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Accumulating evidence suggests that atherosclerosis (AS) is the underlying cause of vascular diseases, including heart disease and stroke. Ultrasound-targeted microbubble destruction (UTMD) technology provides a tolerable, efficient and effective system for drug delivery and gene transfection, which has broad application prospects in the treatment of AS. In addition, glycogen synthase kinase (GSK)-3β has been implicated as a potentially valuable therapeutic agent for AS treatment; however, the specific molecular mechanisms remain unknown. Therefore, this study was conducted to explore the effect of downregulation of GSK-3β expression via UTMD on atherosclerotic plaque stability. We established a THP-1 macrophage-derived foam cell model in vitro and an atherosclerotic plaque model in the right common carotid artery of New Zealand rabbits. We determined levels of the relevant vulnerable plaque stability elements. The results indicate that GSK-3β was upregulated in the foam cells and in atherosclerotic rabbits. Downregulation of GSK-3β expression by UTMD suppressed vulnerable plaque factors and inflammation in vitro and in vivo, changed the cytoskeleton of the foam cells in vitro, increased Young's modulus and decreased the peak intensity of atherosclerotic plaque in vivo. Moreover, GSK-3β inhibition by UTMD did not influence the viability of the foam cells. Collectively, our results indicate that GSK-3β could be a potential target for anti-atherogenic interventions and, in particular, can improve the stability of AS plaques in combination with UTMD.

Tonalite–trondhjemite–granodiorite (TTG) suites constitute dominant components of Precambrian continental crust and provide important insights into the crustal evolution history of the early Earth. Here we investigate a suite of TTGs and associated greenstones from the Luxi Terrane in the south–eastern part of the North China Craton (NCC). We present data from petrology, geochemistry, zircon U–Pb geochronology and Lu–Hf isotopes to characterize these rocks and understand their genesis. Mineral assemblage in the greenstones and TTGs suggests that the rocks have undergone amphibolite–facies metamorphism with regression under greenschist–facies. Zircon U–Pb data from the magmatic grains yield upper intercept ages of 2753 ± 37 and 2582 ± 40 Ma for greenstone, 2552 ± 13 Ma for TTG gneiss and 2476 ± 18 Ma for tonalite, and weighted mean 207Pb/206Pb age of 2507 ± 22 Ma for granodiorite. Lu–Hf isotope systematics show eHf(t) values ranging from −2.13 to 7.29 and crustal model ages (TCDM) in the range of 2603–3125 Ma for the TTGs, whereas the eHf(t) values are up to 8.53 with TCDM ages of 2644–3006 Ma for the greenstone. The results suggest that the protolith for the greenstone was derived from a Meso- to Neoarchean mantle contaminated by the crust source, whereas the TTGs were mostly sourced from juvenile crustal sources with reworking of older basement. The geochemical features of greenstone are similar to island arc basalt, with low Na2O, K2O and TiO2, low total rare earth elements (REEs) values, relative enrichment in light REEs and depletion in heavy REEs absence of obvious Ce anomaly, and negative Nb, Ta and Ti anomalies. The TTGs show similar features, except for the high K2O content and moderate total REEs values. We propose that the greenstone likely represent a part of the early and initial crustal growth at ca. 2750–2600 Ma, and the TTGs were generated subsequently at ca. 2550–2450 Ma. Our results are consistent with the previous models on the crustal growth models in the NCC and provide further insights into the Neoarchean to Paleoproterozoic tectonic history of the craton.

Research on history of the Earth’s continents and the genesis of mineral deposits has been one of the hotspots in geology. But only limited studies have been completed on iron deposits hosted by banded iron-formations (BIFs), such as the large Hanwang iron deposit located in the eastern North China Craton (NCC). In this contribution, we present the petrology, zircon U–Pb geochronology, Lu–Hf isotopes and whole-rock geochemistry on Hanwang iron deposit hosted by the metamorphosed Neoarchean to early Paleoproterozoic Taishan Group and orthogneiss derived from tonalite–trondhjemite–granodiorite (TTGs). Magnetite-bearing amphibolite, magnetite-bearing quartz amphibolite, and gneiss host the Hanwang iron deposit, which is characterised by subhedral to euhedral magnetite, pyrite with minor galena and BIF laminations. Gangue minerals include hornblende, plagioclase and quartz with minor amounts of biotite, chlorite, epidote and microcline. This mineral assemblage is indicative of amphibolite-facies metamorphism with regression to greenschist-facies. The deposit is located in a transition zone between metamorphosed mafic to felsic volcanic rocks. The age of the Hanwang BIF-hosted iron deposit is late Neoarchean. Lu–Hf isotope systematics indicate that the protolith for the biotite amphibolite is derived from a Neoarchean mantle contaminated by the crust, and orthogneiss is derived from the Neoarchean crust. The biotite amphibolite is characterised by high Na, Fe and low K assays, enrichment in light rare earth elements (LREE), and relatively depletion in heavy REEs (HREE) without an obvious Ce anomaly. The geochemistry of the orthogneiss is characteristic of a volcanic–arc granite, although this must be accepted with caution given that the orthogneiss is metamorphosed and deformed at amphibolite-facies. It is proposed that Hanwang iron deposit was deposited in a marine volcanic–arc environment and derived from hydrothermally leached volcanic units, and similar to the Algoma-type iron deposit. Most BIFs occurring in Neoarchean granite-greenstone succession of the eastern NCC belong to the Algoma-type iron deposits. Globally, this sequence appears to be coeval with the Yilgarn Craton in Western Australia.

