Genomic analysis uncovers prognostic and immunogenic characteristics of ferroptosis for clear cell renal cell carcinoma

In this study, the characteristic patterns of ferroptosis in clear cell renal cell carcinoma (ccRCC) were systematically investigated with the interactions between ferroptosis and the tumor microenvironment (TME). On the mRNA expression profiles of 57 ferroptosis-related genes (FRGs), three ferroptosis patterns were constructed, with distinct prognosis and immune cell infiltrations (especially T cells and dendritic cells). The high ferroptosis scores were characterized by poorer prognosis, increased T cell infiltration, higher immune and stromal scores, elevated tumor mutation burden, and enhanced response to anti-CTLA4 immunotherapy. Meanwhile, the low ferroptosis scores were distinctly associated with enhanced tumor purity and amino acid and fatty acid metabolism pathways. Following validation, the ferroptosis score was an independent and effective prognostic factor. Collectively, ferroptosis could be involved in the diverse and complex TME. Evaluation of the ferroptosis patterns may heighten the comprehension about immune infiltrations in the TME, assisting oncologists to generate individualized immunotherapeutic strategies

Toward targeted therapy in chemotherapy-resistant pancreatic cancer with a smart triptolide nanomedicine

Chemoresistance is the major impediment for treating pancreatic cancer. Herb-derived compound triptolide (TP) can inhibit proliferation of chemo-resistant pancreatic cancer (CPC) cell lines through multiple mechanisms, which exhibited superior anticancer efficacy compared with gemcitabine. However, toxicity due to non-specific exposure to healthy tissues hindered its clinical translation. Herein we successfully achieved targeting CPC cells and avoiding exposure to healthy tissues for TP by nucleolin-specific aptamer (AS1411) mediated polymeric nanocarrier. We conjugated AS1411 aptamer to carboxy terminated poly(ethylene glycol)–block–poly(d, l-lactide) (HOOC-PEG-PDLLA), then prepared AS1411-PEG-PDLLA micelle loading TP (AS-PPT) through solid dispersion technique. AS-PPT showed more antitumor activity than TP and equivalent specific binding ability with gemcitabine-resistant human pancreatic cancer cell (MIA PaCa-2) to AS1411 aptamer in vitro. Furthermore, we studied the distribution of AS-PPT (Cy3-labed TP) at tissue and cellular levels using biophotonic imaging technology. The results showed AS1411 facilitated TP selectively accumulating in tumor tissues and targeting CPC cells. The lifetime of the MIA PaCa-2 cell-bearing mice administrated with AS-PPT was efficiently prolonged than that of the mice subjected to the clinical anticancer drug Gemzar®in vivo. Such work provides a new strategy for overcoming the drug resistance of pancreatic cancer

Altered Gut Microbiota Composition in Subjects Infected With Clonorchis sinensis

Clonorchiasis is an infectious disease caused by helminths of Clonorchis sinensis (C. sinensis). The adult parasite mainly inhabits the bile duct and gall bladder, and results in various complications to the hepatobiliary system. The amount of bile secreted into the intestine is reduced in cases of C. sinensis infection, which may alter the pH of the gut and decrease the amount of surfactant protein D released from the gallbladder. However, the impact of parasitic infection on the human gut microbiome remains unclear. To this end, we examined the gut microbiota composition in 47 modified Kato–Katz thick smear-positive (egg-positive) volunteers and 42 healthy controls from five rural communities. Subjects were grouped into four sub-populations based on age and infection status. High-throughput 16S rRNA gene sequencing revealed significant changes in alpha diversity between EP1 and EN1. The beta diversity showed alterations between C. sinensis-infected subjects and healthy controls. In C. sinensis infected patients, we found the significant reduction of certain taxa, such as Bacteroides and anti-inflammatory Bifidobacterium (P < 0.05). Bacteroides, a predominant gut bacteria in healthy populations, was negatively correlated with the number of C. sinensis eggs per gram (EPG, r = −0.37, P adjust < 0.01 in 20–60 years old group; r = −0.64, P adjust = 0.04 in the 60+ years old group). What’s more, the reduction in the abundance of Bifidobacterium, a common probiotic, was decreased particularly in the 60 + years old group (r = −0.50, P = 0.04). The abundance of Dorea, a potentially pro-inflammatory microbe, was higher in infected subjects than in healthy individuals (P < 0.05). Variovorax was a unique bacteria that was only detected in infected subjects. These results clearly demonstrate the significant influence of C. sinensis infection on the human gut microbiota and provided new insights into the control, prevention, diagnosis, and clinical study of clonorchiasis through the human gut microbiota

