Hypolipidemic Effect of Rice Bran Oil Extract Tocotrienol in High-Fat Diet-Induced Hyperlipidemia Zebrafish (Danio Rerio) Induced by High-Fat Diet.

In recent years, the potent influence of tocotrienol (T3) on diminishing blood glucose and lipid concentrations in both Mus musculus (rats) and Homo sapiens (humans) has been established. However, the comprehensive exploration of tocotrienol's hypolipidemic impact and the corresponding mechanisms in aquatic species remains inadequate. In this study, we established a zebrafish model of a type 2 diabetes mellitus (T2DM) model through high-fat diet administration to zebrafish. In the T2DM zebrafish, the thickness of ocular vascular walls significantly increased compared to the control group, which was mitigated after treatment with T3. Additionally, our findings demonstrate the regulatory effect of T3 on lipid metabolism, leading to the reduced synthesis and storage of adipose tissue in zebrafish. We validated the expression patterns of genes relevant to these processes using RT-qPCR. In the T2DM model, there was an almost two-fold upregulation in pparγ and cyp7a1 mRNA levels, coupled with a significant downregulation in cpt1a mRNA (p < 0.01) compared to the control group. The ELISA revealed that the protein expression levels of Pparγ and Rxrα exhibited a two-fold elevation in the T2DM group relative to the control. In the T3-treated group, Pparγ and Rxrα protein expression levels consistently exhibited a two-fold decrease compared to the model group. Lipid metabolomics showed that T3 could affect the metabolic pathways of zebrafish lipid regulation, including lipid synthesis and decomposition. We provided experimental evidence that T3 could mitigate lipid accumulation in our zebrafish T2DM model. Elucidating the lipid-lowering effects of T3 could help to minimize the detrimental impacts of overfeeding in aquaculture.

Low serum apolipoprotein A1 level predicts poor prognosis of patients with diffuse large B-cell lymphoma in the real world: a retrospective study.

BACKGROUND: Apolipoprotein A1 (ApoA1) is a member of the apolipoprotein family with diverse functions. It is associated with the pathogenesis and prognosis of several types of tumors. However, the role of serum apolipoprotein A1 (ApoA1) in the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. This study aimed to elucidate its influence on clinical outcomes in patients with DLBCL. METHODS: We retrospectively analyzed a cohort of 1583 consecutive DLBCL patients admitted to the Fujian Medical University Union Hospital between January 2011 and December 2021. 949 newly diagnosed DLBCL patients who met the inclusion criteria were enrolled for statistical analysis. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off value for serum ApoA1 levels for prognostic prediction among patients with DLBCL. The correlations between serum ApoA1 levels and clinical and laboratory parameters were analyzed. Prognostic significance was analyzed using univariate and multivariate Cox proportional hazards models. RESULTS: Newly diagnosed patients with DLBCL demonstrated low serum ApoA1 levels (< 0.925 g/L), had more B symptoms, higher levels of serum lactate dehydrogenase (LDH) (>upper limit of normal), poorer performance status (Eastern Cooperative Oncology Group score of 2-4), higher percentage of advanced stage and non-germinal center B-cell (non-GCB) subtype, more cases of > 1 extranodal site, higher International Prognostic Index (IPI) score (3-5), and higher incidence of relapse or refractory diseases compared with those with high serum ApoA1 levels (≥ 0.925 g/L). Low serum ApoA1 levels were an independent adverse prognostic factor for overall survival (OS) but not progression-free survival (PFS). CONCLUSIONS: Low serum ApoA1 levels were associated with poor treatment response and inferior survival in newly diagnosed patients with DLBCL.

SUMOylation of TEAD1 Modulates the Mechanism of Pathological Cardiac Hypertrophy.

