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Simple Summary In Chronic Myeloid Leukemia (CML), intra-clonal heterogeneity is a major factor in the response to tyrosine kinase inhibitors and in leukemia stem cell persistence. This intra-clonal heterogeneity could be partially explained by epigenetic abnormalities. This review focuses on DNA methylation abnormalities in CML and its potential implications for the development of new biomarkers of the treatment response and new therapy opportunities. DNA methylation abnormalities are considered an important event in the CML progression phase. Moreover, in recent years, DNA methylation abnormalities have also been characterized at CML diagnosis (in the chronic phase), with specific alterations in the immature cells of the tumor clone. Lastly, the review discusses the importance of these finding for understanding the disease emergence, for developing new therapeutic strategies, and for a personalized management of CML. Abstract Chronic Myeloid Leukemia (CML) is a model to investigate the impact of tumor intra-clonal heterogeneity in personalized medicine. Indeed, tyrosine kinase inhibitors (TKIs) target the BCR-ABL fusion protein, which is considered the major CML driver. TKI use has highlighted the existence of intra-clonal heterogeneity, as indicated by the persistence of a minority subclone for several years despite the presence of the target fusion protein in all cells. Epigenetic modifications could partly explain this heterogeneity. This review summarizes the results of DNA methylation studies in CML. Next-generation sequencing technologies allowed for moving from single-gene to genome-wide analyses showing that methylation abnormalities are much more widespread in CML cells. These data showed that global hypomethylation is associated with hypermethylation of specific sites already at diagnosis in the early phase of CML. The BCR-ABL-independence of some methylation profile alterations and the recent demonstration of the initial intra-clonal DNA methylation heterogeneity suggests that some DNA methylation alterations may be biomarkers of TKI sensitivity/resistance and of disease progression risk. These results also open perspectives for understanding the epigenetic/genetic background of CML predisposition and for developing new therapeutic strategies.

International audience; Many methods of storage are currently used to delay the postharvest senescence and the ensuing quality losses of detached lettuce leaves. This transcriptome study explores the senescence mechanisms of packaged lettuce leaves over 7 d of cold storage in darkness. At the end of the storage, the detached lettuce leaves showed a 10% water loss and 24% cut-edge discoloration. No chlorophyll fluorescence variation was observed. A total of 1048 and 1846 genes were differentially expressed (DE) after 2 and 7 d of storage, respectively. In terms of gene expression modulation, the data showed a global shutdown of primary-metabolism but no obvious chlorophyll breakdown. Although an early stress-response clearly takes place, the cold storage under darkness appeared to delay senescence by protecting chloroplasts from degradation and enhancing an antioxidative response. Then, a progressive global expression shutdown appeared, concomitantly with the dehydration stress. Among the transcripts that showed an early high expression, the data highlighted many stress-related genes (PIN, bzip TF, Heat-shock, stress A-like), 30 redox-regulation associated transcripts, the majority of the phenylpropanoid pathway markers and ethylene and auxin-related genes. Later (day 7), many dehydration-responsive markers showed an increased expression, as did some abscisic acid related markers. Phytohormones (cytokinins) and transcriptions factors (WRKYs) appeared to play complex roles as senescence progressed. No simple link between cut-edge discoloration and PPO-related genes expression was made. The main known process of senescence induction through the phaephorbide a oxygenase and phospholipase D pathways were not highlighted in this study. To the best of our knowledge, this study is the first to explore the transcriptional response of postharvest senescence in detached lettuce leaves. Deeper analysis of several markers will help to dissect the crosstalk between wounding, dehydration and senescence mechanisms. In addition, post-transcriptional studies are needed to conclude about the described patterns.

