Publications by authors named "Delphine Ménard"

18 Publications

  • Page 1 of 1

Inter-individual differences in foraging tactics of a colonial raptor: consistency, weather effects, and fitness correlates.

Mov Ecol 2020 24;8:28. Epub 2020 Jun 24.

Dipartimento di Scienze e Politiche Ambientali, Università degli Studi di Milano, via Celoria 26, I-20133 Milan, Italy.

Background: Consistent inter-individual differences in behavioural phenotypes may entail differences in energy efficiency and expenditure, with different fitness payoffs. In colonial-breeding species, inter-individual differences in foraging behaviour may evolve to reduce resource use overlap among conspecifics exploiting shared foraging areas. Furthermore, individual differences in foraging behaviour may covary with individual characteristics, such as sex or physiological conditions.

Methods: We investigated individual differences in foraging tactics of a colonial raptor, the lesser kestrel (). We tracked foraging trips of breeding individuals using miniaturized biologgers. We classified behaviours from GPS data and identified tactics at the foraging trip level by cluster analysis. We then estimated energy expenditure associated to each tactic from tri-axial accelerometer data.

Results: We obtained 489 foraging trips by 36 individuals. Two clusters of trips were identified, one (SF) characterized by more static foraging behaviour and the other (DF) by more dynamic foraging behaviour, with a higher proportion of flying activity and a higher energy expenditure compared to SF. Lesser kestrels showed consistent inter-individual differences in foraging tactics across weather condition gradients, favouring DF trips as solar radiation and crosswind intensity increased. DF trips were more frequent during the nestling-rearing than during the egg incubation stage. Nestlings whose tracked parent was more prone to perform DF trips experienced higher daily mass increase, irrespective of nestling feeding rates.

Conclusions: Our study provided evidence that breeding lesser kestrels flexibly adopted different foraging tactics according to contingent weather landscapes, with birds showing consistent inter-individual differences in the tendency to adopt a given tactic. The positive correlation between the tendency to perform more energy-demanding DF trips and nestling growth suggests that individual differences in foraging behaviour may play a role in maintaining key life-history trade-offs between reproduction and self-maintenance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40462-020-00206-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313117PMC
June 2020

Light affects tissue patterning of the hypocotyl in the shade-avoidance response.

PLoS Genet 2020 03 23;16(3):e1008678. Epub 2020 Mar 23.

Copenhagen Plant Science Centre, University of Copenhagen, Thorvaldsensvej, Denmark.

Plants have evolved strategies to avoid shade and optimize the capture of sunlight. While some species are tolerant to shade, plants such as Arabidopsis thaliana are shade-intolerant and induce elongation of their hypocotyl to outcompete neighboring plants. We report the identification of a developmental module acting downstream of shade perception controlling vascular patterning. We show that Arabidopsis plants react to shade by increasing the number and types of water-conducting tracheary elements in the vascular cylinder to maintain vascular density constant. Mutations in genes affecting vascular patterning impair the production of additional xylem and also show defects in the shade-induced hypocotyl elongation response. Comparative analysis of the shade-induced transcriptomes revealed differences between wild type and vascular patterning mutants and it appears that the latter mutants fail to induce sets of genes encoding biosynthetic and cell wall modifying enzymes. Our results thus set the stage for a deeper understanding of how growth and patterning are coordinated in a dynamic environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1008678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153905PMC
March 2020

Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure-Activity Relationships.

J Med Chem 2019 06 23;62(12):5863-5884. Epub 2019 May 23.

Cancer Research UK Centre for Cancer Therapeutics , The Institute of Cancer Research , 15 Cotswold Road , London SM2 5NG , United Kingdom.

Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy, and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High-throughput screening provided the initial hits. Structure-activity relationship (SAR) studies led to the discovery of AMT inhibitors with sub-micromolar half-maximal inhibitory concentrations (IC) in a LOX enzyme activity assay. Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b00335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937593PMC
June 2019

Spatial segregation of home ranges between neighbouring colonies in a diurnal raptor.

Sci Rep 2018 08 6;8(1):11762. Epub 2018 Aug 6.

Dipartimento di Scienze e Politiche Ambientali, Università degli Studi di Milano, via Celoria 26, I-20133, Milano, Italy.

