Publication Date: 2008 Nov 20 PMID: 19046974br/Authors: Pathuri, P. - Nguyen, E. T. - Ozorowski, G. - Svard, S. G. - Luecke, H.br/Journal: J Mol Biolbr/br/Alpha-14 giardin (annexin E1), a member of the alpha giardin family of annexins, has been shown to localize to the flagella of the intestinal protozoan parasite Giardia lamblia. Alpha giardins show a common ancestry with the annexins, a family of proteins most of which bind to phospholipids and cellular membranes in a Ca(2+)-dependent manner and are implicated in numerous membrane-related processes including cytoskeletal rearrangements and membrane organization. It has been proposed that alpha-14 giardin may play a significant role during the cytoskeletal rearrangement during differentiation of Giardia. To gain a better understanding of alpha-14 giardin's mode of action and its biological role, we have determined the three-dimensional structure of alpha-14 giardin and its phospholipid-binding properties. Here, we report the apo crystal structure of alpha-14 giardin determined in two different crystal forms as well as the Ca(2+)-bound crystal structure of alpha-14 giardin, refined to 1.9, 1.6 and 1.65 A, respectively. Although the overall fold of alpha-14 giardin is similar to that of alpha-11 giardin, multiwavelength anomalous dispersion phasing was required to solve the alpha-14 giardin structure, indicating significant structural differences between these two members of the alpha giardin family. Unlike most annexin structures, which typically possess N-terminal domains, alpha-14 giardin is composed of only a core domain, followed by a C-terminal extension that may serve as a ligand for binding to cytoskeletal protein partners in Giardia. In the Ca(2+)-bound structure we detected five bound calcium ions, one of which is a novel, highly coordinated calcium-binding site not previously observed in annexin structures. This novel high-affinity calcium-binding site is composed of seven protein donor groups, a feature rarely observed in crystal structures. In addition, phospholipid-binding assays suggest that alpha-14 giardin exhibits calcium-dependent binding to phospholipids that coordinate cytoskeletal disassembly/assembly during differentiation of the parasite.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19046974title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Dec 1 PMID: 19046436br/Authors: Su, S. Y. - White, J. - Balding, D. J. - Coin, L. J.br/Journal: BMC Bioinformaticsbr/br/ABSTRACT: BACKGROUND: The power of haplotype-based methods for association studies, identification of regions under selection, and ancestral inference, is well-established for diploid organisms. For polyploids, however, the difficulty of determining phase has limited such approaches. Polyploidy is common in plants and is also observed in animals. Partial polyploidy is sometimes observed in humans (e.g. trisomy 21; Down's syndrome), and it arises more frequently in some human tissues. Local changes in ploidy, known as copy number variations (CNV), arise throughout the genome. Here we present a method, implemented in the software polyHap, for the inference of haplotype phase and missing observations from polyploid genotypes. RESULTS: PolyHap allows each individual to have a different ploidy, but ploidy cannot vary over the genomic region analysed. It employs a hidden Markov model (HMM) and a sampling algorithm to infer haplotypes jointly in multiple individuals and to obtain a measure of uncertainty in its inferences. In the simulation study, we combine real haplotype data to create artificial diploid, triploid, and tetraploid genotypes, and use these to demonstrate that polyHap performs well, in terms of both switch error rate in recovering phase and imputation error rate for missing genotypes. To our knowledge, there is no comparable software for phasing a large, densely genotyped region of chromosome from triploids and tetraploids, while for diploids we found polyHap to be more accurate than fastPhase. We also compare the results of polyHap to SATlotyper on an experimentally haplotyped tetraploid dataset of 12 SNPs, and show polyHap is more accurate. With the availability of large SNP data in polyploids and CNV regions, CONCLUSIONS: We believe that polyHap, our proposed method for inferring haplotypic phase from genotype data, will be useful in enabling researchers analysing such data to exploit the power of haplotype-based analyses.