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Abstract The inadequate tumor accumulation of anti-cancer agents is a major shortcoming of current therapeutic drugs and remains an even more significant concern in the clinical prospects for nanomedicines. Various strategies aiming at regulating the intratumoral permeability of therapeutic drugs have been explored in preclinical studies, with a primary focus on vascular regulation and stromal reduction. However, these methods may trigger or facilitate tumor metastasis as a tradeoff. Therefore, there is an urgent need for innovative strategies that boost intratumoral drug accumulation without compromising treatment outcomes. As another important factor affecting drug tumor accumulation besides vasculature and stroma, the impact of tumor-associated lymphatic vessels (LVs) has not been widely considered. In the current research, we verified that anlotinib, a tyrosine kinase inhibitor with anti-lymphangiogenesis activity, and SAR131675, a selective VEGFR-3 inhibitor, effectively decreased the density of tumor lymphatic vessels in mouse cancer models, further enhancing drug accumulation in tumor tissue. By combining anlotinib with therapeutic drugs, including doxorubicin (Dox), liposomal doxorubicin (Lip-Dox), and anti-PD-L1 antibody, we observed improved anti-tumor efficacy in comparison with monotherapy regimens. Meanwhile, this strategy significantly reduced tumor metastasis and elicited stronger anti-tumor immune responses. Our work describes a new, clinically transferrable approach to augmenting intratumoral drug accumulation, which shows great potential to address the current, unsatisfactory efficacies of therapeutic drugs without introducing metastatic risk.

Abstract One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated pancreatic stellate cells (a‐PSCs). These a‐PSCs generate abundant extracellular matrix and secrete various cytokines to form biophysical and biochemical barriers, impeding drug access to tumor tissues. Therefore, it is imperative to develop a strategy for reversing PSC activation and thereby removing the barriers to facilitate PDAC drug treatment. Herein, by integrating chromatin immunoprecipitation (ChIP)‐seq, Assays for Transposase‐Accessible Chromatin (ATAC)‐seq, and RNA‐seq techniques, this work reveals that super‐enhancers (SEs) promote the expression of various genes involved in PSC activation. Disruption of SE‐associated transcription with JQ1 reverses the activated phenotype of a‐PSCs and decreases stromal fibrosis in both orthotopic and patient‐derived xenograft (PDX) models. More importantly, disruption of SEs by JQ1 treatments promotes vascularization, facilitates drug delivery, and alters the immune landscape in PDAC, thereby improving the efficacies of both chemotherapy (with gemcitabine) and immunotherapy (with IL‐12). In summary, this study not only elucidates the contribution of SEs of a‐PSCs in shaping the PDAC tumor microenvironment but also highlights that targeting SEs in a‐PSCs may become a gate‐opening strategy that benefits PDAC drug therapy by removing stromal barriers.

Browning of white adipose tissue is a novel approach for the management of obesity and obesity-related metabolic disorders. Kaempferol (KPF) is a common dietary nutrient found abundantly in many fruits and vegetables and has been shown to have the potential to regulate lipid metabolism. However, the detailed mechanism by which it affects the browning of white adipose tissue remains unclear. In the present study, we sought to determine how KPF induces adipocytes to undergo a browning transformation by establishing a primary adipocyte model and an obese mouse model. Our results showed that KPF-treated mice were rescued from diet-induced obesity, glucose tolerance and insulin resistance, associated with increased expression of adaptive thermogenesis-related proteins. KPF-promoted white adipose browning correlated with the AMPK/SIRT1/PGC-1α pathway, as the use of an AMPK inhibitor in preadipocytes partially reversed the observed browning phenotype of KPF-treated cells. Taken together, these data suggest that KPF promotes browning of white adipose tissue through activation of the AMPK/SIRT1/PGC-1α pathway. This study demonstrates that KPF is a promising natural product for the treatment of obesity by promoting white fat browning.

As a representative chemotherapeutic drug, docetaxel (DTX) has been used for breast cancer treatment for decades. However, the poor solubility of DTX limits its efficacy, and the DTX based therapy increases the metastasis risk due to the upregulation of C–X–C chemokine receptor type 4 (CXCR4) expression during the treatment. Herein, we conjugated CXCR4 antagonist peptide (CTCE) with DTX (termed CTCE–DTX) as an anti-metastasis agent to treat breast cancer. CTCE–DTX could self-assemble to nanoparticles, targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy. Thus, the CTCE–DTX NPs achieved promising efficacy on inhibiting both bone-specific metastasis and lung metastasis of triple-negative breast cancer. Our work provided a rational strategy on designing peptide–drug conjugates with synergistic anti-tumor efficacy.

Background: Genetic information is stored in the bases of double-stranded DNA. However, the integrity of DNA molecules is constantly threatened by various mutagenic agents, including pollutants, ultraviolet light (UV), and medications. To counteract these environmental damages, cells have established multiple mechanisms, such as producing molecules to identify and eliminate damaged DNA, as well as reconstruct the original DNA structures. Failure or insufficiency of these mechanisms can cause genetic instability. However, the role of genome stability in eye diseases is still under-researched, despite extensive study in cancer biology. Main text: As the eye is directly exposed to the external environment, the genetic materials of ocular cells are constantly under threat. Some of the proteins essential for DNA damage repair, such as pRb, p53, and RAD21, are also key during the ocular disease development. In this review, we discuss five ocular diseases that are associated with genomic instability. Retinoblastoma and pterygium are linked to abnormal cell cycles. Fuchs’ corneal endothelial dystrophy and age-related macular degeneration are related to the accumulation of DNA damage caused by oxidative damage and UV. The mutation of the subunit of the cohesin complex during eye development is linked to sclerocornea. Conclusions: Failure of DNA damage detection or repair leads to increased genomic instability. Deciphering the role of genomic instability in ocular diseases can lead to the development of new treatments and strategies, such as protecting vulnerable cells from risk factors or intensifying damage to unwanted cells.

