WNT4 (wingless-type MMTV integration site family, member 4) plays a key role in the ovarian differentiation and development in mammals. However, the possible roles of Wnt4 during gonadal differentiation and development need further clarification in teleosts. In this study, we cloned and characterized the full-length cDNA of Qi river crucian carp (Carassius auratus) wnt4a gene (CA-wnt4a). The cDNA of CA-wnt4a is 2337 bp, including the ORF of 1059 bp, encoding a putative protein with a transmembrane domain and a WNT family domain. Sequence and phylogenetic analyses revealed that the CA-Wnt4a identified is a genuine Wnt4a. Tissue distribution analysis showed that CA-wnt4a is expressed in all the tissues examined, including ovary. CA-wnt4a undergoes a stepwise increase in the embryonic stages, suggesting that CA-wnt4a might be involved in the early developmental stage. Ontogenic analysis demonstrated that CA-wnt4a expression is upregulated in the ovaries at 30-50 days after hatching (dah), the critical period of sex determination/differentiation in Qi river crucian carp. From 90 dah, the expression of CA-wnt4a was gradually downregulated in the developing ovaries. Immunohistochemistry demonstrated that CA-Wnt4a was expressed in the somatic and germ cells of the ovary by 30 dah, thereafter, positive signals of Wnt4a were detected in the somatic cells, oogonia and primary growth oocytes from 60 dah. In the sex-reversed testis induced by letrozole treatment, the expression level of CA-wnt4a was significantly downregulated. When CA-wnt4a expression was inhibited by injection of FH535 (an inhibitor of canonical Wnt/β-catenin signal pathway) in the ovaries, levels of cyp19a1a, foxl2 mRNA were significantly downregulated, while sox9b and cyp11c1 were upregulated, which suggested that together with Foxl2-leading estrogen pathway, CA-wnt4a signaling pathway might be involved in ovarian differentiation and repression of the male pathway gene expression in Qi river crucian carp.

Cholangiocarcinoma (CCA) is a malignant cancer with an unknown etiology and an unfavorable prognosis. Most patients are diagnosed at an advanced stage, thus making it essential to find novel curative targets for CCA. Metabolic reprogramming of the tumor cells includes metabolic abnormalities in glucose (known as the Warburg effect) and other substances such as amino acids and fats. Metabolic reprogramming produces anti-oxidant substances, reduces tumor oxidative stress, and finally promotes the proliferation of tumors. There is increasing evidence to imply that SIRT2, a histone deacetylase, and its downstream target cMYC, play metabolic regulatory roles in tumor cells. However, the role of the SIRT2/cMYC pathway in CCA is unclear. To assess the metabolic reprogramming function of the SIRT2/cMYC pathway in CCA and to determine the downstream targets as well as evaluate the therapeutic effect, the CCA RNA-Seq data were downloaded from the TCGA database. Differentially expressed genes were confirmed and KEGG pathway enrichment analysis was performed. Overall, 48 paired CCA samples were collected and subjected to immunohistochemical detection, and the clinical characteristics of participants were summarized. The CCA cells were suppressed or overexpressed with different downstream targets of SIRT2 and then subjected to apoptosis, immunoblotting, seahorse, and metabolites tracing analysis. In vivo experiments were also performed. We found that the SIRT2/cMYC pathway contributed to the proliferation of CCA cells and confirmed that the downstream target is PHDA1 and the serine synthesis pathway. The up-regulated SIRT2 and cMYC levels resulted in low levels of mitochondrial oxidative phosphorylation and increased conversion of glucose to serine and led to poor patient survival. The highly active SIRT2/cMYC pathway up-regulated the serine synthesis pathway pyruvate and increased antioxidant production, thus consequently protecting the CCA cells from oxidative stress-induced apoptosis. Our data revealed that the SIRT2/cMYC pathway plays a critical role in transforming glucose oxidative metabolism to serine anabolic metabolism, thus providing antioxidants for stress resistance. SIRT2/cMYC-induced metabolic reprogramming may represent a new therapeutic target for treating CCA.