Enhancement of information transfer has been proposed as a key driver of the evolution of coloniality. Transfer of information on location of food resources implies that individuals from the same colony share foraging areas and that each colony can be associated to a specific foraging area. In colonial breeding vertebrates, colony-specific foraging areas are often spatially segregated, mitigating intercolony intraspecific competition. By means of simultaneous GPS tracking of lesser kestrels (Falco naumanni) from neighbouring colonies, we showed a clear segregation of space use between individuals from different colonies. Foraging birds from different neighbouring colonies had home ranges that were significantly more segregated in space than expected by chance. This was the case both between large and between small neighbouring colonies. To our knowledge, the lesser kestrel is the only terrestrial species where evidence of spatial segregation of home ranges between conspecifics from neighbouring colonies has been demonstrated. The observed spatial segregation pattern is consistent with the occurrence of public information transfer about foraging areas and with the avoidance of overexploited areas located between neighbouring colonies. Our findings support the idea that spatial segregation of exploited areas may be widespread among colonial avian taxa, irrespective of colony size.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-29933-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078973PMC
August 2018

Analysis of Lignin Composition and Distribution Using Fluorescence Laser Confocal Microspectroscopy.

Methods Mol Biol 2017 ;1544:233-247

Umeå Plant Science Centre (UPSC), Department of Plant Physiology, Umeå University, 901 87, Umeå, Sweden.

Lignin is a polyphenolic polymer specifically accumulating in the cell walls of xylem cells in higher vascular plants. Far from being homogeneous, the lignification of xylem cell walls varies in deposition site, quantity, composition and macromolecular conformation depending on the cell wall compartment, cell type, cell developmental stage and plant species. Here, we describe how confocal microspectroscopy methods using lignin autofluorescence can be used to evaluate the relative lignin amounts, its spatial distribution and composition at the cellular and sub-cellular levels in both isolated cells and histological cross-sections of plant tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-6722-3_17DOI Listing
February 2018

Establishment and Utilization of Habituated Cell Suspension Cultures for Hormone-Inducible Xylogenesis.

Methods Mol Biol 2017 ;1544:37-57

Umeå Plant Science Centre (UPSC), Department of Plant Physiology, Umeå University, 901 87, Umeå, Sweden.

The development of inducible cell differentiation in suspension cultures led to multiple breakthroughs. It enabled the understanding of the chronology, duration, regulation and interdependency of the multiple events leading to fully functional specialized cells. The most studied cell differentiation in plants using inducible suspension cultures is the formation of tracheary elements (TEs) - the hydro-mineral sap conducting cells. Several in vitro systems established in different plant species have been developed to trigger TE formation on-demand. Here, we describe the establishment, harvesting and analysis of Arabidopsis thaliana stable habituated cell lines inducible by hormones to differentiate into TEs on-demand. Moreover, we explain the means to monitor and modify the chronology, duration and regulation of the progression of TE formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-6722-3_4DOI Listing
February 2018

Proteomic Analysis of Microtubule Interacting Proteins over the Course of Xylem Tracheary Element Formation in Arabidopsis.

Plant Cell 2015 Oct 2;27(10):2709-26. Epub 2015 Oct 2.

John Innes Centre, Norwich Research Park, Norwich NR4 7UH, United Kingdom Umeå Plant Science Centre, Department of Plant Physiology, Umeå University, 901 87 Umeå, Sweden

Plant vascular cells, or tracheary elements (TEs), rely on circumferential secondary cell wall thickenings to maintain sap flow. The patterns in which TE thickenings are organized vary according to the underlying microtubule bundles that guide wall deposition. To identify microtubule interacting proteins present at defined stages of TE differentiation, we exploited the synchronous differentiation of TEs in Arabidopsis thaliana suspension cultures. Quantitative proteomic analysis of microtubule pull-downs, using ratiometric (14)N/(15)N labeling, revealed 605 proteins exhibiting differential accumulation during TE differentiation. Microtubule interacting proteins associated with membrane trafficking, protein synthesis, DNA/RNA binding, and signal transduction peaked during secondary cell wall formation, while proteins associated with stress peaked when approaching TE cell death. In particular, CELLULOSE SYNTHASE-INTERACTING PROTEIN1, already associated with primary wall synthesis, was enriched during secondary cell wall formation. RNAi knockdown of genes encoding several of the identified proteins showed that secondary wall formation depends on the coordinated presence of microtubule interacting proteins with nonoverlapping functions: cell wall thickness, cell wall homogeneity, and the pattern and cortical location of the wall are dependent on different proteins. Altogether, proteins linking microtubules to a range of metabolic compartments vary specifically during TE differentiation and regulate different aspects of wall patterning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1105/tpc.15.00314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682315PMC
October 2015

Cellular interactions during tracheary elements formation and function.

