Blood-brain barrier dysfunction mediated by the EZH2-Claudin-5 axis drives stress-induced TNF-α infiltration and depression-like behaviors.

Growing evidence suggests that neurovascular dysfunction characterized by blood-brain barrier (BBB) breakdown underlies the development of psychiatric disorders, such as major depressive disorder (MDD). Tight junction (TJ) proteins are critical modulators of homeostasis and BBB integrity. TJ protein Claudin-5 is the most dominant BBB component and is downregulated in numerous depression models; however, the underlying mechanisms remain elusive. Here, we demonstrate a molecular basis of BBB breakdown that links stress and depression. We implemented an animal model of depression, chronic unpredictable mild stress (CUMS) in male C57BL/6 mice, and showed that hippocampal BBB breakdown was closely associated with stress vulnerability. Concomitantly, we found that dysregulated Cldn5 level coupled with repression of the histone methylation signature at its promoter contributed to stress-induced BBB dysfunction and depression. Moreover, histone methyltransferase enhancer of zeste homolog 2 (EZH2) knockdown improved Cldn5 expression and alleviated depression-like behaviors by suppressing the tri-methylation of lysine 27 on histone 3 (H3K27me3) in chronically stressed mice. Furthermore, the stress-induced excessive transfer of peripheral cytokine tumor necrosis factor-α (TNF-α) into the hippocampus was prevented by Claudin-5 overexpression and EZH2 knockdown. Interestingly, antidepressant treatment could inhibit H3K27me3 deposition at the Cldn5 promoter, reversing the loss of the encoded protein and BBB damage. Considered together, these findings reveal the importance of the hippocampal EZH2-Claudin-5 axis in regulating neurovascular function and MDD development, providing potential therapeutic targets for this psychiatric illness.

High glucose-increased miR-200c contributes to cellular senescence and DNA damage in neural stem cells.

BACKGROUND: Maternal diabetes increases the risk for neural tube defects (NTDs). It is unclear if miRNAs, senescence, and DNA damage are involved in this process. In this study, we used neural stem cells as an in vitro proxy of embryonic neuroepithelium to investigate whether high glucose triggers neural stem cell senescence and DNA damage by upregulating miR-200c, which may be responsible for NTDs. METHODS: C17.2 neural stem cells were cultured with normal glucose (5 mM) or high glucose (≥16.7 mM) at different doses and time points for detecting miR-200c levels, markers of senescence and DNA damage. Neural stem cells were exposed to antioxidant SOD1 mimetic Tempol and high glucose for 48 h to test roles of oxidative stress on the miR-200c, senescence, and DNA damage levels. An miR-200c mimic and an inhibitor were transfected into neural stem cells to increase or decrease miR-200c activities. RESULTS: High glucose upregulated miR-200c in neural stem cells. A time course study of the effect of high glucose revealed that miR-200c initially increased at 12 h and reached its zenith at 18 h. Tempol reduced miR-200c levels caused by high glucose. High glucose induced markers of senescence and DNA damage in neural stem cells. Tempol abolished high glucose-induced markers of senescence and DNA damage. The miR-200c inhibitor suppressed high glucose-induced markers of senescence and DNA damage. Treatment with miR-200c mimic imitates high glucose-induced markers of senescence and DNA damage. CONCLUSIONS: We show that high glucose increases miR-200c, which contributes to cellular senescence and DNA damage in neural stem cells and provides a potential pathway for maternal diabetes-induced neural tube defects.

Printing 3D mesh-like grooves on zinc surface to enhance the stability of aqueous zinc ion batteries.

