Inductive queries for a drug designing robot scientist

It is increasingly clear that machine learning algorithms need to be integrated in an iterative scientific discovery loop, in which data is queried repeatedly by means of inductive queries and where the computer provides guidance to the experiments that are being performed. In this chapter, we summarise several key challenges in achieving this integration of machine learning and data mining algorithms in methods for the discovery of Quantitative Structure Activity Relationships (QSARs). We introduce the concept of a robot scientist, in which all steps of the discovery process are automated; we discuss the representation of molecular data such that knowledge discovery tools can analyse it, and we discuss the adaptation of machine learning and data mining algorithms to guide QSAR experiments

The Tabby cat locus maps to feline chromosome B1.

The Tabby markings of the domestic cat are unique coat patterns for which no causative candidate gene has been inferred from other mammals. In this study, a genome scan was performed on a large pedigree of cats that segregated for Tabby coat markings, specifically for the Abyssinian (Ta-) and blotched (tbtb) phenotypes. There was linkage between the Tabby locus and eight markers on cat chromosome B1. The most significant linkage was between marker FCA700 and Tabby (Z = 7.56, theta = 0.03). Two additional markers in the region supported linkage, although not with significant LOD scores. Pairwise analysis of the markers supported the published genetic map of the cat, although additional meioses are required to refine the region. The linked markers cover a 17-cM region and flank an evolutionary breakpoint, suggesting that the Tabby gene has a homologue on either human chromosome 4 or 8. Alternatively, Tabby could be a unique locus in cats

Characteristics of survivors: growth and nutritional condition of early stages of the hake species <i>Merluccius paradoxus</i> and <i>M. capensis</i> in the southern Benguela ecosystem

Larval mortality in marine fish is strongly linked to characteristic traits such as growth and condition, but the variability in these traits is poorly understood. We tried to identify the variability in growth in relation to conditions leading to greater survival chances for early stages of Cape hake, Merluccius paradoxus and M. capensis, in the Benguela upwelling ecosystem. During two cruises in 2007 and one cruise in 2008, hake larvae and juveniles were caught. Otolith microstructures revealed a larval age ranging from 2 to 29 days post-hatching (dph), whereas juvenile age was 67–152 dph. RNA:DNA ratios, used to evaluate nutritional condition, were above the relevant threshold level for growth. No strong coupling between growth and condition was detected, indicating a complex relationship between these factors in the southern Benguela ecosystem. Merluccius paradoxus juveniles caught in 2007 (the surviving larvae of 2006) had significantly higher larval growth rates than larvae hatched in 2007 and 2008, possibly indicating selection for fast growth in 2006. High selection pressure on growth could be linked to predation avoidance, including cannibalism

Future challenges in cephalopod research

We thank Anto´nio M. de Frias Martins, past President of the Unitas Malacologica and Peter Marko, President of the American Malacological Society for organizing the 2013 World Congress of Malacology, and the Cephalopod International Advisory Committee for endorsing a symposium held in honour of Malcolm R. Clarke. In particular, we would like to thank the many professional staff from the University of the Azores for their hospitality, organization, troubleshooting and warm welcome to the Azores. We also thank Malcolm Clarke’s widow, Dorothy, his daughter Zoe¨, Jose´ N. Gomes-Pereira and numerous colleagues and friends of Malcolm’s from around the world for joining us at Ponta Delgada. We are grateful to Lyndsey Claro (Princeton University Press) for granting copyright permissions.Peer reviewedPublisher PD

Rab6 and Rab11 Regulate Chlamydia trachomatis Development and Golgin-84-Dependent Golgi Fragmentation

Many intracellular pathogens that replicate in special membrane bound compartments exploit cellular trafficking pathways by targeting small GTPases, including Rab proteins. Members of the Chlamydiaceae recruit a subset of Rab proteins to their inclusions, but the significance of these interactions is uncertain. Using RNA interference, we identified Rab6 and Rab11 as important regulators of Chlamydia infections. Depletion of either Rab6 or Rab11, but not the other Rab proteins tested, decreased the formation of infectious particles. We further examined the interplay between these Rab proteins and the Golgi matrix components golgin-84 and p115 with regard to Chlamydia-induced Golgi fragmentation. Silencing of the Rab proteins blocked Chlamydia-induced and golgin-84 knockdown-stimulated Golgi disruption, whereas Golgi fragmentation was unaffected in p115 depleted cells. Interestingly, p115-induced Golgi fragmentation could rescue Chlamydia propagation in Rab6 and Rab11 knockdown cells. Furthermore, transport of nutrients to Chlamydia, as monitored by BODIPY-Ceramide, was inhibited by Rab6 and Rab11 knockdown. Taken together, our results demonstrate that Rab6 and Rab11 are key regulators of Golgi stability and further support the notion that Chlamydia subverts Golgi structure to enhance its intracellular development

Potent inhibitory activity of chimeric oligonucleotides targeting two different sites of human telomerase

Suppression of telomerase activity in tumor cells has been considered as a new anticancer strategy. Here, we present chimeric oligonucleotides (chimeric ODNs) as a new type of telomerase inhibitor that contains differently modified oligomers to address two different sites of telomerase: the RNA template and a suggested protein motif. We have shown previously that phosphorothioate-modified oligonucleotides (PS ODNs) interact in a length-dependent rather than in a sequence-dependent manner, presumably with the protein part of the primer-binding site of telomerase, causing strong inhibition of telomerase. In the present study, we demonstrate that extensions of these PS ODNs at their 3'-ends with an antisense oligomer partial sequence covering 11 bases of the RNA template cause significantly increased inhibitory activity, with IC(50) values between 0.60 and 0.95 nM in a Telomeric Repeat Amplification Protocol (TRAP) assay based on U-87 cell lysates. The enhanced inhibitory activity is observed regardless of whether the antisense part is modified (phosphodiester, PO; 2'-O-methylribosyl, 2'-OMe/PO; phosphoramidate, PAM). However, inside intact U-87 cells, these modifications of the antisense part proved to be essential for efficient telomerase inhibition 20 hours after transfection. In particular, the chimeric ODNs containing PAM or 2'-OMe/PO modifications, when complexed with lipofectin, were most efficient telomerase inhibitors (ID(50) = 0.04 and 0.06 microM, respectively). In conclusion, ODNs of this new type emerged as powerful inhibitors of human telomerase and are, therefore, promising candidates for further investigations of the anticancer strategy of telomerase inhibition

Chokka squid on the Agulhas Bank: life history and ecology

Available knowledge is reviewed and new data incorporated in a synthesis of the life history and ecology of the chokka squid Loligo vulgaris reynaudii. We attempt to show that these aspects are essential to rational management of the resource. The life cycle is descriptionbed in detail from the egg to adult stage, mainly in biological terms, including a comprehensive descriptionption of maturation, migration and reproduction. Possible ecological interactions, particularly those of paralarvae and copepods, are discussed. Predator-prey relationships and the current state of knowledge on the effect of the physical environment on squid availability and abundance are summarized

Application of Hansch’s Model to Capsaicinoids and Capsinoids: A Study Using the Quantitative Structure−Activity Relationship. A Novel Method for the Synthesis of Capsinoids

We describe a synthetic approach for two families of compounds, the capsaicinoids and capsinoids, as part of a study of the quantitative relationship between structure and activity