Publications by authors named "Olivier Mathieu"

76 Publications

In vivo exposure of marine mussels to venlafaxine: bioconcentration and metabolization.

Environ Sci Pollut Res Int 2021 Jul 19. Epub 2021 Jul 19.

HydroSciences Montpellier, Université Montpellier, IRD, CNRS, 15 Avenue Charles Flahault, BP 14491, 34093, Montpellier cedex 5, France.

Pharmaceuticals are present in natural waters, thus contributing to the general exposure of aquatic organisms, but few data are available on the accumulation of these substances in marine organisms. The present study evaluated the in vivo bioconcentration of an antidepressant-venlafaxine (VLF)-in marine mussels (Mytilus galloprovincialis) during 7 days of exposure at nominal 10 μg/L concentration, followed by a 7-day depuration period. The bioconcentration factor (BCF) was 265 mL/g dry weight (dw). VLF accumulation reached an average tissue concentration of 2146 ± 156 ng/g dw within 7 days, showing a first-order kinetics process. N-desmethylvenlafaxine (N-VLF) and O-desmethylvenlafaxine (O-VLF) metabolites were quantified in mussel tissues, whereas N,N-didesmethylvenlafaxine (NN-VLF) was only recorded as being detected. These three metabolites were also quantified in water, indicating an active metabolism and VLF excretion in Mediterranean mussels. Complementary experiments conducted at nominal concentrations of 1, 10, and 100 μg/L for 7 days confirmed the VLF bioconcentration and metabolism and allowed us to quantify a supplementary metabolite, i.e., N,O-didesmethylvenlafaxine (NO-VLF), in mussel tissues. These results encourage further research on a more complete characterization of metabolism and on any disturbances linked to bioconcentration of VLF on bivalves.
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http://dx.doi.org/10.1007/s11356-021-14893-4DOI Listing
July 2021

Measuring residual anti-Xa activity of direct factor Xa inhibitors after reversal with andexanet alfa.

Int J Lab Hematol 2021 Jun 5. Epub 2021 Jun 5.

Diagnostica Stago R&D, Gennevilliers, France.

Introduction: Andexanet alfa (AnXa) was developed for anticoagulant effect reversal of direct factor Xa inhibitors (DXaI) (apixaban, rivaroxaban, edoxaban) in emergency situations. Regular anti-Xa assays are not suitable to evaluate anti-Xa activity after AnXa administration because of the high sample dilution resulting in the AnXa-DXaI dissociation which gives inaccurately high DXaI measured concentrations. This study aimed at developing dedicated STA-Liquid anti-Xa test set-ups for accurately measuring DXaI after reversal with AnXa.

Methods: Modified anti-Xa test set-ups, with reduced sample dilution, were developed to overcome regular assays limitations and to improve measured accuracy with results comparable to Portola microplate reference method used in clinical studies. Both regular and optimized assays were used to measure DXaI concentration in AnXa-containing samples. Quality controls, normal pooled plasma spiked with five DXaI and three AnXa concentrations, samples from DXaI-treated patients spiked with AnXa and ex vivo healthy volunteers having received both DXaI and AnXa were used.

Results: The lower limit of quantitation of optimized anti-Xa assays was <10 ng/mL with CVs ≤10%. DXaI samples containing 300 ng/mL and 1 µmol/L AnXa resulted in DXaI residual concentrations of 29-72 ng/mL depending on the DXaI (76%-90% reversal), compared to 20-28 ng/mL with reference method (92%-94% reversal) and 135-165 ng/mL with regular assays (about 50% reversal).

Conclusion: Modified test set-ups are automated alternative to reference method with improved precision and reproducibility. They can be run in all laboratories where regular anti-Xa assays are performed using commercially available reagents.
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http://dx.doi.org/10.1111/ijlh.13591DOI Listing
June 2021

Crosstalk between H2A variant-specific modifications impacts vital cell functions.

PLoS Genet 2021 Jun 4;17(6):e1009601. Epub 2021 Jun 4.

Gregor Mendel Institute, Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria.

Selection of C-terminal motifs participated in evolution of distinct histone H2A variants. Hybrid types of variants combining motifs from distinct H2A classes are extremely rare. This suggests that the proximity between the motif cases interferes with their function. We studied this question in flowering plants that evolved sporadically a hybrid H2A variant combining the SQ motif of H2A.X that participates in the DNA damage response with the KSPK motif of H2A.W that stabilizes heterochromatin. Our inventory of PTMs of H2A.W variants showed that in vivo the cell cycle-dependent kinase CDKA phosphorylates the KSPK motif of H2A.W but only in absence of an SQ motif. Phosphomimicry of KSPK prevented DNA damage response by the SQ motif of the hybrid H2A.W/X variant. In a synthetic yeast expressing the hybrid H2A.W/X variant, phosphorylation of KSPK prevented binding of the BRCT-domain protein Mdb1 to phosphorylated SQ and impaired response to DNA damage. Our findings illustrate that PTMs mediate interference between the function of H2A variant specific C-terminal motifs. Such interference could explain the mutual exclusion of motifs that led to evolution of H2A variants.
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http://dx.doi.org/10.1371/journal.pgen.1009601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208582PMC
June 2021

The histone variant H2A.W and linker histone H1 co-regulate heterochromatin accessibility and DNA methylation.

Nat Commun 2021 05 11;12(1):2683. Epub 2021 May 11.

CNRS, Université Clermont Auvergne, Inserm, Institut Génétique Reproduction et Développement (iGReD), Clermont-Ferrand, France.

