RIscoper 2.0: A deep learning tool to extract RNA biomedical relation sentences from literature.

RNA plays an extensive role in a multi-dimensional regulatory system, and its biomedical relationships are scattered across numerous biological studies. However, text mining works dedicated to the extraction of RNA biomedical relations remain limited. In this study, we established a comprehensive and reliable corpus of RNA biomedical relations, recruiting over 30,000 sentences manually curated from more than 15,000 biomedical literature. We also updated RIscoper 2.0, a BERT-based deep learning tool to extract RNA biomedical relation sentences from literature. Benefiting from approximately 100,000 annotated named entities, we integrated the text classification and named entity recognition tasks in this tool. Additionally, RIscoper 2.0 outperformed the original tool in both tasks and can discover new RNA biomedical relations. Additionally, we provided a user-friendly online search tool that enables rapid scanning of RNA biomedical relationships using local and online resources. Both the online tools and data resources of RIscoper 2.0 are available at http://www.rnainter.org/riscoper.

Dynamic pathological analysis reveals a protective role against skin fibrosis for TREM2-dependent macrophages.

Rationale: Systemic sclerosis (SSc) is a chronic and incurable autoimmune disease with high mortality rates, and skin fibrosis is one of distinguishing hallmarks in the pathogenesis. However, macrophage heterogeneity regulating skin fibrosis remain largely unknown. Methods: We established mouse disease model and performed single-cell RNA-sequencing (scRNA-seq) to resolve the dynamic and heterogenous characteristics of macrophages in skin fibrosis, and the role of TREM2-dependent macrophages in the pathological process was investigated using knockout mice and intraperitoneal transferring TREM2+ macrophages combining with functional assays. Results: We show that TREM2-expressing macrophages (TREM2+ MФs) accumulate in injured skin of mice treated by bleomycin (BLM) and human SSc, and their gene signatures and functional pathways are identified in the course of disease. Genetic ablation of Trem2 in mice globally accelerates and aggravates skin fibrosis, whereas transferring TREM2hi macrophages improves and alleviates skin fibrosis. Amazingly, we found that disease-associated TREM2+ MФs in skin fibrosis exhibit overlapping signatures with fetal skin counterparts in mice and human to maintain skin homeostasis, but each has merits in skin remodeling and development respectively. Conclusion: This study identifies that TREM2 acts as a functional molecule and a major signaling by which macrophage subpopulations play a protective role against fibrosis, and disease-associated TREM2+ MФs in skin fibrosis might undergo a fetal-like reprogramming similar to fetal skin counterparts.

Enzymatically prepared neoagarooligosaccharides improve gut health and function through promoting the production of spermidine by Faecalibacterium in chickens.

Maintaining animal gut health through modulating the gut microbiota is a constant need when antibiotics are not used in animal feed during the food animal production process. Prebiotics is regarded as one of the most promising antibiotic alternatives for such purpose. As an attractive prebiotic, the role and mechanisms of neoagarooligosaccharides (NAOS) in promoting animal growth and gut health have not been elucidated. In this study, we first cloned and expressed marine bacterial ß-agarase in yeast to optimize the NAOS preparation and then investigated the role and the underlying mechanisms of the prepared NAOS in improving chicken gut health and function. The marine bacterial ß-agarase PDE13B was expressed in Pichia pastoris GS115 and generated even-numbered NAOS. Dietary the prepared NAOS promoted chicken growth and improved intestinal morphology, its barrier, and digestion capabilities, and absorption function. Metagenomic analysis indicated that NAOS modulated the chicken gut microbiota structure and function, and microbial interactions, and promoted the growth of spermidine-producing bacteria especially Faecalibacterium. Through integration of gut metagenome, gut content metabolome, and gut tissue transcriptome, we established connections among NAOS, gut microbes, spermidine, and chicken gut gene expression. The spermidine regulation of genes related to autophagy, immunity, and inflammation was further confirmed in chicken embryo intestinal epithelium cells. We also verified that NAOS can be utilized by Faecalibacterium prausnitzii to grow and produce spermidine in in vitro experiments. Collectively, we provide a systematic investigation of the role of NAOS in regulating gut health and demonstrate the microbial spermidine-mediated mechanism involved in prebiotic effects of NAOS, which lays foundation for future use of NAOS as a new antibiotic alternative in animal production.

