Control of shoot and root growth by water deficit in Arabidopsis thaliana (a parallel analysis using artificial and natural mapping populations)

Le maintien de la croissance foliaire en situation de déficit hydrique résulte du maintien de l absorption racinaire et de la production de biomasse au niveau foliaire. Pour optimiser les deux processus, la plante ajuste la croissance de ses organes, et la répartition de la biomasse produite, entre les différents organes (root/shoot ratio) ou au sein de chaque organe (surface foliaire spécifique, longueur racinaire spécifique). Les principaux objectifs de ce travail de thèse étaient (i) d évaluer l impact des modifications de répartition de biomasse sur le maintien de la croissance foliaire en situation de déficit hydrique, (ii) de relier la réponse de la croissance d un génotype aux caractéristiques de son habitat d origine, and (iii) d identifier les régions du génome responsables de la variation des croissances foliaires et racinaires en situation de déficit hydrique. Différent types de populations d Arabidopsis thaliana ont été utilisés, une population de lignées recombinantes, ainsi que différents groupes d accessions collectées dans des environnements naturels contrastés. Une analyse des relations allométriques entre les variables foliaires et racinaires en conditions de culture optimales puis en situation de déficit hydrique a permis de mettre en évidence le rôle clé de la surface foliaire spécifique dans l amélioration de la tolérance au déficit hydrique. Une caractérisation détaillée du climat des régions dans lesquelles les accessions avaient été collectées a permis de faire le lien entre la tolérance accrue de certains génotypes et la faible balance climatique dans laquelle ils évoluaient. Enfin, en utilisant ces génotypes, une analyse de génétique quantitative (combinant recherche de QTL et génétique d association) a été menée. Les régions génomiques controllant les croissances foliaires et racinaires étaient très liées, en particulier en situation hydrique optimale, mais le calcul de variables utilisant la croissance de la plante comme cofacteur a permis d identifier des régions spécifiques de la croissance racinaire, dont une a été confirmée en utilisant des lignées quasi isogéniques. En situation de contrainte hydrique, les déterminants génétiques des croissances foliaires et racinaires étaient moins liés, et plusieurs régions très fortement associées spécifiquement aux variations de croissance racinaire ou foliaire ont été détectées. Des régions associées au maintien de la croissance foliaire en situation de déficit hydrique ont pu être mises en évidence, et la précision des études de génétique d association a permis de réveler la présence de gènes d intéret dans ces régions.Growth maintenance under water deficit mainly results from the maintenance of water uptake at the root level,and assimilates production by leaves. To optimize both processes, plant need to adjust organ growth and biomassallocation patterns between roots and shoots (root/shoot ratio), but also within the organs, through specific leaf areaand specific root length variations. The main objectives of this study were (i) to evaluate the impact of growth andbiomass allocation patterns modifications on growth maintenance under drought conditions, (ii) to rely the genotypicresponses to water deficit conditions and the climatic features of the natural environment in which they evolved, and(iii) to identify the key genetic regions responsible for shoot and root growth variation in response to water deficitconditions. We used different sets of genotypes, a population of recombinant inbred lines, and different sets ofaccessions of Arabidopsis thaliana, collected in a wide range of environments. An analysis of the allometricrelationships between shoot and root growth related variables under both well watered and water deficit conditionsallowed to highlight the importance of specific leaf area plasticity to maintain plant growth under water deficit. Adetailed climatic characterization of the natural habitats of the accessions studied, combined to the evaluation ofgrowth response to water deficit in these accessions allowed connecting low climatic water balance to better toleranceto water deficit conditions in specific regions, suggesting that this climatic feature could have shaped the evolution ofgenotypes in certain regions. Finally, using these two sets of genotypes, joint linkage and linkage disequilibriumanalysis were performed on growth related traits under well watered and water deficit conditions. Some genetic regionsinvolved in the control of root and shoot related traits were strongly coupled, especially in well watered experiments,but we managed to identify root specific regions using calculated variables that takes global plant growth as a cofactor.Under water deficit, the regions controlling root and shoot growth were less associated, and very strong QTL weredetected, specifically associated to one or the other part. Genomic regions associated to growth response to waterdeficit were also detected, and the accuracy of association mapping enabled to identify target genes that could be playa role in growth maintenance under drought.MONTPELLIER-SupAgro La Gaillarde (341722306) / SudocSudocFranceF

