Evaluation Method of Fatigue Life for Asphalt Pavement on the Steel Bridge Deck Based on the Inhomogeneous Poisson Stochastic Process.

The paving layer on the steel box girder bridge deck is widely used when constructing pavements for steel bridges. Owing to the orthotropic feature of steel decks, a transverse clapboard and rib can lead to a concentration of stress. Consequently, fatigue cracks are often identified in asphalt concrete pavement layers due to re-compaction caused by heavy vehicles. This study aims to derive an evaluation method of fatigue life for asphalt pavement based on the inhomogeneous Poisson stochastic process in view of the highly random and uncertain working conditions of layered composite structures. According to the inhomogeneous Poisson stochastic process, along with Miner's fatigue damage accumulation theory and the linear elastic fracture mechanics theory, the fatigue life formula could be deduced. Meanwhile, fatigue experiments for asphalt concrete are designed to investigate the correlation between the theoretical formula and the actual fatigue damage life of the material. Compared with the test, the accuracy error is within 10%, which is better than other traditional methods. Therefore, the fatigue life prediction model could better reflect the loading order effect and the interaction between loads, providing a new path for the fatigue reliability design of steel bridge deck asphalt pavement.

NOD1 deficiency ameliorates the progression of diabetic retinopathy by modulating bone marrow-retina crosstalk.

BACKGROUND: Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) plays a pivotal role in inducing metabolic inflammation in diabetes. Additionally, the NOD1 ligand disrupts the equilibrium of bone marrow-derived hematopoietic stem/progenitor cells, a process that has immense significance in the development of diabetic retinopathy (DR). We hypothesized that NOD1 depletion impedes the advancement of DR by resolving bone marrow dysfunction. METHODS: We generated NOD1-/--Akita double-mutant mice and chimeric mice with hematopoietic-specific NOD1 depletion to study the role of NOD1 in the bone marrow-retina axis. RESULTS: Elevated circulating NOD1 activators were observed in Akita mice after 6 months of diabetes. NOD1 depletion partially restored diabetes-induced structural changes and retinal electrical responses in NOD1-/--Akita mice. Loss of NOD1 significantly ameliorated the progression of diabetic retinal vascular degeneration, as determined by acellular capillary quantification. The preventive effect of NOD1 depletion on DR is linked to bone marrow phenotype alterations, including a restored HSC pool and a shift in hematopoiesis toward myelopoiesis. We also generated chimeric mice with hematopoietic-specific NOD1 ablation, and the results further indicated that NOD1 had a protective effect against DR. Mechanistically, loss of hematopoietic NOD1 resulted in reduced bone marrow-derived macrophage infiltration and decreased CXCL1 and CXCL2 secretion within the retina, subsequently leading to diminished neutrophil chemoattraction and NETosis. CONCLUSIONS: The results of our study unveil, for the first time, the critical role of NOD1 as a trigger for a hematopoietic imbalance toward myelopoiesis and local retinal inflammation, culminating in DR progression. Targeting NOD1 in bone marrow may be a potential strategy for the prevention and treatment of DR.

Fusobacterium nucleatum-triggered neutrophil extracellular traps facilitate colorectal carcinoma progression.

