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The aim of this study was to investigate the effects of dietary protein inclusion level on growth, protein absorption pathway and liver metabolism-related pathway in triploid crucian carp (Carassius carassius triploid). Six experimental diets with different protein levels (26%, 29%, 32%, 35%, 38%, 41%) were formulated. A total of 540 fish with an initial weight of 11.79 ± 0.09 g were randomly assigned to 18 cages and six treatments with three replicates of 30 fish each for 8 weeks feeding. The results showed that the specific growth rate (SGR) and feed efficiency (FE) of triploid crucian carp were highly positively correlated with protein content (p < 0.05). The broken-line regression analysis showed that the optimal dietary inclusion level was determined to be 39% considering SGR of triploid crucian carp. In addition, genes related to protein absorption were influenced by the protein inclusion level of dietary. The mRNA expressions of pept1, lat2, cdx2, jak2 and sp1 exhibited similar change tendency and promoted to highest expression at 41% groups, 32% followed. Furthermore, the expressions of hepatic metabolism genes tor, s6k1, igf1, ampd1 and adsl reached peak at 38% dietary protein inclusion level, while 4e-bp2 gene showed the highest expression levels at 41% dietary protein inclusion level. Finally, igf1 expression in liver and cdx2 in intestine showed high pearson coefficients with dietary protein level suggesting their expressions were significant positively regulated by dietary protein level. In conclusion, this study evidenced the influence of dietary protein level on growth, protein absorption pathway, TOR and IGF pathways of hepatic metabolism related in triploid crucian carp. 39% dietary protein inclusion level would be optimum level of triploid crucian carp dietary, which will lead to a better growth and high feed efficiency of triploid crucian carp.

Abstract Background New-onset neurological symptoms such as numbness and pain in lower extremities might appear immediately after conventional lumbar interbody fusion (LIF) surgery performed in patients with lumbar spinal stenosis. Methods and analysis This is a multicenter, randomized, open-label, parallel-group, active-controlled trial investigating the clinical outcomes of modified LIF sequence versus conventional LIF sequence in treating patients with lumbar spinal stenosis. A total of 254 eligible patients will be enrolled and randomized in a 1:1 ratio to either modified LIF sequence or conventional LIF sequence group. The primary outcome measure is the perioperative incidence of new-onset lower extremity neurological symptoms, including new adverse events of pain, numbness, and foot drop of any severity. Important secondary endpoints include visual analogue scale (VAS) pain score and lumbar Japanese Orthopaedic Association (JOA) recovery rate. Other safety endpoints will also be evaluated. The safety set used for safety data analysis by the actual surgical treatment received and the full analysis set for baseline and efficacy data analyses according to the intent-to-treat principle will be established as the two analysis populations in the study. Conclusion This study is designed to investigate the clinical outcomes of modified LIF sequences in patients with lumbar spinal stenosis. It aims to provide clinical evidence that the modified “fixation-fusion” sequence of LIF surgery is effective in treating lumbar spinal stenosis. Trial registration http://www.chictr.org.cn/index.aspx ID: ChiCTR2100048507.

AbstractThe R-spondin protein family comprises four members (RSPO1-4), which are agonists of the canonical Wnt/β-catenin pathway. Emerging evidence revealed that RSPOs should not only be viewed as agonists of the Wnt/β-catenin pathway but also as regulators for tumor development and progression. Aberrant expression of RSPOs is related to tumorigenesis and tumor development in multiple cancers and their expression of RSPOs has also been correlated with anticancer immune cell signatures. More importantly, the role of RSPOs as potential target therapies and their implication in cancer progressions has been studied in the preclinical and clinical settings. These findings highlight the possible therapeutic value of RSPOs in cancer medicine. However, the expression pattern, effects, and mechanisms of RSPO proteins in cancer remain elusive. Investigating the many roles of RSPOs is likely to expand and improve our understanding of the oncogenic mechanisms mediated by RSPOs. Here, we reviewed the recent advances in the functions and underlying molecular mechanisms of RSPOs in tumor development, cancer microenvironment regulation, and immunity, and discussed the therapeutic potential of targeting RSPOs for cancer treatment. In addition, we also explored the biological feature and clinical relevance of RSPOs in cancer mutagenesis, transcriptional regulation, and immune correlation by bioinformatics analysis.KEY MESSAGESAberrant expressions of RSPOs are detected in various human malignancies and are always correlated with oncogenesis.Although extensive studies of RSPOs have been conducted, their precise molecular mechanism remains poorly understood.Bioinformatic analysis revealed that RSPOs may play a part in the development of the immune composition of the tumor microenvironment.

Abstract Background Accurate preoperative assessment of the efficacy of high-intensity focused ultrasound (HIFU) ablation for uterine fibroids is essential for good treatment results. The aim of this study was to develop robust radiomics models for predicting the prognosis of HIFU-treated uterine fibroids and to explain the internal predictive process of the model using Shapley additive explanations (SHAP). Methods This retrospective study included 300 patients with uterine fibroids who received HIFU and were classified as having a favorable or unfavorable prognosis based on the postoperative nonperfusion volume ratio. Patients were divided into a training set (N = 240) and a test set (N = 60). The 1295 radiomics features were extracted from T2-weighted imaging (T2WI) and contrast-enhanced T1-weighted imaging (CE-T1WI) scans. After data preprocessing and feature filtering, radiomics models were constructed by extreme gradient boosting and light gradient boosting machine (LightGBM), and the optimal performance was obtained by Bayesian optimization. Finally, the SHAP approach was used to explain the internal prediction process. Results The models constructed using LightGBM had the best performance, and the AUCs of the T2WI and CE-T1WI models were 87.2 (95% CI = 87.1–87.5) and 84.8 (95% CI = 84.6–85.7), respectively. The use of SHAP technology can help physicians understand the impact of radiomic features on the predicted outcomes of the model from a global and individual perspective. Conclusion Multiparametric radiomic models have shown their robustness in predicting HIFU prognosis. Radiomic features can be a potential source of biomarkers to support preoperative assessment of HIFU treatment and improve the understanding of uterine fibroid heterogeneity. Clinical relevance statement An interpretable radiomics model can help clinicians to effectively predict the prognosis of HIFU treatment for uterine fibroids. The heterogeneity of fibroids can be characterized by various radiomics features and the application of SHAP can be used to visually explain the prediction process of radiomics models. Graphical Abstract

Abstract There have been contradictory reports on the biological role of transforming growth factor‐βs (TGFβs) in breast cancer (BC), especially with regard to their ability to promote epithelial‐mesenchymal transition (EMT). Here, we show that TGFβ2 is preferentially expressed in mesenchymal‐like BCs and maintains the EMT phenotype, correlating with cancer stem cell‐like characteristics, growth, metastasis and chemo‐resistance and predicting worse clinical outcomes. However, this is only true in ERα− BC. In ERα+ luminal‐type BC, estrogen receptor interacts with p‐Smads to block TGFβ signalling. Furthermore, we also identify a microRNAs (miRNAs) signature (miRNAsTGFβ2) that is weakened in TGFβ2‐overexpressing BC cells. We discover that TGFβ2‐Snail1 recruits enhancer of zeste homolog‐2 to convert miRNAsTGFβ2 promoters from an active to repressive chromatin configuration and then repress miRNAsTGFβ2 transcription, forming a negative feedback loop. On the other hand, miRNAsTGFβ2 overexpression reverses the mesenchymal‐like traits in agreement with the inhibition of TGFβ2‐Snail1 signalling in BC cells. These findings clarify the roles of TGFβ2 in BC and suggest novel therapeutic strategies based on the TGFβ2‐Snail1‐miRNAsTGFβ2 loop for a subset type of human BCs.

