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Legumes provide several ecological services to agroecosystems, but there is a lack of references on services related to N flows for a wide range of legume crops. N2O emissions were measured in two field experiments using a two-year legume-cereal crop sequence. In the first year (2014 and 2016), different legume crops were grown (lupin, pea, fava bean, common bean, soybean, chickpea) and compared to fertilized cereals (barley and sorghum). Once the seeds were harvested and the residues incorporated in the soil, unfertilized wheat was sown and harvested in the second year (2015 and 2017). N2O emissions, as well as soil temperature and moisture, were measured continuously using an automated chamber method during the two years of each experiment. Daily N2O emissions were less than 10 g N-N2O ha-1 d-1, with higher values (ranging from 10 to 90 g N-N2O ha-1 d-1) being measured during exceptionally rainy conditions. Daily N2O emissions were mainly influenced by climatic conditions for field experiments and far less by inorganic N content, except for N-fertilized cereals. For both field experiments, cumulative N2O emissions during legume and cereal pre-crops + fallow period between pre-crop harvest and wheat sowing (1st year) (mean values 365.4 and 318.1 g N-N2O ha-1 for experiment I and II, respectively) were higher than during wheat crop cultivation (2nd year) (155.8 and 101.5 g N-N2O ha-1 for experiment I and II, respectively). For field experiment II, N2O emissions were slightly higher for the N fertilized cereal pre-crops (529.8 and 523.3 g N-N2O ha-1 for barley and sorghum, respectively) compared to legume pre-crops (mean values 380.6 and 417.2 g N-N2O ha-1 for legumes sown in March and May, respectively), while no significant difference was measured for field experiment I. There was no difference in N2O emissions during the cultivation of the different legume species. Furthermore, when wheat was grown after legumes or N fertilized cereals, N2O emissions were comparable for the different experimental treatments with no relation established with the amounts of N present in crop residues or their C: N ratios. Despite the small differences in emissions between N-fertilized cereals and grain legumes, introducing these leguminous species in crop rotation and in these pedoclimatic conditions makes it possible to substitute synthetic N fertilizer and mitigate the greenhouse gases emitted from these cropping systems. However, further research is still needed to clarify and quantify the value of legumes in mitigating and reducing greenhouse gas emissions from cropping systems.

X-linked inhibitor of apoptosis protein (XIAP) exercises its biological function by locking up and inhibiting essential caspase-3, -7 and -9 toward apoptosis execution. It is overexpressed in multiple human cancers, and it plays an important role in cancer cells’ death skipping. Inhibition of XIAP-BIR3 domain and caspase-9 interaction was raised as a promising strategy to restore apoptosis in malignancy treatment. However, XIAP-BIR3 antagonists also inhibit cIAP1-2 BIR3 domains, leading to serious side effects. In this study, we worked on a theoretical model that allowed us to design and optimize selective synthetic XIAP-BIR3 antagonists. Firstly, we assessed various MM-PBSA strategies to predict the XIAP-BIR3 binding affinities of synthetic ligands. Molecular dynamics simulations using hydrogen mass repartition as an additional parametrization with and without entropic term computed by the interaction entropy approach produced the best correlations. These simulations were then exploited to generate 3D pharmacophores. Following an optimization with a training dataset, five features were enough to model XIAP-BIR3 synthetic ligands binding to two hydrogen bond donors, one hydrogen bond acceptor and two hydrophobic groups. The correlation between pharmacophoric features and computed MM-PBSA free energy revealed nine residues as crucial for synthetic ligand binding: Thr308, Glu314, Trp323, Leu307, Asp309, Trp310, Gly306, Gln319 and Lys297. Ultimately, and three of them seemed interesting to use to improve XIAP-BR3 versus cIAP-BIR3 selectivity: Lys297, Thr308 and Asp309.

International audience; The development of inhibitors of anti-apoptotic proteins, such as Mcl-1, is currently a very active area in the field of cancer research. One of the very first reported inhibitor of Mcl-1 was the molecule MIM1, but we have demonstrated recently that the structure of this compound had to be revised from 2 to the derivative 1 (FJ-809). In this paper we first develop a strategy to prepare unambiguously molecules such as 1 with a thiazol-3(2H)-yl)imino core, instead of the [2(3H)thiazolylidene]hydrazine previously found in MIM1 (2). Next a series of biological studies have been performed on 1, using IGROV1-R10 ovarian cancer cells as models, and they have been complemented by Fluorescence Polarisation Assays. These studies demonstrated that the new compound FJ-809 (1) was devoid of any significant activity on Mcl-1, contrary to 2. Then molecular modelling and molecular dynamic studies have been performed in order to elucidate the differences between FJ-809 and MIM1 in their interaction with the Mcl-1 protein.

