p53 modeling as a route to mesothelioma patients stratification and novel therapeutic identification

Background Malignant pleural mesothelioma (MPM) is an orphan disease that is difficult to treat using traditional chemotherapy, an approach which has been effective in other types of cancer. Most chemotherapeutics cause DNA damage leading to cell death. Recent discoveries have highlighted a potential role for the p53 tumor suppressor in this disease. Given the pivotal role of p53 in the DNA damage response, here we investigated the predictive power of the p53 interactome model for MPM patients’ stratification. Methods We used bioinformatics approaches including omics type analysis of data from MPM cells and from MPM patients in order to predict which pathways are crucial for patients’ survival. Analysis of the PKT206 model of the p53 network was validated by microarrays from the Mero-14 MPM cell line and RNA-seq data from 71 MPM patients, whilst statistical analysis was used to identify the deregulated pathways and predict therapeutic schemes by linking the affected pathway with the patients’ clinical state. Results In silico simulations demonstrated successful predictions ranging from 52 to 85% depending on the drug, algorithm or sample used for validation. Clinical outcomes of individual patients stratified in three groups and simulation comparisons identified 30 genes that correlated with survival. In patients carrying wild-type p53 either treated or not treated with chemotherapy, FEN1 and MMP2 exhibited the highest inverse correlation, whereas in untreated patients bearing mutated p53, SIAH1 negatively correlated with survival. Numerous repositioned and experimental drugs targeting FEN1 and MMP2 were identified and selected drugs tested. Epinephrine and myricetin, which target FEN1, have shown cytotoxic effect on Mero-14 cells whereas marimastat and batimastat, which target MMP2 demonstrated a modest but significant inhibitory effect on MPM cell migration. Finally, 8 genes displayed correlation with disease stage, which may have diagnostic implications. Conclusions Clinical decisions related to MPM personalized therapy based on individual patients’ genetic profile and previous chemotherapeutic treatment could be reached using computational tools and the predictions reported in this study upon further testing in animal models

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Cumulative effects of roads and logging on landscape structure in the San Juan Mountains, Colorado (USA)

In the southern Rocky Mountains of temperate North America, the effects of Euro-American activities on disturbance regimes and landscape patterns have been less ubiquitous and less straightforward in high-elevation landscapes than in low-elevation landscapes. Despite apparently little change in the natural disturbance regime, there is increasing concern that forest management activities related mainly to timber harvest and to the extensive network of roads constructed to support timber harvest, fire control, and recreation since the late 1800s have altered disturbance regimes and landscape structure. We investigated the magnitude of change in landscape structure resulting from roads and logging since the onset of timber harvest activities in 1950. We found limited evidence for significant impacts in our study area when all lands within the landscape were considered. The relatively minor changes we observed reflected the vast buffering capacity of the large proportion of lands managed for purposes other than timber (e.g., wilderness). Significant changes in landscape structure and fragmentation of mature forest were, however, evident on lands designated as suitable timberlands. Roughly half of the mature coniferous forest was converted to young stands; mean patch size and core area declined by 40% and 25%, respectively, and contrast-weighted edge density increased 2- to 3-fold. Overall, roads had a greater impact on landscape structure than logging in our study area. Indeed, the 3-fold increase in road density between 1950–1993 accounted for most of the changes in landscape configuration associated with mean patch size, edge density, and core area. The extent of area evaluated and the period over which change was evaluated had a large impact on the magnitude of change detected and our conclusions regarding the ecological significance of those changes. Specifically, the cumulative impact on landscape structure was negligible over a 10-year period, but was notable over a 40-year period. In addition, the magnitude of change in landscape structure between 1950–1993 varied as a function of landscape extent. At the scale of the 228 000 ha landscape, change in landscape structure was trivial, suggesting that the landscape was capable of fully incorporating the disturbances with minimal impact. However, at intermediate scales of 1000–10 000 ha landscapes, change in landscape structure was quite evident, suggesting that there may be an optimal range of scales for detecting changes in landscape structure within the study area

The taming of a tragic heroine: Electra in eighteenth-century art

The article explores two cases of the reception of the tragic heroine Electra in the visual culture of the eighteenth century. The British artist John Flaxman (1755-1826) created three drawings of the heroine, two based on Aeschylus’ Choephori (1795) and a third, unfinished one modelled on Sophocles’ Electra. Angelika Kauffman (1741-1807), a Swiss artist, portrayed Electra’s meeting with her sister in her painting Electra giving her sister Chrysothemis her girdle and a lock of hair from Orestes for the grave of Agamemnon (circa 1778). Flaxman’s drawings stress Electra’s devotion to her dead father Agamemnon and her love for her brother Orestes. Kauffman’s more unusual painting emphasizes instead the collaboration of the two sisters. As a female painter Kauffman chose to portray Electra in a more active role drawing on Sophocles’ source text in which she persuades her sister to replace her mother’s gifts with her own. Both receptions, however, chose to marginalise the more ambiguous aspects of Electra’s portrayal in Greek tragedy, especially her desire for revenge. Thus, in order for Electra to be acceptable to an eighteenth century audience she had to be ‘tamed’ and her passionate voice silenced