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Predation by generalist predators is difficult to study in the field because of the complex effects of positive and negative interactions within and between predator species and guilds. Predation can be monitored by molecular means, through identification of prey DNA within predators. However, polymerase chain reaction (PCR) amplification of prey DNA from predators cannot discriminate between primary and secondary predation (hyperpredation), in which one predator feeds on another that has recently eaten the target prey. Here we quantify, for the first time, the potential error caused by detection of prey DNA following secondary predation, using an aphid-spider-carabid model. First, the aphid Sitobion avenae was fed to the spider Tenuiphantes tenuis and the carabid Pterostichus melanarius, and the postconsumption detection periods, for prey DNA within predators, were calculated. Aphids were then fed to spiders and the spiders to carabids. Aphid DNA was detected in the predators using primers that amplified 245- and 110-bp fragments of the mitochondrial cytochrome oxidase I gene. Fragment size and predator sex had no significant effect on detection periods. Secondary predation could be detected for up to 8 h, when carabids fed on spiders immediately after the latter had consumed aphids. Beetles tested positive up to 4 h after eating spiders that had digested their aphid prey for 4 h. Clearly, the extreme sensitivity of PCR makes detection of secondary predation more likely, and the only reliable answer in future may be to use PCR to identify, in parallel, instances of intraguild predation.
Mol Ecol 2005 Dec
PMID:Detection of secondary predation by PCR analyses of the gut contents of invertebrate generalist predators. 1631 6

The apparent inter-lake morphological similarity among East African Great Lakes' cichlid species/genera has left evolutionary biologists asking whether such similarity is due to sharing of common ancestor or mere convergent evolution. In order to answer such question, we first used Geometric Morphometrics, GM, to quantify morphological similarity and then subsequently used Amplified Fragment Length Polymorphism, AFLP, to determine if similar morphologies imply shared ancestry or convergent evolution. GM revealed that not all presumed morphological similar pairs were indeed similar, and the dendrogram generated from AFLP data indicated distinct clusters corresponding to each lake and not inter-lake morphological similar pairs. Such results imply that the morphological similarity is due to convergent evolution and not shared ancestry. The congruency of GM and AFLP generated dendrograms imply that GM is capable of picking up phylogenetic signal, and thus GM can be potential tool in phylogenetic systematics.
Mol Phylogenet Evol 2006 Aug
PMID:Nuclear markers reveal that inter-lake cichlids' similar morphologies do not reflect similar genealogy. 1663 90

To unravel the relationship between the European wild apple, Malus sylvestris (L.) Mill., and its domesticated relative M. domestica Borkh., we studied chloroplast DNA variation in 634 wild and 422 domesticated accessions originating from different regions. Hybridization between M. sylvestris and M. domestica was checked using 10 nuclear microsatellites and a Bayesian assignment approach. This allowed us to identify hybrids and feral plants escaped from cultivation. Sixty-eight genotypes belonging to 12 other wild Malus species, including 20 M. sieversii (Ledeb.) Roem. accessions were also included in the analysis of chloroplast diversity. Marker techniques were developed to type a formerly described duplication and a newly detected transversion in the matK gene. Chloroplast DNA variation was further investigated using PCR-RFLP (Polymerase Chain Reaction-Random Fragment Length Polymorphism), and haplotypes were constructed based on all mutational combinations. A closer relationship than presently accepted between M. sylvestris and M. domestica was established at the cytoplasmic level, with the detection of eight chloroplast haplotypes shared by both species. Hybridization between M. sylvestris and M. domestica was also apparent at the local level with sharing of rare haplotypes among local cultivars and sympatric wild trees. Indications of the use of wild Malus genotypes in the (local) cultivation process of M. domestica and cytoplasmic introgression of chloroplast haplotypes into M. sylvestris from the domesticated apple were found. Only one of the M. sieversii trees studied displayed one of the three main chloroplast haplotypes shared by M. sylvestris and M. domestica. This is surprising as M. sieversii has formerly been described as the main maternal progenitor of the domesticated apple. This study hereby reopens the exciting discussion on the origin of M. domestica.
Mol Ecol 2006 Jul
PMID:Chloroplast diversity in the genus Malus: new insights into the relationship between the European wild apple (Malus sylvestris (L.) Mill.) and the domesticated apple (Malus domestica Borkh.). 1678 Apr 33

