Analogs of iso-azepinomycin as potential transition-state analog inhibitors of guanase: Synthesis,biochemical screening,and structure–activity correlations of various selectively substituted imidazo[4,5-e][1,4]diazepines

Guanase is an important enzyme of the purine salvage pathway of nucleic acid metabolism and its inhibition has beneficial implications in viral, bacterial, and cancer therapy. The work described herein is based on a hypothesis that azepinomycin, a heterocyclic natural product and a purported transition state analog inhibitor of guanase, does not represent the true transition state of the enzyme-catalyzed reaction as closely as does iso-azepinomycin, wherein the 6-hydroxy group of azepinomycin has been translocated to the 5-position. Based on this hypothesis, and assuming that iso-azepinomycin would bind to guanase at the same active site as azepinomycin, several analogs of iso-azepinomycin were designed and successfully synthesized in order to gain a preliminary understanding of the hydrophobic and hydrophilic sites surrounding the guanase binding site of the ligand. Specifically, the analogs were designed to explore the hydrophobic pockets, if any, in the vicinity of N1, N3, and N4 nitrogen atoms as well as O⁵ oxygen atom of iso-azepinomycin. Biochemical inhibition studies of these analogs were performed using a mammalian guanase. Our results indicate that (1) increasing the hydrophobicity near O⁵ results in a negative effect, (2) translocating the hydrophobicity from N3 to N1 also results in decreased inhibition, (3) increasing the hydrophobicity near N3 or N4 produces significant enhancement of inhibition, (4) increasing the hydrophobicity at either N3 or N4 with a simultaneous increase in hydrophobicity at O⁵ considerably diminishes any gain in inhibition made by solely enhancing hydrophobicity at N3 or N4, and (5) finally, increasing the hydrophilic character near N3 has also a deleterious effect on inhibition. The most potent compound in the series has a K_i value of 8.0 ± 1.5 μM against rabbit liver guanase.     

His-234是毛白杨对香豆酸 ∶ CoA连接酶的重要酶催化活性残基

对香豆酸∶CoA连接酶(4-coumarate: coenzyme A ligase,4CL)是植物苯丙烷类代谢途径中的一个重要的酶．4CL以肉桂酸衍生物(香豆酸、咖啡酸、阿魏酸等)、ATP和CoA为底物合成相应的酰基-CoA酯,这些酰基-CoA酯是一系列重要化合物(如木质素)的前体．4CL的酶催化反应分两步进行：第一步以肉桂酸衍生物和Mg² -ATP为底物合成酰基-AMP,第二步用CoA取代AMP,产生酰基-CoA酯,催化过程中酶的构象产生明显的变化．因为4CL在木质素的合成中所起的作用,这个酶是通过蛋白质工程方法改进林产品质量的重要靶标．我们通过X射线衍射技术,解析了毛白杨对香豆酸∶CoA连接酶1(Pt4CL1)与其中间产物对香豆酰-AMP的复合物晶体结构,与同家族成员结构比对,确定所获得的蛋白质结构为Pt4CL1催化第二步反应,即酰基-CoA酯合成的构象．结构分析表明：His-234残基在Pt4CL1的酶催化机理中起着多重作用,即通过侧链与AMP磷酸基团形成氢键,降低磷酸基团的负电荷,催化CoA的亲核取代反应;侧链可以采取两种不同的构象以调节CoA进入Pt4CL1的催化中心;His-234的侧链还可能夺取CoA巯基的质子,从而增强CoA的亲核反应活性．突变体酶活数据结果也显示His-234对Pt4CL1的活性非常重要,是Pt4CL1催化中心的活性残基．     

植物间正相互作用对种群动态和群落结构的影响:基于个体模型的研究进展

植物间的相互作用对种群动态和群落结构有着重要的影响。大量的野外实验已经揭示了正相互作用(互利)在群落中的普遍存在及其重要性。为了弥补野外实验方法的不足, 模型方法被越来越多地应用于正相互作用及其生态学效应的研究中。该文基于个体模型研究, 探讨了植物间正相互作用对种群动态和群落结构的影响。介绍了植物间正相互作用的定义和发生机制、植物间相互作用与环境梯度的关系。正相互作用是指发生在相邻的植物个体之间, 至少对其中一个个体有益的相互作用。植物通过直接(生境改善或资源富集)或间接(协同防御等)作用使局部环境有利于邻体而发生正相互作用。胁迫梯度假说认为互利的强度或重要性随着环境胁迫度的增加而增加, 但是越来越多的经验研究认为胁迫梯度假说需要改进。以网格模型和影响域模型为例, 介绍了基于个体的植物间相互作用模型方法。基于个体模型, 对近年来国内外正相互作用对种群时间动态(如生物量-密度关系)、空间分布格局和群落结构(如群落生物量-物种丰富度关系)影响的研究进行了总结。指出未来的研究应集中在对正相互作用概念和机制的理解, 新的模型, 新的种群、群落, 甚至生态系统问题, 以及在全球变化背景下进行相关的研究。     

