E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET. Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-MET. Significance: This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes.</p

Cerebral Falx Mature Teratoma with Rare Imaging in an Adult

Intracranial mature teratoma is a rare lesion in adults. Despite several intracranial mature teratomas had been reported not to be located at the midline region, no one was found to be within cerebral falx. Herein, we reported a 37-year-old female patient with an intracranial mature teratoma confined within frontal cerebral falx. Her main complaint was intermitted headache, which could not be relieved recently by taking painkiller. Excepting for mild papilledema, we did not find positive neurological signs on physical examination. CT scanning showed it was a round homogenously hypodense lesion with hyperdense signal at its rim. MRI revealed the lesion was 3.5cm×3.6cm×4.5cm in volume, with uniformed hypointensity on T1WI, hyperintensity on T2WI and enhancement in the capsule. It was totally removed via inter-hemispheric approach, and we found the lesion was confined within the frontal cerebral falx. Postoperatively, it was proved histologically to be a mature teratoma. At three years of fellow up, neither neurological deficits nor recurrent sings on MRI was found. To our best knowledge, this is the first case of intracranial mature teratoma within cerebral falx

Spatiotemporal View of Malignant Histogenesis and Macroevolution via Formation of Polyploid Giant Cancer Cells

To understand how malignant tumors develop, we tracked cell membrane, nuclear membrane, spindle, and cell cycle dynamics in polyploid giant cancer cells (PGCCs) during the formation of high-grade serous carcinoma organoids using long-term time-lapse imaging. Single cells underwent traditional mitosis to generate tissue with uniform nuclear size, while others formed PGCCs via asymmetric mitosis, endoreplication, multipolar endomitosis, nuclear fusion, and karyokinesis without cytokinesis. PGCCs underwent restitution multipolar endomitosis, nuclear fragmentation, and micronuclei formation to increase nuclear contents and heterogeneity. At the cellular level, the development of PGCCs was associated with forming transient intracellular cells, termed fecundity cells. The fecundity cells can be decellularized to facilitate nuclear fusion and synchronized with other nuclei for subsequent nuclear replication. PGCCs can undergo several rounds of entosis to form complex tissue structures, termed fecundity structures. The formation of PGCCs via multiple modes of nuclear replication in the absence of cytokinesis leads to an increase in the nuclear-to-cytoplasmic (N/C) ratio and intracellular cell reproduction, which is remarkably similar to the mode of nuclear division during pre-embryogenesis. Our data support that PGCCs may represent a central regulator in malignant histogenesis, intratumoral heterogeneity, immune escape, and macroevolution via the de-repression of suppressed pre-embryogenic program in somatic cells

N-(4-Chloro­phen­yl)-4-meth­oxy-3-(propanamido)­benzamide cyclo­hexane hemisolvate

The title compound, C17H17ClN2O3·0.5C6H12, was prepared by the condensation reaction of 4-meth­oxy-3-(propanamido)­benzoic acid with 4-chloro­aniline. The Cl atom, the propionyl CH3 group and the cyclo­hexyl CH2 group are disordered over two sets of sites of equal occupancy in both mol­ecules. The cyclo­hexane solvent mol­ecule is disordered over two orientations which were modelled with relative occupancies of 0.484 (4) and 0.516 (4). In the crystal, there are a number of N—H⋯O hydrogen bonds, forming layers perpendicular to (001)

Synthesis of a carbon nanotube and carbon sphere coexisting catalyst for enhanced oxygen reduction reaction and its applications

Fe and N co-doped carbon nanocomposites exhibit great potential as low-cost and highly active non-precious metal catalysts for the oxygen reduction reaction (ORR). In this study, a method is demonstrated for synthesizing polymer nanospheres, which are subsequently carbonized and functionalized by anchoring Fe[sbnd]N complexes onto the carbon matrix to fabricate a composite catalyst. Characterization reveals that the as-prepared material consists of carbon nanotubes (CNTs) intricately interwoven with carbon nanospheres (CNSs) (denoted as Fe–N–CNT/CNS). Moreover, it is demonstrated that trace amounts of Fe nanoparticles can serve as active sites to significantly enhance the electrocatalytic activity. The composite catalyst with the unique structure achieves a very high specific surface area of 1790 m2/g, providing more active sites to enhance the ORR activity for application in both acidic and alkaline environment. The half-wave potential of the composite catalyst reaches 0.79 V and 0.925 V under the acidic and alkaline conditions, respectively.</p