Tumor-infiltrating lymphocytes (TILs), including but not limited to neutrophils, M2 macrophages, cytotoxic CD8 T cells and dendritic cells, will play a role in the acidic tumor microenvironment mediated by monocarboxylate transporter 4 (MCT4) in esophageal squamous cell carcinoma (ESCC). However, the roles they play and their significance in ESCC remain less clear. To understand the clinicopathological and prognostic significance of neutrophils, M2 macrophages, CD8 T cells and dendritic cells in the tumor acidic microenvironment mediated by MCT4, we investigated the distribution of these TILs in the epithelial and stromal compartments of ESCC by means of multiplexed immunohistochemistry on a tissue microarray containing 87 paired dots of ESCC and its adjacent normal tissue (ANT) and an additional 6 cases of unpaired ESCC dots. The density of cells stained with MCT4 in the epithelium was significantly associated with overall survival. Dendritic cells stained with S100 in epithelial compartmentalization were found to markedly correlate with clinical stage and tumor invasion depth. No other significant association could be identified in terms of prognostic and clinicopathological significance. The potential correlation between the number of cells stained with MCT4 versus the number of TILs was also explored, showing that only in epithelial cells were there significant and positive correlations identified between the number of cells stained with MCT4 versus the number of neutrophils stained with CD15, M2 macrophages stained with CD163 and CD8 T cells stained by CD8a. However, no significant correlation was found along the stromal line. Together, the data we described here, although somewhat discouraging, showed that in epithelial cells from which ESCC originated, acidicity mediated by MCT4 may be responsible for lactate release and may have an effect on the infiltration of TILs we assessed.

Absract The influence of oxygen-related thermal donors (TDs) on the performance of silicon heterojunction (SHJ) solar cells was explored experimentally in this paper. It is found that a certain number of thermal donors could do much harm to the performance of SHJ solar cells. The efficiency of SHJ solar cells is usually reduced by a value of ~ 1% absolute in the case of thermal donors with a concentration of nearly 1015 cm−3. The microwave photoconductance decay and Hall Effect studies have proved that the TDs can significantly reduce the carrier lifetime of n-type silicon substrate, but have no influence on the carrier mobility. Deep level transient spectroscopy (DLTS) measurements have further demonstrated that the TDs cause an energy level at Ec-0.13 eV with carrier capture cross-section of 10−15 cm2, which is responsible for the reduction of carrier lifetime and solar cell efficiency.

Liancheng is an important Cu–Mo deposit hosted by red-beds in the Mesozoic to Cenozoic Lanping Basin located in the Sanjiang Tethyan Orogen of SW China. The deposit is fault controlled where it has been affected and enriched by four hydrothermal events indicated by four distinct sets of veins and their cross-cutting relationships. A detailed Cu–S–H–O isotopic study is reported here on the mineralization focusing on the source of the metals and fluid, and on the mineralizing processes. The first two hydrothermal events are characterised by CO2 and fluid-rich inclusions with homogenisation temperatures of 124–446 °C and salinities ranging from 0.4 to 24.6 wt% NaCl equiv. The next two hydrothermal events are characterised by liquid–rich fluid inclusions that homogenise at 145–256 °C, with salinities ranging from 1.4 to 22.9 wt% NaCl equiv. The H–O isotope values obtain from the fluid inclusions indicate that the first three hydrothermal events relate to mineralizing fluids derived from a metamorphic source, but the last event includes a mixed metamorphic and meteoric source. Chalcopyrite, tennantite, and bornite from the deposit have δ34S values between −11.5 and 3‰. The δ65Cu values for quartz-Cu sulfide mineralization associated with the second hydrothermal event range from −0.31 to 0.2‰, but carbonate-Cu sulfide mineralization associated with the third hydrothermal event ranges from −1.01 to −1.08‰. The combination of the Cu and S isotopic values and field observations indicate that the controlling factors include structures, the temperature of regional metamorphism, and the pH of the mineralizing fluid. The zation is, therefore, characteristic of an orogenic-type deposit.

