Search

This paper introduces a nested sinusoidal re-entrant (NSR) metamaterial characterized by tunable complete bandgaps (CBGs) and dynamic responsiveness in thermal-mechanical dual fields. NSR comprises shape memory polymer and features a sinusoidal modification with nested re-entrant hexagonal and star-shape re-entrant structure. Dynamic response of NSR is studied using the representative volume element method, specifically focusing on the effective modulus and Poisson's ratio and CBGs under varying average strains. The findings indicate that both the mechanical properties and CBGs exhibit dynamic responses to mechanical field, demonstrating interrelation between mechanical adjustments and functional performance. Moreover, the study examines how temperature fluctuations influence the NSR's elastic modulus, thereby altering its CBGs. Hence, manipulating both compression and temperature variations presents a viable approach to control and adjust the CBGs of NSR effectively. These results are validated by computations of the frequency response function under various average strains. Overall, this design presents a promising approach for developing mechanical metamaterials with tunable functionality.

Abstract Background Lysine methyltransferase 2D (KMT2D) mediates mono‐methylation of histone H3 lysine 4 (H3K4me1) in mammals. H3K4me1 mark is involved in establishing an active chromatin structure to promote gene transcription. However, the precise molecular mechanism underlying the KMT2D‐mediated H3K4me1 mark modulates gene expression in triple‐negative breast cancer (TNBC) progression is unresolved. Methods and Results We recognized Y‐box‐binding protein 1 (YBX1) as a “reader” of the H3K4me1 mark, and a point mutation of YBX1 (E121A) disrupted this interaction. We found that KMT2D and YBX1 cooperatively promoted cell growth and metastasis of TNBC cells in vitro and in vivo. The expression levels of KMT2D and YBX1 were both upregulated in tumour tissues and correlated with poor prognosis for breast cancer patients. Combined analyses of ChIP‐seq and RNA‐seq data indicated that YBX1 was co‐localized with KMT2D‐mediated H3K4me1 in the promoter regions of c‐Myc and SENP1, thereby activating their expressions in TNBC cells. Moreover, we demonstrated that YBX1 activated the expressions of c‐Myc and SENP1 in a KMT2D‐dependent manner. Conclusion Our results suggest that KMT2D‐mediated H3K4me1 recruits YBX1 to facilitate TNBC progression through epigenetic activation of c‐Myc and SENP1. These results together unveil a crucial interplay between histone mark and gene regulation in TNBC progression, thus providing novel insights into targeting the KMT2D‐H3K4me1‐YBX1 axis for TNBC treatment. Highlights YBX1 is a KMT2D‐mediated H3K4me1‐binding effector protein and mutation of YBX1 (E121A) disrupts its binding to H3K4me1. KMT2D and YBX1 cooperatively promote TNBC proliferation and metastasis by activating c‐Myc and SENP1 expression in vitro and in vivo. YBX1 is colocalized with H3K4me1 in the c‐Myc and SENP1 promoter regions in TNBC cells and increased YBX1 expression predicts a poor prognosis in breast cancer patients.

In recent years, 3D hydrogels based on alginate (Alg) have undergone substantial advancements, holding transformative potential for biomedicine and regenerative medicine. Nevertheless, the viscosity of Alg needs to be further increased, in order to print complex 3D structures. Attempts to adjust printability often employ rheological modifiers like methylcellulose (MC), but these still lack mechanical integrity for broader biomedical applications. Our study sought to chemically modify Alg/MC to create a photopolymerizable hydrogel by incorporating acrylate-based monomers, which would enhance the curing ability of the base hydrogel, leading to better mechanical properties of Alg/MC, such as stretchability and stability with shape recovery. Comprehensive mechanical assessments unveiled remarkable tensile properties, achieving a notable specific strength benchmark of 44.72 kPa/(g.cm-3) before reaching the point of fracture. This represents a substantial 250 % improvement compared to samples lacking the acrylate monomer. Biomedical assessments confirmed the hydrogel's promising potential, especially with the MG-63 cell line, underscoring its suitability for advanced applications like tissue engineering.

The intricate mechanical interplay between cell membranes and enclosed filaments or filament networks plays an essential role in governing cellular morphological transformations and various cellular activities. A profound understanding of fundamental mechanical mechanisms underlying these interactions can be gained by exploring mechanical behaviors of a filament–vesicle system. Here we theoretically investigate the axial stretching of a lipid vesicle containing an enclosed filament loop. The vesicle either freely adjusts its volume or maintains a fixed volume. Depending on the relative stiffness and size of the filament loop to the vesicle as well as the vesicle scenario, the vesicle prior to stretching exhibits a spherical, prolate or oblate shape, and during stretching it undergoes morphological transformations with pronounced filament distortion and reorientation. The filament–vesicle system could exhibit a spring-softening or -stiffening response during stretching. Moreover, effects of filament inhomogeneity on the stretching process are studied. Our results could serve as a quantitative benchmark for further investigations into cellular complexity.

Repairing defects in alveolar bone is essential for regenerating periodontal tissue, but it is a formidable challenge. One promising therapeutic approach involves using a strategy that specifically recruits periodontal ligament cells (PDLCs) with high regenerative potential to achieve in situ regeneration of alveolar bone. In this study, we have created a new type of microsphere conjugated with an antibody to target p75 neurotrophin receptor (p75NTR), which is made of nano-hydroxyapatite (nHA) and chitosan (CS). The goal of this design is to attract p75NTR+hPDLCs selectively and promote osteogenesis. In vitro experiments demonstrated that the antibody-conjugated microspheres attracted significantly more PDLCs compared to non-conjugated microspheres. Incorporating nHA not only enhances cell adhesion and proliferation on the surface of the microsphere but also augments its osteoinductive properties. Microspheres effectively recruited p75NTR+ cells at bone defect sites in SD rats, as observed through immunofluorescent staining of p75NTR antibodies. This p75NTR antibody-conjugated nHA/CS microsphere presents a promising approach for selectively recruiting cells and repairing bone defects.

