were below 10%, demonstrating the exceptional repeatability of the method. This method can detect the positive standard serum at a dilution as high as 1:512. Subsequently, an exceptional blocking ELISA assay was established with high diagnostic sensitivity and specificity, providing a novel tool for detecting ASFV antibodies. KEY POINTS: • Four strains of ASFV monoclonal antibodies against p72 were prepared and their epitopes were identified. • Blocking ELISA method was established based on monoclonal antibody 4C4 with an identified conservative epitope. • The established blocking ELISA method has a good effect on the detection of ASFV antibody.

Solibacillus ferritrahens sp. nov., a novel siderophore-producing bacterium isolated from Wumeng Mountain National Nature Reserve in Yunnan Province.

A gram-stain-positive, aerobic, rod-shaped bacterial strain capable of producing siderophores, named YIM B08730T, was isolated from a soil sample collected from Wumeng Mountain National Nature Reserve, Zhaotong City, Yunnan Province. Growth occurred at 10-45 °C (optimum, 35-40 â„ƒ), pH 7.0-9.0 (optimum, 7.0) and in the presence of 0-5 % (w/v) NaCl (optimum, 0-1 %, w/v). A comparative analysis of the 16S rRNA gene sequence (1558 bp) of strain YIM B08730T showed the highest similarity to Solibacillus isronensis JCM 13838T (96.2 %), followed by Solibacillus silvestris DSM 12223T (96.0 %) and Solibacillus kalamii ISSFR-015T (95.4 %). The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine and one unidentified lipid. The main respiratory quinone of strain YIM B08730T was menaquinone 7 (MK-7). The major fatty acids were iso-C15:0 and C16:1ω7c alcohol. The digital DNA-DNA hybridization and average nucleotide identity values between strain YIM B08730T and the reference strain S. isronensis JCM 13838T were 24.8 % and 81.2 %, respectively. The G + C content of the genomic DNA was 37.1 mol%. The genome of the novel strain contained genes associated with the production of siderophores, and it also revealed other functional gene clusters involved in plant growth promotion and soil bioremediation. Based on these phenotypic, chemotaxonomic and phylogenetic analyses, strain YIM B08730T is considered to be a novel species of the genus Solibacillus, for which the name Solibacillus ferritrahens sp. nov. is proposed. The type strain is YIM B08730T (= NBRC 116268T = CGMCC 1.60169T).

Inhibition of HOXC11 by artesunate induces ferroptosis and suppresses ovarian cancer progression through transcriptional regulation of the PROM2/PI3K/AKT pathway.

BACKGROUND: Ferroptosis, a non-apoptotic form of regulated cell death, plays a critical role in the suppression of various tumor types, including ovarian cancer. Artesunate (ART), a derivative of artemisinin, exhibits extensive antitumor effects and is associated with ferroptosis. This study aimed to investigate the mechanisms through which ART induces ferroptosis to inhibit ovarian cancer. METHODS: RNA sequencing was conducted to identify differentially expressed genes associated with ART-induced ferroptosis. Dual-luciferase reporter assays and electrophoretic mobility shift assays were performed to confirm the interaction between Homeobox C11 (HOXC11) and the Prominin 2 (PROM2) promoter. Cell Counting Kit-8 (CCK-8) assays, flow cytometry, and wound healing assays were used to analyze the antitumor effects of ART. Western blot, biochemical assays and transmission electron microscope were utilized to further characterize ART-induced ferroptosis. In vivo, the effects of ART on ferroptosis were examined using a xenograft mouse model. RESULTS: RNA sequencing analysis revealed that the HOXC11, PROM2 and Phosphatidylinositol 3-Kinase/ Protein Kinase B (PI3K/AKT) pathways were downregulated by ART. HOXC11 was found to regulate PROM2 expression by binding to its promoter directly. HOXC11 overexpression reversed ART-induced effects on ovarian cancer cell proliferation, migration, apoptosis and ferroptosis by activating the PROM2/PI3K/AKT signaling axis. Conversely, silencing PROM2 in HOXC11-overexpressing cells restored ART-induced ferroptosis and its associated antitumor effects by inhibiting the PI3K/AKT pathway. Consistently, in vivo studies using a xenograft mouse model confirmed that ART-induced tumor inhibition was mediated by ferroptosis through the suppression of the HOXC11/PROM2/PI3K/AKT pathway. CONCLUSION: This study identifies the HOXC11/PROM2/PI3K/AKT axis as a novel regulatory mechanism underlying ART-induced ferroptosis in ovarian cancer. Targeting the HOXC11/PROM2 axis may represent a promising therapeutic strategy for enhancing ferroptosis, offering new insights for the treatment of ovarian cancer.

