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Xiao J, Sheng X, Zhang X, Guo M, Ji X. Drug Des Devel Ther. 2016;10:1267–1277. The authors have advised due to an error at the time of figure assembly, Figure 5A on page 1274 is incorrect. The correct Figure 5 is shown in Download Article. The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

Background: Doxorubicin (DOX)-induced cardiotoxicity is a highly concerning issue, and the mechanism by which DOX induces cardiotoxicity is likely to be multifactorial. NADPH oxidase (NOX) is associated with DOX-induced cardiotoxicity. Setanaxib (GKT137831), a preferential direct inhibitor of NOX1 and NOX4, can delay or prevent the progression of many cardiovascular disorders by inhibiting reactive oxygen species (ROS) generation. In this study, we investigated the role of GKT137831 in ameliorating DOX-induced cardiotoxicity and the potential mechanisms of its action.Methods and Results: The mice model of cardiotoxicity induced by DOX was established, and GKT137831 treatment was performed at the same time. Neonatal rat cardiomyocytes (NRCMs) were treated with DOX or GKT137831 for in vitro experiments. We found that DOX administration impaired cardiac function in vivo, reflected by decreased left ventricular ejection fraction (LVEF) and fractional shortening (FS%). DOX also impaired the viability of NRCMs in vitro. In addition, DOX increased the levels of NOX1 and NOX4 expression and ROS production and the cardiomyocyte apoptosis rate, both in vivo and in vitro. GKT137831 improved cardiac function, as indicated by the increased LVEF and FS%. In vitro, GKT137831 improved NRCM viability. It also decreased ROS production and the cardiomyocyte apoptosis rate. Apoptotic indices, such as cleaved PARP (c-PARP), cleaved caspase 3 (CC3) and BAX expression levels, were decreased, and the antiapoptotic index of Bcl-2 expression was increased. DOX markedly activated phosphorylated JNK, ERK and p38 proteins in NRCMs. Specific inhibitors of JNK (SP600125), ERK (PD98059) or p38 (SB203580) inhibited DOX-induced apoptosis of NRCMs. GKT137831 pretreatment inhibited excessive DOX-induced MAPK pathway activation.Conclusion: This study revealed that GKT137831 can alleviate DOX-induced cardiomyocyte apoptosis by inhibiting NOX1/4-driven ROS production. The upregulation of MAPK pathway induced by NOX1/4-derived ROS production may be the potential mechanism of GKT137831 action. GKT137831 may be a potential drug candidate to ameliorate DOX-induced cardiotoxicity.

The high pavement temperature plays an important role in the development of urban heat island (UHI) in summer. The objective of this study was to develop water retentive and thermal resistant cement concrete (WTCC) to enhance the pavement cooling effects. The WTCC was prepared by combining a water retentive material and a high aluminum refractory aggregate (RA) with porous cement concrete (PCC). Water retention capacity test, fluidity test, and compressive strength test were used to determine the composition ratio of the water retentive material. Mechanical performance and cooling effects of WTCC were evaluated by compressive and flexural strength tests and temperature monitoring test. The mass ratios of fly ash, silica fume, cement, and water in the water retentive material were determined as 65:35:15:63.9. The compressive strength and the flexural strength of WTCC after 28 days curing were 30.4 MPa and 4.6 MPa, respectively. Compared with stone mastic asphalt (SMA) mixture, PCC, and water retentive cement concrete (WCC), surface temperature of WTCC decreased by 11.4 °C, 5.5 °C, and 4.1 °C, respectively, and the internal temperatures of WTCC decreased by 10.3 °C, 6.1 °C, and 4.6 °C, respectively. The water retentive material has benefits of strength improvements and temperature reduction for WTCC. Based on the results, WTCC proved to have superior cooling effects and the potential to efficiently mitigate the UHI effects and be used in medium traffic roads.