Raspberry ketone accounts for the characteristic aroma of the raspberry fruit. In order to explore the genes involved in raspberry ketone synthesis, the transcriptome in fruit tissues of two red raspberry varieties "Polka" and "Orange legend", were sequenced and 24213 single genes were obtained. As the red raspberry fruit ripening, genes involved in flavonoid and anthocyanin synthesis were up-regulated, while those associated with lignin synthesis were down-regulated. A gene (RinPKS4) highly related to raspberry ketone synthesis was identified by transcriptome analysis, and RinPKS4 gene was over-expressed in raspberry in order to further understand the function of RinPKS4 gene in raspberry ketone synthesis. The results showed that the gene expression level of RinPKS4 in the leaf tissues of a transgenic lines increased by about 4-fold and the content of raspberry ketone increased by 42.64% compared with the wide type. This study lays a theoretical foundation for further study on the synthesis and regulation of raspberry ketone in red raspberry.

Abstract In this article, we study the quasilinear Schrödinger equation − △ ( u ) + V ( x ) u − △ ( u 2 ) u = g ( x , u ) , x ∈ R N , $$ -\triangle (u)+V(x)u-\triangle \bigl(u^{2}\bigr)u=g(x,u), \quad x\in \mathbb{R}^{N}, $$ where the potential V ( x ) $V(x)$ and the primitive of g ( x , u ) $g(x,u)$ are allowed to be sign-changing. Under more general superlinear conditions on g, we obtain the existence of infinitely many nontrivial solutions by using the mountain pass theorem. Recent results in the literature are significantly improved.

Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology; however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.

Acute liver injury is a common clinical disease, which easily leads to liver failure and endangers life, seriously threatening human health. Naringenin is a natural flavonoid that holds therapeutic potential against various liver injuries; however it has poor water solubility and bioavailability. In this study, we aimed to develop naringenin-loaded bovine serum albumin nanoparticles (NGNPs) and to evaluate their hepatoprotective effect and underlying mechanisms against acetaminophen overdose toxicity. In vitro data indicated that NGNPs significantly increased the drug solubility and also more effectively protected the hepatocyte cells from oxidative damage during hydrogen peroxide exposure or lipopolysaccharide (LPS) stimulation. In vivo results confirmed that NGNPs showed an enhanced accumulation in the liver tissue. In the murine model of acetaminophen-induced hepatotoxicity, NGNPs could effectively alleviate the progression of acute liver injury by reducing drug overdose-induced levels of oxidative stress, inflammation and apoptosis in hepatocytes. In conclusion, NGNPs has strong hepatoprotective effects against acetaminophen induced acute liver injury.

A 56-day feeding trial was conducted to evaluate the effect of different dietary protein sources on the growth performance, muscle flavor substances, and quality structure of Triploid Crucian Carp. Three isonitrogenous (32.00%), isolipidic (8.00%), and isoenergetic (18.00 MJ kg−1) practical diets were formulated. These diets consisted of fishmeal as the animal-derived protein source (AP), a combination of soybean meal and rapeseed meal as the plant-derived protein source (PP), and a mixture of fishmeal, soybean meal, and rapeseed meal as the mixed protein source (MP). Each diet was randomly assigned to triplicate tanks of fish and each tank was stocked with 25 fish (11.5 ± 0.4 g). The fish were fed until apparent satiation twice a day. The results showed a significant enhancement in the growth performance of Triploid Crucian Carp in the AP group compared with both the MP and PP groups (p < 0.05). Dietary plant derived protein can remarkably reduce the crude lipid content and increase the moisture content of the whole body and the dorsal muscle (p < 0.05). The antioxidant ability of fish in the PP group and MP group was better than that in the AP group (p < 0.05). Regarding free amino acids composition of muscle, the contents of glycine, methionine, and lysine were significantly enhanced in the AP group, while the histidine content was significantly increased in the PP group (p < 0.05). In terms of texture, dietary plant protein significantly improved the muscular hardness, gumminess, and chewiness. The activities of intestinal trypsin and alkaline phosphatase (ALP) of fish in the PP group were significantly higher than that in the AP group (p < 0.05). The expression levels of hepatopancreas TOR and IGF1 genes in the PP group were significantly higher than that in the MP group (p < 0.05). The present results indicate dietary fishmeal significantly improved the growth performance and muscular flavor glycine content, while dietary plant-based protein increased crude protein content, antioxidant ability, and muscular texture performance of Triploid Crucian Carp.

In vehicle-to-everything, the high-speed distribution and sharing of perception and safety data is crucial to road safety.However, the instability of communication links caused by high-speed vehicle movement will make the existing communication resource allocation methods based on vehicle location information reporting no longer efficient.Therefore, a downlink wireless resource allocation method based on wireless sensing assistance of communication nodes was proposed.Firstly, a joint optimization problem of communication mode selection and wireless resource allocation under the orthogonality of communication and sensing resources was constructed.Then, a communication mode selection based on clustering by Delaunay triangulation and a resource allocation strategy based on improved graph coloring to improve the downlink throughput was proposed to solve the problem of construction.Finally, the impact of wireless sensing estimation error and the number of vehicles on the performance of the algorithm was simulated and analyzed.Simulation results show that compared with traditional methods, the proposed algorithm can obtain better downlink communication performance gain under the same proportion of sensing bandwidth resources, and can withstand the impact of larger sensing errors on performance.At the same time, the computational complexity of the proposed algorithm is lower and the network computing resources can be saved.

Abstract Background To investigate the differences in HPV genotypes and clinical indicators between cervical squamous cell carcinoma and adenocarcinoma and to identify independent predictors for differentiating cervical squamous cell carcinoma and adenocarcinoma. Methods A total of 319 patients with cervical cancer, including 238 patients with squamous cell carcinoma and 81 patients with adenocarcinoma, were retrospectively analysed. The clinical characteristics and laboratory indicators, including HPV genotypes, SCCAg, CA125, CA19-9, CYFRA 21–1 and parity, were analysed by univariate and multivariate analyses, and a classification model for cervical squamous cell carcinoma and adenocarcinoma was established. The model was validated in 96 patients with cervical cancer. Results There were significant differences in SCCAg, CA125, CA19-9, CYFRA 21–1, HPV genotypes and clinical symptoms between cervical squamous cell carcinoma and adenocarcinoma (P

Abstract Background Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment. As a major component of the tumor microenvironment, tumor-associated macrophages (TAMs) play an important role in facilitating the aggressive behavior of TNBC. This study aimed to explore the novel mechanism of TAMs in the regulation of epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) properties in TNBC. Methods Expression of the M2-like macrophage marker CD163 was evaluated by immunohistochemistry in human breast cancer tissues. The phenotype of M2 macrophages polarized from Tohoku-Hospital-Pediatrics-1 (THP1) cells was verified by flow cytometry. Transwell assays, wound healing assays, western blotting, flow cytometry, ELISA, quantitative polymerase chain reaction (qPCR), luciferase reporter gene assays, and immunofluorescence assays were conducted to investigate the mechanism by which TAMs regulate EMT and CSC properties in BT549 and HCC1937 cells. Results Clinically, we observed a high infiltration of M2-like tumor-associated macrophages in TNBC tissues and confirmed that TAMs were associated with unfavorable prognosis in TNBC patients. Moreover, we found that conditioned medium from M2 macrophages (M2-CM) markedly promoted EMT and CSC properties in BT549 and HCC1937 cells. Mechanistically, we demonstrated that chemokine (C–C motif) ligand 2 (CCL2) secretion by TAMs activated Akt signaling, which in turn increased the expression and nuclear localization of β-catenin. Furthermore, β-catenin knockdown reversed TAM-induced EMT and CSC properties. Conclusions This study provides a novel mechanism by which TAMs promote EMT and enhance CSC properties in TNBC via activation of CCL2/AKT/β-catenin signaling, which may offer new strategies for the diagnosis and treatment of TNBC. Video Abstract