Pathological cardiac hypertrophy is the leading cause of heart failure and has an extremely complicated pathogenesis. TEA domain transcription factor 1 (TEAD1) is recognized as an important transcription factor that plays a key regulatory role in cardiovascular disease. This study aimed to explore the role of TEAD1 in cardiac hypertrophy and to clarify the regulatory role of small ubiquitin-like modifier (SUMO)-mediated modifications. First, the expression level of TEAD1 in patients with heart failure, mice, and cardiomyocytes is investigated. It is discovered that TEAD1 is modified by SUMO1 during cardiac hypertrophy and that the process of deSUMOylation is regulated by SUMO-specific protease 1 (SENP1). Lysine 173 is an essential site for TEAD1 SUMOylation, which affects the protein stability, nuclear localization, and DNA-binding ability of TEAD1 and enhances the interaction between TEAD1 and its transcriptional co-activator yes-associated protein 1 in the Hippo pathway. Finally, adeno-associated virus serotype 9 is used to construct TEAD1 wild-type and KR mutant mice and demonstrated that the deSUMOylation of TEAD1 markedly exacerbated cardiomyocyte enlargement in vitro and in a mouse model of cardiac hypertrophy. The results provide novel evidence that the SUMOylation of TEAD1 is a promising therapeutic strategy for hypertrophy-related heart failure.

LAMB3 Promotes Intestinal Inflammation Through SERPINA3 and Is Directly Transcriptionally Regulated by P65 in Inflammatory Bowel Disease.

BACKGROUND: Various extracellular matrix (ECM) reshaping events are involved in inflammatory bowel disease (IBD). LAMB3 is a vital subunit of laminin-332, an important ECM component. Data on the biological function of LAMB3 in intestinal inflammation are lacking. Our aim is to discuss the effect of LAMB3 in IBD. METHODS: LAMB3 expression was assessed in cultured intestinal epithelial cells, inflamed mucosal tissues of patients and mouse colitis models. RNA sequencing, quantitative real-time polymerase chain reaction and Western blotting were used to detect the LAMB3 expression distribution and potential downstream target genes. Dual-luciferase assays and chromatin immunoprecipitation-quantitative polymerase chain reaction were used to determine whether P65 could transcriptionally activate LAMB3 under tumor necrosis factor α stimulation. RESULTS: LAMB3 expression was increased in inflammatory states in intestinal epithelial cells and colonoids and was associated with adverse clinical outcomes in Crohn's disease. Knockdown of LAMB3 inhibited the expression of proinflammatory cytokines. Mechanistically, LAMB3 expression was directly transcriptionally activated by P65 and was inhibited by nuclear factor kappa B inhibitors under tumor necrosis factor α stimulation. Furthermore, RNA sequencing and replenishment experiments revealed that LAMB3 upregulated SERPINA3 to promote intestinal inflammation via the integrin α3ß1/FAK pathway. CONCLUSION: We propose that LAMB3 could serve as a potential therapeutic target of IBD and a predictor of intestinal stenosis of Crohn's disease. Our findings demonstrate the important role of ECM in the progression of IBD and offer an experimental basis for the treatment and prognosis of IBD.

[Expression and Clinical Significance of Exosome Component 4 in Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To explore the expression of Exosome Component 4（EXOSC4） in the tissues of newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) and its clinical significance. METHODS: The expression of EXOSC4 protein in the tissues of 181 newly diagnosed DLBCL patients was analyzed by immunohistochemical staining. Clinical data were collected. The correlation between EXOSC4 protein expression in the tissues of newly diagnosed DLBCL patients and clinical features were analyzed and its prognostic significance. RESULTS: The positive rate of EXOSC4 protein expression was 68.51% in the tissues of 181 newly diagnosed DLBCL patients. These patients were divided into two groups, with 44 cases in high expression group and 137 cases in low expression group. There were no significant differences in age, gender, B symptoms, serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group (ECOG) score, Ann Arbor stage, extranodal disease, International Prognostic Index (IPI) score, National Comprehensive Cancer Network IPI (NCCN-IPI) score, and cell origin between the two groups (P>0.05). Cox multivariate regression analysis showed that high EXOSC4 protein expression in tissues was an independent poor prognostic factor for OS and PFS in newly diagnosed DLBCL patients (all P<0.05). K-M survival analysis showed that newly diagnosed DLBCL patients with high EXOSC4 protein expression had significantly shorter overall survival (OS) and progression free survival (PFS) than those patients with low EXOSC4 protein expression (all P<0.05). CONCLUSION: High EXOSC4 protein expression in tissues of newly diagnosed DLBCL patients is an independent poor prognostic factor for survival.