Two varieties of lettuce (Lactuca sativa L. var. crispa and capitata) and one variety of escarole (Cichorium endivia var. latifolium) were chosen due to their different browning sensitivity during storage as minimally processed products. The changes in the compositions and contents of the primary polyphenolic compounds were investigated during the first few hours of storage and then after 1, 2, 3, and 6 days of storage at 6°C and revealed sharp variations. Browning development, activity of phenylalanine ammonia lyase, and concentration of ascorbic acid were also examined during storage. The content of chicoric acid, which was the most abundant phenolic compound, varied substantially during the first 24 hr of storage and between the different varieties. Oak leaf lettuce, which was the most sensitive variety to browning, was characterized by a higher maintained chicoric acid level with a constant decreased chlorogenic acid level during the storage period. PRACTICAL APPLICATIONS: Browning development is responsible for the short shelf life of minimally processed vegetables, such as lettuce (Lactuca sativa). Polyphenolic compounds, as substrates of enzymatic reactions, are involved in the browning susceptibility of leaves. Comparisons of the profiles and contents of these compounds in different leaves showed dramatic variations during storage. This study provides additional information to better control, optimize minimally processed produce and select more suitable leaves for the fresh-cut industry.

The effect of the alternation of light/dark periods (AL) (16/8 min light/dark cycles and a photosynthetic photon flux density (PPFD) of 50 μmol photons m−2 s−1 for three days) to clarify the mechanisms involved in the clomazone tolerance of tobacco plantlets primed with AL was studied. Clomazone decreased PSII activity, the net photosynthetic rate (Pn), and the ascorbate and total polyphenol contents and increased H2O2 and starch grain accumulation and the number of the cells that underwent programmed cell death (PCD). The pretreatment with AL reduced the inhibitory effect of clomazone on the PSII activity and photosynthesis, as indicated by the decreases in the H2O2 and starch grain accumulation and the PCD levels, and increased the content of ascorbate and certain phenolic compounds, such as chlorogenic acid, neochlorogenic acid and rutin. The AL treatment could promote photorespiration via post-illumination burst (PIB) effects. This alternative photorespiratory electron pathway may reduce H2O2 generation via the consumption of photochemical energy, such as NADH + H+. At 10 days (D10) of AL treatment, this process induced moderate stress which stimulates H2O2 detoxification systems by increasing the activity of antioxidant enzymes and the biosynthesis of antioxidant components. Therefore, the PCD levels provoked by clomazone were noticeably decreased.

International audience; Aims We tested here the effect of low nitrogen (N) availability and of UV-C radiations (a physical agent) on the susceptibility of Lactuca sativa L. towards Botrytis cinerea (BC 87) and Sclerotinia minor (SM). Methods We assessed first that a dose of UV-C radiation of 0.85 kJ. m−2 is effective in triggering a positive effect without entailing any negative effect on plants. We then tested the effect of this dose on 62-day-old lettuce plants grown at three N concentrations: 2 (low), 10 (normal) and 20 mM (high). Plants were inoculated 24 h after exposure to UV-C radiation and monitored for 4 days. Results Analysis of lesion areas showed that leaf susceptibility towards Botrytis cinerea (BC 87) and Sclerotinia minor (SM) substantially increased with the increasing N concentrations. Results also showed that the UV-C treatment can reduce MDA and H2O2 concentrations and lesion areas. Reduction of lesion areas reached 67 % on day 4 in the Sclerotinia minor (SM)-10 mM N trial and 52 % in the Botrytis cinerea (BC 87)-20 mM N trial. The UV-C treatment also resulted in an increase in the concentration of total phenolics in leaves which could be observed on days 1, 2 and 4 in Sclerotinia minor SM trial and days 1 and 2 in Botrytis cinerea BC 87 trial. Conclusions Taken together, our observations suggest that UV-C irradiation stimulate the capacity of lettuce plants to resist against Sclerotinia minor (SM) and Botrytis cinerea (BC 87) and that phenolic compounds may be involved in this resistance.