Abstract Previously, our lab explored that tongue cancer resistance-associated protein (TCRP1) plays a central role in cancer chemo-resistance and progression. Absolutely, TCRP1 was significantly increased in lung cancer. But the mechanism is far from elucidated. Here, we found that TCRP1 was increased in p53-mutant non-small-cell lung cancer (NSCLC), comparing to that in NSCLC with wild type p53. Further study showed that mutant p53 couldn’t bind to the promoter of TCRP1 to inhibit its expression. While the wild type p53 did so. Next, loss-and gain-of-function assays demonstrated that TCRP1 promoted cell proliferation and tumor growth in NSCLC. Regarding the mechanism, TCRP1 encouraged AKT phosphorylation and blocked FOXO3a nuclear localization through favoring FOXO3a ubiquitination in cytoplasm, thus, promoted cell cycle progression. Conclusionly, TCRP1 was upregulated in NSCLC cells with mutant p53. TCRP1 promoted NSCLC progression via regulating cell cycle.

The tight focusing properties of circular partially coherent radially polarized circular Airy vortex beams (CPCRPCAVBs) are theoretically studied in this paper. After deriving the cross-spectral density matrix of CPCRPCAVBs in the focal region of a high-NA objective, numerical calculations were performed to indicate the influence of the topological charge of the vortex phase on intensity distribution, degree of coherence and degree of polarization of the tightly focused beam. An intensity profile along the propagation axis shows that a super-length optical needle (~15 λ) can be obtained with a topological charge of 1, and a super-length dark channel (~15 λ) is observed with a topological charge of 2 or 3. In the focal plane, the rise in the number of topological charge does not distort the shapes of the coherence distribution pattern and the polarization distribution pattern, but enlarges their sizes.

Psoriasis is a chronic inflammatory skin disease characterized by erythema, scaling, and skin thickening. Topical drug application is recommended as the first-line treatment. Many formulation strategies have been developed and explored for enhanced topical psoriasis treatment. However, these preparations usually have low viscosity and limited retention on the skin surface, resulting in low drug delivery efficiency and poor patient satisfaction. In this study, we developed the first water-responsive gel (WRG), which has a distinct water-triggered liquid-to-gel phase transition property. Specifically, WRG was kept in a solution state in the absence of water, and the addition of water induced an immediate phase transition and resulted in a high viscosity gel. Curcumin was used as a model drug to investigate the potential of WRG in topical drug delivery against psoriasis. In vitro and in vivo data showed that WRG formulation could not only extend skin retention but also facilitate the drug permeating across the skin. In a mouse model of psoriasis, curcumin loaded WRG (CUR-WRG) effectively ameliorated the symptoms of psoriasis and exerted a potent anti-psoriasis effect by extending drug retention and facilitating drug penetration. Further mechanism study demonstrated that the anti-hyperplasia, anti-inflammation, anti-angiogenesis, anti-oxidation, and immunomodulation properties of curcumin were amplified by enhanced topical drug delivery efficiency. Notably, neglectable local or systemic toxicity was observed for CUR-WRG application. This study suggests that WRG is a promising formulation for topically psoriasis treatment.

This paper introduces a machine vision system based on polarization imaging, which is applicable for automatically counting the number of internal layers in plywood. Industrial machine vision usually suffers from a low accuracy due to low contrast and high complexity of the images, which could be overcome by the introduction of polarization imaging. A polarization camera was utilized to capture images with polarization angles of 0°, 45°, 90°, and 135°, and then a degree of polarization (DOP) distribution image was obtained by calculating the DOP for each pixel. Compared with the intensity distribution image, the contrast of the DOP distribution image was increased by about 60% and the excessive information in the image including wood’s natural texture, dirty spots, dicing marks, and artifacts was mostly filtered. A gray value difference algorithm was applied to the images to determine the edges of the internal layers of plywood and count them up automatically. The experimental results illustrated that polarization imaging could improve the counting accuracy of the algorithm effectively.

Abstract Background Tumour repopulation initiated by residual tumour cells in response to cytotoxic therapy has been described clinically and biologically, but the mechanisms are unclear. Here, we aimed to investigate the mechanisms for the tumour‐promoting effect in dying cells and for tumour repopulation in surviving tongue cancer cells. Methods Tumour repopulation in vitro and in vivo was represented by luciferase activities. The differentially expressed cytokines in the conditioned medium (CM) were identified using a cytokine array. Gain or loss of function was investigated using inhibitors, neutralising antibodies, shRNAs and ectopic overexpression strategies. Results We found that dying tumour cells undergoing cytotoxic therapy increase the growth of living tongue cancer cells in vitro and in vivo. Dying tumour cells create amphiregulin (AREG)‐ and basic fibroblast growth factor (bFGF)‐based extracellular environments via cytotoxic treatment‐induced endoplasmic reticulum stress. This environment stimulates growth by activating lysine acetyltransferase 6B (KAT6B)‐dependent nuclear factor‐kappa B (NF‐κB) signalling in living tumour cells. As direct targets of NF‐κB, miR‐22 targets KAT6B to repress its expression, but long noncoding RNAs (lncRNAs) (XLOC_003973 and XLOC_010383) counter the effect of miR‐22 to enhance KAT6B expression. Moreover, we detected increased AREG and bFGF protein levels in the blood of tongue cancer patients with X‐box binding protein‐1 (XBP1) activation in tumours under cytotoxic therapy and found that XBP1 activation is associated with poor prognosis of patients. We also detected activation of miR‐22/lncRNA/KAT6B/NF‐κB signalling in recurrent cancers compared to paired primary tongue cancers. Conclusions We identified the molecular mechanisms of cell death‐induced tumour repopulation in tongue cancer. Such insights provide new avenues to identify predictive biomarkers and effective strategies to address cancer progression.

Considering parameters of corrosion area ratio and mass loss degree, the half-cell potential method and linear polarization method were applied to study the corrosion state of steel bars under the influence of carbonation, chloride salt and compound environmental action. X-ray photoelectron spectroscopy (XPS) was used to measure steel corrosion under coupling action and the effect of sodium nitrite rust inhibitor in the compound environment was studied. The results show that the corrosion rate of steel under carbonation, chloride salt and compound environment increases in the beginning and then decreases. In the chloride environment, sufficient moisture inside the concrete at the initial stage of curing induces a faster corroding. With the destruction of the passive film on the surface of the steel bars together with the balance of internal and external humidity, the corrosion rate tends to stabilize. At the following curing stage, the corrosion rate decreases as the degree of steel corrosion increases and the corrosion layer is formed. Carbonation reduces the alkalinity around the passive film and damages the passive film, which accelerates the corrosion happening. The following development of the corrosion layer of steel bars limits the corrosion rate. The corrosion degree in the compound environment is more serious than that under the condition of single factor action. Under electrochemical action, the order of product components resulting from steel corrosion are Fe2O3, Fe3+-Ca2SiO4 and FeO from high to low. Nitrite oxidizes the unstable Fe2+ into stable Fe3+ and precipitates on the surface of the steel to form a passivation film, which has a good anti-rust effect.