Abstract Endometriosis is an estrogen-dependent chronic inflammatory disease. Hormonal and surgical treatments are the most commonly used clinical therapies, but they have many sides effects or are traumatic to the body. Therefore, specific drugs for endometriosis treatment are urgently needed to develop. In this study, we identified two features of endometriosis, namely the continuous recruitment of neutrophils into the ectopic lesions and the higher uptake of glucose by ectopic cells. For the above features, we designed a glucose oxidase-loaded bovine serum albumin nanoparticle (BSA-GOx-NPs) that is inexpensive and facilitates large-scale production. After injection, BSA-GOx-NPs were high specifically delivered to ectopic lesions in a neutrophil-dependent manner. Furthermore, BSA-GOx-NPs deplete glucose and induce apoptosis in the ectopic lesions. Whereupon BSA-GOx-NPs produced excellent anti-endometriosis effects when administrated in both acute and chronic inflammatory phases. These results reveal for the first time that the neutrophil hitchhiking strategy is effective in chronic inflammatory disease and provide a non-hormonal and easy-to-achieve approach for endometriosis treatment.

Gout is a metabolic disease that seriously affects people's health. Polydatin, a stilbene compound isolated from Polygonum cuspidatum, has attracted much attention because of its rich biological activity and high safety. This study aimed to investigate the therapeutic effect and mechanism of polydatin on hyperuricemia (HUA) combined with gouty arthritis (GA). The results showed that polydatin reduced the levels of uric acid and inflammatory cytokines, indicating that polydatin had the effect of reducing uric acid and anti-GA. Then the inhibitors of ABCG2, NLRP3 inflammasome and NF-κB pathway (Ko143, MCC950 and QNZ) were used to demonstrate that polydatin played a role in reducing uric acid and anti-GA via regulating urate transporters, NLRP3 inflammasome and NF-κB pathway. Taken together, these results provided evidence that polydatin might be used as a potential functional ingredient for the synchronous treatment of HUA and GA.

Aiming at solving the problems of bad imperceptibility and low embedding rate of existing algorithms, a novel large-capacity reversible image watermarking based on improved difference expansion (DE) is proposed. Firstly, the smoothness calculation algorithm is used to calculate and sort the smoothness values of the divided image sub-blocks; then, the scrambled watermark is embedded into the sub-blocks with less smoothness after removing the abrupt point by using the generalized difference expansion (GDE); finally, the absolute difference operation is applied to the generated overflow pixels to make their pixel values within a reasonable range for embedding watermark information. Under the premise of ensuring a certain visual quality, multiple watermark embedding can effectively improve the embedding rate. The simulation results show that this algorithm not only realizes blind extraction, but also recovers the original images without loss. At the same time, this algorithm achieves a high embedding rate (the average embedding rate is as high as 77.91 dB) without decreasing the visual quality.

Brown adipocytes contribute to energy balance, and adipocyte development and brown adipocyte thermogenesis are in part regulated by epigenetic modifications. Here the authors report that the histone demethylase Utx maintains brown adipocyte identity via demethylation of PRDM16, which in turn represses myogenic remodelling via DNMT1-mediated Myod1 promoter hypermethylation in mice.

Activation of brown adipose tissue thermogenesis increases energy expenditure and promotes weight loss in mice. Here the authors identify neurotrophic factor neurotrophin 3 (NT-3) as an adipokine that regulates sympathetic nervous system growth and innervation in adipose tissue and increases white adipose beiging.

Object detection from remote sensing images serves as an important prerequisite to many applications. However, caused by scale and orientation variations, appearance and distribution diversities, occlusion and shadow contaminations, and complex environmental scenarios of the objects in remote sensing images, it brings great challenges to realize highly accurate recognition of geospatial objects. This paper proposes a novel one-stage anchor-free capsule network (OA-CapsNet) for detecting geospatial objects from remote sensing images. By employing a capsule feature pyramid network architecture as the backbone, a pyramid of high-quality, semantically strong feature representations are generated at multiple scales for object detection. Integrated with two types of capsule feature attention modules, the feature quality is further enhanced by emphasizing channel-wise informative features and class-specific spatial features. By designing a centreness-assisted one-stage anchor-free object detection strategy, the proposed OA-CapsNet performs effectively in recognizing arbitrarily-orientated and diverse-scale geospatial objects. Quantitative evaluations on two large remote sensing datasets show that a competitive overall accuracy with a precision, a recall, and an Fscore of 0.9625, 0.9228, and 0.9423, respectively, is achieved. Comparative studies also confirm the feasibility and superiority of the proposed OA-CapsNet in geospatial object detection tasks.