Phylogenetic beta diversity in bacterial assemblages across ecosystems: deterministic versus stochastic processes

Increasing evidence has emerged for non-random spatial distributions of microbes, but knowledge of the processes that cause variation in microbial assemblage among ecosystems is lacking. For instance, some studies showed that deterministic processes such as habitat specialization are important, while other studies hold that bacterial communities are assembled by stochastic forces. Here we examine the relative influence of deterministic and stochastic processes for bacterial communities from subsurface environments, stream biofilm, lake water, lake sediment and soil using pyrosequencing of the 16S ribosomal RNA gene. We show that there is a general pattern in phylogenetic signal in species ecological niches across recent evolutionary time for all studied habitats, enabling us to infer the influences of community assembly processes from patterns of phylogenetic turnover in community composition. The phylogenetic dissimilarities among-habitat types were significantly higher than within them, and the communities were clustered according to their original habitat types. For communities within-habitat types, the highest phylogenetic turnover rate through space was observed in subsurface environments, followed by stream biofilm on mountainsides, whereas the sediment assemblages across regional scales showed the lowest turnover rate. Quantifying phylogenetic turnover as the deviation from a null expectation suggested that measured environmental variables imposed strong selection on bacterial communities for nearly all sample groups. For three sample groups, spatial distance reflected unmeasured environmental variables that impose selection, as opposed to spatial isolation. Such characterization of spatial and environmental variables proved essential for proper interpretation of partial Mantel results based on observed beta diversity metrics. In summary, our results clearly indicate a dominant role of deterministic processes on bacterial assemblages and highlight that bacteria show strong habitat associations that have likely emerged through evolutionary adaptation.     

On Cannabis indica,Indian hemp

Background: The South Aegean Volcanic Arc (SAVA), one of the most notable geological structures of the Mediterranean Sea, is floristically well known. Nevertheless, the factors that contribute to shaping the plant species richness of the SAVA remain unclear.

Aims: To investigate the factors that affect plant species richness and identify plant diversity hotspots in the SAVA and other central Aegean islands.

Methods: We used stepwise multiple regression to test the relationship between a number of environmental factors and plant species richness in the SAVA, as well as the residuals from the species–area linear regressions of native, Greek and Cycladian endemic taxa as indicators of relative species richness.

Results: The area was confirmed to be the most powerful single explanatory variable of island species richness, while geodiversity, maximum elevation and mean annual precipitation explained a large proportion of variance for almost all the species richness measures. Anafi, Amorgos and Folegandros were found to be endemic plant diversity hotspots.

Conclusions: We have demonstrated that geodiversity is an important factor in shaping plant species diversity in the Cyclades, while mean annual precipitation, human population density and maximum elevation were significant predictors of the Greek endemics present in the Cyclades. Finally, Anafi was found to be a plant diversity hotspot in the South Aegean Sea.     

Individual identification from genetic marker data: developments and accuracy comparisons of methods

Genetic marker‐based identification of distinct individuals and recognition of duplicated individuals has important applications in many research areas in ecology, evolutionary biology, conservation biology and forensics. The widely applied genotype mismatch (MM) method, however, is inaccurate because it relies on a fixed and suboptimal threshold number (T_M) of mismatches, and often yields self‐inconsistent pairwise inferences. In this study, I improved MM method by calculating an optimal T_M to accommodate the number, mistyping rates, missing data and allele frequencies of the markers. I also developed a pairwise likelihood relationship (LR) method and a likelihood clustering (LC) method for individual identification, using poor‐quality data that may have high and variable rates of allelic dropouts and false alleles at genotyped loci. The 3 methods together with the relatedness (RL) method were then compared in accuracy by analysing an empirical frog data set and many simulated data sets generated under different parameter combinations. The analysis results showed that LC is generally one or two orders more accurate for individual identification than the other methods. Its accuracy is especially superior when the sampled multilocus genotypes have poor quality (i.e. teemed with genotyping errors and missing data) and highly replicated, a situation typical of noninvasive sampling used in estimating population size. Importantly, LC is the only method that guarantees to produce self‐consistent results by partitioning the entire set of multilocus genotypes into distinct clusters, each cluster containing one or more genotypes that all represent the same individual. The LC and LR methods were implemented in a computer program COLONY for free download from the Internet.     