The effect of proton pump inhibitors (PPIs) on cancer risk has received much attention recently. Over the last two decades, we and others have disclosed that PPIs exerted anticancer effects. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance. The activation of TERT is considered a crucial step in tumorigenesis; therefore, it is a potential therapeutic target against cancer. However, whether PPIs suppress gastric cancer by targeting TERT remains elusive. Our study demonstrated that PPZ treatment repressed TERT expression in gastric cancer cells via regulating TERT promoter activity by disturbing the interaction of STAT3 with the TERT gene. Additionally, PPZ led to chromatin remodeling within the TERT gene and resulted in a more compacted spatial conformation that is known to be associated with gene silencing. PPZ downregulated the TERT gene to inactivate the Wnt/β-catenin signaling pathway and reverse the EMT process, finally inhibiting gastric cancer metastasis both in vitro and in vivo. Our results suggest that PPIs may be potentially developed as effective as well as relatively safe and specific anticancer agents.

In this study, the actual anti-biofouling (AF) efficacy of three protective coatings, including a chlorinated rubber-based coating (C₀) and two polydimethylsiloxane (PDMS)-based coatings (P₀ and PF), were estimated via the static field exposure assays. The surface properties of these protective coatings, including surface wettability and morphology features, were characterized using the static water contact angle (WCA) and scanning electron microscope (SEM). The colonization and succession dynamics of the early-adherent biofilm-forming eukaryotic microbial communities occupied on these protective coatings were explored using the Single-stranded Conformation Polymorphism (SSCP) technique. The field data clearly revealed that coating P₀ and PF performed better in the long-term static submergence, as compared with the C₀ surface, while coating PF showed excellent AF efficacy in the field. Fingerprinting analysis suggested that the diversity, abundance, the clustering patterns, and colonization dynamics of the early-colonized eukaryotic microbes were significantly perturbed by these protective coatings, particularly by the PF surfaces. These differential AF efficacy and perturbation effects would be largely ascribed to the differences in the wettability and surface nanostructures between the C₀, P₀ and PF surfaces, as evidenced by WCA and SEM analysis.

Single-walled carbon nanotubes (SWCNTs) incorporated with π-conjugated polymers, have proven to be an effective approach in the production of advanced thermoelectric composites. However, the studied polymers are mainly limited to scanty conventional conductive polymers, and their performances still remain to be improved. Herein, a new planar moiety of platinum acetylide in the π-conjugated system is introduced to enhance the intermolecular interaction with the SWCNTs via π⁻π and d⁻π interactions, which is crucial in regulating the thermoelectric performances of SWCNT-based composites. As expected, SWCNT composites based on the platinum acetylides embedded polymers displayed a higher power factor (130.7 ± 3.8 μW·m-1·K-2) at ambient temperature than those without platinum acetylides (59.5 ± 0.7 μW·m-1·K-2) under the same conditions. Moreover, the strong interactions between the platinum acetylide-based polymers and the SWCNTs are confirmed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) measurements.

Low socioeconomic status (SES) is associated with a higher probability of multiple exposures (e.g., neighborhood violence, poor nutrition, housing instability, air pollution, and insensitive caregiving) known to affect structural development of subcortical brain regions that subserve threat and reward processing, however, few studies have examined the relationship between SES and such subcortical structures in adolescents. We examined SES variations in volume and surface morphometry of subcortical regions. The sample comprised 256 youth in eighth grade (mean age = 13.9 years), in whom high dimensional deformation mapping of structural 3T magnetic resonance imaging scans was performed. Vertex-wise linear regression analyses examined associations between income to poverty ratio and surfaces of the hippocampus, amygdala, thalamus, caudate, putamen, nucleus accumbens and pallidum, with the covariates age, pubertal status, and intracranial volume. Given sex differences in pubertal development and subcortical maturation at this age, the analyses were stratified by sex. Among males, who at this age average an earlier pubertal stage than females, the relationship between SES and local shape variation in subcortical regions was almost entirely positive. For females, the relationship between SES and local shape variation was negative. Racial identity was associated with SES in our sample, however supplementary analyses indicated that most of the associations between SES and subcortical structure were independent of it. Although these cross-sectional results are not definitive, they are consistent with a scenario where low SES delays structural maturation of subcortical regions involved with threat and reward processing. Future longitudinal studies are needed to test this hypothesis.

This study aimed to determine the association of asymptomatic sexually transmitted infections (STIs), including Ureaplasma urealyticum (UU), Mycoplasma hominis (MH), Mycoplasma genitalium, Chlamydia trachomatis, and herpes simplex virus type 2, with high-risk human papillomavirus (hrHPV) in cervical intraepithelial lesions and neoplasms.

