Kernel learning for ligand-based virtual screening:discovery of a new PPARgamma agonist
- Poster presentation at 5th German Conference on Cheminformatics: 23. CIC-Workshop Goslar, Germany. 8-10 November 2009 We demonstrate the theoretical and practical application of modern kernel-based machine learning methods to ligand-based virtual screening by successful prospective screening for novel agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) . PPARgamma is a nuclear receptor involved in lipid and glucose metabolism, and related to type-2 diabetes and dyslipidemia. Applied methods included a graph kernel designed for molecular similarity analysis , kernel principle component analysis , multiple kernel learning , and, Gaussian process regression . In the machine learning approach to ligand-based virtual screening, one uses the similarity principle  to identify potentially active compounds based on their similarity to known reference ligands. Kernel-based machine learning  uses the "kernel trick", a systematic approach to the derivation of non-linear versions of linear algorithms like separating hyperplanes and regression. Prerequisites for kernel learning are similarity measures with the mathematical property of positive semidefiniteness (kernels). The iterative similarity optimal assignment graph kernel (ISOAK)  is defined directly on the annotated structure graph, and was designed specifically for the comparison of small molecules. In our virtual screening study, its use improved results, e.g., in principle component analysis-based visualization and Gaussian process regression. Following a thorough retrospective validation using a data set of 176 published PPARgamma agonists , we screened a vendor library for novel agonists. Subsequent testing of 15 compounds in a cell-based transactivation assay  yielded four active compounds. The most interesting hit, a natural product derivative with cyclobutane scaffold, is a full selective PPARgamma agonist (EC50 = 10 ± 0.2 microM, inactive on PPARalpha and PPARbeta/delta at 10 microM). We demonstrate how the interplay of several modern kernel-based machine learning approaches can successfully improve ligand-based virtual screening results.
The C-terminus of p63 contains multiple regulatory elements with different functions
Wesley E. Straub
Tobias Alexander Weber
Horng Der Ou
- The transcription factor p63 is expressed as at least six different isoforms, of which two have been assigned critical biological roles within ectodermal development and skin stem cell biology on the one hand and supervision of the genetic stability of oocytes on the other hand. These two isoforms contain a C-terminal inhibitory domain that negatively regulates their transcriptional activity. This inhibitory domain contains two individual components: one that uses an internal binding mechanism to interact with and mask the transactivation domain and one that is based on sumoylation. We have carried out an extensive alanine scanning study to identify critical regions within the inhibitory domain. These experiments show that a stretch of ~13 amino acids is crucial for the binding function. Further, investigation of transcriptional activity and the intracellular level of mutants that cannot be sumoylated suggests that sumoylation reduces the concentration of p63. We therefore propose that the inhibitory function of the C-terminal domain is in part due to direct inhibition of the transcriptional activity of the protein and in part due to indirect inhibition by controlling the concentration of p63. Keywords: p63, transcriptional regulation, auto-inhibition, sumoylation
Neuromuscular development of Aeolidiella stephanieae Valdez, 2005 (Mollusca, Gastropoda, Nudibranchia)
- Background: Studies on the development of the nervous system and the musculature of invertebrates have become more sophisticated and numerous within the last decade and have proven to provide new insights into the evolutionary history of organisms. In order to provide new morphogenetic data on opisthobranch gastropods we investigated the neuromuscular development in the nudibranch Aeolidiella stephanieae Valdez, 2005 using immunocytochemistry as well as F-actin labelling in conjunction with confocal laser scanning microscopy (cLSM). Results: The ontogenetic development of Aeolidiella stephanieae can be subdivided into 8 stages, each recognisable by characteristic morphological and behavioural features as well as specific characters of the nervous system and the muscular system, respectively. The larval nervous system of A. stephanieae includes an apical organ, developing central ganglia, and peripheral neurons associated with the velum, foot and posterior, visceral part of the larva. The first serotonergic and FMRFamidergic neural structures appear in the apical organ that exhibits an array of three sensory, flask-shaped and two non-sensory, round neurons, which altogether disappear prior to metamorphosis. The postmetamorphic central nervous system (CNS) becomes concentrated, and the rhinophoral ganglia develop together with the anlage of the future rhinophores whereas oral tentacle ganglia are not found. The myogenesis in A. stephanieae begins with the larval retractor muscle followed by the accessory larval retractor muscle, the velar or prototroch muscles and the pedal retractors that all together degenerate during metamorphosis, and the adult muscle complex forms de novo. Conclusions: Aeolidiella stephanieae comprises features of the larval and postmetamorphic nervous as well as muscular system that represent the ground plan of the Mollusca or even the Trochozoa (e. g. presence of the prototrochal or velar muscle ring). On the one hand, A. stephanieae shows some features shared by all nudibranchs like the postmetamorphic condensation of the CNS, the possession of rhinophoral ganglia and the lack of oral tentacle ganglia as well as the de novo formation of the adult muscle complex. On the other hand, the structure and arrangement of the serotonergic apical organ is similar to other caenogastropod and opisthobranch gastropods supporting their sister group relationship.