Targeting selective estrogen subtype receptors through typical medicinal chemistry approaches is based on occupancy-driven pharmacology. In occupancy-driven pharmacology, molecules are developed in order to inhibit the protein of interest (POI), and their popularity is based on their virtue of faster kinetics. However, such approaches have intrinsic flaws, such as pico-to-nanomolar range binding affinity and continuous dosage after a time interval for sustained inhibition of POI. These shortcomings were addressed by event-driven pharmacology-based approaches, which degrade the POI rather than inhibit it. One such example is PROTACs (Proteolysis targeting chimeras), which has become one of the highly successful strategies of event-driven pharmacology (pharmacology that does the degradation of POI and diminishes its functions). The selective targeting of estrogen receptor subtypes is always challenging for chemical biologists and medicinal chemists. Specifically, estrogen receptor α (ER-α) is expressed in nearly 70% of breast cancer and commonly overexpressed in ovarian, prostate, colon, and endometrial cancer. Therefore, conventional hormonal therapies are most prescribed to patients with ER + cancers. However, on prolonged use, resistance commonly developed against these therapies, which led to selective estrogen receptor degrader (SERD) becoming the first-line drug for metastatic ER + breast cancer. The SERD success shows that removing cellular ER-α is a promising approach to overcoming endocrine resistance. Depending on the mechanism of degradation of ER-α, various types of strategies of developed.

Publisher Copyright: © 2022 by the authors. Nonselective cell damage remains a significant limitation of radiation therapies in cancer. Decades of successful integration of radiation therapies with other medicinal chemistry strategies significantly improved therapeutic benefits in cancer. Advancing in such technologies also led to the development of specific photopharmcology-based approaches that improved the cancer cell selectivity and provided researchers with spatiotemporal control over the degradation of highly expressed proteins in cancer (proteolysis targeting chimeras, PROTACs) using a monochrome wavelength light source. Two specific strategies that have achieved notable successes are photocage and photoswitchable PROTACs. Photocaged PROTACs require a photolabile protecting group (PPG) that, when radiated with a specific wavelength of light, irreversibly release PPG and induce protein degradation. Thus far, diethylamino coumarin for estrogen-related receptor α (ERRα), nitropiperonyloxymethyl (BRD4 bromodomain protein), and 4,5-dimethoxy-2-nitrobenzyl for (BRD4 bromodomain protein, as well as BTK kinase protein) were successfully incorporated in photocaged PROTACs. On the other hand, photoswitches of photoswitchable PROTACs act as an actual ON/OFF switch to target specific protein degradation in cancer. The ON/OFF function of photoswitches in PROTACs (as photoswitchable PROTACs) provide spatiotemporal control over protein degradation, and to an extent are correlated with their photoisomeric state (cis/trans-configuration), showcasing an application of the photochemistry concept in precision medicine. This study compiles the photoswitchable PROTACs targeted to bromodomain proteins: BRD 2, 3, and 4; kinases (BCR-ABL fusion protein, ABL); and the immunophilin FKBP12. Photocaging of PROTACs found successes in selective light-controlled degradation of kinase proteins, bromodomain-containing proteins, and estrogen receptors in cancer cells.

Publisher Copyright: © 2022 The Authors. ChemistrySelect published by Wiley-VCH GmbH. The photoswitchable-PROTACs have photoswitches that work as an actual ON/OFF switch for any particular bioactivity. In reported studies, the ON/OFF activity correlates with the photostationary state and quantum yield of a specific isomer under a definite wavelength of light, providing a spatiotemporal control over protein degradation (an example of photochemistry-based precision medicine). The studies reported the role of azobenzenes as photoswitches (ortho-tetramethoxybenzenes, ortho-tetraflurobenzenes as push-pull and push-push) to develop light-controlled PROTACs. This paper discussed the photophysical properties of photoswitchable-PROTACs (such as photoisomerization, quantum yield, and thermal relaxation states) and correlated their photochemical-based structural bioactivity relationships. The proteins studied under photoswitchable-PROTACs are kinase proteins: BCR-ABL fusion protein, ABL; Bromodomain proteins: BRD2, 3, 4; Immunophilins: FKBP12.

Publisher Copyright: © 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH Apoptosis is a highly regulated cellular process. Aberration in apoptosis is a common characteristic of various disorders. Therefore, proteins involved in apoptosis are prime targets in multiple therapies. Bcl-xL is an antiapoptotic protein. Compared to other antiapoptotic proteins, the expression of Bcl-xL is common in solid tumors and, to an extent, in some leukemias and lymphomas. The overexpression of Bcl-xL is also linked to survival and chemoresistance in cancer and senescent cells. Therefore, Bcl-xL is a promising anticancer and senolytic target. Various nanomolar range Bcl-xL inhibitors have been developed. ABT-263 was successfully identified as a Bcl-xL/Bcl-2 dual inhibitor. But it failed in the clinical trial (phase-II) because of its on-target platelet toxicity, which also implies an essential role of Bcl-xL protein in the survival of human platelets. Classical Bcl-xL inhibitor designs utilize occupancy-driven pharmacology with typical shortcomings (such as dose-dependent off-target and on-target platelet toxicities). Hence, event-driven pharmacology-based approaches, such as proteolysis targeting chimeras (PROTACs) and SNIPERs (specific non-genetic IAP-based protein erasers) have been developed. The development of Bcl-xL based PROTACs was expected, as 600 E3-ligases are available in humans, while some (such as cereblon (CRBN), von Hippel-Lindau (VHL)) are relatively less expressed in platelets. Therefore, E3 ligase ligand-based Bcl-xL PROTACs (CRBN: XZ424, XZ739; VHL: DT2216, PZ703b, 753b) showed a significant improvement in platelet therapeutic index than their parent molecules (ABT-263: DT2216, PZ703b, 753b, XZ739, PZ15227; A1155463: XZ424). Other than their distinctive pharmacology, PROTACs are molecularly large, which limits their cell permeability and plays a role in improving their cell selectivity. We also discuss prodrug-based approaches, such as antibody-drug conjugates (ABBV-155), phosphate prodrugs (APG-1252), dendrimer conjugate (AZD0466), and glycosylated conjugates (Nav-Gal). Studies of in-vitro, in-vivo, structure-activity relationships, biophysical characterization, and status of preclinical/clinical inhibitors derived from these strategies are also discussed in the review.