Aqueous zinc ion batteries (AZIBs) are receiving broad attention owing to their high safety and low cost. However, the high mechanical strength and irreversible growth of zinc dendrites limit the practical application of AZIBs. Herein, regular mesh-like gullies are built on the surface of zinc foil (M150 Zn) by using simple model pressing method and stainless steel mesh as a mold. Due to the charge-enrichment effect, zinc ion deposition and stripping will be preferentially carried out in the grooves to keep the outer surface flat. In addition, zinc is exposed to 002 crystal surface in the gully after being pressed, and the deposited zinc is more inclined to grow at a small angle, so that it has a sedimentary morphology parallel to the basement. Consequently, at a current density of 0.5 mA cm-2, the M150 zinc anode has a voltage hysteresis of only 35 mV and a cycle life of up to 400 h (relative to a zinc foil of 96 mV and 160 h). Even more imposing is that the full cell has a capacity retention of approximately 100% after 1000 cycles at 2 A g-1 and a specific capacity of almost 60 mAh g-1 when activated carbon is used as the cathode. It is a promising method to improve the stable cycle performance of AZIBs by using a simple method to realize the non-prominent dendrites on the surface of zinc electrode.

Nitrogen-rich Graphite Flake from Hemp as Anode Material for High Performance Lithium-ion Batteries.

Biomass-derived carbon (BC) has attracted extensive attention as anode material for lithium ion batteries (LiBs) due to its natural hierarchical porous structure and rich heteroatoms that can adsorb Li+ . However, the specific surface area of pure biomass carbon is generally small, so we can help NH3 and inorganic acid produced by urea decomposition to strip biomass, improve its specific surface area and enrich nitrogen elements. The nitrogen-rich graphite flake obtained by the above treatment of hemp is named NGF. The product that has a high nitrogen content of 10.12% has a high specific surface area of 1151.1 m2 g-1 . In the lithium ion battery test, the capacity of NGF is 806.6 mAh g-1 at 30 mA g-1 , which is twice than that of BC. NGF also showed excellent performance that is 429.2 mAh g-1 under high current testing at 2000 mA g-1 . The reaction process kinetics is analyzed and we found that the outstanding rate performance is attributed to the large-scale capacitance control. In addition, the results of the constant current intermittent titration test indicate that the diffusion coefficient of NGF is greater than that of BC. This work proposes a simple method of nitrogen-rich activated carbon, which has a significantly commercial prospect.

Exact Analytic Spectra of Asymmetric Modulation Instability in Systems with Self-Steepening Effect.

Nonlinear waves become asymmetric when asymmetric physical effects are present within the system. One example is the self-steepening effect. When exactly balanced with dispersion, it leads to a fully integrable system governed by the Chen-Lee-Liu equation. The latter provides a natural basis for the analysis of asymmetric wave dynamics just as nonlinear Schrödinger or Korteweg-de Vries equations provide the basis for analyzing solitons with symmetric profile. In this work, we found periodic wave trains of the Chen-Lee-Liu equation evolved from fully developed modulation instability and analyzed a highly nontrivial spectral evolution of such waves in analytic form that shows strong asymmetry of its components. We present the conceptual basis for finding such spectra that can be used in analyzing asymmetric nonlinear waves in other systems.

Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2.

Rationale: Tanshinone, a type of diterpenes derived from salvia miltiorrhiza, is a particularly promising herbal medicine compound for the treatment of cancers including acute myeloid leukemia (AML). However, the therapeutic function and the underlying mechanism of Tanshinone in AML are not clear, and the toxic effect of Tanshinone limits its clinical application. Methods: Our work utilizes human leukemia cell lines, zebrafish transgenics and xenograft models to study the cellular and molecular mechanisms of how Tanshinone affects normal and abnormal hematopoiesis. WISH, Sudan Black and O-Dianisidine Staining were used to determine the expression of hematopoietic genes on zebrafish embryos. RNA-seq analysis showed that differential expression genes and enrichment gene signature with Tan I treatment. The surface plasmon resonance (SPR) method was used with a BIAcore T200 (GE Healthcare) to measure the binding affinities of Tan I. In vitro methyltransferase assay was performed to verify Tan I inhibits the histone enzymatic activity of the PRC2 complex. ChIP-qPCR assay was used to determine the H3K27me3 level of EZH2 target genes. Results: We found that Tanshinone I (Tan I), one of the Tanshinones, can inhibit the proliferation of human leukemia cells in vitro and in the xenograft zebrafish model, as well as the normal and malignant definitive hematopoiesis in zebrafish. Mechanistic studies illustrate that Tan I regulates normal and malignant hematopoiesis through direct binding to EZH2, a well-known histone H3K27 methyltransferase, and inhibiting PRC2 enzymatic activity. Furthermore, we identified MMP9 and ABCG2 as two possible downstream genes of Tan I's effects on EZH2. Conclusions: Together, this study confirmed that Tan I is a novel EZH2 inhibitor and suggested MMP9 and ABCG2 as two potential therapeutic targets for myeloid malignant diseases.