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19046436title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 20 PMID: 19046973br/Authors: Synowsky, S. A. - van Wijk, M. - Raijmakers, R. - Heck, A. J.br/Journal: J Mol Biolbr/br/Here we combined tandem affinity purification with several mass-spectrometry-based approaches to gain more insight into the composition and structure of the yeast nuclear-cytoplasmic exosome protein complex. The yeast exosome fulfills several different functions in RNA metabolism and can be localized in both the cytoplasm and the nucleus. These two exosome complexes differ in protein composition, although they share several constituents. We focused on these differences in composition by selecting a nuclear-specific exosome protein (Rrp6) and a cytoplasmic-specific protein (Ski7) as the tandem-affinity-purification-tagged affinity bait protein. First, we investigated both these purified exosome assemblies by macromolecular mass spectrometry (MS) to determine the stability and mass of the intact protein complexes and to obtain information on composition and core constituents. We used tandem MS on these intact protein complexes to further probe the composition and to obtain insight into the peripheral nature of some of the constituents. Finally, we combine stable isotope labeling with MS to quantitate differences in exosome composition and their posttranslational modifications. We identified a few phosphorylation sites that are differentially regulated between the cytoplasmic exosome and the nuclear exosome. From all of these data, we conclude that the yeast nuclear exosome and the cytoplasmic exosome share a common stable core complex, but are decorated with quite a few differing peripheral proteins. We show that the nuclear exosome selectively copurifies with the alpha/beta importin heterodimer, which is known to be involved in the transport of proteins across the nuclear membrane.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19046973title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Dec 1 PMID: 19046434br/Authors: Blangiardo, M. - Richardson, S.br/Journal: BMC Bioinformaticsbr/br/ABSTRACT: BACKGROUND: In gene expression studies a key role is played by the so called ;;pre-processing'', a series of steps designed to extract the signal and account for the sources of variability due to the technology used rather than to biological differences between the RNA samples. At the moment there is no commonly agreed gold standard pre-processing method and each researcher has the responsibility to choose one method, incurring the risk of false positive and false negative features arising from the particular method chosen. RESULTS: We propose a Bayesian calibration model that makes use of the information provided by several pre-processing methods and we show that this model gives a better assessment of the ;true' unknown differential expression between two conditions. We demonstrate how to estimate the posterior distribution of the differential expression values of interest from the combined information. CONCLUSIONS: On simulated data and on the spike-in Latin Square dataset from Affymetrix the Bayesian calibration model proves to have more power than each pre-processing method. Its biological interest is demonstrated through an experimental example on publicly available data.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19046434title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Dec 1 PMID: 19046431br/Authors: Oscamou, M. - McDonald, D. - Yap, V. B. - Huttley, G. A. - Lladser, M. E. - Knight, R.br/Journal: BMC Bioinformaticsbr/br/ABSTRACT: BACKGROUND: The nucleotide substitution rate matrix is a key parameter of molecular evolution. Several methods for inferring this parameter have been proposed, with different mathematical bases. These methods include counting sequence differences and taking the log of the resulting probability matrices, methods based on Markov triples, and maximum likelihood methods that infer the substitution probabilities that lead to the most likely model of evolution. However, the speed and accuracy of these methods has not been compared. RESULTS: Different methods differ in performance by orders of magnitude (ranging from 1 ms to 10 s per matrix), but differences in accuracy of rate matrix reconstruction appear to be relatively small. Encouragingly, relatively simple and fast methods can provide results at least as accurate as far more complex and computationally intensive methods, especially when the sequences to be compared are relatively short. CONCLUSIONS: Based on the conditions tested, we recommend the use of method of Gojobori et al. (1982) for long sequences (300 nucleotides), and the method of Goldman et al. (1996) for shorter sequences (300 nucleotides). The method of Barry and Hartigan (1987) can provide somewhat more accuracy, measured as the Euclidean distance between the true and inferred matrices, on long sequences (2000 nucleotides) at the expense of substantially longer computation time. The availability of methods that are both fast and accurate will allow us to gain a global picture of change in the nucleotide substitution rate matrix on a genomewide scale across the tree of life.