Mucosal immunity and microbiota change in the rainbow trout (Oncorhynchus mykiss) gills after being challenged with infectious hematopoietic necrosis virus.

Respiratory structures are crucial for vertebrate survival, as they serve not only to perform gas-exchange processes but also as entry points for opportunistic pathogens. Previous studies have demonstrated that fish contain gill mucosal-associated lymphoid tissue, and harbor a large number of commensal bacteria on their surface and contribute to maintaining fish health. However, by far, very limited information is known regarding the effects of viral infection on gill mucosal immunity and microbiota homeostasis. In this study, we conducted an infection model by bath with infectious hematopoietic necrosis virus (IHNV) and revealed a 27 % mortality rate among rainbow trout in the first two weeks after infection. Moreover, we found that diseased fish with the highest IHNV loads in gills exhibiting severe damage, as well as increased goblet cell counts in both primary lamellae (PL) and secondary lamellae (SL). Additionally, RT-qPCR and RNA-seq analyses revealed that IHNV infection induced a strong innate and adaptive antiviral immune responses. Interestingly, an antibacterial immune response was also observed, suggesting that a secondary bacterial infection occurred in trout gills after viral infection. Furthermore, 16S rRNA analysis of trout gills revealed a profound dysbiosis marked by a loss of beneficial taxa and expansion of pathobionts following IHNV infection. Overall, our finding demonstrates that IHNV infection induces significant changes of the microbial community in the fish respiratory surface, thus triggering local antiviral and bacterial mucosal immunity.

ELK4 Promotes Colorectal Cancer Progression by Activating the Neoangiogenic Factor LRG1 in a Noncanonical SP1/3-Dependent Manner.

Although the MAPK/MEK/ERK pathway is prevalently activated in colorectal cancer (CRC), MEK/ERK inhibitors show limited efficiency in clinic. As a downstream target of MAPK, ELK4 is thought to work primarily by forming a complex with SRF. Whether ELK4 can serve as a potential therapeutic target is unclear and the transcriptional regulatory mechanism has not been systemically analyzed. Here, it is shown that ELK4 promotes CRC tumorigenesis. Integrated genomics- and proteomics-based approaches identified SP1 and SP3, instead of SRF, as cooperative functional partners of ELK4 at genome-wide level in CRC. Serum-induced phosphorylation of ELK4 by MAPKs facilitated its interaction with SP1/SP3. The pathological neoangiogenic factor LRG1 is identified as a direct target of the ELK4-SP1/SP3 complex. Furthermore, targeting the ELK4-SP1/SP3 complex by combination treatment with MEK/ERK inhibitor and the relatively specific SP1 inhibitor mithramycin A (MMA) elicited a synergistic antitumor effect on CRC. Clinically, ELK4 is a marker of poor prognosis in CRC. A 9-gene prognostic model based on the ELK4-SP1/3 complex-regulated gene set showed robust prognostic accuracy. The results demonstrate that ELK4 cooperates with SP1 and SP3 to transcriptionally regulate LRG1 to promote CRC tumorigenesis in an SRF-independent manner, identifying the ELK4-SP1/SP3 complex as a potential target for rational combination therapy.

Analysis of the microbiota composition in the genital tract of infertile patients with chronic endometritis or endometrial polyps.