Integrated multi-omics reveals the roles of cecal microbiota and its derived bacterial consortium in promoting chicken growth.

IMPORTANCE: The improvement of chicken growth performance is one of the major concerns for the poultry industry. Gut microbes are increasingly evidenced to be associated with chicken physiology and metabolism, thereby influencing chicken growth and development. Here, through integrated multi-omics analyses, we showed that chickens from the same line differing in their body weight were very different in their gut microbiota structure and host-microbiota crosstalk; microbes in high body weight (HBW) chickens contributed to chicken growth by regulating the gut function and homeostasis. We also verified that a specific bacterial consortium consisting of isolates from the HBW chickens has the potential to be used as chicken growth promoters. These findings provide new insights into the potential links between gut microbiota and chicken phenotypes, shedding light on future manipulation of chicken gut microbiota to improve chicken growth performance.

Inulin-enriched Megamonas funiformis ameliorates metabolic dysfunction-associated fatty liver disease by producing propionic acid.

Accumulated evidence supports the beneficial role of inulin in alleviating metabolic dysfunction-associated fatty liver disease (MAFLD) by modulating gut microbiota. However, the underlying mechanisms are not fully understood. Here we used high-fat diet (HFD)-induced laying hen model of MAFLD to investigate the effect of inulin on ameliorating MAFLD and found that the inulin-enriched Megamonas genus was inversely correlated with hepatic steatosis-related parameters. Oral administration of a newly isolated commensal bacterium by culturomics, M. funiformis CML154, to HFD-fed hens and mice ameliorated MAFLD, changed liver gene expression profiles, and increased intestinal propionate concentration. Further evidence demonstrated that the anti-MAFLD effect of M. funiformis CML154 is attributed to propionate-mediated activation of the APN-AMPK-PPARα signaling pathway, thereby inhibiting fatty acid de novo synthesis and promoting ß-oxidation. These findings establish the causal relationships among inulin, M. funiformis, and MAFLD, and suggest that M. funiformis CML154 is a probiotic candidate for preventative or therapeutic intervention of MAFLD.

Quercetin-enriched Lactobacillus aviarius alleviates hyperuricemia by hydrolase-mediated degradation of purine nucleosides.

The development of hyperuricemia (HUA) and gout is associated with dysbiosis of the gut microbiota. Quercetin can reduce serum uric acid levels and thus alleviate HUA by modulating the gut microbiota. However, the detailed mechanisms involved in this process are not fully understood. Here, we showed that quercetin significantly reduced the serum uric acid level in a chicken HUA model by altering the chicken cecal microbiota structure and function and increasing the abundance of Lactobacillus aviarius. An L. aviarius strain, CML180, was isolated from the quercetin-treated chicken gut microbiota. Strain characterization indicated that quercetin promoted the growth of L. aviarius CML180 and increased its adhesion, hydrophobicity, and co-aggregation abilities. Gavage of live L. aviarius CML180 to a mouse model of HUA-established by adenosine and potassium oxonate-reduced the serum uric acid level and alleviated HUA. The ability of L. aviarius CML180 to decrease the level of uric acid was due to its degradation of purine nucleosides, which are the precursors for uric acid production. A nucleoside hydrolase gene, nhy69, was identified from the genome of L. aviarius CML180, and the resulting protein, Nhy69, exhibited strong purine nucleoside-hydrolyzing activity at mesophilic temperature and neutral pH conditions. These findings provide mechanistic insights into the potential of quercetin to treat HUA or gout diseases via a specific gut microbe.

Ginkgo biloba extract alleviates fatty liver hemorrhagic syndrome in laying hens via reshaping gut microbiota.