Diabetes induces neurovascular dysfunction leading to peripheral neuropathy. MicroRNAs (miRNAs) affect many biological processes and the development of diabetic peripheral neuropathy. In the present study, we investigated whether thymosin-β4 (Tβ4) ameliorates diabetic peripheral neuropathy and whether miR-146a mediates the effect of Tβ4 on improved neurovascular function. Male Type II diabetic BKS. Cg-m+/+Leprdb/J (db/db) mice at age 20 weeks were treated with Tβ4 for 8 consecutive weeks, and db/db mice treated with saline were used as a control group. Compared to non-diabetic mice, diabetic mice exhibited substantially reduced miR-146a expression, and increased IL-1R-associated kinase-1 (IRAK1), tumor necrosis factor (TNFR)-associated factor 6 (TRAF6) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) activity in sciatic nerve tissues. Treatment of diabetic mice with Tβ4 significantly elevated miR-146a levels and overcame the effect of diabetes on these proteins. Tβ4 treatment substantially improved motor and sensory conduction velocity of the sciatic nerve, which was associated with improvements in sensory function. Tβ4 treatment significantly increased intraepidermal nerve fiber density and augmented local blood flow and the density of fluorescein isothiocyanate (FITC)-dextran perfused vessels in the sciatic nerve tissue. In vitro, treatment of dorsal root ganglion (DRG) neurons and mouse dermal endothelial cells (MDEs) with Tβ4 significantly increased axonal outgrowth and capillary-like tube formation, whereas blocking miR-146a attenuated Tβ4-induced axonal outgrowth and capillary tube formation, respectively. Our data indicate that miR-146a may mediate Tβ4-induced neurovascular remodeling in diabetic mice, by suppressing pro-inflammatory signals.

In biomedical research, patents contain the significant amount of information, and biomedical text mining has received much attention in patents recently. To accelerate the development of biomedical text mining for patents, the BioCreative V.5 challenge organized three tracks, i.e., chemical entity mention recognition (CEMP), gene and protein related object recognition (GPRO) and technical interoperability and performance of annotation servers, to focus on biomedical entity recognition in patents. This paper describes our neural network approach for the CEMP and GPRO tracks. In the approach, a bidirectional long short-term memory with a conditional random field layer is employed to recognize biomedical entities from patents. To improve the performance, we explored the effect of additional features (i.e., part of speech, chunking and named entity recognition features generated by the GENIA tagger) for the neural network model. In the official results, our best runs achieve the highest performances (a precision of 88.32%, a recall of 92.62%, and an F-score of 90.42% in the CEMP track; a precision of 76.65%, a recall of 81.91%, and an F-score of 79.19% in the GPRO track) among all participating teams in both tracks.

This research aimed to comparatively evaluate the influences of root restriction (RR) cultivation and traditional cultivation (RC) on grape berry skin metabolomics using a non-targeted metabolomics method. Two-hundred-and-ninety-one metabolites were annotated and the kinetics analyses showed that berry skin metabolome is stage- and cultivation-dependent. Our results showed that RR influences significantly the metabolomes of berry skin tissues, particularly on secondary metabolism, and that this effect is more obvious at pre-veraison stage, which was evidenced by the early and fast metabolic shift from primary to secondary metabolism. Altogether, this study provided an insight into metabolic adaptation of berry skin to RR stress and expanded general understanding of berry development.

Citrus pomace (CP) is a by-product occurred during juice or other products processing. The enormous amount of CP caused serious environmental issues. However, CP is rich in a variety of bioactive compounds. In the present study, a water extract of CP (CPW) was prepared from the by-product and the in vitro and in vivo antioxidant activities of CPW were investigated. The in vitro antioxidant activities of CPW were evaluated by measuring the free radical scavenging activity and protective effects against 2,2-azobis(2-amidinopropane) hydrochloride (AAPH)-induced oxidative stress in Vero cells. CPW scavenges 1,1-diphenyl-2-picrylhydrazyl, alkyl, and hydroxyl radicals at IC50 of 0.16±0.00, 0.31±0.01, and 0.86±0.02 mg/mL, respectively. In addition, CPW improved cell viability and scavenged intracellular reactive oxygen species (ROS) in AAPH-stimulated Vero cells in a dose-dependent manner. The in vivo antioxidant activities of CPW were investigated in a model of AAPH-induced zebrafish embryos. CPW significantly improved the survival rates and reduced heartbeat rates in AAPH-stimulated zebrafish. Furthermore, the intracellular ROS and cell death levels were remarkably decreased in CPW-treated zebrafish. Therefore, the present results indicated that CPW possesses potent in vitro and in vivo antioxidant properties and could be a potential ingredient used in food, pharmaceutical, and cosmetic industries.