Abstract Mono‐methylation of histone H3 on Lys 4 (H3K4me1), which is catalyzed by histone‐lysine N‐methyltransferase 2D (KMT2D), serves as an important epigenetic regulator in transcriptional control. In this study, the authors identify early B‐cell factor 2 (EBF2) as a binding protein of H3K4me1. Combining analyses of RNA‐seq and ChIP‐seq data, the authors further identify killin (KLLN) as a transcriptional target of KMT2D and EBF2 in pancreatic ductal adenocarcinoma (PDAC) cells. KMT2D‐dependent H3K4me1 and EBF2 are predominantly over‐lapped proximal to the transcription start site (TSS) of KLLN gene. Comprehensive functional assays show that KMT2D and EBF2 cooperatively inhibit PDAC cells proliferation, migration, and invasion through upregulating KLLN. Such inhibition on PDAC progression is also achieved through increasing H3K4me1 level by GSK‐LSD1, a selective inhibitor of lysine‐specific demethylase 1 (LSD1). Taken together, these findings reveal a new mechanism underlying PDAC progression and provide potential therapeutic targets for PDAC treatment.

While auxetic metamaterials exhibit impressive mechanical traits, they frequently grapple with inherent conflict between their stiffness and auxeticity. In this study, we introduced an optimized lozenge-chiral auxetic metamaterial (oLCAM) with the dual objectives of balancing the auxeticity and stiffness and achieving tunable properties concurrently. The mechanical performance of the proposed oLCAM was first compared with that of conventional lozenge auxetic metamaterial (cLAM) through both experimental and numerical studies. Herein, the transition stiffness (Etrans) was initially proposed as the typical metric evaluating the overall structural stiffness. Subsequently, the study proceeded to investigate the impact of crucial design parameters, specifically the angle of inclination and the radius of the circular core. The design method of oLCAM with tunable auxeticity and stiffness was finally established based on a multi-objective optimization model, achieving the balance between the auxeticity and stiffness of oLCAM. The results revealed the proposed oLCAM obtained a more stable deformation mode than cLAM. Two geometric parameters verified their significance on the above mechanical properties of oLCAM. The resulting optimal oLCAM structure has been proven to obtain both comparatively prominent auxeticity and stiffness. The established design method may have the potential to broaden the possibilities for metamaterial design and performance tuning.

The circadian clock plays a critical role in dentomaxillofacial development. Tooth biomineralization is characterized by the circadian clock; however, the mechanisms underlying the coordination of circadian rhythms with tooth development and biomineralization remain unclear. The p75 neurotrophin receptor (p75NTR) is a clock factor that regulates the oscillatory components of the circadian rhythm. This study aims to investigate the impact of p75NTR on the rhythmic mineralization of teeth and elucidate its underlying molecular mechanisms. We generated p75NTR knockout mice to examine the effects of p75NTR deficiency on tooth mineralization. Ectomesenchymal stem cells (EMSCs), derived from mouse tooth germs, were used for in vitro experiments. Results showed a reduction in tooth mineral density and daily mineralization rate in p75NTR knockout mice. Deletion of p75NTR decreased the expression of DMP1, DSPP, RUNX2, and ALP in tooth germ. Odontogenic differentiation and mineralization of EMSCs were activated by p75NTR. Histological results demonstrated predominant detection of p75NTR protein in odontoblasts and stratum intermedium cells during rapid formation phases of dental hard tissue. The mRNA expression of p75NTR exhibited circadian variations in tooth germs and EMSCs, consistent with the expression patterns of the core clock genes Bmal1 and Clock. The upregulation of BMAL1/CLOCK expression by p75NTR positively regulated the mineralization ability of EMSCs, whereas BMAL1 and CLOCK exerted a negative feedback regulation on p75NTR by inhibiting its promoter activity. Our findings suggest that p75NTR is necessary to maintain normal tooth biomineralization. Odontogenic differentiation and mineralization of EMSCs is regulated by the p75NTR-BMAL1/CLOCK signaling axis. These findings offer valuable insights into the associations between circadian rhythms, tooth development, and biomineralization.

Alcoholic liver disease (ALD) is primarily caused by long-term excessive alcohol consumption. Cyanidin-3-O-glucoside (C3G) is a widely occurring natural anthocyanin with multiple biological activities. This study aims to investigate the effects of C3G isolated from black rice on ALD and explore the potential mechanism. C57BL/6J mice (male) were fed with standard diet (CON) and Lieber-DeCarli liquid-fed (Eth) or supplemented with a 100 mg/kg/d C3G Diet (Eth-C3G), respectively. Our results showed that C3G could effectively ameliorate the pathological structure and liver function, and also inhibited the accumulation of liver lipids. C3G supplementation could partially alleviate the injury of intestinal barrier in the alcohol-induced mice. C3G supplementation could increase the abundance of Norank_f_Muribaculaceae, meanwhile, the abundances of Bacteroides, Blautia, Collinsella, Escherichia-Shigella, Enterococcus, Prevotella, [Ruminococcus]_gnavus_group, Methylobacterium-Methylorubrum, Romboutsia, Streptococcus, Bilophila, were decreased. Spearman’s correlation analysis showed that 12 distinct genera were correlated with blood lipid levels. Non-targeted metabolic analyses of cecal contents showed that C3G supplementation could affect the composition of intestinal metabolites, particularly bile acids. In conclusion, C3G can attenuate alcohol-induced liver injury by modulating the gut microbiota and metabolites, suggesting its potential as a functional food ingredient against alcoholic liver disease.