SuperMatching: feature matching using supersymmetric geometric constraints

Feature matching is a challenging problem at the heart of numerous computer graphics and computer vision applications. We present the SuperMatching algorithm for finding correspondences between two sets of features. It does so by considering triples or higher order tuples of points, going beyond the pointwise and pairwise approaches typically used. SuperMatching is formulated using a supersymmetric tensor representing an affinity metric that takes into account feature similarity and geometric constraints between features: Feature matching is cast as a higher order graph matching problem. SuperMatching takes advantage of supersymmetry to devise an efficient sampling strategy to estimate the affinity tensor, as well as to store the estimated tensor compactly. Matching is performed by an efficient higher order power iteration approach that takes advantage of this compact representation. Experiments on both synthetic and real data show that SuperMatching provides more accurate feature matching than other state-of-the-art approaches for a wide range of 2D and 3D features, with competitive computational cost

Pan-genome analysis of Streptococcus suis serotype 2 highlights genes associated with virulence and antibiotic resistance

Streptococcus suis serotype 2 (SS2) is a Gram-positive bacterium. It is a common and significant pathogen in pigs and a common cause of zoonotic meningitis in humans. It can lead to sepsis, endocarditis, arthritis, and pneumonia. If not diagnosed and treated promptly, it has a high mortality rate. The pan-genome of SS2 is open, and with an increasing number of genes, the core genome and accessory genome may exhibit more pronounced differences. Due to the diversity of SS2, the genes related to its virulence and resistance are still unclear. In this study, a strain of SS2 was isolated from a pig farm in Sichuan Province, China, and subjected to whole-genome sequencing and characterization. Subsequently, we conducted a Pan-Genome-Wide Association Study (Pan-GWAS) on 230 strains of SS2. Our analysis indicates that the core genome is composed of 1,458 genes related to the basic life processes of the bacterium. The accessory genome, consisting of 4,337 genes, is highly variable and a major contributor to the genetic diversity of SS2. Furthermore, we identified important virulence and resistance genes in SS2 through pan-GWAS. The virulence genes of SS2 are mainly associated with bacterial adhesion. In addition, resistance genes in the core genome may confer natural resistance of SS2 to fluoroquinolone and glycopeptide antibiotics. This study lays the foundation for further research on the virulence and resistance of SS2, providing potential new drug and vaccine targets against SS2

Pan-genome wide association study of Glaesserella parasuis highlights genes associated with virulence and biofilm formation

Glaesserella parasuis is a gram-negative bacterium that causes fibrotic polyserositis and arthritis in pig, significantly affecting the pig industry. The pan-genome of G. parasuis is open. As the number of genes increases, the core and accessory genomes may show more pronounced differences. The genes associated with virulence and biofilm formation are also still unclear due to the diversity of G. parasuis. Therefore, we have applied a pan-genome-wide association study (Pan-GWAS) to 121 strains G. parasuis. Our analysis revealed that the core genome consists of 1,133 genes associated with the cytoskeleton, virulence, and basic biological processes. The accessory genome is highly variable and is a major cause of genetic diversity in G. parasuis. Furthermore, two biologically important traits (virulence, biofilm formation) of G. parasuis were studied via pan-GWAS to search for genes associated with the traits. A total of 142 genes were associated with strong virulence traits. By affecting metabolic pathways and capturing the host nutrients, these genes are involved in signal pathways and virulence factors, which are beneficial for bacterial survival and biofilm formation. This research lays the foundation for further studies on virulence and biofilm formation and provides potential new drug and vaccine targets against G. parasuis

An Integrative Pharmacology Model for Decoding the Underlying Therapeutic Mechanisms of Ermiao Powder for Rheumatoid Arthritis