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19046431title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Dec 1 PMID: 19046430br/Authors: Liu, B. - Wang, X. - Lin, L. - Dong, Q. - Wang, X.br/Journal: BMC Bioinformaticsbr/br/ABSTRACT: BACKGROUND: Protein remote homology detection and fold recognition are central problems in bioinformatics. Currently, discriminative methods based on support vector machine (SVM) are the most effective and accurate methods for solving these problems. A key step to improve the performance of the SVM-based methods is to find a suitable representation of protein sequences. RESULTS: In this paper, a novel building block of proteins called Top-n-grams is presented, which contains the evolutionary information extracted from the protein sequence frequency profiles. The protein sequence frequency profiles are calculated from the multiple sequence alignments outputted by PSI-BLAST and converted into Top-n-grams. The protein sequences are transformed into fixed-dimension feature vectors by the occurrence times of each Top-n-gram. The training vectors are evaluated by SVM to train classifiers which are then used to classify the test protein sequences. We demonstrate that the prediction performance of remote homology detection and fold recognition can be improved by combining Top-n-grams and latent semantic analysis (LSA), which is an efficient feature extraction technique from natural language processing. When tested on superfamily and fold benchmarks, the method combining Top-n-grams and LSA gives significantly better results compared to related methods. CONCLUSIONS: The method based on Top-n-grams significantly outperforms the methods based on many other building blocks including N-grams, patterns, motifs and binary profiles. Therefore, Top-n-gram is a good building block of the protein sequences and can be widely used in many tasks of the computational biology, such as the sequence alignment, the prediction of domain boundary, the designation of knowledge-based potentials and the prediction of protein binding sites.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19046430title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Dec 1 PMID: 19046422br/Authors: Naiser, T. - Kayser, J. - Mai, T. - Michel, W. - Ott, A.br/Journal: BMC Bioinformaticsbr/br/ABSTRACT: BACKGROUND: The propensity of oligonucleotide strands to form stable duplexes with complementary sequences is fundamental to a variety of biological and biotechnological processes as various as microRNA signalling, microarray hybridization and PCR. Yet our understanding of oligonucleotide hybridization, in particular in presence of surfaces, is rather limited. Here we use oligonucleotide microarrays made in-house by optically controlled DNA synthesis to produce probe sets comprising all possible single base mismatches and base bulges for each of 20 sequence motifs under study. RESULTS: We observe that mismatch discrimination is mostly determined by the defect position (relative to the duplex ends) as well as by the sequence context. We investigate the thermodynamics of the oligonucleotide duplexes on the basis of double-ended molecular zipper. Theoretical predictions of defect positional influence as well as long range sequence influence agree well with the experimental results. CONCLUSIONS: Molecular zipping at thermodynamic equilibrium explains the binding affinity of mismatched DNA duplexes on microarrays well. The position dependent nearest neighbor model (PDNN) can be inferred from it. Quantitative understanding of microarray experiments from first principles is in reach.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19046422title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Dec PMID: 19043846br/Authors: Rakic, P. - Grillner, S. - Jessell, T.br/Journal: Nat Rev Neuroscibr/br/br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19043846title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 20 PMID: 19043832br/Authors: Ledford, H.br/Journal: Naturebr/br/br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19043832title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 28 PMID: 19043077br/Authors: Kitamura, N. - Akazawa, K. - Miyashita, A. - Kuwano, R. - Toyabe, S. I. - Nakamura, J. - Nakamura, N. - Sato, T. - Hoque, M. A.br/Journal: Bioinformaticsbr/br/MOTIVATION: A two-stage association study is the most commonly used method among multistage designs to efficiently identify disease susceptibility genes. Recently, some SNP studies have utilized more than two stages to detect disease genes. However, there are few available programs for calculating statistical powers and positive predictive values of arbitrary n-stage designs RESULTS: We developed programs for a multistage case-control association study using R language. In our programs, input parameters include numbers of samples and candidate loci, genome-wide false positive rate, and proportions of samples and loci to be selected at the k th stage (k = 1,..., n). The programs output statistical powers, positive predictive values and numbers of typings in arbitrary n-stage designs. The programs can contribute to prior simulations under various conditions in planning a genome-wide association study. AVAILABILITY: The R programs are freely available for academic users and can be downloaded from http://www.med.niigata-u.ac.jp/eng/resources/informatics/gwa.html CONTACT: nktmr@m12.alpha-net.ne.