Reduced aboveground tree growth associated with higher arbuscular mycorrhizal fungal diversity in tropical forest restoration

Establishing diverse mycorrhizal fungal communities is considered important for forest recovery, yet mycorrhizae may have complex effects on tree growth depending on the composition of fungal species present. In an effort to understand the role of mycorrhizal fungi community in forest restoration in southern Costa Rica, we sampled the arbuscular mycorrhizal fungal (AMF) community across eight sites that were planted with the same species (Inga edulis, Erythrina poeppigiana, Terminalia amazonia, and Vochysia guatemalensis) but varied twofold to fourfold in overall tree growth rates. The AMF community was measured in multiple ways: as percent colonization of host tree roots, by DNA isolation of the fungal species associated with the roots, and through spore density, volume, and identity in both the wet and dry seasons. Consistent with prior tropical restoration research, the majority of fungal species belonged to the genus Glomus and genus Acaulospora, accounting for more than half of the species and relative abundance found on trees roots and over 95% of spore density across all sites. Greater AMF diversity correlated with lower soil organic matter, carbon, and nitrogen concentrations and longer durations of prior pasture use across sites. Contrary to previous literature findings, AMF species diversity and spore densities were inversely related to tree growth, which may have arisen from trees facultatively increasing their associations with AMF in lower soil fertility sites. Changes to AMF community composition also may have led to variation in disturbance susceptibility, host tree nutrient acquisition, and tree growth. These results highlight the potential importance of fungal–tree–soil interactions in forest recovery and suggest that fungal community dynamics could have important implications for tree growth in disturbed soils.     

3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis,molecular modeling and QSAR studies

A new series of 3-substituted-4-hydroxycoumarin derivatives was designed, synthesized, and evaluated for CDK inhibiting and anticancer activities. All the synthesized target compounds showed remarkably high affinity and selectivity towards CDK1B, compared to flavopiridol, with Ki values in the low nanomolar range (Ki = 0.35–0.88 nM). Most of them elicited considerable inhibiting effect against CDK9T1 (Ki = 3.26–23.45 nM). Moreover, all the target compounds were tested in vitro against eighteen types of human tumor cell lines. The hydrazone 3a, N-phenylpyrazoline derivative 6b and 2-aminopyridyl-3-carbonitrile derivative 8c were the most potent anticancer agents against MCF-7 breast cancer cell line (IC₅₀ = 0.21, 0.21 and 0.23 nM, respectively). The target compounds 3a, 6b and 8c were further evaluated in MCF-7 breast cancer mouse xenograft model and showed in vivo efficacy at 10 mg/kg dose. The docking study confirmed a unique binding mode in the active site of CDK1B with better score than flavopiridol. Quantitative structure activity relationship study was done and revealed a highly predictive power R² of 0.81.     

A multi‐basin approach determines variability in host fish suitability for unionids in tributaries of the Laurentian Great Lakes

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Biodiversity and ecosystem stability across scales in metacommunities

Although diversity–stability relationships have been extensively studied in local ecosystems, the global biodiversity crisis calls for an improved understanding of these relationships in a spatial context. Here, we use a dynamical model of competitive metacommunities to study the relationships between species diversity and ecosystem variability across scales. We derive analytic relationships under a limiting case; these results are extended to more general cases with numerical simulations. Our model shows that, while alpha diversity decreases local ecosystem variability, beta diversity generally contributes to increasing spatial asynchrony among local ecosystems. Consequently, both alpha and beta diversity provide stabilising effects for regional ecosystems, through local and spatial insurance effects respectively. We further show that at the regional scale, the stabilising effect of biodiversity increases as spatial environmental correlation increases. Our findings have important implications for understanding the interactive effects of global environmental changes (e.g. environmental homogenisation) and biodiversity loss on ecosystem sustainability at large scales.