BACKGROUND: Ginkgo biloba extract (GBE) is evidenced to be effective in the prevention and alleviation of metabolic disorders, including obesity, diabetes and fatty liver disease. However, the role of GBE in alleviating fatty liver hemorrhagic syndrome (FLHS) in laying hens and the underlying mechanisms remain to be elucidated. Here, we investigated the effects of GBE on relieving FLHS with an emphasis on the modulatory role of GBE in chicken gut microbiota. RESULTS: The results showed that GBE treatment ameliorated biochemical blood indicators in high-fat diet (HFD)-induced FLHS laying hen model by decreasing the levels of TG, TC, ALT and ALP. The lipid accumulation and pathological score of liver were also relieved after GBE treatment. Moreover, GBE treatment enhanced the antioxidant activity of liver and serum by increasing GSH, SOD, T-AOC, GSH-PX and reducing MDA, and downregulated the expression of genes related to lipid synthesis (FAS, LXRα, GPAT1, PPARγ and ChREBP1) and inflammatory cytokines (TNF-α, IL-6, TLR4 and NF-κB) in the liver. Microbial profiling analysis revealed that GBE treatment reshaped the HFD-perturbed gut microbiota, particularly elevated the abundance of Megasphaera in the cecum. Meanwhile, targeted metabolomic analysis of SCFAs revealed that GBE treatment significantly promoted the production of total SCFAs, acetate and propionate, which were positively correlated with the GBE-enriched gut microbiota. Finally, we confirmed that the GBE-altered gut microbiota was sufficient to alleviate FLHS by fecal microbiota transplantation (FMT). CONCLUSIONS: We provided evidence that GBE alleviated FLHS in HFD-induced laying hens through reshaping the composition of gut microbiota. Our findings shed light on mechanism underlying the anti-FLHS efficacy of GBE and lay foundations for future use of GBE as additive to prevent and control FLHS in laying hen industry.

Enzymatically prepared alginate oligosaccharides improve broiler chicken growth performance by modulating the gut microbiota and growth hormone signals.

BACKGROUND: Alginate oligosaccharide (AOS) holds great potential as a novel feed supplement in farm animals. However, the effects of AOS on chicken health and the underlying mechanisms are not fully understood. This study aimed to optimize the enzymatic preparation of AOS by using bacterial alginate lyases expressed in yeast, investigate the effects of the prepared AOS on the growth performance and gut health of broiler chickens, and reveal the underlying mechanisms. RESULTS: Five alginate lyases from bacteria were cloned into Pichia pastoris GS115 and the alginate lyase PDE9 was expressed at relatively high yield, activity and stability in P. pastoris. Animal trials were carried out using 320 1-day-old male Arbor Acres broilers (four groups; 8 replicates/group × 10 chicks/replicate) receiving either a basal diet or the same diet supplemented with 100, 200 and 400 mg/kg PDE9-prepared AOS for 42 d. The results showed that dietary supplementation of 200 mg/kg AOS displayed the highest activity in promoting the birds' ADG and ADFI (P < 0.05). AOS ameliorated the intestinal morphology, absorption function and barrier function, as indicated by the enhanced (P < 0.05) intestinal villus height, maltase activity, and the expression of PEPT, SGLT1, ZNT1, and occludin. AOS also increased serum insulin-like growth factor-1, ghrelin (P < 0.05), and growth hormone (P < 0.1). Moreover, the concentrations of acetate, isobutyrate, isovalerate, valerate, and total SCFAs in cecum of birds fed AOS were significantly higher than the control birds (P < 0.05). Metagenomic analysis indicated that AOS modulated the chicken gut microbiota structure, function, and microbial interactions and promoted the growth of SCFAs-producing bacteria, for example, Dorea sp. 002160985; SCFAs, especially acetate, were found positively correlated with the chicken growth performance and growth-related hormone signals (P < 0.05). We further verified that AOS can be utilized by Dorea sp. to grow and to produce acetate in vitro. CONCLUSIONS: We demonstrated that the enzymatically produced AOS effectively promoted broiler chicken growth performance by modulating the chicken gut microbiota structure and function. For the first time, we established the connections among AOS, chicken gut microbiota/SCFAs, growth hormone signals and chicken growth performance.

Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis.

The gut microbiota (GM) plays a crucial role in maintaining the overall health and well-being of the host. Recent studies have demonstrated that the GM may significantly influence bone metabolism and degenerative skeletal diseases, such as osteoporosis (OP). Interventions targeting GM modification, including probiotics or antibiotics, have been found to affect bone remodeling. This review provides a comprehensive summary of recent research on the role of GM in regulating bone remodeling and seeks to elucidate the regulatory mechanism from various perspectives, such as the interaction with the immune system, interplay with estrogen or parathyroid hormone (PTH), the impact of GM metabolites, and the effect of extracellular vesicles (EVs). Moreover, this review explores the potential of probiotics as a therapeutic approach for OP. The insights presented may contribute to the development of innovative GM-targeted therapies for OP.