In flowering plants, heterochromatin is demarcated by the histone variant H2A.W, elevated levels of the linker histone H1, and specific epigenetic modifications, such as high levels of DNA methylation at both CG and non-CG sites. How H2A.W regulates heterochromatin organization and interacts with other heterochromatic features is unclear. Here, we create a h2a.w null mutant via CRISPR-Cas9, h2a.w-2, to analyze the in vivo function of H2A.W. We find that H2A.W antagonizes deposition of H1 at heterochromatin and that non-CG methylation and accessibility are moderately decreased in h2a.w-2 heterochromatin. Compared to H1 loss alone, combined loss of H1 and H2A.W greatly increases accessibility and facilitates non-CG DNA methylation in heterochromatin, suggesting co-regulation of heterochromatic features by H2A.W and H1. Our results suggest that H2A.W helps maintain optimal heterochromatin accessibility and DNA methylation by promoting chromatin compaction together with H1, while also inhibiting excessive H1 incorporation.
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http://dx.doi.org/10.1038/s41467-021-22993-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113232PMC
May 2021

Comparison of four immunoassays to an HPLC method for the therapeutic drug monitoring of methotrexate: Influence of the hydroxylated metabolite levels and impact on clinical threshold.

J Oncol Pharm Pract 2021 Jan 11:1078155220983407. Epub 2021 Jan 11.

Department of Clinical Pharmacology, University Hospital of Montpellier, Montpellier, France.

Objectives: Methotrexate requires therapeutic drug monitoring in oncology because of narrow therapeutic index, especially the metabolite 7-hydroxymethotrexate exhibits nephrotoxicity. The goal of this study was to evaluate different assays and their impact on clinical decisions.

Methods: Following routine measurement with Abbott TDxFLx® assay (MTX-TDX), 62 samples were analysed on Architect®i1000 (MTX-ARCHI), Xpand® (ARK/XPND), Indiko® (ARK/INDI), and HPLC (MTX-HPLC) as the reference method. The influence of 7-hydroxymethotrexate was explored on ARK reagent to document the cause of the observed bias. ROC curves were built to study the impact of the method on the discharge thresholds for the patients at three levels.

Results: Total imprecision was below 2.60% for the methotrexate-ARCHI and close to 10% for both ARK assays for plasma pools. The correlation coefficients were 0.93, 0.93, 0.89 and 0.95, the Bland-Altman difference plot revealed a bias of 0.075, 0.037, 0.049 and -0.002, and the number of results exceeding the TE criteria of 0.1 µM was 17 (27%), 13 (21%), 15 (24%) and 15 (24%) for MTX-TDX, ARK/INDI, ARK/XPND and MTX-ARCHI, respectively. Cross reactivity with 7-hydroxymethotrexate was between 1 and 9%. Overestimation of methotrexate concentration was between -4% and +32%. The most robust clinical level was found to be the highest level (0.2 µM) with ROC curves.

Conclusions: The authors found the best results for imprecision with chemiluminescent microparticle immunoassay method on methotrexate-ARCHI, with bias below to the RICOS recommendations and best correlation to the reference method. Impact on the threshold values for clinical decision need to be clearly exposed to clinicians.
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http://dx.doi.org/10.1177/1078155220983407DOI Listing
January 2021

DNA polymerase epsilon is required for heterochromatin maintenance in Arabidopsis.

Genome Biol 2020 11 25;21(1):283. Epub 2020 Nov 25.

Institute of Genetics Reproduction and Development (iGReD), Université Clermont Auvergne, CNRS, Inserm, F-63000, Clermont-Ferrand, France.

Background: Chromatin organizes DNA and regulates its transcriptional activity through epigenetic modifications. Heterochromatic regions of the genome are generally transcriptionally silent, while euchromatin is more prone to transcription. During DNA replication, both genetic information and chromatin modifications must be faithfully passed on to daughter strands. There is evidence that DNA polymerases play a role in transcriptional silencing, but the extent of their contribution and how it relates to heterochromatin maintenance is unclear.

Results: We isolate a strong hypomorphic Arabidopsis thaliana mutant of the POL2A catalytic subunit of DNA polymerase epsilon and show that POL2A is required to stabilize heterochromatin silencing genome-wide, likely by preventing replicative stress. We reveal that POL2A inhibits DNA methylation and histone H3 lysine 9 methylation. Hence, the release of heterochromatin silencing in POL2A-deficient mutants paradoxically occurs in a chromatin context of increased levels of these two repressive epigenetic marks. At the nuclear level, the POL2A defect is associated with fragmentation of heterochromatin.

Conclusion: These results indicate that POL2A is critical to heterochromatin structure and function, and that unhindered replisome progression is required for the faithful propagation of DNA methylation throughout the cell cycle.
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http://dx.doi.org/10.1186/s13059-020-02190-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687843PMC
November 2020

A Shock-Tube Study of the Rate Constant of PH + M ⇄ PH + H + M (M = Ar) Using PH Laser Absorption.

J Phys Chem A 2020 Sep 2;124(37):7380-7387. Epub 2020 Sep 2.

J. Mike Walker '66 Department of Mechanical Engineering, Texas A&M University, College Station 3123 TAMU, Texas, 77843, United States.

Phosphine (PH) is a highly reactive and toxic gas. Prior experimental investigations of PH pyrolysis reactions have included only low-temperature measurements. This study reports the first shock-tube measurements of PH pyrolysis using a new PH laser absorption technique near 4.56 μm. Experiments were conducted in mixtures of 0.5% PH/Ar behind reflected shock waves at temperatures of 1460-2013 K and pressures of ∼1.3 and ∼0.5 atm. The PH time histories displayed two-stage behavior similar to that previously observed for NH decomposition, suggesting by analogy that the rate constant for PH + M ⇄ PH + H + M (R1) could be determined. A simple three-step mechanism was assembled for data analysis. In a detailed kinetic analysis of the first-stage PH decomposition, values of were obtained and best described by (in cm·mol·s) = 7.78 × 10 exp(-80,400/), with units of cal, mol, K, s, and cm. Agreement between the 1.3 and 0.5 atm data confirmed that the measured was in the low-pressure limit. Agreement of the experimental with ab initio estimates resolved the question of the main pathway of PH decomposition: it proceeds as PH ⇄ PH + H instead of PH ⇄ PH + H.
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http://dx.doi.org/10.1021/acs.jpca.0c04917DOI Listing
September 2020

Oral Primo-Colonizing Bacteria Modulate Inflammation and Gene Expression in Bronchial Epithelial Cells.

