Met signaling mutants as tools for developmental studies

The Met receptor is widely expressed in embryonic and adult epithelial tissues; its ligand (hepatocyte growth factor/scatter factor, HGF/SF) is expressed in the mesenchymal component of various organs. The generation of hgf and met null mice has revealed an essential role for this ligand-receptor pair in the development of the placenta, liver, and limb muscles. However the early lethality of the null mutants has precluded analysis of Met function in late development. To extend the possible observation period, we generated mutant metalleles of different severity. This was done by impairing the ability of the receptor to transduce the HGF/SF signal, via mutation of consensus sequences in the multifunctional docking site present in the C-terminal tail of the receptor. Mice expressing a Met mutant still active as a kinase, but unable to recruit its effectors, died in mid-gestation with the same phenotype as the metknockout, proving the importance of phosphotyrosine-SH2 interactions in vivo. Mice expressing a Met receptor with partial loss of signaling function survived until birth and revealed novel aspects of HGF/SF-Met function during muscle development

An evaluation of operational and research weather forecasts for Southern West Africa using observations from the DACCIWA field campaign in June‐July 2016

Reliable and accurate weather forecasts have the potential to improve living conditions in densely populated southern West Africa (SWA), in particularly those of rainfall and its extremes. A limited availability of observations has long impeded a rigorous evaluation of current state‐of‐the‐art forecast models. The field campaign of the Dynamics‐Aerosol‐Chemistry‐Cloud Interactions in West Africa (DACCIWA) project in June‐July 2016 has created an unprecedentedly dense set of measurements from surface stations and radiosondes. Here we present results from a comprehensive evaluation of both numerical model forecasts and satellite products using these data on a regional and local level. Results reveal a substantial observational uncertainty showing considerable underestimations in satellite estimates of rainfall and low‐cloud cover with little correlation at the local scale. Models have a dry bias of 0.1–1.9 mmday−1 in rainfall and too low column relative humidity. They tend to underestimate low clouds, leading to excess surface solar radiation of 43 Wm−2. Remarkably, most models show some skill in representing regional modulations of rainfall related to synoptic‐scale disturbances, while local variations in rainfall and cloudiness are hardly captured. Slightly better results are found with respect to temperature and for the post‐onset rather than for the pre‐onset period. Delicate local features such as the Maritime Inflow phenomenon are also rather poorly represented, leading to too cool, dry and cloudy conditions at the coast. Differences between forecast days 1 and 2 are relatively small and hardly systematic, suggesting a relatively quick error saturation. Using explicit convection leads to more realistic spatial variability in rainfall, but otherwise no marked improvement. Future work should aim at improving the subtle balance between the diurnal cycles of low clouds, surface radiation, the boundary layer and convection. Further efforts are also needed to improve the observational system beyond field campaign periods

The contexts and early Acheulean archaeology of the EF-HR paleo-landscape (Olduvai Gorge, Tanzania).

Renewed fieldwork at the early Acheulean site of EF-HR (Olduvai Gorge, Tanzania) has included detailed stratigraphic studies of the sequence, extended excavations in the main site, and has placed eleven additional trenches within an area of nearly 1 km2, to sample the same stratigraphic interval as in the main trench across the broader paleo-landscape. Our new stratigraphic work suggests that EF-HR is positioned higher in the Bed II sequence than previously proposed, which has implications for the age of the site and its stratigraphic correlation to other Olduvai Middle Bed II sites. Geological research shows that the main EF-HR site was situated at the deepest part of an incised valley formed through river erosion. Archaeological excavations at the main site and nearby trenches have unearthed a large new assemblage, with more than 3000 fossils and artefacts, including a hundred handaxes in stratigraphic position. In addition, our test-trenching approach has detected conspicuous differences in the density of artefacts across the landscape, with a large cluster of archaeological material in and around the main trench, and less intense human activity at the same level in the more distant satellite trenches. All of these aspects are discussed in this paper in the light of site formation processes, behavioral contexts, and their implications for our understanding of the early Acheulean at Olduvai Gorge

New excavations at the HWK EE site: Archaeology, paleoenvironment and site formation processes during late Oldowan times at Olduvai Gorge, Tanzania