Integrated network pharmacology, molecular docking, and lipidomics to reveal the regulatory effect of Qingxuan Zhike granules on lipid metabolism in lipopolysaccharide-induced acute lung injury.

Qingxuan Zhike granules (QXZKG), a traditional Chinese patent medication, has shown therapeutic potential against acute lung injury (ALI). However, the precise mechanism underlying its lung-protective effects requires further investigation. In this study, integrated network pharmacology, molecular docking, and lipidomics were used to elucidate QXZKG's regulatory effect on lipid metabolism in lipopolysaccharide-induced ALI. Animal experiments were conducted to substantiate the efficacy of QXZKG in reducing pro-inflammatory cytokines and mitigating pulmonary pathology. Network pharmacology analysis identified 145 active compounds that directly targeted 119 primary targets of QXZKG against ALI. Gene Ontology function analysis emphasized the roles of lipid metabolism and mitogen-activated protein kinase (MAPK) cascade as crucial biological processes. The MAPK1 protein exhibited promising affinities for naringenin, luteolin, and kaempferol. Lipidomic analysis revealed that 12 lipids showed significant restoration following QXZKG treatment (p < 0.05, FC >1.2 or <0.83). Specifically, DG 38:4, DG 40:7, PC O-40:8, TG 18:1_18:3_22:6, PI 18:2_20:4, FA 16:3, FA 20:3, FA 20:4, FA 22:5, and FA 24:5 were downregulated, while Cer 18:0;2O/24:0 and SM 36:1;2O/34:5 were upregulated in the QXZKG versus model groups. This study enhances our understanding of the active compounds and targets of QXZKG, as well as the potential of lipid metabolism in the treatment of ALI.

Supercritical CO2 fluid extract from Stellariae Radix ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis by inhibit M1 macrophages polarization via AMPK activation.

Yin chai hu (Radix Stellariae) is a root medicine that is frequently used in Chinese traditional medicine to treat fever and malnutrition. In modern medicine, it has been discovered to have anti-inflammatory, anti-allergic, and anticancer properties. In a previous study, we were able to extract lipids from Stellariae Radix using supercritical CO2 extraction (SRE), and these sterol lipids accounted for up to 88.29% of the extract. However, the impact of SRE on the development of atopic dermatitis (AD) has not yet been investigated. This study investigates the inhibitory effects of SRE on AD development using a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. Treatment with SRE significantly reduced the dermatitis score and histopathological changes compared with the DNCB group. The study found that treatment with SRE resulted in a decrease of pro-inflammatory cytokines TNF-α, CXC-10, IL-12, and IL-1ß in skin lesions. Additionally, immunohistochemical analysis revealed that SRE effectively suppressed M1 macrophage infiltration into the AD lesion. Furthermore, the anti-inflammatory effect of SRE was evaluated in LPS + INF-γ induced bone marrow-derived macrophages (BMDMs) M1 polarization, SRE inhibited the production of TNF-α, CXC-10, IL-12, and IL-1ß and decreased the expression of NLRP3. Additionally, SRE was found to increase p-AMPKT172, but had no effect on total AMPK expression, after administration of the AMPK inhibitor Compound C, the inhibitory effect of SRE on M1 macrophages was partially reversed. The results indicate that SRE has an inhibitory effect on AD, making it a potential therapeutic agent for this atopic disorder.

Correlation between Circle of Willis configuration and intracranial arterial dolichoectasia, and genetic contributions.

