KRAS G12C fragment screening renders new binding pockets.

KRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found in a third of lung, half of colorectal and pancreatic cancer cases, is believed to be responsible for a substantial number of cancer deaths. For 30 years, KRAS has been the subject of extensive drug-targeting efforts aimed at targeting KRAS protein itself, but also its post-translational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. So far, most KRAS targeting strategies have failed, and there are no KRAS-specific drugs available. However, clinical candidates targeting the KRAS G12C protein have recently been developed. MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders.

Temporal dynamics in animal community assembly during post-logging succession in boreal forest.

Species assemblages can result from deterministic processes, such as niche differentiation and interspecific interactions, and from stochastic processes, such as random colonisation and extinction events. Although changes in animal communities following disturbances have been widely examined, few studies have investigated the mechanisms structuring communities during ecological succession. We assessed the impact of logging on small mammal and beetle assemblages in landscapes dominated by old-growth boreal forests. Our objectives were to 1) characterize variations in communities during the first 66 years of post-harvest forest succession, 2) determine if there are non-random patterns of species co-occurrence (i.e., deterministic processes), and if there are, 3) establish whether non-random co-occurrences are best explained by habitat attributes or by interspecific interactions. We captured small mammals and beetles along a gradient of forest succession (5-66 years) and in old-growth forest, and characterized key vegetation attributes. First, we tested whether community compositions in clear-cut stands became similar to those in natural stands after 66 years. We then used null models, which were either unconstrained or constrained by habitat attributes, to address the last two objectives and distinguish effects of vegetation attributes from interspecific interactions on community assembly. We showed that beetle assemblages differed in stands 21-30 years post-harvest compared to old-growth forests. In contrast, harvesting did not influence the composition of small mammal communities. Overall, our results suggest that community assembly during forest succession is driven by both stochastic and deterministic processes, the latter being linked to interspecific interactions more strongly than to vegetation attributes.

Ecological processes determining the distribution dynamics of vole populations during forest succession.

The size and distribution of animal populations may vary drastically over time following a disturbance event. While both competition and predation can control the size of animal populations, changes in the relative importance of these two density-dependent processes remain poorly documented during ecological succession. Here, we combined habitat selection and optimal foraging theory to identify the processes that can explain the increase in red-backed voles (Myodes gapperi) during post-logging forest succession in boreal ecosystems. Specifically, we assessed the extent to which changes in intra- and interspecific competition and in predation risk can explain variation in abundance and distribution of voles during post-harvest forest succession. We estimated the abundances of the red-backed vole and of its main competitor, the deer mouse (Peromyscus maniculatus), in adjacent pairs of logged (5-66 years old) forest stands and uncut stands (> 120 years old). We found that voles increased their preference for uncut stands with increasing conspecific density. Foraging experiments revealed that in early-seral forest stands, voles increased their feeding effort in the presence of deer mice, particularly in safer food patches. This behaviour is expected from foraging theory when interspecific competitors increase predation risk. Apparent competition would thus limit the density of red-backed voles, and changes in the relative strength of this process during forest succession would control patterns of distribution and abundance of the species.

Maintaining animal assemblages through single-species management: the case of threatened caribou in boreal forest.

With the intensification of human activities, preserving animal populations is a contemporary challenge of critical importance. In this context, the umbrella species concept is appealing because preserving a single species should result in the protection of multiple co-occurring species. Practitioners, though, face the task of having to find suitable umbrellas to develop single-species management guidelines. In North America, boreal forests must be managed to facilitate the recovery of the threatened boreal caribou (Rangifer tarandus). Yet, the effect of caribou conservation on co-occurring animal species remains poorly documented. We tested if boreal caribou can constitute an effective umbrella for boreal fauna. Birds, small mammals, and insects were sampled along gradients of post-harvest and post-fire forest succession. Predictive models of occupancy were developed from the responses of 95 species to characteristics of forest stands and their surroundings. We then assessed the similarity of species occupancy expected between simulated harvested landscapes and a 90 000-km2 uncut landscape. Managed landscapes were simulated based on three levels of disturbance, two timber-harvest rotation cycles, and dispersed or aggregated cut-blocks. We found that management guidelines that were more likely to maintain caribou populations should also better preserve animal assemblages. Relative to fragmentation or harvest cycle, we detected a stronger effect of habitat loss on species assemblages. Disturbing 22%, 35%, and 45% of the landscape should result, respectively, in 80%, 60%, and 40% probability for caribou populations to be sustainable; in turn, this should result in regional species assemblages with Jaccard similarity indices of 0.86, 0.79, and 0.74, respectively, relative to the uncut landscape. Our study thus demonstrates the value of single-species management for animal conservation. Our quantitative approach allows for the evaluation of management guidelines prior to implementation, thereby providing a tool for establishing suitable compromises between economic and environmental sustainability of human activities.