Improving Compound Quality through in vitro and in silico Physicochemical Profiling

Many compounds entering clinical studies do not survive the numerous hurdles for a good pharmacological lead to a drug on the market. The reasons for attrition have been widely studied which resulted in more early attention to compound quality related to physical chemistry, drug metabolism and pharmacokinetics (DMPK), and toxicology/safety. This paper will briefly review current physicochemical in vitro assays and in silico predictions to support compound and library design through to lead optimization. The most important physicochemical properties include lipophilicity (log P/D), pK_a, solubility, and permeability. These drive key ADMET properties such as absorption, cell penetration, access to the brain, volume of distribution, plasma protein binding, metabolism, and toxicity, as well as biopharmaceutical behavior. Much data are now available from medium‐ to high‐throughput physchem and ADMET in vitro assays, either in the public domain (see, e.g., PubChem, PubMed) or in drug companies' in‐house databases. Such data are increasingly being computer‐modelled and used in predictive chemistry. New pipelining technology makes it easier to build and update QSAR models so that such models can use the latest available data to produce robust local and global predictive in silico ADMET models.     

帽儿山天然次生林10种主要阔叶树冠径与胸径关系研究

根据帽儿山天然次生林30块标准地每木检尺的实测数据,建立帽儿山天然次生林10种主要阔叶树冠径与胸径以及胸径和冠径与胸径比值（cd/D）之间的关系,并且简要论述冠径与胸径比值在树木空间、断面积和林分密度和间伐强度的应用。研究表明：胸径在10~30 cm之间,相关系数（R²）在0.8以上时,冠径与胸径关系近似一条直线。通过对不同树种的不同大小树木(cd/D)比值的分析,得出随着胸径的增加的比值是逐渐减小的,并且减小的趋势随着胸径的增加趋于平稳,最后趋于一个常数。     

Origin and domestication history of Peking ducks deltermined through microsatellite and mitochondrial marker analysis

In order to elucidate the domestication history of Peking ducks, 190 blood samples from six Chinese indigenous duck breeds were collected with186 individualsgenotyped by 15 microsatellite markers. Both the F_ST and Nei’s standard genetic distances (D_s) from the microsatellite data indicated high genetic differentiation between Peking duck and other Chinese indigenous breeds. The haplotype network with mtDNA data showed that most of the Peking duck haplotypes were distinctly different from those of other domestic breeds. Although the H01 haplotype was shared by all domesticated duck breeds, Peking ducks displayed 12 specific domestic duck haplotypes, including four similar haplotypes H02, H04, H08 and H22, that formed a single haplogroup (A). Both H02 and H22 haplotypes were also shared by mallard and Peking ducks, indicating that Peking ducks originated from wild mallard ducks.     

Biodiversity scales from plots to biomes with a universal species–area curve

Classic theory predicts species richness scales as the quarter-power of area, yet species–area relationships (SAR) vary widely depending on habitat, taxa, and scale range. Because power-law SAR are used to predict species loss under habitat loss, and to scale species richness from plots to biomes, insight into the wide variety of observed SAR and the conditions under which power-law behavior should be observed is needed. Here we derive from the maximum entropy principle, a new procedure for upscaling species richness data from small census plots to larger areas, and test empirically, using multiple data sets, the prediction that up to an overall scale displacement, nested SAR lie along a universal curve, with average abundance per species at each scale determining the local slope of the curve. Power-law behaviour only arises in the limit of increasing average abundance, and in that limit, the slope approaches zero, not ¼. An extrapolation of tree species richness in the Western Ghats to biome scale (60 000 km²) using only census data at plot scale (¼ ha) is presented to illustrate the potential for applications of our theory.     

A flexible multi-scale approach for standardised recording of plant species richness patterns

A sound monitoring of appropriate biodiversity indicators is necessary in order to assess the progress towards the internationally agreed target of halting the loss of biodiversity by 2010. However, existing monitoring schemes often do not address species richness as a key component of biodiversity directly or do so with insufficient methods. I provide an overview and assessment of the large variety of different sampling approaches for small-scale plant species richness. Major shortcomings of many of these are (i) non-uniform plot sizes or shapes; (ii) analysis of only one spatial scale despite the scale dependence of nearly all biodiversity parameters; (iii) lack of replication of smaller subplots; and (iv) exclusion of bryophytes and lichens despite their often large contribution to total plant diversity. Based on this review, I propose a new standardised sampling approach for plant diversity patterns at small scales that is applicable for a multitude of purposes and in any biome. In its basic variant, species composition is recorded on nested squares of 0.01 m², 0.1 m², 1 m², 10 m², and 100 m², with all smaller subplots being replicated at least 3-fold and evenly spaced within the next larger plot. Not only terricolous vascular plants, but also bryophytes, lichens, macro-algae as well as non-terricolous taxa should be recorded with the any-part system, i.e. those plants are counted within a plot whose superficial parts reach over it. This approach can be used to assess plant diversity patterns (i) of individual plots of interest, (ii) along environmental gradients, (iii) within specific vegetation types, or (iv) for landscape sectors. In the latter case, the series of nested plots must be placed randomly or systematically, but irrespective of plot homogeneity. The proposed approach allows the calculation of many meaningful biodiversity indicators, while being well compatible with a range of other sampling schemes, but avoiding their shortcomings. As this approach is not very time-consuming in its basic variant, but can easily be extended for specific purposes, I suggest its use for any kind of biodiversity studies and particularly for monitoring.     