There are clearly many different philosophies associated with adapting fragment screening into mainstream Drug Discovery Lead Generation strategies. Scientists at Astex, for instance, focus entirely on strategies involving use of X-ray crystallography and NMR. However, AstraZeneca uses a number of different fragment screening strategies. One approach is to screen a 2000 compound fragment set (with close to "lead-like" complexity) at 100 microM in parallel with every HTS such that the data are obtained on the entire screening collection at 10 microM plus the extra samples at 100 microM; this provides valuable compound potency data in a concentration range that is usually unexplored. The fragments are then screen-specific "privileged structures" that can be searched for in the rest of the HTS output and other databases as well as having synthesis follow-up. A typical workflow for a fragment screen within AstraZeneca is shown below (Figure 24) and highlights the desirability (particularly when screening >100 microM) for NMR and X-ray information to validate weak hits and give information on how to optimise them. In this chapter, we have provided an introduction to the theoretical and practical issues associated with the use of fragment methods and lead-likeness. Fragment-based approaches are still in an early stage of development and are just one of many interrelated techniques that are now used to identify novel lead compounds for drug development. Fragment based screening has some advantages, but like every other drug hunting strategy will not be universally applicable. There are in particular some practical challenges associated with fragment screening that relate to the generally lower level of potency that such compounds initially possess. Considerable synthetic effort has to be applied for post-fragment screening to build the sort of potency that would be expected to be found from a traditional HTS. However, if there are no low-hanging fruit in a screening collection to be found by HTS then the use of fragment screening can help find novelty that may lead to a target not being discarded as intractable. As such, the approach offers some significant advantages by providing less complex molecules, which may have better potential for novel drug optimisation and by enabling new chemical space to be more effectively explored. Many literature examples that cover examples of fragment screening approaches are still at the "proof of concept" stage and although delivering inhibitors or ligands, may still prove to be unsuitable when further ADMET and toxicity profiling is done. The next few years should see a maturing of the area, and as our understanding of how the concepts can be best applied, there are likely to be many more examples of attractive, small molecule hits, leads and candidate drugs derived from the approaches described.
Mol Biosyst 2006 Sep
PMID:Fragment screening: an introduction. 1715 40

Amplified Fragment Length Polymorphism (AFLP) markers are formed by selective amplification of DNA fragments from digested total genomic DNA. The technique is popular because it is a relatively inexpensive way to produce large numbers of reproducible genetic markers. In this paper, we describe a Bayesian approach to modeling AFLP marker evolution by nucleotide substitution and an MCMC approach to estimate phylogeny from AFLP marker data. We demonstrate the method on species in Carex section Ovales, a group of sedges common in North America. We compare the results of our analysis with a clustering method based on Nei and Li's restriction-site distance and a two-state Bayesian analysis using MrBayes.
Stat Appl Genet Mol Biol 2007
PMID:A Bayesian model of AFLP marker evolution and phylogenetic inference. 1747 77

Different processes have contributed to shaping the present distribution of the European biotas. Up to three different tertiary- to quaternary-time-scale evolutionary scenarios have been proposed to interpret the divergence and genetic structuring of plant species in Europe. In the present study, the Amplified Fragment Length Polymorphisms technique has been used to unravel the species and regional phylogeography of the European sweet vernal grasses (Anthoxanthum L. Poaceae). Forty-six populations belonging to all seven European species of Anthoxanthum and covering a broad geographical and ecological range were selected. Different phylogeography and population genetics diversity and structure estimates indicated a clear divergence of old Messinian Mediterranean lineages, followed by a pre-Pliocene split between Mediterranean annuals and Eurosiberian perennials and a more recent Pleistocene differentiation of Arctic-Alpine, Atlantic and Submediterranean diploid to polyploid landraces. Regional and population correlation tests between geographical and genetic distances allowed to postulate distinct pre- and post-glacial colonization pathways across Europe for the taxa of this widespread genus.
Mol Phylogenet Evol 2007 Aug
PMID:Genetic diversity and spatial correlation patterns unravel the biogeographical history of the European sweet vernal grasses (Anthoxanthum L., Poaceae). 1753 9

A previous report demonstrated that one site in a nucleosome assembled onto a synthetic positioning sequence known as Fragment 67 is hypersensitive to permanganate. The site is required for positioning activity and is located 1.5 turns from the dyad, which is a region of high DNA curvature in the nucleosome. Here, the permanganate sensitivity of the nucleosome positioning Fragment 601 was examined in order to expand the dataset of nucleosome sequences containing KMnO(4) hypersensitive sites. The hyperreactive T residue in the six sites detected as well as the one in Fragment 67 and three in the 5 S rDNA positioning sequence were contained within a TA step. Seven of the ten sequences were of the form CTAGPuG or the related sequence TTAAPu. These motifs were also found in the binding sites of several transcriptional regulatory proteins that kink DNA. In order to assess the significance of these sites, the 10 bp positioning determinant in Fragment 67 was removed and replaced by the nine sequences from the 5 S rDNA and Fragment 601. The results demonstrated that these derivative fragments promoted high nucleosome stability and positioning as compared to a control sequence that contained an AT step in place of the TA step. The importance of the TA step was further tested by making single base-pair substitutions in Fragment 67 and the results revealed that stability and positioning activity followed the order: TA>TG>TT>/=TC approximately GG approximately GA approximately AT. Sequences flanking the TA step were also shown to be critical for nucleosome stability and positioning. Nucleosome positioning was restored to near wild-type levels with (CTG)(3), which can form slipped stranded structures and with one base bulges that kink DNA. The results of this study suggest that local DNA structures are important for positioning and that single base-pair changes at these sites could have profound effects on those genomic functions that depend on ordered nucleosomes.
J Mol Biol 2007 Aug 17
PMID:Nucleosome positioning determinants. 1758 22

