A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Background

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties by gene expression profile. Lamb et al first proposed the Connectivity Map [Lamb et al (2006), Science 313, 1929–1935] to make successful connections among small molecules, genes, and diseases using genomic signatures.

Results

Here we have built on the principles of the Connectivity Map to present a simpler and more robust method for the construction of reference gene-expression profiles and for the connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with two randomly generated gene signatures and three experimentally derived gene signatures (for HDAC inhibitors, estrogens, and immunosuppressive drugs, respectively). Our testing with this method indicates that it achieves a higher level of specificity and sensitivity and so advances the original method.

Conclusion

The method presented here not only offers more principled statistical procedures for testing connections, but more importantly it provides effective safeguard against false connections at the same time achieving increased sensitivity. With its robust performance, the method has potential use in the drug development pipeline for the early recognition of pharmacological and toxicological properties in chemicals and new drug candidates, and also more broadly in other 'omics sciences.

Satellite flies (Leucophora personata, Diptera : Anthomyiidae) and other dipteran parasites of the communal bee Andrena agilissima (Hymenoptera : Andrenidae) on the island of Elba, Italy

Solitary and presocial aculueate Hymenoptera are parasitized by a range of dipteran species in the families Axithomyiidae, Bombyliidae, Conopidae, Phoridae, and Sarcophagidae that are likely to impact on their hosts. We undertook a study over several years of a univoltine and communal bee, Andrena agilissima, and its main dipteran parasites, in particular the satellite fly Leucophora personata (Diptera: Anthomyiidae). Behavioural and ecological data were collected from one nesting aggregation of the host bee on the island of Elba, Italy, from 1993 to 2003, and from a foraging site of the bee, ca 5 km from the nesting aggregation. Other Diptera associated with A. agilissmia at the field site were the bee fly Bombylius fimbriatus (Bombyliidae), the conopid fly Zodion cinereum (Conopidae), and the scuttle fly Megaselia andrenae (Phoridae). The phenology of the Diptera broadly overlapped with that of their host across the season of activity (end of April and all of May). Diurnal activity patterns differed slightly; L. personata in particular was active at the host's nesting site before A. agilissima. Female satellite flies also showed a range of behaviours in gaining entry to a host nest. We summarize published data on this and other Leucophora species that parasitize Andrena host bees. Host bees returning to their nests occasionally undertook zig-zag flight manoeuvres if followed by a satellite fly that were generally successful in evading the fly. Satellite flies that entered a nest, presumably to oviposit, were less likely to remain therein if another host bee entered the same nest, suggesting that one advantage to communal nesting for this host is a reduction in brood cell parasitism by L. personata. We provide the first clear evidence for parasitism by a Zodion of any Andrena host. Both L. personata and M. andrenae concentrated their parasitic activities in the zone of the host nesting aggregation with highest nest densities. Three of the Diptera, L. personata, B. fimbriatus, and Z. cinereum, seemed to have extremely low rates of parasitism whilst that of M. andrenae appeared low. Though they have refined parasitic behaviour that allows them to gain entry into host nests (L. personata, B. fimbriatus, and M. andrenae) or to parasitize adults (Z. cinercum), these parasites seem not to impact upon the dynamics of the host A. agilissima at the nesting aggregation, and the host possesses traits to reduce parasitism.

Some properties of the speciation model for food-web structure - Mechanisms for degree distributions and intervality

We present a mathematical analysis of the speciation model for food-web structure, which had in previous work been shown to yield a good description of empirical data of food-web topology. The degree distributions of the network are derived. Properties of the speciation model are compared to those of other models that successfully describe empirical data. It is argued that the speciation model unities the underlying ideas of previous theories. In particular, it offers a mechanistic explanation for the success of the niche model of Williams and Martinez and the frequent observation of intervality in empirical food webs. (c) 2005 Elsevier Ltd. All rights reserved.

Zoonotic helminth infections with particular emphasis on fasciolosis and other trematodiases

Zoonotic infections are among the most common on earth and are responsible for >60 per cent of all human infectious diseases. Some of the most important and well-known human zoonoses are caused by worm or helminth parasites, including species of nematodes (trichinellosis), cestodes (cysticercosis, echinococcosis) and trematodes (schistosomiasis). However, along with social, epidemiological and environmental changes, together with improvements in our ability to diagnose helminth infections, several neglected parasite species are now fast-becoming recognized as important zoonotic diseases of humans, e.g. anasakiasis, several fish-borne trematodiasis and fasciolosis. In the present review, we discuss the current disease status of these primary helminth zoonotic infections with particular emphasis on their diagnosis and control. Advances in molecular biology, proteomics and the release of helminth genome-sequencing project data are revolutionizing parasitology research. The use of these powerful experimental approaches, and their potential benefits to helminth biology are also discussed in relation to the future control of helminth infections of animals and humans.

Why are you tall while others are short? Agricultural production and other proximate determinants of global heights

We analyze the proximate determinants of the biological standard of living from a global perspective, namely high-quality nutrition and the disease environment during the nineteenth and twentieth centuries. Until the mid-twentieth century, the local availability of cattle, meat, and milk per capita and the local disease environment mainly determined the stature of the population – and, by implication, how long they lived and how healthy they were. During the late twentieth century, the trade of agricultural products and health-promoting technologies increased in relative importance; hence, the local availabilities became less decisive in explaining height differences.

Levels of Arsenic and Other Trace Elements in Southern Libyan Agricultural Irrigated Soil and Non-irrigated Soil Projects

The levels of As and various other trace elements found in the irrigated agricultural soil (Tsoil) of southern Libya were compared with non-irrigated soil (Csoil) from the same sampling campaign collected between April and May 2008. The soil samples represented agronomic practice in the southern Libyan regions of Maknwessa (MAK), Aril (ARL) and Taswaa (TAS), and were analyzed by Inductively coupled plasma mass spectrometry (ICP-MS) for Co, Ni, Cu, Se, Mo, Zn, As, Pb, Cd and P. Concentrations of P and As in TAS and MAK were found to be higher in Tsoil compared to Csoil, while the opposite was true for ARL. In general, As concentrations in these areas were 2-3 times lower than the global average. In ARL, the average P concentrations of the Csoil samples were significantly higher than those of Tsoil samples: this site is composed mainly of pasture for animal production, where phosphate fertilizers are used regularly. Distance from the source of irrigation was found to be of an important influence on the heavy metal concentration of the soil, with greater concentrations found closer to the irrigation source. It can be concluded from the results that irrigation water contains elevated levels of As, which finds its way into the soil profile and can lead to accumulation of As in the soil over time.