In direct seeding, hypoxia is a major stress faced by rice plants. Therefore, dissecting the response mechanism of rice to hypoxia stress and the molecular regulatory network is critical to the development of hypoxia-tolerant rice varieties and direct seeding of rice. This review summarizes the morphological, physiological, and ecological changes in rice under hypoxia stress, the discovery of hypoxia-tolerant and germination-related genes/QTLs, and the latest research on candidate genes, and explores the linkage of hypoxia tolerance genes and their distribution in indica and japonica rice through population variance analysis and haplotype network analysis. Among the candidate genes, OsMAP1 is a typical gene located on the MAPK cascade reaction for indica–japonica divergence; MHZ6 is involved in both the MAPK signaling and phytohormone transduction pathway. MHZ6 has three major haplotypes and one rare haplotype, with Hap3 being dominated by indica rice varieties, and promotes internode elongation in deep-water rice by activating the SD1 gene. OsAmy3D and Adh1 have similar indica–japonica varietal differentiation, and are mainly present in indica varieties. There are three high-frequency haplotypes of OsTPP7, namely Hap1 (n = 1109), Hap2 (n = 1349), and Hap3 (n = 217); Hap2 is more frequent in japonica, and the genetic background of OsTPP7 was derived from the japonica rice subpopulation. Further artificial selection, natural domestication, and other means to identify more resistance mechanisms of this gene may facilitate future research to breed superior rice cultivars. Finally, this study discusses the application of rice hypoxia-tolerant germplasm in future breeding research.

Abstract Despite significant advancements in in vitro cardiac modeling approaches, researchers still lack the capacity to obtain in vitro measurements of a key indicator of cardiac function: contractility, or stroke volume under specific loading conditions—defined as the pressures to which the heart is subjected prior to and during contraction. This work puts forward a platform that creates this capability, by providing a means of dynamically controlling loading conditions in vitro. This dynamic tissue loading platform consists of a thin magnetoresponsive hydrogel cantilever on which 2D engineered myocardial tissue is cultured. Exposing the cantilever to an external magnetic field—generated by positioning magnets at a controlled distance from the cantilever—causes the hydrogel film to stretch, creating tissue load. Next, cell contraction is induced through electrical stimulation, and the force of the contraction is recorded, by measuring the cantilever's deflection. Force–length‐based measurements of contractility are then derived, comparable to clinical measurements. In an illustrative application, the platform is used to measure contractility both in untreated myocardial tissue and in tissue exposed to an inotropic agent. Clear differences are observed between conditions, suggesting that the proposed platform has significant potential to provide clinically relevant measurements of contractility.

Abstract Mage-D1 (MAGE family member D1) is involved in a variety of cell biological effects. Recent studies have shown that Mage-D1 is closely related to tooth development, but its specific regulatory mechanism is unclear. The purpose of this study was to investigate the expression pattern of Mage-D1 in rat dental germ development and its differential mineralization ability to ectomesenchymal stem cells (EMSCs), and to explore its potential mechanism. Results showed that the expression of Mage-D1 during rat dental germ development was temporally and spatially specific. Mage-D1 promotes the proliferation ability of EMSCs but inhibits their migration ability. Under induction by mineralized culture medium, Mage-D1 promotes osteogenesis and tooth-forming ability. Furthermore, the expression pattern of Mage-D1 at E19.5 d rat dental germ is similar to p75 neurotrophin receptor (p75NTR), distal-less homeobox 1 (Dlx1) and msh homeobox 1 (Msx1). In addition, Mage-D1 is binding to p75NTR, Dlx1, and Msx1 in vitro. These findings indicate that Mage-D1 is play an important regulatory role in normal mineralization of teeth. p75NTR, Dlx1, and Msx1 seem to be closely related to the underlying mechanism of Mage-D1 action.

Root architecture is a determinant factor of drought resistance in rice and plays essential roles in the absorption of water and nutrients for the survival of rice plants. Dissection of the genetic basis for root structure can help to improve stress-resistance and grain yield in rice breeding. In this study, a total of 391 rice (Oryz asativa L.) accessions were used to perform a genome-wide association study (GWAS) on three root-related traits in rice, including main root length (MRL), average root length (ARL), and total root number (TRN). As a result, 13 quantitative trait loci (QTLs) (qMRL1.1, qMRL1.2, qMRL3.1, qMRL3.2, qMRL3.3, qMRL4.1, qMRL7.1, qMRL8.1, qARL1.1, qARL9.1, qTRN9.1, qTRN9.2, and qTRN11.1) significantly associated with the three traits were identified, among which three (qMRL3.2, qMRL4.1 and qMRL8.1) were overlapped with OsGNOM1, OsARF12 and qRL8.1, respectively, and ten were novel QTLs. Moreover, we also detected epistatic interactions affecting root-related traits and identified 19 related genetic interactions. These results lay a foundation for cloning the corresponding genes for rice root structure, as well as provide important genomic resources for breeding high yield rice varieties.