In this study, plantlets of two tobacco ( Nicotiana tabacum L.) varieties that are clomazone-tolerant (cv. Xanthi ) and clomazone-sensitive (cv. Virginie vk51 ) were subjected to low concentration of clomazone herbicide. The oxygen-evolving rate of isolated chloroplasts, chlorophyll a fluorescence transients, JIP-test responses, hydrogen peroxide contents, antioxidant enzyme activities, cytohistological results and photosynthetic pigment contents were recorded. The results indicated that the carotenoid content was 2-fold higher in Virginie , which had greater clomazone sensitivity than Xanthi . Virginie exhibited noticeable decreases in the LHC content (Chl a / b ratio), the maximum photochemical quantum efficiency of PSII ( F v / F m ), the performance index on the absorption basis (PI abs ), and the electron flux beyond the first PSII Q A evaluated as (1 − V J ) with V J = ( F J − F 0 )/( F m − F 0 ) as well as increases in the rate of photon absorption (ABS/RC) and the energy dissipation as heat (DI0/RC). These results suggest that PSII photoinhibition occurred as a consequence of more reduced PQ-pool and accumulated Q A − . The oxygen evolution measurements indicate that PSI electron transport activity was not affected by clomazone. The more significant accumulation of H 2 O 2 in Virginie compared to Xanthi was due to the absence of ROS-scavenging enzymes, and presumably induced programmed cell death (PCD). The symptoms of PCD were observed by cytohistological analysis, which also indicated that the leaf tissues of clomazone-treated Virginie exhibited significant starch accumulation compared to Xanthi . Taken together, these results indicate that the variable tolerance to clomazone observed between Virginie and Xanthi is independent of the carotenoid content and could be related to the state of the LHC, the redox state of the PQ-pool, and the activity of detoxification enzymes.

This study investigated the impact of pulsed light treatment on physical and nutritional quality of fresh-cut “Kent” mangoes. Pulsed light treatments were carried out using an automatic flash lamp system (Mulieribus, Claranor) composed of eight lamps situated all around the sample with a total fluence of 8 J cm − 2 . Firmness, colour, phenol, carotenoid, ascorbic acid contents and enzyme activities (Phenylalanineammonialyase, PAL and Polyphenoloxydase, PPO) were analysed. Pulsed light treatment maintained the firmness, the colour and the carotenoid content of fresh-cut mangoes. The treatment increased PPO activities after 3 days and maintained PAL activity. For the nutritional aspect, pulsed light maintained phenol and total ascorbic acid contents such as the control. Our results suggest that the application of pulsed light could be used with fresh-cut mangoes to improve physical quality and maintain nutritional properties. Industrial Relevance Mango is one of the most important tropical fruit worldwide with an increasing demand for “ready to eat” products, because of convenience and fresh-like quality. However, fresh-cut mangoes suffer from browning and softening. Conventional thermal treatments decreased the browning but may contribute to the degradation of certain component. Nowadays, alternative nonthermal technologies are more and more studied such as Pulsed Light. In industry, Pulsed light is used to decontaminate surfaces, packaging or food (bread). No application is available on fruits and vegetables. This work estimated the feasibility of pulsed light treatment to improve the quality of fresh-cut mangoes. The results obtained are promising and could improve the use of pulsed light treatment to extend the shelf-life of fresh-cut products.

Les modifications chimiques des protéines alimentaires sont réalisées dans le but d’ améliorer leurs propriétés fonctionnelles. Elles sont également pratiquées pour des études fondamentales des relations structure/fonction des protéines. Les principales modifications chimiques des protéines alimentaires sont présentées ainsi que leurs incidences sur les propriétés fonctionnelles telles les propriétés émulsifiantes, moussantes, visqueuses, d’hydratation et de gélification.

Silica-supported tantalum and tungsten hydrides present unusual properties in the activation of alkanes. They activate the C H bonds of cycloalkanes to form the corresponding surface metal–cycloalkyl complexes. They catalyse the metathesis reaction of alkanes which is an unprecedented process affording the formation of higher and lower homologues. They also catalyse the hydrogenolysis of alkanes and especially ethane which cannot be cleaved by the corresponding group-4 metal hydrides.

The mutual exchange of methyl groups of ethane molecules is catalyzed by a silica-supported tantalum hydride surface complex (see the schematic representation of the transition states). This process, which resembles degenerate olefin metathesis, is five times faster than the productive alkane metathesis.