Soil physiochemical properties and bacterial community changes under long-term polycyclic aromatic hydrocarbon stress insitu steel plant soils.

In situ soils were collected at two depths in Jinan and Hangzhou steel plants, which both have a long history of operation and polycyclic aromatic hydrocarbons (PAHs) contamination. The richness of 16 S rRNA gene and bacterial community of the soil were determined by real-time PCR and high-throughput sequencing. Soil physicochemical properties, PAHs contamination characteristics, and their interrelationships were also analyzed. In general, the PAHs contamination decreased with increasing soil depths. The physicochemical properties and PAH concentration of soil had synergistic impacts on the composition of the bacterial community. The long-term higher PAHs stress in Hangzhou contaminated soil (982 mg kg-1) increased the bacterial abundance and diversity, while that of Jinan contaminated soil (63 mg kg-1) decreased bacterial abundance and diversity. The pH value, sand content of the soil were positively correlated (P < 0.05) with the bacterial diversity including Simpson, Shannon, Observed_species and Chao1 indexes., and the other soil properties exhibited negative correlations with different strengths. The abundances of Curvibacter, Pseudomonas, Thiobacillus, Lysobacter, and Limnobacter were positively correlated with the PAHs concentration (P < 0.01). Additionally, the network structure of the PAHs-contaminated soils was more complex compared to that of uncontaminated soils, with stronger linkages and correlations between the different bacteria. These findings provide a theoretical basis for microbial remediation of PAHs-polluted soil.

The temporal dynamics of antimicrobial-resistant Salmonella enterica and predominant serovars in China.

Salmonella enterica is one of the most common bacterial pathogens in humans and animals. Systematic studies on the trends and geographical distribution of antimicrobial-resistant Salmonella and dominant serovars have been well studied in European and American countries while not in China. Here, taking the One-Health strategy, we used >35 000 Salmonella enterica isolates to explore the temporal and spatial dynamics of dominant serovars in China. We found that Salmonella Typhimurium was the dominant serovar causing human infection in China, which was consistent with Australia but inconsistent with North American and European countries. The proportion of Salmonella serovars Typhimurium, London, Rissen, Corvallis, Meleagridis, Kentucky, and Goldcoast showed an increasing trend during 2006-2019. We randomly selected 1962 isolates for comparative genomics and antimicrobial resistance studies and found that the number of antibiotic resistance genes (ARGs) per isolate increased 1.84 and 2.69 times of human and non-human origins, respectively, spanning 14 years. The proportion of antimicrobial-resistant Salmonella isolates had an increasing trend during 2006-2019, especially beta-lactam, quinolone, tetracycline, and rifampicin resistance. Moreover, we found that higher diversity of sequence types (STs) in S. Typhimurium than in other serovars, ST34 from pig and ST19 from chicken origin, were mainly associated with isolates causing child and adult gastro-infection, respectively. Our results fill in the data gap on the trends of dominant serovars and antimicrobial resistance of Salmonella enterica in China. These data provide useful information for public health decision-makers prioritizing interventions for foodborne diseases and food safety.

Integration of SNP genotyping and 16S rRNA amplicon sequencing to identify heritable gut microbes in chickens.

The effect of host genetics on the gut microbiota is not fully understood. Here, we introduce a protocol that describes the steps necessary to analyze the SNP genotyping and amplicon sequencing data to identify heritable microbes in chicken gut. We apply this protocol to infer the cecal heritable taxa and their associated SNPs in chicken genome sequence. This will be beneficial for the identification of gut microbes that are influenced by host genetics in both humans and animals. For complete details on the use and execution of this protocol, please refer to Feng et al. (2022).1.

Mining chicken ileal microbiota for immunomodulatory microorganisms.

