Investigation of the Seroprevalence of Brucella Antibodies and Characterization of Field Strains in Immunized Dairy Cows by B. abortus A19.

(1) Background: One method of eradicating brucellosis is to cull cattle that test positive for antibodies 12 months after being vaccinated with the 19-strain vaccine. Variations in immunization regimens and feeding practices may contribute to differences in the rate of persistent antibodies. We conducted this study to investigate the real positive rate of Brucella antibody in field strains of Brucella spp. after immunization over 12 months in dairy cows. This research aims to provide data to support the development of strategies for preventing, controlling, and eradicating brucellosis. (2) Method: We employed the baseline sampling method to collect samples from cows immunized with the A19 vaccine for over 12 months in Lingwu City from 2021 to 2023. Serological detection was conducted using the RBPT method. An established PCR method that could distinguish between 19 and non-19 strains of Brucella was utilized to investigate the field strains of Brucella on 10 dairy farms based on six samples mixed into one using the Mathematical Expectation strategy. (3) Results: We analyzed the rates of individual seropositivity and herd seropositive rates in dairy cattle in Lingwu City from 2021 to 2023 and revealed that antibodies induced by the Brucella abortus strain A19 vaccine persist in dairy herds for more than 12 months. We established a PCR method for identifying both Brucella A19 and non-A19 strains, resulting in the detection of 10 field strains of Brucella abortus from 1537 dairy cows. By employing a Mathematical Expectation strategy, we completed testing of 1537 samples after conducting only 306 tests, thereby reducing the workload by 80.1%. (4) Conclusions: There was a certain proportion of cows with a persistent antibody titer, but there was no evidence that all of these cattle were naturally infected with Brucella. The established PCR method for distinguishing between Brucella abortus strain 19 and non-19 strains can be specifically utilized for detecting natural Brucella infection in immunized cattle. We propose that relying solely on the detection of antibodies in cattle immunized with the A19 vaccine more than 12 months previously should not be solely relied upon as a diagnostic basis for brucellosis, and it is essential to complement this approach with PCR analysis to specifically identify field Brucella spp. Brucella abortus was the predominant strain identified in the field during this study. Detection based on the Mathematical Expectation strategy can significantly enhance detection efficiency.

Rumen microbiome-driven insight into bile acid metabolism and host metabolic regulation.

Gut microbes play a crucial role in transforming primary bile acids (BAs) into secondary forms, which influence systemic metabolic processes. The rumen, a distinctive and critical microbial habitat in ruminants, boasts a diverse array of microbial species with multifaceted metabolic capabilities. There remains a gap in our understanding of BA metabolism within this ecosystem. Herein, through the analysis of 9371 metagenome-assembled genomes and 329 cultured organisms from the rumen, we identified two enzymes integral to BA metabolism: 3-dehydro-bile acid delta4,6-reductase (baiN) and the bile acid:Na + symporter family (BASS). Both in vitro and in vivo experiments were employed by introducing exogenous BAs. We revealed a transformation of BAs in rumen and found an enzyme cluster, including L-ribulose-5-phosphate 3-epimerase and dihydroorotate dehydrogenase. This cluster, distinct from the previously known BA-inducible operon responsible for 7α-dehydroxylation, suggests a previously unrecognized pathway potentially converting primary BAs into secondary BAs. Moreover, our in vivo experiments indicated that microbial BA administration in the rumen can modulate amino acid and lipid metabolism, with systemic impacts underscored by core secondary BAs and their metabolites. Our study provides insights into the rumen microbiome's role in BA metabolism, revealing a complex microbial pathway for BA biotransformation and its subsequent effect on host metabolic pathways, including those for glucose, amino acids, and lipids. This research not only advances our understanding of microbial BA metabolism but also underscores its wider implications for metabolic regulation, offering opportunities for improving animal and potentially human health.

Exploring the metabolomic landscape: Perilla frutescens as a promising enhancer of production, flavor, and nutrition in Tan lamb meat.