Introduction. Recent years have seen a pressing need to dispose of municipal solid waste due to rapid urbanization. The municipal solid waste incineration fly ash (MSWIFA) produced from solid waste incineration power plant exhibits pozzolanic properties and poses concern of toxicity leaching when used directly as building materials. This paper presents an alkali-activation method to produce sustainable alkali-activated MSWIFA materials (AAFMs) with various MSWIFA dosages and investigate the corresponding fabrication and performance. Materials and Methods. Composited alkali activators activate the MSWIFA with constant alkalinity of 5% and the molar ratio of Si/Na = 0.86. The resulting geopolymers' bulk densities, mineral composites, morphology, and compression strength are thoroughly examined. Results and discussions. Results show that the use of MSWIFA may lead to more loose structures because the bubbles are generated from metallic aluminum and alkali activators. Additionally, the production of multiple crystals also accounts for increasing porosity. The generated multi-crystals such as Sylvite, Halite, Hydrocalumite, Calcium Hydroxide, and Ettringite are further detected from the morphology and mineral analysis. Furthermore, compression tests and toxicity characteristic leaching procedures (TCLP) are conducted to investigate the mechanical performance and heavy metals solidification performance of AAFMs, with an optimal compression strength of 19.99MPa at 28 days for AAFM-10 while toxicity leaching is subject to regularity limits. Conclusions. This study shows that great potential of using the alkali-activation method to recycle hazardous municipal solid fly ash into construction materials with both ecological safety and high performance.

The disposal of municipal solid waste incineration fly ash (MSWIFA) has become a prominent issue due to high environmental risks. In this study, as a potential aluminosilicate precursor, MSWIFA was further alkali-activated as a sustainable construction material in the form of an alkali-activated MSWIFA-based material (AAFM), with a low leaching level of heavy metals. Various 3D-printed polymeric lattices were designed and inserted into the AAFM to promote its inherent brittleness. A special coating was also considered to enhance the alkali resistance of the PEGT lattices. Through a flexural tension test with a 3D digital image correlation (3D-DIC) technique, the failure patterns and strain distributions of the 3D-printed polymeric lattice-enhanced MSWIFA-based composites were tracked. These polymeric lattice-containing composites indicated the promotion of mechanical performance, i.e., higher flexural strengths and good ductility. The 3D polymeric lattice-enhanced MSWIFA-based composites showed application prospects as sustainable construction materials, gaining both environmental benefits and good mechanical performance.

Various artificial bone graft substitutes based on ceramics have been developed over the last 20 years. Among them, calcium-silicate-based ceramics, which are osteoconductive and can attach directly to biological organs, have received great attention for bone tissue engineering applications. However, the degradation rate of calcium-silicate and bone formation is often out of balance, resulting in stress shielding (osteopenia). A new strategy to improve the drawbacks of these ceramics is incorporating trace elements such as Zn, Mg, and Zr into their lattice structures, enhancing their physical and biological properties. Recently, baghdadite (Ca3ZrSi2O9) ceramic, one of the most appealing calcium-silicate-based ceramics, has demonstrated high bioactivity, biocompatibility, biodegradability, and cell interaction. Because of its physical, mechanical, and biological properties and ability to be shaped using various fabrication techniques, baghdadite has found high potential in various biomedical applications such as coatings, fillers, cement, scaffolds, and drug delivery systems. Undoubtedly, there is a high potential for this newly developed ceramic to contribute significantly to therapies to provide a tremendous clinical outcome. This review paper aims to summarize and discuss the most relevant studies performed on baghdadite-based ceramics and composites by focusing on their behavior in vivo and in vitro.

Objective: Tooth morphogenesis and the formation of hard tissues have been reported to be closely related to circadian rhythms. This study investigates the spatiotemporal expression and relationship of p75NTR with core clock genes, mineralization-related or odontogenesis-related genes, and aims to derive the potential role of p75NTR in regulating circadian rhythm and incrementality growth line formation during tooth development.Materials and methods: The dynamic morphology of the rat dental germ was observed at seven stages (E14.5 d, E16.5 d, E18.5 d, P.N. 4 d, P.N. 7 d, P.N. 10 d, and P.N. 15 d). Next, the expressions of p75NTR and other target factors were traced. The ectomesenchymal stem cells (EMSCs) were isolated from the E18.5d rat dental germs and synchronized using 50% of fetal bovine serum. Then, they were cultured in light/light (L.L.), dark/dark (D.D.), and light/dark (L.D.) conditions for 48 h. The total RNA was collected every 4 h, and the circadian rhythm dynamics of target factors were observed. To reveal the mechanism further, p75NTR was down-regulated in p75NTRExIII−/− mice and up-regulated in immortalized mouse dental apical papilla progenitor cells. The change tendencies of other target factors were also detected.Results: The clock genes Bmal1, Clock, Per1, and Per2 were all expressed in tooth germs before the formation of dental hard tissues and demonstrated a regular oscillating expression pattern in EMSCs from dental germs. Their expression was affected by the L.D. stimulus, and most of them were promoted by D.D. conditions. p75NTR presented a similar expression pattern and a positive or negative relationship with most clock genes, mineralization-related and odontogenesis-related factors, such as brain and muscle ARNT-like protein-1 (Bmal1), runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), MSH-like 1 (MSX1), dentin matrix acidic phosphoprotein 1 (Dmp1), and dentin sialophosphoprotein (Dspp). Moreover, the arrangement, morphology, and even boundary in pre-odontoblast/pre-ameloblast layers were disordered in the p75NTRExIII−/− mice.Conclusion: Circadian rhythm was found to affect tooth development. p75NTR might play a crucial role in regulating clock genes in the mineralization and formation of the dental hard tissues. p75NTR is actively involved in the odontoblast-ameloblast junction and cell polarity establishment during tooth morphogenesis.

