A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation.

BACKGROUND: The mammalian DNA-damage response (DDR) has evolved to protect genome stability and maximize cell survival following DNA-damage. One of the key regulators of the DDR is p53, itself tightly regulated by MDM2. Following double-strand DNA breaks (DSBs), mediators including ATM are recruited to the site of DNA-damage. Subsequent phosphorylation of p53 by ATM and ATM-induced CHK2 results in p53 stabilization, ultimately intensifying transcription of p53-responsive genes involved in DNA repair, cell-cycle checkpoint control and apoptosis. METHODS: In the current study, we investigated the stabilization and activation of p53 and associated DDR proteins in response to treatment of human colorectal cancer cells (HCT116p53+/+) with the MDM2 antagonist, Nutlin-3. RESULTS: Using immunoblotting, Nutlin-3 was observed to stabilize p53, and activate p53 target proteins. Unexpectedly, Nutlin-3 also mediated phosphorylation of p53 at key DNA-damage-specific serine residues (Ser15, 20 and 37). Furthermore, Nutlin-3 induced activation of CHK2 and ATM - proteins required for DNA-damage-dependent phosphorylation and activation of p53, and the phosphorylation of BRCA1 and H2AX - proteins known to be activated specifically in response to DNA damage. Indeed, using immunofluorescent labeling, Nutlin-3 was seen to induce formation of γH2AX foci, an early hallmark of the DDR. Moreover, Nutlin-3 induced phosphorylation of key DDR proteins, initiated cell cycle arrest and led to formation of γH2AX foci in cells lacking p53, whilst γH2AX foci were also noted in MDM2-deficient cells. CONCLUSION: To our knowledge, this is the first solid evidence showing a secondary role for Nutlin-3 as a DDR triggering agent, independent of p53 status, and unrelated to its role as an MDM2 antagonist

Left gaze bias in humans, rhesus monkeys and domestic dogs

While viewing faces, human adults often demonstrate a natural gaze bias towards the left visual field, that is, the right side of the viewee’s face is often inspected first and for longer periods. Using a preferential looking paradigm, we demonstrate that this bias is neither uniquely human nor limited to primates, and provide evidence to help elucidate its biological function within a broader social cognitive framework. We observed that 6-month-old infants showed a wider tendency for left gaze preference towards objects and faces of different species and orientation, while in adults the bias appears only towards upright human faces. Rhesus monkeys showed a left gaze bias towards upright human and monkey faces, but not towards inverted faces. Domestic dogs, however, only demonstrated a left gaze bias towards human faces, but not towards monkey or dog faces, nor to inanimate object images. Our findings suggest that face- and species-sensitive gaze asymmetry is more widespread in the animal kingdom than previously recognised, is not constrained by attentional or scanning bias, and could be shaped by experience to develop adaptive behavioural significance

Genetic Diversity and Population Parameters of Sea Otters, Enhydra lutris, before Fur Trade Extirpation from 1741–1911

All existing sea otter, Enhydra lutris, populations have suffered at least one historic population bottleneck stemming from the fur trade extirpations of the eighteenth and nineteenth centuries. We examined genetic variation, gene flow, and population structure at five microsatellite loci in samples from five pre-fur trade populations throughout the sea otter's historical range: California, Oregon, Washington, Alaska, and Russia. We then compared those values to genetic diversity and population structure found within five modern sea otter populations throughout their current range: California, Prince William Sound, Amchitka Island, Southeast Alaska and Washington. We found twice the genetic diversity in the pre-fur trade populations when compared to modern sea otters, a level of diversity that was similar to levels that are found in other mammal populations that have not experienced population bottlenecks. Even with the significant loss in genetic diversity modern sea otters have retained historical structure. There was greater gene flow before extirpation than that found among modern sea otter populations but the difference was not statistically significant. The most dramatic effect of pre fur trade population extirpation was the loss of genetic diversity. For long term conservation of these populations increasing gene flow and the maintenance of remnant genetic diversity should be encouraged

Biodiversity of the Deep-Sea Continental Margin Bordering the Gulf of Maine (NW Atlantic): Relationships among Sub-Regions and to Shelf Systems

Background: In contrast to the well-studied continental shelf region of the Gulf of Maine, fundamental questions regarding the diversity, distribution, and abundance of species living in deep-sea habitats along the adjacent continental margin remain unanswered. Lack of such knowledge precludes a greater understanding of the Gulf of Maine ecosystem and limits development of alternatives for conservation and management. Methodology/Principal Findings: We use data from the published literature, unpublished studies, museum records and online sources, to: (1) assess the current state of knowledge of species diversity in the deep-sea habitats adjacent to the Gulf of Maine (39–43uN, 63–71uW, 150–3000 m depth); (2) compare patterns of taxonomic diversity and distribution of megafaunal and macrofaunal species among six distinct sub-regions and to the continental shelf; and (3) estimate the amount of unknown diversity in the region. Known diversity for the deep-sea region is 1,671 species; most are narrowly distributed and known to occur within only one sub-region. The number of species varies by sub-region and is directly related to sampling effort occurring within each. Fishes, corals, decapod crustaceans, molluscs, and echinoderms are relatively well known, while most other taxonomic groups are poorly known. Taxonomic diversity decreases with increasing distance from the continental shelf and with changes in benthic topography. Low similarity in faunal composition suggests the deep-sea region harbours faunal communities distinct from those of the continental shelf. Non-parametric estimators of species richness suggest a minimum of 50% of the deep-sea species inventory remains to be discovered. Conclusions/Significance: The current state of knowledge of biodiversity in this deep-sea region is rudimentary. Our ability to answer questions is hampered by a lack of sufficient data for many taxonomic groups, which is constrained by sampling biases, life-history characteristics of target species, and the lack of trained taxonomists