[Effect of Oxidation Strengthening on In-situ Phosphorus Immobilization of Calcium Hydroxide].

In this research, calcium hydroxide[Ca(OH)2] and hydrogen peroxide (H2O2) were injected into the bottom mud in the form of plum blossom scatterers to investigate the effect on the control of endogenous phosphorus. The results showed that Ca(OH)2 used singly effectively immobilized in the order of 90% of endogenous phosphorus approximately 20 mm below the sediment-water interface (SWI); however, at the same time, the anaerobic environment was enhanced, resulting in the transformation of stable phosphorus to easily released phosphorus and the accumulation of potential active phosphorus. Nevertheless, the addition of H2O2 greatly reduced the amount of potential active phosphorus in deep sediments after adding Ca(OH)2. The vertical diffusion depth of Ca(OH)2 in the sediments was significantly increased, having an influence across the depth range of 0-40mm below the SWI; the improvement at depths greater than 40 mm was not notable, which was mainly attributed to an 18-fold increase of redox potential due to the addition of the oxidant. The change of phosphorus forms in the sediment also demonstrated the excellent immobilization effect of the oxidant on phosphorus. In the 0-20 mm layer, the content of readily released phosphorus decreased significantly, while compared with a control test, Ca-P increased by approximately 10%. However, at greater depths, the amount of easily released phosphorus decreased and the rate of Ca-P increase gradually slowed.

[Adsorption Behavior of Phosphate by CaO2 Remolded Sediment].

This study simulated the state of CaO2 loss after in situ coverage and examined the bottom 2 cm of sediment after restoration. Observations and elemental analysis of the sediment using scanning electron microscopy (SEM) and X-ray energy spectrometry (EDX) were also performed. The CaO2 remodeling notably changed the structure of the sediment; most of the organic matter and iron-manganese oxide attached to the sediment surface was removed, the porosity of the sediment particles increased, and the Ca2+ content was also increased. CaO2 remodeling stabilized the endogenous phosphorus in the sediment; total phosphorous (TP) was reduced by approximately 20% and potential active phosphorus content was reduced by approximately 30%. Furthermore, the contents of Ca-P and Res-P were significantly increased. The amount of phosphorus released from the remodeled sediment under anaerobic conditions was significantly lower than the original sediment, indicating that the CaO2 remodeling greatly reduced the risk of endogenous phosphorus release. The Langmuir model was more suitable than the Freundlich and Dubinin-Radushkevich models for describing the isothermal adsorption behavior of the CaO2 remodeling, which significantly improved the adsorption capacity of the sediment with respect to phosphate from 1.44 mg·g-1 to 20.91 mg·g-1. The mechanism of adsorption was switched from chemical adsorption to physicochemical adsorption. In addition, the adsorption kinetics of the CaO2 remodeled sediment with respect to phosphate could be best described using the quasi-second-order kinetic model.

Optimal number of harvested lymph nodes for curatively resected gallbladder adenocarcinoma based on a Bayesian network model.