The aging of the population has led to an annual increase in the incidence of vascular calcification (VC). Specific protein 1 (Sp1) is a transcriptional activator that serves an important role in VC. The deacetylation of transcription factors represses their binding to the promoters of downstream genes, thereby causing their downregulation. The present study aimed to investigate the role of deacetylated Sp1 in the development of VC. In the present study, western blotting and immunoprecipitation (IP) were performed to detect the protein levels of acetylated Sp1. Western blotting and immunofluorescence staining were used to analyze phenotypic switching in vascular smooth muscle cells (VSMCs). Alizarin red S, alkaline phosphatase (ALP) activity and calcium content assays were used to assess calcium deposition in VSMCs. Western blotting, flow cytometry, TUNEL staining and caspase3 activity assay were used to evaluate apoptosis of VSMCs. Chromatin immunoprecipitation (ChIP) assay was used to detect Sp1 binding to the BMP2 promoter. The results indicated that, in a β-glycerophosphate (β-GP)-induced VSMC calcification model, the level of acetylated Sp1 was increased. Western blotting and immunofluorescence staining results showed that, compared with the Sp1 overexpression group (Sp1-WT), deacetylated Sp1 (Sp1-K704A) downregulated the expression of osteogenic markers runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 2 (BMP2), and upregulated the expression of contraction marker α-smooth muscle actin (α-SMA) and calponin 1. In addition, deacetylated Sp1 also reduced the ALP activity and calcium content of calcified VSMCs, and the Alizarin red S assay revealed that the calcium crystallization of Sp1-K704A group was markedly decreased. Western blotting, flow cytometry, TUNEL staining and caspase-3 activity assay were detected to indicate that the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein ratio was increased, and caspase-3 activity and the apoptotic rate of VSMCs were decreased, in the Sp1-K704A group, as compared with the Sp1-WT group. ChIP assay revealed that Sp1 binding to the BMP2 promoter was downregulated in the Sp1-K704A group, compared with that in theSp1-WT group. In conclusion, a deacetylated mutant of Sp1 decreased Sp1 binding to the BMP2 promoter, thus decreasing apoptosis, phenotypic switching and calcium deposition in calcified VSMCs. This finding may indicate potential therapeutic targets for VC.

Different newborn screening (NBS) programs have been practiced in many countries since the 1960s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing (NESTS) program to screen 11,484 babies in eight Women and Children’s hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85% (902/11,484). With 45.89% (414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07% (50/414), estimating an average of 0.95% (7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3,923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period less than 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.

In this study, the effects of virgin aggregate content, such as mineral filler, machine-made sand, and coarse aggregate, on the performance of emulsified asphalt cold recycled mixtures (ECRMs) prod...

Vascular calcification (VC) is a pathological process underpinning major cardiovascular conditions and has attracted public attention due to its high morbidity and mortality. Chronic kidney disease (CKD) is a common disease related to VC. Ginsenoside Rb1 (Rb1) has been reported to protect the cardiovascular system against vascular diseases, yet its role in VC and the underlying mechanisms remain unclear. In this study, we established a CKD‐associated VC rat model and a β‐glycerophosphate (β‐GP)‐induced vascular smooth muscle cell (VSMC) calcification model to investigate the effects of Rb1 on VC. Our results demonstrated that Rb1 ameliorated calcium deposition and VSMC osteogenic transdifferentiation both in vivo and in vitro. Rb1 treatment inhibited the Wnt/β‐catenin pathway by activating peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), and confocal microscopy was used to show that Rb1 inhibited β‐catenin nuclear translocation in VSMCs. Furthermore, SKL2001, an agonist of the Wnt/β‐catenin pathway, compromised the vascular protective effect of Rb1. GW9662, a PPAR‐γ antagonist, reversed Rb1's inhibitory effect on β‐catenin. These results indicate that Rb1 exerted anticalcific properties through PPAR‐γ/Wnt/β‐catenin axis, which provides new insights into the potential theraputics of VC.

The use of sensors to monitor concealed cracks in asphalt pavement has become a research topic of interest. In this paper, piezoelectric aggregates (PAs) were embedded into an asphalt pavement. One was used as an actuator for transmitting a signal, and the other as a sensor for receiving the signal. The coefficient of acoustic wave attenuation a, referring to the amplitude ratio of the excitation signal to receiving signal, decreases as crack width in an asphalt pavement increases, indicating that the application of acoustic waves excited by PA to monitor concealed cracks of asphalt pavement is feasible. The driving frequency imposes obvious influence on the a, which is at its maximum when the driving frequency is 500 Hz. The value of a decreases as asphalt viscosity, nominal maximum particle size and air voids increase, and as asphalt content decreases. Temperature and moisture have obvious influences on wave attenuation, and the value of a increases as temperature and moisture increase. A more universal indicator–average absolute deviation (AAD) was proposed, which is independent of the asphalt mixture properties and grows linearly with the crack width in an asphalt pavement. In practical engineering, the pavement concealed cracks can be monitored by the acoustic saves excited by PA and be calculated by ADD. This study provides a reference for the development and application of intelligent monitoring of concealed damage in asphalt pavements.