The Jinding Zn–Pb deposit located in the Mesozoic-Cenozoic Lanping Basin of southwest China has ore reserves of ∼ 220 Mt with an average grade of 6.1% Zn and 1.3% Pb. The mineralization is hosted by sandstone in the Early Cretaceous Jingxing Formation and limestone breccia in the Paleocene Yunlong Formation. Mineralization in both types of host rocks is characterized by a paragenetic sequence beginning with marcasite–sphalerite (Stage 1) followed by pyrite–marcasite–sphalerite–galena (Stage 2), and then galena–sphalerite–pyrite–sulfate–carbonate (Stage 3). Pyrite from these stages have different δ 33 S compositions with pyrite from Stage 1 averaging − 9.6‰, Stage 2 averaging − 8.9‰, and Stage 3 averaging + 0.3‰. Sphalerite hosted by the sandstone has similar δ 66 Zn values ranging from 0.10 to 0.30‰ in all stages of the mineralization, but sphalerite samples from the limestone breccia-hosted ore show variable δ 66 Zn values between − 0.03 and 0.20‰. Our data on sphalerite precipitated during the earlier stages of mineralization has a constant δ 66 Zn value and cogenetic pyrite displays a very light sulfur isotope signature, which we believe to reflect a sulfur source that formed during bacterial sulfate reduction (BSR). The Stage 3 sphalerite and pyrite precipitated from a late influx of metal-rich basinal brine, which had a relatively constant variable δ 66 Zn isotopic composition due to open system isotope fractionation, and a near zero δ 33 S composition due to the influence of abiotic thermochemical sulfate reduction from observed sulfates in the host rock.

Background: Increased microvascular leakage is a cardinal feature of many critical diseases. Regular exercise is associated with improved endothelial function and reduced risk of cardiorespiratory disease. Irisin, secreted during exercise, contributes to many health benefits of exercise. However, the effects of irisin on endothelial function in the context of lung injury remain unknown. Methods: The direct effect of irisin on endothelial barrier function was studied in human microvascular endothelial cells (HMVECs) and human umbilical vein endothelial cells (HUVECs). The therapeutic effect of irisin was evaluated in 4 preclinical models of acute lung injuey (ALI). Serum irisin levels were measured and associated with disease severity in 60 ARDS patients. Findings: In this study, we found that irisin remarkably strengthened endothelial junctions and barrier function via binding to integrin αVβ5 receptor in LPS-treated endothelial cells. The beneficial effect of irisin was associated with suppression of the Src-MLCK-β-catenin pathway, activation of the AMPK-Cdc42/Rac1 pathway and improvement of mitochondrial function. In preclinical models of ALI, exogenous irisin improved pulmonary function, decreased lung edema and injury, suppressed inflammation, and increased survival. In ARDS patients, serum irisin levels were decreased and inversely correlated with disease severity and mortality. Interpretation: Irisin enhances endothelial barrier function and mitigates microvascular leakage related lung injury. Irisin may assist with the urgent medical need for preventing or minimizing ARDS and other microvascular leakage related diseases. Funding Statement: National Nature Science Foundation of China (No. 81770491) and the Ministry of Education Innovation Team Development Program of China (No. IRT16R57). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: The study was approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University. All study participants provided informed consent in accordance with the Declaration of Helsinki.

The Sanjiang Orogen is important for us to better understand the tectonic evolution of the Paleo-Tethys Ocean. However, the petrogenesis and tectonic setting of the Late Triassic igneous rocks in the central part of the orogen are poorly understood. In this study, we present new whole-rock elemental and isotopic compositions for the Biluoxueshan Pluton, which consists of quartz diorite, granodiorite, and alkali-feldspar granite. Zircon U-Pb dating yields crystallisation ages of 231 ± 1 Ma for the quartz diorite, 227 ± 1 Ma for the granodiorite, and 227 ± 2, 224 ± 2, 222 ± 1, and 217 ± 3 Ma for alkali-feldspar granites, indicating a prolonged emplacement of the pluton. Quartz diorites are metaluminous, high-potassium calc-alkaline, and magnesian in composition. Granodiorites are characterized by peraluminous composition and the existence of normative-corundum, resembling S-type granite. They have negative zircon eHf(t) values (−13 to −10.8) and old Hf crustal model ages (2060–1920 Ma), indicating a Paleoproterozoic crustal source. Alkali-feldspar granites are metaluminous to weakly peraluminous, have higher SiO2 content, FeOT/MgO ratio and differentiation index (DI) than other samples, and pronouncedly negative Eu anomalies, which are characteristics of highly fractionated granites. They have narrow eHf(t) values of −2.7 to +2.6 with corresponding Hf crustal model ages of 1410–1060 Ma, indicating a Mesoproterozoic juvenile crustal source modified by mantle-derived magma. By combining previous and the new data, we proposed a new tectonic evolution model of a Late Triassic northward scissor-like post-collisional extension during ca. 235–223 Ma in the Changning-Menglian Suture Zone.