Background: The previous researches show that infertile patients have a higher incidence of endometritis and endometrial polyps, and the occurrence of these two diseases is related to changes in the microbiota of the genital tract. We aim to determine the composition and changing characteristics of the microbiota in the genital tract (especially the endometrium) of infertile patients with chronic endometritis or endometrial polyps, and find the correlation between it and the occurrence of diseases. Methods: This is a prospective study. We collected genital tract biopsy samples from 134 asymptomatic infertile patients receiving assisted reproductive therapy before embryo transfer. Through pathological examination and 16S ribosomal RNA(16S rRNA) sequencing, we determined the distribution of chronic endometritis and endometrial polyps in these patients, as well as their distribution of reproductive tract microorganisms. Results: Compared with the normal control group, the microbial group of reproductive tract in patients with chronic endometritis and endometrial polyps is changed, and there are significant species differences and relative abundance differences in the vagina, cervix and uterine cavity. Lactobacillus, the dominant flora of female genital tract, showed a change in abundance in patients with endometrial diseases. Endometrial microbiota composed of Staphylococcus, Gardnerella, Atopobium, Streptococcus, Peptostreptococcus, Chlamydia, Fusobacterium, Acinetobacter, etc. are related to chronic endometritis and endometrial polyps. Conclusion: The results showed that, compared with the normal control group, the endometrial microbiota of infertile patients with chronic endometritis or endometrial polyps did have significant changes in the relative abundance distribution of species, suggesting that changes in local microecology may be an important factor in the occurrence of disease, or even adverse pregnancy outcomes. The further study of endometrial microecology may provide a new opportunity to further improve the diagnosis and treatment strategy of chronic endometritis.

KISL: knowledge-injected semi-supervised learning for biological co-expression network modules.

The exploration of important biomarkers associated with cancer development is crucial for diagnosing cancer, designing therapeutic interventions, and predicting prognoses. The analysis of gene co-expression provides a systemic perspective on gene networks and can be a valuable tool for mining biomarkers. The main objective of co-expression network analysis is to discover highly synergistic sets of genes, and the most widely used method is weighted gene co-expression network analysis (WGCNA). With the Pearson correlation coefficient, WGCNA measures gene correlation, and uses hierarchical clustering to identify gene modules. The Pearson correlation coefficient reflects only the linear dependence between variables, and the main drawback of hierarchical clustering is that once two objects are clustered together, the process cannot be reversed. Hence, readjusting inappropriate cluster divisions is not possible. Existing co-expression network analysis methods rely on unsupervised methods that do not utilize prior biological knowledge for module delineation. Here we present a method for identification of outstanding modules in a co-expression network using a knowledge-injected semi-supervised learning approach (KISL), which utilizes apriori biological knowledge and a semi-supervised clustering method to address the issue existing in the current GCN-based clustering methods. To measure the linear and non-linear dependence between genes, we introduce a distance correlation due to the complexity of the gene-gene relationship. Eight RNA-seq datasets of cancer samples are used to validate its effectiveness. In all eight datasets, the KISL algorithm outperformed WGCNA when comparing the silhouette coefficient, Calinski-Harabasz index and Davies-Bouldin index evaluation metrics. According to the results, KISL clusters had better cluster evaluation values and better gene module aggregation. Enrichment analysis of the recognition modules demonstrated their effectiveness in discovering modular structures in biological co-expression networks. In addition, as a general method, KISL can be applied to various co-expression network analyses based on similarity metrics. Source codes for the KISL and the related scripts are available online at https://github.com/Mowonhoo/KISL.git.

Neural functions in cancer: Data analyses and database construction.