To characterize the mechanical-strength growth of cement-stabilized macadam (CSM), the effects of different cement dosages, aggregate types, aggregate gradations, and curing times on the mechanical strength of CSM produced using the vertical-vibration-compaction method (VVCM) are studied. Then, a mechanical-strength-prediction equation and model for VVCM-compacted CSMs are proposed. The mechanical-strength ratio between the VVCM-compacted CSM laboratory specimens and the field cores exceeds 92%. The strength-growth rate of the VVCM-compacted CSM is very high at a curing time within 14 days and tends to be gentle after 28 days, settling eventually after 90 days. The correlation coefficient R2 of the proposed mechanical-strength-growth equation exceeds 0.98; the mechanical strength can be predicted when the cement dosage, aggregate type, and aggregate gradation are known. R2 of the established mechanical-strength-prediction model of CSM is as high as 0.97; thus, when the aggregate types and the mechanical strength at the curing time of 3 days are known, this prediction model can effectively predict the mechanical strength of the CSM with any curing time (T ≥ 3). Empirical on-field data, in comparison with proposed growth equation and prediction model, deviates only slightly, which can facilitate the design and construction of unique CSM bases.

Macrophages play an important role in inflammation and cardiac remodeling in response to myocardial infarction (MI). Earlier shift of inflammtory M1 macrophages to reparative M2 macrophages has demonstrated significant improvements in MI wound modeling and cardiac function. Here, we reported that TSLP could promote M1 to M2 macrophage polarization, and AngII skewed the macrophage phenotype towards M2 by inducing TSLP expression in vitro. Meanwhile, AngII could inhibit the expression of MMP2 and MMP9 in macrophages, which are engaged in ECM degradation and cardiac remodeling. In post-MI mice, TSLP expression were up-regulated in cardiac tissue and serum, probably induced by renin-angiotensin system activation and AngII level up-regulation following MI. Our study mapped the continuum of changes that occured in cardiac macrophages over the first week of MI, and found that rTSLP treatment promoted earlier phenotype shift of M1 to M2 macrophages, improving cardiac healing and ventricular function recovery. Taken together, this work identified a very promising therapeutic opportunity to manage macrophage phenotype and enhance resolution of inflammation in the post-MI heart.

To carry out prenatal diagnosis for a fetus with Pallister-killian syndrome (PKS).The fetus was found to have limb malformations at 23rd gestational week. With informed consent from its parents, amniotic fluid sample was taken from the fetus and subjected to chromosomal karyotyping, chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) assay.G-banding analysis suggested the fetus has a mos47,XY,+mar[55]/46,XY[10] karyotype. CMA analysis of the cultured amniocytes with CytoScan 750K microarray revealed a segmental tetrasomy duplication of 12p13.33p11.1. FISH confirmed a 70% mosaicism of tetrasomy 12p in the metaphase amniocytes with 12pter/12qter probes.Combined use of G-banding karyotyping, CMA and FISH analysis has enabled diagnosis of PKS in the fetus. Although short limb is a common feature of PKS, unequal femur length has not been reported previously, which has expanded the spectrum of PKS-associated limb abnormalities.

The surface energy and bonding coefficient of asphalt are important factors that affect the adhesion performance of asphalt/aggregate. In this study, the micro-bee-like-structure of asphalt and force curves between the microscope-probe and asphalt were measured via atomic force microscopy (AFM). To investigate the influence of asphalt properties on micro-adhesion of asphalt, five types of asphalt were used in four states: original, aged at 163 &deg, C, immersed in water and added anti-stripping agent. The results demonstrate that the surface energy of grade 90 asphalt is greater than that of grade 70 asphalt when oil source is the same and that of modified asphalt is greater than matrix asphalt. The surface energies and bonding coefficients of asphalts decreased after aging and immersion. The surface energies of asphalts were greatly improved by adding anti-stripping agent and the bonding coefficients of the asphalts increased by 5.04&ndash, 37.14% after adding an anti-stripping agent.