International audience; In the area of cancer research, the development of new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic. The small molecule MIM1 has been reported earlier as one of the first selective inhibitors of the anti-apoptotic protein Mcl-1. In the present paper, we first revised the structure of this molecule based on extensive physicochemical analyses. Then we designed and synthesized a focused library of analogues for the corrected structure of MIM1. Next, these molecules were subjected to a panel of in cellulo biological studies, allowing the identification of dual Bcl-x(L)/Mcl-1 inhibitors, as well as selective Mcl-1 inhibitors. These results have been complemented by fluorescence polarization assays with the Mcl-1 protein. Preliminary structure-activity relationships were discussed and extensive molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the selectivity of inhibition of Mcl-1 versus Bcl-x(L).

Apoptosis is a highly regulated cellular process. Aberration in apoptosis is a common characteristic of various disorders. Therefore, proteins involved in apoptosis are prime targets in multiple therapies. Bcl-x

Introduction With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1. Results A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. Conclusion Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor., Graphical Abstract

Target Protein Degradation TPD is a new avenue and revolutionary for therapeutics because redefining the principles of classical drug discovery and guided by event-based target activity rather than the occupancy-driven activity. Since the discovery of the first PROTAC in 2001, TPD represents a rapidly growing technology, with applications in both drug discovery and chemical biology. Over the last decade, many questions have been raised and today the knowledge gained by each team has elucidated a number of them, although there is still a long way to go. The objective of this work is to present the challenges that the PROTAC strategy has very recently addressed in drug design and discovery by presenting extremely recent results from the literature and to provide guidelines in the drug design of new PROTACs as successful therapeutic modality for medicinal chemists.

Tauopathies are neurodegenerative disorders associated with the accumulation of abnormal tubulin associated unit (tau) protein in the brain. Tau pathologies include a broad spectrum of diseases, with Alzheimer's disease (AD) being the most common tauopathy. The pathophysiological mechanisms of AD are still only partially understood. As a consequence, attempts to establish therapeutic approaches have led to numerous clinical trial failures and, to date, no curative treatment is available for AD despite the considerable number of research programs. Therefore, over the past decade, the aggregation of the tau protein in AD has become a therapeutic target of interest. In this review, we gather in silico, in vitro, and in vivo methodologies that are relevant to assess compounds targeting tau aggregation, from early drug design to clinical trials.

Protein-protein interactions (PPIs) control many important physiological processes within human cells. Apoptosis or programmed cell death is closely regulated by pro- and antiapoptotic signals. Dysregulation of this homeostasis is implicated in tumorigenesis and acquired resistance to treatments. The emerging importance of Mcl-1 protein in chemotherapeutic resistance makes it a high priority therapeutic target. Targeting PPIs associated with Mcl-1 presents many challenges for the design of inhibitors. This review focuses on the characterization of the Mcl-1 hot-spots which are related to four hydrophobic pockets P1-P4 and one major electrostatic interaction. Analysis of structural data highlights the high importance of the P2/P3 pockets for the binding of nonpeptide ligands. In order to guide medicinal chemists into making more selective and potent Mcl-1 inhibitors, the Mcl-1 protein is compared to other antiapoptotic proteins.

Early-life represents a critically sensitive window to endocrine disrupting chemicals, potentially leading to long-term repercussions on the phenotype later in life. The mechanisms underlying this phenomenon, referred to as the Developmental Origins of Health and Disease (DOHaD), are still poorly understood. To gain molecular understanding of these effects, we exposed mangrove rivulus (Kryptolebias marmoratus) for 28 days post hatching (dph) to 4 and 120 ng/L 17-α-ethinylestradiol, a model xenoestrogen. After 28 days, fish were raised for 140 days in clean water and we performed quantitative label-free proteomics on brain, liver and ovotestis of 168 dph adults. A total of 820, 888 and 420 proteins were robustly identified in the brain, liver and ovotestis, respectively. Effects of 17-α-ethinylestradiol were tissue and dose-dependent: a total of 31, 51 and 18 proteins were differentially abundant at 4 ng/L in the brain, liver and ovotestis, respectively, compared to 20, 25 and 39 proteins at 120 ng/L. Our results suggest that estrogen-responsive pathways, such as lipid metabolism, inflammation, and the innate immune system were affected months after the exposure. In addition, the potential perturbation of S-adenosylmethionine metabolism encourages future studies to investigate the role of DNA methylation in mediating the long-term effects of early-life exposures. Significance The Developmental Origins of Health and Disease (DOHaD) states that early life stages of humans and animals are sensitive to environmental stressors and can develop health issues later in life, even if the stress has ceased. Molecular mechanisms supporting DOHaD are still unclear. The mangrove rivulus is a new fish model species naturally reproducing by self-fertilization, making it possible to use isogenic lineages in which all individuals are highly homozygous. This species therefore permits to strongly reduce the confounding factor of genetic variability in order to investigate the effects of environmental stress on the phenotype. After characterizing the molecular phenotype of brain, liver and ovotestis, we obtained true proteomic reaction norms of these three organs in adults after early life stages have been exposed to the common endocrine disruptor 17-α-ethinylestradiol (EE2). Our study demonstrates long-term effects of early-life endocrine disruption at the proteomic level in diverse estrogen-responsive pathways 5 months after the exposure. The lowest tested and environmentally relevant concentration of 4 ng/L had the highest impact on the proteome in brain and liver, highlighting the potency of endocrine disruptors at low concentrations.