Addressing health-related concerns linked to the metabolite profile of lamb meat has become paramount, in line with the growing demand for enhanced flavor and taste. We examined the impact of Perilla frutescens seeds on Tan lamb growth, carcass traits, and metabolite profiles. Three diets were employed: a low-concentrate group (LC), a high-concentrate group (HC), and a PFS group (the LC diet supplemented with 3% Perilla frutescens seeds) on a dry matter basis. Forty-five male Tan-lambs (approximately six months) with similar body weights (25.1 kg ± 1.12 SD) were randomly assigned to one of these three groups for 84-day feeding, including an initial 14-day adjustment phase. The supplementation of PFS resulted in increased average daily gain (P < 0.01) and improved carcass quality and meat color (P < 0.05). Additionally, it led to an enhancement in omega-3 polyunsaturated fatty acids (P < 0.05) and a reduction in the omega-6/omega-3 ratio (P < 0.05). Using gas chromatography-mass spectrometry, 369 volatile compounds were identified with enhanced levels of acetaldehyde and 1,2,4-trimethyl-benzene associated with PFS (P < 0.05). Among the 807 compounds identified by ultra-high performance liquid chromatography-mass spectrometry, there were 66 significantly differential compounds (P < 0.05), including 43 hydrophilic metabolites and 23 lipids. PFS supplementation led to significant alterations in 66 metabolites, with three metabolites including 2,5-diisopropyl-3-methylphenol, 3-hydroxydecanoic acid, and lysophosphatidylcholine (15:0) emerging as potential PFS-related biomarkers. The study indicates that PFS supplementation can enhance Tan-lamb growth, feed efficiency, and meat quality, potentially providing lamb meat with improved flavor and nutritional characteristics.

(P)ppGpp synthetase Rsh participates in rifampicin tolerance of persister cells in Brucella abortus in vitro.

Brucella abortus is facultative intracellular pathogen that causes chronic persistent infections and results in abortion and infertility in food animals. Recurrent infections can be one of the results of persister cells formation that transiently displays phenotypic tolerance to high dose of antibiotics treatment. We examined persister cells formation of B. abortus strain A19 in stationary phase and investigated a potential role for the (p)ppGpp synthetase Rsh in this process. We found that B. abortus stationary phase cells can produce higher levels of multi-drugs tolerant persister cells in vitro under high dose of antibiotics (20 × MIC) exposure than do exponential phase cells. Persister cell formation was also induced with environmental stressors pH 4.5, 0.01 M PBS (pH7.0), 2% NaCl and 25 °C, upon exposure to ampicillin, enrofloxacin and rifampicin. Persister cells were not formed following exposure to 1 mM H2O2. The numbers of persister cells were significantly increased following uptake of B. abortus stationary phase cells by RAW264.7 macrophages in contrast with cultures in TSB liquid medium. Environmental stressors to B. abortus significantly increased expression of rsh mRNA level. The rsh null mutant (Δrsh) formed significantly fewer persister cells than the complemented (CΔrsh) and wildtype (WT) strains under high dose of rifampicin in vitro. These data for the first time demonstrate that B. abortus can produce multi-drug tolerant persister cells in stationary phase. The (p)ppGpp synthetase Rsh is necessary for persister cell formation in B. abortus in the presence of rifampicin. On this basis, a new understanding of the recurrent infections of Brucella was advanced, thus provided a new basis for revelation of pathogenic mechanism of the chronic persistent infection in Brucella.

Hyocholic acid retards renal fibrosis by regulating lipid metabolism and inflammatory response in a sheep model.

The kidneys are vital organs that regulate metabolic homeostasis in the body, filter waste products from the blood, and remove extrahepatic bile acids. We previously found that the dietary supplementation of hyocholic acid alleviated the sheep body lipid deposition and decreased kidney weight. This study evaluated hyocholic acid's (HCA) roles and mechanisms on lipid metabolism and anti-inflammatory function in the kidney under a high-energy diet. Histomicrograph showing the apparent improvement by HCA by attenuating structural damage. The HCA treatment reduced the renal accumulation of cholesterol. Bile acid receptors such as LXR and FXR were activated at the protein level. HCA significantly altered several genes related to immune response (NF-κB, IL-6, and MCP1) and fibrosis (TGF-ß, Col1α1, and α-SMA). These significant changes correlated with renal lipid accumulation. The KEGG pathways including non-alcoholic fatty liver disease, insulin resistance, TNF signaling pathway, and Th17 cell differentiation were enriched and NF-κB, IL-6, and TGF-ß were identified as the core interconnected genes. This study revealed that HCA plays an efficient role in alleviating kidney lipids accumulation and inflammatory response through crucial genes such as FXR, LXR, HMGCR, NF-κB, IL-6, MCP1, and TGF-ß, and expand our understanding of HCA's role in kidney function. In conclusion, HCA mitigated kidney fibrosis, lipid metabolism disorders and immune responses induced by a high-energy diet by regulating a potential LXR/SREBP2/TGF-ß-NF-κB signaling pathway.