Recent studies have revealed that neural functions are involved in possibly every aspect of a cancer development, serving as bridges connecting microenvironmental stressors, activities of intracellular subsystems, and cell survival. Elucidation of the functional roles played by the neural system could provide the missing links in developing a systems-level understanding of cancer biology. However, the existing information is highly fragmented and scattered across the literature and internet databases, making it difficult for cancer researchers to use. We have conducted computational analyses of transcriptomic data of cancer tissues in TCGA and tissues of healthy organs in GTEx, aiming to demonstrate how the functional roles by the neural genes could be derived and what non-neural functions they are associated with, across different stages of 26 cancer types. Several novel discoveries are made, including i) the expressions of certain neural genes can predict the prognosis of a cancer patient; ii) cancer metastasis tends to involve specific neural functions; iii) cancers of low survival rates involve more neural interactions than those with high survival rates; iv) more malignant cancers involve more complex neural functions; and v) neural functions are probably induced to alleviate stresses and help the associated cancer cells to survive. A database, called NGC, is developed for organizing such derived neural functions and associations, along with gene expressions and functional annotations collected from public databases, aiming to provide an integrated and publicly available information resource to enable cancer researchers to take full advantage of the relevant information in their research, facilitated by tools provided by NGC.

The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer.

The secreted protein collagen and calcium-binding EGF domain 1 (CCBE1) is critical for embryonic lymphatic development through its role in the proteolytic activation of mature vascular endothelial growth factor C (VEGFC). We previously reported that CCBE1 is overexpressed in colorectal cancer (CRC) and that its transcription is negatively regulated by the TGFß-SMAD pathway, but the transcriptional activation mechanism of CCBE1 in CRC remains unknown. Recent studies have revealed the vital role of the hippo effectors YAP/TAZ in lymphatic development; however, the role of YAP/TAZ in tumor lymphangiogenesis has not been clarified. In this study, we found that high nuclear expression of transcription factor TEAD4 is associated with lymph node metastasis and high lymphatic vessel density in patients with CRC. YAP/TAZ-TEAD4 complexes transcriptionally upregulated the expression of CCBE1 by directly binding to the enhancer region of CCBE1 in both CRC cells and cancer-associated fibroblasts, which resulted in enhanced VEGFC proteolysis and induced tube formation and migration of human lymphatic endothelial cells in vitro and lymphangiogenesis in a CRC cell-derived xenograft model in vivo. In addition, the bromodomain and extraterminal domain (BET) inhibitor JQ1 significantly inhibited the transcription of CCBE1, suppressed VEGFC proteolysis, and inhibited tumor lymphangiogenesis in vitro and in vivo. Collectively, our study reveals a new positive transcriptional regulatory mechanism of CCBE1 via YAP/TAZ-TEAD4-BRD4 complexes in CRC, which exposes the protumor lymphangiogenic role of YAP/TAZ and the potential inhibitory effect of BET inhibitors on tumor lymphangiogenesis.

Comparative Study on Immune Function of the Head and Trunk Kidney in Rainbow Trout Responding to IHNV Infection.

A teleost's kidney was divided into head kidney and trunk kidney. The head kidney is an important lymphatic organ, while the trunk kidney mainly performs osmotic pressure regulation and excretion functions. Previous studies have shown that the teleost's head kidney exerts a strong immune response against pathogen invasion, while the mechanism of immune response in the trunk kidney is still rarely reported. Therefore, in this study, we established an Infectious hematopoietic necrosis virus (IHNV) immersion infection model to compare the similarities and differences of immune response mechanisms between the head kidney and trunk kidney against viral infection. The results showed that IHNV infection causes severe tissue damage and inflammatory reaction in the head and trunk kidney, triggers a series of interferon cascade reactions, and produces strong immune response. In addition, the transcriptome data showed that the head kidney and trunk kidney had similar immune response mechanisms, which showed that the NOD-like receptor signaling pathway and Toll-like receptor signaling pathway were activated. In conclusion, despite functional differentiation, the teleost's trunk kidney still has a strong immune response, especially the interferon-stimulated genes, which have stronger immune response in the trunk kidney than in the head kidney when responding to IHNV infection. This study contributes to a more comprehensive understanding of the teleost immune system and enriches the theory of kidney immunity in teleosts.