In this study, images of 2450 benign thyroid nodules and 2557 malignant thyroid nodules were collected and labeled, and an automatic image recognition and diagnosis system was established by deep learning using the YOLOv2 neural network. The performance of the system in the diagnosis of thyroid nodules was evaluated, and the application value of artificial intelligence in clinical practice was investigated.

Skin secretions are known as a highly-complex mixture of abundant and diverse bioactive molecules and its study has attracted increasing attention over recent years. Phylloseptin is a unique family of antimicrobial peptides which have been only isolated from frogs of the Phyllomedusinae subfamily. Here, three novel peptide precursors were successfully cloned from a cDNA library, which was constructed from the skin secretion of Phyllomedusa burmeisteri, as pair of primers (one nested universal primer and a designed degenerate sense primer) were employed for "shotgun" cloning. The encoded mature peptides were validated by MS/MS sequencing, and subsequently termed as Phylloseptin-PBa1, -PBa2 and -PBa3. Phylloseptin-PBa1 and -PBa2 were demonstrated to possess potent antimicrobial activities against Gram-positive bacteria and yeast, as well as broad-spectrum anticancer activities, while they possess varying haemolytic activity at the effective concentration. In contrast, Phylloseptin-PBa3 was found to exhibit a strong haemolytic activity even though it was only found to possess a weak antimicrobial activity and inconspicuous anticancer activity.

Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and a critical regulator of a variety of cellular processes as well as tumor progression. Therefore, more substrates must be identified in the physiology or disease context. Here, we found that TRIM65 is upregulated and associated with poor survival in colorectal cancer (CRC). More specifically, high expression of TRIM65 is associated with CRC metastasis and recurrence. Ectopic overexpression of TRIM65 in CRC cell lines enhanced proliferation, invasion, and migration, while knockdown of TRIM65 expression had the opposite effects. Furthermore, we identified a new substrate of TRIM65, namely ARHGAP35, a Rho GTPase-activating protein (GAP) that is involved in polarized cell migration. Phenotypically, forced expression of TRIM65 induces increased production of migration-related structures, focal adhesions, and/or filopodia and enhances CRC metastasis to the liver or the lung in a mouse model. Mechanistic studies revealed that TRIM65 mediates ubiquitination of ARHGAP35, whose degradation leads to elevated Rho GTPase activity. In addition, we identified several phosphorylation sites on TRIM65. In sum, we reveal a novel TRIM65-GAP-Rho regulatory axis that modulates the actin cytoskeleton and the migration behavior of CRC cells, and the TRIM65-ARHGAP35 interaction might be a valuable therapeutic target in CRC.

Growing evidence indicates that the gut microbiota plays a significant role in the pathophysiological processes of obesity and its related metabolic symptoms in the host. Puerarin, an active ingredient in the root of Pueraria lobate has been suggested to have a potent anti-obesity effect. Herein, we tested whether this effect of puerarin is associated with changes in the gut microbiota. In addition to reducing body weight, inflammation, and insulin resistance, puerarin administration significantly altered the composition of the gut microbiota. Notably, puerarin treatment greatly increased the abundance of Akkermansia muciniphila, a mucin-degrading bacterium known to be beneficial for host metabolism and significantly downregulated in high-fat diet-fed mice. Further experiments revealed that puerarin increased intestinal expression levels of Muc2 and Reg3g and protected intestinal barrier function (normal permeability) by increasing the expression of ZO-1 and occludin in vivo and in vitro. These data suggest that puerarin's enriching effect on A. muciniphila is mediated, at least in part, by a host cellular response to protect the host from diet-induced metabolic disorders and other diseases.

Development of safe and effective chemopreventive agents is a winning strategy in reducing the morbidity and mortality of breast cancer. The current study was to investigate the mechanism-based chemopreventive potential of a Chinese herb formula Yanghe Huayan (YHHY) Decoction on the classical 7,12-dimethylbenz(a)anthracene (DMBA) induced rat mammary carcinogenesis model.

Gastric cancer is one of the most common and deadly malignancies worldwide. Despite recent medical progress, the 5-year survival rate of gastric cancer is still unsatisfactory. 5-fluorouracil (5-Fu) is one of the first-line antineoplastic treatments for gastric cancer, as it can effectively induce cancer cell apoptosis. However, the effect of 5-Fu is limited due to drug resistance of the malignant tumor. Previous studies have reported that Sotetsuflavone from Cycas revoluta Thunb. can markedly suppress lung cancer cell proliferation by apoptosis, though its effect on gastric cancer remains unknown.