Cinnamic acid mitigates left ventricular hypertrophy and heart failure in part through modulating FTO-dependent N6-methyladenosine RNA modification in cardiomyocytes.

Left ventricular hypertrophy leads to heart failure, a serious medical condition associated with high rates of hospitalization and mortality. Limited success with the existing pharmacological treatments necessitates the development of mechanisms-based new therapies to better control the progression from left ventricular hypertrophy to heart failure. The current work investigated the pharmacological potentials and mechanisms of naturally occurring cinnamic acid in the treatment of left ventricular hypertrophy and heart failure. The in vitro findings reveal that cinnamic acid attenuates the hypertrophic responses and mitochondrial dysfunction in the phenylephrine (PE)-stimulated cardiomyocytes. Furthermore, cinnamic acid offsets PE-induced increases in N6-methyladenosine (m6A) RNA modification and reductions in the expression of the key m6A demethylase FTO in cardiomyocytes. Most importantly, FTO knockdown abrogates anti-hypertrophic and mitochondrial protective effects of cinnamic acid in the PE-stimulated cardiomyocytes. The in vivo results further demonstrate that cinnamic acid mitigates left ventricular hypertrophy, left ventricular systolic dysfunction and ultrastructural impairment of cardiomyocyte mitochondria and myofibrils in the mice subjected to transverse aortic constriction (TAC)-induced pressure overload. Moreover, FTO knockdown abolishes these beneficial effects of cinnamic acid in the TAC mice. In conclusion, the work here demonstrates for the first time that cinnamic acid is effective at mitigating pressure overload-induced left ventricular hypertrophy and heart failure in part by modulating the expression of FTO and the level of FTO-dependent m6A RNA modification in cardiomyocytes. These novel findings warrant further evaluation of cinnamic acid as a pharmacological agent/component to complement the existing treatment of pressure overload-mediated left ventricular hypertrophy and heart failure.

A novel epithelial-mesenchymal transition (EMT)-related gene signature of predictive value for the survival outcomes in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a remarkably heterogeneous and aggressive disease with dismal prognosis of patients. The identification of promising prognostic biomarkers might enable effective diagnosis and treatment of LUAD. Aberrant activation of epithelial-mesenchymal transition (EMT) is required for LUAD initiation, progression and metastasis. With the purpose of identifying a robust EMT-related gene signature (E-signature) to monitor the survival outcomes of LUAD patients. In The Cancer Genome Atlas (TCGA) database, least absolute shrinkage and selection operator (LASSO) analysis and cox regression analysis were conducted to acquire prognostic and EMT-related genes. A 4 EMT-related and prognostic gene signature, comprising dickkopf-like protein 1 (DKK1), lysyl oxidase-like 2 (LOXL2), matrix Gla protein (MGP) and slit guidance ligand 3 (SLIT3), was identified. By the usage of datum derived from TCGA database and Western blotting analysis, compared with adjacent tissue samples, DKK1 and LOXL2 protein expression in LUAD tissue samples were significantly higher, whereas the trend of MGP and SLIT3 expression were opposite. Concurrent with upregulation of epithelial markers and downregulation of mesenchymal markers, knockdown of DKK1 and LOXL2 impeded the migration and invasion of LUAD cells. Simultaneously, MGP and SLIT3 silencing promoted metastasis and induce EMT of LUAD cells. In the TCGA-LUAD set, receiver operating characteristic (ROC) analysis indicated that our risk model based on the identified E-signature was superior to those reported in literatures. Additionally, the E-signature carried robust prognostic significance. The validity of prediction in the E-signature was validated by the three independent datasets obtained from Gene Expression Omnibus (GEO) database. The probabilistic nomogram including the E-signature, pathological T stage and N stage was constructed and the nomogram demonstrated satisfactory discrimination and calibration. In LUAD patients, the E-signature risk score was associated with T stage, N stage, M stage and TNM stage. GSEA (gene set enrichment analysis) analysis indicated that the E-signature might be linked to the pathways including GLYCOLYSIS, MYC TARGETS, DNA REPAIR and so on. In conclusion, our study explored an innovative EMT based prognostic signature that might serve as a potential target for personalized and precision medicine.

TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA.

Tripartite motif-containing 44 (TRIM44) has recently been implicated in various pathological processes in numerous cancers, including lung adenocarcinoma (LUAD); however, its functional roles in chemoresistance are poorly understood. Herein, TRIM44 knockdown sensitized LUAD cells to cisplatin and enhanced cisplatin-induced apoptosis. Microarray analysis indicated that the "Role of BRCA1 in DNA damage" and the BRCA1 gene expression were positively regulated by TRIM44, which was further verified by immunofluorescence, qRT-PCR, and Western blotting. BRCA1 depletion effectively abolished TRIM44-modulated cisplatin resistance and regulation of homologous recombination (HR) repair. Interestingly, TRIM44 interacted with FLNA, an upstream regulator of BRCA1 as specified by STRING V 11.5, and facilitated its stability and deubiquitination. FLNA was also found to be required for the functions of TRIM44 in drug resistance. Using animal models, overexpression of TRIM44 was shown to confer resistance to cisplatin in a BRCA1- and FLNA-dependent manner. TRIM44 expression levels in tissues from cisplatin-resistant LUAD patients were significantly higher than those in tissues from cisplatin-sensitive LUAD patients. Collectively, our study results demonstrate that the TRIM44/FLNA/BRCA1 axis is involved in cisplatin chemoresistance, providing potential therapeutic targets for LUAD patients with cisplatin resistance.

Circulating MicroRNA-505 May Serve as a Prognostic Biomarker for Hypertension-Associated Endothelial Dysfunction and Inflammation.

Our previous study has reported that the plasma microRNA-505 (miR-505) is elevated in hypertensive patients. However, the pathophysiological significance of miR-505 in hypertension remains to be elucidated. Hypertension is not only a vascular disorder, but also an inflammatory condition. The current study therefore aims to further investigate the pathophysiological implications of miR-505 in hypertension-associated vascular and inflammatory changes. In vivo experiments reveal that the plasma level of miR-505 is elevated in spontaneously hypertensive rats and angiotensin II-infused mice. In addition, miR-505 agomir treatment results in elevated blood pressure, endothelial dysfunction, increased vascular expression of inflammatory genes and renal inflammatory injuries as well as pre-activation of PBMCs in mice. In vitro experiments further demonstrate that miR-505 agomir increases the expression of IL1B and TNFA, whereas miR-505 antagomir attenuates TNF-α-induced upregulation of IL1B and TNFA in endothelial cells, HUVECs. In addition, miR-505 modulates the levels of endothelial activation markers VCAM1 and E-selectin in HUVECs as well as the adhesion of THP-1 monocytes to HUVECs. Lastly, the plasma level of miR-505 is positively correlated with systolic blood pressure and the level of C-reactive protein in human subjects. Our work links for the first time miR-505 to endothelial dysfunction and inflammation under hypertensive conditions, supporting the translational value of miR-505 in prognosticating hypertension-associated endothelial impairment and inflammatory injuries in target organs such as the vessels and kidneys.

A novel EHD1/CD44/Hippo/SP1 positive feedback loop potentiates stemness and metastasis in lung adenocarcinoma.