In this paper, the customer to manufacturer (C2M) platform in e-commercial business which connects the customers and the manufacturers is studied. The platform is organized in a centralized collaboration framework where an e-commercial company and multiple manufacturers form a collaborative alliance to satisfy the product orders of multiple customers and maximize a total profit of the alliance. The key issue of the C2M platform is to seek a fair allocation of the profit among the manufacturers. A profit allocation mechanism is proposed for the platform that can assure the stability of the alliance and the sustainability of the platform. The mechanism is based on core allocation and considers each manufacturer’s contribution in fulfilling orders. The effectiveness of the mechanism is evaluated by numerical experiments on 60 instances generated from real data of Alibaba. The experiment results display that the participation of more manufacturers in the C2M platform is profitable. The proposed mechanism can create a profit allocation that keeps in the core in 31 of 60 instances and produce a feasible profit allocation in other 29 instances, which is more reasonable than the current mechanism of C2M platform and easier applied in practice.

Background: Gouty arthritis is a common and complex inflammatory disease that will reduce the life quality of human beings (−)-Epicatechin (EC) is famous for antioxidant and anti-inflammatory activities. Thus, the aim of this study was to investigate the therapeutic effect of EC on gouty arthritis and its mechanisms.Methods and results: EC was added into a monosodium urate (MSU)-stimulated THP-1 cell that was induced by phorbol 12-myristate 13-acetate and lipopolysaccharide (LPS) in advance to establish a gout model in vitro. The efficiency of EC on acute gouty arthritis mice induced by MSU was further investigated. The results showed that EC concentration-dependently improved the cell viability of LPS and MSU stimulated THP-1 cells, and significantly alleviated MSU-induced ankle edema in mice in a dose-dependent manner. In addition, EC inhibited the infiltration of inflammatory cells and local cascular congestion in ankle joint tissue. Furthermore, the secretion of inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α) activation of NLRP3 inflammasome and NF-κB signaling pathway were markedly suppressed by EC in vitro and in vivo.Conclusion: These results indicated that EC could effectively improve MSU-induced acute gouty arthritis via inhibiting NLRP3 inflammasome and the NF-κB signaling pathway in vitro and in vivo, which suggested that EC might be a promising active ingredient for the prevention and treatment of gouty arthritis.

Cross-efficiency in data envelopment analysis is widely used for performance evaluation of decision-making units (DMUs), but it neglects the reference relationship between each pair of DMUs. In order to address the problem, this paper introduces the concept of social network to clearly describe the reference relationship between DMUs and then a fully ranking can be made. A novel cross-efficiency approach is developed by integrating social network analysis in this study. Firstly, we propose a pairwise comparison model based on cross-efficiency evaluation to identify the superiority and inferiority between any pair of DMUs. Secondly, based on pairwise comparison, we build a non-weighted directed social network where a direction generates from one DMU to another DMU if the former one references the latter one. Each edge in the unweighted social network captures the learning procedure from worse-performance DMU to better-performance DMU. Comparing with traditional cross-efficiency approaches, our proposed approach considers the reference relationship among DMUs rather than only cross-efficiency scores. Thus, the importance of each DMU in the network can be measured by its centrality. Finally, the proposed approach is employed to environmental efficiency evaluation of the cities along the Xiangjiang River Basin, then, some beneficial universal policies have been summarized.

Super-porous hydrogels are considered a potential drug delivery network for the sedation of gastric mechanisms with retention windows in the abdomen and upper part of the gastrointestinal tract (GIT). In this study, a novel pH-responsive super-porous hybrid hydrogels (SPHHs) was synthesized from pectin, poly 2-hydroxyethyl methacrylate (2HEMA), and N, N methylene-bis-acrylamide (BIS) via the gas-blowing technique, and then loaded with a selected drug (amoxicillin trihydrate, AT) at pH 5 via an aqueous loading method. The drug-loaded SPHHs-AT carrier demonstrated outstanding (in vitro) gastroretentive drug delivery capability. The study attributed excellent swelling and delayed drug release to acidic conditions at pH 1.2. Moreover, in vitro controlled-release drug delivery systems at different pH values, namely, 1.2 (97.99%) and 7.4 (88%), were studied. These exceptional features of SPHHs—improved elasticity, pH responsivity, and high swelling performance—should be investigated for broader drug delivery applications in the future.

2-naphthol is a low-molecular-weight (LMW) polycyclic aromatic hydrocarbon (PAH) and air pollutant associated with childhood obesity. There has been a recent emergence of studies on the consequences of PAHs on human health. Current epidemiological reports suggest LMW-PAHs may contribute to obesity incidences in children, yet most studies focus on high-molecular-weight PAHs. This study explores 2-naphthol’s impact on obesity and obesity-associated metabolic disorders. To investigate 2-naphthol’s effect on lipid metabolism and inflammation, we employed 3T3-L1 and BAT1 cell lines to model white and brown adipocytes, respectively, alongside a murine macrophage cell line (RAW264.7). We found that 2-naphthol increased the expression of key adipogenic and lipogenic genes while decreasing lipolytic gene expression in chronically treated 3T3-L1 and BAT1 adipocytes. In addition, chronic 2-naphthol treatment also suppressed adrenergic-stimulated thermogenic gene expression in BAT1 brown adipocytes. In consistence, an increase in lipid accumulation was demonstrated in BODIPY and Oil Red O-stained adipocytes. Additionally, 3T3-L1 adipocytes and RAW264.7 macrophages chronically exposed to 2-naphthol showed upregulated mRNA expression of major inflammatory cytokines (e.g., tumor necrosis factor α (Tnfα), interleukin-1β (Il-1β), and Il-6). In summary, chronic exposure to 2-naphthol stimulates lipid accumulation in adipocytes and inflammation in adipocytes and macrophages. These findings support previous research that demonstrates 2-naphthol has obesogenic potential.