The silica-supported transition metal hydrides (≡Si-O-Si≡)(≡Si-O-)2Ta-H and (≡Si-O-)xM-H (M, chromium or tungsten) catalyze the metathesis reaction of linear or branched alkanes into the next higher and lower alkanes at moderate temperature (25° to 200°C). With (≡Si-O-Si≡)(≡Si-O-)2Ta-H, ethane was transformed at room temperature into an equimolar mixture of propane and methane. Higher and lower homologs were obtained from propane, butane, and pentane as well as from branched alkanes such as isobutane and isopentane. The mechanism of the step leading to carbon-carbon bond cleavage and formation likely involves a four-centered transition state between a tantalum-alkyl intermediate and a carbon-carbon -bond of a second molecule of alkane.

International audience; Depending on the position of the fruit in the tree, mango fruit may be exposed to high temperature and intense light conditions that may lead to metabolic and physiological disorders and affect yield and quality. The present study aimed to determine how mango fruit adapted its functioning in terms of fruit water relations, epicarp characteristics and the antioxidant defence system in peel, to environmental conditions. The effect of contrasted temperature and light conditions was evaluated under natural solar radiation and temperature by comparing well-exposed and shaded fruit at three stages of fruit development. The sun-exposed and shaded peels of the two sides of the well-exposed fruit were also compared. Depending on fruit position within the canopy and on the side of a well-exposed fruit, the temperature gradient over a day affected fruit characteristics such as transpiration, as revealed by the water potential gradient as a function of the treatments, and led to a significant decrease in water conductance for wellexposed fruits compared to fruits within the canopy. Changes in cuticle thickness according to fruit position were consistent with those of fruit water conductance. Osmotic potential was also affected by climatic environment and harvest stage. Environmental conditions that induced water stress and greater light exposure, like on the sunny side of well-exposed fruit, increased the hydrogen peroxide, malondialdehyde and total and reduced ascorbate contents, as well as SOD, APX and MDHAR activities, regardless of the maturity stage. The lowest values were measured in the peel of the shaded fruit, that of the shaded side of well-exposed fruit being intermediate. Mango fruits exposed to water-stress-induced conditions during growth adapt their functioning by reducing their transpiration. Moreover, oxidative stress was limited as a consequence of the increase in antioxidant content and enzyme activities. This adaptive response of mango fruit to its climatic environment during growth could affect postharvest behaviour and quality. (Résumé d'auteur)

Reaction of Ta[CH2C(CH3)3]3[CHC(CH3)3] (1) with a silica dehydroxylated at 500 °C has been previously reported to produce a mixture of ⋮SiOTa[CH2C(CH3)3]2[CHC(CH3)3] (2a) and (⋮SiO)2Ta[CH2C(CH3)3][CHC(CH3)3] (2b). Treatment of these two surface organometallic complexes under 1 atm of hydrogen up to 200 °C leads to the formation of a surface tantalum(III) monohydride: (⋮SiO)2TaIIIH (3) as a major product and surface Si−H groups. 3 has been characterized in the following way: it reversibly exchanges with deuterium to give the corresponding [Ta]−D species; 3 reacts with CH3I to give methane; 3 reacts quantitatively with di(tert-butyl)ketone to form the corresponding tantalum di(tert-butyl)methoxide; 3 reacts with D2O to give a mixture of HD and D2 (2 ± 0.2 mol equiv per tantalum); and 3 activates the C−H bond of cycloalkanes (C5 to C8) at room temperature to form the corresponding surface tantalum(III) monoalkyls (⋮SiO)2Ta-alkyl, with liberation of 1 ± 0.1 equiv of hydrogen. The surface tantalum-alkyls are...