Because of the large amount of gravel with particle sizes over 40 mm in the soil-rock mixture (SRM), it is impossible to determine its California Bearing Ratio (CBR) via the indoor test method, which is a key parameter for designing the backfill in underground mined cavities or the road subgrade constructed with SRM. In this paper, X-ray computed tomography (CT) scanning and 3D reconstruction technology were used to construct the 3D structure of SRM particles with a particle size greater than 5 mm. Based on the vertical vibration test method (VVTM) and PFC3D, the numerical simulation method (NSM-CBR) of SRM was established. The CBR of the SRM with a maximum particle size over 40 mm (SRM-G) was studied by NSM-CBR, and the effects of factors such as maximum particle size, soil content, and large-size particle content (d ≥ 40 mm) on the CBR were investigated via NSM-CBR. Based on the laboratory tests and NSM-CBR, the prediction model and the determining method of CBR of SRM-G were established and verified. The results show that the maximum deviation between the CBR obtained from NSM-CBR and laboratory tests was 7.4%. The CBR of SRM-G decreases linearly with the increase in soil content and increases with the increase in maximum particle size and large-size particle content. The practical project shows that the maximum deviation between the predictive and measured values of the CBR of SRM-G was less than 1.5%, indicating that the prediction model and the method established in this paper have high reliability.

The fatigue performance of Solution Road RomixSoilfix (SRX)-stabilized crushed rock material (SRX-CRM) has rarely been studied. This study investigated the fatigue performance of SRX-CRM ob...

The interlocking force of aggregates, which is closely related to mixture gradation, is one of the main factors that influence the shear strength and rutting resistance of an asphalt mixture. Grada...

Ginsenoside 20(R/S)‐Rg3, as a natural peroxisome proliferator‐activated receptor gamma (PPARγ) ligand, has been reported to exhibit differential biological effects. It is of great interest to understand the stereochemical selectivity of 20(R/S)‐Rg3 and explore whether differential PPARγ activation by Rg3 stereoisomers, if it exists, could lead to differential physiological outcome and therapeutic effects in diabetic atherosclerosis. Here, we investigated the binding modes of 20(R/S)‐Rg3 stereoisomers in the PPARγ ligand‐binding domain (PPARγ‐LBD) using molecular modelling and their effects on smooth muscle cell proliferation and migration induced by advanced glycation end products (AGEs). The results revealed that 20(S)‐Rg3 exhibited stronger antiproliferative and antimigratory effects due to stronger PPARγ activation. To validate the in vitro results, we used a mice model with diabetic atherosclerosis and obtained that 20(S)‐Rg3 markedly reduced the plaque size secondary to reducing the proliferation and migration of VSMCs, while the plaques were more stable due to improvements in other plaque compositions. The results shed light on the structural difference between Rg3 stereoisomers that can lead to significant differential physiological outcome, and the (S)‐isomer seems to be the more potent isomer to be developed as a promising drug for diabetic atherosclerosis.

This paper presents a comparison of the properties of cement-stabilised gravel (CSG) prepared in laboratory by the static pressuring compaction method (SPCM) and the vibration compaction method (VC...

