Synthesis and evaluation of apoptosis induction of thienopyrimidine compounds on KRAS and BRAF mutated colorectal cancer cell lines

Monoclonal antibodies (MoAb) and tyrosine kinase inhibitors (TKI) targeting the EGFR (Epidermal Growth Factor Receptor) pathways are currently used in colorectal cancer treatment. Despite the improvement of median overall survival, resistance is observed notably due to KRAS and BRAF gene mutations. We synthesized four series of thienopyrimidines whose scaffold is structurally close to TKI used in clinical practice. We evaluated apoptosis induced by these compounds using flow cytometry on KRAS and BRAF mutated cell lines. Our results confirm that the mutated cell lines (HCT116 and HT29) are more resistant to apoptosis than the non-mutated cell line (Hela). Interestingly, among the 13 compounds tested, three of them (5b, 6b and 6d) and gefitinib exhibited a noteworthy pro-apoptotic effect, especially on mutated cell lines with an IC₅₀ value between 70 and 110 μM. These three compounds seem particularly attractive for the development of novel treatments for colorectal cancer patients harboring EGFR pathway mutations.     

Correction to: Managing biological invasions: the cost of inaction

Biological Invasions -     

Plant functional traits capture species richness variations along a flooding gradient

Local species coexistence is the outcome of abiotic and biotic filtering processes which sort species according to their trait values. However, the capacity of trait‐based approaches to predict the variation in realized species richness remains to be investigated. In this study, we asked whether a limited number of plant functional traits, related to the leaf‐height‐seed strategy scheme and averaged at the community level, is able to predict the variation in species richness over a flooding disturbance gradient. We further investigated how these mean community traits are able to quantify the strength of abiotic and biotic processes involved in the disturbance–productivity–diversity relationship. We thus tested the proposal that the deviation between the fundamental species richness, assessed from ecological niche‐based models, and realized species richness, i.e. field‐observed richness, is controlled by species interactions. Flooding regime was determined using a detailed hydrological model. A precise vegetation sampling was performed across 222 quadrats located throughout the flooding gradient. Three core functional traits were considered: specific leaf area (SLA), plant height and seed mass. Species richness showed a hump‐shaped response to disturbance and productivity, but was better predicted by only two mean community traits: SLA and height. On the one hand, community SLA that increased with flooding, controlled the disturbance‐diversity relationship through habitat filtering. On the other hand, species interactions, the strength of which was captured by community height values, played a strong consistent role throughout the disturbance gradient by reducing the local species richness. Our study highlights that a limited number of simple, quantitative, easily measurable functional traits can capture the variation in plant species richness at a local scale and provides a promising quantification of key community assembly mechanisms.     

Integrated population modeling reveals the impact of climate on the survival of juvenile emperor penguins

Early‐life demographic traits are poorly known, impeding our understanding of population processes and sensitivity to climate change. Survival of immature individuals is a critical component of population dynamics and recruitment in particular. However, obtaining reliable estimates of juvenile survival (i.e., from independence to first year) remains challenging, as immatures are often difficult to observe and to monitor individually in the field. This is particularly acute for seabirds, in which juveniles stay at sea and remain undetectable for several years. In this work, we developed a Bayesian integrated population model to estimate the juvenile survival of emperor penguins (Aptenodytes forsteri), and other demographic parameters including adult survival and fecundity of the species. Using this statistical method, we simultaneously analyzed capture–recapture data of adults, the annual number of breeding females, and the number of fledglings of emperor penguins collected at Dumont d'Urville, Antarctica, for the period 1971–1998. We also assessed how climate covariates known to affect the species foraging habitats and prey [southern annular mode (SAM), sea ice concentration (SIC)] affect juvenile survival. Our analyses revealed that there was a strong evidence for the positive effect of SAM during the rearing period (SAMR) on juvenile survival. Our findings suggest that this large‐scale climate index affects juvenile emperor penguins body condition and survival through its influence on wind patterns, fast ice extent, and distance to open water. Estimating the influence of environmental covariates on juvenile survival is of major importance to understand the impacts of climate variability and change on the population dynamics of emperor penguins and seabirds in general and to make robust predictions on the impact of climate change on marine predators.     

Robots, pipelines, polyproteins: enabling multiprotein expression in prokaryotic and eukaryotic cells

Multiprotein complexes catalyze vital biological functions in the cell. A paramount objective of the SPINE2 project was to address the structural molecular biology of these multiprotein complexes, by enlisting and developing enabling technologies for their study. An emerging key prerequisite for studying complex biological specimens is their recombinant overproduction. Novel reagents and streamlined protocols for rapidly assembling co-expression constructs for this purpose have been designed and validated. The high-throughput pipeline implemented at IGBMC Strasbourg and the ACEMBL platform at the EMBL Grenoble utilize recombinant overexpression systems for heterologous expression of proteins and their complexes. Extension of the ACEMBL platform technology to include eukaryotic hosts such as insect and mammalian cells has been achieved. Efficient production of large multicomponent protein complexes for structural studies using the baculovirus/insect cell system can be hampered by a stoichiometric imbalance of the subunits produced. A polyprotein strategy has been developed to overcome this bottleneck and has been successfully implemented in our MultiBac baculovirus expression system for producing multiprotein complexes.