Patient-derived organoids (PDO), based on the advanced three-dimensional (3D) culture technology, can provide more relevant physiological and pathological cancer models, which is especially beneficial for developing and optimizing cancer therapeutic strategies. Radiotherapy (RT) is a cornerstone of curative and palliative cancer treatment, which can be performed alone or integrated with surgery, chemotherapy, immunotherapy, or targeted therapy in clinical care. Among all cancer therapies, RT has great local control, safety and effectiveness, and is also cost-effective per life-year gained for patients. It has been reported that combing RT with chemotherapy or immunotherapy or radiosensitizer drugs may enhance treatment efficacy at faster rates and lower cost. However, very few FDA-approved combinations of RT with drugs or radiosensitizers exist due to the lack of accurate and relevant preclinical models. Meanwhile, radiation dose escalation may increase treatment efficacy and induce more toxicity of normal tissue as well, which has been studied by conducting various clinical trials, very expensive and time-consuming, often burdensome on patients and sometimes with controversial results. The surged PDO technology may help with the preclinical test of RT combination and radiation dose escalation to promote precision radiation oncology, where PDO can recapitulate individual patient’ tumor heterogeneity, retain characteristics of the original tumor, and predict treatment response. This review aims to introduce recent advances in the PDO technology and personalized radiotherapy, highlight the strengths and weaknesses of the PDO cancer models, and finally examine the existing RT-related PDO trials or applications to harness personalized and precision radiotherapy.

In a proton exchange membrane fuel cell (PEMFC) system, the flow of air and hydrogen is the main factor affecting the output characteristics of the PEMFC, and there is a coordination problem in the flow control of both. To ensure real-time gas supply in the fuel cell and improve the output power and economic benefits of the system, a deep reinforcement learning controller with continuous state based on fusion optimization (FO-DDPG) and a control optimization strategy based on net power optimization are proposed in this paper, and the effects of whether the two gas controls are decoupled or not are compared. The experimental results show that the undecoupled FO-DDPG algorithm has a faster dynamic response and more stable static performance compared to the fuzzy PID, DQN, traditional DRL algorithm, and decoupled controllers, demonstrated by a dynamic response time of 0.15 s, an overshoot of less than 5%, and a steady-state error of 0.00003.

Our previous study found that CpG oligodeoxynucleotides 1826 (CpG 1826), combined with mucin 1 (MUC1)-maltose-binding protein (MBP) (M-M), had certain antitumor activity. However, this combination is less than ideal for tumor suppression (tumors vary in size and vary widely among individuals), with a drawback being that CpG 1826 is unstable. To solve these problems, here, we evaluate MF59/CpG 1826 as a compound adjuvant with M-M vaccine on immune response, tumor suppression and survival. The results showed that MF59 could promote the CpG 1826/M-M vaccine-induced tumor growth inhibition and a Th1-prone cellular immune response, as well as reduce the individual differences of tumor growth and prolonged prophylactic and therapeutic mouse survival. Further research showed that MF59 promotes the maturation of DCs stimulated by CpG1826/M-M, resulting in Th1 polarization. The possible mechanism is speculated to be that MF59 could significantly prolong the retention time of CpG 1826, or the combination of CpG 1826 and M-M, as well as downregulate IL-6/STAT3 involved in MF59 combined CpG 1826-induced dendritic cell maturation. This study clarifies the utility of MF59/CpG 1826 as a vaccine compound adjuvant, laying the theoretical basis for the development of a novel M-M vaccine.

In this paper, an improved double inputs direct contact and single output capacitively coupled conductivity detector (DISODCD) based on traditional contactless capacitively coupled conductivity detector (C4D) is developed. The sensor uses double inputs of the contact electrode and capacitively coupled output of the contactless electrode and a lock-in amplifier to reduce interfering noise signals and amplify gain. Parallel circuit counteracts the part of the adverse capacitance reactance introduced by electrode polarization and reduces the effect of the impedance caused by the coupled wall capacitance to measure the resistance of solution. The sensor reduces limit of detection (LOD) of analyte and improves the sensitivity of the device. The LOD of the potassium chloride solution is 1 nM, and the detection range is 0.01 μM to 10 mM in actual testing for a single sample. The ratio of the response of potassium chloride solution to background ultrapure water at low concentrations is better than that of double input capacitively coupled contactless conductivity detector (DIC4D) and direct contact conductivity detection (DCD) under the same condition. In the case that the test cell is contaminated with impurities, pollution of impurities has little effect on the response of DISODCD. In practical application, it has a good service life.