BACKGROUND: There is growing evidence that endocytosis plays a pivotal role in cancer metastasis. In this study, we first identified endocytic and metastasis-associated genes (EMGs) and then investigated the biological functions and mechanisms of EMGs. METHODS: Cancer stem cells (CSCs)-like characteristics were evaluated by tumour limiting dilution assays, three-dimensional (3D) spheroid cancer models. Microarray analysis was used to identify the pathways significantly regulated by mammalian Eps15 homology domain protein 1 (EHD1) knockdown. Mass spectrometry (MS) was performed to identify EHD1-interacting proteins. The function of EHD1 as a regulator of cluster of differentiation 44 (CD44) endocytic recycling and lysosomal degradation was determined by CD44 biotinylation and recycling assays. RESULTS: EHD1 was identified as a significant EMG. Knockdown of EHD1 suppressed CSCs-like characteristics, epithelial-mesenchymal transition (EMT), migration and invasion of lung adenocarcinoma (LUAD) cells by increasing Hippo kinase cascade activation. Conversely, EHD1 overexpression inhibited the Hippo pathway to promote cancer stemness and metastasis. Notably, utilising MS analysis, the CD44 protein was identified as a potential binding partner of EHD1. Furthermore, EHD1 enhanced CD44 recycling and stability. Indeed, silencing of CD44 or disruption of the EHD1/CD44 interaction enhanced Hippo pathway activity and reduced CSCs-like traits, EMT and metastasis. Interestingly, specificity protein 1 (SP1), a known downstream target gene of the Hippo-TEA-domain family members 1 (TEAD1) pathway, was found to directly bind to the EHD1 promoter region and induce its expression. Among clinical specimens, the EHD1 expression level in LUAD tissues of metastatic patients was higher than that of non-metastatic patients. CONCLUSIONS: Our findings emphasise that EHD1 might be a potent anti-metastatic target and present a novel regulatory mechanism by which the EHD1/CD44/Hippo/SP1 positive feedback circuit plays pivotal roles in coupling modules of CSCs-like properties and EMT in LUAD. Targeting this loop may serve as a remedy for patients with advanced metastatic LUAD.

Assessment of components related to flavor and taste in Tan-lamb meat under different silage-feeding regimens using integrative metabolomics.

Two untargeted metabolomics approaches based on gas chromatography mass spectrometry and ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry were used to identify the effects of different feeding regimes (concentrate, corn silage, alfalfa silage, mulberry leaf silage) on the potential meat flavor and taste components of Tan-lamb. Among 31 identified volatiles, hexanal was affected by the alfalfa silage diet, and 3-hydroxydodecanoic acid was changed by the mulberry leaf silage diet. l-Pipecolic acid (area under the curve = 1, fold change = 0.18-0.48) and trimethylamine N-oxide (area under the curve = 1, fold change = 5.26-22.84) was the potential best discriminant biomarker under alfalfa silage and concentrate feeding, respectively. The hydrophilic components were more readily changed by feeding regimes than volatile flavor compounds. Our findings are helpful for the illustration of Tan-lamb meat chemistry and producing high-quality lamb meat with improved flavor and taste by corn silage, alfalfa silage, or mulberry leaf silage.

Identification of Differentially Expressed Circular RNAs as miRNA Sponges in Lung Adenocarcinoma.

BACKGROUND: Circular RNAs (circRNAs) may function as the decoys for microRNAs (miRNAs) or proteins, the templates for translation, and the sources of pseudogene generation. The purpose of this study is to determine the diagnostic circRNAs, which are related to lung adenocarcinoma (LUAD), that adsorb miRNAs on the basis of the competing endogenous RNA (ceRNA) hypothesis. METHODS: The differentially expressed circRNAs (DEcircRNAs) in LUAD were revealed by the microarray data (GSE101586 and GSE101684) that were obtained from the Gene Expression Omnibus (GEO) database. The miRNAs that were targeted by the DEcircRNAs were predicted with the CircInteractome, and the target mRNAs of the miRNAs were found by the miRDB and the TargetScan. The ceRNA network was built by the Cytoscape. The potential biological roles and the regulatory mechanisms of the circRNAs were investigated by the Gene Ontology (GO) enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The expression of the host genes of circRNAs was examined by the Ualcan. The survival analysis was performed by the Kaplan-Meier plotter. RESULTS: In comparison with normal lung tissues, LUAD tissues contained 7 overlapping cancer-specific DEcircRNAs with 294 miRNA response elements (MREs). Among the 7 DEcircRNAs, 3 circRNAs (hsa_circ_0072088, hsa_circ_0003528, and hsa_circ_0008274) were upregulated and 4 circRNAs (hsa_circ_0003162, hsa_circ_0029426, hsa_circ_0049271, and hsa_circ_0043256) were downregulated. A circRNA-miRNA-mRNA regulatory network, which included 33 differentially expressed miRNAs (DEmiRNAs) and 2007 differentially expressed mRNAs (DEmRNAs), was constructed. These mRNAs were enriched in the biological function of cell-cell adhesion, response to hypoxia, and stem cell differentiation and were involved in the PI3K-Akt signaling, HIF-1 signaling, and cAMP signaling pathways. CONCLUSION: Our results indicated that 7 DEcircRNAs could have diagnostic value for LUAD. Additionally, the circRNAs-mediated ceRNA network might provide a novel perspective into unraveling the pathogenesis and progression of LUAD.