Organisms exposed to endocrine disruptors in early life can show altered phenotype later in adulthood. Although the mechanisms underlying these long-term effects remain poorly understood, an increasing body of evidence points towards the potential role of epigenetic processes. In the present study, we exposed hatchlings of an isogenic lineage of the self-fertilizing fish mangrove rivulus for 28 days to 4 and 120 ng/L of 17-α-ethinylestradiol. After a recovery period of 140 days, reduced representation bisulphite sequencing (RRBS) was performed on the liver in order to assess the hepatic genome-wide methylation landscape. Across all treatment comparisons, a total of 146 differentially methylated fragments (DMFs) were reported, mostly for the group exposed to 4 ng/L, suggesting a non-monotonic effect of EE2 exposure. Gene ontology analysis revealed networks involved in lipid metabolism, cellular processes, connective tissue function, molecular transport and inflammation. The highest effect was reported for nipped-B-like protein B (NIPBL) promoter region after exposure to 4 ng/L EE2 (+ 21.9%), suggesting that NIPBL could be an important regulator for long-term effects of EE2. Our results also suggest a significant role of DNA methylation in intergenic regions and potentially in transposable elements. These results support the ability of early exposure to endocrine disruptors of inducing epigenetic alterations during adulthood, providing plausible mechanistic explanations for long-term phenotypic alteration. Additionally, this work demonstrates the usefulness of isogenic lineages of the self-fertilizing mangrove rivulus to better understand the biological significance of long-term alterations of DNA methylation by diminishing the confounding factor of genetic variability.

A woman’s nutritional status during pregnancy and breastfeeding is not only critical for her health, but also for that of future generations. Nutritional requirements during pregnancy differ considerably from those of non-pregnant women. Thus, a personalized approach to nutritional advice is recommended. Currently, some countries recommend routine supplementation for all pregnant women, while others recommend supplements only when necessary. Maternal physiological adaptations, as well as nutritional requirements during pregnancy and lactation, will be reviewed in the literature examining the impacts of dietary changes. All of these data have been studied deeply to facilitate a discussion on dietary supplement use and the recommended doses of nutrients during pregnancy and lactation. The aim of this review is to evaluate the knowledge in the scientific literature on the current recommendations for the intake of the most common micronutrients and omega-3 fatty acids during pregnancy and lactation in the United States, Canada, and Europe. Taking into account these considerations, we examine minerals, vitamins, and omega-3 fatty acid requirements. Finally, we conclude by discussing the potential benefits of each form of supplementation.

The positive effect of grain legume pre-crops on the yield of the subsequent crop has been studied widely, whereas less information is available on the nitrogen (N) processes related to this positive effect, especially for a wide range of grain legume species. The objective was to quantify and understand the effect of grain legume compared to cereal pre-crops (sown in 2014 and 2016) on grain and shoot N yields and shoot N concentration of wheat (Triticum aestivum) grown the following year (2015 and 2017). Spring legumes (faba bean (Vicia faba), fenugreek (Trigolia foenum-graecum), common vetch (Vicia sativa), lentil (Lens culinaris), lupin (Lupinus albus), and pea (Pisium sativum)) were compared to barley (Hordeum vulgare). Summer legumes (chickpea (Cicer arietinum),common bean (Phaseolus vulgaris), soybean (Glycine max) and Narbonne vetch (Vicia narbonensis)) were compared to sorghum (Sorghum bicolor). Inorganic N remaining in the soil at pre-crop harvest (N sparing) was measured. The STICS model which accurately predicted soil humidity and soil inorganic N in the pedoclimatic conditions of the field experiments was used to calculate N mineralisation from pre-crop residues and N leaching between pre-crop harvest and wheat harvest. Grain and shoot N yields of unfertilised N wheat were respectively 27 and 25 % higher after faba bean and lentil compared to barley pre-crops, and 66 and 51 % higher after summer legumes compared to sorghum pre-crop. In the second experiment, N fertilisation reduced the positive effect of fenugreek, and lentil on wheat yield compared to barley while it did not modify the pre-crop effect of the other legumes. A positive relationship between N mineralisation from pre-crop residues and wheat shoot N yield was established, with higher amounts of N available for the subsequent wheat after legume pre-crops. In 2014, N sparing was higher after spring pre-crops compared to summer pre-crops inducing higher N leaching after spring legume pre-crops, especially in the first experiment which was characterised by heavy rain in summer and autumn. Estimating N availability by taking into account N sparing, N mineralisation from soil and pre-crop residues and N leaching explained 49 % of wheat shoot N yield variability. Unquantified N processes and non-N processes might also have contributed to the positive effects of legumes on the subsequent wheat.

Protein-protein interactions (PPIs) constitute many potential therapeutic targets for the discovery of new drugs. Given their specificity, PPIs are more challenging to target than other ligands. Thus, finding the best screening process can be difficult. Moreover, PPIs often have no direct accessible activity readout. Therefore, it can be unclear which test to choose for the screening of small molecules targeting PPIs. Given that noncellular assays are the most suitable both as first screening assays and for high-throughput screening (HTS), here we focus on noncellular screening assays. For each assay, we discuss the principles and advantages/drawbacks and provide a recent example. We also highlight the crucial parameters to take into account to select the most suitable assays to screen PPI modulators.