Background: Triple negative breast cancer (TNBC) patients (pts) left with a residual tumor (RT) after neoadjuvant treatment (NAT) have a poor prognosis, often developing fatal metastases within first 3 years post-NAT. We investigated TNBCs which showed no response or progression under the pioneer anti-EGFR/cytotoxics-based NAT (PMID 24827135), in order to see whether tumor gene expression (GE), associated with a powerful response-predictive biomarker, the amount of tumor-infiltrating lymphocytes (TIL) can help identifying that highly resistant TNBC category and its possible therapeutic targets. Methods: The study included 27 TNBCs treated with panitumumab combined to standard fluorouracil-epirubicin-cyclophosphamide and docetaxel. Response was evaluated according to the Chevallier (Ch) classification (PMID 8338056). TIL amount was reported as the % of pre-NAT tumor stroma occupied by them (PMID 25214542). EGFR protein expression was assessed by immunohistochemistry and reported as a histoscore (% of positive cells x signal intensity as 0, 1, 2 or 3). Pre-NAT tumor RNA was hybridized on Agilent's Human SurePrint microarrays. Data were extracted and analyzed by Feature Extraction 10.7, Genespring GX 12.0 and TNBCtype softwares and Man-Whitney test. Results: The responses were: Ch-1 (pathologic complete response): 14 pts, Ch-3 (partial response): 8 pts, Ch-4 (no response / progression): 5 pts. The Ch-4 group showed significantly lower TIL level as compared to Ch-1 (5±4 vs 60±31, p=0.0014) and a trend of lower TIL in comparison to Ch-3 (5±4 vs 32±27, p=0.053). With regards to the TNBCtype-determined molecular classification, the only remarkable difference was the predominant mesenchymal subtype in Ch-4 (4/5 cases) while Ch-1 and Ch-3 contained a mixture of 6 TNBCtype subtypes. Interestingly, ERBB1 (EGFR) GE was significantly lower in Ch-4 compared to Ch-3 (p Conclusion: In this pilot study, the TNBC highly resistant to NAT were mostly of the mesenchymal molecular subtype, with low EGFR gene/protein expression and immunologically "calm". Some genes overexpressed in this group worth further investigating as therapeutic targets, since the anti-EGFR or immunotherapy approaches are likely ineffective for those tumors. Citation Format: Radosevic-Robin N, Ponelle F, Chabaud V, Rouzaire P-O, Privat M, Vidal V, Bignon Y-J, Penault-Llorca F. Transcriptome analysis reveals possible therapeutic targets in a non-immunogenic, mesenchymal-type triple negative breast cancer, resistant to anti-EGFR/cytoxics-based neoadjuvant treatment: A pilot study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-04-06.

International audience; The metathesis of 13C-monolabeled ethane leads to the parallel occurrence of degenerate and productive reactions, affording the statistical distribution of the various product isotopomers, which can be rationalized in terms of a mechanistic reaction scheme combining both processes.

The silica-supported transition metal hydrides (≡Si-O-Si≡)(≡Si-O-)2Ta-H and (≡Si-O-)xM-H (M, chromium or tungsten) catalyze the metathesis reaction of linear or branched alkanes into the next higher and lower alkanes at moderate temperature (25° to 200°C). With (≡Si-O-Si≡)(≡Si-O-)2Ta-H, ethane was transformed at room temperature into an equimolar mixture of propane and methane. Higher and lower homologs were obtained from propane, butane, and pentane as well as from branched alkanes such as isobutane and isopentane. The mechanism of the step leading to carbon-carbon bond cleavage and formation likely involves a four-centered transition state between a tantalum-alkyl intermediate and a carbon-carbon -bond of a second molecule of alkane.

Der gegenseitige Austausch von Methylgruppen zwischen Ethanmolekulen wird von einem Tantalhydrid-Oberflachenkomplex auf einem Silicat-Trager katalysiert (siehe schematisch dargestellte Ubergangszustande). Dieser Prozes, der der entarteten Olefinmetathese ahnelt, verlauft funfmal schneller als die produktive Alkanmetathese.

A set of 27 rice varieties were evaluated for their morphological grain characteristics (length, width, thickness, thousand kernel weight, TKW), chemical composition (amylose, protein, and ash content) and starch properties (gelatinization temperature and enthalpy, amylose-lipid complex). In addition, cell walls were characterized by the arabinoxylan and [bêta]-glucan contents. A rapid method for determining optimum rice cooking time was developed based on the swelling ratio; a fixed value of 2.55 gave a gelatinization level of 95% assessed by differential scanning calorimetry and translucence testing. Optimum cooking time appears positively correlated with kernel thickness and TKW but also with ash content. Confocal laser and scanning electron microscope observation of uncooked rice grains revealed different structural features (cell size) and fracture behavior: for some cultivars, the fracture showed ruptured cells, whereas for others most cells were intact. These structural differences, which may be linked to pectin content, could partly explain rice kernel cooking behavior.