One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and prevent immune surveillance. One such element associated with breast cancer is stromal fibrosis, a histopathologic criterion for invasive cancer and poor survival. Fibrosis is caused by inflammatory factors and remodeling of the extracellular matrix that elicit an immune tolerant microenvironment. To address the role of fibrosis in tumorigenesis, we developed NeuT/ATTAC transgenic mice expressing a constitutively active NeuT/erbB2 transgene, and an inducible, fat-directed caspase-8 fusion protein, which upon activation results in selective and partial ablation of mammary fat and its replacement with fibrotic tissue. Induction of fibrosis in NeuT/ATTAC mice led to more rapid tumor development and an inflammatory and fibrotic stromal environment. In an effort to explore therapeutic options that could reduce fibrosis and immune tolerance, mice were treated with the oxysterol liver X receptor (LXR) pan agonist, N,N-dimethyl-3-β-hydroxy-cholenamide (DMHCA), an agent known to reduce fibrosis in non-malignant diseases. DMHCA reduced tumor progression, tumor multiplicity and fibrosis, and improved immune surveillance by reducing infiltrating myeloid-derived suppressor cells and increasing CD4 and CD8 effector T cells. These effects were associated with downregulation of an LXR-dependent gene network related to reduced breast cancer survival that included Spp1, S100a9, Anxa1, Mfge8 and Cd14. These findings suggest that the use of DMHCA may be a potentially effective approach to reduce desmoplasia and immune tolerance and increase the efficacy of cancer therapy.

Background/Aims: High levels of cancer stem cells (CSCs) in patients with triple-negative breast cancer (TNBC) correlate with risk of poor clinical outcome and possibly contribute to chemoresistance and metastasis in patients with highly malignant TNBC. Aberrant microRNA expression is associated with the dysfunction of self-renewal and proliferation in cancer stem cells, while there is little information about the TNBC-specific microRNAs in regulating CSC ability. Methods: Solexa deep sequencing was performed to detect the expression levels of TNBC or non-TNBC stem cells (CSCs) microRNAs. Mammosphere formation assay, qRT-PCR and the xenograft model in nude mice were performed. Bioinformatic analysis and microarray were used to select the target gene, and luciferase reporter assays were used to confirm the binding sites. Results: Solexa sequencing data exhibited differential expression of 193 microRNAs between TNBC and non-TNBC stem cells. The gene ontology analysis and pathways analyses showed that genes were involved in the maintenance of stemness. MiR-4319 could suppress the self-renewal and formation of tumorspheres in TNBC CSCs through E2F2, and also inhibited tumor initiation and metastasis in vivo. Moreover, increased E2F2 could reverse the effect of miR-4319 on the self-renewal in TNBC CSCs. Conclusions: MiR-4319 suppresses the malignancy of TNBC by regulating self-renewal and tumorigenesis of stem cells and might be a remarkable prognostic factor or therapeutic target for patients with TNBC.

Abstract Lithium metal is the most ideal anode for next‐generation lithium‐ion batteries. However, the formation of lithium dendrites and the continuous consumption of electrolyte during cycling lead to a serious safety problems. Developing stable lithium metal anode with uniform lithium deposition is highly desirable. Herein, a nitrogen plasma strengthening strategy is proposed for copper oxide nanosheet–decorated Cu foil as an advanced current collector, and deep insights into the plasma regulating mechanism are elaborated. The plasma‐treated electrode can maintain a high coulombic efficiency of 99.6% for 500 cycles. The symmetric cell using the lithium‐plated electrode can be cycled for more than 600 h with a low‐voltage hysteresis (23.1 mV), which is much better than those of electrodes without plasma treatment. It is well confirmed that this plasma‐induced nitrogen doping method can provide sufficient active sites for lithium nucleation to enhance the stability of lithium deposition on copper oxide nanosheets decorated on Cu foil and improve the electrical conductivity to greatly reduce the overpotential of the lithium nucleation, which can be extended to other modified current collectors for stable lithium metal anode.

Background/Aims: Osterix (Osx), a key regulator of osteoblast differentiation and bone formation, has been recently reported to be associated with the progression of breast cancer. However, the precise roles of Osx in breast cancer remain unclear. Methods: Drug sensitivity of the cancer cells was assessed using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Target genes were obtained by high-throughput Illumina sequencing and were confirmed in vitro and in vivo. Apoptosis was analysed by Hoechst staining and western blotting. A tissue microarray including 129 samples from breast cancer patients was used for immunohistochemistry (IHC) assays. Results: Overexpression of Osx decreased the chemosensitivity of breast cancer cells, while knockdown of Osx increased the chemosensitivity of breast cancer cells. In particular, we found that the decreased chemosensitivity effect was significantly associated with elevated expression of the polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14). Silencing of GALNT14 in Osx-overexpressed cells restored the decreased chemosensitivity. Conversely, overexpression of GALNT14 in Osx-knockdown cells abrogated the increased chemosensitivity in breast cancer cells. In addition, we revealed that Osx decreased GALNT14-dependent chemosensitivity by enhancing anti-apoptosis. GALNT14 expression exhibited a significant association with breast cancer stages as well as the disease-free survival (DFS) rate. Conclusion: Osx plays an important role in the chemosensitivity and inhibition of Osx expression may represent a therapeutic strategy to enhance the chemosensitivity of breast cancer.

Use of shock waves to temporarily increase the permeability of the cell membrane is a promising approach in drug delivery and gene therapy to allow the translocation of macromolecules and small polar molecules into the cytoplasm. Our understanding of how the characteristics of the pressure profile of shock waves, such as peak pressure and pulse duration, influences membrane properties is limited. Here we study the response of lipid bilayer membranes to shock pulses with different pressure profiles using atomistic molecular dynamics simulations. From our simulation results, we find that the transient deformation/disordering of the membrane depends on both the magnitude and the pulse duration of the pressure profile of the shock pulse. For a low pressure impulse, peak pressure has a dominant effect on membrane structural changes, while for the high pressure impulse, we find that there exists an optimal pulse duration at which membrane deformation/disordering is maximized.