OBJECTIVES: Intracranial arterial dolichoectasia (IADE) is characterized by the dilation, elongation, and tortuosity of intracranial arteries. We aimed to investigate the association between variations of the Circle of Willis (COW) and IADE in the general population, as well as estimate the genetic correlation between COW variations and IADE. METHODS: A total of 981 individuals from a population-based cohort were included. Brain magnetic resonance angiography was performed to assess COW variants and measure the diameters of intracranial arteries. IADE was defined as a total intracranial volume-adjusted diameter ≥ 2 standard deviations. Logistic regression models were used to analyze the association between COW variations and IADE. The heritability and genetic correlation were estimated using genome-wide complex trait analysis (GCTA) based on single nucleotide polymorphism (SNP) array data. RESULTS: The prevalence of IADE was 6.2 %. Hypoplastic/absent A1 segments were associated with an increase in contralateral ICA diameter (ß ± SE, 0.279 ± 0.049; p = 0.001) and a decrease in ipsilateral ICA diameter (ß ± SE, -0.300 ± 0.050; p = 0.001). Fetal-type posterior cerebral artery (FTP) was associated with a larger ICA diameter (ß ± SE, 0.326 ± 0.048; p = 0.001) and a smaller BA diameter (ß ± SE, -0.662 ± 0.043; p = 0.001). FTP revealed a positive genetic correlation with ICA dilation (rG = 0.259 ± 0.175; p = 0.0009) and a negative genetic correlation with BA dilation (rG = -0.192 ± 0.153, p = 0.015). CONCLUSIONS: There was an association between COW variations and larger intracranial arterial diameters in the general population. Genetic factors may play a role in the development of intracranial arterial dilation and the formation of COW variants.

Escherichia coli-Based In Situ Triggerable Probe as an Amplifier for Sensitive Diagnosis and Penetrated Therapy of Cancer.

Escherichia coli (E. coli) was used for cancer therapy due to the tumor-targeting, catalytic, and surface-reducing properties. Effective diagnosis combined with treatment of cancer based on E. coli, however, was rarely demonstrated. In this study, E. coli was used to surface reduce HAuCl4 and as a carrier to modify riboflavin (Rf) and luminol (E-Au@Rf@Lum). After targeted delivery to tumor, the E-Au@Rf@Lum probe could actively emit 425 nm blue-violet chemiluminescence (CL) to achieve cell imaging for cancer diagnosis. Furthermore, this light could in situ trigger the photosensitizer (Rf) through CL resonance energy transfer, which produces reactive oxygen species (ROS) for accurate photodynamic therapy. In return, the excessive ROS enhanced the blue-violet light which was further absorbed by Rf, and ROS production was cyclically amplified. Abundant ROS broke down the dense extracellular matrix network and penetrated deep into tumors. Besides, E. coli with excellent catalytic property could decompose H2O2 to O2 to relieve tumor hypoxia for a long time and enhance the photosensitized process of Rf. By self-illumination, effective penetration, and tumor hypoxia relief, this work opens a self-amplified therapy modality to tumor.

Histone acetylation gene-based biomarkers as novel markers of the immune microenvironment in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a primary malignant tumour with high intracranial morbidity, high malignancy and poor prognosis. Abnormal changes in histone acetylation are closely related to the occurrence and development of cancer. However, there is still a lack of systematic research on histone acetylation in GBM. METHODS: Whole-transcriptome sequencing data and clinical data of GBM patients were obtained through the TCGA database. Single-cell RNA-sequencing (scRNA-seq) data from GBM patients were obtained from GSE146711 in the Gene Expression Omnibus database. Cell descending fractionation was first performed for scRNA-seq on GBM. The CellChat and PROGENy scores explore the impact of the histone acetylation pathway in GBM on intercellular chat and tumour pathways. The AddModuleScore function evaluates the enrichment score of histone acetylation in cells and divides them into high-histone acetylation and low-histone acetylation groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the differential genes between different histone acetylation states, and the biological processes and pathways that may be affected by histone acetylation were evaluated. Based on this, a prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) analysis, and survival analysis was performed to evaluate its prognostic performance. Finally, we also analysed the main effects of the constructed histone acetylation-related model on GBM immune infiltration by multiple methods, and analysed the main mutation data of its different subgroups. RESULTS: GBM samples mainly include seven large cell populations: oligodendrocyte precursor cells (OPCs), myeloid, neoplastic, oligodendrocytes, astrocytes, vascular and neurons. Cellchat and ProgenY scores revealed that in GBM tumours, histone acetylation interacts closely with multiple immune cells and tumour pathways. GO and KEGG analyses revealed the main impact proteins and pathway correlates of histone acetylation. Five histone acetylation genes were screened using LASSO analysis and a prognostic model was constructed. The results revealed that prognostic models were significant in the prognostic stratification of patients in both the training and validation groups of GBM patients. Immune infiltration analysis revealed that the mechanism of histone acetylation in GBM may be related to the immune infiltration of multiple effector immune cells. CONCLUSIONS: Our histone acetylation-based biomarkers are closely associated with immune microenvironmental infiltration and functional mutations in multiple tumour pathways in GBM. This suggests that histone acetylation may reveal microscopic alterations in the tumour microenvironment, and may provide potential evidence and a research basis for the development of novel therapeutic targets for GBM. On this basis, a novel perspective on the spatial biology and immunological understanding of GBM is provided.

