Single Intraperitoneal Injection of Monocrotaline as a Novel Large Animal Model of Chronic Pulmonary Hypertension in Tibet Minipigs

Objective

The purpose of this study was to establish an animal model of chronic pulmonary hypertension with a single-dose intraperitoneal injection of monocrotaline (MCT) in young Tibet minipigs, so as to enable both invasive and noninvasive measurements and hence facilitate future studies.

Methods

Twenty-four minipigs (8-week-old) were randomized to receive single-dose injection of 12.0 mg/kg MCT (MCT group, n = 12) or placebo (control group, n = 12 each). On day 42, all animals were evaluated for pulmonary hypertension with conventional transthoracic echocardiography, right heart catheterization (RHC), and pathological changes. Findings of these studies were compared between the two groups.

Results

At echocardiography, the MCT group showed significantly higher pulmonary arterial mean pressure (PAMP) compared with the controls (P<0.001). The pulmonary valve curve showed v-shaped signals with reduction of a-waves in minipigs treated with MCT. In addition, the MCT group had longer pulmonary artery pre-ejection phases, and shorter acceleration time and ejection time. RHC revealed higher mean pulmonary arterial pressure (mPAP) in the MCT group than in the control group (P<0.01). A significant and positive correlation between the mPAP values and the PAMP values (R = 0.974, P<0.0001), and a negative correlation between the mPAP and ejection time (R = 0.680, P<0.0001) was noted. Pathology demonstrated evidence of pulmonary vascular remodeling and higer index of right ventricular hypertrophy in MCT-treated minipigs.

Conclusion

A chronic pulmonary hypertension model can be successfully established in young minipigs at six weeks after MCT injection. These minipig models exhibited features of pulmonary arterial hypertension that can be evaluated by both invasive (RHC) and noninvasive (echocardiography) measurements, and may be used as an easy and stable tool for future studies on pulmonary hypertension.     

Nitrotyrosine Level Was Associated with Mortality in Patients with Acute Kidney Injury

Background

To examine the characteristics of oxidative stress in patients with acute kidney injury (AKI) and investigate the association between plasma nitrotyrosine levels and 90-day mortality in patients with AKI.

Methodology/Principal Findings

158 patients with hospital-acquired AKI were recruited to this prospective cohort study according to RIFLE (Risk, Injury, Failure, Lost or End Stage Kidney) criteria. Twelve critically ill patients without AKI and 15 age and gender-matched healthy subjects served as control. Plasma 3-nitrotyrosine was analyzed in relation to 90-day all cause mortality of patients with AKI. The patients with AKI were followed up for 90 days and grouped according to median plasma 3-nitrotyrosine concentrations. Highest 3-NT/Tyr was detected in patients with AKI compared with healthy subjects, and critically ill patients without AKI (ANOVA p<0.001). The 90-day survival curves of patients with high 3-NT/Tyr showed significant differences compared with the curves of individuals with low 3-NT/Tyr (p = 0.001 by log rank test). Multivariate analysis (Cox regression) revealed that 3-NT/Tyr (p = 0.025) was independently associated with mortality after adjustment for age, gender, sepsis and Acute Physiology and Chronic Health Evaluation (APACHE) II score.

Conclusions/Significance

There is excess plasma protein oxidation in patients with AKI, as evidenced by increased nitrotyrosine content. 3-NT/Tyr level was associated with mortality of AKI patients independent of the severity of illness.     

Epigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β‐catenin signalling and apoptosis regulation in breast cancer cells

Dickkopf‐related protein 3 (DKK3) is an antagonist of Wnt ligand activity. Reduced DKK3 expression has been reported in various types of cancers, but its functions and related molecular mechanisms in breast tumorigenesis remain unclear. We examined the expression and promoter methylation of DKK3 in 10 breast cancer cell lines, 96 primary breast tumours, 43 paired surgical margin tissues and 16 normal breast tissues. DKK3 was frequently silenced in breast cell lines (5/10) by promoter methylation, compared with human normal mammary epithelial cells and tissues. DKK3 methylation was detected in 78% of breast tumour samples, whereas only rarely methylated in normal breast and surgical margin tissues, suggesting tumour‐specific methylation of DKK3 in breast cancer. Ectopic expression of DKK3 suppressed cell colony formation through inducing G0/G1 cell cycle arrest and apoptosis of breast tumour cells. DKK3 also induced changes of cell morphology, and inhibited breast tumour cell migration through reversing epithelial‐mesenchymal transition (EMT) and down‐regulating stem cell markers. DKK3 inhibited canonical Wnt/β‐catenin signalling through mediating β‐catenin translocation from nucleus to cytoplasm and membrane, along with reduced active‐β‐catenin, further activating non‐canonical JNK signalling. Thus, our findings demonstrate that DKK3 could function as a tumour suppressor through inducing apoptosis and regulating Wnt signalling during breast tumorigenesis.     