Alterations of the Mucosal Immune Response and Microbial Community of the Skin upon Viral Infection in Rainbow Trout (Oncorhynchus mykiss).

The skin is the largest organ on the surface of vertebrates, which not only acts as the first line of defense against pathogens but also harbors diverse symbiotic microorganisms. The complex interaction between skin immunity, pathogens, and commensal bacteria has been extensively studied in mammals. However, little is known regarding the effects of viral infection on the skin immune response and microbial composition in teleost fish. In this study, we exposed rainbow trout (Oncorhynchus mykiss) to infectious hematopoietic necrosis virus (IHNV) by immersion infection. Through pathogen load detection and pathological evaluation, we confirmed that IHNV successfully invaded the rainbow trout, causing severe damage to the epidermis of the skin. qPCR analyses revealed that IHNV invasion significantly upregulated antiviral genes and elicited strong innate immune responses. Transcriptome analyses indicated that IHNV challenge induced strong antiviral responses mediated by pattern recognition receptor (PRR) signaling pathways in the early stage of the infection (4 days post-infection (dpi)), and an extremely strong antibacterial immune response occurred at 14 dpi. Our 16S rRNA sequencing results indicated that the skin microbial community of IHNV-infected fish was significantly richer and more diverse. Particularly, the infected fish exhibited a decrease in Proteobacteria accompanied by an increase in Actinobacteria. Furthermore, IHNV invasion favored the colonization of opportunistic pathogens such as Rhodococcus and Vibrio on the skin, especially in the later stage of infection, leading to dysbiosis. Our findings suggest that IHNV invasion is associated with skin microbiota dysbiosis and could thus lead to secondary bacterial infection.

CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis.

Dysregulation of Hippo pathway leads to hyperactivation of YAP-TEAD transcriptional complex in various cancers, including colorectal cancer (CRC). In this study, we observed that HHEX (Hematopoietically expressed homeobox) may enhance transcription activity of the YAP-TEAD complex. HHEX associates with and stabilizes the YAP-TEAD complex on the regulatory genomic loci to coregulate the expression of a group of YAP/TEAD target genes. Also, HHEX may indirectly regulate these target genes by controlling YAP/TAZ expression. Importantly, HHEX is required for the pro-tumorigenic effects of YAP during CRC progression. In response to serum stimulation, CK2 (Casein Kinase 2) phosphorylates HHEX and enhances its interaction with TEAD4. A CK2 inhibitor CX-4945 diminishes the interaction between HHEX and TEAD4, leading to decreased expression of YAP/TEAD target genes. CX-4945 synergizes the antitumor activity of YAP-TEAD inhibitors verteporfin and Super-TDU. Elevated expression of HHEX is correlated with hyperactivation of YAP/TEAD and associated with poor prognosis of CRC patients. Overall, our study identifies HHEX as a positive modulator of YAP/TEAD to promote colorectal tumorigenesis, providing a new therapeutic strategy for targeting YAP/TEAD in CRC.

IHNV Infection Induces Strong Mucosal Immunity and Changes of Microbiota in Trout Intestine.

The fish intestinal mucosa is among the main sites through which environmental microorganisms interact with the host. Therefore, this tissue not only constitutes the first line of defense against pathogenic microorganisms but also plays a crucial role in commensal colonization. The interaction between the mucosal immune system, commensal microbiota, and viral pathogens has been extensively described in the mammalian intestine. However, very few studies have characterized these interactions in early vertebrates such as teleosts. In this study, rainbow trout (Oncorhynchus mykiss) was infected with infectious hematopoietic necrosis virus (IHNV) via a recently developed immersion method to explore the effects of viral infection on gut immunity and microbial community structure. IHNV successfully invaded the gut mucosa of trout, resulting in severe tissue damage, inflammation, and an increase in gut mucus. Moreover, viral infection triggered a strong innate and adaptive immune response in the gut, and RNA-seq analysis indicated that both antiviral and antibacterial immune pathways were induced, suggesting that the viral infection was accompanied by secondary bacterial infection. Furthermore, 16S rRNA sequencing also revealed that IHNV infection induced severe dysbiosis, which was characterized by large increases in the abundance of Bacteroidetes and pathobiont proliferation. Moreover, the fish that survived viral infection exhibited a reversal of tissue damage and inflammation, and their microbiome was restored to its pre-infection state. Our findings thus demonstrated that the relationships between the microbiota and gut immune system are highly sensitive to the physiological changes triggered by viral infection. Therefore, opportunistic bacterial infection must also be considered when developing strategies to control viral infection.

