Multi-Region Markovian Gaussian Process: An Efficient Method to Discover Directional Communications Across Multiple Brain Regions.

Studying the complex interactions between different brain regions is crucial in neuroscience. Various statistical methods have explored the latent communication across multiple brain regions. Two main categories are the Gaussian Process (GP) and Linear Dynamical System (LDS), each with unique strengths. The GP-based approach effectively discovers latent variables with frequency bands and communication directions. Conversely, the LDS-based approach is computationally efficient but lacks powerful expressiveness in latent representation. In this study, we merge both methodologies by creating an LDS mirroring a multi-output GP, termed Multi-Region Markovian Gaussian Process (MRM-GP). Our work establishes a connection between an LDS and a multi-output GP that explicitly models frequencies and phase delays within the latent space of neural recordings. Consequently, the model achieves a linear inference cost over time points and provides an interpretable low-dimensional representation, revealing communication directions across brain regions and separating oscillatory communications into different frequency bands.

Assessing the impact of industrial intelligence on urban carbon emission performance: Evidence from China.

With the growing emphasis on sustainable development, there has been increasing attention given to measures aimed at promoting environmental improvements and reducing carbon emissions, including the adoption of intelligent industry. Recent studies have analyzed the influence of industrial intelligence on urban carbon emission performance while ignore the spatial spillover effects and lack in-depth discussion of the mechanisms, which reduces the reliability of the assessment of industrial intelligence's impact on carbon emission performance. To address this issue, the paper examines direct effect, spatial spillover effects, and mechanisms, utilizing a balanced panel data from 2008 to 2019 for 238 Chinese cities. The findings reveal that a 1 % improvement in industrial intelligence results in a 2.747 % enhancement of local carbon emission performance. Moreover, through the spatial spillover analysis, we determined that industrial intelligence has a notable negative impact on the carbon emission performance of surrounding areas. The mechanism analysis demonstrated that industrial intelligence affects the carbon emission performance of local and neighboring areas by influencing the agglomeration of productive services. Furthermore, our study illustrates that the industrial intelligence's enhancement effect on carbon emission performance shows more significantly in eastern, resource-dependent, and ordinary prefecture-level cities. Finally, endogeneity and robustness tests conducted yielded consistent conclusions. Our study provides a new perspective on industrial intelligence's carbon reduction effect and contributes to the development of policies related to industrial upgrading and green development.

Predicting pragmatic functions of Chinese echo questions using prosody: evidence from acoustic analysis and data modeling.

Echo questions serve two pragmatic functions (recapitulatory and explicatory) and are subdivided into two types (yes-no echo question and wh-echo question) in verbal communication. Yet to date, most relevant studies have been conducted in European languages like English and Spanish. It remains unknown whether the different functions of echo questions can be conveyed via prosody in spoken Chinese. Additionally, no comparison was made on the diversified algorithmic models in predicting functions by the prosodity of Chinese echo questions, a novel linguistic cognition in nature. This motivated us to use different acoustic cues to predict different pragmatic functions of Chinese echo questions by virtue of acoustic experiment and data modeling. The results showed that for yes-no echo question, explicatory function exhibited higher pitch and intensity patterns than recapitulatory function whereas for wh-echo question, recapitulatory function demonstrated higher pitch and intensity patterns than explicatory function. With regard to data modeling, the algorithm Support Vector Machine (SVM) relative to Random Forest (RF) and Logistic Regression (LR) performed better when predicting different functions using prosodic cues in both yes-no and wh-echo questions. This study from a digitized perspective adds evidence to the cognition of echo questions' functions on a prosodic basis.

Trichinella spiralis -induced immunomodulation signatures on gut microbiota and metabolic pathways in mice.