Graphene has attracted great research interests due to its unique mechanical, electrical and optical properties, which opens up a huge number of opportunities for applications. Recently, Graphene-Silicon (Gr Si) solar cell has been recognized as one interesting candidate for the future photovoltaic. Since the first Gr Si solar cell reported in 2010, Gr Si solar cell has been intensively investigated and the power converse efficiency (PCE) of it has been developed to 15.6%. This review presents and discusses current development of Gr Si solar cell. Firstly, the basic concept and mechanism of Gr Si solar cell are introduced. Then, several key technologies are introduced to improve the performance of Gr Si solar cells, such as chemical doping, annealing, Si surface passivation and interlayer insertion. Particular emphasis is placed on strategies for Gr Si interface engineering. Finally, new pathways and opportunities of “MIS-like structure” Gr Si solar cells are described.

The aims of this study were to evaluate the effects of biweekly bevacizumab administration on a tumor microenvironment and to investigate the mechanisms of radiosensitization that were induced by it. Briefly, bevacizumab was administered intravenously to Balb/c nude mice bearing non-small cell lung cancer (NSCLC) H1975 xenografts; in addition, bevacizumab was added to NSCLC or endothelial cells (ECs) in vitro, followed by irradiation (IR). The anti-tumor efficacy, anti-angiogenic efficacy and repair of DNA double-strand breaks (DSBs) were evaluated. The activation of signaling pathways was determined using immunoprecipitation (IP) and WB analyses. Finally, biweekly bevacizumab administration inhibited the growth of H1975 xenografts and induced vascular normalization periodically. Bevacizumab more significantly increased cellular DSB and EC apoptosis when administered 1 h prior to 12 Gy/1f IR than when administered 5 days prior to IR, thereby inhibiting tumor angiogenesis and growth. In vitro, bevacizumab more effectively increased DSBs and apoptosis prior to IR and inhibited the clonogenic survival of ECs but not NSCLC cells. Using IP and WB analyses, we confirmed that bevacizumab can directly inhibit the phosphorylation of components of the VEGR2/PI3K/Akt/DNA-PKcs signaling pathway that are induced by IR in ECs. In conclusion, bevacizumab radiosensitizes NSCLC xenografts mainly by inhibiting DSB repair in ECs rather than by inducing vascular normalization.

Summary The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination., Graphical Abstract, Highlights • Removal of N-glycans proximal to the CD4 binding site increases B cell accessibility • Heterologous Env trimer-liposome regimen drives B cells to cross-conserved sites • Vaccine elicitation of an N-glycan-dependent CD4 binding site neutralizing antibody • Elicitation of an interface-directed antibody with 87% HIV neutralization breadth, Eliciting broadly neutralizing HIV antibodies by vaccination remains a challenge. Dubrovskaya et al. use an immunization regimen incorporating targeted N-glycan removal and heterologous prime:boosting with NFL trimer-liposomes in rabbits to elicit broadly neutralizing responses to cross-conserved HIV-1 epitopes, including an antibody with 87% neutralization breadth. Further structural analyses highlight similarities between the vaccine-elicited antibodies and the human broadly neutralizing antibodies.

The purpose of this work is to improve the precision of the elemental analysis of coal using laser-induced breakdown spectroscopy (LIBS). The LIBS technique has the ability to allow simultaneous elemental analysis and on-line determination, so it could be used in the elemental analysis of coal. Organic components such as C, H, O, N and inorganic components such as Ca, Mg, Fe, Al, Si, Ti, Na, and K of coal have been identified. The precision of the LIBS technique depends strongly on the experimental conditions, and the choice of experimental parameters should be aimed at optimizing the repeatability of the measurements. The dependences of the relative standard deviation (RSD) of the LIBS measurements on the experimental parameters including the sample preparation parameters, lens-to-sample distance, sample operation mode, and ambient gas have been investigated. The results indicate that the precision of LIBS measurements for the coal sample can be improved by using the optimum experimental parameters.