Microorganisms 2020 Jul 22;8(8). Epub 2020 Jul 22.

Micalis Institute, AgroParisTech, INRAE, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

The microbiota of the mouth disperses into the lungs, and both compartments share similar phyla. Considering the importance of the microbiota in the maturation of the immunity and physiology during the first days of life, we hypothesized that primo-colonizing bacteria of the oral cavity may induce immune responses in bronchial epithelial cells. Herein, we have isolated and characterized 57 strains of the buccal cavity of two human newborns. These strains belong to , , , and genera, with being the most represented. The strains were co-incubated with a bronchial epithelial cell line (BEAS-2B), and we established their impact on a panel of cytokines/chemokines and global changes in gene expression. The strains, which appeared soon after birth, induced a high production of IL-8, suggesting they can trigger inflammation, whereas the strains were less associated with inflammation pathways. The genera , and induced differential profiles of cytokine/chemokine/growth factor and set of genes associated with maturation of morphology. Altogether, our results demonstrate that the microorganisms, primo-colonizing the oral cavity, impact immunity and morphology of the lung epithelial cells, with specific effects depending on the phylogeny of the strains.
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http://dx.doi.org/10.3390/microorganisms8081094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464694PMC
July 2020

[Water, lithium and sodium: watch out for dangerous injuries].

Ann Biol Clin (Paris) 2020 08;78(4):449-453

Laboratoire de biochimie, Hôpital Lapeyronie, CHU Montpellier, France, Phymedexp, Université de Montpellier, Inserm, CNRS, CHU de Montpellier, Montpellier, France.

Nephrogenic diabetes insipidus due to the inability of the kidneys to concentrate urine is frequently observed during lithium therapy. Lithium concentrates into principal cells in collecting ducts in the kidney and downregulates aquaporin 2 expression, which reduces renal reabsorption of water. This disease is characterized by polyuria - polydipsia leading to intracellular dehydration and hypernatremia. Water deprivation test is performed to confirm insipidus diabetes. The desmopressin permits to distinguish nephrogenic from cranial insipidus diabetes. We report the case of a 64 years old women who presented with global dehydration and severe hypernatremia. Four years ago, she was hospitalized for nephrogenic diabetes insipidus related to a self-induced lithium intoxication. Persistent nephrogenic insipidus diabetes after cessation of lithium therapy are described in literature, and this hypothesis may be consistent with this case report.
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http://dx.doi.org/10.1684/abc.2020.1570DOI Listing
August 2020

Evaluation of DOAC Filter, a new device to remove direct oral anticoagulants from plasma samples.

Int J Lab Hematol 2020 Oct 22;42(5):636-642. Epub 2020 Jun 22.

Prospective Research, Diagnostica Stago, Gennevilliers, France.

Introduction: Directs oral anticoagulants (DOACs) can interfere with coagulation assays, especially in thrombophilia workup. To avoid these interferences, a new device, DOAC Filter, allows the removal of DOACs from citrated plasma. This study aims to confirm that DOAC Filter efficiently removes DOACs and to ascertain that coagulation assays are not impacted by filtration.

Methods: Directs oral anticoagulants Filter (Diagnostica Stago, France) is a filtration cartridge in which DOAC molecules are trapped by noncovalent binding, while plasma is filtered through a solid phase. Normal pool plasma (NPP) spiked with DOACs up to 300 ng/mL, with dabigatran etexilate (n = 27), rivaroxaban (n = 35), apixaban (n = 33), and edoxaban (n = 27) or 120 ng/mL for betrixaban (n = 4), and 18 plasma's samples from DOAC-treated patients were used to assess efficacy. The potential impact of DOAC Filter on coagulation assays was evaluated with NPP and plasma's samples from positive and negative lupus anticoagulant (LA) patients.

Results: Directs oral anticoagulants concentrations measured after filtration were below the limit of detection (LoD) of DOAC-specific assays for all plasmas tested, except for one apixaban plasma sample, with postfiltration concentration slightly higher than anti-Xa assay LoD (25.1 ng/mL). Coagulation assays results varied between -4 and +8% after filtration and between -6 and +8% for LA plasmas. Such limited variations are not expected to have any clinical impact.

Conclusion: Directs oral anticoagulants Filter efficiently removes DOACs from plasma and achieves concentrations below DOAC-specific assays LoD, except in the case of one apixaban sample. The integrity of plasma is respected, and the cartridge seems not to impact LA diagnosis.
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http://dx.doi.org/10.1111/ijlh.13267DOI Listing
October 2020

Secretome-Mediated Interactions with Intestinal Epithelial Cells: A Role for Secretome Components from R0011 in the Attenuation of Serovar Typhimurium Secretome and TNF-α-Induced Proinflammatory Responses.

J Immunol 2020 05 1;204(9):2523-2534. Epub 2020 Apr 1.

Applied Bioscience Graduate Program and the Faculty of Science, Ontario Technical University, Oshawa, Ontario L1G 0C5, Canada; and

Recent evidence suggests that lactic acid bacteria communicate with host cells via secretome components to influence immune responses but less is known about gut-pathogen secretomes, impact of lactic acid bacteria secretomes on host-pathogen interactions, and the mechanisms underlying these interactions. Genome-wide microarrays and cytokine profiling were used to interrogate the impact of the R0011 secretome (LrS) on TNF-α and subsp. serovar Typhimurium secretome (STS)-induced outcomes in human intestinal epithelial cells. The LrS attenuated both TNF-α- and STS-induced gene expression involved in NF-κB and MAPK activation, as well as expression of genes involved in other immune-related signaling pathways. Specifically, the LrS induced the expression of dual specificity phosphatase 1 (), activating transcription factor 3 (), and tribbles pseudokinase 3 (), negative regulators of innate immune signaling, in HT-29 intestinal epithelial cells challenged with TNF-α or STS. TNF-α- and STS-induced acetylation of H3 and H4 histones was attenuated by the LrS, as was the production of TNF-α- and STS-induced proinflammatory cytokines and chemokines. Interestingly, the LrS induced production of macrophage migration inhibitory factor (MIF), a cytokine involved in host-microbe interactions at the gut interface. We propose that the LrS attenuates proinflammatory mediator expression through increased transcription of negative regulators of innate immune activity and changes in global H3 and H4 histone acetylation. To our knowledge, these findings provide novel insights into the complex multifaceted mechanisms of action behind secretome-mediated interdomain communication at the gut-mucosal interface.
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http://dx.doi.org/10.4049/jimmunol.1901440DOI Listing
May 2020

PP7L is essential for MAIL1-mediated transposable element silencing and primary root growth.

Plant J 2020 05 25;102(4):703-717. Epub 2020 Jan 25.

Molecular Plant Physiology, Institute for Plant Science and Microbiology, Universität Hamburg, Hamburg, 22609, Germany.

The two paralogous Arabidopsis genes MAINTENANCE OF MERISTEMS (MAIN) and MAINTENANCE OF MERISTEMS LIKE1 (MAIL1) encode a conserved retrotransposon-related plant mobile domain and are known to be required for silencing of transposable elements (TE) and for primary root development. Loss of function of either MAIN or MAIL1 leads to release of heterochromatic TEs, reduced condensation of pericentromeric heterochromatin, cell death of meristem cells and growth arrest of the primary root soon after germination. Here, we show that they act in one protein complex that also contains the inactive isoform of PROTEIN PHOSPHATASE 7 (PP7), which is named PROTEIN PHOSPHATASE 7-LIKE (PP7L). PP7L was previously shown to be important for chloroplast biogenesis and efficient chloroplast protein synthesis. We show that loss of PP7L function leads to the same root growth phenotype as loss of MAIL1 or MAIN. In addition, pp7l mutants show similar silencing defects. Double mutant analyses confirmed that the three proteins act in the same molecular pathway. The primary root growth arrest, which is associated with cell death of stem cells and their daughter cells, is a consequence of genome instability. Our data demonstrate so far unrecognized functions of an inactive phosphatase isoform in a protein complex that is essential for silencing of heterochromatic elements and for maintenance of genome stability in dividing cells.
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http://dx.doi.org/10.1111/tpj.14655DOI Listing
May 2020

Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

Pharmaceutics 2019 Oct 31;11(11). Epub 2019 Oct 31.

Department of Medical Pharmacology, EA3801, SFR Cap-Santé, Reims University Hospitals, 51100 Reims, France.

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2-3 g/day and should be slightly increased to reach the therapeutic index of 14-20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.
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http://dx.doi.org/10.3390/pharmaceutics11110566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920765PMC
October 2019

Population Pharmacokinetics of Levobupivacaine During Transversus Abdominis Plane Block in Children.

Ther Drug Monit 2020 06;42(3):497-502

Department of Pharmacokinetics, School of Pharmacy, Montpellier University.

Background: Levobupivacaine is commonly used during transversus abdominis plane (TAP) block in pediatric patients. However, the dosing regimen is still empirical, and the pharmacokinetic properties of levobupivacaine are not considered. Here, the pharmacokinetics of levobupivacaine during an ultrasound-guided TAP block were evaluated to optimize dosing regimen, regarding the between-subject variability (BSV) and the volume of levobupivacaine injected.

Method: The clinical trial (prospective, randomized, double-blind study protocol) was conducted in 40 children aged 1-5 years, who were scheduled for inguinal surgery. Each patient received 0.4 mg/kg of levobupivacaine with a volume of local anesthesia solution adjusted to 0.2 mL/kg of 0.2% or 0.4 mL/kg of 0.1% levobupivacaine. Blood samples were collected at 5, 15, 20, 25, 30, 45, 60, and 75 minutes after the block injection. The population pharmacokinetic analysis was performed using the NONMEM software.

Results: From the pharmacokinetic parameters obtained, median Cmax, tmax,, and area under the concentration versus time curve were 0.315 mg/L, 17 minutes, and 41 mg/L·min, respectively. BSV of clearance was explained by weight. At the dose regimen of 0.4 mg/kg, none of the infants showed signs of toxicity, but in 13 patients, TAP block failed. After analysis, BSV for absorption rate constant, distribution volume, and clearance were 81%, 47%, and 41%, respectively. Residual unexplained variability was estimated to be 14%.

Conclusions: For improved efficiency in the pediatric population, the dose of levobupivacaine should be greater than 0.4 mg/kg. Children's weight should be considered to anticipate any risk of toxicity.
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http://dx.doi.org/10.1097/FTD.0000000000000702DOI Listing
June 2020

Acute Psychiatric Disorders Related to Fake Cathinone: Ephylone.

J Anal Toxicol 2019 Aug;43(7):e1-e2

Département de Pharmacologie Médicale et Toxicologie, Centre Hospitalier Universitaire, Montpellier, France.

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http://dx.doi.org/10.1093/jat/bkz020DOI Listing
August 2019

Transversus Abdominal Plane Block in Children: Efficacy and Safety: A Randomized Clinical Study and Pharmacokinetic Profile.

Anesth Analg 2019 06;128(6):1234-1241

From the Pediatric Anesthesia Unit, Department of Anesthesia and Critical Care Medicine, Lapeyronie University Hospital, Montpellier University, Montpellier, France.

Background: The transversus abdominis plane (TAP) block has become a common regional anesthesia technique for pain management in a wide variety of abdominal procedures. Evidence to support any particular local anesthetic regimen as well as pharmacokinetic and systemic toxicity risks of TAP block remain insufficiently studied in children. The aim of this study was to compare the analgesic effects and investigate pharmacokinetic profile of levobupivacaine after ultrasound-guided TAP block using a low volume/high concentration (LVHC) or a high volume/low concentration (HVLC) solution in children.

Methods: This prospective randomized study included children scheduled for day-case inguinal surgery. Children were randomized to receive TAP block using 0.4 mg·kg levobupivacaine as either HVLC (0.2 mL·kg of 0.2% levobupivacaine) or LVHC (0.1 mL·kg of 0.4% levobupivacaine). The primary outcome was the number of children who required opioid rescue analgesia postoperatively. Pharmacokinetic profile study of levobupivacaine was also performed.

Results: Seventy patients were equally randomized, and 65 were included in the final analysis. Seventy-one percent of patients did not require any postoperative opioid analgesia. The number of patients who received rescue analgesia was 12 (35%) in the LVHC group and 7 (23%) in the HVLC group (relative risk, 0.64; 95% confidence interval [CI], 0.29-1.42; P = .26). Mean pain scores (FLACC [faces, legs, activity, cry, and consolability]) at postanesthesia care unit discharge did not differ between LVHC and HVLC groups, respectively, 0.39 ± 0.86 and 1 ± 1.71 with mean group difference -0.60 (95% CI, -1.27 to 0.06; P = .08). The pharmacokinetic profile of levobupivacaine was comparable in the 2 groups: the mean total and free levobupivacaine peak concentrations were 379 ± 248 and 3.95 ± 3.16 ng·mL, respectively, occurring 22.5 ± 11 minutes after injection. The highest total and free levobupivacaine concentrations collected, respectively, 1360 and 15.1 ng·mL, remained far below theoretical toxic thresholds.

Conclusions: In children, quality of postoperative pain control provided by TAP block using levobupivacaine 0.4 mg·kg administered as either HVLC or LVHC did not differ and was associated with a very low risk of local anesthetic systemic toxicity.
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http://dx.doi.org/10.1213/ANE.0000000000003736DOI Listing
June 2019

A role for MED14 and UVH6 in heterochromatin transcription upon destabilization of silencing.

Life Sci Alliance 2018 Dec 12;1(6):e201800197. Epub 2018 Dec 12.

Génétique Reproduction et Développement, Centre National de la Recherche Scientifique (CNRS), Inserm, Université Clermont Auvergne, Clermont-Ferrand, France.

Constitutive heterochromatin is associated with repressive epigenetic modifications of histones and DNA which silence transcription. Yet, particular mutations or environmental changes can destabilize heterochromatin-associated silencing without noticeable changes in repressive epigenetic marks. Factors allowing transcription in this nonpermissive chromatin context remain poorly known. Here, we show that the transcription factor IIH component UVH6 and the mediator subunit MED14 are both required for heat stress-induced transcriptional changes and release of heterochromatin transcriptional silencing in . We find that MED14, but not UVH6, is required for transcription when heterochromatin silencing is destabilized in the absence of stress through mutating the MOM1 silencing factor. In this case, our results raise the possibility that transcription dependency over MED14 might require intact patterns of repressive epigenetic marks. We also uncover that MED14 regulates DNA methylation in non-CG contexts at a subset of RNA-directed DNA methylation target loci. These findings provide insight into the control of heterochromatin transcription upon silencing destabilization and identify MED14 as a regulator of DNA methylation.
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http://dx.doi.org/10.26508/lsa.201800197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291795PMC
December 2018

Loss of CG Methylation in Marchantia polymorpha Causes Disorganization of Cell Division and Reveals Unique DNA Methylation Regulatory Mechanisms of Non-CG Methylation.

Plant Cell Physiol 2018 Dec;59(12):2421-2431

Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France.

DNA methylation is an epigenetic mark that ensures silencing of transposable elements (TEs) and affects gene expression in many organisms. The function of different DNA methylation regulatory pathways has been largely characterized in the model plant Arabidopsis thaliana. However, far less is known about DNA methylation regulation and functions in basal land plants. Here we focus on the liverwort Marchantia polymorpha, an emerging model species that represents a basal lineage of land plants. We identified MpMET, the M. polymorpha ortholog of the METHYLTRANSFERASE 1 (MET1) gene required for maintenance of methylation at CG sites in angiosperms. We generated Mpmet mutants using the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein9) system, which showed a significant loss of CG methylation and severe morphological changes and developmental defects. The mutants developed many adventitious shoot-like structures, suggesting that MpMET is required for maintaining differentiated cellular identities in the gametophyte. Even though numerous TEs were up-regulated, non-CG methylation was generally highly increased at TEs in the Mpmet mutants. Closer inspection of CHG methylation revealed features unique to M. polymorpha. Methylation of CCG sites in M. polymorpha does not depend on MET1, unlike in A. thaliana and Physcomitrella patens. Our results highlight the diversity of non-CG methylation regulatory mechanisms in plants.
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http://dx.doi.org/10.1093/pcp/pcy161DOI Listing
December 2018

Gut Bacterial Microbiota and its Resistome Rapidly Recover to Basal State Levels after Short-term Amoxicillin-Clavulanic Acid Treatment in Healthy Adults.