BACKGROUND: Fusobacterium nucleatum (Fn) acts as a procarcinogenic bacterium in colorectal carcinoma (CRC) by regulating the inflammatory tumor microenvironment (TME). Neutrophil extracellular traps (NETs), which can be generated by persistent inflammation, have been recently considered to be significant contributors in promoting cancer progression. However, whether NETs are implicated in Fn-related carcinogenesis is still poorly characterized. Here, we explored the role of NETs in Fn-related CRC as well as their potential clinical significance. METHODS: Fn was measured in tissue specimens and feces samples from CRC patients. The expression of NET markers were also detected in tissue specimens, freshly isolated neutrophils and blood serum from CRC patients, and the correlation of circulating NETs levels with Fn was evaluated. Cell-based experiments were conducted to investigate the mechanism by which Fn modulates NETs formation. In addition, we clarified the functional mechanism of Fn-induced NETs on the growth and metastasis of CRC in vitro and in vivo experiments. RESULTS: Tissue and blood samples from CRC patients, particularly those from Fn-infected CRC patients, exhibited greater neutrophil infiltration and higher NETs levels. Fn infection induced abundant NETs production in in vitro studies. Subsequently, we demonstrated that Fn-induced NETs indirectly accelerated malignant tumor growth through angiopoiesis, and facilitated tumor metastasis, as manifested by epithelial-mesenchymal transition (EMT)-related cell migration, matrix metalloproteinase (MMP)-mediated basement membrane protein degradation, and trapping of CRC cells. Mechanistically, the Toll-like receptor (TLR4)-reactive oxygen species (ROS) signaling pathway and NOD-like receptor (NOD1/2)-dependent signaling were responsible for Fn-stimulated NETs formation. More importantly, circulating NETs combined with carcinoembryonic antigen (CEA) could predict CRC occurrence and metastasis, with areas under the ROC curves (AUCs) of 0.92 and 0.85, respectively. CONCLUSIONS: Our findings indicated that Fn-induced NETs abundance by activating TLR4-ROS and NOD1/2 signalings in neutrophils facilitated CRC progression. The combination of circulating NETs and CEA was identified as a novel screening strategy for predicting CRC occurrence and metastasis.

Mechanochemical preparation of low cost kaolinite-based BiVO4hybrid pigments with high near infrared reflectance.

For accelerate construction of the energy and resource-saving and environmental-friendly society, cleaner preparation of low-cost and high-performance colorful near-infrared reflective inorganic pigments with the decorative function is indispensable to reduce the hazards of urban heat island and simultaneously beautify the appearance of the buildings. Due to the non-toxicity, good chemical stability and narrow band gap, BiVO4has been becoming a promising environment-friendly yellow inorganic pigments among the conventional heavy metals-containing inorganic pigments. In this study, the low-cost and brilliant kaolinite-based BiVO4hybrid pigments were fabricated by cleaner mechanochemical method based on cheap and abundant kaolinite using crystal water of the hydrated metal salts as trace solvent, which could effectively promote the interaction of the involved components at the molecular level during grinding and then decreased the mass transfer resistance for the formation of monoclinic scheelite BiVO4in the following calcination. The obtained hybrid pigments at the optimal preparation conditions exhibited brilliant color properties (D65-10°,L*= 83.45 ± 0.08,a*= 4.17 ± 0.08,b*= 88.59 ± 0.17), high near-infrared reflectance of 86.22%, infrared solar reflectance of 88.14% and high emissivity of 0.9369 in the waveband of 8-13µm. Furthermore, the hybrid pigments could be used for coloring epoxy resin with high emissivity of 0.8782 in 8-13µm. Therefore, the brilliant and low-cost kaolinite-based bismuth yellow hybrid pigments have the enormous potential to be served as colorful functional nanofillers for cooling roofing materials.

The roles of stress-induced premature senescence and Akt/FoxO1 signaling in periapical lesions.

OBJECTIVES: There is little knowledge about oxidative stress-induced senescence involvement in apical periodontitis. Here, we explored its molecular mechanism in periapical lesions. METHODS: Ten cases of radicular cysts and five cases of periapical granulomas were randomly selected. Immunohistochemical analysis was performed to detect the expression and correlation between Senescence-associated factor polymerase I and transcript release factor (PTRF) and Akt/FoxO1 signaling. Human periodontal ligament cells (hPDLCs) pretreated with LY294002 were exposed to H2 O2 -induced oxidative stress conditions and then cell proliferation, senescence, apoptosis, and associated signaling were evaluated by EdU labeling, ß-galactosidase assay, RT-qPCR, and western blot analysis, respectively. RESULTS: Polymerase I and transcript release factor and Akt/FoxO1 signaling were more frequently expressed in the radicular cyst than in periapical granulomas. Notably, cells in radicular cysts showed Akt activation, FoxO1 phosphorylation, and cytoplasmic translocation. In vitro, prominent H2 O2 -induced senescence was observed in hPDLCs. LY294002, a PI3K inhibitor, attenuated the expression levels of senescence (Klotho, P16INK4), apoptosis (Bad, Fas), phosphorylated Akt, and phosphorylated FoxO1; however, did not affect cell proliferation. CONCLUSIONS: Our data indicated that senescence is present in clinical periapical lesions, and Akt/FoxO1 signaling is involved in the H2 O2 -induced cellular senescence, which could serve as a potential therapeutic target.