Aflatoxin B1 (AFB1) is a mycotoxin mainly produced by Aspergillus flavus and Aspergillus parasiticus contaminating food, feed ingredients and products of animal origin. In mammals, this toxin causes widespread organ-specific damage; it is immunotoxicity and could promote hepatotoxicity, alter intestinal functions and so on. In this study, we conducted transcriptome and histomorphology analyses of hepatopancreas and intestinal in Litopenaeus vannamei (L. vannamei) challenged with AFB1. Totally 12,014 and 1387 differentially expression genes (DEGs) were identified in the hepatopancreas and intestine, respectively. In hepatopancreas, a total of 1995 DEGs were mainly annotated and grouped into 18 processes or pathways related to animal immune system. With respect to intestine, a total of 152 DEGs were mainly annotated to 7 processes or pathways related to animal immune system. Meanwhile, we determined the relative mRNA expression of several crucial representative immune genes including Toll, immune deficiency (IMD), prophenoloxidase (proPO), Rab and glutathione S-transferase (GST) in the hepatopancreas and intestines of shrimp at 3-, 6-, 12-, 18-, 24- and 30-d after challenged by AFB1. Exposure to AFB1 increased mortality, decrease weight gain rate, severely destroyed the histomorphology of hepatopancreas and intestine, and resulted in the damaged of immune system of shrimp. The present data reveals the different roles between hepatopancreas and intestine of L. vannamei in immune response to AFB1 challenge, and provides insight into the molecular basis of the relationship between hepatopancreas and intestinal immunity during either homeostasis or inflammation.

Rho GTPase-activating proteins (RhoGAPs) have been reported to be of great importance in the initiation and development of many different cancers. However, their biological roles and regulatory mechanisms in lung cancer development and progression are poorly defined. Real-time PCR or western blotting analysis was used to detect Rho GTPase-activating protein 24 (ARHGAP24), WWP2, p27, p-STAT6 and STAT6 expression levels as well as the activity of RhoA and Rac1 in lung cancer. Cell proliferation, apoptosis and cell cycle were measured by CCK-8 and flow cytometry analysis. Tumor growth of lung cancer cells was measured using a nude mouse xenograft experiment model in vivo. The correlation between WWP2 and p27 was measured by co-immunoprecipitation and ubiquitination analysis. We found that ARHGAP24 expression was lower in lung cancer tissues collected from the The Cancer Genome Atlas and independent hospital database. Overexpression of ARHGAP24 significantly suppressed cell proliferation and the activity of RhoA and Rac1, induced cell apoptosis and arrested cell cycle at the G0-G1 phase. ARHGAP24 overexpression also inhibited tumor growth in nude mice, whereas knockdown of ARHGAP24 significantly promoted cell proliferation and WWP2 expression and inhibited cell cycle arrest at G1 phase through activating STAT6 signaling. ARHGAP24 overexpression inhibited WWP2 overexpression-induced cell proliferation, cell cycle progression and the decreased p27 expression. Moreover, WWP2 was found interacted with p27, and WWP2 overexpression promoted the ubiquitination of p27. In conclusion, our findings suggest that ARHGAP24 inhibits cell proliferation and cell cycle progression and induces cell apoptosis of lung cancer via a STAT6-WWP2-p27 axis.

A lot of research studies have shown that many complex human diseases are associated not only with microRNAs (miRNAs) but also with long noncoding RNAs (lncRNAs). However, most of the current existing studies focus on the prediction of disease-related miRNAs or lncRNAs, and to our knowledge, until now, there are few literature studies reported to pay attention to the study of impact of miRNA-lncRNA pairs on diseases, although more and more studies have shown that both lncRNAs and miRNAs play important roles in cell proliferation and differentiation during the recent years. The identification of disease-related genes provides great insight into the underlying pathogenesis of diseases at a system level. In this study, a novel model called PADLMHOOI was proposed to predict potential associations between diseases and lncRNA-miRNA pairs based on the higher-order orthogonal iteration, and in order to evaluate its prediction performance, the global and local LOOCV were implemented, respectively, and simulation results demonstrated that PADLMHOOI could achieve reliable AUCs of 0.9545 and 0.8874 in global and local LOOCV separately. Moreover, case studies further demonstrated the effectiveness of PADLMHOOI to infer unknown disease-related lncRNA-miRNA pairs.