Changes in the breeding wader populations of the machair of the Western Isles,Scotland, between 2000 and 2007

Capsule The machair of the Uists continues to support one of the most important assemblages of breeding waders in Europe, but there have been major variations in population change across the archipelago, the causes of which are poorly understood.     

Effect of intraspecific interactions on seasonal decline in productivity of Common Terns Sterna hirundo

Capsule Kleptoparasitic activities of older chicks from earlier nests did not contribute to late reproductive declines.

Aims To determine whether intraspecific interactions, such as kleptoparasitism and aggression, were experienced more frequently by birds breeding late in the season as a result of exposure to breeders at a more advanced stage. If so, to investigate whether this was the cause of the observed seasonal decline in reproductive parameters observed at Bird Island, where nesting density is high and interactions are more probable.

Methods Plots were fenced within the colony, exploiting natural variability in distribution of early and peak breeders to create two treatments: plots with only late-laying terns and those with a mixture of early-, peak- and late-layers. Hatching success, productivity and the growth and survival of chicks were measured for all late-laying pairs. Intraspecific interactions, adult attendance and provisioning of chicks were recorded during 9600 minutes of nest observations made within two periods: a few days after hatching and one week later.

Results The frequency of intraspecific interactions was maintained by the kleptoparasitic activities of older chicks within the mixed-laying-date treatment and was significantly lower in plots containing only late breeders with chicks of similar ages (mean 11.0 days). The overall rate was rarely greater than two interactions per nest per hour and there was no corresponding reduction in the growth or survival of chicks from late nests or any change in the provisioning activities of late-breeding adults.

Conclusion Increased frequency of intraspecific interactions experienced by late breeders in the presence of early-breeding conspecifics resulted from the kleptoparasitic activities of older chicks but was not sufficient to contribute to the observed seasonal reproductive decline at this dense breeding colony.     

Latitudinal and seasonal patterns in clutch size of some single‐brooded British birds

Capsule Daylength, rather than latitude, was found to be an important determinant of variation in clutch size.

Aims To describe the nature of spatial and temporal variation in clutch size, and explore the ecological correlates of these patterns.

Methods We tested the prediction that seasonal declines in clutch size will be greater at higher latitudes. The environmental variables focused on were the influence of daylength, plant productivity, seasonality (i.e. Ashmole's hypothesis) and physiological mechanisms that relate clutch size to ambient temperature. We used data from 1980 to 2003 on spatial variation in clutch size across Britain for single‐brooded species, in which clutch size can be taken as a measure of annual reproductive investment. We included all seven species, from five families, with sufficient data in the British Trust for Ornithology's Nest Record Scheme.

Results There are strong seasonal declines in clutch size but little evidence for latitudinal gradients in clutch size or in latitudinal gradients in the rate of seasonal clutch size decline. Of the environmental variables investigated, daylength had the most marked effect on clutch size; this was positive in diurnal species and negative in the one nocturnal species.

Conclusions Although this study was confined to a relatively small latitudinal range of 8°, we found marked latitudinal gradients in a number of factors thought to drive spatial patterns in clutch size. Moreover, such variation is of sufficient magnitude to generate spatial patterns in other ecological variables in Britain. There is thus no simple explanation for the lack of a latitudinal gradient in clutch size. The results concerning daylength indicate that the time available for foraging is an important determinant of variation in clutch size.     

Scribble is required for normal epithelial cell–cell contacts and lumen morphogenesis in the mammalian lung

During lung development, proper epithelial cell arrangements are critical for the formation of an arborized network of tubes. Each tube requires a lumen, the diameter of which must be tightly regulated to enable optimal lung function. Lung branching and lumen morphogenesis require close epithelial cell–cell contacts that are maintained as a result of adherens junctions, tight junctions and by intact apical–basal (A/B) polarity. However, the molecular mechanisms that maintain epithelial cohesion and lumen diameter in the mammalian lung are unknown. Here we show that Scribble, a protein implicated in planar cell polarity (PCP) signalling, is necessary for normal lung morphogenesis. Lungs of the Scrib mouse mutant Circletail (Crc) are abnormally shaped with fewer airways, and these airways often lack a visible, ‘open’ lumen. Mechanistically we show that Scrib genetically interacts with the core PCP gene Vangl2 in the developing lung and that the distribution of PCP pathway proteins and Rho mediated cytoskeletal modification is perturbed in Scrib^Crc/Crc lungs. However A/B polarity, which is disrupted in Drosophila Scrib mutants, is largely unaffected. Notably, we find that Scrib mediates functions not attributed to other PCP proteins in the lung. Specifically, Scrib localises to both adherens and tight junctions of lung epithelia and knockdown of Scrib in lung explants and organotypic cultures leads to reduced cohesion of lung epithelial cells. Live imaging of Scrib knockdown lungs shows that Scrib does not affect bud bifurcation, as previously shown for the PCP protein Celsr1, but is required to maintain epithelial cohesion. To understand the mechanism leading to reduced cell–cell association, we show that Scrib associates with β-catenin in embryonic lung and the sub-cellular distribution of adherens and tight junction proteins is perturbed in mutant lung epithelia. Our data reveal that Scrib is required for normal lung epithelial organisation and lumen morphogenesis by maintaining cell–cell contacts. Thus we reveal novel and important roles for Scrib in lung development operating via the PCP pathway, and in regulating junctional complexes and cell cohesion.     