Preparation of Hybrid Nanopigments with Excellent Environmental Stability, Antibacterial and Antioxidant Properties Based on Monascus Red and Sepiolite by One-Step Grinding Process.

This study is focused on the preparation, characterization, and multifunctional properties of intelligent hybrid nanopigments. The hybrid nanopigments with excellent environmental stability and antibacterial and antioxidant properties were fabricated based on natural Monascus red, surfactant, and sepiolite via a facile one-step grinding process. The density functional theory calculations demonstrated that the surfactants loaded on sepiolite were in favor of enhancing the electrostatic, coordination, and hydrogen bonding interactions between Monascus red and sepiolite. Thus, the obtained hybrid nanopigments exhibited excellent antibacterial and antioxidant properties, with an inhibition effect on Gram-positive bacteria that was superior to that of Gram-negative bacteria. In addition, the scavenging activity on DPPH and hydroxyl free radicals as well as the reducing power of hybrid nanopigments were higher than those of hybrid nanopigments prepared without the addition of the surfactant. Inspired by nature, gas-sensitive reversible alochroic superamphiphobic coatings with excellent thermal and chemical stability were successfully designed by combining hybrid nanopigments and fluorinated polysiloxane. Therefore, intelligent multifunctional hybrid nanopigments have great application foreground in related fields.

Incorporation of silver nanoparticles/curcumin/clay minerals into chitosan film for enhancing mechanical properties, antioxidant and antibacterial activity.

It is popular that natural organics are served as green reducing and end-capping reagent for synthesis of functional nanoparticles. In this study, curcumin, a natural pigment, was employed to prepare silver nanoparticles (AgNPs) as a coloring, reducing and end-capping agent by an eco-friendly, economic and facile approach in the presence of different clay minerals, including palygorskite, montmorillonite and mixed-dimensional palygorskite clay. It was found that the phenolic hydroxyl groups or carbonyl groups of curcumin played a crucial role to reduce silver ions into AgNPs with the ginger color. Meanwhile, incorporation of clay minerals could induce the in-situ heterogeneous nucleation of AgNPs on the surface or/and interlayer of the involved clay minerals. It effectively prevented from the aggregations and resulted in uniform dispersion of AgNPs with a diameter of 30-40 nm. Furthermore, the as-prepared nanocomposites exhibited a higher antioxidant (>90%) and antibacterial activity. Due to the synergistic effect of each component among the nanocompositions, the nanocomposites derived from different clay minerals were employed as multifunctional nanofillers to design functional chitosan composite films. By contrast, the chitosan composite films containing curcumin-capped AgNPs/mixed-dimensional palygorskite clay nanocomposites exhibited the best mechanical properties, antioxidant and antibacterial activities. Compared with the chitosan films, the tensile strength and elongation at break of composite films increased by 15.90 MPa and 27.27%, respectively. The inactivation rate of the composite films against Escherichia coli and Staphylococcus aureus had reached 100%. Therefore, the obtained composite film with the ginger color exhibited excellent mechanical, water resistance, antioxidant and antibacterial properties, and it was expected to develop a great potential functional packaging materials.

Phospholipid and antioxidant responses of oleaginous fungus Cunninghamella echinulata against hydrogen peroxide stress.