The hygiene hypothesis proposes that decreased exposure to infectious agents in developed countries may contribute to the development of allergic and autoimmune diseases. Trichinella spiralis, a parasitic roundworm, causes trichinellosis, also known as trichinosis, in humans. T. spiralis had many hosts, and almost any mammal could become infected. Adult worms lived in the small intestine, while the larvae lived in muscle cells of the same mammal. T. spiralis was a significant public health threat because it could cause severe illness and even death in humans who eat undercooked or raw meat containing the parasite. The complex interactions between gastrointestinal helminths, gut microbiota, and the host immune system present a challenge for researchers. Two groups of mice were infected with T. spiralis vs uninfected control, and the experiment was conducted over 60 days. The 16S rRNA gene sequences and untargeted LC/MS-based metabolomics of fecal and serum samples, respectively, from different stages of development of the Trichinella spiralis-mouse model, were examined in this study. Gut microbiota alterations and metabolic activity accompanied by parasite-induced immunomodulation were detected. The inflammation parameters of the duodenum (villus/crypt ratio, goblet cell number and size, and histological score) were involved in active inflammation and oxidative metabolite profiles. These profiles included increased biosynthesis of phenylalanine, tyrosine, and tryptophan while decreasing cholesterol metabolism and primary and secondary bile acid biosynthesis. These disrupted metabolisms adapted to infection stress during the enteral and parenteral phases and then return to homeostasis during the encapsulated phase. There was a shift from an abundance of Bacteroides in the parenteral phase to an abundance of probiotic Lactobacillus and Treg-associated-Clostridia in the encapsulated phase. Th2 immune response (IL-4/IL-5/IL-13), lamina propria Treg, and immune hyporesponsiveness metabolic pathways (decreased tropane, piperidine and pyridine alkaloid biosynthesis and biosynthesis of alkaloids derived from ornithine, lysine, and nicotinic acid) were all altered. These findings enhanced our understanding of gut microbiota and metabolic profiles of Trichinella -infected mice, which could be a driving force in parasite-shaping immune system maintenance.

Anoikis-related CTNND1 is associated with immuno-suppressive tumor microenvironment and predicts unfavorable immunotherapeutic outcome in non-small cell lung cancer.

Background: Immunotherapy has greatly changed the treatment of advanced non-small cell lung cancer (NSCLC). Anoikis is a programmed cell death process associated with cancer. However, the correlation between anoikis-related genes and the tumor microenvironment (TME) features and immunotherapeutic outcome in NSCLC has not been fully explored. Methods: The bulk and single-cell transcriptome data of NSCLC were downloaded from TCGA and GEO databases. The distribution of anoikis-related genes on different cell types at the single-cell level was analyzed, and these genes specifically expressed by tumor cells and immunotherapy-related were further extracted. Next, the candidate gene CTNND1 was identified and its correlations with the TME features and immunotherapeutic outcome in NSCLC were explored in multiple public cohorts. Finally, an in-house cohort was used to determine the CTNND1 expression and immuno-correlation in NSCLC. Results: At single-cell atlas, we found that anoikis-related genes expressed specifically in tumor cells of NSCLC. By intersecting anoikis-related genes, immunotherapy-associated genes, and the genes expressed in tumor cells, we obtained a special biomarker CTNND1. In addition, cell-cell communication analysis revealed that CTNND1+ tumor cells communicated with immune subpopulations frequently. Moreover, we found that high expression of CTNND1 was related to immuno-suppressive status of NSCLC. The expression of CTNND1 and its immuno-correlation were also validated, and the results showed that CTNND1 was highly expressed in NSCLC tissues and tumors with high CTNND1 expression accompanied with low CD8+ T cells infiltration. Conclusions: Overall, our study reported that CTNND1 can be considered as a novel biomarker for the predication of immunotherapeutic responses and a potential target for NSCLC therapy.

Pioneer Factor Foxa2 Mediates Chromatin Conformation Changes for Activation of Bile Acid Targets of FXR.