Curr Opin Plant Biol 2015 Feb 29;23:109-15. Epub 2014 Dec 29.

Umeå Plant Science Centre (UPSC), Department of Plant Physiology, Umeå University, S-901 87 Umeå, Sweden. Electronic address:

The survival of higher plant species on land depends on the development and function of an efficient vascular system distributing water and minerals absorbed by roots to all aerial organs. This conduction and distribution of plant sap relies on specialized cells named tracheary elements (TEs). In contrast to many other cell types in plants, TEs are functionalized by cell death that hollows the cell protoplast to make way for the sap. To maintain a stable conducting function during plant development, recovery from vascular damages as well as to adapt to environmental changes, TEs are completely dependent on direct cellular interactions with neighboring xylem parenchyma cells (XPs).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbi.2014.12.001DOI Listing
February 2015

Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.

Cancer Cell 2015 Jan 11;27(1):85-96. Epub 2014 Dec 11.

Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. Electronic address:

BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2014.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297292PMC
January 2015

Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents.

Bioorg Med Chem 2013 Mar 3;21(5):1284-304. Epub 2013 Jan 3.

The Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.

The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC(50)=190 nM and with cellular GI(50)=2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC(50)=9 nM and GI(50)=220 nM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2012.12.035DOI Listing
March 2013

A novel, selective, and efficacious nanomolar pyridopyrazinone inhibitor of V600EBRAF.

Cancer Res 2010 Oct 31;70(20):8036-44. Epub 2010 Aug 31.

Signal Transduction Team, Section of Cell and Molecular Biology, Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.

Oncogenic BRAF is a critical driver of proliferation and survival and is thus a validated therapeutic target in cancer. We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, (V600E)BRAF. 1t inhibits signaling downstream of (V600E)BRAF in cancer cells, blocking DNA synthesis, and inhibiting proliferation. Importantly, we show that 1t is considerably more selective for mutated BRAF cancer cell lines compared with wild-type BRAF lines. The inhibitor is well tolerated in mice and exhibits excellent oral bioavailability (F = 71%). Suppression of (V600E)BRAF-mediated signaling in human tumor xenografts was observed following oral administration of a single dose of 1t. As expected, the growth rate in vivo of a wild-type BRAF human tumor xenograft model is unaffected by inhibitor 1t. In contrast, 1t elicits significant therapeutic responses in mutant BRAF-driven human melanoma xenografts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-10-1366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001191PMC
October 2010

Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds.

Bioorg Med Chem 2010 Sep 15;18(18):6934-52. Epub 2010 Jun 15.

Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin-4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2010.06.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956513PMC
September 2010

Novel hinge binder improves activity and pharmacokinetic properties of BRAF inhibitors.

J Med Chem 2010 Aug;53(15):5639-55

The Institute of Cancer Research, Cancer Research UK Centre for Cancer Therapeutics, Sutton, Surrey, UK.

Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A-B-C system featuring an imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A-B-C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm100383bDOI Listing
August 2010

Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): increasing cellular potency through optimization of a distal heteroaromatic group.

J Med Chem 2010 Apr;53(7):2741-56

The Institute of Cancer Research, Cancer Research UK Centre for Cancer Therapeutics, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.

We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A-B-C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified (V600E)BRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H-pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated (V600E)BRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, (V600E)BRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm900607fDOI Listing
April 2010

BRAF inhibitors based on an imidazo[4,5]pyridin-2-one scaffold and a meta substituted middle ring.

J Med Chem 2010 Mar;53(5):1964-78

Cancer Research UK Centre of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.

We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo[4,5]pyridin-2-one scaffold and a substituted urea linker. Here, we present a new series of BRAF inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm901509aDOI Listing
March 2010

Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring.

J Med Chem 2009 Jul;52(13):3881-91

The Institute of Cancer Research, UK Centre for Cancer Therapeutics, Sutton, Surrey SM2 5NG, United Kingdom.

BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number of substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogenic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC(50) of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm900242cDOI Listing
July 2009

Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

J Med Chem 2009 Apr;52(8):2255-64

Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.

BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm801509wDOI Listing
April 2009