Hydrogen peroxide (H2O2) is one of the major oxidative stress intracellularly and extracellularly, which may affect lipid membrane or cell membrane. However, the mechanism remains unclear. The present study investigated phospholipid and antioxidant responses of Cunninghamella echinulata under exogenous H2O2 stress by integrating lipidomics and transcriptomics. H2O2 significantly affected phospholipid profile of C. echinulata exposed to exogenous H2O2. The phospholipid content was reduced from 6.41% to 2.47% on the first day, and to 1.03% on the 7th day, which was 5-6 times lower than that in the control. Phosphatidyl choline was reduced significantly from 29.71% to 2.73% on the 7th day. The lipid-related metabolic maps of C. echinulata responding to H2O2 were constructed based on transcriptomics, lipidomics and biochemical analysis. Results showed that H2O2 almost mobilized all the signaling pathways in the cell, especially the AMPK and cAMP signaling pathway, which regulated the metabolism of proteins and fatty acids. H2O2-stress triggered the high expression of heat shock genes. The antioxidant enzymes were activated to supply more NADPH, which contributed to the modulation of intracellular redox balance, and continuously scavenged active substances, thus improving the mycelial resistance to oxidative stress.

Computed Tomography Image under Artificial Intelligence Algorithm to Evaluate the Nursing and Treatment Effect of Pemetrexed Combined Platinum-Based Chemotherapy on Elderly Lung Cancer.

This study was to evaluate the clinical efficacy of pemetrexed combined with platinum-based chemotherapy in the treatment of elderly lung cancer using electronic computed tomography (CT) images based on artificial intelligence algorithms. In this study, 80 elderly patients with lung cancer treated were selected and randomly divided into two groups: patients treated with pemetrexed combined with cisplatin were included in the pemetrexed group and patients treated with docetaxel combined with cisplatin were included in the docetaxel group, with 40 cases in each group. The DenseNet network was compared with the Let Net-5 and ResNet model and applied to the CT images of 80 elderly patients with lung cancer. The diagnosis accuracy of the DenseNet network (97.4%) was higher than that of the Let Net-5 network (80.1%) and ResNet model (95.5%). Carcinoembryonic antigen (CEA), cytokeratin fragment antigen 21-1 (CYFRA 21-1), and squamous cell-associated antigen (SCC) after chemotherapy in the pemetrexed group and docetaxel group were all lower than those before chemotherapy, showing statistically obvious differences (P < 0.05). The satisfaction degree of nursing care in the pemetrexed group (92.67%) was significantly higher than that in the docetaxel group (85.62%), and the difference was statistically significant (P < 0.05). Adverse reactions such as fatigue, diarrhea, and neutrophils in the pemetrexed group were lower than those in the docetaxel group, and the difference was statistically great (P < 0.05). The DenseNet convolutional neural network has high diagnostic accuracy; methotrexate combined with platinum chemotherapy can improve the chemotherapy effect in elderly patients with lung cancer, with low degree of adverse reactions and good overall tolerance, which can be used as the first-line treatment for elderly patients with lung cancer.

Hybrid adipose graft materials synthesized from chemically modified adipose extracellular matrix.

Decellularized extracellular matrix (ECM) from tissues is a promising biomaterial that can provide a complex 3D microenvironment capable of modulating cell response and tissue regeneration. In this study, we have integrated the decellularized thiolated adipose-derived ECM, at different concentrations, with polyethylene glycol (PEG) using Michael addition between thiol and acrylate moieties. The potential for this material to support adipogenic differentiation of human adipose-derived stem cells was evaluated by encapsulating cells in hydrogels with increasing concentrations of chemically modified ECM (mECM). Our results demonstrated a positive correlation between the ECM content in the hydrogels and cell proliferation, adipogenic marker expression, and lipid formation and accumulation. Furthermore, we have shown host cell infiltration and enhanced adipogenesis in vivo after implantation. These findings support the graft as a potential alternative for adipose tissue regeneration.

Histochemical localization of putative stem cells in irreversible pulpitis.