We discovered a unique expression pattern of two histone methyltransferases Suv39h1 and Suv39h2 during 3T3-L1 adipogenesis, both of which preferentially catalyse the formation of H3K9 dimethylation (H3K9me2) and further H3K9 trimethylation (H3K9me3), a transcriptional repressive mark. The expression of Suv39h1 and Suv39h2 displayed a sharp increase at the early stage of 3T3-L1 differentiation, which peaked after differentiation induction, and then declined towards later stage of differentiation, suggesting a key role for these two histone methyltransferases in adipogenesis. Indeed, inactivating Suv39h1 or Suv39h2 via lentiviral shRNA knockdown inhibited adipogenesis, while overexpressing Suv39h1 promoted adipogenesis. Notably, overexpressing or knocking down Suv39h1 in 3T3-L1 cells was associated with reciprocal changes in the expression of Wnt10a, an anti-adipogenic regulator. Further, Wnt10a knockdown largely prevented the inhibitory effect of Suv39h1 on adipogenesis, indicating Wnt10a as a downstream target mediating Suv39h1’s action in adipogenesis. Mechanistically, our comprehensive approaches involving ChIP, co-immunoprecipitation and pyrosequencing analysis demonstrated that Suv39h1 may regulate Wnt10a expression via H3K9 methylation and interaction with DNA methyltransferase 1 (DNMT1) at the Wnt10a promoter, resulting in altered DNA methylation at the promoter. We conclude that Suv39h promotes adipogenesis by epigenetically down-regulating Wnt10a expression via H3K9me3 and DNA methylation at the Wnt10a promoter.Abbreviated title: Suv39h and 3T3-L1 Adipogenesis

Abstract Background Discs large homolog 5 (Dlg5) is a member of the membrane-associated guanylate kinase (MAGUK) adaptor family of proteins and its deregulation has been implicated in the malignancy of several cancer types. Dlg5 was down-regulated in hepatocellular carcinoma (HCC) and lower Dlg5 expression was associated with poor survival of HCC patients. However, how to regulate Dlg5 remains largely unknown. Methods The co-immunoprecipitation assay was used to determine the interaction between Dlg5 and β-TrCP. The in vivo ubiquitination assay was performed to determine the regulation of Dlg5 by β-TrCP. CCK-8 and colony formation assay were implemented to detect the biological effect of Dlg5 on the growth of HCC cells in vitro. The effect of Dlg5 on HCC tumor growth in vivo was studied in a tumor xenograft model in mice. Results Here we report that Dlg5 is regulated by the ubiquitin proteasome system and depletion of either Cullin 1 or β-TrCP led to increased levels of Dlg5. β-TrCP regulated Dlg5 protein stability by targeting it for ubiquitination and subsequent destruction in a phosphorylation-dependent manner. We further demonstrated a crucial role of Ser730 in the non-canonical phosphodegron of Dlg5 in governing β-TrCP-mediated Dlg5 degradation. Importantly, failure to degrade Dlg5 significantly inhibited HCC cells proliferation both in vitro and in vivo. Conclusion Collectively, our finding provides a novel molecular mechanism for the negative regulation of Dlg5 by β-TRCP in HCC cells. It further suggests that preventing Dlg5 degradation could be a possible novel strategy for clinical treatment of HCC.

Deep learning has been proved effective in multiple object tracking, which confronts the difficulties of frequent occlusions, confusing appearance, in‐and‐out objects, and lack of enough labelled data. Recently, deep learning based multi‐object tracking methods make a rapid progress from representation learning to network modelling due to the development of deep learning theory and benchmark setup. In this study, the authors summarise and analyse deep learning based multi‐object tracking methods which are top‐ranked in the public benchmark test. First, they investigate functionality of deep networks in these methods, and classify the methods into three categories as description enhancement using deep features, deep network embedding, and end‐to‐end deep network construction. Second, they review deep network structures in these methods, and detail the usage and training of these networks for multi‐object tracking problem. Through experimental comparison of tracking results in the benchmarks in total and by group, they finally show the effectiveness of deep networks for tracking employed in different manners, and compare the advantages of these networks and their robustness under different tracking conditions. Moreover, they analyse the limitations of current methods, and draw some useful conclusions to facilitate the exploration of new directions for multi‐object tracking.