We present a new algorithm for the enumeration of chemical fragment spaces under constraints. Fragment spaces consist of a set of molecular fragments and a set of rules that specifies how fragments can be combined. Although fragment spaces typically cover an infinite number of molecules, they can be enumerated in case that a physicochemical profile of the requested compounds is given. By using min-max ranges for a number of corresponding properties, our algorithm is able to enumerate all molecules which obey these properties. To speed up the calculation, the given ranges are used directly during the build-up process to guide the selection of fragments. Furthermore, a topology based fragment filter is used to skip most of the redundant fragment combinations. We applied the algorithm to 40 different target classes. For each of these, we generated tailored fragment spaces from sets of known inhibitors and additionally derived ranges for several physicochemical properties. We characterized the target-specific fragment spaces and were able to enumerate the complete chemical subspaces for most of the targets.
J Comput Aided Mol Des 2007 Jun
PMID:Exploring fragment spaces under multiple physicochemical constraints. 1759 75

Cucumber (Cucumis sativus) is a monoecious plant that serves as a model for the study of floral sex determination. The genetic background, hormonal and environmental factors regulating unisexual flower development are well characterized, however, the molecular mechanisms are less well understood. To isolate genes involved in male and female flower development we conducted a differential cDNA-Amplified Fragment Length Polymorphism analysis using plant growth apices of predominantly male (monoecious) and female (gynoecious) near isogenic cucumber lines. The plant apices of monoecious cucumbers carry bisexual and unisexual male floral buds while gynoecious ones carry bisexual and unisexual female floral buds. We isolated a cDNA fragment that encodes a putative GTP binding tyrosine phosphorylated protein A (CsTypA1) that is developmentally regulated. CsTypA1 is expressed in stamen primordia and its transcript is more abundant in monoecious plant apices implying a role for CsTypA1 in the early stages of male reproductive organ development. At later stages of flower development a higher transcript level is observed in female flowers in stigmatic papilla, nectary and in particular ovule/ovary tissue. The differential expression of CsTypA1 during male and female flower development indicates a role for CsTypA1 in female flower development, in particular that of the ovary/ovule. Thus, CsTypA1 might have a dual role, one in the early stages of flower development, possibly during sex determination, and the other in the development of the ovary/ovule. This is the first report of a gene encoding a putative TypA in the plant kingdom that is differentially expressed during plant development.
Plant Mol Biol 2007 Dec
PMID:A developmentally regulated GTP binding tyrosine phosphorylated protein A-like cDNA in cucumber (Cucumis sativus L.). 1792 61

Amino azobenzenes are important dyes in the food and textile industry but their application is limited due to their mutagenicity. Computational modeling techniques were used to help understand the factors responsible for mutagenicity, and several quantitative structure toxicity relationship (QSTR) models have been derived. HQSTR (hologram QSTR) analyses indicated that different substituents at sites on both rings contribute to mutagenicity. Fragment parameters such as bond (B) and connectivity(C), as well as donor-acceptor (DA)-based model provide significant results (q(2) = 0.59, r(2) = 0.92, r(2)predictive = 0.63) explaining these harmful effect. HQSTR results indicated that a bulky group at ring "Y" and small group at ring "X" might help to decrease mutagenicity. 3D-QSTR based on comparative molecular field analyses (CoMFA) and comparative molecular similarity index analyses (CoMSIA) are also in agreement with HQSTR. The 3D QSTR studies reveal that steric and electrostatic field effects have a strong relationship with mutagenicity (for CoMFA: q(2) = 0.51, r(2 )= 0.95, r(2) predictive = 0.65 and for CoMSIA: q(2) = 0.51, r(2) = 0.93 and r(2) predictive = 0.84). In summary, negative groups and steric bulk at ring "Y" and small groups at carbon-3 of ring "X" might be helpful in reducing the mutagenicity of azo dyes.
J Mol Model 2008 Apr
PMID:Hologram and 3D-quantitative structure toxicity relationship studies of azo dyes. 1825 61


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