OBJECTIVES: Our study aimed to observe the distribution of putative stem cells in irreversible pulpitis and to investigate the expression of specific molecules. SUBJECTS AND METHODS: Extracted third molar teeth were collected and divided into two groups: the normal pulp group and inflamed pulp group. Real-time PCR was applied to detect the expression of several embryonic and dentinogenic genes. The expression of mesenchymal cell markers (STRO-1, CD90, and CD146) and stromal cell-derived factor 1α (SDF-1α)/CXC chemokine receptor 4 (CXCR4) proteins was examined by immunohistochemical analysis. RESULTS: The expression levels of most embryonic and dentinogenic genes were not statistically different between the two groups. Immunohistochemical analysis revealed that in inflamed pulp, cells with positive expression for STRO-1, CD90, and CD146 mainly resided in two specific niches, both adjacent to inflammatory sites: one in the pulp core and another in the odontoblast layer. SDF-1α- and CXCR4-positive cells were significantly correlated with STRO-1-positive cells. Double immunofluorescence analysis indicated that STRO-1-positive cells overlapped with SDF-1α- and CXCR4-positive cells near the inflammatory site. CONCLUSIONS: This study gave a direct observation of putative stem cells distributed in irreversible pulpitis and implied a role of SDF-1α/CXCR4 signaling in stem cell-based therapies for reparative dentinogenesis.

Bcl-2 Interacts with Beclin 1 and Regulates Autophagy in 7, 12-Dimethylbenz[a]anthracene-Induced Hamster Buccal-Pouch Squamous-Cell Tumorigenesis.

OBJECTIVE: Autophagy is a programmed cell death procedure, which has essential functions in tumorigenesis. However, its temporal expression and function under different status are yet to be determined. This study aims to investigate the temporal expression of autophagy and its possible function in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal-pouch cancer model (HBPCM). METHODS: A total of 50 hamster buccal-pouch tumorigenesis models were established by painting DMBA for 4, 8, 10 and 13 weeks. The expression and subcellular localization of LC3, Beclin 1 and Bcl-2 in buccal lesions were evaluated by immunohistochemical staining and Western blotting. DNA damage was observed by immunohistochemical staining of 8-oHdG. The relationship between Beclin 1 and Bcl-2 was analyzed by immunofluorescence colocalization. RESULTS: The expression levels of LC3 and Beclin 1 associated with autophagy in the experimental buccal pouch of HBPCM were significantly upregulated after 4 weeks (P<0.05), but gradually downregulated after 13 weeks of HBPCM induction. By contrast, the expression level of Bcl-2 was significantly upregulated after 13 weeks. The co-localized regions of Bcl-2 and Beclin 1 peaked after 4 weeks and then decreased gradually. The DNA damage in epithelial cells increased slightly after 4 weeks, and then rapidly decreased over the next 2 months. CONCLUSION: Autophagy is motivated by a tumor suppressor that diminishes carcinogen-induced DNA damage. However, autophagy is gradually suppressed, which may be attributed to the interaction between Bcl-2 and Beclin 1. This result indicates that the promotion of autophagy may suppress malignant transformation and provide new insights on future potential treatments of HBPCM.

Incorporation of Different Metal Ion for Tuning Color and Enhancing Antioxidant Activity of Curcumin/Palygorskite Hybrid Materials.

Curcumin is one of the dietary dyes extracted from turmeric and used for prevention and treatment of various illnesses. However, the low bioavailability and poor stability of curcumin limits its relevant applications. Therefore, different metal ions including Cu2+, Zn2+, Mg2+, Al3+, or Fe3+ were incorporated to tune the color, enhance the environmental stability and antioxidant activity of curcumin in the presence of palygorskite in this study. The as-prepared samples were studied using X-ray diffraction, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, Zeta potential, and transmission electron microscopy. In addition, the density functional theory calculation was also performed to explore the possible interaction among metal ions, curcumin and palygorskite. It was found that the color changing and stability enhancing were ascribed to the curcumin-metal ions coordination as well as chemical interactions between curcumin-metal complex and palygorskite. Moreover, the as-prepared composites showed more excellent color, thermal stability, antioxidant activity, and fluorescence properties than that of the curcumin/palygorskite composites due to the presence of metal ions. The finding of this investigation may contribute to developing the multifunctional composites with different colors and good antioxidant activity for relevant applications based on curcumin and palygorskite.

Characterization of Molecular Subtypes in Head and Neck Squamous Cell Carcinoma With Distinct Prognosis and Treatment Responsiveness.