Sci Rep 2018 07 25;8(1):11192. Epub 2018 Jul 25.

Lallemand Health Solutions Inc., 6100 Royalmount Avenue, Montreal, Quebec, H4P 2R2, Canada.

Clinical effects of antimicrobials and probiotics in combination have been reported, however, little is known about their impact on gut microbiota and its resistome. In this study 16S rRNA gene amplicon, shotgun metagenomics sequencing and antibiotic resistance (ABR) microarray were used on fecal samples of 70 healthy participants, taken at four time points in probiotic (Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0052) and placebo groups to profile the gut bacterial microbiota and its resistome following administration of amoxicillin-clavulanic acid for one week. Significant shifts in microbiota family composition caused by the antimicrobial in both groups that included decreases in the proportion of Lachnospiraceae, Coriobacteriaceae and unidentified Clostridiales; and notable increases for the proportion of Enterobacteriaceae, Bacteroidaceae and Porphyromonadaceae compared to baseline levels. Resistome showed a corresponding enrichment of ABR genes compared to baseline from such classes as aminoglycosides and beta-lactams that were linked, by in silico inference, to the enrichment of the family Enterobacteriaceae. Despite perturbations caused by short-term antibiotic treatment, both gut microbiota and resistome showed prompt recovery to baseline levels one week after cessation of the antimicrobial. This rapid recovery may be explained by the hypothesis of community resilience.
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http://dx.doi.org/10.1038/s41598-018-29229-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060159PMC
July 2018

High Microbial Diversity Promotes Soil Ecosystem Functioning.

Appl Environ Microbiol 2018 05 16;84(9). Epub 2018 Apr 16.

UMR 1347 Agroécologie, AgroSup Dijon, INRA, Université de Bourgogne Franche-Comté, Dijon, France.

In soil, the link between microbial diversity and carbon transformations is challenged by the concept of functional redundancy. Here, we hypothesized that functional redundancy may decrease with increasing carbon source recalcitrance and that coupling of diversity with C cycling may change accordingly. We manipulated microbial diversity to examine how diversity decrease affects the decomposition of easily degradable (i.e., allochthonous plant residues) versus recalcitrant (i.e., autochthonous organic matter) C sources. We found that a decrease in microbial diversity (i) affected the decomposition of both autochthonous and allochthonous carbon sources, thereby reducing global CO emission by up to 40%, and (ii) shaped the source of CO emission toward preferential decomposition of most degradable C sources. Our results also revealed that the significance of the diversity effect increases with nutrient availability. Altogether, these findings show that C cycling in soil may be more vulnerable to microbial diversity changes than expected from previous studies, particularly in ecosystems exposed to nutrient inputs. Thus, concern about the preservation of microbial diversity may be highly relevant in the current global-change context assumed to impact soil biodiversity and the pulse inputs of plant residues and rhizodeposits into the soil. With hundreds of thousands of taxa per gram of soil, microbial diversity dominates soil biodiversity. While numerous studies have established that microbial communities respond rapidly to environmental changes, the relationship between microbial diversity and soil functioning remains controversial. Using a well-controlled laboratory approach, we provide empirical evidence that microbial diversity may be of high significance for organic matter decomposition, a major process on which rely many of the ecosystem services provided by the soil ecosystem. These new findings should be taken into account in future studies aimed at understanding and predicting the functional consequences of changes in microbial diversity on soil ecosystem services and carbon storage in soil.
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http://dx.doi.org/10.1128/AEM.02738-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930326PMC
May 2018

Water status and must composition in grapevine cv. Chardonnay with different soils and topography and a mini meta-analysis of the δ C/water potentials correlation.

J Sci Food Agric 2018 Jan 17;98(2):691-697. Epub 2017 Aug 17.

UMR CNRS/uB 6282 Biogéosciences, Université de Bourgogne-Franche-Comté, Dijon, France.

Background: The measurement of carbon isotopic discrimination in grape sugars at harvest (δ C) is an integrated assessment of water status during ripening. It is an efficient alternative to assess variability in the field and discriminate between management zones in precision viticulture, but further work is needed to completely understand the signal.

Results: This work, spanning over 3 years, performed in a hillslope toposequence in Burgundy, delineates the relationships between main soil properties (gravel amount, slope, texture) and the grapevine water status assessed by δ C. The highest δ C, indicating most severe water deficit, was recorded in gravelly soils on steep slopes. The amount of sugars and malic and tartaric acids was also related to δ C. The relationship between δ C and predawn leaf water potentials (Ψ ) was also investigated, because the absolute values of measured δ C were lower than the values currently found in the literature.

Conclusions: A mini-meta-analysis was performed, which showed that the slope of the relationships between minimum Ψ and δ C was stable across studies (a change of 1‰ in δ C corresponded to a change of -0.2 MPa in the minimum Ψ ), while the intercept of the comparison δ C/Ψ changed, probably because of genetic variations between varieties, or environmental differences. © 2017 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.8516DOI Listing
January 2018

Water status and must composition in grapevine cv. Chardonnay with different soils and topography and a mini meta-analysis of the δ C/water potentials correlation.

J Sci Food Agric 2018 Jan 17;98(2):691-697. Epub 2017 Aug 17.

UMR CNRS/uB 6282 Biogéosciences, Université de Bourgogne-Franche-Comté, Dijon, France.

Background: The measurement of carbon isotopic discrimination in grape sugars at harvest (δ C) is an integrated assessment of water status during ripening. It is an efficient alternative to assess variability in the field and discriminate between management zones in precision viticulture, but further work is needed to completely understand the signal.