Aims Cardiac pressure and humoral factors induce cardiac hypertrophy and fibrosis, which are characterized by increased stiffness, reduced contractility and altered perfusion. Angiotensin II (AngII) is well known to promote this pathology. Angiotensin-converting enzyme (ACE) 2, which cleaves AngII and forms Ang-(1–7), exerts protective anti-hypertrophy and anti-fibrosis effects. A disintegrin and metalloproteinase 17 (ADAM17), a membrane-bound enzyme reported to cleave ACE2, may participate in the pathological process of AngII perfusion-induced heart damage. However, researchers have not clearly determined whether dickkopf-3 (DKK3) regulates the ADAM17/ACE2 pathway and, if so, whether DKK3-mediated regulation is related to the glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway. In this study, we explored whether DKK3 overexpression ameliorates the development of AngII-induced cardiac fibrosis and hypertrophy through the ADAM17/ACE2 and GSK-3β/β-catenin pathways. Methods Mice were injected with a DKK3-overexpressing adenovirus or vehicle and then infused with AngII or saline using subcutaneously implanted mini-pumps for four weeks. Hearts were stained with hematoxylin-eosin, Masson's trichrome and immunohistochemical markers for histology. Primary fibroblasts were treated with the adenovirus and AngII and then examined using western blotting, EdU (5-ethynyl-2′-deoxyuridine) assays and immunofluorescence. Additionally, siRNA silencing was performed to study the role of DKK3 and the involved pathways. Results AngII-induced cardiac hypertrophy and interstitial and perivascular fibrosis were less severe in DKK3-overexpressing mice than in control mice. Moreover, the expression levels of fibrotic genes, such as collagen I and III, and the hypertrophic genes atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC) were decreased. DKK3 overexpression also exerted a protective effect by inhibiting ADAM17 phosphorylation, thus increasing ACE2 expression and subsequently promoting AngII degradation. Furthermore, this process was mediated by the inhibition of GSK-3β and β-catenin and decreased translocation of β-catenin to the nucleus. On the other hand, the DKK3 knockdown by siRNA achieved opposite results. Conclusion DKK3 overexpression substantially alleviated AngII infusion-induced cardiac hypertrophy and fibrosis by regulating ADAM17/ACE2 pathway activity and inhibiting the GSK-3β/β-catenin pathway.

Human papillomavirus (HPV) is one of the most common sexually transmitted infectious pathogens. Persistent infection has been linked to cancer development, in particular to cervical cancer. This study aims to investigate the epidemiology of HPV infection in women in Inner Mongolia of China and to dissect the disparities between the Han and Mongolian ethnic populations. Cervical cell samples from 5655 women (17-68 years old) were collected during routine gynecologic examination. HPV infection was established using the HPV GenoArray kit detecting 21 HPV genotypes. The overall HPV prevalence was 14.5%. HPV16 (5.0%), HPV58 (2.2%), and HPV52 (1.5%) are the most common genotypes. Of the 21 genotypes investigated, high-risk HPV genotypes dominate in all age groups. HPV16 and HPV58 are the most common genotypes in patients with cervical lesions. HPV prevalence among Han women is 11.5% and the most common genotypes are HPV16 (4%) and HPV58 (2.1%). HPV prevalence is significantly higher in Mongolian women (32.6%), with the most common genotypes being HPV16 (10.7%), HPV31 (7.1%), and HPV52 (4.3%). The multiple infection rate in Mongolian participants (14.9%) is also higher than that of Han participants (4.3%). Urbanization, the number of sex partners, and PAP history appear as risk factors for HPV infection in Han, but not in Mongolian participants. HPV infection is highly prevalent in women in Inner Mongolia, China. HPV16 remains the most common genotype in this area. However, there are clear ethnical disparities in respect to the HPV epidemiology between the Han and Mongolian population.

The surface morphology of aggregates has a significant effect on the aggregates, which in turn affects the technical performance of asphalt mixtures and cement concrete. In this study, the surface micro-morphology (SMM) of a) four typical natural aggregates, b) recycled concrete aggregate (RCA), and c) recycled brick aggregate (RCB) were investigated using laser scanning confocal microscope, and combined with image analysis technology, roughness theory and fractal theory for quantitative evaluation. Limewater immersion and physical abrasion were performed on each aggregate to investigate the effect of these processes on SMM. Results show that the surface micro-roughness and fractal dimensions of different aggregates varied predictably with the formation conditions of aggregates. After being immersed in limewater, the surface micro-roughness of basalt, limestone and diabase increased, but their fractal dimensions did not change, while the surface micro-roughness of granite, RCA and RCB decreased by 20–30%, and their fractal dimensions increased by 0.65.%, 1.69% and 0.43%, respectively. The effect of physical abrasion on the SMM of aggregates was related to the hardness of the aggregates. After physical abrasion, the surface micro-roughness and fractal dimensions of the six aggregates were reduced.

