High-speed AFM imaging reveals DNA capture and loop extrusion dynamics by cohesin-NIPBL.

3D chromatin organization plays a critical role in regulating gene expression, DNA replication, recombination, and repair. While initially discovered for its role in sister chromatid cohesion, emerging evidence suggests that the cohesin complex (SMC1, SMC3, RAD21, and SA1/SA2), facilitated by NIPBL, mediates topologically associating domains and chromatin loops through DNA loop extrusion. However, information on how conformational changes of cohesin-NIPBL drive its loading onto DNA, initiation, and growth of DNA loops is still lacking. In this study, high-speed atomic force microscopy imaging reveals that cohesin-NIPBL captures DNA through arm extension, assisted by feet (shorter protrusions), and followed by transfer of DNA to its lower compartment (SMC heads, RAD21, SA1, and NIPBL). While binding at the lower compartment, arm extension leads to the capture of a second DNA segment and the initiation of a DNA loop that is independent of ATP hydrolysis. The feet are likely contributed by the C-terminal domains of SA1 and NIPBL and can transiently bind to DNA to facilitate the loading of the cohesin complex onto DNA. Furthermore, high-speed atomic force microscopy imaging reveals distinct forward and reverse DNA loop extrusion steps by cohesin-NIPBL. These results advance our understanding of cohesin by establishing direct experimental evidence for a multistep DNA-binding mechanism mediated by dynamic protein conformational changes.

In vitro and in vivo antiproliferative activity on lung cancer of two acylhydrazone based zinc(II) complexes.

Two acylhydrazone based zinc(II) complexes [Zn(HL)2Cl2(CH3OH)2] (Zn1) and [ZnL(AC)]2 (Zn2) were synthesized from 3-(1-(salicyloylhydrazono)ethyl) pyridine (HL). Single crystal X-ray structure analyses showed that complexes Zn1 and Zn2 have a zero-dimensional monomer or dimer structure. Antiproliferative activity studies revealed that Zn1 and Zn2 are both more effective against A549 cells than cisplatin. The results of the reactive oxygen species (ROS) generation assay on A549 cells showed that both Zn1 and Zn2 induced apoptosis through ROS accumulation. The apoptosis-inducing and cell cycle arrest effects of Zn1 and Zn2 on A549 cells indicated that the antitumor effect was achieved through apoptosis induction and inhibition of DNA synthesis by blocking the G0/G1 phase of the cell cycle. What's more, the results of wound-healing assay showed that Zn1 and Zn2 could inhibit the migration of A549 cells. Western blot analysis further demonstrated that Zn1 and Zn2 induced cell apoptosis through the mitochondrial pathway, in which process, the expression level of cytochrome C, cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 proteins increased while pro-caspase 3 and pro-caspase 9 expression decreased. In vivo anticancer evaluation demonstrated that both Zn1 and Zn2 complexes effectively inhibited tumor growth without causing significant toxicity in systemic organs.

The Sialyl Lewis X Glycan Receptor Facilitates Infection of Subtype H7 Avian Influenza A Viruses.

Subtype H7 avian influenza A viruses (IAVs) are enzootic in wild aquatic birds and have caused sporadic spillovers into domestic poultry and humans. Here, we determined the distribution of fucosylated α2,3 sialoglycan (i.e., sialyl Lewis X [SLeX]) in chickens and five common dabbling duck species and the association between SLeX and cell/tissue/host tropisms of H7 IAVs. Receptor binding analyses showed that H7 IAVs bind to both α2,3-linked (SA2,3Gal) and α2,6-linked sialic acids (SA2,6Gal), but with a higher preference for SLeX; H7 IAVs replicated more efficiently in SLeX-overexpressed than SLeX-deficient MDCK cells. While chickens and all tested dabbling ducks expressed abundant SA2,3Gal and SA2,6Gal, SLeX was detected in both respiratory and gastrointestinal tissues of chickens and mallard ducks and in only the respiratory tissues of gadwall, green-wing teal, and northern shoveler but not in wood ducks. Viral-tissue binding assays showed that H7 IAVs bind to chicken colon crypt cells that express SLeX but fewer bind to mallard colon crypt cells, which do not express SLeX; H7 IAVs bind efficiently to epithelial cells of all tissues expressing SA2,3Gal. High viral replication was identified in both chickens and mallards infected with an H7 virus, regardless of SLeX expression, and viruses were detected in all cells to the same degree as viruses detected in the viral-tissue binding assays. In summary, this study suggests that SLeX facilitates infection of H7 viruses, but other types of SA2,3Gal glycan receptors shape the tissue/host tropisms of H7 IAVs. IMPORTANCE In addition to causing outbreaks in domestic poultry, subtype H7 IAVs can cause sporadic spillover infections in lower mammals and humans. In this study, we showed that SLeX expression varies among wild dabbling ducks. Although it facilitated virus binding and affected infection of H7 IAV in cells, SLeX expression is not the only determinant of viral replication at either the tissue or host level. This study suggested that access to heterologous SA2,3Gal glycan receptors, including fucosylated α2,3-linked sialoglycans, shape tissue and host tropism of H7 IAVs in aquatic wild birds.