Gouty arthritis (GA) is a frequent inflammatory disease characterized by pain, swelling, and stiffness of joints. Neoastilbin is a flavonoid isolated from the rhizome of Smilax glabra, which possesses various anti-inflammatory effects. However, the mechanism of neoastilbin in treating GA has not yet been clarified. Thus, this study was to investigate the protective effects of neoastilbin in both monosodium urate (MSU) stimulated THP-1-derived macrophages and the animal model of GA by injecting MSU into the ankle joints of mice. The levels of key inflammatory cytokines in MSU stimulated THP-1-derived macrophages were detected by enzyme-linked immunosorbent assay (ELISA) kits. Protein expressions of nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome pathways were further detected by Western blotting. In addition, swelling degree of ankle joints, the levels of inflammatory factors, infiltration of inflammatory cells and the expressions of related proteins were determined. Swelling degree and histopathological injury in ankle joints of MSU-injected mice were significantly decreased after being treated with neoastilbin. Moreover, neoastilbin significantly diminished the secretion of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), suppressing the activation of NF-κB and NLRP3 inflammasome pathways in both MSU stimulated THP-1-derived macrophages and the mouse model of GA. In summary, neoastilbin could alleviate GA by inhibiting the NF-κB and NLRP3 inflammasome pathways, which provided some evidence for neoastilbin as a promising therapeutic agent for GA treatment.

Supplier selection is an important decision-making problem, which involves many quantitative and qualitative factors incorporating vagueness and imprecision. This study proposes a novel fuzzy multi-criteria decision-making framework for supplier selection, which integrates quality function deployment (QFD) and interval data envelopment analysis (DEA). The proposed methodology allows for considering the relationships among the product features and supplier evaluation criteria (SEs) and the impacts of inner dependence among SEs by constructing a house of quality (HOQ). Considering that the number of supplier evaluation indicators is greater than the number of suppliers in some cases, the curse of dimensionality problem usually exists. To solve this problem, we combine the HOQ, interval DEA models, and forward-stepwise selection approach to screen supplier evaluation indicators and select the best supplier(s). Through the two-stage supplier selection method, we can achieve the double screening of indicators and determine the final supplier(s). Finally, the application of the proposed framework is demonstrated through a numerical example and a sensitivity analysis is also carried out to verify the stability of the proposed methodology. This study focuses on supplier selection based on the combination of fuzzy QFD and interval DEA, and also provide a new two-phase methodology for DEA indicator screening.

While the main function of white adipose tissue (WAT) is to store surplus of energy as triacylglycerol, that of brown adipose tissue (BAT) is to burn energy as heat. Epigenetic mechanisms participate prominently in both WAT and BAT energy metabolism. We previously reported that the histone demethylase ubiquitously transcribed tetratricopeptide (Utx) is a positive regulator of brown adipocyte thermogenesis. Here, we aimed to investigate whether Utx also regulates WAT metabolism in vivo. We generated a mouse model with Utx deficiency in adipocytes (AUTXKO). AUTXKO animals fed a chow diet had higher body weight, more fat mass and impaired glucose tolerance. AUTXKO mice also exhibited cold intolerance with an impaired brown fat thermogenic program. When challenged with high-fat diet (HFD), AUTXKO mice displayed adipose dysfunction featured by suppressed lipogenic pathways, exacerbated inflammation and fibrosis with less fat storage in adipose tissues and more lipid storage in the liver; as a result, AUTXKO mice showed a disturbance in whole body glucose homeostasis and hepatic steatosis. Our data demonstrate that Utx deficiency in adipocytes limits adipose tissue expansion under HFD challenge and induces metabolic dysfunction via adipose tissue remodeling. We conclude that adipocyte Utx is a key regulator of systemic metabolic homeostasis.

The preventive role of polysaccharide from the seeds of Plantago asiatica L. (PLCP) against reproductive system injury induced by nonylphenol (NP) was investigated. Male Sprague-Dawley rats were exposed orally to NP 1 h after PLCP intragastric administration continuously for 45 days. The results showed that NP induced significant decrease in relative weight of testes and epididymis, changed testicular histomorphology, and disrupted hormone secretions. Moreover, oxidative stress occurred after NP exposure by overproduction of Malondialdehyde, lipid peroxidation, inducible nitric oxide synthase, and low activities of superoxide dismutase and catalase. Furthermore, the induction of apoptosis and disturbance of PI3K/Akt/mTOR pathway by NP were also proved. Interestingly, PLCP alleviated NP toxicity by improving antioxidant enzymes, recovering hormone secretions, inhibiting apoptosis and autophagy, which involves PI3K/Akt/mTOR pathway. These findings provide a good direction that PLCP may be a good candidate to help body defend against toxic substance, particularly endocrine disrupting chemicals induced reproductive toxicity.

As two-dimensional materials with a high specific surface area, strength, and electrical and thermal conductivity, graphene (Gr) and its derivatives have great application prospects in various fields such as structural reinforcement, energy storage, optics, and electrical and thermal conductivity. However, the current preparation method of Gr is complicated and expensive. Its preparation cost can be reduced using Gr composites that include inorganic materials or other polymers. Composite materials comprising Gr and inorganic materials are generally prepared using sinter molding, chemical reduction, or chemical deposition. Gr should be able to mitigate several of the defects resulting from inorganic materials, including their poor toughness, small specific capacity, and low photoelectric conversion rate. The mitigation of these defects should result in the expansion of the applications of Gr composites for use in capacitors, catalysts, and sensors, among other devices. Although solution blending or in situ polymerization produces a relatively good mixing effect, in general, melt blending is used in the large-scale processing of Gr composites with polymer materials. Gr can be used to partially mitigate several weaknesses of polymer materials, including their low strength, poor electrical and thermal conductivities, and poor isolation performance, and expand the applications of Gr composites for use in electrical and thermal conductive materials and functional membrane materials, among other applications. The goal of the present paper is to introduce the structural properties of Gr and a surface modification method for Gr. In addition, the preparation methods and application fields of different Gr composite materials are reviewed. Finally, the development prospects and key issues are discussed.