Convergent Phenotypic Evolution of Rhodopsin for Dim-Light Sensing across Deep-Diving Vertebrates.

Rhodopsin comprises an opsin attached to a retinal chromophore and is the only visual pigment conferring dim-light vision in vertebrates. On activation by photons, the retinal group becomes detached from the opsin, which is then inactive until it is recharged. Of all vertebrate species, those that dive face unique visual challenges, experiencing rapid decreases in light level and hunting in near darkness. Here, we combine sequence analyses with functional assays to show that the rhodopsin pigments of four divergent lineages of deep-diving vertebrates have undergone convergent increases in their retinal release rate. We compare gene sequences and detect parallel amino acids between penguins and diving mammals and perform mutagenesis to show that a single critical residue fully explains the observed increases in retinal release rate in both the emperor penguin and beaked whale. At the same time, we find that other shared sites have no significant effect on retinal release, implying that convergence does not always signify adaptive significance. We propose that accelerated retinal release confers rapid rhodopsin recharging, enabling the visual systems of diving species to adjust quickly to changing light levels as they descend through the water column. This contrasts with nocturnal species, where adaptation to darkness has been attributed to slower retinal release rates.

A feedback circuit comprising EHD1 and 14-3-3ζ sustains ß-catenin/c-Myc-mediated aerobic glycolysis and proliferation in non-small cell lung cancer.

Mammalian Eps15 homology domain 1 (EHD1) participates in the development of non-small cell lung cancer (NSCLC). However, its role in mediating aerobic glycolysis remains unclear. Herein, microarray analysis revealed that EHD1 expression was significantly correlated with the glycolysis/gluconeogenesis pathway. Clinically, EHD1 expression was positively correlated with the maximum standard uptake value (SUVmax) in 18F-FDG PET/CT scans. Additionally, EHD1 knockdown inhibited aerobic glycolysis and proliferation in vitro and in vivo. Furthermore, Wnt/ß-catenin signaling was identified as a critical EHD1-regulated pathway. Co-IP, native gel electrophoresis, and immunoblotting showed that EHD1 contributed to 14-3-3 dimerization via 14-3-3ζ and subsequent activation of ß-catenin/c-Myc signaling. Analysis of the EHD1 regulatory region via ENCODE revealed the potential for c-Myc recruitment, leading to transcriptional activation of EHD1 and formation of an EHD1/14-3-3ζ/ß-catenin/c-Myc positive feedback circuit. Notably, blocking this circuit with a Wnt/ß-catenin inhibitor dramatically inhibited tumor growth in vivo. The positive correlations among EHD1, 14-3-3ζ, c-Myc, and LDHA were further confirmed in NSCLC tissues. Collectively, our study demonstrated that EHD1 activates a 14-3-3ζ/ß-catenin/c-Myc regulatory circuit that synergistically promotes aerobic glycolysis and may constitute a promising therapeutic target for NSCLC.

LINC02678 as a Novel Prognostic Marker Promotes Aggressive Non-small-cell Lung Cancer.