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19043077title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 29 PMID: 19040754br/Authors: Foley, J. W. - Katagiri, F.br/Journal: BMC Bioinformaticsbr/br/ABSTRACT: BACKGROUND: Large biological data sets, such as expression profiles, benefit from reduction of random noise. Principal component (PC) analysis has been used for this purpose, but it tends to remove small features as well as random noise. RESULTS: We interpreted the PCs as a mere signal-rich coordinate system and sorted the squared PC-coordinates of each row in descending order. The sorted squared PC-coordinates were compared with the distribution of the ordered squared random noise, and PC-coordinates for insignificant contributions were treated as random noise and nullified. The processed data were transformed back to the initial coordinates as noise-reduced data. To increase the sensitivity of signal capture and reduce the effects of stochastic noise, this procedure was applied to multiple small subsets of rows randomly sampled from a large data set, and the results corresponding to each row of the data set from multiple subsets were averaged. We call this procedure Row-specific, Sorted PRincipal component-guided Noise Reduction (RSPR-NR). Robust performance of RSPR-NR, measured by noise reduction and retention of small features, was demonstrated using simulated data sets. Furthermore, when applied to an actual expression profile data set, RSPR-NR preferentially increased the correlations between genes that share the same Gene Ontology terms, strongly suggesting reduction of random noise in the data set. CONCLUSIONS: RSPR-NR is a robust random noise reduction method that retains small features well. It should be useful in improving the quality of large biological data sets.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19040754title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 14 PMID: 19041879br/Authors: Jehle, S. - van Rossum, B. - Stout, J. R. - Noguchi, S. R. - Falber, K. - Rehbein, K. - Oschkinat, H. - Klevit, R. E. - Rajagopal, P.br/Journal: J Mol Biolbr/br/Atomic-level structural information on alphaB-crystallin (alphaB), a prominent member of the small heat shock protein family, has been a challenge to obtain due its polydisperse oligomeric nature. We show that magic-angle spinning solid-state NMR can be used to obtain high-resolution information on an approximately 580-kDa human alphaB assembled from 175-residue 20-kDa subunits. An approximately 100-residue alpha-crystallin domain is common to all small heat shock proteins, and solution-state NMR was performed on two different alpha-crystallin domain constructs isolated from alphaB. In vitro, the chaperone-like activities of full-length alphaB and the isolated alpha-crystallin domain are identical. Chemical shifts of the backbone and C(beta) resonances have been obtained for residues 64-162 (alpha-crystallin domain plus part of the C-terminus) in alphaB and the isolated alpha-crystallin domain by solid-state and solution-state NMR, respectively. Both sets of data strongly predict six beta-strands in the alpha-crystallin domain. A majority of residues in the alpha-crystallin domain have similar chemical shifts in both solid state and solution state, indicating similar structures for the domain in its isolated and oligomeric forms. Sites of intersubunit interaction are identified from chemical shift differences that cluster to specific regions of the alpha-crystallin domain. Multiple signals are observed for the resonances of M68 in the oligomer, identifying the region containing this residue as existing in heterogeneous environments within alphaB. Evidence for a novel dimerization motif in the human alpha-crystallin domain is obtained by a comparison of (i) solid-state and solution-state chemical shift data and (ii) (1)H-(15)N heteronuclear single quantum coherence spectra as a function of pH. The isolated alpha-crystallin domain undergoes a dimer-monomer transition over the pH range 7.5-6.8. This steep pH-dependent switch may be important for alphaB to function optimally (e.g., to preserve the filament integrity of cardiac muscle proteins such as actin and desmin during cardiac ischemia, which is accompanied by acidosis).br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19041879title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 30 PMID: 19043410br/Authors: Matsumoto, M. - Hikosaka, O.br/Journal: Nat Neuroscibr/br/An action may lead to either a reward or a punishment. Therefore, an appropriate action needs to be chosen on the basis of the values of both expected rewards and expected punishments. To understand the underlying neural mechanisms, we conditioned monkeys using a Pavlovian procedure with two distinct contexts: one in which rewards were available and another in which punishments were feared. We found that the population of lateral habenula neurons was most strongly excited by a conditioned stimulus associated with the most unpleasant event in each context: the absence of the reward or the presence of the punishment. The population of lateral habenula neurons was also excited by the punishment itself and inhibited by the reward itself, especially when they were less predictable. These results suggest that the lateral habenula has the potential to adaptively control both reward-seeking and punishment-avoidance behaviors, presumably through its projections to dopaminergic and serotonergic systems.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19043410title=Entrez+PubmedCiteULike/a