Previous studies have shown that OVATE family proteins (OFPs) participate in various aspects of plant growth and development. How OFPs affect leaf chlorophyll accumulation and leaf senescence has not been reported yet. Here, we found that overexpression of SlOFP20 in tomato not only impacted plant architecture but also enhanced the leaf chlorophyll accumulation and retarded leaf senescence. Gene expression analysis of SlGLK1, SlGLK2, and HY5, encoding transcription factors that are putatively involved in chloroplast development and chlorophyll levels, were significantly up-regulated in SlOFP20-OE lines. Both chlorophyll biosynthesis and degradation genes were distinctly regulated in transgenic plants. Moreover, SlOFP20-OE plants accumulated more starch and soluble sugar than wild-type plants, indicating that an increased chlorophyll content conferred some higher photosynthetic performance in SlOFP20-OE plants. Furthermore, The levels of leaf senescence-related indexes, such as hydrogen peroxide, malondialdehyde, and antioxidant enzymes activities, were differently altered, too. SlOFP20 overexpression repressed the expression of senescence-related genes, SAG12, RAV1, and WRKY53. Moreover, abscisic acid and ethylene synthesis genes were down-regulated in transgenic lines. These results provide new insights into how SlOFP20 regulates chlorophyll accumulation and leaf senescence.

Research on recommendation systems in bipartite networks has mainly been dedicated to enhance the accuracy of recommendations while neglecting the fact that complete historical information can be redundant or even mislead to the recommendations. In this paper, we first investigate the impact of the time window on recommendation models. We gradually expand the time window and find that the performance remains almost unchanged. We set the size of the time window according to the user's temporal and topological information; thus, different users have information backbones of different sizes. The experimental results on real networks show that the computational time complexity can be improved by the algorithm while simultaneously decreasing the data storage requirements.

Obesity results from a chronic energy imbalance due to energy intake exceeding energy expenditure. Activation of brown fat thermogenesis has been shown to combat obesity. Epigenetic regulation, including DNA methylation, has emerged as a key regulator of brown fat thermogenic function. Here we aimed to study the role of Dnmt3b, a DNA methyltransferase involved in de novo DNA methylation, in the regulation of brown fat thermogenesis and obesity. We found that the specific deletion of Dnmt3b in brown fat promotes the thermogenic and mitochondrial program in brown fat, enhances energy expenditure, and decreases adiposity in female mice fed a regular chow diet. With a lean phenotype, the female knockout mice also exhibit increased insulin sensitivity. In addition, Dnmt3b deficiency in brown fat also prevents diet-induced obesity and insulin resistance in female mice. Interestingly, our RNA-seq analysis revealed an upregulation of the PI3K-Akt pathway in the brown fat of female Dnmt3b knockout mice. However, male Dnmt3b knockout mice have no change in their body weight, suggesting the existence of sexual dimorphism in the brown fat Dnmt3b knockout model. Our data demonstrate that Dnmt3b plays an important role in the regulation of brown fat function, energy metabolism and obesity in female mice.

This study proposes a method for resource management and optimisation in the industrial sector of China. Differing from previous research on the green assessment of industrial systems focusing on “black box” evaluation, our approach contributes to the two-stage structure of an industrial system that consists of an industrial production process and a pollution treatment process. The corresponding network slack-based model (SBM) is proposed to analyse the performance of China’s provincial industry sector. Based on our network SBM, the global Malmquist index is built to analyse the total factor productivity changes of system and individual processes to evaluate the consistency of sustainable development where dynamic green growth assessment is realized. The results show that the whole system and its pollution treatment process performance are poor and disorganised, while the industrial production process maintains a stable ranking for the 30 regions in China. We find that the main cause of this phenomenon is the variable technical efficiency change in the 30 regions, which reflects the immaturity of the management of the pollution treatment process. System performance is also highly related to regionalism.

Increasing energy expenditure through activation of brown fat thermogenesis is a promising therapeutic strategy for the treatment of obesity. Epigenetic regulation has emerged as a key player in regulating brown fat development and thermogenic program. Here, we aimed to study the role of DNA methyltransferase 3b (Dnmt3b), a DNA methyltransferase involved in de novo DNA methylation, in the regulation of brown fat function and energy homeostasis. We generated a genetic model with Dnmt3b deletion in brown fat-skeletal lineage precursor cells (3bKO mice) by crossing Dnmt3b-floxed (fl/fl) mice with Myf5-Cre mice. Female 3bKO mice are prone to diet-induced obesity, which is associated with decreased energy expenditure. Dnmt3b deficiency also impairs cold-induced thermogenic program in brown fat. Surprisingly, further RNA-seq analysis reveals a profound up-regulation of myogenic markers in brown fat of 3bKO mice, suggesting a myocyte-like remodeling in brown fat. Further motif enrichment and pyrosequencing analysis suggests myocyte enhancer factor 2C (Mef2c) as a mediator for the myogenic alteration in Dnmt3b-deficient brown fat, as indicated by decreased methylation at its promoter. Our data demonstrate that brown fat Dnmt3b is a key regulator of brown fat development, energy metabolism and obesity in female mice.