Quantitation of Ten Urinary Nicotine Metabolites, Including 4-Hydroxy-4-(3-pyridyl) Butanoic Acid, a Product of Nicotine 2'-Oxidation, and CYP2A6 Activity in Japanese Americans, Native Hawaiians, and Whites.

Smoking intensity varies across smokers and is influenced by individual variability in the metabolism of nicotine, the major addictive agent in tobacco. Therefore, lung cancer risk, which varies by racial ethnic group, is influenced by the primary catalyst of nicotine metabolism, cytochrome P450 2A6 (CYP2A6). In smokers, CYP2A6 catalyzes nicotine 5'-oxidation. In vitro, CYP2A6 also catalyzes, to a much lower extent, 2'-oxidation, which leads to the formation of 4-hydroxy-4-(3-pyridyl) butanoic acid (hydroxy acid). The urinary concentration of hydroxy acid has been quantified in only a few small studies of White smokers. To quantitatively assess the importance of nicotine 2'-oxidation in smokers, an LC-MS/MS-based method was developed for the analysis of nicotine and ten metabolites in urine. The concentrations of nicotine and these metabolites were measured in 303 smokers (99 Whites, 99 Native Hawaiians, and 105 Japanese Americans), and the relative metabolism of nicotine by four pathways was determined. Metabolism by these pathways was also compared across quartiles of CYP2A6 activity (measured as the plasma ratio of 3-hydroxycotinine to cotinine). As reported previously and consistent with their average CYP2A6 activity, nicotine 5'-oxidation was highest in Whites and lowest in Japanese Americans. Nicotine N-glucuronidation and N-oxidation increased with decreasing CYP2A6 activity. However, the relative urinary concentration of hydroxy acid (mean, 2.3%; 95% CI, 2.2-2.4%) did not vary by ethnic group or by CYP2A6 activity. In summary, CYP2A6 is not an important catalyst of nicotine 2'-oxidation in smokers, nor does nicotine 2'-oxidation compensate for decreased CYP2A6 activity.

Floquet Engineering Hz-Level Rabi Spectra in Shallow Optical Lattice Clock.

Quantum metrology with ultrahigh precision usually requires atoms prepared in an ultrastable environment with well-defined quantum states. Thus, in optical lattice clock systems deep lattice potentials are used to trap ultracold atoms. However, decoherence, induced by Raman scattering and higher order light shifts, can significantly be reduced if atomic clocks are realized in shallow optical lattices. On the other hand, in such lattices, tunneling among different sites can cause additional dephasing and strongly broadening of the Rabi spectrum. Here, in our experiment, we periodically drive a shallow ^{87}Sr optical lattice clock. Counterintuitively, shaking the system can deform the wide broad spectral line into a sharp peak with 5.4 Hz linewidth. With careful comparison between the theory and experiment, we demonstrate that the Rabi frequency and the Bloch bands can be tuned, simultaneously and independently. Our work not only provides a different idea for quantum metrology, such as building shallow optical lattice clock in outer space, but also paves the way for quantum simulation of new phases of matter by engineering exotic spin orbit couplings.

Doubly Modulated Optical Lattice Clock: Interference and Topology.

The quantum system under periodical modulation is the simplest path to understand the quantum nonequilibrium system because it can be well described by the effective static Floquet Hamiltonian. Under the stroboscopic measurement, the initial phase is usually irrelevant. However, if two uncorrelated parameters are modulated, their relative phase cannot be gauged out so that the physics can be dramatically changed. Here, we simultaneously modulate the frequency of the lattice laser and the Rabi frequency in an optical lattice clock (OLC) system. Thanks to the ultrahigh precision and ultrastability of the OLC, the relative phase could be fine-tuned. As a smoking gun, we observed the interference between two Floquet channels. Finally, by experimentally detecting the eigenenergies, we demonstrate the relation between the effective Floquet Hamiltonian and the one-dimensional topological insulator with a high winding number. Our experiment not only provides a direction for detecting the phase effect but also paves a way in simulating the quantum topological phase in the OLC platform.