This paper reports the results of renewed fieldwork at the HWK EEsite(Olduvai Gorge, Tanzania). HWK EEis positioned across the boundary between Lower andMiddle Bed II, a crucialinterval for studyingthe emergence of the Acheulean at Olduvai Gorge. Our excavations at HWK EEhave produced one of the largest collections of fossils and artefacts from any Oldowan site, distributed across several archaeological units and a large excavation surface in four separate trenches thatcan be stratigraphically correlated. Here we present the main stratigraphic and archaeological units and discuss site formation processes.Results show a great density of fossils and stone tools vertically through two stratigraphic intervals (Lemuta and Lower Augitic Sandstone)and laterally across an area of around 300 m2, and highlight the confluence of biotic and abiotic agents in the formation of the assemblage. The large size and diversityof the assemblage, as well as its good preservation, qualify HWK EEas a reference sitefor the study of the late Oldowan at Olduvai Gorge and elsewhere in Africa. In addition, thedescriptionof the stratigraphic and archaeological sequenceof HWK EE presented in this paper constitutesthe foundation for further studies on hominin behaviour and palaeoecologyin Lower and Middle Bed II

Deep-Sea Origin and In-Situ Diversification of Chrysogorgiid Octocorals

The diversity, ubiquity and prevalence in deep waters of the octocoral family Chrysogorgiidae Verrill, 1883 make it noteworthy as a model system to study radiation and diversification in the deep sea. Here we provide the first comprehensive phylogenetic analysis of the Chrysogorgiidae, and compare phylogeny and depth distribution. Phylogenetic relationships among 10 of 14 currently-described Chrysogorgiidae genera were inferred based on mitochondrial (mtMutS, cox1) and nuclear (18S) markers. Bathymetric distribution was estimated from multiple sources, including museum records, a literature review, and our own sampling records (985 stations, 2345 specimens). Genetic analyses suggest that the Chrysogorgiidae as currently described is a polyphyletic family. Shallow-water genera, and two of eight deep-water genera, appear more closely related to other octocoral families than to the remainder of the monophyletic, deep-water chrysogorgiid genera. Monophyletic chrysogorgiids are composed of strictly (Iridogorgia Verrill, 1883, Metallogorgia Versluys, 1902, Radicipes Stearns, 1883, Pseudochrysogorgia Pante & France, 2010) and predominantly (Chrysogorgia Duchassaing & Michelotti, 1864) deep-sea genera that diversified in situ. This group is sister to gold corals (Primnoidae Milne Edwards, 1857) and deep-sea bamboo corals (Keratoisidinae Gray, 1870), whose diversity also peaks in the deep sea. Nine species of Chrysogorgia that were described from depths shallower than 200 m, and mtMutS haplotypes sequenced from specimens sampled as shallow as 101 m, suggest a shallow-water emergence of some Chrysogorgia species

Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

Chromosome 1p is frequently deleted in neuroblastoma (NB) tumours. The commonly deleted region has been narrowed down by loss of heterozygosity studies undertaken by different groups. Based on earlier mapping data, we have focused on a region on 1p36 (chr1: 7 765 595–11 019 814) and performed an analysis of 30 genes by exploring features such as epigenetic regulation, that is DNA methylation and histone deacetylation, mutations at the DNA level and mRNA expression. Treatment of NB cell lines with the histone deacetylase inhibitor trichostatin A led to increased gene transcription of four of the 30 genes, ERRFI1 (MIG-6), PIK3CD, RBP7 (CRBPIV) and CASZ1, indicating that these genes could be affected by epigenetic downregulation in NBs. Two patients with nonsynonymous mutations in the PIK3CD gene were detected. One patient harboured three variations in the same exon, and p.R188W. The other patient had the variation p.M655I. In addition, synonymous variations and one variation in an intronic sequence were also found. The mRNA expression of this gene is downregulated in unfavourable, compared to favourable, NBs. One nonsynonymous mutation was also identified in the ERRFI1 gene, p.N343S, and one synonymous. None of the variations above were found in healthy control individuals. In conclusion, of the 30 genes analysed, the PIK3CD gene stands out as one of the most interesting for further studies of NB development and progression

Dynamics of Lamin-A Processing Following Precursor Accumulation

Lamin A (LaA) is a component of the nuclear lamina, an intermediate filament meshwork that underlies the inner nuclear membrane (INM) of the nuclear envelope (NE). Newly synthesized prelamin A (PreA) undergoes extensive processing involving C-terminal farnesylation followed by proteolysis yielding non-farnesylated mature lamin A. Different inhibitors of these processing events are currently used therapeutically. Hutchinson-Gilford Progeria Syndrome (HGPS) is most commonly caused by mutations leading to an accumulation of a farnesylated LaA isoform, prompting a clinical trial using farnesyltransferase inhibitors (FTI) to reduce this modification. At therapeutic levels, HIV protease inhibitors (PI) can unexpectedly inhibit the final processing step in PreA maturation. We have examined the dynamics of LaA processing and associated cellular effects during PI or FTI treatment and following inhibitor washout. While PI reversibility was rapid, with respect to both LaA maturation and associated cellular phenotype, recovery from FTI treatment was more gradual. FTI reversibility is influenced by both cell type and rate of proliferation. These results suggest a less static lamin network than has previously been observed