Blood brain barrier permeability and immune function of brain in rainbow trout responding to IHNV infection.

Viral infection of the central nervous system (CNS) is often associated with blood-brain barrier (BBB) disruption. Mammals have developed complicated and efficient immune strategies to protect the BBB. However, the immune defense of brain and BBB permeability changes are not well-understood in teleost during virus invading. In this study, we constructed an infectious hematopoietic necrosis virus (IHNV) immersion infected rainbow trout model. After IHNV infection, pathological changes occurred in the brain, and MPO and ROS activities were significantly increased. In addition, the expression levels of BBB permeability-related genes were also changed. Transcriptome analysis showed that immune-related genes and signaling pathways in the brain were activated after IHNV infection. These results showed that the permeability of BBB increased significantly after IHNV infection, thus activating immune related factors and cells to enter the CNS through blood circulation to resist pathogenic infection.

Identification of Prognosis Biomarkers for High-Grade Serous Ovarian Cancer Based on Stemness.

In this paper, high-grade serous ovarian cancer (HGSOC) is studied, which is the most common histological subtype of ovarian cancer. We use a new analytical procedure to combine the bulk RNA-Seq sample for ovarian cancer, mRNA expression-based stemness index (mRNAsi), and single-cell data for ovarian cancer. Through integrating bulk RNA-Seq sample of cancer samples from TCGA, UCSC Xena and single-cell RNA-Seq (scRNA-Seq) data of HGSOC from GEO, and performing a series of computational analyses on them, we identify stemness markers and survival-related markers, explore stem cell populations in ovarian cancer, and provide potential treatment recommendation. As a result, 171 key genes for capturing stem cell characteristics are screened and one vital cancer stem cell subpopulation is identified. Through further analysis of these key genes and cancer stem cell subpopulation, more critical genes can be obtained as LCP2, FCGR3A, COL1A1, COL1A2, MT-CYB, CCT5, and PAPPA, are closely associated with ovarian cancer. So these genes have the potential to be used as prognostic biomarkers for ovarian cancer.

Laser Needle Knife's Effects on Rabbits Cervical Spondylopathy of Vertebral Artery, Fibrinogen, and Blood Viscosity.

Objective: To determine the effect of laser needle-knife on vertebroarterial morphology, fibrinogen and blood viscosity in a rabbit model of cervical spondylotic arteriopathy (CSA) and the mechanism of action involved. Methods: A number of 40 healthy common grade rabbits were divided into four groups: normal control, model, acupuncture, and laser needle knife group. The normal control group does not establish a CSA rabbit model, and the other groups all establish a CSA rabbit model, but they are treated in different ways. CSA model rabbits were treated with acupuncture and moxibustion at "fengchi" and "cervical Jiaji" points, rabbits in the laser needle knife group were treated with "Jiaji" points, and the acupuncture points were punctured with the laser needle knife. The location of the acupuncture points is determined according to the acupoint map of the experimental map. The right vertebroarterial morphology before and after the treatment was analyzed by scanning electron microscope, and FIB concentration and blood viscosity were determined using the coagulation method. Results: After the treatment, the capillary and micropore hyperplasia in the laser needle knife group were more evident than that in the model group. Acupuncture and laser needle knife therapy can reduce whole blood viscosity (1/s, 5/s), and that the distinction between the two treatments is not statistically evident. Conclusion: Acupuncture and laser needle knife can regulate the coagulation and fibrinolysis system in CSA, stimulate capillary and micropore hyperplasia, reduce blood viscosity, and improve blood circulation, which may be one of the therapeutic mechanisms behind the laser needle knife treatment of CSA.

Spatial distribution and source apportionment of polycyclic aromatic hydrocarbons in typical oasis soil of north-western China and the bacterial community response.

Oases environments in oases to be sensitive to anthropogenic activity because of ecological fragility. Polycyclic aromatic hydrocarbon (PAH) pollution resulting from anthropogenic activity leads to ecological degradation in oases. To examine the impact of anthropogenic activity on the oasis ecological environment, the present study focused on the spatial distribution and source apportionment of soil PAHs and bacterial community responses in typical oases in Xinjiang, China. The results showed that the soil PAH level were higher in the city centres of Urumqi (9-6340 µg kg-1), Aksu (8-957 µg kg-1) and Korla (8-1103 µg kg-1) and lower in the centres of Hotan city (11-268 µg kg-1) and Qira county (7-163 µg kg-1). Source apportionment suggested that gasoline emissions, diesel emissions, vehicle emissions, coal combustion, coke processing and biomass burning were the sources of soil PAHs. The integrated lifetime cancer risks of soil PAH exceeding the guideline safety values (10-6) recommended by United States Environmental Protection Agency. The ingestion and dermal exposure pathways caused the greatest health risk (contribution ≤82%). Additionally, in the soil with low PAH concentrations, the richness and evenness of the soil bacterial community were great, and the molecular ecological network (MEN) structure was complex. Among populations, Proteobacteria and Actinobacteria (relative abundance ≥17%) are the main dominant species in the bacterial communities and the keystone species in the MEN.

Increased expression of yes-associated protein/YAP and transcriptional coactivator with PDZ-binding motif/TAZ activates intestinal fibroblasts to promote intestinal obstruction in Crohn's disease.

BACKGROUND: Intestinal obstruction caused by intestinal fibrosis is a common and serious complication of Crohn's disease (CD). Intestinal fibroblasts, the main effector cells mediating gastrointestinal fibrosis, are activated during chronic inflammation. However, the mechanism of fibroblast activation in CD has not been well elucidated. METHODS: Fibroblasts isolated from stenotic and nonstenotic intestines of CD patients were used for RNA sequencing. Immunohistochemical and immunofluorescent staining was performed to evaluate the correlation between intestinal fibrosis and YAP/TAZ expression in our CD cohort and a DSS-induced chronic colitis murine model. A Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) inhibitor was used to explore the ROCK1-YAP/TAZ axis in intestinal fibroblasts in vitro and DSS-induced chronic colitis murine model in vivo. FINDINGS: The expression of YAP/TAZ was significantly upregulated in stenotic fibroblasts, which was associated with the YAP/TAZ target gene signature. YAP/TAZ knockdown suppressed the activation of intestinal fibroblasts. In intestinal fibroblasts, YAP/TAZ were activated by the Rho-ROCK1 signalling pathway. High YAP/TAZ expression was positively correlated with ROCK1 expression, which is a prognostic marker for intestinal obstruction in CD patients. INTERPRETATION: YAP/TAZ activation can lead to fibroblast activation and intestinal obstruction in CD. The effect of ROCK1 inhibitor on alleviating intestinal fibrosis is associated with YAP/TAZ inhibition. Targeted inhibition of YAP/TAZ in fibroblasts may be a potential therapeutic strategy to suppress intestinal fibrosis in CD. FUNDING: This work was supported by the National Key R&D Program of China (2019YFC1316002), the NSFC (81873547, 82073201, 81874177, 82000481) and the Shanghai Sailing Program (20YF1429400).