Replisome pausing in mutagenesis

E. coli cells containing a temperature-sensitivednaE mutation, in the α-subunit of holoenzyme DNA polymerase III, do not survive at the restrictive temperature. Such cells may survive in the presence of thepcbA1 mutation, an allele of thegyrB gene. Such survival is dependent on an active DNA polymerase I. Evidence indicates that DNA polymerase I interacts directly in the replisome (REP·A). Despite normal survival for cells using thepcbA replication pathway after some type of DNA damage, we have noted a failure of damage-induced mutagenesis. Here we present evidence supporting a model of replisome pausing in cells dependent upon thepcbA replication pathway. The model argues that the (REP·A) complex pauses longer at the site of the lesion, allowing excision repair to occur completely. In the normal replication pathway (REP·E) bypass of the lesion occurs, fixing the mutation.     

Hereditary retinoblastoma: can balanced insertion entirely explain the differences of expressivity among families?

Summary Although the retinoblastoma gene has been isolated and sequenced, the difference in penetrance and expressivity among families has not yet been fully explained. Balanced chromosomal insertion involving the 13q14 regions has been shown to account for some families with several unaffected carriers. Since there could be cases with karyotypically undetectable insertions, we tested whether this mechanism was general enough to explain the whole difference in expressivity among families. Using 166 pedigrees, reported in nine series available in the literature (including our own), we conclude that balanced insertion cannot entirely explain the familial data, even if we allow for a reduced viability of unbalanced gametes. Other mechanisms are proposed and discussed in this paper.     

Linking micromorphism,brooding, and hermaphroditism in brachiopods: Insights from Caribbean Argyrotheca (Brachiopoda)

In extant brachiopods, parental brooding of the larvae occurs exclusively within Rhynchonelliformea. Methods of larval protection range from simple retention of the larvae within the mantle cavity, to sophisticated brood care within highly specialized brood pouches found in Argyrotheca and Joania (Terebratulida, Megathyridoidea), Gwynia (Terebratulida, Gwynioidea), and all Thecideoidea (Thecideida). Previous studies on the reproductive biology of Argyrotheca yielded contrasting results on the epithelial origin of the brood pouches in this genus. Here, representatives of different species of Argyrotheca from the Belize Barrier Reef were examined using histological section series. Brood pouches of four species, A. cf. schrammi and Argyrotheca sp. 1–3, are of the same basic structure, formed by invaginations of the anterior body wall and connected to the visceral cavity via the metanephridia. The same four species are simultaneously hermaphroditic, suggesting that fertilization is achieved, at least partly, through selfing. One species, Argyrotheca rubrocostata, differs significantly from all others as it has no brood pouch and gonochoric gonads. Thus, the presence of brood pouches and simultaneous hermaphroditism are concluded to be correlated within Megathyridoidea and proposed to be homologous traits of Joania and several but not all species of Argyrotheca, questioning the monophyletic status of both genera. In contrast to the brood pouches of Thecideoidea, lophophoral epithelium is not involved in the formation of the pouches of Argyrotheca and Joania. Therefore, megathyridoid and thecideoid brood pouches are not homologous but evolved independently within rhynchonelliform brachiopods. All brachiopods with brood pouches share a micromorphic form and a short life span, limiting the space and time available for gamete and larval development. We suggest that the brood pouches and the hermaphroditic gonads of Argyrotheca spp. and Joania compensate these limitations by minimizing the loss of gametes and larvae, and by maximizing the chances of successful fertilization. J. Morphol., 2013. © 2013 Wiley Periodicals, Inc.     

Wildcat population density in NE Portugal: A regional stronghold for a nationally threatened felid

Population density data on depleted and endangered wildlife species are essential to assure their effective management and, ultimately, conservation. The European wildcat is an elusive and threatened species inhabiting the Iberian Peninsula, with fragmented populations and living in low densities. We fitted spatial capture–recapture models on camera-trap data, to provide the first estimate of wildcat density for Portugal and assess the most influential drivers determining it. The study was implemented in Montesinho Natural Park (NE Portugal), where we identified nine individuals, over a total effort of 3,477 trap-nights. The mean density estimate was 0.032 ± 0.012 wildcat/km², and density tended to increase with distance to humanized areas, often linked to lower human disturbance and domestic cat presence, with forest and herbaceous vegetation cover and with European rabbit abundance. Although, this density estimate is within the range of values estimated for protected areas elsewhere in the Iberian Peninsula, our estimates are low at the European level. When put in context, our results highlight that European wildcats may be living in low population densities across the Iberian Mediterranean biogeographic region. No phenotypic domestic or hybrid cats were detected, suggesting potentially low admixture rates between the two species, although genetic sampling would be required to corroborate this assertion. We provide evidence that Montesinho Natural Park may be a suitable area to host a healthy wildcat population, and thus be an important protected area in this species' conservation context.     

Identification and design of a novel series of MGAT2 inhibitors

[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to na?ve, p <0.01) in plasma triacylglycerol (TAG) concentration.