BACKGROUND AND OBJECTIVES: To identify the optimal range and the minimum number of lymph nodes (LNs) to be examined to maximize survival time of patients with curatively resected gallbladder adenocarcinoma (GBAC). METHODS: Data were collected from the surveillance, epidemiology, and end results database on patients with GBAC who underwent curative resection between 2004 and 2015. A Bayesian network (BN) model was constructed to identify the optimal range of harvested LNs. Model accuracy was evaluated using the confusion matrix and receiver operating characteristic (ROC) curve. RESULTS: A total of 1268 patients were enrolled in this study. Accuracy of the BN model was 72.82%, and the area under the curve of the ROC for the testing dataset was 78.49%. We found that at least seven LNs should be harvested to maximize survival time, and that the optimal count of harvested LNs was in the range of 7 to 10 overall, with an optimal range of 10 to 11 for N+ patients, 7 to 10 for stage T1-T2 patients, and 7 to 11 for stage T3-T4 patients. CONCLUSIONS: According to a BN model, at least seven LNs should be retrieved for GBAC with curative resection, with an overall optimal range of 7 to 10 harvested LNs.

Complete chloroplast genome sequence of Chimonanthus praecox link (Calycanthaceae): an endemic plant species in China.

Chimonanthus praecox, a deciduous shrub tree, is endemic to China and widely cultivated in the world as a popular garden and ornamental plant. Here, we have reported its complete chloroplast genome with a length of 153,181 bp, containing a large single copy (LSC) region of 86,916 bp, a small single copy (SSC) region of 19,767 bp and two identical inverted repeat regions (IRs) of 23,249 bp. The overall GC contents of the plastome were 39.27%. A total of 114 unique genes were successfully annotated consisting of 80 protein-coding genes, 30 tRNA genes and four rRNA genes. Sixteen genes each possessed one intron and three genes had two introns. The ML phylogenetic analysis supports Chimonanthus as sister to Calycanthus. This result will be helpful for genetic breeding and population genetics of C. praecox, DNA barcoding of Chimonanthus, and phylogenetic studies of Calycanthaceae.

Electrospun Poly (Aspartic Acid)-Modified Zein Nanofibers for Promoting Bone Regeneration.

BACKGROUND: Critical-sized bone defects raise great challenges. Zein is of interest for bone regeneration, but it has limited ability to stimulate cell proliferation. In this regard, a poly (aspartic acid) (PAsp)-zein hybrid is promising, as PAsp can promote rat bone marrow stromal cell (rBMSCs) proliferation and osteogenic differentiation. This research aimed to develop electrospun PAsp-modified zein nanofibers to realize critical-sized bone defects repair. METHODS: Three groups of PAsp-modified zein nanofibers were prepared, they were PAsp grafting percentages of 0% (zein), 5.32% (ZPAA-1), and 7.63% (ZPAA-2). Using rBMSCs as in vitro cell model and SD rats as in vivo animal model, fluorescence staining, SEM, CCK-8, ALP, ARS staining, µCT and histological analysis were performed to verify the biological and osteogenic activities for PAsp-modified zein nanofibers. RESULTS: As the Asp content increased from 0% to 7.63%, the water contact angle decreased from 129.8 ± 2.3° to 105.5 ± 2.5°. SEM, fluorescence staining and CCK-8 assay showed that ZPAA-2 nanofibers had a superior effect on rBMSCs spreading and proliferation than did zein and ZPAA-1 nanofibers, ALP activity and ARS staining showed that ZPAA-2 can improve rBMSCs osteogenic differentiation. In vivo osteogenic activities was evaluated by µCT analysis, HE, Masson and immunohistochemical staining, indicating accelerated bone formation in ZPAA-2 SD rats after 4 and 8 weeks treatment, with a rank order of ZPAA-2 > ZPAA-1 > zein group. Moreover, the semiquantitative results of the Masson staining revealed that the maturity of the new bone was higher in the ZPAA-2 group than in the other groups. CONCLUSION: Electrospun PAsp-modified zein can provide a suitable microenvironment for osteogenic differentiation of rBMSCs, as well as for bone regeneration; the optimal membrane appears to have a PAsp grafting percentage of 7.63%.