Red-light receptor phytochrome B inhibits BZR1-NAC028-CAD8B signaling to negatively regulate rice resistance to sheath blight.

Phytochrome (Phy)-regulated light signalling plays important roles in plant growth, development, and stress responses. However, its function in rice defence against sheath blight disease (ShB) remains unclear. Here, we found that PhyB mutation or shade treatment promoted rice resistance to ShB, while resistance was reduced by PhyB overexpression. Further analysis showed that PhyB interacts with phytochrome-interacting factor-like 15 (PIL15), brassinazole resistant 1 (BZR1), and vascular plant one-zinc-finger 2 (VOZ2). Plants overexpressing PIL15 were more susceptible to ShB in contrast to bzr1-D-overexpressing plants compared with the wild-type, suggesting that PhyB may inhibit BZR1 to negatively regulate rice resistance to ShB. Although BZR1 is known to regulate brassinosteroid (BR) signalling, the observation that BR signalling negatively regulated resistance to ShB indicated an independent role for BZR1 in controlling rice resistance. It was also found that the BZR1 ligand NAC028 positively regulated resistance to ShB. RNA sequencing showed that cinnamyl alcohol dehydrogenase 8B (CAD8B), involved in lignin biosynthesis was upregulated in both bzr1-D- and NAC028-overexpressing plants compared with the wild-type. Yeast-one hybrid, ChIP, and transactivation assays demonstrated that BZR1 and NAC028 activate CAD8B directly. Taken together, the analyses demonstrated that PhyB-mediated light signalling inhibits the BZR1-NAC028-CAD8B pathway to regulate rice resistance to ShB.

Smoke promotes germination of peatland bryophyte spores.

Northern peatlands are globally important carbon stores. With increasing fire frequency, the re-establishment of bryophytes becomes crucial for their carbon sequestration. Smoke-responsive germination is a common trait of seeds in fire-prone ecosystems but has not been demonstrated in bryophytes. To investigate the potential role of smoke in post-fire peatland recovery, we tested the germination of spores of 15 bryophyte species after treatment with smoke-water. The smoke responsiveness of spores with different laboratory storage times and burial depths/age (3-200 years) was subsequently tested. Smoke increased the germination percentage for 10 of the species and the germination speed for four of these. Smoke responsiveness increased along the fire frequency gradient from open expanse to forest margin, consistent with the theory that this selects for the maintenance of fire-adapted traits. Smoke enhanced the germinability of 1-year but not 4-year laboratory-stored spores, and considerably increased the germinability of spores naturally buried in peat for up to ~200 years. The effect of fire may be overlooked in non-fire-prone ecosystems, such as those in which wetland bryophytes dominate. Our study reveals a mechanism by which an increase in fire frequency may lead to shifts in species dominance, which may affect long-term carbon sequestration in peatlands.

Association between Anatomical Variations of the Circle of Willis and Covert Vascular Brain Injury in the General Population.

BACKGROUND AND PURPOSE: The circle of Willis (COW) is a circulatory anastomosis located at the base of the brain. Little is known about the association between covert vascular brain injury and COW configurations in the general population. We explored this relationship in a community-based Chinese sample. METHODS: A total of 1,055 patients (mean age, 54.8 ± 8.9 years; 36.0% men) without intracranial arterial stenosis were included in the analysis. Magnetic resonance imaging was performed to evaluate the presence of imaging markers of covert vascular brain injury, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces, and brain atrophy. Magnetic resonance angiography was used to classify the COW configurations according to the completeness, symmetry, and presence of the fetal posterior cerebral artery (FTP). The association between vascular lesions and variations in COW was analyzed. RESULTS: Among the 1,055 patients, 104 (9.9%) had a complete COW. Completeness correlated with age (p = 0.001). Incomplete COW was positively associated with WMH severity (OR = 2.071; 95% CI, 1.004-4.270) and CMB presence (OR = 1.542; 95% CI, 1.012-2.348), independent of age and sex. The presence of FTP was associated with lacunes (OR = 1.878; 95% CI, 1.069-3.298), more severe WMHs (OR = 1.739; 95% CI, 1.064-2.842), and less severe enlarged perivascular spaces (OR = 0.562; 95% CI, 0.346-0.915). CONCLUSIONS: COW configuration was significantly related to various covert vascular brain injuries.