[Effects of interleukin-17 antibody on polarization of macrophages in adipose tissue of high-fat diet fed mice exposed to bisphenol A].

OBJECTIVE: To investigate the effects of interleukin-17(IL-17) antibody on polarization of adipose tissue macrophages(ATM) in mice fed with high-fat diet(HFD) exposed to bisphenol A(BPA). METHODS: Four week-old male C57 BL/6 mice were divided into control group, IgG group, IL-17 antibody group, 1000 nmol/L BPA group, 1000 nmol/L BPA+IgG group, and 1000 nmol/L BPA+IL-17 antibody group according to random number table method. Eight mice per group were fed with HFD and BPA was exposed by drinking water. The IgG group and the 1000 nmol/L BPA+IgG group were intraperitoneally injected with 100 µg IgG antibody once a week, and the IL-17 group and the 1000 nmol/L BPA+IL-17 antibody group were intraperitoneally injected with 100 µg IL-17 antibody once a week. After 16 weeks, the mice were sacrificed, and serum samples were collected for serum separation. Leptin level was measured by enzyme-linked immunosorbent assay(ELISA). The expression of IL-1ß, IL-6 and monocyte chemoattractant protein-1(MCP-1)inflammatory cytokines were observed by immunohistochemistry(IHC) of adipose tissue of epididymis. The activity of inducible nitric oxide synthase(iNOS)and arginase-1(Arg-1)was measured by ELISA, and the proportion of M1 and M2 ATMs was measured by flow cytometry(FCM). The expression of CD11 c and CD206 mRNA was measured by qRT-PCR. RESULTS: Compared with the control group, serum leptin, the expressions of inflammatory cytokines IL-6, IL-1ß and MCP-1 in adipose tissue were increased in 1000 nmol/L BPA group, the proportion of M1 type ATM was increased(22.000%±0.500% vs. 31.467%±0.379%), iNOS activity was increased, CD11 c mRNA expression was increased, Arg-1 activity was decreased, CD206 mRNA expression was decreased, the differences were statistically significant(P<0.05), but the proportion of M2 type ATM was decreased insignificantly(P>0.05). There was no significant change in IgG group. Compared with 1000 nmol/L BPA group, IgG+1000 nmol/L BPA group had no significant change. In 1000 nmol/L BPA+IL-17 antibody group, serum leptin was decreased, the expressions of inflammatory factors IL-6, IL-1ß and MCP-1 in adipose tissue were down-regulated, and the proportion of M1 type ATM was decreased(31.467%±0.379% vs. 22.933%±0.153%), iNOS activity was decreased, CD11 c mRNA expression was decreased, and the proportion of M2 type ATM was increased(4.847%±0.655% vs. 7.840%±0.555%), Arg-1 activity was enhanced, and CD206 mRNA expression was up-regulated, the differences were statistically significant(P<0.05). CONCLUSION: IL-17 antibody may reduce the secretion of ATM inflammatory factors by inhibiting the polarization of ATM to M1 type, thus improving the inflammation of adipose tissue in BPA-infected HFD-fed mice.

[Human factors engineering of brain-computer interface and its applications: Human-centered brain-computer interface design and evaluation methodology].

Brain-computer interface (BCI) is a revolutionizing human-computer Interaction, which is developing towards the direction of intelligent brain-computer interaction and brain-computer intelligent integration. However, the practical application of BCI is facing great challenges. The maturity of BCI technology has not yet reached the needs of users. The traditional design method of BCI needs to be improved. It is necessary to pay attention to BCI human factors engineering, which plays an important role in narrowing the gap between research and practical application, but it has not attracted enough attention and has not been specifically discussed in depth. Aiming at BCI human factors engineering, this article expounds the design requirements (from users), design ideas, objectives and methods, as well as evaluation indexes of BCI with the human-centred-design. BCI human factors engineering is expected to make BCI system design under different use conditions more in line with human characteristics, abilities and needs, improve the user satisfaction of BCI system, enhance the user experience of BCI system, improve the intelligence of BCI, and make BCI move towards practical application.

Feeding on tea GH19 chitinase enhances tea defense responses induced by regurgitant derived from Ectropis grisescens.