Background Pyridoclax is an original lead, recently identified as very promising in treatment of chemoresistant ovarian cancers. To correct the unfavorable intrinsic physico-chemical properties of this BCS II drug, a formulation strategy was implied in the drug discovery step. Pyridoclax-loaded nanoemulsions (NEs) were developed to permit its preclinical evaluation. Results The resulting nanoemulsions displayed a mean size of about 100 nm and a high encapsulation efficiency (>95%) at a drug loading of 2 wt%, enabling a 1,000-fold increase of the Pyridoclax apparent solubility. NEs have enabled a sustained release of the drug as assayed by a dialysis bag method. In addition, anti-tumor effects of the Pyridoclax-loaded nanoemulsions (PNEs) showed a 2.5-fold higher activity on chemoresistant ovarian cancer cells than free Pyridoclax. This effect was confirmed by a drastic increase of caspase 3/7 activation from 10 µM PNEs, as newly objectified by real time apoptose imaging. The Pyridoclax bioavailability was kept unchanged after encapsulation in nanoemulsions as determined in a mice model after oral administration. Conclusion Thus, NEs should permit valuable Pyridoclax oral administration, and valorization of this promising anticancer drug by maintaining its original anticancer activity, and by reducing the Pyridoclax therapeutic concentration.

National audience; Aims The architecture of root systems determines where and how much resources plants can extract from the soil, how they compete for soil resources, and how they interact with soil organisms. We aimed to develop a 3D root-system model called RSCone for future inclusion into multispecies individual-based canopy models suitable to design integrated weed management or intercropping strategies. Methods We (1) proposed a conceptual root-system model consisting of empirical equations predicting root-system envelope, root length and biomass distribution from environmental conditions, species and plant stage, (2) calibrated the model from simulations with an existing architectural root-system model (ArchiSimple) to benefit from its knowledge on root functioning and the many parameterized crop and weed species, (3) identified the root-system architectural processes driving the key root state variables and (4) established species functional groups with Principal Component Analyses and clustering. Results RSCone consists of 17 equations and 14 parameters; it was calibrated for 22 weeds and 22 crop species and varieties. Six species functional groups were established, depending on their family (Poaceae, Fabaceae, other), root-extension rates, specific root length (SRL) and the time to reach maximum SRL. Conclusion RSCone is ready to be included into multispecies (crop and/or weed) dynamics models.

International audience; Protein-protein interactions are attractive targets because they control numerous cellular processes. In oncology, apoptosis regulating Bcl-2 family proteins are of particular interest. Apoptotic cell death is controlled via PPIs between the anti-apoptotic proteins hydrophobic groove and the pro-apoptotic proteins BH3 domain. In ovarian carcinoma, it has been previously demonstrated that Bcl-x L and Mcl-1 cooperate to protect tumor cells against apoptosis. Moreover, Mcl-1 is a key regulator of cancer cell survival and is a known resistance factor to Bcl-2/Bcl-x L pharmacological inhibitors making it an attractive therapeutic target. Here, using a structure-guided design from the oligopyridine lead Pyr-idoclax based on Noxa/Mcl-1 interaction we identified a new derivative, active at lower concentration as compared to Pyridoclax. This new derivative selectively binds to the Mcl-1 hydrophobic groove and releases Bak and Bim from Mcl-1 to induce cell death and sensitize cancer cells to Bcl-2/Bcl-x L targeting strategies.

International audience; AimsA better understanding of how plant growth, N nutrition and symbiotic nitrogen fixation (SNF) are influenced by soil inorganic N availability, for a wide range of legume species, is crucial to optimise legume productivity, N2 fixation, while limiting environmental risks such as N leaching. MethodsA comparative analysis was performed for ten legume crops, grown in a field experiment and supplied with four N fertiliser rates. Dry matter, N concentration and SNF were measured. In parallel, root elongation rates were studied in a greenhouse experiment. ResultsFor most species, N fertilisation had little effect on plant growth and N accumulation. SNF was reduced by soil inorganic N available at sowing but with large differences in the magnitude of the response among species. The response varied according to plant N requirements for growth and plant ability to retrieve inorganic N. Accordingly, root lateral expansion rate measured in RhizoTubes was highly correlated with plant ability to retrieve inorganic N measured in the field experiment. Conclusion Combining SNF response to soil inorganic N, shoot N and plant ability to retrieve inorganic N, allowed a robust evaluation of differential response to soil inorganic N among a wide range of legume species.