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies with complex phenotypic, etiological, biological, and clinical heterogeneities. Previous studies have proposed different clinically relevant subtypes of HNSCC, but little is known about its corresponding prognosis or suitable treatment strategy. Here, we identified 101 core genes from three prognostic pathways, including mTORC1 signaling, unfold protein response, and UV response UP, in 124 pairs of tumor and matched normal tissues of HNSCC. Moreover, we identified three robust subtypes associated with distinct molecular characteristics and clinical outcomes using consensus clustering based on the gene expression profiles of 944 HNSCC patients from four independent datasets. We then integrated the genomic information of The Cancer Genome Atlas (TCGA) HNSCC cohort to comprehensively evaluate the molecular features of different subtypes and screen for potentially effective therapeutic agents. Cluster 1 had more arrested oncogenic signaling, the highest immune cell infiltration, the highest immunotherapy and chemotherapeutic responsiveness, and the best prognosis. By contrast, Cluster 3 showed more activated oncogenic signaling, the lowest immune cell infiltration, the lowest immunotherapy and chemotherapy responsiveness, and the worst prognosis. Our findings corroborate the molecular diversity of HNSCC tumors and provide a novel classification strategy that may guide for prognosis and treatment allocation.

Circadian rhythms affect bone reconstruction by regulating bone energy metabolism.

Metabolism is one of the most complex cellular biochemical reactions, providing energy and substances for basic activities such as cell growth and proliferation. Early studies have shown that glucose is an important nutrient in osteoblasts. In addition, amino acid metabolism and fat metabolism also play important roles in bone reconstruction. Mammalian circadian clocks regulate the circadian cycles of various physiological functions. In vertebrates, circadian rhythms are mediated by a set of central clock genes: muscle and brain ARNT like-1 (Bmal1), muscle and brain ARNT like-2 (Bmal2), circadian rhythmic motion output cycle stagnates (Clock), cryptochrome 1 (Cry1), cryptochrome2 (Cry2), period 1 (Per1), period 2 (Per2), period 3 (Per3) and neuronal PAS domain protein 2 (Npas2). Negative feedback loops, controlled at both the transcriptional and posttranslational levels, adjust these clock genes in a diurnal manner. According to the results of studies on circadian transcriptomic studies in several tissues, most rhythmic genes are expressed in a tissue-specific manner and are affected by tissue-specific circadian rhythms. The circadian rhythm regulates several activities, including energy metabolism, feeding time, sleeping, and endocrine and immune functions. It has been reported that the circadian rhythms of mammals are closely related to bone metabolism. In this review, we discuss the regulation of the circadian rhythm/circadian clock gene in osteoblasts/osteoclasts and the energy metabolism of bone, and the relationship between circadian rhythm, bone remodeling, and energy metabolism. We also discuss the therapeutic potential of regulating circadian rhythms or changing energy metabolism on bone development/bone regeneration.

In vitro biocompatibility and bioactivity of calcium silicate­based bioceramics in endodontics (Review).

Calcium silicate­based bioceramics have been applied in endodontics as advantageous materials for years. In addition to excellent physical and chemical properties, the biocompatibility and bioactivity of calcium silicate­based bioceramics also serve an important role in endodontics according to previous research reports. Firstly, bioceramics affect cellular behavior of cells such as stem cells, osteoblasts, osteoclasts, fibroblasts and immune cells. On the other hand, cell reaction to bioceramics determines the effect of wound healing and tissue repair following bioceramics implantation. The aim of the present review was to provide an overview of calcium silicate­based bioceramics currently applied in endodontics, including mineral trioxide aggregate, Bioaggregate, Biodentine and iRoot, focusing on their in vitro biocompatibility and bioactivity. Understanding their underlying mechanism may help to ensure these materials are applied appropriately in endodontics.

Fabrication of Eco-Friendly Betanin Hybrid Materials Based on Palygorskite and Halloysite.