Genetic variation in dopamine‐related gene expression influences motor skill learning in mice

Several neurodevelopmental disorders with a strong genetic basis, including attention‐deficit/hyperactivity disorder, autism spectrum disorders and developmental coordination disorder, involve deficits in fine motor skills. This phenotype may depend on heritable variation in components of the dopamine (DA) system, which is known to play a critical role in motor skill learning. In this study, we took advantage of two inbred strains of mice (BALB/c and C57BL/6) that differ markedly in the number of midbrain DA neurons in order to investigate the influence of such naturally occurring genetic variation on the acquisition and performance of fine motor skills. Gene expression analysis of midbrain, frontal cortex and striatum showed significant differences in the expression of presynaptic and postsynaptic dopaminergic (DAergic) markers (e.g. tyrosine hydroxylase, DA transporter, DA D4 receptor, DA D5 receptor and DARPP‐32) between these two strains. BALB/c mice had lower learning rate and performance scores in a complex skilled reaching task when compared with C57BL/6 mice. A negative correlation was found between the motor learning rate and level of DARPP‐32 mRNA expression in the frontal cortex contralateral to the trained forelimb. The rate of motor learning was also negatively correlated with the levels of DARPP‐32 and DA D1 receptor mRNAs in the striatum. Our results suggest that genetically driven variation in frontostriatal DAergic neurotransmission is a major contributor to individual differences in motor skill learning. Moreover, these findings implicate the D1R/cAMP/DARPP‐32 signaling pathway in those neurodevelopmental disorders that are associated with fine motor skill deficits.     

Theoretical study of the triangular bonding complex formed by carbon tetrabromide, a halide, and a solvent molecule in the gas phase

MP2(full)/aug-cc-pVDZ(-PP) computations predict that new triangular bonding complexes (where X^? is a halide and H–C refers to a protic solvent molecule) consist of one halogen bond and two hydrogen bonds in the gas phase. Carbon tetrabromide acts as the donor in the halogen bond, while it acts as an acceptor in the hydrogen bond. The halide (which commonly acts as an acceptor) can interact with both carbon tetrabromide and solvent molecule (CH₃CN, CH₂Cl₂, CHCl₃) to form a halogen bond and a hydrogen bond, respectively. The strength of the halogen bond obeys the order CBr₄???Cl^? > CBr₄???Br^? > CBr₄???I^?. For the hydrogen bonds formed between various halides and the same solvent molecule, the strength of the hydrogen bond obeys the order C-H???Cl^? > C-H???Br^? > C-H???I^?. For the hydrogen bonds formed between the same halide and various solvent molecules, the interaction strength is proportional to the acidity of the hydrogen in the solvent molecule. The diminutive effect is present between the hydrogen bonds and the halogen bond in chlorine and bromine triangular bonding complexes. Complexes containing iodide ion show weak cooperative effects.

Sandwich‐Type Microporous Carbon Nanosheets for Enhanced Supercapacitor Performance

Sandwich‐type microporous hybrid carbon nanosheets (MHCN) consisting of graphene and microporous carbon layers are fabricated using graphene oxides as shape‐directing agent and the in‐situ formed poly(benzoxazine‐co‐resol) as carbon precursor. The reaction and condensation can be readily completed within 45 min. The obtained MHCN has a high density of accessible micropores that reside in the porous carbon with controlled thickness (e.g., 17 nm), a high surface area of 1293 m² g^?1 and a narrow pore size distribution of ca. 0.8 nm. These features allow an easy access, a rapid diffusion and a high loading of charged ions, which outperform the diffusion rate in bulk carbon and are highly efficient for an increased double‐layer capacitance. Meanwhile, the uniform graphene percolating in the interconnected MHCN forms the bulk conductive networks and their electrical conductivity can be up to 120 S m^?1 at the graphene percolation threshold of 2.0 wt.%. The best‐practice two‐electrode test demonstrates that the MHCN show a gravimetric capacitance of high up to 103 F g^?1 and a good energy density of ca. 22.4 Wh kg^?1 at a high current density of 5 A g^?1. These advanced properties ensure the MHCN a great promise as an electrode material for supercapacitors.     