The subtraction game is a well-known problem in the field of game theory, which is often called a one-heap Nim game. There are two players, a heap of tokens, and a strategy matrix, in this game. It is called a restricted subtraction game if some constraints are imposed on the strategy matrix. The subtraction game could be solved by a classical algorithm with a query complexity no less than O(N2) and computed by an O(N32logN) quantum query algorithm with an error probability ϵ≤1N. The restricted subtraction game proposed by Huang et al. can be computed by an exact quantum algorithm with O(N32) queries. They also proved that the classical exact query complexity is Θ(N2). In this study, we use an array and an adjacency list to replace the strategy matrix and propose another more general subtraction game than the one introduced by Huang et al. Based on dynamic programming and the replaced game strategy, two linear classical query algorithms are designed to solve the restricted subtraction game proposed by Huang and this study, respectively.

Phase imaging normally employs coherent a light source while an incoherent light source is not preferred due to its random wavefront. Another challenge for practical phase imaging is imaging through scattering media, which scatter the photons in a random manner and lead to seriously distorted images of speckles. Based on the convolutional neural network (CNN), this paper presents an approach for phase imaging through scattering media using an incoherent light source. A CNN was trained and utilized to reconstruct the target images from the captured images of speckles. Similarities of over 90% between the reconstructed images and their target images have been achieved. It was concluded that an incoherent light source can be used as an illumination source for scattering phase imaging with the assistance of deep learning technology. This phase imaging approach with an incoherent light source through scattering media can be used to record the refractive indices of transparent samples, which might lead to its application in biomedical imaging.

Mitogen-activated protein kinase kinase kinase 3 (MEKK3) is an evolutionarily conserved Ser/Thr protein kinase of the MEKK family that is essential for the host immune response to pathogen challenges in mammals. However, the immune function of MEKK3s in lower vertebrate species, especially in bony fish, remains largely unknown. In this study, a fish MEKK3 (designated CiMEKK3) gene was cloned and identified from grass carp (Ctenopharyngodon idella). The present CiMEKK3 cDNA encoded a 620 amino acid polypeptide containing a conserved S-TKc domain and a typical PB1 domain. Several potential immune-related transcription factor-binding sites, including activating protein 1 (AP-1), nuclear factor kappa B (NF-κB) and signal transducer and activator of downstream transcription 3 (STAT3), were observed in the 5’ upstream DNA sequence of CiMEKK3. A phylogenetic tree showed that CiMEKK3 exhibits a close evolutionary relationship with MEKK3s from Cyprinus carpio and Carassius auratus. Quantitative real-time PCR analysis revealed that CiMEKK3 transcripts were widely distributed in all selected tissues of healthy grass carp, with a relatively high levels observed in the gill, head kidney and intestine. Upon in vitro challenge with bacterial pathogens (Aeromonas hydrophila and Aeromonas veronii) and pathogen-associated molecular patterns (PAMPs) (lipopolysaccharide (LPS), peptidoglycan (PGN), L-Ala-γ-D-Glu-mDAP (Tri-DAP) and muramyl dipeptide (MDP)), the expression levels of CiMEKK3 in the intestinal cells of grass carp were shown to be significantly upregulated in a time-dependent manner. In vivo injection experiments revealed that CiMEKK3 transcripts were significantly induced by MDP challenge in the intestine; however, these effects could be inhibited by the nutritional dipeptides carnosine and Ala-Gln. Moreover, subcellular localization analysis and luciferase reporter assays indicated that CiMEKK3 could act as a cytoplasmic signal-transducing activator involved in the regulation of NF-κB and MAPK/AP-1 signaling cascades in HEK293T cells. Taken together, these findings strongly suggest that CiMEKK3 plays vital roles in the intestinal immune response to bacterial challenges, which will aid in understanding the pathogenesis of inflammatory bowel disease in bony fish.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising antitumor activity in preclinical studies. However, the efficacy of recombinant TRAIL in clinical trials is compromised by its short serum half-life and low in vivo stability. Induction of endogenous TRAIL may overcome the limitations and become a new strategy for cancer treatment. Here, we discovered that metformin increased TRAIL expression and induced apoptosis in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) cells. Metformin did not alter the expression of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Metformin-upregulated TRAIL was secreted into conditioned medium (CM) and found to be functional, since the CM promoted TNBC cells undergoing apoptosis, which was abrogated by a recombinant TRAIL-R2-Fc chimera. Moreover, blockade of TRAIL binding to DR4/DR5 or specific knockdown of TRAIL expression significantly attenuated metformin-induced apoptosis. Studies with a tumor xenograft model revealed that metformin not only significantly inhibited tumor growth but also elicited apoptosis and enhanced TRAIL expression in vivo. Collectively, we have demonstrated that upregulation of TRAIL and activation of death receptor signaling are pivotal for metformin-induced apoptosis in TNBC and NSCLC cells. Our studies identify a novel mechanism of action of metformin exhibiting potent antitumor activity via induction of endogenous TRAIL.

Resistance to Herceptin represents a major challenge for successful treatment of HER2-positive breast cancer. Here, the authors demonstrate that the activation of the IGF2/IRS1 signal caused by disruption of a negative feedback loop between FOXO3a-miR-128/miR-30/miR-193 induces Herceptin resistance.

Grass carp (Ctenopharyngodon idellus, C.idellus) is one of the most important globally cultured freshwater fish species, and its growth trait can be improved by dietary supplementation of oligopeptides which is transported through the intestinal oligopeptide transporter PepT1. However, many aspects of the molecular regulation mechanism of C.idellus PepT1 still remains elusive. In this study, the regulation mechanism of C.idellus PepT1 by CDX2 was extensively studied. Firstly, the interaction of the C.idellus CDX2 and SP1 was investigated by mammalian two hybrid assays and co-localization; The promoter sequence of PepT1 was cloned and its activity was directly up-regualted by CDX2. In the further study, the effect of CDX2 changes at both mRNA and protein levels on the expression of PepT1 was examined in vivo and in vitro. The mRNA expression of PepT1 was significantly decreased when CDX2 was repressed and its expression change profile was almost consistent with that of CDX2. To understand the regulation of CDX2 on the expression of PepT1 at protein level, the stability regulation mechanism of CDX2 was initially studied. The results showed that CDX2 protein was degraded via the ubiquitin-proteasome pathways, and increasing phosphorylation level of CDX2 protein declined its turnover and elevated its accumulation level in cells. The expression of PepT1 was significantly elevated with increasing CDX2 protein stability, and expressions of both CDX2 and PepT1 were stimulated by the oligopeptide. In conclusion, these observations may shed new light on the molecular regulation mechanism of PepT1 by CDX2 in C.idellus and provide new perceptions and strategies for the efficient transportation of intestinal oligopeptides in teleost fish.