The surface discontinuous deformation caused by coal mining has great damage to the ecological environment and threatens the safety of human lives. Focusing on the problem of discontinuous deformation (ground fissures and collapsed pits) in mining areas with a thick loess and thin bedrock, this paper uses a coal panel in southern Shanxi in China as research background, and uses field investigation, theoretical analysis and the particle flow code 2D (PFC2D) numerical simulation method to study the movement of overburden and discontinuous ground deformation of mining areas with a thick loess layer and a thin bedrock. The results show that with the continual advance of the working face, the failure of the overlying rock, the changing of force chain shape and the development of cracks under this geological and mining condition have their unique rules. This study analyzes the law of movement of overburden in coal seam mining, explains why discontinuous deformation of the surface occurs in case of a thick loess layer and thin bedrock, and provides reference for the prediction of fracture development under the same geological conditions and the application of the PFC2D in coal seam mining in different geological conditions.

Surface movement and deformation induced by underground coal mining causes slopes to collapse. Global Navigation Satellite System (GNSS) real-time monitoring can provide early warnings and prevent disasters. A stability analysis of high-steep slopes was conducted in a long wall mine in China, and a GNSS real-time monitoring system was established. The moving velocity and displacement at the monitoring points were an integrated response to the influencing factors of mining, topography, and rainfall. Underground mining provided a continuous external driving force for slope movement, the steep terrain provided sufficient slip conditions in the slope direction, and rainfall had an acceleration effect on slope movement. The non-uniform deformation, displacement field, and time series images of the slope body revealed that ground failure was concentrated in the area of non-uniform deformation. The non-uniform deformation was concentrated ahead of the working face, the speed of deformation behind the working face was reduced, the instability of the slope body was increased, and the movement of the top of the slope was larger than at the foot. The high-steep slope stability in the mine was influenced by the starting deformation (low stability), iso-accelerated deformation (increased stability), deformation deceleration (reduced stability), and deformation remaining unchanged (improved stability).

Placental-specific protein 1 (PLAC1) is an X-linked trophoblast gene that is re-expressed in several malignancies, including breast cancer, and is therefore a potential biomarker to follow disease onset and progression. Sera from 117 preoperative/pretreatment breast cancer patients and 51 control subjects, including those with fibrocystic disease, were analyzed for the presence of PLAC1 protein as well as its expression by IHC in tumor biopsies in a subset of subjects. Serum PLAC1 levels exceeded the mean plus one standard deviation (mean+SD) of the level in control subjects in 67% of subjects with ductal carcinoma in situ (DCIS), 67% with HER2+ tumors, 73% with triple-negative cancer and 73% with ER+/PR+ tumors. Greater sensitivity was achieved using the mean+2 SD of control PLAC1 serum values, where the false positive rate was 3% and was exceeded by 38%, 40%, 60% and 43% of subjects with DCIS, HER2+, TNBC and ER+/PR+/HER2- tumors. PLAC1 was detected in 97% of tumor biopsies, but did not correlate quantitatively with serum levels. There was no significant correlation of serum PLAC1 levels with race, age at diagnosis, body mass index (BMI) or the presence of metastatic disease. It remains to be determined whether PLAC1 serum levels can serve as a diagnostic biomarker for the presence or recurrence of disease post-surgery and/or therapy.

Ricin toxin binding subunit B (RTB) is one of the subunits of the ricin protein. RTB has been used as adjuvant, but little is known about its mechanism. In this study, we found that RTB increased not only nitric oxide (NO) release, but also tumor necrosis factor (TNF)-α and interleukin (IL)-6 production in mouse macrophage cell line RAW264.7 cells. They subsequently exhibited enhanced ConA-induced T-cell and LPS-induced B-cell proliferative responses. We also examined the cytokines that were produced from splenocytes following in vitro RTB administration. Increased levels of IL-2, interferon (IFN)-γ and TNF-α were observed, while IL-4 and IL-5 were unaffected. These results demonstrate that recombinant RTB can act on the immune system and activate T-cells by introducing a Th1 immune response. Th1 cells might be the primary cellular target affected by RTB. Our results suggest that the recombinant RTB can promote the activation of macrophages and has a beneficial effect on immunomodulatory activity.

A spectrofluorimetric method based on the grape skin has been developed for the determination of Fe3+ at pH 5.0. The emission wavelength of the grape skin sensor occurs at 680 nm and the excitation wavelength at 421 nm. The fluorescence of sensor could be quenched by Fe3+ due to the complexing ability of anthocyanin with the metal ions. Anthocyanin, the main pigment in the grape skin, has been found fluorescence sensing material. The sensor based on the grape skin exhibited a calibration response for Fe3+ in two concentration ranges of 1.0 × 10-8 - 1.0 × 10-5 M (r2 = 0.9888) and 3.2 × 10-5 - 3.2 × 10-4 (r2 = 0.9856) M at 60 oC. The detection limit was found to be 7.5×10-9 M, and the other common ions did not interfere.

Mucin 1 (MUC1), being an oncogene, is an attractive target in tumor immunotherapy. Maltose binding protein (MBP) is a potent built-in adjuvant to enhance protein immunogenicity. Thus, a recombinant MUC1 and MBP antitumor vaccine (M-M) was constructed in our laboratory. To enhance the antitumor immune activity of M-M, CpG oligodeoxynucleotides 1826 (CpG 1826), a toll-like receptor-9 agonist, was examined in this study as an adjuvant. The combination of M-M and CpG 1826 significantly inhibited MUC1-expressing B16 cell growth and prolonged the survival of tumor-bearing mice. It induced MUC1-specific antibodies and Th1 immune responses, as well as the Cytotoxic T Lymphocytes (CTL) cytotoxicity in vivo. Further studies showed that it promoted the maturation and activation of the dendritic cell (DC) and skewed towards Th1 phenotype in vitro. Thus, our study revealed that CpG 1826 is an efficient adjuvant, laying a foundation for further M-M clinical research.