BACKGROUND & AIMS: Transcription factors regulate gene expression that orchestrates liver physiology. Many bind at distal enhancers and chromatin looping is required to activate their targets. Chromatin architecture has been linked to essential functions of the liver, including metabolism and sexually dimorphic gene expression. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors farnesoid X receptor (FXR) and liver X receptor-α during acute ligand activation. FXR is activated by bile acids and deletion of Foxa2 in the liver results in intrahepatic cholestasis. We hypothesized that Foxa2 also enables chromatin conformational changes during ligand activation and performed genome-wide studies to test this hypothesis. METHODS: We performed Foxa2 HiChIP (Hi-C and ChIP) to assess Foxa2-dependent long-range interactions in mouse livers treated with either vehicle control or FXR agonist GW4064. RESULTS: HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. Ligand-treated livers exhibit extensive redistribution of topological associated domains and substantial increase in Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes. We demonstrate that chromatin conformation, including genome-wide interactions, topological associated domains, and intrachromosomal and interchromosomal Foxa2-anchored loops, drastically changes on addition of FXR agonist. Additional Foxa2 binding in ligand-activated state leads to formation of Foxa2-anchored loops, leading to distal interactions and activation of gene expression of FXR targets. CONCLUSIONS: Ligand activation of FXR, and likely of related receptors, requires global changes in chromatin architecture. We determine a novel role for Foxa2 in enabling these conformational changes, extending its function in bile acid metabolism.

Current situation and trend of translational research of acupuncture-moxibustion in treatment of aphasia based on knowledge graph analysis. / åŸºäºŽçŸ¥è¯†å›¾è°±æŠ€æœ¯åˆ†æžé’ˆç¸æ²»ç–—å¤±è¯­ç—‡è½¬åŒ–ç ”ç©¶çš„çŽ°çŠ¶ä¸Žè¶‹åŠ¿.

OBJECTIVES: To investigate the hot topics in acupuncture-moxibustion research for treatment of aphasia and explore the current situation and trend of technology transformation in this field through analyzing the relevant Chinese literatures in recent 30 years by means of knowledge graph technology. METHODS: CiteSpace 6.1.R 2 and VOSviewer V1.6.16 software were used to collate the data, draw knowledge graphs and conduct visual analysis of the literatures related to acupuncture-moxibustion treatment of aphasia, searched from CNKI, WanFang and VIP databases.The time line view and strongest bursts of keywords were formed in the field of acupuncture-moxibustion treatment for aphasia. The treatment-based keyword networks were visualized. RESULTS: A total of 773 Chinese articles were included. Through visual analysis of the co-occurrence networks, the top 10 high-frequency overall keywords and the top 10 clusters of overall keywords were listed. The top 5 high-frequency aphasia categories were Broca aphasia, hysterical aphasia, transcortical motor aphasia, nominal aphasia and sensory aphasia. Regarding the keywords of the techniques of acupuncture-moxibustion, the occurrence frequencies of scalp acupuncture, tongue acupuncture, body acupuncture and electroacupuncture were ≥ 10 times.The occurrence frequencies of 16 acupoints were ≥25 times. After collation and cluster analysis of acupoints and techniques of acupuncture-moxibustion, 7 keyword clusters of "acupuncture techniques-acupoints" were obtained. The time line view showed that the strongest burst of keywords were transcranial magnatic stimulation, language rehabilitation training, acupuncture-medicine therapy and stroke, etc. in the recent 5 years. CONCLUSIONS: Acupuncture-moxibustion displays its unique advantage in treatment of aphasia. With the deepening of modern research, the hot topics for aphasia treated with acupuncture-moxibustion are present and the achievements enriched. In future, these therapeutic methods should be further investigated to explore a model of translational medicine for aphasia in line with the characteristics of acupuncture-moxibustion.

Identification of hypervirulent Klebsiella pneumoniae based on biomarkers and Galleria mellonella infection model.

BACKGROUND: Currently, clinical laboratories lack an effective method to differentiate between classical Klebsiella pneumoniae (cKP) and hypervirulent Klebsiella pneumoniae (hvKP) strains, leading to delays in diagnosing and treating hvKP infections. Previous studies have identified peg-344, iroB, iucA, prmpA, prmpA2, and siderophores (SP) yields greater than 30 µg/ml as reliable markers for distinguishing hvKP from cKp strains. However, these diagnostic tests were conducted on a relatively small study population and lacked sufficient clinical data support. In this study, hvKP strains were identified by biomarker analysis and the Galleria mellonella model. Combined with in vitro and in vivo experiments, the reliability of clinical identification method of hvKP was verified, which provided an experimental basis for timely diagnosis of hvKP infection. RESULTS: According to the clinical data, a total of 108 strains of hvKP were preliminary screened. Among them, 94 strains were further identified using PCR analysis of biomarkers and quantitative determination of SP. The high virulence of hvKP was subsequently confirmed through infection experiments on Galleria mellonella. Additionally, susceptibility testing revealed the identification of 58 carbapenem-resistant hvKP (CR-hvKP) strains and 36 carbapenem-sensitive hvKP (CS-hvKP) strains. By comparing molecular diagnostic indexes, molecular characteristics such as high SP production of CR-hvKP were found. CONCLUSION: The combination of clinical data and molecular diagnostic index analysis effectively enables the identification of hvKP, particularly CR-hvKP. This study provides a scientific basis for accurate clinical identification and timely treatment of hvKP.