On the setting of environmental noise and the performance of population dynamical models
Crispin M. Mutshinda
Robert B. O'Hara
- Background: Environmental noise is ubiquitous in population growth processes, with a well acknowledged potential to affect populations regardless of their sizes. It therefore deserves consideration in population dynamics modelling. The usual approach to incorporating noise into population dynamical models is to make some model parameter(s) (typically the growth rate, the carrying capacity, or both) stochastic and responsive to environment fluctuations. It is however still unclear whether including noise in one or/and another parameter makes a difference to the model performance. Here we investigated this issue with a focus on model fit and predictive accuracy. To do this, we developed three population dynamical models of the Ricker type with the noise included in the growth rate (Model 1), in the carrying capacity (Model 2), and in both (Model 3). We generated several population time series under each model, and used a Bayesian approach to fit the three models to the simulated data. We then compared the model performances in fitting to the data and in forecasting future observations. Results: When the mean intrinsic growth rate, r, in the data was low, the three models had roughly comparable performances, irrespective of the true model and the level of noise. As r increased, Models 1 performed best on data generated from it, and Model 3 tended to perform best on data generated from either Models 2 or Model 3. Model 2 was uniformly outcompeted by the other two models, regardless of the true model and the level of noise. The correlation between the deviance information criterion (DIC) and the mean square error (MSE) used respectively as measure of fit and predictive accuracy was broadly positive. Conclusion: Our results suggested that the way environmental noise is incorporated into a population dynamical model may profoundly affect its performance. Overall, we found that including noise in one or/and another parameter does not matter as long as the mean intrinsic growth rate, r, is low. As r increased, however, the three models performed differently. Models 1 and 3 broadly outperformed Model 2, the first having the advantage of being simple and more computationally tractable. A comforting result emerging from our analysis is the broad positive correlation between MSEs and DICs, suggesting that the latter may also be informative about the predictive performance of a model.
Bibliographischer Nachweis botanischer Literatur über Hessen : Stand und Perspektiven
- Die Möglichkeiten zum Recherchieren von botanischer Literatur über Hessen in sieben Online-Datenbanken werden vergleichend betrachtet. Unter anderem werden Testrecherchen zu Beiträgen in den Zeitschriften Hessische Floristische Briefe und Botanik und Naturschutz in Hessen ausgewertet. Es stellt sich heraus, dass im Feld der getesteten Datenbanken die Hessische Bibliographie sowie Biological Abstracts jeweils eine besondere Stellung einnehmen; mehrere weitere, überwiegend lizenzfrei nutzbare Datenbanken liefern ebenfalls substanzielle Beiträge. Die von der Universitätsbibliothek Johann Christian Senckenberg in Frankfurt am Main aufgebaute Virtuelle Fachbibliothek Biologie (vifabio) erleichtert den Zugang zu einigen wesentlichen Ressourcen; unter anderem können Hessische Bibliographie und Biological Abstracts sowie weitere Datenbanken in vifabio mit einer einzigen Suchanfrage parallel durchsucht werden.
SBE13, a newly identified inhibitor of inactive polo-like kinase 1
- Poster presentation at 5th German Conference on Cheminformatics: 23. CIC-Workshop Goslar, Germany. 8-10 November 2009 Protein kinases are important targets for drug development. The almost identical protein folding of kinases and the common co-substrate ATP leads to the problem of inhibitor selectivity. Type II inhibitors, targeting the inactive conformation of kinases, occupy a hydrophobic pocket with less conserved surrounding amino acids . Human polo-like kinase 1 (Plk1) represents a promising target for approaches to identify new therapeutic agents. Plk1 belongs to a family of highly conserved serine/threonine kinases, and is a key player in mitosis, where it modulates the spindle checkpoint at metaphase/anaphase transition. Plk1 is over-expressed in all today analyzed human tumors of different origin and serves as a negative prognostic marker in cancer patients. The newly identified inhibitor, SBE13, a vanillin derivative, targets Plk1 in its inactive conformation . This leads to selectivity within the Plk family and towards Aurora A. This selectivity can be explained by docking studies of SBE13 into the binding pocket of homology models of Plk1, Plk2 and Plk3 in their inactive conformation. SBE13 showed anti-proliferative effects in cancer cell lines of different origins with EC50 values between 5 microM and 39 microM and induced apoptosis. Increasing concentrations of SBE13 result in increasing amounts of cells in G2/M phase 13 hours after double thymidin block of HeLa cells. The kinase activity of Plk1 was inhibited with an IC50 of 200 pM. Taken together, we could show that carefully designed structure-based virtual screening is well-suited to identify selective type II kinase inhibitors targeting Plk1 as potential anti-cancer therapeutics.
Genome sequence of the necrotrophic plant pathogen Pythium ultimum reveals original pathogenicity mechanisms and effector repertoire
C. André Lévesque
John P. Hamilton
Gregg P. Robideau
Marcelo M. Zerillo
Gordon W. Beakes
Jeffrey L. Boore
Susan I. Fuerstenberg
Claire M. M. Gachon
Rays H. Y. Jiang
Harold J. G. Meijer
Jason E. Stajich
Pieter van West
Brett R. Whitty
Pedro M. Coutinho
Paul D. Thomas
Brett M. Tyler
Ronald P. De Vries
C. Robin Buell
- Background: Pythium ultimum (P. ultimum) is a ubiquitous oomycete plant pathogen responsible for a variety of diseases on a broad range of crop and ornamental species. Results: The P. ultimum genome (42.8 Mb) encodes 15,290 genes and has extensive sequence similarity and synteny with related Phytophthora species, including the potato blight pathogen Phytophthora infestans. Whole transcriptome sequencing revealed expression of 86% of genes, with detectable differential expression of suites of genes under abiotic stress and in the presence of a host. The predicted proteome includes a large repertoire of proteins involved in plant pathogen interactions although surprisingly, the P. ultimum genome does not encode any classical RXLR effectors and relatively few Crinkler genes in comparison to related phytopathogenic oomycetes. A lower number of enzymes involved in carbohydrate metabolism were present compared to Phytophthora species, with the notable absence of cutinases, suggesting a significant difference in virulence mechanisms between P. ultimum and more host specific oomycete species. Although we observed a high degree of orthology with Phytophthora genomes, there were novel features of the P. ultimum proteome including an expansion of genes involved in proteolysis and genes unique to Pythium. We identified a small gene family of cadherins, proteins involved in cell adhesion, the first report in a genome outside the metazoans. Conclusions: Access to the P. ultimum genome has revealed not only core pathogenic mechanisms within the oomycetes but also lineage specific genes associated with the alternative virulence and lifestyles found within the pythiaceous lineages compared to the Peronosporaceae.