Intermediate-Valence Ytterbium Compound Yb4Ga24Pt9: Synthesis, Crystal Structure, and Physical Properties.

The title compound was synthesized by a reaction of the elemental educts in a corundum crucible at 1200 °C under an Ar atmosphere. The excess of Ga used in the initial mixture served as a flux for the subsequent crystal growth at 600 °C. The crystal structure of Yb4Ga24Pt9 was determined from single-crystal X-ray diffraction data: new prototype of crystal structure, space group C2/m, Pearson symbol mS74, a = 7.4809(1) Å, b = 12.9546(2) Å, c = 13.2479(2) Å, ß = 100.879(1)°, V = 1260.82(6) Å3, RF = 0.039 for 1781 observed reflections and 107 variable parameters. The structure is described as an ABABB stacking of two slabs with trigonal symmetry and compositions Yb4Ga6 (A) and Ga12Pt6 (B). The hard X-ray photoelectron spectrum (HAXPES) of Yb4Ga24Pt9 shows both Yb2+ and Yb3+ contributions as evidence of an intermediate valence state of ytterbium. The evaluated Yb valence of ∼2.5 is in good agreement with the results obtained from the magnetic susceptibility measurements. The compound is a bad metallic conductor.

A novel method of surface modification by electrochemical deoxidation: Effect on surface characteristics and initial bioactivity of zirconia.

The aim of this study was to investigate and compare the surface characteristics and initial bioactivity of ceria-stabilized zirconia/alumina nanocomposite (NANOZR) with those of yttria-stabilized zirconia (3Y-TZP) and pure titanium (CpTi) following the use of three surface modification methods; polishing, sandblasting/acid-etching (SB-E) and electrochemical deoxidation (ECD). Physical properties including surface morphology, chemical composition, X-ray diffraction, surface wettability, surface roughness, and hardness were measured. Osteoblast-like MC3T3-E1 cells were used to examine cell morphology and attachment to the surfaces of the materials. ECD treated NANOZR (NANOZR-E) showed a well-arranged, self-organized microporous surface structure with significantly low contact angles when compared with the other specimens (p < 0.05). NANOZR-E also demonstrated a slight decrease in monoclinic phase content (-4.4 wt %). The morphology and attachment of MC3T3-E1 cells on NANOZR-E were similar to those on polished and SBE-treated CpTi surfaces. Higher cell affinity was observed on NANOZR-E when compared with ECD treated 3Y-TZP. The findings of this study indicate the effectiveness of the novel technique, ECD, in the formation of a microporous surface on NANOZR when compared with both CpTi and 3Y-TZP. Moreover, this method also appears to improve the biological activity of NANOZR during the initial stage. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2641-2652, 2017.

1s2p resonant inelastic X-ray scattering combined dipole and quadrupole analysis method.

In this study an analysis strategy towards using the resonant inelastic X-ray scattering (RIXS) technique more effectively compared with X-ray absorption spectroscopy (XAS) is presented. In particular, the question of when RIXS brings extra information compared with XAS is addressed. To answer this question the RIXS plane is analysed using two models: (i) an exciton model and (ii) a continuum model. The continuum model describes the dipole pre-edge excitations while the exciton model describes the quadrupole excitations. Applying our approach to the experimental 1s2p RIXS planes of VO2 and TiO2, it is shown that only in the case of quadrupole excitations being present is additional information gained by RIXS compared with XAS. Combining this knowledge with methods to calculate the dipole contribution in XAS measurements gives scientists the opportunity to plan more effective experiments.

Transparent conducting oxide induced by liquid electrolyte gating.