Results: This work, spanning over 3 years, performed in a hillslope toposequence in Burgundy, delineates the relationships between main soil properties (gravel amount, slope, texture) and the grapevine water status assessed by δ C. The highest δ C, indicating most severe water deficit, was recorded in gravelly soils on steep slopes. The amount of sugars and malic and tartaric acids was also related to δ C. The relationship between δ C and predawn leaf water potentials (Ψ ) was also investigated, because the absolute values of measured δ C were lower than the values currently found in the literature.

Conclusions: A mini-meta-analysis was performed, which showed that the slope of the relationships between minimum Ψ and δ C was stable across studies (a change of 1‰ in δ C corresponded to a change of -0.2 MPa in the minimum Ψ ), while the intercept of the comparison δ C/Ψ changed, probably because of genetic variations between varieties, or environmental differences. © 2017 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.8516DOI Listing
January 2018

Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation.

Therapie 2017 Dec 29;72(6):643-647. Epub 2017 May 29.

Toxicology laboratory, department of medical pharmacology and toxicology, Lapeyronie hospital, CHRU of Montpellier, 34295 Montpellier cedex 5, France; University of Montpellier, 34000 Montpellier, France; UMR 5569 hydrosciences, 34090 Montpellier, France.

We report the success of tardive electroconvulsive therapy in a case of loxapine malignant syndrome with catatonia. Loxapine and its metabolites were measured in biological samples by liquid chromatography coupled to tandem mass spectrometry. Genes were studied by sequencing and quantitative polymerase chain reaction (PCR). Plasmatic drug concentrations showed a supratherapeutic concentration of loxapine with a very low 8-hydroxyloxapine/loxapine ratio (range from 0.32 to 0.66, normal value>2 for 100mg) and a very long elimination half-life of loxapine (half-life>140h, normal value from 1 to 4hours). We tried to explain this kinetics by exploring the main pharmacogenes implicated in the metabolism of loxapine. No genetic abnormality for CYP1A2 was observed. The study of associated treatments showed the potential contribution of valproate. Pharmacokinetics and pharmacogenetics investigations revealed a blockade of the CYP1A2 metabolic pathway without genetic abnormalities, probably due to valproate co-medication. Toxicological monitoring of loxapine and its metabolites helped to explain the persistence of symptoms and to adapt the therapeutic management.
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http://dx.doi.org/10.1016/j.therap.2017.03.003DOI Listing
December 2017

High opioids tolerance due to transmucosal fentanyl abuse.

Eur J Clin Pharmacol 2017 Sep 3;73(9):1195-1196. Epub 2017 Jun 3.

Centre Hospitalier Regional Universitaire de Montpellier, Montpellier, France.

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http://dx.doi.org/10.1007/s00228-017-2272-9DOI Listing
September 2017

Arabidopsis proteins with a transposon-related domain act in gene silencing.

Nat Commun 2017 05 3;8:15122. Epub 2017 May 3.

Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand F-63000, France.

Transposable elements (TEs) are prevalent in most eukaryotes, and host genomes have devised silencing strategies to rein in TE activity. One of these, transcriptional silencing, is generally associated with DNA methylation and short interfering RNAs. Here we show that the Arabidopsis genes MAIL1 and MAIN define an alternative silencing pathway independent of DNA methylation and short interfering RNAs. Mutants for MAIL1 or MAIN exhibit release of silencing and appear to show impaired condensation of pericentromeric heterochromatin. Phylogenetic analysis suggests not only that MAIL1 and MAIN encode a retrotransposon-related plant mobile domain, but also that host plant mobile domains were captured by DNA transposons during plant evolution. Our results reveal a role for Arabidopsis proteins with a transposon-related domain in gene silencing.
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http://dx.doi.org/10.1038/ncomms15122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418596PMC
May 2017

Characterization and identification of eight designer benzodiazepine metabolites by incubation with human liver microsomes and analysis by a triple quadrupole mass spectrometer.

Int J Legal Med 2017 Jul 4;131(4):979-988. Epub 2017 Feb 4.

Department of Pharmacology, Service de pharmacologie, toxicologie et pharmacovigilance, CHU de Limoges, Limoges University Hospital, 2 Ave Martin Luther King, 87042, Limoges Cedex, France.

Designer benzodiazepines (DBZDs) have become of particular importance in the past few years. The metabolite monitoring of DBZD in biological fluids could be of great interest in clinical and forensic toxicology. However, DBZD metabolites are not known or not commercially available. The identification of some DBZD metabolites has been mostly explored by self-administration studies or by in vitro studies followed by high-resolution mass spectrometry. The question arose whether a unit resolution instrument could be efficient enough to allow the identification of DBZD metabolites. In this study, we used an in vitro experiment where eight DBZDs (diclazepam, flubromazepam, etizolam, deschloroetizolam, flubromazolam, nifoxipam, meclonazepam and clonazolam) were incubated with human liver microsomes (HLMs) and metabolite identification was carried out by using a UHPLC coupled to a QTRAP triple quadrupole linear iontrap tandem mass spectrometer system. Post-mortem samples obtained from a real poisoning case, involving deschloroetizolam and diclazepam, were also analysed and discussed. Our study using HLM allowed the identification of 26 metabolites of the 8 DBZDs. These were denitro-, mono- or di-hydroxylated and desmethyl metabolites. In the forensic case, diclazepam was not detected whereas its metabolites (lormetazepam and lorazepam) were present at high concentrations in urine. We also identified hydroxy-deschloroetizolam in urine, while the parent compound was not detected in this matrix. This supports the approach that LC coupled to a simple QTRAP could be used by laboratories to identify other not-known/not-commercialized new psychoactive substance (NPS) metabolites.
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http://dx.doi.org/10.1007/s00414-017-1541-6DOI Listing
July 2017

Genome-Wide Immune Modulation of TLR3-Mediated Inflammation in Intestinal Epithelial Cells Differs between Single and Multi-Strain Probiotic Combination.