In addition to genetic variation, epigenetic mechanisms such as DNA methylation might make important contributions to heritable phenotypic diversity in populations. However, it is often difficult to disentangle the contributions of genetic and epigenetic variation to phenotypic diversity. Here, we investigated global DNA methylation and mRNA expression of the methylation-associated enzymes during embryonic development and in adult tissues of one natural isogenic lineage of mangrove rivulus fish, Kryptolebias marmoratus. Being the best-known self-fertilizing hermaphroditic vertebrate affords the opportunity to work with genetically identical individuals to examine, explicitly, the phenotypic effects of epigenetic variance. Using the LUminometric Methylation Assay (LUMA), we described variable global DNA methylation at CpG sites in adult tissues, which differed significantly between hermaphrodite ovotestes and male testes (79.6% and 87.2%, respectively). After fertilization, an immediate decrease in DNA methylation occurred to 15.8% in gastrula followed by re-establishment to 70.0% by stage 26 (liver formation). Compared to zebrafish, at the same embryonic stages, this reprogramming event seems later, deeper, and longer. Furthermore, genes putatively encoding DNA methyltransferases (DNMTs), Ten-Eleven Translocation (TET), and MeCP2 proteins showed specific regulation in adult gonad and brain, and also during early embryogenesis. Their conserved domains and expression profiles suggest that these proteins play important roles during reproduction and development. This study raises questions about mangrove rivulus' peculiar reprogramming period in terms of epigenetic transmission and physiological adaptation of individuals to highly variable environments. In accordance with the general-purpose genotype model, epigenetic mechanisms might allow for the expression of diverse phenotypes among genetically identical individuals. Such phenotypes might help to overcome environmental challenges, making the mangrove rivulus a valuable vertebrate model for ecological epigenetic studies. The mangrove rivulus, Kryptolebias marmoratus, is the best-known self-fertilizing hermaphroditic vertebrate that allows to work with genetically identical individuals to examine, explicitly, the phenotypic effects of epigenetic variance. The reprogramming event is later, more dramatic and longer than in other described vertebrates. High evolutionary conservation and expression patterns of DNMT, TET, and MeCP2 proteins in K. marmoratus suggest biological roles for each member in gametogenesis and development.

International audience; Cereal-legume intercropping is known to improve the sustainability of crop production. However, it remains uncommon on commercial farms in Europe due to a number of socio-technical lock-ins and the many practical issues raised when integrating intercrops in cropping systems (e.g. which species, cultivars, sowing densities). Crop modelling is an option to explore integration scenarios and support farmers' decisions. However, available crop models are not able to simulate bundles of ecosystem services provided by a large diversity of binary cereallegume intercropping scenarios. To address this challenge, we developed a hybrid modelling chain that combines process-based, statistical and knowledge-based models to benefit from the strengths of these three different modelling approaches. The chain (i) simulates potential biomass of the sole cereal and legume crops independently using the crop model STICS; (ii) uses statistical interaction models built in R to convert potential biomass in sole cropping into attainable biomass in intercropping by considering competition effects among species, using a field trial database; (iii) converts attainable biomass into actual biomass by considering pest damage using a knowledge-based multi-attribute DEXi model, and also assesses control of pests (i.e. weeds, insects and diseases); and (iv) uses another set of multi-attribute models to assess five additional ecosystem services (i.e. cereal and legume grain yields, cereal protein content, nitrogen supply to the following crop and impact on soil structure) from the actual biomass of the intercrop at harvest and/or cropping system features. The chain was calibrated for grain cereal-legume intercrops sown simultaneously in a random pattern under low-input French conditions. We used an expert-based approach to assess the performances of each model and evaluate the accuracy of the entire modelling chain. In 18 simulated scenarios, 79% of the predicted levels of ecosystem services were consistent with experts' opinion. Predictions were more accurate for intercropping scenarios that included species from the trial database used to build linear interaction models (relative RMSE of 27-31%) but remained satisfactory for other intercropped species (relative RMSE of 32-37%). This is the first modelling chain able to assess bundles of ecosystem services provided by multiple cereal-legume intercrops in function of their cropping system contexts. This chain is intended to be included in an educational tool that is used face to face with farmers or students to design cropping systems that include intercrops.

Cet article propose une analyse historique du processus de verrouillage du système agroalimentaire en défaveur des légumineuses à graines, à l’aune des théories évolutionnistes. Plusieurs mécanismes d’autorenforcement permettent de comprendre pourquoi ces espèces sont de moins en moins cultivées en France face à un système agro-industriel qui s’est spécialisé en faveur des céréales, favorisant à l’amont l’usage d’engrais azotés de synthèse et limitant à l’aval les investissements pour les légumineuses en alimentation humaine. Cet article s’interroge alors sur les perspectives de déverrouillage.

International audience; Legumes deliver unique functions that are complementary to those of other groups of species (cereals and oil-rich crops), providing many ecosystem services related to nitrogen. However, the choice of grain legumes according to their ability to provide these ecosystem services remains difficult due to a lack of references for a variety of species. During two legume – wheat successions established between 2014 and 2017, five nitrogen pools were measured, and considered as proxies of nitrogen functions supporting ecosystem services and dis-services. Nitrogen pools were analyzed together with several of their explanatory shoot and root characteristics (i.e. plant traits and properties). For the first time, a wide range of grain legumes could be characterized by their contrasted functional profiles relative to nitrogen. For each species, synergies and trade-offs between the different nitrogen functions were highlighted and related to the explanatory plant characteristics. Shoot and root characteristics explained 76.1% of the variability of nitrogen functions among legumes species. Chickpea, common bean, and soybean had high capacity to take up soil nitrogen during their growth cycles, reducing the risk of nitrogen losses after their harvest. These species were characterized by a high root lateral expansion rate and their capacity to invest a large proportion of belowground biomass in nodules. Conversely, common vetch, faba bean, lentil, pea and Narbonne vetch, were less able to take up soil nitrogen, with higher risks of nitrogen losses, but these species induced high amounts of nitrogen in the following wheat crop and were characterized by high crop residue nitrogen concentration. Larger amounts of nitrogen fixed and exported in seeds were measured for species characterized by high shoot dry matter, high nitrogen harvest index, high seed nitrogen concentration, and large seeds. Hence, this study should facilitate the selection of legume species according to the expected objectives.