Immunophenotypic Lymphocyte Profiles in Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is a deadly vector-born disease caused by an extracellular parasite, the trypanosome. Little is known about the cellular immune responses elicited by this parasite in humans. We used multiparameter flow cytometry to characterize leukocyte immunophenotypes in the blood and cerebrospinal fluid (CSF) of 33 HAT patients and 27 healthy controls identified during a screening campaign in Angola and Gabon. We evaluated the subsets and activation markers of B and T lymphocytes. Patients had a higher percentage of CD19+ B lymphocytes and activated B lymphocytes in the blood than did controls, but lacked activated CD4+ T lymphocytes (CD25+). Patients displayed no increase in the percentage of activated CD8+ T cells (HLA-DR+, CD69+ or CD25+), but memory CD8 T-cell levels (CD8+CD45RA−) were significantly lower in patients than in controls, as were effector CD8 T-cell levels (CD8+CD45RA+CD62L−). No relationship was found between these blood immunophenotypes and disease severity (stage 1 vs 2). However, CD19+ B-cell levels in the CSF increased with disease severity. The patterns of T and B cell activation in HAT patients suggest that immunomodulatory mechanisms may operate during infection. Determinations of CD19+ B-cell levels in the CSF could improve disease staging

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism

Fexinidazole – A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness

This article describes the preclinical profile of fexinidazole, a new drug candidate with the potential to become a novel, oral, safe and effective short-course treatment for curing both stage 1 and 2 human African trypanosomiasis and replace the old and highly problematic treatment modalities available today. Fexinidazole is orally available and rapidly metabolized in two metabolites having equivalent biological activity to the parent and contributing significantly to the in vivo efficacy in animal models of both stage 1 and 2 HAT. Animal toxicology studies indicate that fexinidazole has an excellent safety profile, with no particular issues identified. Fexinidazole is a 5-nitroimidazole and, whilst it is Ames-positive, it is devoid of any genetic toxicity in mammalian cells and therefore does not pose a genotoxic risk for use in man. Fexinidazole, which was rediscovered through a process of compound mining, is the first new drug candidate for stage 2 HAT having entered clinical trials in thirty years, and has the potential to revolutionize therapy of this fatal disease at a cost that is acceptable in the endemic regions

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices

Mise en place d'un questionnaire de détection et de gestion des effets indésirables des chimiothérapies anticancéreuses dans un service hospitalier de gynécologie

LYON1-BU Santé (693882101) / SudocSudocFranceF

Onchocercose et épilepsie : état des connaissances actuelles.

International audienc

IMPACT OF AN ANTI-HELMINTHIC TREATMENT ON THE COURSE OF EPILEPSY IN THE NEUROPSYCHIATRY DEPARTMENT OF ALEXANDRIA IN EGYPT : A LINK BETWEEN ASCARIDIASIS AND EPILEPSY ?

ASSOCIATION ENTRE TRAITEMENT DE L'ASCARIDIOSE ET DIMINUTION DE LA FREQUENCE DES CRISES CHEZ LES PATIENTS EPILEPTIQUES A ALEXANDRIE (EGYPTE) RESUME Description et objectif: ce travail recherche une association entre ascaridiose et épilepsie. Méthodes: une étude d'impact du traitement anti-helminthique a été réalisée dans le service de Neuropychiatrie d'un hôpital général d'Alexandrie en Egypte. Résultats: 537 patients épileptiques ont été inclus. Le niveau d'infection d'ascaridiose était sévère à modéré pour 68 % d'entre eux. Après traitement anti-helminthique, le nombre moyen de crises d'épilepsie partielle s'est réduit de 10 % (p< 0,001) alors que le nombre moyen de crises généralisées ne variait pas. Cette diminution a bénéficié surtout aux patients ayant un niveau sévère d'infection. Conclusion: cette étude donne des arguments indirects incitant à poursuivre les études épidémiologiques ou physiopathologiques à la recherche d'un lien causal entre ascaridiose et épilepsie. SUMMARY Background and objective: this work looks for a link between ascaridiasis and epilepsy. Methods: This work has looked for the impact of an anti-helminthic treatment on the course of epilepsy and was performed in the Neuropsychiatry department of a general hospital of Alexandria in Egypt. Results: 537 patients with epilepsy have been included. The level of ascaridiasis infection was severe to moderate for 68 % of them. After anti-helminthic treatment, the average number of partial epilepsy fits has reduced in 10 % (

Incidence des facteurs environnementaux sur la survenue des affections neurologiques en zone tropicale.

International audienc

Etude des mécanismes inflammatoires au cours de la trypanosomose humaine africaine (applications en diagnostic et en thérapeutique)

LIMOGES-BU Médecine pharmacie (870852108) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF