How good is your screening library?

Efficient library design is an ongoing challenge for investigators seeking novel ligands for proteins, whether for drug discovery or chemical biology. Strategies that add neglected chemistry or exclude unproductive compounds are two dominant recent themes, as is a growing awareness of molecular complexity and its implications. The choice of how complex molecules in screening libraries should be often amounts to how big they should be. Small, simple molecules have lower affinities and must be screened at high concentration, but they will also have higher hit rates. Larger compounds, on the other hand, will often more closely resemble final drugs, but because they are more highly functionalized and specific, they will have much lower hit rates. The best general-purpose screening libraries may well be those of intermediate complexity that are free of artifact-causing nuisance compounds.     

How do proteins fold?

This article emphasizes the importance of getting students to understand the ways in which polypeptides fold to form protein molecules with complex higher-ordered structures. Modern views on how this folding occurs in vitro and in the cell are summarized and set within an appropriate biological context.     

Origin of anterior patterning. How old is our head?

Most animals that display a bilateral symmetry (bilaterians) share homologous regulatory genes involved in head development. Recently, homologues of several of these genes have been cloned from animals that are radially organized, such as coral, sea anemones, jellyfish or hydra (cnidarians). Surprisingly, some of these are expressed apically and/or during apical patterning in hydrozoans, suggesting that head patterning is much older than previously thought.     

How old are you now?

Cherkas et al . provide a new, biological approach to a classic problem in anthropology – the estimation of age.     

How old are bacterial pathogens?

Only few molecular studies have addressed the age of bacterial pathogens that infected humans before the beginnings of medical bacteriology, but these have provided dramatic insights. The global genetic diversity of Helicobacter pylori, which infects human stomachs, parallels that of its human host. The time to the most recent common ancestor (tMRCA) of these bacteria approximates that of anatomically modern humans, i.e. at least 100 000 years, after calibrating the evolutionary divergence within H. pylori against major ancient human migrations. Similarly, genomic reconstructions of Mycobacterium tuberculosis, the cause of tuberculosis, from ancient skeletons in South America and mummies in Hungary support estimates of less than 6000 years for the tMRCA of M. tuberculosis. Finally, modern global patterns of genetic diversity and ancient DNA studies indicate that during the last 5000 years plague caused by Yersinia pestis has spread globally on multiple occasions from China and Central Asia. Such tMRCA estimates provide only lower bounds on the ages of bacterial pathogens, and additional studies are needed for realistic upper bounds on how long humans and animals have suffered from bacterial diseases.     

How old are Wet Forest understories?

Abstract Radiocarbon ages were derived from 12 individuals representing four species of woody understorey plants growing in the Eucalyptus regnans dominated Wet Forests of Victoria's Central Highlands. Cyathea australis, Dicksonia antarctica and Olearia argophylla are common and often dominate the understorey. The fourth species, Persoonia arborea, is a small understorey tree endemic to this region. Field observations and radiocarbon ages for these four species (up to 370 ± 70 years BP) indicate they are capable of surviving fire and are long-lived in this environment.     

How old is the most recent ancestor of two copies of an allele?

An important clue to the evolutionary history of an allele is the structure of the neighboring region of the genome, which we term the genomic background of the allele. Consider two copies of the allele. How similar we expect their genomic background to be is strongly influenced by the age of their most recent common ancestor (MRCA). We apply diffusion theory, first used by Motoo Kimura as a tool for predicting the changes in allele frequencies over time and developed by him in many articles in this journal, to prove a variety of new results on the age of the MRCA under the simplest demographic assumptions. In particular, we show that the expected age of the MRCA of two copies of an allele with population frequency f is just 2Nf generations, where N is the effective population size. Our results are a first step in running exact coalescent simulations, where we also simulate the history of the population frequency of an allele.     

How old is the Hawaiian biota? Geology and phylogeny suggest recent divergence.

This study quantifies long-term landscape changes in the Hawaiian archipelago relating to dispersal, speciation and extinction. Accounting for volcano growth, subsidence and erosion, we modelled the elevations of islands at time intervals of 0.5 Myr for the last 32 Myr; we also assessed the variation in the spacing of volcanoes during this period. The size, spacing and total number of volcanic islands have varied greatly over time, with the current landscape of large, closely spaced islands preceded by a period with smaller, more distantly spaced islands. Considering associated changes in rates of dispersal and speciation, much of the present species pool is probably the result of recent colonization from outside the archipelago and divergence within contemporary islands, with limited dispersal from older islands. This view is in accordance with abundant phylogenetic studies of Hawaiian organisms that estimate the timing of colonization and divergence within the archipelago. Twelve out of 15 multi-species lineages have diverged within the lifetime of the current high islands (last 5 Myr). Three of these, and an additional seven (mostly single-species) lineages, have colonized the archipelago within this period. The timing of colonization of other lineages remains uncertain.     

How arbitrary is language?

It is a long established convention that the relationship between sounds and meanings of words is essentially arbitrary—typically the sound of a word gives no hint of its meaning. However, there are numerous reported instances of systematic sound–meaning mappings in language, and this systematicity has been claimed to be important for early language development. In a large-scale corpus analysis of English, we show that sound–meaning mappings are more systematic than would be expected by chance. Furthermore, this systematicity is more pronounced for words involved in the early stages of language acquisition and reduces in later vocabulary development. We propose that the vocabulary is structured to enable systematicity in early language learning to promote language acquisition, while also incorporating arbitrariness for later language in order to facilitate communicative expressivity and efficiency.