Leptin receptor (LEPR) is a type of transmembrane receptor and a member of the class I cytokine receptor family that plays a decisive role in the physiological functions mediated by leptin. In this study, a fish LEPR gene (CiLEPR) was cloned from Ctenopharyngodon idella. The open reading frame (ORF) sequence of the CiLEPR gene included 3504 bp, which encoded 1078 amino acids that formed six functional domains, including five FN3 domains and a lep_receptor_Ig domain. Phylogenetic analysis showed that the CiLEPR amino acid sequence was closely related to that of LEPR from Hypophthalmichthys molitrix. The qRT-PCR results showed that the CiLEPR gene was widely expressed in all investigated tissues of C. idella and was relatively highly expressed in the gills. The results of the circadian rhythm experiment revealed that the intestinal expression of the CiLEPR gene changed regularly over time. In C. idella intestinal cell experiments, it was observed that recombinant leptin could upregulate the expression levels of CiLeptin, CiLEPR and CiPepT1 in the intestines of C. idella. The results of experiments in which fish were fed with various protein sources demonstrated that the mRNA expression levels of CiLeptin, CiLEPR and CiPepT1 in the fish meal group were higher than those in the soybean meal group at 28 d. The data indicated that C. idella fed diets with medium amounts of dietary protein (37%) expressed the highest mRNA levels of CiLeptin, CiLEPR and CiPepT1 after 4 weeks. These results provide a basis for further studies on the nutritional regulation and physiological functions of leptin receptors in fish.

The unreasonable economic development model of human beings has caused the environmental pollution problem to become increasingly serious. In order to achieve a positive relationship and interaction between environmental regulation, research and development (R&D) investment, and green technology innovation, and effectively solve the "strange circle" problem between high-quality economic development and environmental pollution in China and even the world, this paper takes the panel data of industrial enterprises above designated size in Chinese mainland 31 provinces from 2009 to 2019 as a research sample. The comprehensive index of R&D investment and green technology innovation was established by the entropy method, and the panel vector autoregressive (PVAR) model was constructed from the dynamic endogenous perspective, and the dynamic interaction and regional heterogeneity between environmental regulation, R&D investment, and green technology innovation were empirically analyzed by using impulse response function and variance decomposition. We obtain the following findings: (1) Environmental regulation has a two-way interaction relationship with R&D investment and green technology innovation, and R&D investment has a promotion effect on the "green degree" of technological innovation, but its role is still weak and has lagging characteristics. (2) There is significant regional heterogeneity in the dynamic responses of the eastern, central and western parts of China. (3) In the long run, environmental regulation has a "negative crowding out effect" on R&D investment in the central region, and the phenomenon of "central collapse" still exists but will gradually weaken. Environmental regulation has a "positive innovation compensation effect" on green technology innovation. Green technology innovation and R&D investment have an obvious "Pareto improvement" effect on environmental regulation, especially in the eastern region. The conclusions of this study help to clarify the dynamic interaction between environmental regulation, R&D investment, and green technology innovation, further improve environmental regulatory policies and green technology innovation R&D decision-making, and provide an effective way to achieve green and sustainable development in China and other parts of the world.

Rapid detection of marine oil spills is becoming increasingly critical in the face of frequent marine oil spills. Oil slick thickness measurement is critical in the hazard assessment of such oil leaks. As surface plasmon resonance (SPR) sensors are sensitive to slight changes in refractive index, they can monitor offshore oil spills arising from significant differences in the refractive index between oil and water. This study presents a gold-film fiber-optic surface plasmon resonance (FOSPR) sensor prepared by polydopamine accelerated wet chemical plating for rapid and real-time measurement of oil slick thickness. We examined oil thickness detection at two interfaces, namely, water-oil and air-oil. Detection sensitivity of −1.373%/mm is obtained at the water-oil interface in the thickness range of 0–5 mm; detection sensitivity of −2.742%/mm is obtained at the air-oil interface in the thickness range of 0–10 mm. Temperature and salinity present negligible effects on the oil slick thickness measurement. The fabricated FOSPR sensor has the ability to detect the presence of oil as well as quantify the oil thickness. It has favorable repeatability and reusability, demonstrating the significant potential for use in the estimation of marine oil slick thickness.

The Phaeocystis globosa widely exists in the seawater, which becomes a great threat for the health of humans and animals in the ecological ecosystem. In this work, we reported a promising control strategy with quercetin(QT) enhanced cellulose nanocrystals (CNC). The quercetin enhanced cellulose nanocrystals (QT/CNC) was characterized through Atomic Force Microscopy (AFM), Fourier Transform Infrared Spectrometer (FTIR) and X-ray diffractometer (XRD). The effects of concentrations of CNC and QT on controlled Phaeocystis globosa were investigated. The results showed that the removal rate of Phaeocystis globosa exhibited an optimal value (92.1 %) at 0.05 g L-1 CNC and 0.1 g L-1 QT. Furthermore, the chlorophyll-a content in the Phaeocystis globosa exhibited a remarkable decrease from 3.72 mg L-1 to 0.21 mg L-1 when QT/CNC was interacted. On the basis of these results, we concluded that Phaeocystis globosa could be removed by QT/CNC effectively. During the removal of Phaeocystis globosa, the pH of algal solution decreased from 9.45 to 7.36, indicating that QT/CNC could maintain the normal pH of water. In addition, the testing result of the QT/CNC zeta potentials was negative, which revealed that Phaeocystis globosa was removed through inhibition and flocculation. Accordingly, a possible removal mechanism of Phaeocystis globose by QT/CNC was presumed. This study suggested that QT/CNC might be a potential treatment materials on the removal of Phaeocystis globosa.

Calcium silicate hydrate-polycarboxylate (C-S-H-PCE) nanocomposites can greatly increase the hydration speed of cement paste. To obtain the optimal synthesis condition for smaller particle size, C-S-H-PCE was prepared by adding Ca(NO3)2(4H2O and Na2SiO3(5H2O solution into PCE dispersion solution under high speed stirring, and the effects of reaction temperature, drip flow rate, aging time, C-S-H content and molecular weight of PCE on the particle size distribution of C-S-H were studied. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were employed to conduct the analysis of particle size and morphology of the prepared C-S-H-PCE. The application performance of the nano composite was characterized by testing the compressive strength of cement paste added with C-S-H-PCE. The experimental results showed that at 25 ?, C-S-H-PCE synthesized with lower PCE molecular weight, slower drip flow rate, and smaller C-S-H content had better performance. The compressive strength of cement paste with C-S-H-PCE cured under low temperature condition was tested. It turned out that the prepared nanocomposites can remarkably enhance the early strength of cement paste for up to 63.8 % and 24.2 % after 1 d and 3 d.

We theoretically investigated the properties of tightly focused ring Pearcey beams with a cross phase (CPRPB). The expressions of the distributions of both electric field and magnetic field in the focal region of an objective were first derived from the vectorial Debye theory, and then numerical calculations were carried out to obtain the focused intensity distribution and the Poynting vector of CPRPB near the focus. Numerical calculations indicate that as CPRPB is focused on an objective of high numerical aperture (NA), two nonuniform self-focusing spots occur at both sides of the geometrical focus of the objective symmetrically, and the angle between their directions is 90 degrees. The stronger is the strength of cross-phase modulation, the flatter are the ellipses of the self-focusing spots, and the smaller is the intensity at the geometrical focus of the objective. Numerical calculations also demonstrate that the optical gradient force produced by tightly focused CPRPB in the focal region can be manipulated in magnitude and in direction by tuning the strength of cross-phase modulation. Due to these properties of tightly focused CPRPB, they might find applications in the manipulation of micro- and nanoparticles and so on.

Abstract We present a facile and effective method for fabrication of the localized surface plasmon resonance (LSPR) optical fiber sensor assisted by two polydopamine (PDA) layers with enhanced plasmonic sensing performance. The first PDA layer was self-polymerized onto the bare optical fiber to provide the catechol groups for the reduction from Ag+ to Ago through chelating and redox activity. As the reduction of Ag+ proceeds, Ag nanoparticles (NPs) were grown in-situ on the PDA layer with uniform distribution. The second PDA layer was applied to prevent Ag NPs from oxidating and achieve an improvement of LSPR signal. The PDA/Ag/PDA-based optical fiber sensor has an enhanced LSPR sensitivity of 961 nm/RIU and excellent oxidation resistance. The stable PDA/Ag/PDA-based LSPR sensor with high optical performance is very promising for future application in optical sensing field.