In this study, joint inventory replenishment planning of an Alibaba distribution system is investigated, which contributes to the circular economy concept. The distribution system includes suppliers, central distribution centers, and front distribution centers. The total replenishment cost of the distribution system can be reduced by setting up distribution centers at producers’ locations (PDCs), which also helps to reduce the wastages of commodities during the transportation and CO2 emission released by transportation. The joint replenishments of multiple products are constrained by a maximum joint replenishment quantity. Trans-shipments happen among different distribution centers. The considered problem seeks to find the replenishment quantities of products among stocks, which can minimize the total replenishment cost of the system, and is formulated as a novel mathematical model. The effectiveness of our proposed model is validated by computational experiments based on Alibaba’s data. The results indicate that PDCs and trans-shipments can bring about lower replenishment costs if a common service level of the system is given.

Abstract Histone deacetylation is one of the well characterized post-translational modifications related to transcriptional repression in eukaryotes. The process of histone deacetylation is achieved by histone deacetylases (HDACs). Over the last decade, substantial advances in our understanding of the mechanism of fruit ripening have been achieved, but the role of HDACs in this process has not been elucidated. In our study, an RNA interference (RNAi) expression vector targeting SlHDA1 was constructed and transformed into tomato plants. Shorter fruit ripening time and decreased storability were observed in SlHDA1 RNAi lines. The accumulation of carotenoid was increased through an alteration of the carotenoid pathway flux. Ethylene content, ethylene biosynthesis genes (ACS2, ACS4 and ACO1, ACO3) and ripening-associated genes (RIN, E4, E8, Cnr, TAGL1, PG, Pti4 and LOXB) were significantly up-regulated in SlHDA1 RNAi lines. In addition, the expression of fruit cell wall metabolism genes (HEX, MAN, TBG4, XTH5 and XYL) was enhanced compared with wild type. Furthermore, SlHDA1 RNAi seedlings displayed shorter hypocotyls and were more sensitive to ACC (1-aminocyclopropane-1-carboxylate) than the wild type. The results of our study indicate that SlHDA1 functions as a negative regulator of fruit ripening by affecting ethylene synthesis and carotenoid accumulation.

Misuse of antibiotics has recently been considered a global issue because of its harmful effects on human health. Since conventional methods have numerous limitations, it is necessary to develop fast, simple, sensitive, and reproducible methods for the detection of antibiotics. Among numerous recently developed methods, aptasensors are fascinating because of their good specificity, sensitivity and selectivity. These kinds of biosensors combining aptamer with colorimetric applications of gold nanoparticles to recognize small molecules are becoming more popular owing to their advantageous features, for example, low cost, ease of use, on-site analysis ability using naked eye and no prerequisite for modern equipment. In this review, we have highlighted the recent advances and working principle of gold nanoparticles based colorimetric aptasensors as promising methods for antibiotics detection in different food and environmental samples (2011–2020). Furthermore, possible advantages and disadvantages have also been summarized for these methods. Finally, the recent challenges, outlook, and promising future perspectives for developing novel aptasensors are also considered.

Over the past four decades, patients with advanced ovarian cancer (OC) has enjoyed greatly improved survival rate considering advances in combined chemotherapy with platinum and paclitaxel. We investigated the association between polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1 and GSTP1) and short- and long-term efficacy of concurrent chemoradiotherapy (CCRT) in advanced OC. Patients with advanced OC and healthy females were selected in our study. Multiplex polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) were applied to detect homozygous deletions in GSTM1 and GSTT1, as well as codon 105 genetic polymorphisms in GSTP1 exon 5. All the patients with advanced OC were treated with CCRT. Toxicity of chemotherapy, short-term efficacy, recurrence and metastasis, respectively. Long-term survival outcomes were checked with a further examination and all patients were followed up for three years after CCRT.Compared with healthy females, patients with advanced OC showed higher frequencies of GSTT1 non-null genotype and homozygous mutation type GG of GSTP. GSTP1genetic polymorphisms were relevant to neutropenia resulted from CCRT in patients with advanced OC. Compared with patients with GSTT1non-null genotype, those with GSTT1 null genotype appeared to enjoy a better short-term efficacy, lower recurrence and metastasis rate, higher survival rate and longer mean survival time. Compared with patients with GG genotype, those with GSTP1 AA + AG genotype also enjoyed more positive results. Our results reveal that GSTT1 null genotype and GSTP1AA + AG genotype are associated with short- and long-term efficacy of CCRT in advanced OC.

Graphene oxide(GO)/polylactic acid (PLA) nanocomposite, prepared using a solvent-free melt mixing processing, is investigated as a potential oxygen barrier packaging film in this work. In order to disperse GO homogeneously in PLA matrix, hydrophobic silane coupling agent, i.e., γ-(2,3-epoxypropoxy)propyltrimethoxysilane (KH560), is used to modify the graphene oxide sheets. The modified GO is able to be well bonded to the PLA due to the formation of covalent bonds between the epoxy groups of KH560 and the carboxyl and hydroxyl terminal groups of PLA. Furthermore, the thermal stability of GO is enhanced due to the long alkyl side chain of KH560, which could also increase the crystallinity of PLA. As a result, the crystallinity of PLA is significantly improved because of the linear KH560 chains, which can act as nucleating agents to improve the crystallization. The KH560-GO helps to reduce the O2 permeability of KH560-GO/PLA composite films via a dual-action mechanism: (1) providing physical barrier due to their native barrier properties, and (2) by resulting in higher degree of crystallinity. The as-prepared KH560-GO0.75/PLA is able to exhibit ca. 33% and ca. 13% decrease in the PO2 than the neat PLA and GO0.75/PLA film, respectively. Finally, the mechanical properties and impact fractured surfaces indicate that the increase in the tensile strength and elongation at break value of KH560-GO/PLA are due to the strong interfacial adhesion and the strong bonding between the epoxy group of KH560-GO and hydroxyl and carboxyl acid terminal groups of PLA matrix.