Non-small-cell lung carcinoma (NSCLC) is considered to be a fatal disease and characterized by a poor prognosis. Long non-coding RNAs (lncRNAs) have been reported to act as biomarkers and therapeutic targets in solid tumors. However, the expression of lncRNAs and their clinical relevance in NSCLC remain undetermined. The gene expression data profiled in The Cancer Genome Atlas and Gene Expression Omnibus (GSE81089) were employed to screen differentially expressed lncRNAs in NSCLC. LINC02678 was found to be upregulated in NSCLC and exhibited hypomethylation of the promoter region in NSCLC tissues. LINC02678 (also called RP11-336A10.5) was associated with poorer overall survival and relapse-free survival in NSCLC patients. In vitro models of gain- and loss-of-function demonstrated that LINC02678 promotes NSCLC progression by promoting NSCLC cell proliferation and cell cycle progression, as well as inducing NSCLC cell migration, invasion and epithelial-mesenchymal transition. LINC02678 was primarily located in the nucleus and could bind with the enhancer of zeste homolog 2 (EZH2). Moreover, we found that LINC02678 knockdown impaired the occupancy capacity of EZH2 and trimethylation of lysine 27 on histone 3 (H3K27me3) at the promoter region of cyclin dependent kinase inhibitor 1B (CDKN1B) and E-cadherin, as confirmed by ChIP-qPCR. A mouse transplantation model further demonstrated that LINC02678 could promote the tumorigenic and metastatic capacities of NSCLC cells. We identified LINC02678 as a tumor promoter in NSCLC, which enhanced the growth and metastasis of NSCLC cells by binding with EZH2, indicating that LINC02678 may serve as a potential biomarker for cancer diagnosis and treatment.

Dual Activity of Ginsenoside Rb1 in Hypertrophic Cardiomyocytes and Activated Macrophages: Implications for the Therapeutic Intervention of Cardiac Hypertrophy.

PURPOSE: Owing to the important mechanistic implications in the pathogenesis of cardiac hypertrophy and heart failure, inflammation has been proposed as a druggable target for the treatment of cardiac hypertrophy and heart failure. Ginseng is a widely used medicinal herb for the treatment of cardiovascular disorders. As one of the major chemical components of ginseng, ginsenoside Rb1 (Rb1) contributes to the cardiovascular effects of ginseng. Meanwhile, anti-inflammatory activity of Rb1 has also been documented. The current work aims to further delineate the pharmacological implications of Rb1 in the treatment of cardiac hypertrophy. METHODS: Angiotensin II (Ang II) infusion mouse model was adopted to investigate the effects of Rb1 on cardiac hypertrophic remodeling and associated inflammation in vivo. Furthermore, the mechanisms of actions of Rb1 in modulating the hypertrophic and inflammatory responses were investigated in cardiomyocytes and macrophages, respectively. RESULTS: Rb1 mitigates Ang II-induced cardiac hypertrophy, cardiac inflammation and systemic inflammation in vivo. In cardiomyocytes, Rb1 directly counteracts the pro-hypertrophic effects of Ang II and phenylephrine and maintains the mitochondrial function. In lipopolysaccharide (LPS)-stimulated macrophages, Rb1 decreases the phosphorylation of mitogen-activated protein kinases (MAPKs) and mitogen-activated protein kinase kinase 1/2 (MEK1/2) and reduces the production of inflammation mediators such as interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF). Rb1 also suppresses the expression of pro-hypertrophic microRNA-155 (miR-155) in LPS- or Ang II-stimulated macrophages. Furthermore, in activated macrophages, miR-155 is in part accountable for the suppressive effect of Rb1 on the production of IL-6, an inflammation mediator with pro-hypertrophic functions in the heart. CONCLUSION: The work here provides novel experimental evidence supporting the notion that Rb1 protects against cardiac hypertrophy in part through suppressing the inflammatory mechanisms that promotes the pathological remodeling of the heart.

Identification of Differentially Expressed and Prognostic lncRNAs for the Construction of ceRNA Networks in Lung Adenocarcinoma.