Automatic modulation recognition (AMR) is considered one of most important techniques in the non-cooperative wireless communication systems. Traditional algorithms, e.g., support vector machine (SVM) based on high order cumulants (HOC), are hard to achieve the reliable performance. In this paper, we propose an effective AMR algorithm based on deep learning (DL) with capabilities of automatically extracting representative and effective features. Our proposed method resorts to in-phase and quadrature (IQ) samples which are IQ components of received baseband signal, respectively. We adopt convolutional neural networks (CNN) and recurrent neural networks (RNN) to classify six types of signal modulations over additive white Gaussian noise (AWGN) channel and Rayleigh fading channel, respectively. Simulation results show that DL-AMR is much better than traditional algorithms under two fading channels.

The nutritional functions of tributyrin (TB) have been extensively studied, but questions remain regarding its influence on the growth of juvenile grass carp (Ctenopharyngodon idellus) and the regulation pathway to PepT1 in the intestine of grass carp. To answer the remaining questions, feeding trials, cell trials, and peritoneal injection trials were conducted in this study. The results showed that an appropriate level of TB (0.5 g/kg and 1.0 g/kg) supplementation in feed significantly promoted the growth performance of juvenile grass carp. The expressions of intestine genes (CDX2, SP1 and PepT1) related to oligopeptide transportation increased in the 0.5 g/kg TB group of feeding trials and both the 5 mM and 10 mM TB groups of the intestine cell trials, respectively. Subsequently, the injection trials of inhibitors CDX2 and SP1 demonstrated that the inhibition of CDX2 or SP1 decreased the mRNA expression of PepT1. Finally, the results of independent or combined treatments of TB and the inhibitors suggested that CDX2/SP1 mediated TB regulation on PepT1. These findings may help us to better understand the functions of TB on growth and PepT1 oligopeptide transportation, which could be modulated by dietary TB through the CDX2/SP1-PepT1 pathway in juvenile grass carp.

Glutamine synthetase (GS) is a key enzyme that catalyzes the synthesis of glutamine from glutamate, which plays a role in the promotion of muscle cell growth and in improving the flavor of meats. In this study, a GS gene encoding 371 amino acids was cloned from triploid crucian carp and showed the highest level of similarity with the GS gene found in Cyprinus carpio. Meanwhile, GS was differentially expressed in different tissues, and its day–night expression changes showed obvious oscillation. Additionally, the effects of glutamate and glutamine on GS expression in muscle cells were investigated in vitro and in vivo. We found that its expression was obviously increased due to high levels of glutamate (2 mg/mL) but decreased by glutamine in vitro. However, it was significantly promoted by glutamate and glutamine in vivo, with an optimal concentration of 2%. Furthermore, the use of lysine–glutamate dipeptides as feed additives also had a positive influence on GS expression (the optimal concentration is 0.8%). Finally, we explored the effects of different protein levels and sources on the expression of GS, and the results demonstrated that GS had the highest expression at the 35% protein level, but no significant differences were observed in the different protein sources between the fish meal diet (FM) and the mixed diet comprising soybean meal and rapeseed meal (SM). This study sheds new light on the regulation of GS in teleost fish and provides new perceptions and strategies for the formulation of high-quality feed for triploid crucian carp.

Nanoplastics (NPs) are becoming an emerging pollutant of global concern. A potential risk of NPs is that they can serve as carriers and synergistically function with other contaminants to cause diseases. A variety of diseases such as Alzheimer’s disease are related to the generation of amyloid fibrils, and insulin is typically used as a model to study the fibrillation process. In this study, we examined the fibrillation of insulin promoted by polystyrene nanoplastics (PSNPs) alone and synergistically with organic contaminants (denoted as X, X = pyrene, bisphenol A, 2,2′,4,4′-tetrabromodiphenyl ether, 4,4′-dihydroxydiphenylmethane, or 4-nonylphenol) having different polarities using thioflavin T fluorescence assays, dynamic light scattering, and circular dichroism spectroscopy. The presence of PSNPs and small organic contaminants decreased the lag phase time (tlag) for insulin fibrillation from 54.6 h to 35-51 h and their combination (PS-X) enhanced this process (tlag = 21-30 h). Notably, the lag phase time for insulin fibrillation with PS-nonpolar contaminants, PS-weakly polar contaminants, and PS-polar contaminants is around 20.8, 26.7, and 30.1 h, respectively, indicating the synergistic effect of PS-nonpolar contaminants or PS-weakly polar contaminants was more obvious than that of PS-polar contaminants. Moreover, molecular dynamic simulation reveal the interactions between insulin and PSs or small organic contaminants are primarily driven by van der Waals forces and hydrophobic interactions. Overall, the findings of this study underscore the potentially significant environmental impact of small organic contaminants assisting NPs in promoting insulin fibrillation.

Detection of copper ions is important for environmental protection and human healthy. In this study, a ratiometric fluorescent probe was developed by using silica nanoparticles capped carbon dots (CDs) as the core and red quantum dots (CdTe) as the shell linking onto the surface of silica. Cu(II) was found to quench the fluorescence of red-emitting CdTe on the shell, while not changing the fluorescence of the core blue-emitting CDs embedding silica nanoparticles. Based on multiple spectroscopic studies, we propose that selective binding of Cu(II) to CdTe of CDs@SiO2-CdTe via a photoinduced electron transfer (PET) process. The as-proposed sensor allows selective determination of Cu(II) in the range from 0.82 µM to 25 µM, with a detection limit of 0.053 µM.

Hexavalent chromium (Cr(VI)) is one of the most toxic components in heavy metal pollution. The reduction of highly toxic Cr(VI) into much less toxic trivalent chromium (Cr(III)) is a promising and common method of remediating Cr(VI) contamination. Nanoscale zero-valent iron (nZVI) is an important nanoparticle to facilitate environmental remediation. It was reported on the fabrication of a bionanocomposite (nZVI@PGA), i.e. nZVI stabilized and modified by poly (?-glutamic acid) (PGA). The bionanocomposite was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The processes of Cr(VI) conversion by nZVI, PGA and nZVI@PGA were investigated and optimized. Compared to unmodified nZVI, nZVI@PGA displayed higher activity in acidic environment. The pH and PGA loading were optimized. The maximum unit removal of Cr(VI) by nZVI@PGA can reach 340 mg/g in acidic environment. The results demonstrated that nZVI@PGA can convert about 97.3 % Cr(VI) (initial concentration was 20 mg/L) in 30 min at pH=3. nZVI@PGA owns high stability and reactivity, and has potential to remove Cr(VI) of sewage in the future.

Summary: Amyloid are protein aggregates formed by cross β structures assemblies. Inhibiting amyloid aggregation or facilitating its disassembly are considered to be two major effective therapeutic strategies in diseases involving peptide or protein fibrillation such Alzheimer's disease or diabetes. Using thioflavin-T fluorescence, far-UV circular dichroism spectroscopy, and atomic force microscopy, we found nontoxic and biocompatible black phosphorus quantum dots (BPQDs) appear to have an exceptional capacity to inhibit insulin aggregation and to disassemble formed mature fibrils, even at an ultralow concentration (100 ng/mL). The inhibition of fibrillation persists at all stages of insulin aggregation and increases PC12 cells survival when exposed to amyloid fibrils. Molecular dynamics simulations suggest that BPQDs are able to stabilize the α-helix structure of insulin and obliterate the β-sheet structure to promote the fibril formation. These characteristics make BPQDs be promising candidate in preventing amyloidosis, disease treatment, as well as in the storage and processing of insulin.

