Chromatin-modifying agents in anti-cancer therapy

Epigenetic alterations are involved in every step of carcinogenesis. The development of chromatin-modifying agents (CMAs) has provided the ability to fight cancer by reversing these alterations. Currently, four CMAs have been approved for cancer treatment; two DNA demethylating agents and two deacetylase inhibitors. A number of promising CMAs are undergoing clinical trials in several cancer types. Moreover, already approved CMAs are still under clinical investigation to improve their efficacy and to extend their use to a broader panel of cancers. Combinatorial treatments with CMAs are already considered a promising strategy to improve clinical benefits and to limit side effects. The real mechanisms by which these CMAs allow the improvement and remission of patients are still obscure. A deeper analysis of the molecular features expressed by responding patients should be performed to reveal this information. In this review, we focus on clinical trials with CMAs, discussing the success and the pitfalls of this new class of anti-cancer drugs.     

Dynamics induced by β-lactam antibiotics in the active site of Bacillus subtilis L,D-transpeptidase

β-lactams inhibit peptidoglycan polymerization by acting as suicide substrates of essential d,d-transpeptidases. Bypass of these enzymes by unrelated l,d-transpeptidases results in β-lactam resistance, although carbapenems remain unexpectedly active. To gain insight into carbapenem specificity of l,d-transpeptidases (Ldts), we solved the nuclear magnetic resonance (NMR) structures of apo and imipenem-acylated Bacillus subtilis Ldt and show that the cysteine nucleophile is present as a neutral imidazole-sulfhydryl pair in the substrate-free enzyme. NMR relaxation dispersion does not reveal any preexisting conformational exchange in the apoenzyme, and change in flexibility is not observed upon noncovalent binding of β-lactams (K(D) > 37.5 mM). In contrast, covalent modification of active cysteine by both carbapenems and 2-nitro-5-thiobenzoate induces backbone flexibility that does not result from disruption of the imidazole-sulfhydryl proton interaction or steric hindrance. The chemical step of the reaction determines enzyme specificity since no differences in drug affinity were observed.     

WIDESPREAD HOST‐DEPENDENT HYBRID UNFITNESS IN THE PEA APHID SPECIES COMPLEX

Linking adaptive divergence to hybrid unfitness is necessary to understand the ecological factors contributing to reproductive isolation and speciation. To date, this link has been demonstrated in few model systems, most of which encompass ecotypes that occupy relatively early stages in the speciation process. Here we extend these studies by assessing how host‐plant adaptation conditions hybrid fitness in the pea aphid, Acyrthosiphon pisum. We made crosses between and within five pea aphid biotypes adapted to different host plants and representing various stages of divergence within the complex. Performance of F1 hybrids and nonhybrids was assessed on a “universal” host that is favorable to all pea aphid biotypes in laboratory conditions. Although hybrids performed equally well as nonhybrids on the universal host, their performance was much lower than nonhybrids on the natural hosts of their parental populations. Hence, hybrids, rather than being intrinsically deficient, are maladapted to their parents’ hosts. Interestingly, the impact of this maladaptation was stronger in certain hybrids from crosses involving the most divergent biotype, suggesting that host‐dependent postzygotic isolation has continued to evolve late in divergence. Even though host‐independent deficiencies are not excluded, hybrid maladaptation to parental hosts supports the hypothesis of ecological speciation in this complex.     

Is coarse-to-fine strategy sensitive to normal aging?

Theories on visual perception agree that visual recognition begins with global analysis and ends with detailed analysis. Different results from neurophysiological, computational, and behavioral studies all indicate that the totality of visual information is not immediately conveyed, but that information analysis follows a predominantly coarse-to-fine processing sequence (low spatial frequencies are extracted first, followed by high spatial frequencies). We tested whether such processing continues to occur in normally aging subjects. Young and aged participants performed a categorization task (indoor vs. outdoor scenes), using dynamic natural scene stimuli, in which they resorted to either a coarse-to-fine (CtF) sequence or a reverse fine-to-coarse sequence (FtC). The results show that young participants categorized CtF sequences more quickly than FtC sequences. However, sequence processing interacts with semantic category only for aged participants. The present data support the notion that CtF categorization is effective even in aged participants, but is constrained by the spatial features of the scenes, thus highlighting new perspectives in visual models.     

Crop plants with improved culture and quality traits for food,feed and other uses

The large French research project GENIUS (2012–2019, https://www6.inra.genius-project_eng/) provides a good showcase of current genome editing techniques applied to crop plants. It addresses a large variety of agricultural species (rice, wheat, maize, tomato, potato, oilseed rape, poplar, apple and rose) together with some models (Arabidopsis, Brachypodium, Physcomitrella). Using targeted mutagenesis as its work horse, the project is limited to proof of concept under confined conditions. It mainly covers traits linked to crop culture, such as disease resistance to viruses and fungi, flowering time, plant architecture, tolerance to salinity and plant reproduction but also addresses traits improving the quality of agricultural products for industrial purposes. Examples include virus resistant tomato, early flowering apple and low-amylose starch potato. The wide range of traits illustrates the potential of genome editing towards a more sustainable agriculture through the reduction of pesticides and to the emergence of innovative bio-economy sectors based on custom tailored quality traits.

     

<Emphasis Type="Italic">rym15</Emphasis> from the Japanese cultivar Chikurin Ibaraki 1 is a new barley mild mosaic virus (BaMMV) resistance gene mapped on chromosome 6H

Breeding for resistant cultivars is the only way to prevent high yield loss in barley caused by the soil-borne barley mild mosaic virus (BaMMV) complex. We have characterized the BaMMV resistance of barley cv. Chikurin Ibaraki 1. Doubled haploid lines were obtained from the F₁ between the susceptible six-rowed winter barley cultivar, Plaisant, and Chikurin Ibaraki 1. Each line was tested for reaction to BaMMV by mechanical inoculation followed by DAS-ELISA. Of 44 microsatellites that covered the genome, 22 polymorphic markers were tested on one susceptible and one resistant bulk, each comprising 30 lines. Differential markers and additional microsatellite markers in the same region were then tested on the whole population. A bootstrap analysis was used to compute confidence intervals of distances and to test the orders of the resistance gene and the closest markers. A segregation of 84 resistant/98 susceptible lines fitted a 1:1 ratio (²=1.08, P=0.30), which corresponds to a single gene in this DH lines population. The resistance gene was flanked by two markers near the centromeric region of chromosome 6HS—Bmag0173, at 0.6±1.2 cM, and EBmac0874, at 5.8 ± 3.4 cM. We propose to name this new resistance gene rym15. This resistance gene and associated markers will increase the possibilities to breed efficiently for new cultivars resistant to the barley mosaic disease.Communicated by P. Langridge