Multiple isoforms of chitinases participate in plant defense against outside invaders. However, the functions of hydrolase family 19 (GH19) chitinases on pest control remain largely unknown. Here we reported the isolation and functional analysis of a gene CsChi19, which encodes a GH19 endochitinase protein of 332 amino acid residues from tea plant (Camellia sinensis). CsChi19 expression levels were upregulated in response to mechanical wounding, infestation by two important pests: the tea geometrid Ectropis grisescens and the tea green leafhopper Empoasca (Matsumurasca) onukii, a fungal pathogen Colletotrichum fructicola, and treatment with two phytohormones: jasmonic acid (JA) and salicylic acid. CsChi19 was heterologously expressed in Escherichia coli, and its catalytic function was further elucidated. The protein could hydrolyze colloidal chitin, and the optimum temperature and pH for its activity was 40°C and pH 5.0. CsChi19 were found to be toxic to tea pests when they were fed on artificial diets containing this protein. Interestingly, the regurgitant derived from E. grisescens fed with artificial diets containing CsChi19 protein induced stronger expression of CsMPK3, more JA burst, more accumulation of defense-related secondary metabolites, and more emission of volatiles than the regurgitant derived from E. grisescens fed only with artificial diets. Our results provide first evidence that CsChi19 is involved in mediating a novel defense mechanism of tea plant through altering the composition of the regurgitant.

Changes in Peripheral Blood Neutrophils, Lymphocytes and IL-10 in Children with Kawasaki Disease from Different Age Groups Undergoing Intravenous Immunoglobulin: A Retrospective Study.

Immunoglobulin intravenous (IVIG) is widely used in mucocutaneous lymph node syndrome, known as Kawasaki disease (KD). However, the patients' inflammatory response during usage remains unclear. In the present study, the association between inflammatory response and lymphocyte count in children with KD from different ages was evaluated before and after IVIG. The medical records of 50 children with KD were retrospectively reviewed and divided into five groups according to age. As compared with the data from healthy children, the relative neutrophil count of all children with KD was increased, and that of lymphocytes was decreased. The neutrophil/lymphocyte ratio (NLR) was different among all groups and was higher in children aged ≥4 years, as compared with other groups. Following IVIG, the relative neutrophil and lymphocyte counts of all children with KD returned to normal levels. The altered levels of neutrophils and lymphocytes were found to be linearly correlated. The correlation coefficient in the five groups was 0.99, 0.87, 0.91, 0.97 and 0.99, from young to old, respectively (p < 0.01). The age of children with KD was positively correlated with older age (r = 0.91, p = 0.03). In patients aged ≥4 years, the absolute CD19+ B cell count prior to IVIG increased, and that increase was linearly correlated with the decrease in interleukin-10 (IL-10) following IVIG (r = 0.71, p < 0.05). The older the child's age, the better the regulatory effect of IVIG on the KD child's immune response and the recovery of immune equilibrium it achieved. In KD patients aged ≥4 years, the abnormally proliferating CD19+ B cells may be involved in the secretion of IL-10 to balance the humoral immunity. In such patients, the combination of the absolute CD19+ B cell count prior to IVIG and the decreased levels of IL-10 following IVIG may play a crucial role in evaluating the effect of IVIG in the inflammation.

[The role of GSK3ß in adipose tissue inflammation induced by bisphenol-A in high fat diet fed mice].