Myricetin (Myr) is a phytochemical with many functional properties. However, its hydrophobicity, low bioavailability, and stability limit its application. In this study, octadecanoate oat β-glucan (OGE) was synthesized and gained recognition as a self-assembled micelle forming a polymer with a critical micelle concentration (CMC) of 59.4 μg/mL. The Myr-loaded OGE micelle was then prepared and characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), X-ray diffractometer (XRD), and Fourier-transform infrared spectroscopy (FT-IR) spectra. The water solubility of Myr was greatly enhanced by forming the Myr/OGE inclusion complex. Consequently, compared to free Myr, the retention of Myr in Myr-loaded OGE micelle was effectively increased during the intestinal digestion phase, and its antioxidant activity was also improved. Overall, our findings demonstrated the potential applications of OGE polymer for the development of prospective micelle in health food, cosmetics, and pharmaceutical fields because they can aid in the delivery of hydrophobic functional compounds like Myr.

With the rapid expansion of internet, the complex networks has become high-dimensional, sparse and redundant. Besides, the problem of link prediction in such networks has also obatined increasingly attention from different types of domains like information science, anthropology, sociology and computer sciences. It makes requirements for effective link prediction techniques to extract the most essential and relevant information for online users in internet. Therefore, this paper attempts to put forward a link prediction algorithm based on non-negative matrix factorization. In the algorithm, we reconstruct the correlation between different types of matrix through the projection of high-dimensional vector space to a low-dimensional one, and then use the similarity between the column vectors of the weight matrix as the scoring matrix. The experiment results demonstrate that the algorithm not only reduces data storage space but also effectively makes the improvements of the prediction performance during the process of sustaining a low time complexity.

In this study, composite aerogels with excellent mechanical properties were prepared by using carboxymethyl cellulose (CMC) as raw materials, with carboxylic carbon nanotubes (CNTs) as reinforcement. By controlling the mass fraction of CNTs, composite aerogels with different CNTs were prepared, and the surface morphology, specific surface area, compressive modulus, density and adsorption capacities towards different oils were studied. Compared to the pure CMC aerogel, the specific surface areas of CMC/CNTs were decreased because of the agglomeration of CNTs. However, the densities of composite aerogels were lower than pure CMC aerogel. This is because the CNTs were first dispersed in water and then added to CMC solution. The results indicated that it was easy for the low CMC initial concentration to be converted to low density aerogel. The compressive modulus was increased from 0.3 MPa of pure CMC aerogel to 0.5 MPa of 5 wt % CMC/CNTs aerogel. Meanwhile, the prepared aerogels showed promising properties as the adsorption materials. Because of the high viscosity, liquid possesses strong adhesion to the pore wall, the adsorption capacity of the CMC aerogel to the liquid increases as the viscosity of the liquid increases.

Heat transfer performances and flow structures of laminar impinging slot jets with power-law non-Newtonian fluids and corresponding typical industrial fluids (Carboxyl Methyl Cellulose (CMC) solutions and Xanthangum (XG) solutions) have been studied in this work. Investigations are performed for Reynolds number Re less than 200, power-law index n ranging from 0.5 to 1.5 and consistency index K varying from 0.001 to 0.5 to explore heat transfer and flow structure of shear-thinning fluid and shear-thickening fluid. Results indicate that with the increase of n, K for a given Re, wall Nusselt number increases mainly attributing to the increase of inlet velocity U. For a given inlet velocity, wall Nusselt number decreases with the increase of n and K, which mainly attributes to the increase of apparent viscosity and the reduction of momentum diffusion. For the same Re, U and Pr, wall Nusselt number decreases with the increase of n. Among the study of industrial power-law shear-thinning fluid, CMC solution with 100 ppm shows the best heat transfer performance at a given velocity. Moreover, new correlation of Nusselt number about industrial fluid is proposed. In general, for the heat transfer of laminar confined impinging jet, it is best to use the working fluid with low viscosity.

Sirt1, AMPK, and eNOS modulate hepatic energy metabolism and inflammation and are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses of metformin or sildenafil on the AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD in preclinical mouse models. Here we tested a possible multicomponent synergy to yield greater therapeutic efficacy in NAFLD/NASH. Liver cells and macrophages or an atherogenic diet induced NASH mouse model was treated with two-way and three-way combinations. The three-way combination Sild-Met-Leu increased hepatic fatty acid oxidation and reduced lipogenic gene expression and inflammatory marker in vitro. In mice, Sild-Met-Leu reduced the diet induced increases of ALT, TGFβ, PAI-1, IL1β, and TNFα, hepatic collagen expression, and nearly completely reversed hepatocyte ballooning and triglyceride accumulation, while all two-way combinations had only modest effects. Therefore, these data provide preclinical evidence for therapeutic efficacy of Sild-Met-Leu in the treatment of NAFLD and NASH.