Optically transparent conducting materials are essential in modern technology. These materials are used as electrodes in displays, photovoltaic cells, and touchscreens; they are also used in energy-conserving windows to reflect the infrared spectrum. The most ubiquitous transparent conducting material is tin-doped indium oxide (ITO), a wide-gap oxide whose conductivity is ascribed to n-type chemical doping. Recently, it has been shown that ionic liquid gating can induce a reversible, nonvolatile metallic phase in initially insulating films of WO3 Here, we use hard X-ray photoelectron spectroscopy and spectroscopic ellipsometry to show that the metallic phase produced by the electrolyte gating does not result from a significant change in the bandgap but rather originates from new in-gap states. These states produce strong absorption below ∼1 eV, outside the visible spectrum, consistent with the formation of a narrow electronic conduction band. Thus WO3 is metallic but remains colorless, unlike other methods to realize tunable electrical conductivity in this material. Core-level photoemission spectra show that the gating reversibly modifies the atomic coordination of W and O atoms without a substantial change of the stoichiometry; we propose a simple model relating these structural changes to the modifications in the electronic structure. Thus we show that ionic liquid gating can tune the conductivity over orders of magnitude while maintaining transparency in the visible range, suggesting the use of ionic liquid gating for many applications.

Effects of quercetin on LPS-induced disseminated intravascular coagulation (DIC) in rabbits.

INTRODUCTION: Quercetin is widely distributed in plants and has been reported to have effects of anti-inflammation and anti-thrombosis. In this study, we evaluated the protective effect of quercetin on LPS-induced experimental DIC in rabbits, and tried to clarify its mechanism against DIC. MATERIALS AND METHODS: LPS-induced DIC model in rabbits was established through continuous infusion of 100 ug · kg(-1) · h(-1) LPS for a period of 6h. Six groups were divided: quercetin-treated groups (0.5, 1.0, and 2.0 mg·kg(-1) · h(-1), respectively), LPS-control group, heparin-control group (100 IU · kg(-1) · h(-1)), and saline-control group. APTT, PT, and plasma FIB level were measured, the plasma levels of ALT, BUN, and TNF-α were detected, and the activity of Protein C and ATIII was recorded. RESULTS: A continuous injection of LPS induced a gradual impairment of hemostatic parameters, a rise in plasma level of TNF-α, and damage in renal and hepatic function. The intravenous administration of quercetin significantly attenuated the increase of APTT, PT, ALT, BUN, and TNF-α, and the decrease of plasma FIB level and activity of Protein C and ATIII. CONCLUSION: Quercetin may have a protective effect against LPS-induced DIC in rabbits through anti-inflammation and anticoagulation.

Evaluation of short-axis and long-axis myocardial function with two-dimensional strain echocardiography in patients with different degrees of coronary artery stenosis.

This study was designed to characterize the changes in the peak systolic longitudinal, circumferential and radial strains by using 2-D strain echocardiography in patients with coronary artery stenosis without segmental wall motion abnormalities on conventional 2-D echocardiography. 2D strain echocardiography was performed in 44 patients with different degrees of coronary artery stenosis. Myocardial longitudinal, circumferential and radial strain profiles were obtained and peak systolic strain values were measured. The peak systolic longitudinal strain was significantly reduced in myocardial segments subtended by coronary arteries with greater than 75% stenosis when compared with those subtended by coronary artery with less than 75% stenosis and those in control. Sensitivity and specificity were 74% and 72%, respectively, for peak systolic longitudinal strain to predict segments subtended by coronary arteries with greater than 75% stenosis (cutoff value--17.7%; area under the receiver operating characteristic curve, 0.825). There were no significant differences in circumferential and radial strains among myocardial segments subtended by coronary arteries with greater than 75% stenosis and those with less than 75% stenosis and in control. In conclusion, our study suggests that analysis of long-axis cardiac function by using the 2-D strain echocardiography may help to identify the myocardial segments subtended by coronary arteries with severe stenosis.