Bacillus licheniformis Suppresses Clostridium perfringens Infection via Modulating Inflammatory Response, Antioxidant Status, Inflammasome Activation and Microbial Homeostasis in Broilers

Pathogenic bacteria infection, especially Clostridium perfringens (C. perfringens), markedly threatened the health of animals, and further caused huge economic loss. In this study, Bacillus licheniformis HJ0135 (BL) was used. Oxford cup bacteriostatic test and inhibitory rate test were conducted to evaluate the antibacterial ability of BL. Results showed the strongest inhibitory role of BL on C. perfringens (P \u3c 0.05). Afterwards, 540 one-day-old yellow-feather broilers (32.7 ± 0.2 g) were randomly allocated into 3 groups, including CON group (basal diet), CP group (basal diet + 1 × 109 CFU C. perfringens in gavage), and BL + CP group (basal diet containing 7.5 × 106 CFU/g BL + 1 × 109 CFU C. perfringens in gavage). At d 70, broilers in the CP and BL + CP groups were treated with C. perfringens by continuously oral administration for 5 d. The experiment lasted for 75 d. The serum, immune organs, jejunal mucosa, and cecal contents were collected for analysis. In vivo experiment showed that BL supplementation markedly improved (P \u3c 0.05) BW, ADG, thymus index, serum immunoglobins and antioxidases, reduced feed conversion ratio (FCR) and serum pro-inflammatory cytokines of C. perfringens-infected broilers. Furthermore, the increased jejunal injury and levels of pro-inflammatory cytokines, decreased gene expressions of tight junction proteins in the jejunal mucosa were significantly alleviated (P \u3c 0.05) by BL. More importantly, the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome was inhibited (P \u3c 0.05) by BL to further attenuate jejunal damage. Besides, BL supplementation markedly increased (P \u3c 0.05) the cecal isobutyric acid and isovaleric acid. Microbial analysis showed that BL changed the composition and relative abundances of microbiota in the cecal contents (P \u3c 0.05), especially the short chain fatty acids (SCFAs)-producing bacteria including Eubacterium_coprostanoligenes_group, Megamonas, Faecalibacterium, and Lactobacillus, which further protected against C. perfringens-induced jejunal inflammation in broilers. Our study laid a theoretical basis for the application of probiotics in lessening C. perfringens-related diseases in poultry farming

Beneficial Effects of Lactobacillus plantarum on Growth Performance, Immune Status, Antioxidant Function and Intestinal Microbiota in Broilers

Lactobacillus plantarum (L. plantarum) has been globally regarded as antibiotic alternative in animal farming in the past few years. However, the potential function of L. plantarum in broilers has not been systemically explored. In this study, a total of 560 one-day-old yellow-feathered broilers were randomly divided into 3 groups, fed with basal diet and drank with L. plantarum HJZW08 (LP) at the concentration of 0 (CON), 1000 × 10^5 (LP1000), and 2000 × 10^5 CFU/L (LP2000) for 70 d. Results showed that the body weight (BW), average daily gain (ADG), average daily feed intake (ADFI), immunoglobulin A (IgA), IgY, and anti-inflammatory interleukin 10 (IL-10) were markedly improved (P \u3c 0.05), while the levels of pro-inflammatory IL-2, IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in serum were decreased (P \u3c 0.05) in the LP2000 group comparing with the CON group. Besides, LP treatment groups prominently increased the levels and activities of antioxidant enzymes and decreased the content of malondialdehyde (MDA). Additionally, the levels of isobutyric acid in the LP1000 and LP2000 groups and isovaleric acid in the LP2000 group were significantly improved. More importantly, the α-diversity and microbial structure of intestinal microbiota were pronounced altered by LP supplementation. The results showed that only the relative abundance of Actinobacteriota was significantly increased in the LP2000 group, while 6 kinds of bacteria on genus level were significantly changed. For further validation, linear discriminant analysis with effect size (LEfSe) plots revealed that 8 amplicon sequence variants (ASVs) were predominant in the CON group, while Bacteroides and other beneficial species such as Lactimicrobium massiliense (ASV4 and ASV36), Intestinimonas butyriciproducens (ASV71), and Barnesiella viscericola (ASV152 and ASV571) were enriched in the LP groups. Taken together, dietary supplementation with LP obviously enhanced the immune status, antioxidant capacity, and stabilized the cecal microbiota and SCFAs, contributing to the improvement of growth performance of broilers. Our study laid good foundation for the application of probiotic Lactobacillus in animal industry in the future