A new method to prepare silver nanoparticles was reported in this paper, whichbased on aqueous-gaseous phase reaction of silver nitrate solution and ammonia gas. Theproposed method is effective, rapid, and convenient. Transmission electron microscope(TEM) and X-ray diffraction (XRD) were used to characterize the structure of the particles,respectively. It was found that the average diameter of the particles was about 10 nm and theshape was spherical. And the strong fluorescence signal of the silver nanoparticles solutioncan be quenched after the adding of the calf thymus DNA (ct-DNA) solution. Thequenched fluorescence intensity was linear with the concentration of ct-DNA in the range of0.5 to 5.0 Ã��— 104 ng mL-1 with a detection limit of 0.3 ng mL-1.

A novel flow-injection chemiluminescence(CL)method has been developedfor the determination of hydroquinone (HQ) and catechol (CT), based on their inhibition ofthe chemiluminescence reaction of luminol–KMnO4–β-cyclodextrin (β-CD). It was foundthat β-cyclodextrin could effectively enhance the chemiluminescence produced from thereaction of luminol with KMnO4 in basic media. The proposed method is simple, rapid,convenient and sensitive, has a linear range of 1–20 ng/mL for catechol with a detectionlimit of 0.4 ng/mL, and 1–10 ng/mL for hydroquinone with a detection limit of 0.1 ng/mL,respectively. The possible mechanism of the CL reaction is also discussed

Mechanics of the bilayer membrane play an important role in many biological and bioengineering problems such as cell–substrate and cell–nanomaterial interactions. In this work, we study the effect of thermal fluctuation and the substrate elasticity on the cell membrane–substrate adhesion. We model the adhesion of a fluctuating membrane on an elastic substrate as a two-step reaction comprised of the out-of-plane membrane fluctuation and the receptor–ligand binding. The equilibrium closed bond ratio as a function of substrate rigidity was computed by developing a coupled Fourier space Brownian dynamics and Monte Carlo method. The simulation results show that there exists a crossover value of the substrate rigidity at which the closed bond ratio is maximal.

Peroxisome proliferator-activated receptorδ (PPARδ) is a transcription factor that is associated with metabolic gene regulation and inflammation. It has been implicated in tumor promotion and in the regulation of 3-phosphoinositide-dependent kinase-1 (PDK1). PDK1 is a key regulator of the AGC protein kinase family, which includes the proto-oncogene AKT/PKB implicated in several malignancies, including breast cancer. To assess the role of PDK1 in mammary tumorigenesis and its interaction with PPARδ, transgenic mice were generated in which PDK1 was expressed in mammary epithelium under the control of the MMTV enhancer/promoter region. Transgene expression increased pT308AKT and pS9GSK3β, but did not alter phosphorylation of mTOR, 4EBP1, ribosomal protein S6 and PKCα. The transgenic mammary gland also expressed higher levels of PPARδ and a gene expression profile resembling wild-type mice maintained on a diet containing the PPARδ agonist, GW501516. Both wild-type and transgenic mice treated with GW501516 exhibited accelerated rates of tumor formation that were more pronounced in transgenic animals. GW501516 treatment was accompanied by a distinct metabolic gene expression and metabolomic signature that was not present in untreated animals. GW501516-treated transgenic mice expressed higher levels of fatty acid and phospholipid metabolites than treated wild-type mice, suggesting the involvement of PDK1 in enhancing PPARδ-driven energy metabolism. These results reveal that PPARδ activation elicits a distinct metabolic and metabolomic profile in tumors that is in part related to PDK1 and AKT signaling.

The highly effectiveness and robustness of receptor-mediated viral invasion of living cells shed lights on the biomimetic design of nanoparticle(NP)-based therapeutics. Through thermodynamic analysis, we elucidate that the mechanisms governing both the endocytic time of a single NP and the cellular uptake can be unified into a general energy-balance framework of NP-membrane adhesion and membrane deformation. Yet the NP-membrane adhesion strength is a globally variable quantity that effectively regulates the NP uptake rate. Our analysis shows that the uptake rate interrelatedly depends on the particle size and ligand density, in contrast to the widely reported size effect. Our model predicts that the optimal radius of NPs for maximal uptake rate falls in the range of 25-30 nm, and optimally several tens of ligands should be coated onto NPs. These findings are supported by both recent experiments and typical viral structures, and serve as fundamental principles for the rational design of NP-based nanomedicine.

PPARγ and PPARδ agonists represent unique classes of drugs that act through their ability to modulate gene transcription associated with intermediary metabolism, differentiation, tumor suppression, and in some instances proliferation and cell adhesion. PPARγ agonists are used by millions of people each year to treat type 2 diabetes but may also find additional utility as relatively nontoxic potentiators of chemotherapy. PPARδ agonists produce complex actions as shown by their tumor promoting effects in rodents and their cholesterol-lowering action in dyslipidemias. There is now emerging evidence that PPARs regulate tumor suppressor genes and developmental pathways associated with transformation and cell fate determination. This review discusses the role of PPARγ and PPARδ agonists as modulators of these processes.