Composition and mean residence time of molecular weight fractions of organic matter extracted from two soils under different forest species

The organic matter extracted from various mineral horizons of two forest soils, one under silver fir (Abies alba Mill.), the other under European beech (Fagus sylvatica L.), was fractionated by dialysis into three fractions, 100–1000, 1000–8000, and >8000Da. On a C basis, in all horizons the recovered organic matter amounted to less than a half of the total and was mainly composed of molecules >8000Da. The 100–1000Da fraction had a principal elemental composition profoundly different from the other two fractions, which, instead differed from each other significantly only for the S content and the molar ratio of C with N. No significant difference in this regard was found between soils. The richness in O and some typical absorption bands in the FT-IR spectra indicated that the 100–1000Da fraction had a lot of carboxyl moieties. The spectroscopic (¹³C NMR) investigation showed that the 1000–8000 and >8000Da fractions had a prevalently aliphatic nature and signals attributable to polysaccharides (O-alkyl C) revealed overall a high presence of non-humic biopolymers. These latter were significantly more abundant, suggesting a lower degree of humification, in the >8000Da fraction than in the 1000–8000Da fraction. Comparing soils, that under beech appeared significantly richer in O-alkyl C than that under fir. The organics extracted from the A horizon of both soils had positive ¹⁴C values, indicating recent synthesis mainly due to the present forest cover. The mean residence time (MRT) of the combined 100–1000Da and 1000–8000Da fractions and the >8000Da fraction increased with depth, even to about 5000 years in the more than 1-m deep BC horizons under beech. In some cases, and especially in the soil under fir, despite higher values of ¹³C denoting stronger microbial decomposition, the 100–8000Da fraction showed a higher MRT than that of the >8000Da fraction, perhaps due to its ascertained lower content of non-humic biopolymers.     

Circulating muscle-specific microRNA, miR-206, as a potential diagnostic marker for rhabdomyosarcoma

Presently there is no serum biomarker of rhabdomyosarcoma (RMS). Several studies have shown that profiles of microRNA (miRNA) expression differ among tumor types. Here we evaluated the feasibility of using muscle-specific miRNAs (miR-1, -133a, -133b and -206) as biomarkers of RMS. Expression of muscle-specific miRNAs, especially miR-206, was significantly higher in RMS cell lines than in other tumor cell lines, as well as in RMS tumor specimens. Further, serum levels of muscle-specific miRNAs were significantly higher in patients with RMS tumors than in patients with non-RMS tumors. Normalized serum miR-206 expression level could be used to differentiate between RMS and non-RMS tumors, with sensitivity of 1.0 and specificity of 0.913. These results raise the possibility of using circulating muscle-specific miRNAs, especially miR-206, as landmark biomarkers for RMS.     

Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125

We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.     

Design and synthesis of alkyl substituted pyridino[2,3-D]pyrimidine compounds as PI3Kα/mTOR dual inhibitors with improved pharmacokinetic properties and potent in vivo antitumor activity

Using pyridino[2,3-D]pyrimidine as the core, total 13 pyridino[2,3-D]pyrimidine derivatives with different alkyl substituents at C2 site have been designed and synthesized to search for novel PI3Kα/mTOR dual inhibitors. Most of the target compounds showed potent mTOR inhibition activity with IC₅₀ values ranging from single to double digit nanomole. Five target compounds exhibited pronounced PI3Kα inhibition activity. In vitro cellular assay indicated that most of the target compounds showed excellent antiproliferative activity, especially 3j whose potency against SKOV3 was 8-fold higher than the positive control AZD8055. In vitro metabolic stability study found that 3j had a comparable stability to that of AZD8055. More importantly, 3j showed better antitumor activity and pharmacokinetic properties in vivo as compared with AZD8055.     

Ferrocene-based inhibitors of hepatitis C virus replication that target NS5A with low picomolar in vitro antiviral activity

An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1′-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat.     

Potent antiobesity effect of a short-length peptide YY-analogue continuously administered in mice

The gastrointestinal peptide, peptide YY_3–36 (PYY_3–36) and its shorter peptide analogues have been reported to reduce appetite by activating the neuropeptide Y2 receptor (Y2R), which is associated with obesity and other metabolic diseases. A 14-amino acid PYY analogue, Ac-[d-Pro²⁴,Cha^27,28,36,Aib³¹]PYY(23–36) (3), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY_3–36, but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4)²⁶, Aib²⁸, Lys³⁰], which contributed to the decreased hydrophobicity of 3, efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[d-Pro²⁴,Pya(4)²⁶,Cha^27,36,Aib^28,31,Lys³⁰]PYY(23–36) (22), exerted more potent and durable food intake suppression than that by PYY_3–36 in lean mice, as well as excellent Y2R agonist activity (EC₅₀: 0.20 nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1 mg/kg/day successfully produced antiobese and antidiabetic effects, with more than 20% body weight loss in obese and Type 2 diabetes ob/ob model mice.     