BACKGROUND: Long noncoding RNAs (lncRNAs) could function as competitive endogenous RNAs (ceRNAs) to competitively adsorb microRNAs (miRNAs), thereby regulating the expression of their target protein-coding mRNAs. In this study, we aim to identify more effective diagnostic and prognostic markers for lung adenocarcinoma (LUAD). METHODS: We obtained differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) for LUAD by using The Cancer Genomes Atlas (TCGA) portal. Weighted gene coexpression network analysis (WGCNA) was performed to unveil core gene modules associated with LUAD. The Cox proportional hazards model was performed to determine the prognostic significance of DElncRNAs. The diagnostic and prognostic significance of DElncRNAs was further verified based on the receiver operating characteristic curve (ROC). Cytoscape was used to construct the ceRNA networks comprising the lncRNAs-miRNAs-mRNAs axis based on the correlation obtained from the miRcode, miRDB, and TargetScan. RESULTS: Compared with normal lung tissues, 2355 DElncRNAs, 820 DEmiRNAs, and 17289 DEmRNAs were identified in LUAD tissues. We generated 8 WGCNA core modules in the lncRNAs coexpression network, 5 modules in the miRNAs, and 12 modules in the mRNAs coexpression network, respectively. One lncRNA module (blue) consisting of 441 lncRNAs, two miRNA modules (blue and turquoise) containing 563 miRNAs, and one mRNA module (turquoise), which consisted of 15162 mRNAs, were mostly significantly related to LUAD status. Furthermore, 67 DEmRNAs were found to be tumor-associated as well as the target genes of the DElncRNAs-DEmiRNAs axis. Survival analyses showed that 6 lncRNAs (LINC01447, WWC2-AS2, OGFRP1, LINC00942, LINC01168, and AC005863.1) were significantly correlated with the prognosis of LUAD patients. Ultimately, the potential ceRNA networks including 6 DElncRNAs, 4 DEmiRNAs, and 22 DEmRNAs were constructed. CONCLUSION: Our study indicated that 6 DElncRNAs had the possibilities as diagnostic and prognostic biomarkers for LUAD. The lncRNA-mediated ceRNA networks might provide novel insights into the molecular mechanisms of LUAD progression.

Convergent spectral shifts to blue-green vision in mammals extends the known sensitivity of vertebrate M/LWS pigments.

Daylight vision in most mammals is mediated predominantly by a middle/long wavelength-sensitive (M/LWS) pigment. Although spectral sensitivity and associated shifts in M/LWS are mainly determined by five critical sites, predicted phenotypic variation is rarely validated, and its ecological significance is unclear. We experimentally determine spectral tuning of M/LWS pigments and show that two highly divergent taxa, the gerbil and the elephant-shrew, have undergone independent dramatic blue-green shifts to 490 nm. By generating mutant proteins, we identify additional critical sites contributing to these shifts. Our results, which extend the known range of spectral tuning of vertebrate M/LWS, provide a compelling case of functional convergence, likely related to parallel adaptive shifts from nocturnal to brighter light conditions in similar habitats.

Scotopic rod vision in tetrapods arose from multiple early adaptive shifts in the rate of retinal release.

The ability of vertebrates to occupy diverse niches has been linked to the spectral properties of rhodopsin, conferring rod-based vision in low-light conditions. More recent insights have come from nonspectral kinetics, including the retinal release rate of the active state of rhodopsin, a key aspect of scotopic vision that shows strong associations with light environments in diverse taxa. We examined the retinal release rates in resurrected proteins across early vertebrates and show that the earliest forms were characterized by much faster rates of retinal release than more recent ancestors. We also show that scotopic vision at the origin of tetrapods is a derived state that arose via at least 4 major shifts in retinal release rate. Our results suggest that early rhodopsin had a function intermediate to that of modern rod and cone pigments and that its well-developed adaptation to low light is a relatively recent innovation since the origin of tetrapods.

Prevention of human papillomavirus (HPV) infection and cervical cancer in China: how does HPV vaccination bring about benefits to Chinese women?

Cervical cancer is the second leading cause of cancer deaths among women in the world and more than 85% of cervical cancer cases occur in women living in developing countries. Human papillomavirus (HPV) infection is the major cause of cervical cancer. Since 2006, two prophylactic vaccines against the high-risk strains of HPV have been developed and approved in more than 100 countries around the world. However, in China, HPV vaccines are still under clinical trials for government approval. In this paper feasibility and justification of HPV vaccine introduction into China is examined by reviewing experiences in both developed and developing countries where the vaccination program has been implemented. The vaccination program has showed significant cost-effectiveness and great health and economic impacts on cervical cancer prevention and control in both high-income and middle- and low-income countries. On the other hand, based on the lessons from both developed and developing countries, secondary prevention alone cannot fully play a role to reduce the incidence and the disease burden, and neither does the vaccination program. The epidemiological characteristics in China suggest an urgent need to introduce the vaccines and the geographically diversified prevalence of oncogenic HPV types as well as socioeconomic status also highlight the importance of region-driven approaches for cervical cancer prevention and control by integration of a screening and vaccination program.