Compositing all-carbon materials with distinct dimensions and structures has demonstrated the great potential to bring synergistic promotion to individual components for the electrocatalytic activity of oxygen reduction reaction (ORR). Fullerene-derived porous carbon fibers (FPCFs) offer unique one-dimensional (1D) nanostructures with abundant defects and a large specific surface area while graphene features two-dimensional (2D) nanostructures with fast electron transfer. Both carbon materials are promising alternatives to Pt-based electrocatalysts for ORR. Herein, a novel hierarchical composite (FPCFs@rGO) composed of FPCFs and reduced graphene oxide (rGO) is constructed by sonication-assisted mixing and high-temperature pyrolysis. When tested as an electrocatalyst for ORR, the 1D/2D FPCFs@rGO composite presents significantly enhanced performance compared to each individual component, indicating an eminent synergistic effect between FPCFs and rGO. The improved ORR performance of FPCFs@rGO is attributed to the unique hierarchical structure with abundant structural defects, a large specific surface area, and high porosity.

Abstract Background Biological pretreatment is an environmentally safe method for disrupting recalcitrant structures of lignocellulose and thereby improving their hydrolysis efficiency. Expansin and expansin-like proteins act synergistically with cellulases during hydrolysis. A systematic analysis of the adsorption behavior and mechanism of action of expansin family proteins can provide a basis for the development of highly efficient pretreatment methods for cellulosic substrates using expansins. Results Adsorption of Bacillus subtilis expansin (BsEXLX1) onto cellulose film under different conditions was monitored in real time using a quartz crystal microbalance with dissipation. A model was established to describe the adsorption of BsEXLX1 onto the film. High temperatures increased the initial adsorption rate while reducing the maximum amount of BsEXLX1 adsorbed onto the cellulose. Non-ionic surfactants (polyethylene glycol 4000 and Tween 80) at low concentrations enhanced BsEXLX1 adsorption; whereas, high concentrations had the opposite effect. However, sodium dodecyl sulfate inhibited adsorption at both low and high concentrations. We also investigated the structural changes of cellulose upon BsEXLX1 adsorption and found that BsEXLX1 adsorption decreased the crystallinity index, disrupted hydrogen bonding, and increased the surface area of cellulose, indicating greater accessibility of the substrate to the protein. Conclusions These results increase our understanding of the interaction between expansin and cellulose, and provide evidence for expansin treatment as a promising strategy to enhance enzymatic hydrolysis of lignocellulose.

Background/Aims: An increasing body of evidence shows that long noncoding RNAs (lncRNAs) are involved in many different cancers. In this study, we aimed to investigate the competing endogenous RNA (ceRNA)-dependent mechanism by which the lncRNA GAS5 contributes to the development of breast cancer. Methods: A total of 68 breast cancer patients were enrolled, and breast cancer and adjacent normal tissues were collected. The human breast cancer cell lines MDA-MB-231, MDA-MB-453, BT549, SK-BR-3 and MCF-7 and human breast cell line MCF10A were utilized in this study. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were performed to detect expression of relative factors. RNA immunoprecipitation (RIP) was used to evaluate the relationship between GAS5 and miR-23a, and a dual luciferase reporter gene assay was employed to assess the relationship between ATG3 and miR-23a. A subcutaneous xenograft nude mouse model was generated to examine the role of GAS5 and its regulatory pathway in autophagy. Results: GAS5 levels were frequently decreased in breast cancer tissues and cell lines, and its relatively low expression was closely related to a larger tumour size, advanced tumour-node-metastasis (TNM) stage and estrogen receptor-negative (ER-) breast cancer tissues. More importantly, we found that GAS5 promoted autophagy, with enhanced autophagosome formation after GAS5 overexpression. GAS5 was found to act as a microRNA sponge in a pathway that included miR-23a and its target gene ATG3. The GAS5-miR-23a-ATG3 axis significantly regulated autophagy in vivo and in vitro. Conclusions: In summary, we report that the GAS5-miR-23a-ATG3 axis can be regarded as a key regulator of autophagy pathways in breast cancer; it may constitute a promising biomarker and therapeutic target in the future.

Abstract Nanoscale zero-valent iron (nZVI) has shown considerable promise in the treatment of chlorinated organic compounds, but rapid aggregation and inactivation hinder its application. In this study, palladium-doped zero-valent iron nanoparticles involving poly (γ-glutamic acid) (Fe-Pd@PGA NPs) were synthesized. The nanoparticles were small (~100 nm), uniformly distributed, and highly stable. The dechlorination performance of Fe-Pd@PGA NPs was evaluated using p-CP as a model. The results demonstrated that Fe-Pd@PGA NPs show high activity even in weakly alkaline conditions. The maximum rate constant reached 0.331 min− 1 at pH 9.0 with a Fe to p-CP ratio of 100. Additionally, the dechlorination activity of Fe-Pd@PGA NPs is more than ten times higher than that of the bare Fe-Pd NPs, demonstrating the crucial role of PGA in this system. Furthermore, we investigated the dechlorination performance in the presence of different anions. The results indicated that Fe-Pd@PGA NPs can maintain high activity in the presence of Cl−, H2PO4 −, and humic acid, while HPO4 2−and HCO3 − ions slightly reduce the dechlorination activity. We believed that PGA is a promising stabilizer and promoter for Fe-Pd NPs and the Fe-Pd@PGA NPs have the potential for practical applications.

Abstract Background Tongue squamous cell carcinoma (TSCC) is the most common oral cancer. Neoadjuvant systemic treatment before or after surgery for advanced TSCC is considered one of the most crucial factors in reducing mortality. However, the therapeutic benefits of chemotherapy are usually attenuated due to intrinsic and/or acquired drug resistance, and a large proportion of TSCC are resistant to chemotherapy, which may result in more aggressive tumor behavior and an even worse clinical outcome. Recently, the potential application of using miRNAs to predict therapeutic response to cancer treatment holds high promise, but miRNAs with predictive value remain to be identified and underlying mechanisms remain to be understood in TSCC. Methods The expression of miR-22 in tissues from patients diagnosed with TSCC was analyzed using real-time PCR. The effects of miR-22 on cell proliferation and tumorigenesis in TSCC cells were analyzed by MTS assay, and flow cytometry. The tumor growth in vivo was observed in xenograft model. Luciferase reporter assay, real-time PCR and western blot were performed to validate a potential target of miR-22 in TC. The correlation between miR-22 expression and KAT6B expression, as well as the mechanisms by which miR-22 regulates PI3k-Akt-NF-kB pathway in TSCC were also addressed. Results We found a strong correlation between miR-22 expression and chemosensitivity to cisplatin (CDDP) in TSCC patients. Ectopic overexpression of miR-22 enhanced TSCC cells apoptosis in response to CDDP in experimental models performed in vitro and in vivo. Moreover, we found that KAT6B is a direct functional target of miR-22. Ectopic expression of KAT6B attenuated the efficiency of miR-22 in TSCC cells upon CDDP treatment. Mechanistically, miR-22 overexpression or KAT6B knockdown inhibited PI3K/Akt/NF-κB signaling in TSCC cells, possibly via downregulating the activators of PI3K/Akt/NF-κB signaling, such as S100A8, PDGF and VEGF. Furthermore, the activation of miR-22 depended on the intensity of the stresses in the presence of p53 activation. Conclusions Our findings define miR-22 as an intrinsic molecular switch that determines p53-dependent cellular fate through KAT6B/ PI3K-Akt/ NF-kB pathway.