Publication Date: PMID: br/Authors: br/Journal: br/br/br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3Dtitle=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 20 PMID: 19043831br/Authors: Gewin, V.br/Journal: Naturebr/br/br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19043831title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 27 PMID: 19042916br/Authors: Yilmaz, S. - Jonveaux, P. - Bicep, C. - Pierron, L. - Smail-Tabbone, M. - Devignes, M.br/Journal: Bioinformaticsbr/br/MOTIVATION: Computational methods are widely used to discover gene-disease relationships hidden in vast masses of available genomic and post-genomic data. In most current methods, a similarity measure is calculated between gene annotations and known disease genes or disease descriptions. However, more explicit gene-disease relationships are required for better insights into the molecular bases of diseases, especially for complex multi-gene diseases. RESULTS: Explicit relationships between genes and diseases are formulated as candidate gene definitions that may include intermediary genes, e.g., orthologous or interacting genes. These definitions guide data modelling in our database approach for gene-disease relationship discovery and are expressed as views which ultimately lead to the retrieval of documented sets of candidate genes. A system called ACGR (Approach for Candidate Gene Retrieval) has been implemented and tested with three case-studies including a rare orphan gene disease. AVAILABILITY: The ACGR sources are freely available at http://bioinfo.loria.fr/projects/acgr/acgr-software/. CONTACT: devignes@loria.fr SUPPLEMENTARY INFORMATION: See the file disease_description and the folders Xcollect_scenarios and ACGR_views at http://bioinfo.loria.fr/projects/acgr .br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19042916title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 28 PMID: 19040747br/Authors: Xia, J. - Bjorndahl, T. C. - Tang, P. - Wishart, D. S.br/Journal: BMC Bioinformaticsbr/br/ABSTRACT: BACKGROUND: One-dimensional (1D) 1H nuclear magnetic resonance (NMR) spectroscopy is widely used in metabolomic studies involving biofluids and tissue extracts. There are several software packages that support compound identification and quantification via 1D 1H NMR by spectral fitting techniques. Because 1D 1H NMR spectra are characterized by extensive peak overlap or spectral congestion, two-dimensional (2D) NMR, with its increased spectral resolution, could potentially improve and even automate compound identification or quantification. However, the lack of dedicated software for this purpose significantly restricts the application of 2D NMR methods to most metabolomic studies. RESULTS: We describe a standalone graphics software tool, called MetaboMiner, which can be used to automatically or semi-automatically identify metabolites in complex biofluids from 2D NMR spectra. MetaboMiner is able to handle both 1H-1H total correlation spectroscopy (TOCSY) and 1H-13C heteronuclear single quantum correlation (HSQC) data. It identifies compounds by comparing 2D spectral patterns in the NMR spectrum of the biofluid mixture with specially constructed libraries containing reference spectra of ~500 pure compounds. Tests using a variety of synthetic and real spectra of compound mixtures showed that MetaboMiner is able to identify 80% of detectable metabolites from good quality NMR spectra. CONCLUSIONS: MetaboMiner is a freely available, easy-to-use, NMR-based metabolomics tool that facilitates automatic peak processing, rapid compound identification, and facile spectrum annotation from either 2D TOCSY or HSQC spectra. Using comprehensive reference libraries coupled with robust algorithms for peak matching and compound identification, the program greatly simplifies the process of metabolite identification in complex 2D NMR spectra.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19040747title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 18 PMID: 19041878br/Authors: Davis, I. W. - Baker, D.br/Journal: J Mol Biolbr/br/Computational docking of small-molecule ligands into protein receptors is an important tool for modern drug discovery. Although conformational adjustments are frequently observed between the free and ligand-bound states, the conformational flexibility of the protein is typically ignored in protein-small molecule docking programs. We previously described the program RosettaLigand, which leverages the Rosetta energy function and side-chain repacking algorithm to account for flexibility of all side chains in the binding site. Here we present extensions to RosettaLigand that incorporate full ligand flexibility as well as receptor backbone flexibility. Including receptor backbone flexibility is found to produce more correct docked complexes and to lower the average RMSD of the best-scoring docked poses relative to the rigid-backbone results. On a challenging set of retrospective and prospective cross-docking tests, we find that the top-scoring ligand pose is correctly positioned within 2 A RMSD for 64% (54/85) of cases overall.