Amino‐functionalized macroporous silica for efficient tryptic digestion in acidic solutions

Amino‐functionalized macroporous silica foam (NH₂‐MOSF) has been developed as a host reactor to realize highly efficient proteolysis in acidic solutions where normal tryptic reactions cannot occur. The digestion protocol consists simply of adding the functionalized NH₂‐MOSF into the protein and trypsin solutions without altering the bulk pH or preloading the enzymes on the materials. With this protocol, digestion of sample fractions from LC can be efficiently realized in the acidic solutions directly. Digestion of a protein fraction extracted from rat liver tissue after LC separation was performed to illustrate this principle, where 103 proteins were successfully identified at pH 3 after 1.5 h of tryptic digestion.     

肌动蛋白基因和β-微管蛋白基因用于真黏菌系统发育的可行性研究

真黏菌是一类独特的菌物。目前对其进行的系统发育研究主要是基于形态特征,分子水平的系统发育研究上小亚基核糖体RNA基因和蛋白质合成延长因子基因研究相对较多。为了扩充能有效地进行真黏菌系统发育研究的基因资源,探讨了肌动蛋白基因和β-微管蛋白基因用于真黏菌系统发育的可行性。共获得14个基因序列,肌动蛋白基因和β-微管蛋白基因各7个。在GenBank中除多头绒泡菌Physarum polycephalum外并无其他真黏菌的肌动蛋白基因和β-微管蛋白基因序列,研究获得的14个基因序列为真黏菌基因的新序列。系统发育分析表明,肌动蛋白基因能够有效地将无丝菌目、团毛菌目、绒泡菌目和发网菌目区分为4个分支,其中发网菌目为一个独立的进化支,支持了根据子实体发育所认识的真黏菌纲内部具有两条进化路线的观点,因此显示出肌动蛋白基因对于真黏菌系统发育研究的重要价值。     

Spectral Characteristics of Near-Infrared Surface Plasmon Resonance

Intrinsic properties of surface plasmons (SPs) excited with Kretschmann configuration were analyzed as a function of wavelength, including the propagation length, the penetration depth, the Goos–Hänchen (GH) shift, and the field enhancement. The calculated results indicate that there exists a critical thickness (t _cr) of the gold layer and that the maximum GH shift occurring exactly at the SP resonance wavelength (λ _R) rapidly varies from positive to negative with changing of the gold layer thickness from t?<?t _cr to t?>?t _cr. The maximum field enhancement happens not at λ _R but at a wavelength smaller than λ _R due to the phase retardation between the transmitted and reflected light. Simulations also reveal that a broadband collimated near-infrared beam can simultaneously excite two SPs with different responses to a refractive index (RI) change: the shorter-wavelength SP able to make a small redshift and the longer-wavelength SP capable of yielding a large blueshift. Only the shorter-wavelength SP was experimentally observed and its RI sensitivity was measured to increase from 3,539 nm/RIU at λ _R?=?707.6 nm to 57,143 nm/RIU at λ _R?=?1,398 nm. The SP at λ _R?=?1,013 nm moved to λ _R?=?1,029 nm in response to the saturation adsorption of bovine serum albumin, and the corresponding surface coverage was determined to be Γ?=?1.565 ng/mm² based on a quasilinear dependence of Γ on the resonance wavelength shift (?λ _R) deduced theoretically. Butyrylcholinesterase adsorption from a dilute solution of 10 nM protein in phosphate buffer solution leads to a redshift of ?λ _R?=?10 nm, corresponding to Γ?≈?0.97 ng/mm².     

Effect of Edge Rounding on the Extinction Properties of Hollow Metal Nanoparticles

The optical responses of metal nanoparticles induced by subtle variations in geometry, especially by the rounding of the edges and corners, have generated great interest at present due to the requirement of fabricating refined structures of metal nanoparticles and theoretical simulations of the real particles. We study the effect of both inner and outer edge rounding on the optical properties of gold nanobox and gold nanobox dimer with small interparticle distances by using the discrete dipole approximation method. The shift of extinction peaks, the electric field distribution, and the variation of refractive index sensitivities by changing the curvature of the inner and outer edges of gold nanobox are investigated. We demonstrate that the optical properties of nanobox are more sensitive to the outer edge rounding than the inner edge rounding. By edge rounding of two very close gold nanoboxes, the blue shift of the dipolar and the quadrupolar plasmonic resonances of nanobox dimer are shown. Comparing with the inner edge rounding of nanobox dimer, we find that rounding of the outer edges causes the larger shift of the quadrupolar mode and approximate shift of the dipole mode.