International audience; Pyridoclax is considered a promising anticancer drug, acting as a protein-protein interaction disruptor, with potential applications in the treatment of ovarian, lung, and mesothelioma cancers. Eighteen sensibly selected structural analogues of Pyridoclax were synthesized, and their physicochemical properties were systematically assessed and analyzed. Moreover, considering that drug-membrane interactions play an essential role in understanding the mode of action of a given drug and its eventual toxic effects, membrane models were used to investigate such interactions in bulk (liposomes) and at the air-water interface. The measured experimental data on all original oligopyridines allowed the assessment of relative differences in terms of physicochemical properties, which could be determinant for their druggability, and hence for drug development.

Diversification of cropping systems has been proposed as a major mechanism to move towards sustainable cropping systems. To date, a diversification option that has received little attention is introduction of ley pastures into cropping systems, but the use of ley pastures is challenged by most future-oriented scenarios aiming to feed the world sustainably. In these scenarios, ruminant livestock feed only on permanent pastures, while cropping systems focus completely on production of crop-based human food. Diversification of cropping systems with ley pastures is thus compromised by knowledge gaps and future-oriented policy options. Here, we review ecosystem services provided by introducing ley pastures into cropping systems to increase sustainability of agriculture, discuss types of ley pastures and their management liable to promote these services, and raise future challenges related to introducing ley pastures into cropping systems. We conclude that (1) ley pastures provide a large set of input (soil conservation, nutrient provision and recycling, soil water retention, biological control of pests) and output (water purification, climate regulation, habitat provision for biodiversity conservation, forage production) ecosystem services of primary importance to cropping systems and society, respectively, as long as their spatial and temporal insertion within cropping systems is well-managed; otherwise, disservices may be produced. (2) To benefit from ecosystem services provided by ley pastures in cropping systems while limiting their disservices, it appears necessary to define a safe operating space for ley pastures in cropping systems. Moving towards this space requires changing plant breeding programs towards multiservice ley pastures, producing knowledge about emerging ways of introducing ley pastures into cropping systems (e.g., living mulch, green manure) and better quantifying the bundles of ecosystem services provided by ley pastures in cropping systems.

Grain-legume crops are important for ensuring the sustainability of agrofood systems. Among them, pulse production is subject to strong lock-in compared to soya, the leading worldwide crop. To unlock the situation and foster more grain-legume crop diversity, scientific research is essential for providing new knowledge that may lead to new development. Our study aimed to evaluate whether research activity on grain-legumes is also locked in favor of soya. Considering more than 80 names grouped into 19 main grain-legume species, we built a dataset of 107,823 scholarly publications (articles, book, and book chapters) between 1980 and 2018 retrieved from the Web of Science (Clarivate Analytics) reflecting the research activity on grain-legumes. We delineated 10 scientific themes of interest running the gamut of agrofood research (e.g., genetics, agronomy, and nutrition). We indexed grain-legume species, calculated the percentage of records for each one, and conducted several analyses longitudinally and by country. Globally, we found an unbalanced research output: soya remains the main crop studied, even in the promising field of food sciences advanced by FAO as the &ldquo, future of pulses&rdquo, Our results raise questions about how to align research priorities with societal demand for more crop diversity.

Protein-protein interactions (PPIs) control many important physiological processes within human cells. Apoptosis or programmed cell death is closely regulated by pro- and antiapoptotic signals. Dysregulation of this homeostasis is implicated in tumorigenesis and acquired resistance to treatments. The emerging importance of Mcl-1 protein in chemotherapeutic resistance makes it a high priority therapeutic target. Targeting PPIs associated with Mcl-1 presents many challenges for the design of inhibitors. This review focuses on the characterization of the Mcl-1 hot-spots which are related to four hydrophobic pockets P1-P4 and one major electrostatic interaction. Analysis of structural data highlights the high importance of the P2/P3 pockets for the binding of nonpeptide ligands. In order to guide medicinal chemists into making more selective and potent Mcl-1 inhibitors, the Mcl-1 protein is compared to other antiapoptotic proteins.

International audience; Lipophilicity must be necessarily determined in drug discovery since this physicochemical property will directly influence the pharmacokinetics of a drug as its pharmacodynamics profile. Pyridoclax is an original lead, recently identified as very promising in treatment of chemoresistant cancers. The partition coefficient (Kp) of this anticancer drug was determined by microplate assays, well adapted in drug discovery, since being rapid, and requiring only poor drug amounts. The analytical approach was performed either by UV derivative spectrophotometry after validation thanks to a set of basic, neutral and acid reference substances, or originally, by raw fluorescence spectrophotometry by taking advantage of the pyridoclax intrinsic fluorescence. Large unilamellar vesicles (LUVs) were formulated from soybean-, egg-, or dipalmitoyl-phosphatidylcholine, characterized in terms of granulometric properties, ζ potential (determined by DLS), and of phospholipid content (quantified by 1H NMR, also in presence of cholesterol). Whatever the detection method used, log Kp of pyridoclax were in the same magnitude order, and pyridoclax appeared as a lipophilic compound. It was also established that interactions between this lead and biomimetic membranes were influenced by the relative fluidity of the membranes, as confirmed by results of a liposome leakage assay