Abstract 4-Nitrophenol (4-NP) is a priority pollutant in water and is both carcinogenic and genotoxic to humans and wildlife even at very low concentrations. Thus, we herein fabricated a novel molecularly imprinted core-shell nanohybrid as a ratiometric fluorescent sensor for the highly sensitive and selective detection of 4-NP. This sensor was functioned by the transfer of fluorescence resonance energy between photoluminescent carbon dots (CDs) and 4-NP. This sensor was synthesized by linking organosilane-functionalized CDs to silica-coated CdSe quantum dots (CdSe@SiO2) via Si–O bonds. The nanohybrids were further modified by anchoring a molecularly imprinted polymer (MIP) layer on the ratiometric fluorescent sensor through a facile sol–gel polymerization method. The morphology, chemical structure, and optical properties of the resulting molecularly imprinted dual-emission fluorescent probe were characterized by transmission electron microscopy and spectroscopic analysis. The probe was then applied in the detection of 4-NP and exhibited good linearity between 0.051 and 13.7 μg/mL, in addition to a low detection limit of 0.026 μg/mL. Furthermore, the simplicity, reliability, high selectivity, and high sensitivity of the developed sensor demonstrate that the combination of MIPs and ratiometric fluorescence allows the preparation of excellent fluorescent sensors for the detection of trace or ultra-trace analytes.

TFIIB‐related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase‐dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer (HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC. Two hundred and eighteen samples of HBC were collected to determine Brf1 expression by cytological and molecular biological approaches. We utilized colocalization, coimmunoprecipitation, and chromatin immunoprecipitation methods to explore the interaction of Brf1 with estrogen receptor alpha (ERα). We determined how Brf1 and ERα modulate Pol III genes. The results indicated that Brf1 is overexpressed in most cases of HBC, which is associated with an ER‐positive status. The survival period of the cases with high Brf1 expression is significantly longer than those with low levels of Brf1 after hormone treatment. ERα mediates Brf1 expression. Brf1 and ERα are colocalized in the nucleus. These results indicate an interaction between Brf1 and ERα, which synergistically regulates the transcription of Pol III genes. Inhibition of ERα by its siRNA or tamoxifen reduces cellular levels of Brf1 and Pol III gene expression and decreases the rate of colony formation of breast cancer cells. Together, these studies demonstrate that Brf1 is a good biomarker for the diagnosis and prognosis of HBC. This interaction of Brf1 with ERα and Brf1 itself are potential therapeutic targets for this disease.

Abstract Background Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. We previously identified that Annexin A2 is significantly up-regulated in cisplatin-resistant non-small cell lung cancer (NSCLC) A549/DDP cells. However, the exact function and molecular mechanism of Annexin A2 in cisplatin resistance of NSCLCs has not been determined. Methods Western blot and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. Immunohistochemistry was performed to analyze the expression of Annexin A2 in NSCLC tissue samples. MTS assay, Colony formation assays, AnnexinV/PI apoptosis assay, Luciferase Reporter Assay, Chromatin-immunoprecipitation, and nude mice xenograft assay were used to visualize the function of Annexin A2 on cisplatin resistance. Results Our results demonstrated that knockdown of Annexin A2 increased cisplatin sensitivity of cisplatin-resistant A549/DDP cells both in vitro and in vivo, whereas overexpression of Annexin A2 increased cisplatin resistance of A549, H460 and H1650 cells. Moreover, we found that Annexin A2 enhanced cisplatin resistance via inhibition of cisplatin-induced cell apoptosis. Our studies showed that Annexin A2 suppressed the expression of p53 through activation of JNK/c-Jun signaling, which in turn resulted in a decrease in the expression of p53-regulated apoptotic genes p21, GADD45 and BAX, as well as p53-dependent cell apoptosis. Furthermore, we found that in NSCLC cases that Annexin A2 is highly expressed; it is positively correlated with a poor prognosis, as well as correlated with short disease-free survival for patients who received chemotherapy after surgery. Conclusions These data suggested that Annexin A2 induces cisplatin resistance of NSCLCs via regulation of JNK/c-Jun/p53 signaling, and provided an evidence that blockade of Annexin A2 could serve as a novel therapeutic approach for overcoming drug resistance in NSCLCs.

Abstract Background The potential mechanisms regarding how methylation of microRNA(miRNA) CpG Island could regulate cancer cell chemo-resistance remains unclear. This study aims to explore the epigenetic dysregulation mechanism of miRNA-493 and the ability to modulate lung cancer cell chemotherapy resistance. Methods Real-time quantitative PCR (qRT-PCR) and In situ hybridization (ISH) were used to analyze the expression of miR-493 in lung cancer cell lines and tumor tissue, respectively. Bisulfite sequencing PCR (BSP) was used to exam the promoter CpG Island of miR-493. The effect of miR-493 on chemosensitivity was evaluated by cell viability assays, apoptosis assays and in vivo experiment. The DNA damage was measured by γ-H2AX immunofluorescence. Luciferase reporter assay was used to assess the target genes of miR-493. Expression of target proteins and downstream molecules were analyzed by Western blot. Results miR-493 is silenced in resistant lung cancer cell due to the aberrant DNA methylation. Enforced expression of miR-493 in lung cancer cells promotes chemotherapy sensitivity to cisplatin through impairing the DNA damage repair and increasing the cells apoptosis in vitro and in vivo. Furthermore, we identify that TCRP1 is a direct functional target of miR-493. Ectopic expression of TCRP1 attenuated increased apoptosis in miR-493-overexpressing lung cancer cells upon cisplatin treatment. Meanwhile, miR-493 level is negatively correlated with TCRP1 expression in lung cancer patients and TCRP1 expression were correlated with poor survival. Conclusions Our results highlight that hyper-methylation of miR-493CpG island might play important roles in the development of lung cancer chemo-resistance by targeting TCRP1, which might be used as a potential therapeutic target in preventing the chemo-resistance of lung cancer.

Abstract Previously, we cloned a new gene termed ‘tongue cancer resistance-associated protein 1’ (TCRP1), which modulates tumorigenesis, enhances cisplatin (cDDP) resistance in cancers, and may be a potential target for reversing drug resistance. However, the mechanisms for regulating TCRP1 expression remain unclear. Herein, we combined bioinformatics analysis with luciferase reporter assay and ChIP assay to determine that c-Myc could directly bind to TCRP1 promoter to upregulate its expression. TCRP1 upregulation in multidrug resistant tongue cancer cells (Tca8113/PYM) and cisplatin-resistant A549 lung cancer cells (A549/DDP) was accompanied by c-Myc upregulation, compared to respective parental cells. In tongue and lung cancer cells, siRNA-mediated knockdown of c-Myc led to decrease TCRP1 expression, whereas overexpression c-Myc did the opposite. Moreover, TCRP1 knockdown attenuated chemoresistance resulting from c-Myc overexpression, but TCRP1 overexpression impaired the effect of c-Myc knockdown on chemosensitivity. Additionally, in both human tongue and lung cancer tissues, c-Myc protein expression positively correlated with TCRP1 protein expression and these protein levels were associated with worse prognosis for patients. Combined, these findings suggest that c-Myc could transcriptionally regulate TCRP1 in cell lines and clinical samples and identified the c-Myc-TCRP1 axis as a negative biomarker of prognosis in tongue and lung cancers.