Eco-friendly betanin/clay minerals hybrid materials with good stability were synthesized by combining with adsorption, grinding, and heating treatment using natural betanin extracted from beetroot and natural 2:1 type palygorskite or 1:1 type halloysite. After incorporation of clay minerals, the thermal stability and solvent resistance of natural betanin were obviously enhanced. Due to the difference in the structure of palygorskite and halloysite, betanin was mainly adsorbed on the outer surface of palygorskite or halloysite through hydrogen-bond interaction, but also part of them also entered into the lumen of Hal via electrostatic interaction. Compared with palygorskite, hybrid materials prepared with halloysite exhibited the better color performance, heating stability and solvent resistance due to the high loading content of betanin and shielding effect of lumen of halloysite.

Bmal1 Regulates Coagulation Factor Biosynthesis in Mouse Liver in Streptococcus oralis Infection.

Streptococcus oralis (S. oralis) has been recognized as a fatal pathogen to cause multiorgan failure by contributing to the formation of microthrombus. Coagulation and fibrinolysis systems have been found under the control of circadian clock genes. This study aimed to explore the correlation between BMAL1 and coagulation factor biosynthesis in S. oralis infection. Mice were administered S. oralis to induce sepsis, and HepG2 cells were also infected by S. oralis. The expression of BMAL1 of hepatocytes was downregulated in the S. oralis infection group, leading to the downregulation of coagulation factor VII (FVII) and the upregulation of the coagulation factor XII (FXII) in vitro and in vivo. Furthermore, we confirmed that the deficiency of BAML1 contributed to the elevation of FVII and the decline in FXII by constructing BMAL1-deficiency (Bmal1-/-) mice. The current result showed that BMAL1 regulates FVII directly. Thus, a novel insight into the coagulation abnormality in S. oralis infection was gained that may optimize the treatment of sepsis by rescuing the expression of BMAL1 in the liver.

Photocontrolled miR-148b nanoparticles cause apoptosis, inflammation and regression of Ras induced epidermal squamous cell carcinomas in mice.

Despite evidence that microRNAs (miRNAs) are essential in modulating tumorigenesis, a major challenge in cancer treatment is to achieve tumor-specific selectivity and efficient yet safe delivery of miRNAs in vivo. In this study, we have developed a light-inducible silver nanoparticle nucleic acid delivery system that demonstrates precise spatiotemporal control, high cellular uptake, low cytotoxicity, escape from endosomes and release of functional miRNA into the cytosol. Using this approach, we delivered exogenous miR-148b to induce apoptosis in Ras-expressing keratinocytes and murine squamous cell carcinoma cells while avoiding cytotoxicity in untransformed keratinocytes. When administered to transgenic mice with HRasG12V-driven skin tumors, a single dose of silver nanoparticle conjugates followed by 415 nm LED irradiation at the tumor site caused a rapid and sustained reduction in tumor volume by 92.8%, recruited T cells to the tumor site, and acted as a potent immunomodulator by polarizing the cytokine balance toward Th1 both locally and systemically. In summary, our results demonstrate that spatiotemporal controlled miR-148b mimic delivery can promote tumor regression efficiently and safely.

The biological function of BMAL1 in skeleton development and disorders.

BMAL1 is a core component of the circadian clock loop, which directs the sophisticated circadian expression of clock-controlled genes. Skeletal Bone development is a complex biological process involving intramembranous ossification, endochondral ossification and bone remodeling, as well as specific cells, such as mesenchymal cells, osteoblasts, osteoclasts, chondrocytes, etc. Growing evidences suggest that BMAL1 is indispensable for hard tissue development, including bone, cartilage and teeth. Loss of BMAL1 in animals can inhibit bone and cartilage development, and result in abnormal bone mass. In mesenchymal cells, BMAL1 defect inhibits osteoblastic and chondrocytic differentiation. Inactivation of BMAL1 also can promote the differentiation and formation of osteoclasts and increase bone resorption. Specifically, preclinical data demonstrate that the abnormity of BMAL1 expression is associated with skeletal disorders such as skeletal mandibular hypoplasia, osteoarthritis, osteoporosis, etc. In this review, we systemically describe the impact of BMAL1 in skeletal development and homeostasis, and devote to searching new therapy strategies for bone disorders.