Evaluation of the serum tRNA-derived fragment tRF-5022B as a potential biomarker for the diagnosis of osteoarthritis.

Osteoarthritis (OA) is a degenerative disease. It is common in middle-aged and elderly people and is one of the main causes of disability. Currently, the etiology of OA is unclear, and no specific biomarkers for the diagnosis of OA have been identified. Therefore, finding a highly sensitive biomarker is essential for a proper diagnosis.TRNA-derived fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs) are newly discovered classes of noncoding RNAs. tRF has been proven in several studies to have significant associations with tumor diagnosis, making it a promising biomarker in cancer research. However, the diagnostic utility of tRF in OA patients and the correlation between OA progression and trf differential expression have yet to be elaborated. The purpose of this research was to identify tRFs with differential expression in OA to assess their potential as OA biomarkers. To determine the tRF-5022B expression level in this research, real-time fluorescence quantitative PCR has been employed. Agarose gel electrophoresis, Sanger sequencing, and other investigations have been employed for evaluating tRF-5022B's molecular properties. Receiver operating characteristic curve analysis has been utilized for assessing the diagnostic effectiveness of the tRF-5022B. The findings demonstrated that tRF-5022B expression was considerably lower in OA serum. The Kellgren-Lawrence grading scale was shown to correspond with serum expression levels. The ROC curve confirmed that tRF-5022B serum expression levels might differentiate OA cases from healthy individuals and RA patients. According to the aforementioned findings, tRF-5022B may be employed as a novel biomarker for OA diagnosis due to its excellent diagnostic value.

Repeated Transcranial Photobiomodulation with Light-Emitting Diodes Improves Psychomotor Vigilance and EEG Networks of the Human Brain.

Transcranial photobiomodulation (tPBM) has been suggested as a non-invasive neuromodulation tool. The repetitive administration of light-emitting diode (LED)-based tPBM for several weeks significantly improves human cognition. To understand the electrophysiological effects of LED-tPBM on the human brain, we investigated alterations by repeated tPBM in vigilance performance and brain networks using electroencephalography (EEG) in healthy participants. Active and sham LED-based tPBM were administered to the right forehead of young participants twice a week for four weeks. The participants performed a psychomotor vigilance task (PVT) during each tPBM/sham experiment. A 64-electrode EEG system recorded electrophysiological signals from each participant during the first and last visits in a 4-week study. Topographical maps of the EEG power enhanced by tPBM were statistically compared for the repeated tPBM effect. A new data processing framework combining the group's singular value decomposition (gSVD) with eLORETA was implemented to identify EEG brain networks. The reaction time of the PVT in the tPBM-treated group was significantly improved over four weeks compared to that in the sham group. We observed acute increases in EEG delta and alpha powers during a 10 min LED-tPBM while the participants performed the PVT task. We also found that the theta, beta, and gamma EEG powers significantly increased overall after four weeks of LED-tPBM. Combining gSVD with eLORETA enabled us to identify EEG brain networks and the corresponding network power changes by repeated 4-week tPBM. This study clearly demonstrated that a 4-week prefrontal LED-tPBM can neuromodulate several key EEG networks, implying a possible causal effect between modulated brain networks and improved psychomotor vigilance outcomes.

[Study on the explicitation of implicit knowledge and the construction of knowledge graph on moxibustion in medical case records of ZHOU Mei-sheng's Jiusheng].