Interaction of magnetite-based receptors in the beak with the visual system underlying "fixed direction" responses in birds
- Background: European robins, Erithacus rubecula, show two types of directional responses to the magnetic field: (1) compass orientation that is based on radical pair processes and lateralized in favor of the right eye and (2) so-called 'fixed direction' responses that originate in the magnetite-based receptors in the upper beak. Both responses are light-dependent. Lateralization of the 'fixed direction' responses would suggest an interaction between the two magnetoreception systems. Results: Robins were tested with either the right or the left eye covered or with both eyes uncovered for their orientation under different light conditions. With 502 nm turquoise light, the birds showed normal compass orientation, whereas they displayed an easterly 'fixed direction' response under a combination of 502 nm turquoise with 590 nm yellow light. Monocularly right-eyed birds with their left eye covered were oriented just as they were binocularly as controls: under turquoise in their northerly migratory direction, under turquoise-and-yellow towards east. The response of monocularly left-eyed birds differed: under turquoise light, they were disoriented, reflecting a lateralization of the magnetic compass system in favor of the right eye, whereas they continued to head eastward under turquoise-and-yellow light. Conclusion: 'Fixed direction' responses are not lateralized. Hence the interactions between the magnetite-receptors in the beak and the visual system do not seem to involve the magnetoreception system based on radical pair processes, but rather other, non-lateralized components of the visual system.
Vogelkundliche Fachliteratur und Internetquellen mit www.vifabio.de recherchieren
- Die Virtuelle Fachbibliothek Biologie (www.vifabio.de) bündelt die Recherche nach wissenschaftlich hochwertigen Quellen aus Bibliotheken, Aufsatzbanken und Internet. Zentrales Element von vifabio ist dabei der Virtuelle Katalog: Mit einer Suchanfrage werden mehrere Kataloge zoologisch bzw. ornithologisch relevanter Bibliotheken, Zeitschriftendatenbanken wie Zoological Record (Nationallizenz 1864 bis 2007 für Nutzer in akademischen Einrichtungen), BioLIS und der Aufsatzkatalog OLC, sowie Landesbibliographien und der Internetquellen-Führer von vifabio durchsucht. Verlinkungen zur Elektronischen Zeitschriftenbibliothek Regensburg (EZB), zum Lieferdienst subito sowie zum Karlsruher Virtuellen Katalog (KVK) erleichtern den Zugang zum Volltext oder zum gedruckten Exemplar. Weitere Module von vifabio wie der Internetquellen-Führer bzw. der Datenbank-Führer eröffnen zusätzliche Rechercheoptionen.
Locally adapted fish populations maintain small-scale genetic differentiation despite perturbation by a catastrophic flood event
Francisco J. Garcia de Leon
- Background: Local adaptation to divergent environmental conditions can promote population genetic differentiation even in the absence of geographic barriers and hence, lead to speciation. Perturbations by catastrophic events, however, can distort such parapatric ecological speciation processes. Here, we asked whether an exceptionally strong flood led to homogenization of gene pools among locally adapted populations of the Atlantic molly (Poecilia mexicana, Poeciliidae) in the Cueva del Azufre system in southern Mexico, where two strong environmental selection factors (darkness within caves and/or presence of toxic H2S in sulfidic springs) drive the diversification of P. mexicana. Nine nuclear microsatellites as well as heritable female life history traits (both as a proxy for quantitative genetics and for trait divergence) were used as markers to compare genetic differentiation, genetic diversity, and especially population mixing (immigration and emigration) before and after the flood. Results: Habitat type (i.e., non-sulfidic surface, sulfidic surface, or sulfidic cave), but not geographic distance was the major predictor of genetic differentiation. Before and after the flood, each habitat type harbored a genetically distinct population. Only a weak signal of individual dislocation among ecologically divergent habitat types was uncovered (with the exception of slightly increased dislocation from the Cueva del Azufre into the sulfidic creek, El Azufre). By contrast, several lines of evidence are indicative of increased flood-induced dislocation within the same habitat type, e.g., between different cave chambers of the Cueva del Azufre. Conclusions: The virtual absence of individual dislocation among ecologically different habitat types indicates strong natural selection against migrants. Thus, our current study exemplifies that ecological speciation in this and other systems, in which extreme environmental factors drive speciation, may be little affected by temporary perturbations, as adaptations to physico-chemical stressors may directly affect the survival probability in divergent habitat types.