To investigate the coordinated occurrence of loss of heterozygosity (LOH) at the BRCA1 locus and microsatellite instability (MI) in sporadic breast carcinomas, 56 tumors were analysed for both genetic alterations. The comparison of clinicopathological features with the obtained data revealed that LOH at the BRCA1 locus was significantly correlated with features specific for familial BRCA1 tumors and with absence of hormone receptors. No correlation was found between LOH and MI. These results suggest that sporadic and familial breast tumors, where BRCA1 is altered, could display similar clinicopathological features and that LOH and MI are distinct genetic events in sporadic breast carcinogenesis.

The Werner's syndrome (WS) is a rare recessive disease characterized by an early onset of geriatric disorders. The Werner's syndrome gene (WRN), recently cloned, encodes for an helicase and therefore plays a role in DNA metabolism and DNA repair. Here, we report the study of a French family with two affected members and numerous cancers. Using the protein truncation test and sequencing, we identified a homozygous mutation in the WRN gene. This mutation generates a frame shift leading to a very short 391 amino acids truncated protein without the helicase motif. A particularly severe phenotype of the affected patient was associated with an unusual vulvar cancer traditionaly observed in elderly patients and therefore likely to be related to the Werner's syndrome. An additional substitution of G for A at nucleotidic position 1392 was also described. We suggest that a relation between genotype and phenotype could exist in the studied family. Hum Mutat 11:413–414, 1998. © 1998 Wiley-Liss, Inc.

Silica-supported tantalum hydride activates at low temperature the C–H and the C–D bonds of cyclooctane and CD4, respectively, to form the corresponding cyclooctyl and perdeuteriomethyl-tantalum surface complexes; these complexes are transformed under molecular oxygen into the corresponding tantalum-alkoxy derivatives which with acetic acid give rise to the corresponding alkylacetates.

Background Previous research programmes have described muscle biochemical traits and gene expression levels associated with beef tenderness. One of our results concerning the DNAJA1 gene (an Hsp40) was patented. This study aims to confirm the relationships previously identified between two gene families (heat shock proteins and energy metabolism) and beef quality. Results We developed an Agilent chip with specific probes for bovine muscular genes. More than 3000 genes involved in muscle biology or meat quality were selected from genetic, proteomic or transcriptomic studies, or from scientific publications. As far as possible, several probes were used for each gene (e.g. 17 probes for DNAJA1). RNA from Longissimus thoracis muscle samples was hybridised on the chips. Muscles samples were from four groups of Charolais cattle: two groups of young bulls and two groups of steers slaughtered in two different years. Principal component analysis, simple correlation of gene expression levels with tenderness scores, and then multiple regression analysis provided the means to detect the genes within two families (heat shock proteins and energy metabolism) which were the most associated with beef tenderness. For the 25 Charolais young bulls slaughtered in year 1, expression levels of DNAJA1 and other genes of the HSP family were related to the initial or overall beef tenderness. Similarly, expression levels of genes involved in fat or energy metabolism were related with the initial or overall beef tenderness but in the year 1 and year 2 groups of young bulls only. Generally, the genes individually correlated with tenderness are not consistent across genders and years indicating the strong influence of rearing conditions on muscle characteristics related to beef quality. However, a group of HSP genes, which explained about 40% of the variability in tenderness in the group of 25 young bulls slaughtered in year 1 (considered as the reference group), was validated in the groups of 30 Charolais young bulls slaughtered in year 2, and in the 21 Charolais steers slaughtered in year 1, but not in the group of 19 steers slaughtered in year 2 which differ from the reference group by two factors (gender and year). When the first three groups of animals were analysed together, this subset of genes explained a 4-fold higher proportion of the variability in tenderness than muscle biochemical traits. Conclusion This study underlined the relevance of the GENOTEND chip to identify markers of beef quality, mainly by confirming previous results and by detecting other genes of the heat shock family as potential markers of beef quality. However, it was not always possible to extrapolate the relevance of these markers to all animal groups which differ by several factors (such as gender or environmental conditions of production) from the initial population of reference in which these markers were identified.