The gut microbiota makes important contributions to host immune system development and resistance to pathogen infections, especially during early life. However, studies addressing the immunomodulatory functions of gut microbial individuals or populations are limited. In this study, we explore the systemic impact of the ileal microbiota on immune cell development and function of chickens and identify the members of the microbiota involved in immune system modulation. We initially used a time-series design with six time points to prove that ileal microbiota at different succession stages is intimately connected to immune cell maturation. Antibiotics perturbed the microbiota succession and negatively affected immune development, whereas early exposure to the ileal commensal microbiota from more mature birds promoted immune cell development and facilitated pathogen elimination after Salmonella Typhimurium infection, illustrating that early colonization of gut microbiota is an important driver of immune development. Five bacterial strains, Blautia coccoides, Bacteroides xylanisolvens, Fournierella sp002159185, Romboutsia lituseburensis, and Megamonas funiformis, which are closely related to the immune system development of broiler chickens, were then screened out and validated for their immunomodulatory properties. Our results provide insight into poultry immune system-microbiota interactions and also establish a foundation for targeted immunological interventions aiming to combat infectious diseases and promote poultry health and production.

Comparison of DNA targeting CRISPR editors in human cells.

BACKGROUND: Profiling and comparing the performance of current widely used DNA targeting CRISPR systems provide the basic information for the gene-editing toolkit and can be a useful resource for this field. In the current study, we made a parallel comparison between the recently reported miniature Cas12f1 (Un1Cas12f1 and AsCas12f1) and the widely used Cas12a and Cas9 nucleases in mammalian cells. RESULTS: We found that as a CRISPRa activator, Un1Cas12f1 could induce gene expression with a comparable level to that of Cas12a and Cas9, while as a DNA cleavage editor, Cas12f1 exhibited similar properties to Cas12a, like high specificity and dominantly induced deletions over insertions, but with less activity. In contrast, wild-type SpCas9 showed the highest activity, lowest specificity, and induced balanced deletions and insertions. Thus, Cas12f1 is recommended for gene-activation-based applications, Cas12a is for therapy applications, and wild-type Cas9 is for in vitro and animal investigations. CONCLUSION: The comparison provided the editing properties of the widely used DNA-targeting CRISPR systems in the gene-editing field.

RNADisease v4.0: an updated resource of RNA-associated diseases, providing RNA-disease analysis, enrichment and prediction.

Numerous studies have shown that RNA plays an important role in the occurrence and development of diseases, and RNA-disease associations are not limited to noncoding RNAs in mammals but also exist for protein-coding RNAs. Furthermore, RNA-associated diseases are found across species including plants and nonmammals. To better analyze diseases at the RNA level and facilitate researchers in exploring the pathogenic mechanism of diseases, we decided to update and change MNDR v3.0 to RNADisease v4.0, a repository for RNA-disease association (http://www.rnadisease.org/ or http://www.rna-society.org/mndr/). Compared to the previous version, new features include: (i) expanded data sources and categories of species, RNA types, and diseases; (ii) the addition of a comprehensive analysis of RNAs from thousands of high-throughput sequencing data of cancer samples and normal samples; (iii) the addition of an RNA-disease enrichment tool and (iv) the addition of four RNA-disease prediction tools. In summary, RNADisease v4.0 provides a comprehensive and concise data resource of RNA-disease associations which contains a total of 3 428 058 RNA-disease entries covering 18 RNA types, 117 species and 4090 diseases to meet the needs of biological research and lay the foundation for future therapeutic applications of diseases.

LncReader: identification of dual functional long noncoding RNAs using a multi-head self-attention mechanism.

Long noncoding ribonucleic acids (RNAs; LncRNAs) endowed with both protein-coding and noncoding functions are referred to as 'dual functional lncRNAs'. Recently, dual functional lncRNAs have been intensively studied and identified as involved in various fundamental cellular processes. However, apart from time-consuming and cell-type-specific experiments, there is virtually no in silico method for predicting the identity of dual functional lncRNAs. Here, we developed a deep-learning model with a multi-head self-attention mechanism, LncReader, to identify dual functional lncRNAs. Our data demonstrated that LncReader showed multiple advantages compared to various classical machine learning methods using benchmark datasets from our previously reported cncRNAdb project. Moreover, to obtain independent in-house datasets for robust testing, mass spectrometry proteomics combined with RNA-seq and Ribo-seq were applied in four leukaemia cell lines, which further confirmed that LncReader achieved the best performance compared to other tools. Therefore, LncReader provides an accurate and practical tool that enables fast dual functional lncRNA identification.