As a systemic inflammatory arthritis disease, rheumatoid arthritis (RA) is complex and hereditary. Traditional Chinese medicine (TCM) has evident advantages in treating complex diseases, and a variety of TCM formulas have been reported that have effective treatment on RA. Clinical and pharmacological studies showed that Ermiao Powder, which consists of Phellodendron amurense Rupr. (PAR) and Atractylodes lancea (Thunb.) DC. (ALD), can be used in the treatment of RA. Currently, most studies focus on the anti-inflammatory mechanism of PAR and ALD and are less focused on their coordinated molecular mechanism. In this research, we established an integrative pharmacological strategy to explore the coordinated molecular mechanism of the two herbs of Ermiao Powder in treating RA. To explore the potential coordinated mechanism of PAR and ALD, we firstly developed a novel mathematical model to calculate the contribution score of 126 active components and 85 active components, which contributed 90% of the total contribution scores that were retained to construct the coordinated functional space. Then, the knapsack algorithm was applied to identify the core coordinated functional components from the 85 active components. Finally, we obtained the potential coordinated functional components group (CFCG) with 37 components, including wogonin, paeonol, ethyl caffeate, and magnoflorine. Also, functional enrichment analysis was performed on the targets of CFCG to explore the potential coordinated molecular mechanisms of PAR and ALD. The results indicated that the CFCG could treat RA by coordinated targeting to the genes involved in immunity and inflammation-related signal pathways, such as phosphatidylinositol 3‑kinase/protein kinase B signaling pathway, mitogen-activated protein kinase signaling pathway, tumor necrosis factor signaling pathway, and nuclear factor-kappa B signaling pathway. The docking and in vitro experiments were used to predict the affinity and validate the effect of CFCG and further confirm the reliability of our method. Our integrative pharmacological strategy, including CFCG identification and verification, can provide the methodological references for exploring the coordinated mechanism of TCM in treating complex diseases and contribute to improving our understanding of the coordinated mechanism

The genome of hibiscus hamabo reveals its adaptation to saline and waterlogged habitat

Hibiscus hamabo is a semi-mangrove species with strong tolerance to salt and waterlogging stress. However, the molecular basis and mechanisms that underlie this strong adaptability to harsh environments remain poorly understood. Here, we assembled a high-quality, chromosome-level genome of this semi-mangrove plant and analyzed its transcriptome under different stress treatments to reveal regulatory responses and mechanisms. Our analyses suggested that H. hamabo has undergone two recent successive polyploidy events, a whole-genome duplication followed by a whole-genome triplication, resulting in an unusually large gene number (107 309 genes). Comparison of the H. hamabo genome with that of its close relative Hibiscus cannabinus, which has not experienced a recent WGT, indicated that genes associated with high stress resistance have been preferentially preserved in the H. hamabo genome, suggesting an underlying association between polyploidy and stronger stress resistance. Transcriptomic data indicated that genes in the roots and leaves responded differently to stress. In roots, genes that regulate ion channels involved in biosynthetic and metabolic processes responded quickly to adjust the ion concentration and provide metabolic products to protect root cells, whereas no such rapid response was observed from genes in leaves. Using co-expression networks, potential stress resistance genes were identified for use in future functional investigations. The genome sequence, along with several transcriptome datasets, provide insights into genome evolution and the mechanism of salt and waterlogging tolerance in H. hamabo, suggesting the importance of polyploidization for environmental adaptation.DATA AVAILABILITY: The data supporting the findings of this work are available within the paper and its Supporting Information files. The data sets generated and analyzed during this study are available from the corresponding author upon request. All the whole-genome raw data generated during this study have been deposited in the SRA database under BioProject number PRJNA759075. Transcriptome clean data have been deposited in the SRA database under BioProject number PRJNA759717. The final chromosome-scale genome assembly and annotation data have been deposited in the Figshare database (https://doi.org/10.6084/m9.figshare.19142558.v1).Six Talent Peaks Project of Jiangsu Province (NY-042); Open Fund of the Jiangsu Key Laboratory for the Research and Utilization of Plant Resources (JSPKLB201928); Talent Training Funds of the Institute of Botany, Jiangsu Province and Chinese Academy of Sciences.https://academic.oup.com/hrBiochemistryGeneticsMicrobiology and Plant Patholog

The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBβ

Heme is a ligand for the human nuclear receptors (NR) REV-ERBα and REV-ERBβ, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcription repression mediated by heme-bound REV-ERBs is reversed by the addition of nitric oxide (NO), and that the heme and NO effects are mediated by the C-terminal ligand-binding domain (LBD). A 1.9 Å crystal structure of the REV-ERBβ LBD, in complex with the oxidized Fe(III) form of heme, shows that heme binds in a prototypical NR ligand-binding pocket, where the heme iron is coordinately bound by histidine 568 and cysteine 384. Under reducing conditions, spectroscopic studies of the heme-REV-ERBβ complex reveal that the Fe(II) form of the LBD transitions between penta-coordinated and hexa-coordinated structural states, neither of which possess the Cys384 bond observed in the oxidized state. In addition, the Fe(II) LBD is also able to bind either NO or CO, revealing a total of at least six structural states of the protein. The binding of known co-repressors is shown to be highly dependent upon these various liganded states. REV-ERBs are thus highly dynamic receptors that are responsive not only to heme, but also to redox and gas. Taken together, these findings suggest new mechanisms for the systemic coordination of molecular clocks and metabolism. They also raise the possibility for gas-based therapies for the many disorders associated with REV-ERB biological functions