PLoS One 2017 18;12(1):e0169847. Epub 2017 Jan 18.

Lallemand Health Solutions Inc., 6100 avenue Royalmount, Montreal, QC, Canada.

Genome-wide transcriptional analysis in intestinal epithelial cells (IEC) can aid in elucidating the impact of single versus multi-strain probiotic combinations on immunological and cellular mechanisms of action. In this study we used human expression microarray chips in an in vitro intestinal epithelial cell model to investigate the impact of three probiotic bacteria, Lactobacillus helveticus R0052 (Lh-R0052), Bifidobacterium longum subsp. infantis R0033 (Bl-R0033) and Bifidobacterium bifidum R0071 (Bb-R0071) individually and in combination, and of a surface-layer protein (SLP) purified from Lh-R0052, on HT-29 cells' transcriptional profile to poly(I:C)-induced inflammation. Hierarchical heat map clustering, Set Distiller and String analyses revealed that the effects of Lh-R0052 and Bb-R0071 diverged from those of Bl-R0033 and Lh-R0052-SLP. It was evident from the global analyses with respect to the immune, cellular and homeostasis related pathways that the co-challenge with probiotic combination (PC) vastly differed in its effect from the single strains and Lh-R0052-SLP treatments. The multi-strain PC resulted in a greater reduction of modulated genes, found through functional connections between immune and cellular pathways. Cytokine and chemokine analyses based on specific outcomes from the TNF-α and NF-κB signaling pathways revealed single, multi-strain and Lh-R0052-SLP specific attenuation of the majority of proteins measured (TNF-α, IL-8, CXCL1, CXCL2 and CXCL10), indicating potentially different mechanisms. These findings indicate a synergistic effect of the bacterial combinations relative to the single strain and Lh-R0052-SLP treatments in resolving toll-like receptor 3 (TLR3)-induced inflammation in IEC and maintaining cellular homeostasis, reinforcing the rationale for using multi-strain formulations as a probiotic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169847PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242491PMC
August 2017

Microbial Diversity Indexes Can Explain Soil Carbon Dynamics as a Function of Carbon Source.

PLoS One 2016 23;11(8):e0161251. Epub 2016 Aug 23.

UMR SAS 1069, INRA, Rennes, France.

Mathematical models do not explicitly represent the influence of soil microbial diversity on soil organic carbon (SOC) dynamics despite recent evidence of relationships between them. The objective of the present study was to statistically investigate relationships between bacterial and fungal diversity indexes (richness, evenness, Shannon index, inverse Simpson index) and decomposition of different pools of soil organic carbon by measuring dynamics of CO2 emissions under controlled conditions. To this end, 20 soils from two different land uses (cropland and grassland) were incubated with or without incorporation of 13C-labelled wheat-straw residue. 13C-labelling allowed us to study residue mineralisation, basal respiration and the priming effect independently. An innovative data-mining approach was applied, based on generalized additive models and a predictive criterion. Results showed that microbial diversity indexes can be good covariates to integrate in SOC dynamics models, depending on the C source and the processes considered (native soil organic carbon vs. fresh wheat residue). Specifically, microbial diversity indexes were good candidates to help explain mineralisation of native soil organic carbon, while priming effect processes seemed to be explained much more by microbial composition, and no microbial diversity indexes were found associated with residue mineralisation. Investigation of relationships between diversity and mineralisation showed that higher diversity, as measured by the microbial diversity indexes, seemed to be related to decreased CO2 emissions in the control soil. We suggest that this relationship can be explained by an increase in carbon yield assimilation as microbial diversity increases. Thus, the parameter for carbon yield assimilation in mathematical models could be calculated as a function of microbial diversity indexes. Nonetheless, given limitations of the methods used, these observations should be considered with caution and confirmed with more experimental studies. Overall, along with other studies on relationships between microbial community composition and SOM dynamics, this study suggests that overall measures of microbial diversity may constitute relevant ways to include microbial diversity in models of SOM dynamics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161251PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995005PMC
July 2017

Ecophysiological Modeling of Grapevine Water Stress in Burgundy Terroirs by a Machine-Learning Approach.

Front Plant Sci 2016 7;7:796. Epub 2016 Jun 7.

UMR CNRS/uB 6282 Biogéosciences, Université de BourgogneDijon, France; Institut Universitaire de la Vigne et du Vin "Jules Guyot," Université de BourgogneDijon, France.

In a climate change scenario, successful modeling of the relationships between plant-soil-meteorology is crucial for a sustainable agricultural production, especially for perennial crops. Grapevines (Vitis vinifera L. cv Chardonnay) located in eight experimental plots (Burgundy, France) along a hillslope were monitored weekly for 3 years for leaf water potentials, both at predawn (Ψpd) and at midday (Ψstem). The water stress experienced by grapevine was modeled as a function of meteorological data (minimum and maximum temperature, rainfall) and soil characteristics (soil texture, gravel content, slope) by a gradient boosting machine. Model performance was assessed by comparison with carbon isotope discrimination (δ(13)C) of grape sugars at harvest and by the use of a test-set. The developed models reached outstanding prediction performance (RMSE < 0.08 MPa for Ψstem and < 0.06 MPa for Ψpd), comparable to measurement accuracy. Model predictions at a daily time step improved correlation with δ(13)C data, respect to the observed trend at a weekly time scale. The role of each predictor in these models was described in order to understand how temperature, rainfall, soil texture, gravel content and slope affect the grapevine water status in the studied context. This work proposes a straight-forward strategy to simulate plant water stress in field condition, at a local scale; to investigate ecological relationships in the vineyard and adapt cultural practices to future conditions.
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http://dx.doi.org/10.3389/fpls.2016.00796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894889PMC
July 2016