To explore the methods of the explicitation of implicit knowledge and the construction of knowledge graph on moxibustion in medical case records of ZHOU Mei-sheng's Jiusheng. The medical case records data of Jiusheng was collected, the frequency statistic was analyzed based on Python3.8.6, complex network analysis was performed using Gephi9.2 software, community analysis was performed by the ancient and modern medical case cloud platform V2.3.5, and analysis and verification of correlation graph and weight graph were proceed by Neo4j3.5.25 image database. The disease systems with frequency≥10 % were surgery, ophthalmology and otorhinolaryngology, locomotor, digestive and respiratory systems. The diseases under the disease system were mainly carbuncle, arthritis, lumbar disc herniation and headache. The commonly used moxibustion methods were fumigating moxibustion, blowing moxibustion, direct moxibustion and warming acupuncture. The core prescription of points obtained by complex network analysis included Yatong point, Zhiyang(GV 9), Sanyinjiao(SP 6), Dazhui(GV 14), Zusanli(ST 36), Lingtai(GV 10), Xinshu(BL 15), Zhijian point and Hegu(LI 4), which were basically consistent with high-frequency points. A total of 6 communities were obtained by community analysis, corresponding to different diseases. Through the analysis of correlation graph, 13 pairs of strong association rule points were obtained. The correlation between Zhiyang(GV 9)-Dazhui(GV 14) and Yatong point-Lingtai(GV 10) was the strongest. The acupoints with high correlation with Yatong point were Zhiyang(GV 9), Lingtai(GV 10), Dazhui(GV 14), Zusanli(ST 36) and Sanyinjiao(SP 6). In the weight graph of the high-frequency disease system, the relationship of the first weight of the surgery system disease was fumigating moxibustion-carbuncle-Yatong point, and the relationship of the first weight of the ophthalmology and otorhinolaryngology system disease was blowing moxibustion-laryngitis-Hegu (LI 4). The results of correlation graph and weight graph are consistent with the results of data mining, which can be used as an effective way to study the knowledge base of moxibustion diagnosis and treatment in the future.

A cuproptosis-related lncRNAs risk model to predict prognosis and guide immunotherapy for lung adenocarcinoma.

Background: Cuproptosis, one of the newest forms of cell death induction, is attracting mounting attention. However, the role of cuproptosis in lung cancer is currently unclear. In this study, we constructed a prognostic signature utilizing cuproptosis-related long noncoding RNAs (CRL) in lung adenocarcinoma (LUAD) and researched its clinical and molecular function. Methods: RNA-related and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed CRLs were screened using the 'limma' package of R software. We used coexpression analysis and univariate Cox analysis to further identify prognostic CRLs. Applying least absolute shrinkage and selection operator (LASSO) regression and Cox regression models, a prognostic risk model based on 16 prognostic CRLs was constructed. To validate prognostic CRL function in LUAD, vitro experiments were conducted to explore the expression of GLIS2-AS1, LINC01230, and LINC00592 in LUAD. Subsequently, according to a formula, patients in the training, test, and overall groups were split into high- and low-risk groups. Kaplan-Meier and receiver operating characteristic (ROC) analyses were applied to assess the predictability of the risk model. Finally, the associations between risk signature and immunity-related analysis, somatic mutation, principal component analysis (PCA), enriched molecular pathways, and drug sensitivity was investigated. Results: A cuproptosis-related long noncoding RNAs (lncRNAs) signature was constructed. Using quantitative polymerase chain reaction (qPCR) trial, we verified that the expressions of GLIS2-AS1, LINC01230, and LINC00592 in LUAD cell lines and tissues were consistent with the above screening results. Based on this signature, a total of 471 LUAD samples from TCGA data set were split into two risk groups based on the computed risk score. The risk model showed a better capacity in predicting prognosis than traditional clinicopathological features. Moreover, significant differences were found in immune cell infiltration, drug sensitivity, and immune checkpoint expression between the two risk groups. Conclusions: The CRLs signature was shown to be a prospective biomarker to forecast prognosis in patients with LUAD and presents new insights for personalized treatment of LUAD.

Pioneer factor Foxa2 mediates chromatin conformation changes in ligand-dependent activation of nuclear receptor FXR.

Activation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in development of drug targets. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors FXR and LXRα during acute ligand activation. FXR is activated by bile acids and deletion of Foxa2 in the liver results in intrahepatic cholestasis. We hypothesized that Foxa2 also enables chromatin conformational changes during ligand activation. We performed Foxa2 HiChIP to assess Foxa2-dependent long-range interactions in mouse livers treated with either vehicle control or FXR agonist GW4064. HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. Ligand-treated livers exhibit extensive redistribution of topological associated domains (TAD and substantial increase in Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes. We demonstrate that chromatin conformation, including genome-wide interactions, TADs, intra-chromosomal and inter-chromosomal Foxa2-anchored loops, drastically changes upon addition of FXR agonist. Hence, we determine a novel role for Foxa2 in enabling these conformational changes, extending its function in bile acid metabolism.

Comprehensive study of rice YABBY gene family: evolution, expression and interacting proteins analysis.

As plant-specific transcription regulators, YABBYs are involved in plant growth, development and stress responses. However, little information is available about genome-wide screening and identification of OsYABBY-interacting proteins. In this study, phylogenetic relationship, gene structure, protein structure and gene expression profile of eight OsYABBYs were carried out, all of which indicated that OsYABBYs were involved in different developmental processes and had functional differentiation. More importantly, PPI (protein-protein interaction) analysis and molecular docking simulation predicted that WUSCHEL-related homeobox (WOX) proteins might be interacting proteins of OsYABBYs. Yeast two-hybrid (Y2H) and luciferase complementation imaging assays (LCI) further confirmed that OsYABBYs (except for OsYABBY7) could interact with OsWOX3A in vitro and in vivo. In addition, OsYABBY3 and OsYABBY5 also could interact with OsWUS. Taken together, our results provided valuable information for further elucidating OsYABBYs regulation mechanism in improving rice performance.

Optimization of the hongqu starter preparation process for the manufacturing of red mold rice with high gamma-aminobutyric acid production by solid-state fermentation.

Red mold rice (RMR) generally contains gamma-aminobutyric acid (GABA), which has several physiological functions. Monascus purpureus M162, with a high GABA production of 15.10 mg/g was generated by atmospheric and room temperature plasma mutation. Furthermore, we conducted a response surface methodology to produce a premium hongqu starter. The results revealed that under optimal conditions, that is, a substrate containing brown rice and bran in a brown rice: bran ratio of 9:1 (wt/wt), an inoculation size of 21.50 mL/100 g, a mixing frequency of one time/9 h, and a cultivation time of 7.20 days, the number of active spores, α-amylase activity, and saccharification power activity was 4.15 × 107 spores/g, 155 U/g, and 3260 U/g in the high-quality starter, respectively. These values were 224.32-fold, 139.64%, and 141.74% higher than those obtained with M. purpureus M162 inoculated into steamed indica rice, respectively, and 153.70-fold, 267.24%, and 151.63% higher than those obtained with the parent strain M. purpureus M1, respectively. The premium hongqu starter of M. purpureus M162 was inoculated into steamed indica rice to produce RMR with 15.93 mg/g of GABA. In conclusion, we proposed a novel strategy for functional RMR production with high GABA concentrations by solid-state fermentation with Monascus spp.

Platelet membrane-camouflaged nanoparticles carry microRNA inhibitor against myocardial ischaemia‒reperfusion injury.

The incidence of myocardial ischaemia‒reperfusion injury (MIRI) is increasing every year, and there is an urgent need to develop new therapeutic approaches. Nrf2 is thought to play a protective role during MIRI and it is regulated by microRNAs (miRNAs). This study focused on PLGA nanoparticles camouflaged by platelet membrane vesicles (PMVs) (i.e., PMVs@PLGA complexes) carrying microRNA inhibitors, which regulate Nrf2 and can play a therapeutic role in the MIRI process. In vitro and in vivo characterization showed that PMVs@PLGA has excellent transfection efficiency, low toxicity and good targeting. MicroRNAs that effectively regulate Nrf2 were identified, and then PMVs@PLGA-miRNA complexes were prepared and used for in vitro and in vivo treatment. PMVs@PLGA-miRNA complexes can effectively target the delivery of inhibitors to cardiomyocytes. Our results suggest that PMVs@PLGA complexes are a novel delivery system and a novel biological approach to the treatment of MIRI.

Colicins of Escherichia coli Lead to Resistance against the Diarrhea-Causing Pathogen Enterotoxigenic E. coli in Pigs.

Gut microbes can affect host adaptation to various environment conditions. Escherichia coli is a common gut species, including pathogenic strains and nonpathogenic strains. This study was conducted to investigate the effects of different E. coli strains in the gut on the health of pigs. In this study, the complete genomes of two E. coli strains isolated from pigs were sequenced. The whole genomes of Y18J and the enterotoxigenic E. coli strain W25K were compared to determine their roles in pig adaptation to disease. Y18J was isolated from feces of healthy piglets and showed strong antimicrobial activity against W25K in vitro. Gene knockout experiments and complementation analysis followed by modeling the microbe-microbe interactions demonstrated that the antagonistic mechanism of Y18J against W25K relied on the bacteriocins colicin B and colicin M. Compared to W25K, Y18J is devoid of exotoxin-coding genes and has more secondary-metabolite-biosynthetic gene clusters. W25K carries more genes involved in genome replication, in accordance with a shorter cell cycle observed during a growth experiment. The analysis of gut metagenomes in different pig breeds showed that colicins B and M were enriched in Laiwu pigs, a Chinese local breed, but were scarce in boars and Duroc pigs. IMPORTANCE This study revealed the heterogeneity of E. coli strains from pigs, including two strains studied by both in silico and wet experiments in detail and 14 strains studied by bioinformatics analysis. E. coli Y18J may improve the adaptability of pigs toward disease resistance through the production of colicins B and M. Our findings could shed light on the pathogenic and harmless roles of E. coli in modern animal husbandry, leading to a better understanding of intestinal-microbe-pathogen interactions in the course of evolution.

Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin.

BACKGROUND: Circular RNA (circRNA) is crucial to the progression of hepatocellular cancer (HCC). In addition, Mitochondrial calcium uniporter regulatory factor 1 (MCUR1) is commonly overexpressed in HCC to increase cellular ATP levels. Due to the highly aggressive characteristics of HCC, it is essential to identify new diagnostic biomarkers and therapeutic targets that may facilitate the diagnosis of HCC and the development of effective anti-HCC treatments. METHODS: A series of in vitro and in vivo experiments were undertaken to investigate the biological importance and underlying mechanisms of circ_0000098 in HCC. RESULTS: The expression of circ_0000098 was higher in HCC tissues compared to paired adjacent tissues. According to the receiver-operating characteristic curves, circ_0000098 functioned as a potential diagnostic tumor marker in HCC. Our experiments indicated that circ_0000098 served as a key oncogenic circRNA to increase HCC cell proliferation and invasion in vitro and HCC progression in vivo. Furthermore, mechanistic investigation demonstrated that by sequestering miR-383 from the 3'-UTR of MCUR1, circ_0000098 positively regulated MCUR1 expression in HCC cells and finally promoted HCC progression. On the other hand, inhibiting circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing P-glycoprotein (P-gp, MDR1) expression and intracellular ATP levels. Either downregulation of MCUR1 or overexpression of miR-383 improved DOX sensitivity in HCC cells. Subsequently, a short hairpin RNA targeting circ_0000098 (referred to as sh-1) and doxorubicin (DOX) were encapsulated into platelets (PLTs), referred to as DOX/sh-1@PLT. Activated DOX/sh-1@PLT through HCC cells resulted in the creation of platelet-derived particles that were capable of delivering the DOX/sh-1 combination into HCC cells and promoting intracellular DOX accumulation. Furthermore, our in vivo experiments showed that DOX/sh-1@PLT can effectively reduce P-gp expression, promote DOX accumulation, and reverse DOX resistance. CONCLUSIONS: Our results demonstrated that circ_0000098 is an oncogenic circRNA that promotes HCC development through the miR-383/MCUR1 axis and targeting circ_0000098 with DOX/sh-1@PLT may be a promising and practical therapeutic strategy for preventing DOX resistance in HCC.