Control of substrate access to the active site in methane monooxygenase

Methanotrophs consume methane as their major carbon source and have an essential role in the global carbon cycle by limiting escape of this greenhouse gas to the atmosphere. These bacteria oxidize methane to methanol by soluble and particulate methane monooxygenases (MMOs). Soluble MMO contains three protein components, a 251-kilodalton hydroxylase (MMOH), a 38.6-kilodalton reductase (MMOR), and a 15.9-kilodalton regulatory protein (MMOB), required to couple electron consumption with substrate hydroxylation at the catalytic diiron centre of MMOH. Until now, the role of MMOB has remained ambiguous owing to a lack of atomic-level information about the MMOH–MMOB (hereafter termed H–B) complex. Here we remedy this deficiency by providing a crystal structure of H–B, which reveals the manner by which MMOB controls the conformation of residues in MMOH crucial for substrate access to the active site. MMOB docks at the α[subscript 2]β[subscript 2] interface of α[subscript 2]β[subscript 2]γ[subscript 2] MMOH, and triggers simultaneous conformational changes in the α-subunit that modulate oxygen and methane access as well as proton delivery to the diiron centre. Without such careful control by MMOB of these substrate routes to the diiron active site, the enzyme operates as an NADH oxidase rather than a monooxygenase. Biological catalysis involving small substrates is often accomplished in nature by large proteins and protein complexes. The structure presented in this work provides an elegant example of this principle.National Institute of General Medical Sciences (U.S.) (Grant GM 32114

Metadevice for intensity modulation with sub-wavelength spatial resolution

Effectively continuous control over propagation of a beam of light requires light modulation with pixelation that is smaller than the optical wavelength. Here we propose a spatial intensity modulator with sub-wavelength resolution in one dimension. The metadevice combines recent advances in reconfigurable nanomembrane metamaterials and coherent all-optical control of metasurfaces. It uses nanomechanical actuation of metasurface absorber strips placed near a mirror in order to control their interaction with light from perfect absorption to negligible loss, promising a path towards dynamic beam diffraction, light focusing and holography without unwanted diffraction artefacts

Differential Extinction and the Contrasting Structure of Polar Marine Faunas

Background: The low taxonomic diversity of polar marine faunas today reflects both the failure of clades to colonize or diversify in high latitudes and regional extinctions of once-present clades. However, simple models of polar evolution are made difficult by the strikingly different faunal compositions and community structures of the two poles. Methodology/Principal Findings: A comparison of early Cenozoic Arctic and Antarctic bivalve faunas with modern ones, within the framework of a molecular phylogeny, shows that while Arctic losses were randomly distributed across the tree, Antarctic losses were significantly concentrated in more derived families, resulting in communities dominated by basal lineages. Potential mechanisms for the phylogenetic structure to Antarctic extinctions include continental isolation, changes in primary productivity leading to turnover of both predators and prey, and the effect of glaciation on shelf habitats. Conclusions/Significance: These results show that phylogenetic consequences of past extinctions can vary substantially among regions and thus shape regional faunal structures, even when due to similar drivers, here global cooling, and provide the first phylogenetic support for the ‘‘retrograde’ ’ hypothesis of Antarctic faunal evolution

Epidemiology of Exertional Rhabdomyolysis Susceptibility in Standardbred Horses Reveals Associated Risk Factors and Underlying Enhanced Performance

BACKGROUND: Exertional rhabdomyolysis syndrome is recognised in many athletic horse breeds and in recent years specific forms of the syndrome have been identified. However, although Standardbred horses are used worldwide for racing, there is a paucity of information about the epidemiological and performance-related aspects of the syndrome in this breed. The objectives of this study therefore were to determine the incidence, risk factors and performance effects of exertional rhabdomyolysis syndrome in Standardbred trotters and to compare the epidemiology and genetics of the syndrome with that in other breeds. METHODOLOGY/PRINCIPAL FINDINGS: A questionnaire-based case-control study (with analysis of online race records) was conducted following identification of horses that were determined susceptible to exertional rhabdomyolysis (based on serum biochemistry) from a total of 683 horses in 22 yards. Thirty six exertional rhabdomyolysis-susceptible horses were subsequently genotyped for the skeletal muscle glycogen synthase (GYS1) mutation responsible for type 1 polysaccharide storage myopathy. A total of 44 susceptible horses was reported, resulting in an annual incidence of 6.4 (95% CI 4.6-8.2%) per 100 horses. Female horses were at significantly greater risk than males (odds ratio 7.1; 95% CI 2.1-23.4; p = 0.001) and nervous horses were at a greater risk than horses with calm or average temperaments (odds ratio 7.9; 95% CI 2.3-27.0; p = 0.001). Rhabdomyolysis-susceptible cases performed better from standstill starts (p = 0.04) than controls and had a higher percentage of wins (p = 0.006). All exertional rhabdomyolysis-susceptible horses tested were negative for the R309H GYS1 mutation. CONCLUSIONS/SIGNIFICANCE: Exertional rhabdomyolysis syndrome in Standardbred horses has a similar incidence and risk factors to the syndrome in Thoroughbred horses. If the disorder has a genetic basis in Standardbreds, improved performance in susceptible animals may be responsible for maintenance of the disorder in the population