Deciphering the spatiotemporal trade-offs and synergies between ecosystem services and their socio-ecological drivers in the plain river network area

Understanding changes in ecosystem services (ESs) and quantitatively identifying the drivers that influence these changes are essential for achieving sustainable ecosystem development. In this study, multiple data sources and techniques, including meteorological data, land use/cover data, soil data, the InVEST model, and ArcGIS, were used to analyze the spatiotemporal variation characteristics of carbon storage, habitat quality, soil retention, water yield, and crop product supply in Xinghua City from 2000 to 2015. Additionally, we explored the causes of these changes and the interrelationships among these ESs. The results showed that: (1) During the study period, carbon storage and habitat quality declined, water yield fluctuated and increased, and soil retention had small interannual variations. The supply capacity of crop products first increased rapidly and then stabilized. (2) ESs were influenced by multiple drivers, with altitude having the strongest explanatory power for habitat quality and soil retention, and food production having the strongest explanatory power for crop product supply. (3) Relationships between different ESs were variable and changed over time. This study could enrich the understanding of spatial and temporal changes and drivers of ESs in the plain river network area, which has important implications for future land use planning and sustainable development of ESs

Manipulating noncovalent conformational lock via side-chain engineering for luminescence at aggregate level

The unfavorable photochemical processes at the molecular level have become a barrier limiting the use of aromatic amides as high-performance luminescent materials. Herein, we propose a reliable strategy for manipulating noncovalent conformational lock (NCL) via side-chain engineering to burst out eye-catching luminescence at the aggregate level. Contrary to the invisible emission in dilute solutions, dyad OO with a three-centered H-bond gave the wondrous crystallization-induced emission with a quantum yield of 66.8% and clusterization-triggered emission, which were much brighter than those of isomers. Theoretical calculations demonstrate that crystallization-induced planarized intramolecular charge transfer (PICT), conformation rigidification, and through-space conjugation (TSC) are responsible for aggregate-state luminescence. Robust NCL composed of intramolecular N-H···O interactions could boost molecular rigidity and planarity, thus greatly facilitating PICT and TSC. This study would inspire researchers to design efficient luminescent materials at the aggregate level via rational conformational control.</p

The role of mitochondria-related key genes in primary biliary cholangitis was analyzed based on transcriptome sequencing data

IntroductionMitochondrial dysfunction is implicated in the pathogenesis of primary biliary cholangitis (PBC), but the roles of mitochondria-related genes (MRGs) remain unclear. We aimed to identify key MRGs associated with PBC and validate their expression at transcriptional and protein levels.MethodsPeripheral blood from PBC patients and healthy controls underwent RNA-seq. MRGs were sourced from MitoCarta 3.0. After quality control, differentially expressed genes were defined between PBC and controls and integrated with weighted gene co -expression network analysis to obtain candidate genes. LASSO and SVM-RFE selected hub genes, whose diagnostic performance was assessed by ROC in both the discovery cohort and an external validation dataset. Functional enrichment, immune-cell composition analyses, and regulatory network construction (miRNA/lncRNA/TF) were performed. Protein and mRNA expression were validated by liver -tissue immunohistochemistry and peripheral-blood RT-qPCR, respectively. Disease correlation and drug-prediction analyses were conducted.ResultsSHANK2 and TGM2 were identified as hub MRGs, showed higher expression in PBC, and achieved AUC values &gt;0.7. Enrichment linked SHANK2 to Bcell receptor, T-cell receptor, and Wnt signaling pathways, while TGM2 associated with oxidative phosphorylation and nucleotide metabolism. Immune-cell profiles differed between PBC and controls, and selected cell types correlated with hub-gene expression. Regulatory analyses suggested modulation of SHANK2 and TGM2 by molecules including SLFN12L and DNAH10OS. Immunohistochemistry revealed elevated, stage-associated protein expression of both genes in PBC liver tissues, and RT-qPCR confirmed higher peripheralblood mRNA levels. Drug/disease analyses indicated therapeutic potential for targeting these genes.DiscussionSHANK2 and TGM2 emerge as key MRGs linking mitochondrial dysfunction with immune dysregulation in PBC and may serve as diagnostic biomarkers and therapeutic targets; further mechanistic and clinical validation is warranted