OBJECTIVE: To study the effect of glycogen synthase kinase 3ß(GSK3ß) in BPA-induced adipose tissue inflammation in high fat diet(HFD) fed mice. METHODS: Four-week-old male C57 BL/6 mice were randomly divided into normal diet(ND) group, HFD group, HFD + GSK3ß inhibitor group, HFD + 1000 nmol/L BPA group, HFD+1000 nmol/L BPA+GSK3ß inhibitor group. The mice were exposed to BPA via drinking water. From the 14 th week of BPA exposure to the end of 16 weeks, the GSK3ß inhibitor group was intraperitoneally injected with 21. 5 mg/kg lithium chloride(Li Cl) every two days for a total of 10 times. At the end of 16 weeks, the mice were sacrificed after anesthesia, and the epididymal fat tissue was taken aseptically. The pathological changes were observed by H&E staining. The expressions of interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) were detected by immunohistochemistry(IHC). The expression of GSK3ß protein and its S9 serine(GSK3ß-S9) phosphorylation were detected by western blot. RESULTS: Compared with the ND group, the body weight [(34. 97±1. 91) g]and epididymal fat pad coefficient [(3. 25±0. 39) %]of HFD group was significantly up-regulated(P < 0. 05), the adipose tissue inflammatory cell infiltration was increased, the expression of TNF-α(F = 73. 157, P < 0. 05) and IL-1ß(F = 42. 788, P < 0. 05) was significantly enhanced, and the phosphorylation degree of GSK3ß-S9(F = 57. 991, P < 0. 05) was decreased. The inflammatory cell infiltration of adipose tissue in the HFD+1000 nmol/L BPA group was significantly increased, the body weight [(38. 49±1. 34) g]and epididymal fat pad coefficient [(4. 41±0. 33) %] of the mice were significantly increased, the phosphorylation of GSK3ß-S9(F = 57. 991, P <0. 05) was significantly down-regulated, and the expression of TNF-α(F = 73. 157, P <0. 05) and IL-1ß(F = 42. 788, P <0. 05) was significantly enhanced compared with that in the HFD group. Compared with the HFD + 1000 nmol/L BPA group, the HFD + 1000 nmol/L BPA+GSK3 inhibitor group was decreased inflammatory cell infiltration in adipose tissue, significantly decreased body weight [(32. 61 ± 3. 34) g] and epididymal fat pad coefficient [(3. 33±0. 66) %], significantly increased GSK3-S9(F = 57. 991, P < 0. 05)phosphorylation, and significantly decreased TNF-α(F = 73. 157, P < 0. 05) and IL-1ß(F = 42. 788, P<0. 05) expression. CONCLUSION: GSK3ß inhibitor can down-regulate BPA-induced adipose tissue inflammation, inflammatory cytokine expression and upregulate GSK3ß-S9 phosphorylation in HFD-fed mice, suggesting that BPA exposure may regulate the expression of inflammatory cytokines mediating adipose tissue inflammation by affecting the degree of phosphorylation of GSK3ß-S9.

[Effects of IL-17 antibody on inflammation of adipose tissue in obese mice induced by bisphenol A].

OBJECTIVE: To study the effects of IL-17 antibody on adipose tissue inflammation and macrophage accumulation in obese mice induced by BPA. METHODS: 4-week-old male C57 BL/6 mice were fed with high fat diet( HFD) and were randomly divided into solvent control group, IgG treatment group, IL-17 antibody treatment group, 1000 nmol/L BPA group, IgG + 1000 nmol/L BPA group, IL-17 antibody + 1000 nmol/L BPA group, with 8 mice in each group. The BPA exposed group administered 1000 nmol/L BPA by drinking water. The mice in IL-17 treatment group were intraperitoneally injected with 100 µg IL-17 antibody and the mice in IgG treatment group were intraperitoneally injected with 100 µg IgG each week. Mice were sacrificed and epididymal fat pad was obtained after 16 weeks. Histopathological section was used to observe the cells morphological changes and inflammation in epididymal adipose tissue. Immunohistochemistry( IHC) was used to detect the expression of IL-17、TNF-α and IL-1ß in epididymal adipose tissue. Immunofluorescence( IF) was used to detect the location of macrophage in the epididymal adipose tissue. One-Way ANOVA was used to compare the mean values of the two groups, and the Tukey method was used for pairwise comparison. RESULTS: The obesity rate [( 40. 68 ± 9. 43) %]and body weight [( 41. 95 ±2. 81) g]of mice in 1000 nmol/L BPA group higher than the mice in solvent control group( body weight [( 38. 44 ± 4. 23) g], the obesity rate [( 28. 90 ± 14. 19) % ]), the difference was statistically significant( body weight F = 5. 895, P < 0. 05, the obesity rate F = 5. 895, P < 0. 05). Epididymal adipose tissue inflammatory cell infiltration increased. The expression of IL-17( F = 28. 225, P < 0. 05) and IL-1ß( F = 57. 878, P < 0. 05) were upregulated. And the macrophage accumulation was increased( F = 90. 829, P < 0. 05). Compared with the 1000 nmol/L BPA group, IgG treatment groups( the obesity rate[( 35. 98 ± 10. 73) % ]) had less effect on the mice. IL-17 treatment( the obesity rate[( 23. 03 ± 12. 50) % ]) inhibited BPA-induced increased in obesity rate of mice. Also, the inflammatory infiltration and macrophage accumulation of the adipose tissue were reduced( F = 90. 829, P < 0. 05). And the expression of IL-17( F = 28. 225, P < 0. 05), TNF-α( F = 4. 199, P < 0. 05) and IL-1ß( F = 57. 878, P < 0. 05) inflammatory factors were decreased. CONCLUSION: IL-17 antibody can improve BPA-induced mice obesity by reducing adipose tissue macrophage accumulation and reducing adipose tissue inflammation.

[Effects of bisphenol A on inflammation and Th17 cells in adipose tissue of high-fat fed mice].

OBJECTIVE: To study the effects of bisphenol A( BPA) on inflammation and Th17 cells in adipose tissue of high-fat fed mice. METHODS: 4-week-old male C57 BL /6mice were fed on high fat diet( HFD) and were administered 10, 100 and 1000 nmol / L BPA by drinking water. The normal diet( ND) and HFD control groups were set as well. Body weight of mice was recorded weekly. Mice were sacrificed at eighth and sixteenth week and epididymal fat pad was obtained. Hematoxylin-eosin( HE) staining was used to observe the cells morphological changes and inflammation in epididymal adipose tissue. Enzyme linked immunosorbent assay( ELISA) was used to detect TNF-α level in epididymal adipose tissue. Flow cytometry( FCM) was used to detect the proportion of Th17 cells in epididymal fat pad stromal vascular fractions( SVF). Immunohistochemistry( IHC) was used to detect the expression of IL-17 in epididymal adipose tissue. RESULTS: Compared with ND control groups, HFD increased body weight of mice, enhanced theinfiltration of inflammatory cells and the expression of TNF-α in adipose tissue. Also, the proportion of Th17 cells and the expression of IL-17 in adipose tissue were elevated. Compared with HFD control groups, BPA exposure enhanced the infiltration of inflammatory cells and the expression of TNF-α in adipose tissue. Also, the proportion of Th17 cells and the expression of IL-17 in adipose tissue were elevated in a dose-dependent way. And the effects at sixteenth week was more obvious than that at eighth week. CONCLUSION: BPA exposure can promote inflammation in adipose tissue of high-fat fed mice and elevate the proportion of Th17 cells and the expression of IL-17. Th17 cells may play an important role in the effects BPA on adipose tissue inflammation.

Retrospective Analysis of Vancomycin Nephrotoxicity in Elderly Chinese Patients.

This study explored nephrotoxicity in elderly Chinese patients after exposure to vancomycin and other nephrotoxic risk factors. This was a single-center retrospective study. The patient population included those who were ≥60 years of age, had normal baseline serum creatinine values, and received vancomycin for ≥48 h between January 1, 2013 and August 30, 2014. Nephrotoxicity occurred in 29% of 124 patients. A baseline creatinine clearance ≥63.5 ml/min was more common in the nephrotoxic group. Patients with high (≥15 mg/l) rather than low (<15 mg/l) average vancomycin troughs had elevated nephrotoxicity (47.2 vs. 27.3%, p = 0.0001). Of the comorbid conditions evaluated, there were more patients with shock (p = 0.001), hypertension (p = 0.020) and congestive heart failure (p = 0.04) in the nephrotoxic group. Drugs frequently given at the same time with vancomycin, such as angiotensin receptor blockers and furosemide, were also associated with increased nephrotoxic risk. In conclusion, nephrotoxicity was frequently observed in patients with concurrent vancomycin trough concentrations ≥15 µg/ml and hypertension, shock, congestive heart failure. In addition, drugs concurrently used with vancomycin may also increase its nephrotoxicity. Therefore, renal function and vancomycin serum troughs should be closely monitored, especially in patients with other renal injury risk factors.

Vasa vasorum in atherosclerosis and clinical significance.

Atherosclerosis is a chronic inflammatory disease that leads to several acute cardiovascular complications with poor prognosis. For decades, the role of the adventitial vasa vasorum (VV) in the initiation and progression of atherosclerosis has received broad attention. The presence of VV neovascularization precedes the apparent symptoms of clinical atherosclerosis. VV also mediates inflammatory cell infiltration, intimal thickening, intraplaque hemorrhage, and subsequent atherothrombosis that results in stroke or myocardial infarction. Intraplaque neovessels originating from VV can be immature and hence susceptible to leakage, and are thus regarded as the leading cause of intraplaque hemorrhage. Evidence supports VV as a new surrogate target of atherosclerosis evaluation and treatment. This review provides an overview into the relationship between VV and atherosclerosis, including the anatomy and function of VV, the stimuli of VV neovascularization, and the available underlying mechanisms that lead to poor prognosis. We also summarize translational researches on VV imaging modalities and potential therapies that target VV neovascularization or its stimuli.