Herbal monoterpene alcohols inhibit propofol metabolism and prolong anesthesia time

2,6-Diisopropylphenol (Propofol) is a short-acting intravenous anesthetic that is rapidly metabolized by glucuronidation and ring hydroxylation catalyzed by cytochrome P450. The goal of this research was to determine whether dietary monoterpene alcohols (MAs) could be used to prolong the anesthetic effect of propofol by inhibiting propofol metabolism in animals. Mice were injected intraperitoneally (i.p.) with MAs (100-200) mg/kg followed by the administration of 100 mg/kg propofol 40 min later via an i.p. injection. The time of the anesthesia of each mouse was recorded. It was found that (+/-)-borneol, (-)-carveol, trans-sobrerol, and menthol significantly extended the anesthetic effect of propofol (>3 times). The concentration of propofol in the mouse blood over time (up to 180 min) also increased in mice pre-treated with (-)-borneol, (-)-carveol, and trans-sobrerol. The volume of distribution of propofol decreased in the (-)-borneol (p<0.05), pre-treated group as compared to the propofol control group. Moreover, the maximum blood concentration of propofol and the concentration of propofol in the blood as indicated by the area under the curve were significantly increased in (-)-borneol and (-)-carveol pre-treated groups. Additional evidence using rat hepatocytes showed that (-)-borneol inhibited propofol glucuronidation whereas trans-sobrerol and (-)-carveol inhibited cytochrome P450 dependent microsomal aminopyrine N-demethylation. These results suggest that (-)-borneol extends propofol-induced anesthesia by inhibiting its glucuronidation in the mouse whereas trans-sobrerol (-)-carveol extends propofol-induced anesthesia by inhibiting P450 catalyzed propofol metabolism.     

小秦岭森林群落数量分类、排序及多样性垂直格局

采用分层取样的方法,沿小秦岭林区海拔梯度设立56块20 m×20 m样地,用多元回归树(MRT)方法对小秦岭森林群落进行分类,采用除趋势对应分析(DCA)进行排序,用广义可加模型(GAM)研究不同生活型物种多样性沿海拔梯度分布格局。结果表明:(1)56个样地进行MRT分类,经交叉验证并依据植物群落分类和命名原则,本区植物群落可分为5类;(2)样方DCA排序明确地揭示各群落类型生境分布范围,较好地反映小秦岭自然保护区森林群落与环境因子的关系;(3)不同生活型物种多样性指数随海拔梯度变化发生一定的波动,且呈现不同的多样性格局:丰富度指数中,乔木层呈显著的单峰分布格局,灌木层在中海拔段呈明显下降趋势,草本层随着海拔的升高总体呈下降趋势;Shannon-Wiener多样性指数中,不同生活型物种随海拔变化趋势与物种丰富度变化趋势大体相同;不同生活型物种的均匀度指数随海拔变化趋势较平缓。     

Effect of leg kick on active drag in front-crawl swimming: Comparison of whole stroke and arms-only stroke during front-crawl and the streamlined position

The purpose of this study was to examine the effect of leg kick on the resistance force in front-crawl swimming. The active drag in front-crawl swimming with and without leg motion was evaluated using measured values of residual thrust (MRT method) and compared with the passive drag of the streamlined position (SP) for the same swimmers. Seven male competitive swimmers participated in this study, and the testing was conducted in a swimming flume. Each swimmer performed front-crawl under two conditions: using arms and legs (whole stroke: WS) and using arms only (arms-only stroke: AS). Active drag and passive drag were measured at swimming velocities of 1.1 and 1.3 m s⁻¹ using load cells connected to the swimmer via wires. We calculated a drag coefficient to compare the resistances of the WS, AS and SP at each velocity. For both the WS and AS at both swimming velocities, active drag coefficient was found to be about 1.6–1.9 times larger than that in passive conditions. In contrast, although leg movement did not cause a difference in drag coefficient for front-crawl swimming, there was a large effect size (d = 1.43) at 1.3 m s⁻¹. Therefore, although upper and lower limb movements increase resistance compared to the passive condition, the effect of leg kick on drag may depend on swimming velocity.     

Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators

The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30?mg/kg oral dose.