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19041878title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 30 PMID: 19043409br/Authors: Liu, X. - Davis, R. L.br/Journal: Nat Neuroscibr/br/GABAergic neurotransmitter systems are important for many cognitive processes, including learning and memory. We identified a single neuron in each hemisphere of the Drosophila brain, the anterior paired lateral (APL) neuron, as a GABAergic neuron that broadly innervated the mushroom bodies. Reducing GABA synthesis in the APL neuron enhanced olfactory learning, suggesting that the APL neuron suppressed learning by releasing the inhibitory neurotransmitter GABA. Functional optical-imaging experiments revealed that the APL neuron responded to both odor and electric-shock stimuli that was presented to the fly with increases of intracellular calcium and released neurotransmitter. Notably, a memory trace formed in the APL neuron by pairing odor with electric shock. This trace was detected as a reduced calcium response in the APL neuron after conditioning specifically to the trained odor. These results demonstrate a mutual suppression between the GABAergic APL neuron and olfactory learning, and emphasize the functional neuroplasticity of the GABAergic system as a result of learning.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19043409title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 20 PMID: 19043829br/Authors: Chandra, V. - Huang, P. - Hamuro, Y. - Raghuram, S. - Wang, Y. - Burris, T. P. - Rastinejad, F.br/Journal: Naturebr/br/Nuclear receptors are multi-domain transcription factors that bind to DNA elements from which they regulate gene expression. The peroxisome proliferator-activated receptors (PPARs) form heterodimers with the retinoid X receptor (RXR), and PPAR-gamma has been intensively studied as a drug target because of its link to insulin sensitization. Previous structural studies have focused on isolated DNA or ligand-binding segments, with no demonstration of how multiple domains cooperate to modulate receptor properties. Here we present structures of intact PPAR-gamma and RXR-alpha as a heterodimer bound to DNA, ligands and coactivator peptides. PPAR-gamma and RXR-alpha form a non-symmetric complex, allowing the ligand-binding domain (LBD) of PPAR-gamma to contact multiple domains in both proteins. Three interfaces link PPAR-gamma and RXR-alpha, including some that are DNA dependent. The PPAR-gamma LBD cooperates with both DNA-binding domains (DBDs) to enhance response-element binding. The A/B segments are highly dynamic, lacking folded substructures despite their gene-activation properties.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19043829title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 28 PMID: 19040743br/Authors: Kechris, K. - Li, H.br/Journal: BMC Bioinformaticsbr/br/ABSTRACT: BACKGROUND: Computational methods for characterizing novel transcription factor binding sites search for sequence patterns or motifs that appear repeatedly in genomic regions of interest. Correlation-based motif finding strategies are used to identify motifs that correlate with expression data and do not rely on promoter sequences from a pre-determined set of genes. RESULTS: In this work, we describe a method for predicting motifs that combines the correlation-based strategy with phylogenetic footprinting, where motifs are identified by evaluating orthologous sequence regions from multiple species. Our method, c-REDUCE, can account for variability at a motif position inferred from evolutionary information. c-REDUCE has been tested on ChIP-chip data for yeast transcription factors and on gene expression data in Drosophila. CONCLUSION: Our results indicate that utilizing sequence conservation information in addition to correlation-based methods improves the identification of known motifs.br/br/post to: a href = http://www.citeulike.org/posturl?url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26dopt%3DAbstract%26list_uids%3D19040743title=Entrez+PubmedCiteULike/a

Publication Date: 2008 Nov 18 PMID: 19041877br/Authors: Chang, E. S. - Liao, T. Y. - Lim, T. S. - Fann, W. - Chen, R. P.br/Journal: J Mol Biolbr/br/Amyloid plaques, formed from amyloid beta (Abeta) peptides (mainly Abeta40 or Abeta42), are one of the most important pathological characteristics of Alzheimer's disease. Here, a single D-form proline substitution in the 40-amino-acid Abet