Nur77 suppresses pulmonary artery smooth muscle cell proliferation through inhibition of the STAT3/Pim-1/NFAT pathway.

The orphan nuclear receptor 4A (NR4A) family plays critical roles in the regulation of cell proliferation, differentiation, and survival in the cardiovascular system. However, the molecular mechanisms underlying the regulation of NR4A receptor expression and its role in pulmonary artery smooth muscle cell (PASMC) function remain unclear. Here, we investigated whether the NR4A family regulates PASMC proliferation, and if so, which mechanisms are involved. By using quantitative real-time RT-PCR, we showed that the orphan nuclear receptor Nur77 was the most abundant member of NR4A family expressed in rat PASMCs, as compared with the two other members, NOR-1 and Nurr1. In rat PASMCs, expression of Nur77 was robustly induced in response to several pathologic stimuli of pulmonary arterial hypertension (PAH), such as hypoxia, 5-hydroxytryptamine (5-HT), platelet-derived growth factor, and endothelin-1. Importantly, Nur77 was also significantly increased in lungs of rats with monocrotaline-induced PAH. Furthermore, we demonstrated that 5-HT markedly up-regulated Nur77 expression through the mitogen-activated protein kinases/extracellular signal-regulated kinase 1/2 pathway. Overexpression of Nur77 inhibited 5-HT-induced PASMC proliferation, as well as the expression of cyclin D1 and proliferating cell nuclear antigen. Mechanistically, we demonstrated that Nur77 specifically interacts with signal transducer and activator of transcription 3, thus inhibiting its phosphorylation and expression of its target genes, such as Pim-1, nuclear factor of activated T cells c2, and survivin in PASMCs. These results indicate that Nur77 is a novel negative-feedback regulator of PASMC proliferation through inhibition of the signal transducer and activator of transcription 3/Pim-1/nuclear factor of activated T cells axis. Modulation of Nur77 activity may potentially represent a novel therapeutic strategy for the treatment of PAH.

Relationships between PON1 Q192R polymorphism and clinical outcome of antiplatelet treatment after percutaneous coronary intervention: a meta-analysis.

This meta-analysis was performed to assess the relationships between the PON1 Q192R (rs662 T>C) polymorphism and the clinical outcome of antiplatelet treatment after percutaneous coronary intervention (PCI). A range of electronic databases were searched: Web of Science (1945-2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966-2013), EMBASE (1980-2013), CINAHL (1982-2013) and the Chinese Biomedical Database (CBM) (1982-2013) without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. The crude odds ratio (OR) with their 95 % confidence interval (CI) were calculated. Six clinical cohort studies with a total number of 5,189 patients undergoing PCI for coronary heart disease were included. Our meta-analysis revealed that the PON1 Q192R polymorphism was correlated with an increased risk of major adverse cardiovascular events (MACE) in patients receiving antiplatelet treatment after PCI (C allele vs. T allele: OR = 1.22, 95 % CI 1.04-1.43, P = 0.014; CT+CC vs. TT: OR = 1.38, 95 % CI 1.03-1.86, P = 0.029; CC vs. TT: OR = 1.45, 95 % CI 1.05-1.99, P = 0.024; respectively), especially among Asians. Furthermore, we found significantly positive correlations between the PON1 Q192R polymorphism and the incidence of stent thrombosis in patients receiving antiplatelet treatment after PCI (C allele vs. T allele: OR = 1.42, 95 % CI 1.08-1.87, P = 0.011; CT+CC vs. TT: OR = 1.93, 95 % CI 1.01-3.67, P = 0.046; CC vs. TT: OR = 2.18, 95 % CI 1.09-4.35, P = 0.027; respectively). Our meta-analysis of clinical cohort studies provides evidence that the PON1 Q192R polymorphism may increase the risk of MACE and stent thrombosis in patients receiving antiplatelet treatment after PCI.

Pore Structure and Deformation Correlation of an Aluminum Foam Sandwich Subject to Three-Point Bending.