Evolution of seahorses' upright posture was linked to Oligocene expansion of seagrass habitats

Seahorses (Syngnathidae: Hippocampus) are iconic marine teleosts that are readily identifiable by their upright posture. The fossil record is inadequate to shed light on the evolution of this trait because it lacks transitional forms. There are, however, extant syngnathid species (the pygmy pipehorses) that look like horizontally swimming seahorses and that might represent a surviving evolutionary link between the benthic seahorses and other, free-swimming members of the family Syngnathidae. Using sequence data from five nuclear loci, we confirm the sister taxon relationship between seahorses and pygmy pipehorses. Molecular dating indicates that the two taxa diverged during the Late Oligocene. During this time, tectonic events in the Indo-West Pacific resulted in the formation of vast amounts of new shallow-water areas and associated expansion of seagrass habitats that would have favoured the seahorses’ upright posture by improving their camouflage while not affecting their manoeuvrability negatively. The molecular techniques employed here provide new insights into the evolution of a taxon whose fossil record is incomplete, but whose evolutionary history is so recent that the major stages of morphological evolution are still represented in extant species.     

Combined phylogenetic and neighbourhood analysis of the hexose transporters and glucose sensors in yeasts

The sugar porter family in yeasts encompasses a wide variety of transporters including the hexose transporters and glucose sensors. We analysed a total of 75 members from both groups in nine hemiascomycetous species, with complete and well-annotated genomes: Saccharomyces cerevisiae, Candida glabrata, Zygosaccharomyces rouxii, Kluyveromyces thermotolerans, Saccharomyces kluyverii, Kluyveromyces lactis, Eremothecium gossypii, Debaryomyces hansenii and Yarrowia lipolytica . We present a model for the evolution of the hexose transporters and glucose sensors, supported by two types of complementary evidences: phylogeny and neighbourhood analysis. Five lineages of evolution were identified and discussed according to different mechanisms of gene evolution: lineage A for HXT1, HXT3 , HXT4, HXT5 , HXT6 and HXT7 ; lineage B for HXT2 and HXT10 ; lineage C for HXT8 ; lineage D for HXT14 ; and lineage E for SNF3 and RGT2 .     

Short-tandem repeat analysis in seven Chinese regional populations

In the present study, we investigated the application of 13 short tandem repeat (STR) loci (D13S317, D7S820, TH01, D16S539, CSFIPO, VWA, D8S1179, TPOX, FGA, D3S1358, D21S11, D18S51 and D5S818) routinely used in forensic analysis, for delineating population relationships among seven human populations representing the two major geographic groups, namely the southern and northern Chinese. The resulting single topology revealed pronounced geographic and population partitioning, consistent with the differences in geographic location, languages and eating habits. These findings suggest that forensic STR loci might be particularly powerful tools in providing the necessary fine resolution for reconstructing recent human evolutionary history.     

Distance decay of community dynamics in rocky intertidal sessile assemblages evaluated by transition matrix models

It is well known that the similarity in species composition between two communities decays with the geographic distance that separates them. It is thus likely that the similarity in the dynamics of two communities also decays with distance, because the distance–decay relationship is fundamental in nature. However, the distance–decay relationships of community dynamics have not yet been revealed. We used transition matrix models to evaluate distance–decay relationships of seasonal community dynamics (from spring to summer) in rocky intertidal sessile assemblages along the Pacific coast of Japan between 31°N and 43°N. We evaluated the distance–decay relationships of whole-community dynamics and of three dynamics-related components—recruitment, disturbance, and species interaction (competition and facilitation)—for communities separated by distances ranging from several meters to thousands of kilometers. The similarity of the recruitment dynamics among communities declined rapidly with distance within the fine spatial scale, but only moderately within larger scales. The similarity of the disturbance dynamics was independent of distance, and the similarity of species interaction declined slightly with increasing distance. The similarity of whole-community dynamics declined rapidly with distance at a fine spatial scale and moderately at larger scales. The fact that the distance–decay relationship of whole-community dynamics was similar to that of recruitment may suggest that recruitment processes are the most important determinant of spatial variability of community dynamics at our study sites during the study period.