A Recurrent PDGFRB Mutation Causes Familial Infantile Myofibromatosis

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.     

AKAP9 Is Essential for Spermatogenesis and Sertoli Cell Maturation in Mice

Mammalian male fertility relies on complex inter- and intracellular signaling during spermatogenesis. Here we describe three alleles of the widely expressed A-kinase anchoring protein 9 (Akap9) gene, all of which cause gametogenic failure and infertility in the absence of marked somatic phenotypes. Akap9 disruption does not affect spindle nucleation or progression of prophase I of meiosis but does inhibit maturation of Sertoli cells, which continue to express the immaturity markers anti-Mullerian hormone and thyroid hormone receptor alpha in adults and fail to express the maturation marker p27^Kip1. Furthermore, gap and tight junctions essential for blood–testis barrier (BTB) organization are disrupted. Connexin43 (Cx43) and zona occludens-1 are improperly localized in Akap9 mutant testes, and Cx43 fails to compartmentalize germ cells near the BTB. These results identify and support a novel reproductive tissue-specific role for Akap9 in the coordinated regulation of Sertoli cells in the testis.     

Pharmacophore identification of c-Myc inhibitor 10074-G5

A structure–activity relationship (SAR) study of the c-Myc (Myc) inhibitor 10074-G5 (N-([1,1′-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine, 1) – which targets a hydrophobic domain of the Myc oncoprotein that is flanked by arginine residues – was executed in order to determine its pharmacophore. Whilst the 7-nitrobenzofurazan was found to be critical for inhibitory activity, the ortho-biphenyl could be replaced with a para-carboxyphenyl group to furnish the new inhibitor JY-3-094 (3q). Around five times as potent as the lead with an IC₅₀ of 33 μM for disruption of the Myc–Max heterodimer, JY-3-094 demonstrated excellent selectivity over Max–Max homodimers, with no apparent effect at 100 μM. Importantly, the carboxylic acid of JY-3-094 improves the physicochemical properties of the lead compound, which will facilitate the incorporation of additional hydrophobicity that might enhance Myc inhibitory activity further still.     

Design and synthesis of tricyclic cores for kinase inhibition

Interest in therapeutic kinase inhibitors continues to grow beyond success in oncology. To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine. Herein we describe the syntheses of eight alternative tricyclic cores as well as in vitro screening results for representative kinases of potential therapeutic interest.     

Divergent evolutionary processes associated with colonization of offshore islands

Oceanic islands have been a test ground for evolutionary theory, but here, we focus on the possibilities for evolutionary study created by offshore islands. These can be colonized through various means and by a wide range of species, including those with low dispersal capabilities. We use morphology, modern and ancient sequences of cytochrome b (cytb) and microsatellite genotypes to examine colonization history and evolutionary change associated with occupation of the Orkney archipelago by the common vole (Microtus arvalis), a species found in continental Europe but not in Britain. Among possible colonization scenarios, our results are most consistent with human introduction at least 5100 bp (confirmed by radiocarbon dating). We used approximate Bayesian computation of population history to infer the coast of Belgium as the possible source and estimated the evolutionary timescale using a Bayesian coalescent approach. We showed substantial morphological divergence of the island populations, including a size increase presumably driven by selection and reduced microsatellite variation likely reflecting founder events and genetic drift. More surprisingly, our results suggest that a recent and widespread cytb replacement event in the continental source area purged cytb variation there, whereas the ancestral diversity is largely retained in the colonized islands as a genetic ‘ark’. The replacement event in the continental M. arvalis was probably triggered by anthropogenic causes (land‐use change). Our studies illustrate that small offshore islands can act as field laboratories for studying various evolutionary processes over relatively short timescales, informing about the mainland source area as well as the island.     

Life-cycle associations involving pairs of holococcolithophorid species: intraspecific variation or cryptic speciation?

New holococcolith-heterococcolith life-cycle associations are documented based on observations of combination coccospheres. Daktylethra pirus is shown to be a life-cycle phase of Syracosphaera pulchra and Syracolithus quadriperforatus a life-cycle phase of Calcidiscus leptoporus. In addition, new observations from cultures confirm the life-cycle associations of Crystallolithus braarudii with Coccolithus pelagicus and of Zygosphaera hellenica with Coronosphaera mediterranea. In all four cases previous work has shown that the heterococcolithophorid species is associated with another holococcolithophorid. Two other examples of a heterococcolithophorid being associated with two holococcolithophorids have previously been identified, so this seems to be a common phenomenon. The six examples are reviewed to determine whether a single underlying mechanism is likely to be responsible for all cases. It is concluded that there is no single mechanism but rather that the six examples fall into three categories: (a) in two cases the holococcolith types are probably simply ecophenotypic morphotypes; (b) in two other cases the holococcolith types are discrete and are paralleled by morphometric differences in the heterococcolith types; (c) in the final two cases the holococcolith types are discrete but are not paralleled by any obvious morphological variation in the heterococcolith morphology. We infer that cryptic speciation may be widespread in heterococcolithophorid phases and that study of holococcolithophorid phases can provide key data to elucidate this phenomenon.