Protein–protein interactions (PPIs) are involved in many cellular processes; consequently, the discovery of small molecules as modulators of PPIs has become an important challenge in medicinal chemistry. Structural mimetics of α-helices, β-turns or β-strands could maintain or restore biological functions and should possess biological activity. At this time, the most challenging classes of PPIs are those mediated by β-sheet interactions, which are implicated in a number of diseases. Only a few β-strand mimics have been published to date. This study presents an evaluation of oligothienylpyridyl scaffolds in view of their ability for β-strand mimicry. In this study, theoretical ring twist angle predictions for these scaffolds have been validated by X-ray diffraction and molecular dynamics simulations with NMR constraints. Careful choice of substituent and heavy-atom positions in the foldamer units opens the way to produce reasonably coplanar compounds mimicking β-strand side-chain distribution.

17-α-ethinylestradiol (EE2) is one of the most potent endocrine disrupting compounds found in the aquatic environments, and is known to strongly alter fish reproduction and fitness. While the effects of direct exposure to EE2 are well studied in adults, there is an increasing need to assess the impacts of exposure during early life stages. Sensitivity to pollutants during this critical window can potentially affect the phenotype later in life or in subsequent generations. This study investigated phenotypic outcome of early-life exposure to 17-α-ethinylestradiol during development and in adults of the mangrove rivulus, Kryptolebias marmoratus. Being one of the only two known self-fertilizing hermaphroditic vertebrates, this fish makes it possible to work with genetically identical individuals. Therefore, using rivulus makes it possible to examine, explicitly, the phenotypic effects of environmental variance while eliminating the effects of genetic variance. Genetically identical rivulus were exposed for the first 28 days post hatching (dph) to 0, 4 or 120 ng/L of EE2, and then were reared in uncontaminated water until 168 dph. Growth, egg laying and steroid hormone levels (estradiol, cortisol, 11-ketotestosterone, testosterone) were measured throughout development. Exposed fish showed a reduction in standard length directly after exposure (28 dph), which was more pronounced in the 120 ng/L group. This was followed by compensatory growth when reared in clean water: all fish recovered a similar size as controls by 91 dph. There was no difference in the age at maturity and the proportions of mature, non-mature and male individuals at 168 dph. At 4 ng/L, fish layed significantly fewer eggs than controls, while, surprisingly, reproduction was not affected at 120 ng/L. Despite a decrease in fecundity at 4 ng/L, there were no changes in hormones levels at the lower concentration. In addition, there were no significant differences among treatments immediately after exposure. However, 120 ng/L exposed fish exhibited significantly higher levels of testosterone at 91 and 168 dph and 11-ketotestosterone at 168 dph, up to 140 days after exposure. These results indicate that early-life exposure to EE2 had both immediate and delayed impacts on the adult's phenotype. While fish growth was impaired during exposure, compensatory growth, reduced fecundity and modification of the endocrine status were observed after exposure ceased.

International audience; Grain-legume plants fix atmospheric nitrogen in the soil and thus do not need nitrogen fertilizers. Therefore, grain- legumes can potentially decrease global warming, as nitrogen fertilization is responsible for half of all agricultural greenhouse gas emissions. Moreover, grain-legumes have many functional and nutritional properties both as feed and food. Despite the fact that the European Union has granted considerable subsidies to promote grain-legume cultivation, their production continues to fall and there has been no satisfactory explanation as to why. This study provides an answer by showing that a situation of technological lock-in has resulted from the co-evolution of crop systems, based on an agrochemical paradigm, public policies, and market dynamics that promote cereals. This process began with the historical choice by European and French public institutions to relegate grain-legumes to feed in direct competition with imported soybeans. Moreover, interrelated factors, such as breeding selection, public subsidies, and food systems, have favored increasing returns to adoption for cereals to the detriment of grain-legumes. Finally, the evolutionary economics approach used here identified several actions that must be implemented together, such as agricultural cost-accounting methods, nitrogen management, institutional innovations, and market out lets to promote grain-legumes and move towards more sustainable agriculture.

indexation en cours.; International audience; Pro-survival stress-inducible chaperone HSP110 is the only HSP for which a mutation has been found in a cancer. Multicenter clinical studies demonstrated a direct association between HSP110 inactivating mutation presence and excellent prognosis in colorectal cancer patients. Here, we have combined crystallographic studies on human HSP110 and in silico modeling to identify HSP110 inhibitors that could be used in colorectal cancer therapy. Two molecules (foldamers 33 and 52), binding to the same cleft of HSP110 nucleotide-binding domain, were selected from a chemical library (by co-immunoprecipitation, AlphaScreening, Interference-Biolayer, Duo-link). These molecules block HSP110 chaperone anti-aggregation activity and HSP110 association to its client protein STAT3, thereby inhibiting STAT3 phosphorylation and colorectal cancer cell growth. These effects were strongly decreased in HSP110 knockdown cells. Foldamer's 33 ability to inhibit tumor growth was confirmed in two colorectal cancer animal models. Although tumor cell death (apoptosis) was noted after treatment of the animals with foldamer 33, no apparent toxicity was observed, notably in epithelial cells from intestinal crypts. Taken together, we identified the first HSP110 inhibitor, a possible drug-candidate for colorectal cancer patients whose unfavorable outcome is associated to HSP110.

International audience