An Al-Si matrix foam sandwich (AFS) with 6063 Al alloy cover sheets was fabricated by hot rolling combined with melt foaming. A foamable AlSiMg1/SiCp matrix precursor was prepared by the melting route. Hot rolling at 480 °C was carried out to obtain a mechanical bonding interface between the cover sheet and the foamable precursor. Meanwhile, the pore structure of the AFS was deeply affected by the foaming temperature and foaming time during the foaming process. Different pore growth mechanics of the crack-like pore disappearance mechanism (CDM) and pore active expansion mechanism (AEM) were concluded based on the pressure difference in pores inside and outside. Three bending tests were applied to three types of AFSs with different pore structures to evaluate the relation between pore structures and AFS mechanical properties. The bending property of the AFS with fewer layers of pores is like that of a dense material. The bending property of the AFS with a pore size in the range of 0~1 mm presents a typical sandwich shear failure mode. The AFS with a uniform pore structure, in which the shapes of the pores are predominately polygons and the pore diameter is concentrated in the range of 0.5~3 mm, processes a good energy absorption capacity, and the bending stress-strain curve fluctuates greatly after the first stress drop.

Synergizing the interaction of single nucleotide polymorphisms with dosiomics features to build a dual-omics model for the prediction of radiation pneumonitis.

OBJECTIVE: Radiation pneumonitis (RP) is the major dose-limiting toxicity of thoracic radiotherapy. This study aimed to developed a dual-omics (single nucleotide polymorphisms, SNP and dosiomics) prediction model for symptomatic RP. MATERIALS AND METHODS: The potential SNPs, which are of significant difference between the RP grade ≥ 3 group and the RP grade ≤ 1 group, were selected from the whole exome sequencing SNPs using the Fisher's exact test. Patients with lung cancer who received thoracic radiotherapy at our institution from 2009 to 2016 were enrolled for SNP selection and model construction. The factorization machine (FM) method was used to model the SNP epistasis effect, and to construct the RP prediction model (SNP-FM). The dosiomics features were extracted, and further selected using the minimum redundancy maximum relevance (mRMR) method. The selected dosiomics features were added to the SNP-FM model to construct the dual-omics model. RESULTS: For SNP screening, peripheral blood samples of 28 patients with RP grade ≥ 3 and the matched 28 patients with RP grade ≤ 1 were sequenced. 81 SNPs were of significant difference (P < 0.015) and considered as potential SNPs. In addition, 21 radiation toxicity related SNPs were also included. For model construction, 400 eligible patients (including 108 RP grade ≥ 2) were enrolled. Single SNP showed no strong correlation with RP. On the other hand, the SNP-SNP interaction (epistasis effect) of 19 SNPs were modeled by the FM method, and achieved an area under the curve (AUC) of 0.76 in the testing group. In addition, 4 dosiomics features were selected and added to the model, and increased the AUC to 0.81. CONCLUSIONS: A novel dual-omics model by synergizing the SNP epistasis effect with dosiomics features was developed. The enhanced the RP prediction suggested its promising clinical utility in identifying the patients with severe RP during thoracic radiotherapy.

Differential Analysis of Various Moisture Phases on N2 Displacement of CH4 in Coal.

The aim of the study was to elucidate the impact of different moisture phases during gas injection on coalbed methane displacement. The coal samples were treated with two methods: water vapor adsorption and liquid water stirring. The differences in the coal samples treated with various moisture phases during gas injection for coalbed methane displacement were investigated by using the isothermal adsorption curves of CH4, N2, and H2O in coal and N2 displacement of CH4 in coal. The results indicate that variations in the gas adsorption capacity of coal are treated with different moisture phases. The gas adsorption capacities and displacement capacities of the coal samples treated with the water vapor adsorption methods are better than those treated with the stirring methods. In the isothermal adsorption experiment, for the coal samples treated with different moisture phases, at a moisture content of 2.75%, the saturated adsorption capacities of CH4/N2 are 0.204/0.189 (cm3/g), and at a moisture content of 5.63%, the saturated adsorption capacities of CH4/N2 are 0.151/0.139 (cm3/g). In addition, in the displacement experiment, for the coal samples treated with different moisture phases, at a moisture content of 2.75%, the difference in the total gas adsorption capacities is 0.62 cm3/g and the difference in the CH4 adsorption capacities is 0.473 cm3/g, and at a moisture content of 5.63%, the difference in the total gas adsorption capacities is 0.3 cm3/g and the difference in CH4 adsorption capacities is 0.22 cm3/g. For the coal samples treated with various moisture phases, the differences in the CH4/N2 adsorption and displacement capacities are greater at a moisture content of 2.75% than at 5.63%. Notably, the moisture phase has only a marginal influence on the CH4 desorption capacity and desorption rate. The study is important to understand the interactions between coal and moisture.