In this study, the micromechanical properties of aggregates, including the surface energy, nanohardness, and elastic modulus, were investigated using an atomic force microscope (AFM). The Surface energy was quantitatively evaluated by applying a surface energy model, whereas the surface nanohardness and elastic modulus were quantitatively evaluated using the contact-mechanics model. Further, the effects of the aggregate chemical composition and limewater treatment on the surface micromechanics were explored. Four natural aggregates, one recycled concrete aggregate (RCA), and one recycled brick aggregate (RCB) were used for the experiments, for every aggregate, we investigated two states, the original state and that after the limewater treatment. Results showed that the alkaline components (Al2O3 and CaO) on the surface of the aggregate have a positive effect on surface energy, whereas the acidic component (SiO2) has a negative effect. The difference in aggregate composition results in the surface energy of the original basalt, limestone, and diabase being three to four times those of the original granite, RCA, and RCB, respectively. Therefore, after limewater treatment, the surface energies of basalt, diabase, granite, and RCA increased by 18.20%, 12.73%, 71.61%, and 95.45%, respectively, whereas those of limestone and RCB decreased by 10.06% and 8.56%, respectively. The increase in SiO2, Al2O3, and CaO contents have a positive effect on nanohardness and a negative effect on elastic modulus. After limewater treatment, the nanohardness of limestone was found to have increased, whereas those of the remaining five aggregates (basalt, diabase, granite, RCA, and RCB) had decreased. The CaCO3 attached to the aggregate surface, causing the nanohardness (1.5–7.0 GPa) and elastic modulus (21–32 GPa) of the six aggregates to approach each other.

Microcapsules for asphalt pavement containing asphalt rejuvenator as the core material were prepared via interfacial polymerization using high-speed shearing. Isophorone di-isocyanate (IPDI) and distilled water were used as the reaction monomers of the oil and water phases, respectively. Polyvinyl alcohol (PVA) was used as an emulsifier. The preparation process was optimized based on the type and concentration of the emulsifier, shearing speed, shell-core ratio, and reaction temperature. The technical properties of the asphalt pavement microcapsules prepared via the optimal preparation process were evaluated by Fourier transform infrared spectroscopy (FT-IR), Scanning electron microscopy (SEM), laser particle size analyzer, and Thermogravimetric analysis (TGA) from the aspects of micromorphology, particle size, shell thickness, and thermal stability. Results showed that PVA possesses satisfactory emulsifying and shell-forming properties, which made it a suitable emulsifier in the oil phase. The optimized conditions of the microcapsule preparation are as follows: the concentration of the emulsifier solution was 0.4%, the shearing speed was 5000 RPM, the shell-core ratio was 0.6, and the range of reaction temperature was 60–70 °C. The diameter of the optimal microcapsules was primarily distributed between 10 and 17 µm. Furthermore, the average particle size was 14.26 µm; the microcapsule shell thickness was relatively uniform (2–3 µm). The results of FT-IR and TGA demonstrated that the asphalt pavement microcapsules maintain good chemical and quality stability at high temperature, indicating that the microcapsules can withstand the high temperature during the asphalt-mixture production process. The results of salt tolerance test showed that microcapsules have certain salt tolerance. The mean elastic modulus and hardness of microcapsules were 466.86 MPa and 56.27 MPa, respectively obtained by nano indentation test.

Peroxisome proliferator-activated receptors alpha (PPARα) is a therapy target in atherosclerosis and cardiovascular diseases. However, anti-inflammatory effects of PPARα in intracerebral hemorrhage (ICH) remain unknown. We investigated the anti-inflammatory effects of fenofibrate, a ligand of PPARα, in ICH rat model. We found that engagement of fenofibrate increased nissl body and astrocytes, and reduced the neuronal damage, which was observed in paraffin section of ICH rat brain. Fenofibrate also promoted the proliferation of astrocytes that were isolated from adult rat brain. Fenofibrate significantly upregulated heme oxygenase 1 (HO-1) at protein and mRNA levels in human glioblastoma LN-18 cells and rat brain astrocytes respectively, but nuclear factor kappalight- chain-enhancer of activated B cells (NFκB) was downregulated after fenofibrate treatment. Results showed that fenofibrate-induced upregulation of HO-1 expression were inhibited after LN-18 cells were transfected with 50nM small interfering RNA (siRNAs) for 48 hours to knockdown PPARα. Further studies in rat astrocytes confirmed the rescue effects of PPARα silence against fenofibrate induced upregulation of HO-1 expression. Our data indicated that fenofibrate benefits neuronal protection through increasing HO-1 expression level and decreasing NFκB expression in PPARα-dependent manner. In conclusion, PPARα and HO-1 may function as significant targets to protect the brain during ICH.

Additional file 2. The patients' consent.

The purpose is to realize the environmental friendliness and sustainability of pavement active deicing and snow melting. Different types of SBS modified asphalt conductive bonding materials for pavement interlayer bonding and melting ice and snow were prepared. The effects of conductive phase materials, electrodes and spacing on the conductivity and heat generation of conductive bonding layer were studied. The heating effect of SBS modified asphalt conductive bonding layer in pavement structure was analyzed. The feasibility of converting electric energy into heat energy by conductive bonding layer to realize melting ice and snow on pavement was verified. It provides a new direction for the research and application of green active deicing and snow melting. The results show that the carbon fiber conductive bonding layer had the best conductivity. At the constant temperature of −5 °C, the surface temperature of the pavement structure could reach above 0 °C after the conductive bonding layer was electrified for 100 min under 36 V voltage, which can realize the deicing and snow melting of the pavement. The distribution of carbon fiber has a certain adverse effect on the bonding performance of conductive bonding layers, but it still shows good bonding performance, water resistance and temperature change resistance.

The micro- and nano-surface properties of asphalt obviously affect the macro-bonding of asphalt and with aggregates, which is influenced by aging. In this study, the surface morphology and force curves of two asphalts for different degrees of aging (matrix asphalt and SBS modified asphalt) and macro-bonding with the mineral aggregate were measured. Moreover, the micro-nano surface morphology and surface energy were quantitatively evaluated. Furthermore, the micro-nano surface properties of asphalt and the macro-bonding were correlated. Then the evolution mechanisms of asphalt adhesion with aging were revealed by gray correlation analysis on the nano, micro and macro scales. The results showed that the number of microscopic bee-like structures and the nano-roughness of asphalt increased initially and then decreased, the area and maximum length of microscopic bee-like structures, micro-surface energy gradually decreased as the aging time prolongs. Macro-bonding of asphalt with mineral aggregate gradually decreased. The results of grey correlation analysis showed that the attenuation of micro-surface energy caused by aging is the main factor to reduce the value of macro-bonding, further indicating that the main reason for the bonding failure of aged asphalt with aggregate is the weakening of interface chemisorption. The results will provide a good reference for understanding the multi-scale evolution of asphalt performance with aging.

Investigating the movements of aggregates is important for understanding the rutting mechanism and improving the rutting resistance of asphalt mixtures. X-ray computed tomography (CT) was used to obtain the microstructural change of asphalt mixtures before and after asphalt pavement analyzer (APA) testing. A particle tracking technology was developed to track the movement of aggregates during the APA test based on X-ray CT images. Six indicators were proposed to quantitatively describe the downward, upward, and transverse movements of aggregates based on their displacement vectors. The relationships between rutting and aggregate movements were investigated, and the maximum vertically downward displacement along with the average transverse displacement can be used to predict the downward rutting. The maximum vertically upward displacement, the average vertically upward displacement and the average transverse displacement can be used to predict humps. The results indicate that downward rutting is caused by the downward and transverse movements of aggregates and humping is caused by the upward and transverse movements of aggregates. Asphalt mixture types, asphalt properties and gradation have a significant influence on the movement of aggregates, and they greatly affect the downward movement. Polymer-modified asphalt, medium gradation, and small nominal maximum aggregate sizes can be used to improve the rutting resistance of asphalt mixtures.

Proprotein convertase-subtilisin/kexin type 9 (PCSK9) monoclonal antibody is a new therapy to reduce low-density lipoprotein cholesterol (LDL-C) level in patients with familial hypercholesterolemia (FH). This pooled analysis aimed to estimate the efficacy and safety of PCSK9 antibody therapy in FH. Reports of randomized controlled trials (RCTs) comparing PCSK9 antibody to placebo were retrieved by a search of MEDLINE via PubMed, EMBASE, the Cochrane Library databases, ClinicalTrials.gov and Clinical Trial Results (up to November 30, 2015) with no language restriction. Data were abstracted by a standardized protocol. We found eight RCTs (1,879 patients with FH) for the pooled analysis. As compared with placebo, PCSK9 antibody therapy remarkably reduced LDL-C level (mean reduction: -48.54 %, 95 % CI: -53.19 to -43.88), total cholesterol (mean reduction: -31.08%, 95 % CI: -35.20 to -26.95), lipoprotein (a) (mean reduction: -20.44%, 95 % CI: -25.21 to -15.66), and apolipoprotein B (mean reduction: -36.32%, 95 % CI: -40.75 to -31.90) and elevated the level of high-density lipoprotein cholesterol (mean change: 6.29 %, 95 % CI: 5.12 to 7.46) and apolipoprotein A1(mean change: 4.86%, 95 % CI: 3.77 to 5.95). Therapy with and without PCSK9 antibodies did not differ in rate of adverse events (pooled rate: 50.86 % vs. 48.63%; RR: 1.03; 95 % CI: 0.92 to 1.15; P = 0.64; heterogeneity P = 0.13; I2= 40%) or serious adverse events (pooled rate: 7.14% vs. 6.74%; RR: 1.05; 95 % CI: 0.70 to 1.58; P = 0.80; heterogeneity P = 0.69; I2= 0%). PCSK9 antibody may be an effective and safe treatment for FH.

// Qin Hu 1 , Qiji Liu 2 , Shasha Wang 1 , Xi Zhen 1 , Zhimian Zhang 3 , Ruijuan Lv 4 , Guihua Jiang 1 , Zhiyong Ma 1 , Hong He 1 , Daqing Li 1 , Xiaoling Liu 1 , Fei Gao 1 , Jifu Li 1 , Li Li 1 , Mei Zhang 1 , Xiaoping Ji 1 , Yuguo Chen 4 , Daowen Wang 5 , Dejia Huang 6 , Aiqun Ma 7 , Wei Huang 8 , Yuxia Zhao 1 , Yaoqin Gong 2 , Cheng Zhang 1 and Yun Zhang 1 1 Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China 2 Department of Medical Genetics, School of Medicine, Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University, Jinan, Shandong, China 3 Medical Examination Center, Shandong University Qilu Hospital, Jinan, Shandong, China 4 Department of Emergency, Shandong University Qilu Hospital, Jinan, Shandong, China 5 Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China 6 Division of Cardiology, Department of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China 7 Department of Cardiology and Periphery Vascular Medicine, The First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, Shaanxi, China 8 Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Department of Genetics, Chinese National Human Genome Center, Shanghai, China Correspondence to: Cheng Zhang, email: // Yun Zhang, email: // Keywords : natriuretic peptide receptor C, coronary artery disease, genome-wide association studies, single nucleotide polymorphisms, susceptibility gene, Pathology Section Received : November 24, 2015 Accepted : May 04, 2016 Published : May 13, 2016 Abstract To find a new locus that confers significant susceptibility to CAD in Chinese Han population, a genome-wide association study in 200 “extreme individuals” from a Shandong cohort and a pathway-based candidate gene study from a Shanghai cohort (293 CAD/293 controls) were simultaneously performed. Amongst them, 13 SNPs associated with CAD were selected to conduct validation and replication studies in additional 3363 CAD patients and 3148 controls. A novel locus rs700926 in natriuretic peptide receptor C (NPR-C) was identified in Shandong and Hubei cohorts. Then rs700926 and other nine tag SNPs were genotyped in four geographically different populations (Shandong, Shaanxi, Hubei and Sichuan cohorts), and 6 SNPs (rs700926, rs1833529, rs2270915, rs17541471, rs3792758 and rs696831) showed stronger association with CAD, regardless of single or combined analysis. We further genotyped rs2270915 and 10 additional tag SNPs in a central China cohort and identified rs12697273 and rs10066436 as the loci associated with CAD. All these positive associations remained significant after adjustment for traditional risk factors of CAD. NPR-C gene SNPs significantly contribute to CAD susceptibility in the Chinese Han population.

Objective To review possible associations reported between genetic variants and the risk, therapeutic response and prognosis of heart failure. Methods Electronic databases (PubMed, Web of Science and CNKI) were systematically searched for relevant papers, published between January 1995 and February 2015. Results Eighty-two articles covering 29 genes and 39 polymorphisms were identified. Conclusion Genetic association studies of heart failure have been highly controversial. There may be interaction or synergism of several genetic variants that together result in the ultimate pathological phenotype for heart failure.