Dynamic Metastable Characteristics of Carbon Cages Embedded with Er2C2.

Novel endohedral metallofullerenes (EMFs), namely, Er2C2@C2v(5)-C80, Er2C2@Cs(6)-C82, Er2C2@Cs(15)-C84, Er2C2@C2v(9)-C86, Er2C2@Cs(15)-C86, and Er2C2@Cs(32)-C88, had been experimentally synthesized, and the unique structures and many fascinating properties had also been widely explored. Nevertheless, the position of the Er atoms inside the cage shows a severe disorder within the stable EMF monomer, which is difficult to understand and explain from the experimental point of view. In this work, based on the density functional theoretical calculations, the Er2C2@Cs(6)-C82 has 73 directional isomers and 2 Er atoms that are far beyond from Er-Er single bonding and tend to be close to the cage side (marked as "shell"), and the core (Er2C2 units) takes on a butterfly shape as generally revealed. The energy difference between any two of the isomers is in the range of 0.05 to 25.6 kcal/mol, indicating a relatively easy thermodynamic transition between the isomers. The other five Er carbide cluster EMFs (Er2C2@C2v(5)-C80, Er2C2@Cs(15)-C84, Er2C2@C2v(9)-C86, Er2C2@Cs(15)-C86, and Er2C2@Cs(32)-C88) are also studied in the same way, and 30, 37, 39, and 43 most stable Er-oriented sites inside the cage, respectively, are obtained. In addition, the shape of the Er2C2 gradually changed from butterfly to linear. Moreover, the electronic structure and molecular orbital analyses show that it is easy for Er2C2@C80-88 to form a charge transfer state of [Er2C2]4+@[C80-88]4- via the dynamic core-shell coordination equilibrium. Er2C2 with a steep drop in chemical stability is restricted to forming varying degrees of metastable states in the shell, determined by the shell size, to ensure the overall stability. The lowest unoccupied molecular orbital energy level of these EMFs is increased by 0.5-1.1 eV compared with fullerenes C80-88, potentially providing favorable conditions for suitable energy level matching with EMF as an electron acceptor used in organic solar cell devices.

A novel mutation in the TTN gene resulted in left ventricular noncompaction: a case report and literature review.

BACKGROUND: Left ventricular noncompaction (LVNC) is a specific type of cardiomyopathy characterized by coarse trabeculae and interspersed trabecular crypts within the ventricles. Clinical presentation varies widely and may be nonsignificant or may present with progressive heart failure, malignant arrhythmias, and multiorgan embolism. The mode of inheritance is highly heterogeneous but is most commonly autosomal dominant. The TTN gene encodes titin, which is not only an elastic component of muscle contraction but also mediates multiple signalling pathways in striated muscle cells. In recent years, mutations in the TTN gene have been found to be associated with LVNC, but the exact pathogenesis is still not fully clarified. CASE PRESENTATION: In this article, we report a case of an adult LVNC patient with a TTN gene variant, c.87857G > A (p. Trp29286*), that has not been reported previously. This 43-year-old adult male was hospitalized repeatedly for heart failure. Echocardiography showed reduced myocardial contractility, dilated left ventricle with many prominent trabeculae, and a loose texture of the left ventricular layer of myocardium with crypt-like changes. During the out-of-hospital follow-up, the patient had no significant signs or symptoms of discomfort. CONCLUSION: This case report enriches the mutational spectrum of the TTN gene in LVNC and provides a basis for genetic counselling and treatment of this patient. Clinicians should improve their understanding of LVNC, focusing on exploring its pathogenesis and genetic characteristics to provide new directions for future diagnosis and treatment.