Plant mitochondria possess a short-patch base excision DNA repair pathway

Despite constant threat of oxidative damage, sequence drift in mitochondrial and chloroplast DNA usually remains very low in plant species, indicating efficient defense and repair. Whereas the antioxidative defense in the different subcellular compartments is known, the information on DNA repair in plant organelles is still scarce. Focusing on the occurrence of uracil in the DNA, the present work demonstrates that plant mitochondria possess a base excision repair (BER) pathway. In vitro and in organello incision assays of double-stranded oligodeoxyribonucleotides showed that mitochondria isolated from plant cells contain DNA glycosylase activity specific for uracil cleavage. A major proportion of the uracil–DNA glycosylase (UDG) was associated with the membranes, in agreement with the current hypothesis that the DNA is replicated, proofread and repaired in inner membrane-bound nucleoids. Full repair, from uracil excision to thymidine insertion and religation, was obtained in organello following import of a uracil-containing DNA fragment into isolated plant mitochondria. Repair occurred through single nucleotide insertion, which points to short-patch BER. In vivo targeting and in vitro import of GFP fusions showed that the putative UDG encoded by the At3g18 630 locus might be the first enzyme of this mitochondrial pathway in Arabidopsis thaliana

Influence of the laboratory context and the size of the markers set on the tennis serve evaluation

The purpose of this study was to identify the influence on the tennis serve evaluation of 1/ the test environment and 2/ the number of the markers placed of the player. Two different studies were performed. The first compared a 4 vs. 28 marker set in a laboratory the same day. The second compared a 4 markers test in a laboratory with a 4 markers test on an official tennis court one week apart. We observed similar results between the different tests of both studies.Thèse de doctorat - Facteurs de performance du service en tenni

A kinematic and kinetic comparison of the counter movement jump and stop jump receptions

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INFLUENCE OF THE LABORATORY CONTEXT AND THE SIZE OF THE MARKERS SET ON THE TENNIS SERVE EVALUATION

The purpose of this study was to identify the influence on the tennis serve evaluation of 1/ the test environment and 2/ the number of the markers placed of the player. Two different studies were performed. The first compared a 4 vs. 28 marker set in a laboratory the same day. The second compared a 4 markers test in a laboratory with a 4 markers test on an official tennis court one week apart. We observed similar results between the different tests of both studies

465 Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety and pharmacokinetic results of the INTR@PID LUNG 024 study

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1. Here we report cumulative safety and pharmacokinetic (PK) results from the global, phase 1b/2 INTR@PID LUNG 024 study (NCT03840915), which evaluated bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC.MethodsAdult patients with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 were included. Cohorts A, B, and C included patients with no prior systemic therapy; patients in cohort D had disease that progressed with previous anti–PD-(L)1 therapy. Cohorts received bintrafusp alfa 2400 mg every 3 weeks intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or in combination with pemetrexed in cohort A) for up to 31 cycles. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Dose-limiting toxicities (DLTs) were assessed during a 3-week observation period. Serial samples were drawn to assess serum concentration and calculate PK parameters by noncompartmental analysis.ResultsAs of the May 5, 2021, data cutoff, 70 patients received bintrafusp alfa in combination with CT. Of 35 patients included in the DLT analysis, 4 experienced 1 DLT according to a safety monitoring committee (data cutoff May 5, 2021; A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). Cumulative safety data are reported in table 1. PK data were available for 67 patients (A: n=38; B: n=9; C: n=8; D: n=12). PK profiles were similar across cohorts and between patients who did and did not experience a DLT. Observed bintrafusp alfa first-cycle exposures (Cmax, AUC, and Ctrough) were consistent with the published population PK (popPK) model.1Abstract 465 Table 1Safety results from the INTR@PID LUNG 024 studyConclusionsThe safety profile of bintrafusp alfa in combination with CT was manageable and similar to that reported for ICIs in combination with CT, with the exception of TGF-β–related skin lesions known to occur with TGF-β inhibition. No new safety signals were identified and there were no treatment-related deaths. The PK profile was consistent with the predicted monotherapy popPK model, suggesting no victim DDI potential for bintrafusp alfa with CT.AcknowledgementsThe authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, at the healthcare business of Merck KGaA, Darmstadt, Germany, and at EMD Serono, Billerica, Massachusetts, USA.Trial RegistrationNCT03840915ReferenceWilkins JJ, Vugmeyster Y, Dussault I. Population pharmacokinetic analysis of bintrafusp alfa in different cancer types. Adv Ther 2019;36:2414–2433.Ethics ApprovalThe trial was approved by each site's independent ethics committee

La β-alanine dans des épreuves isocinétiques et de sauts répétés, (in)utile?

Introduction La β-alanine (β-A), acide aminé précurseur de la carnosine, a fait l'objet d'un nombre important d'études sans néanmoins parvenir à un consensus quant à son influence sur la performance [1-6] et/ou son mécanisme d'action [7]. Notre étude a pour but d'affiner la connaissance de son impact sur des performances maximales lors d'épreuves isocinétiques et de sauts prolongées: les personnes ayant une faible résistance à la fatigue neuromusculaire bénéficieraient-elles davantage des effets de la β-A? Méthodes Neuf hommes (24,5 ± 1,2 ans, 182,1 ± 6,6 cm, 80,2 ± 9,9 kg), ont réalisé deux épreuves d'exploration de la fatigue neuromusculaire avec 48h à 72h de repos entre chaque: un test analytique mono-articulaire, gold standard de l'évaluation musculaire, et une épreuve poly-articulaire dite "fonctionnelle". Ces deux épreuves, complémentaires de par les informations qu'elles permettent d'obtenir, sont respectivement un test isocinétique de résistance à la fatigue (30 extensions/flexions maximales de genou en concentrique à 180°.s-1 sur une amplitude de 100° sur Cybex Humac CSMI) [8] et un test de countermovement jump répétés (35 sauts maximaux enclenchés toutes les 1,82 secondes). Chaque sujet a réalisé quatre fois chaque testing: avant/après 14 jours de supplémentation en β-A (5g/j.) et avant/après 14 jours de prise d'un placebo (lactose) sous forme d'un crossover randomisé en double aveugle avec un wash-out de 14 jours. Résultats Aucun effet global de la supplémentation en β-A n'a été observé, que ce soit pour l'épreuve isocinétique (entre autres, somme du travail total des extenseurs: ES Cohen = 0,06 [CI95%: -0,57/0,68]; Magnitude-Based Inference (MBI) Hopkins: P (positif) 31% / T (trivial) 51% / N (négatif) 18%) ou de sauts répétés (entre autres, somme des hauteurs des 35 sauts: ES Cohen = -0,09 [CI95%: -0,47/0,28]; MBI: P 5% / T 68% / N 26%). Une corrélation négative (inversement proportionnelle), forte et statistiquement significative a néanmoins été observée entre l'impact de la β-A sur la performance et la capacité de résistance à la fatigue neuromusculaire pour l'épreuve isocinétique (entre autres, pente de la régression linéaire du travail total & différence entre somme du travail total des extenseurs avec β-A et placebo: rPearson = - 0,85 [CI95%: -0,97/-0,44] avec une p-value de 0,002). Pour l'épreuve de sauts répétés, les résultats ne sont pas significatifs (rPearson = - 0,31 [CI95%: -0,81/0,44] avec une p-value de 0,409)

Modular cell-based platform for high throughput identification of compounds that inhibit a viral interferon antagonist of choice

The work was supported by the Medical Research Council, U.K. (University of St Andrews Doctoral Training Grant to AV and CSA), Deutsche Forschungsgemeinschaft (PA 815/2-1) to CP, Tenovus Scotland (T15/38) to MN and Wellcome Trust to CP, MN (ISSF) and RER (101788/Z/13/Z)Viral interferon (IFN) antagonists are a diverse class of viral proteins that counteract the host IFN response, which is important for controlling viral infections. Viral IFN antagonists are often multifunctional proteins that perform vital roles in virus replication beyond IFN antagonism. The critical importance of viral IFN antagonists is highlighted by the fact that almost all viruses encode one of these proteins. Inhibition of viral IFN antagonists has the potential to exert pleiotropic antiviral effects and thus this important protein class represents a diverse plethora of novel therapeutic targets. To exploit this, we have successfully developed and executed a novel modular cell-based platform that facilitates the safe and rapid screening for inhibitors of a viral IFN antagonist of choice. The platform is based on two reporter cell-lines that provide a simple method to detect activation of IFN induction or signaling via an eGFP gene placed under the control of the IFNβ or an ISRE-containing promoter, respectively. Expression of a target IFN antagonist in the appropriate reporter cell-line will block the IFN response and hence eGFP expression. We hypothesized that addition of a compound that inhibits IFN antagonist function will release the block imposed on the IFN response and hence restore eGFP expression, providing a measurable parameter for high throughput screening (HTS). We demonstrate assay proof-of-concept by (i) exploiting hepatitis C virus (HCV) protease inhibitors to inhibit NS3-4A's capacity to block IFN induction and (ii) successfully executing two HTS targeting viral IFN antagonists that block IFN signaling; NS2 and IE1 from human respiratory syncytial virus (RSV) and cytomegalovirus (CMV) respectively, two clinically important viruses for which vaccine development has thus far been unsuccessful and new antivirals are required. Both screens performed robustly and Z′ Factor scores of >0.6 were achieved. We identified (i) four hit compounds that specifically inhibit RSV NS2's ability to block IFN signaling by mediating STAT2 degradation and exhibit modest antiviral activity and (ii) two hit compounds that interfere with IE1 transcription and significantly impair CMV replication. Overall, we demonstrate assay proof-of-concept as we target viral IFN antagonists from unrelated viruses and demonstrate its suitability for HTS.Publisher PDFPeer reviewe

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future.

PURPOSE: Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. DESIGN: Meta-analysis of prevalence data. PARTICIPANTS: A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. METHODS: AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). MAIN OUTCOME MEASURES: Prevalence of early and late AMD, BCVA, and number of AMD cases. RESULTS: Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%-5.0%) in those aged 55-59 years to 17.6% (95% CI 13.6%-21.5%) in those aged ≥85 years; for late AMD these figures were 0.1% (95% CI 0.04%-0.3%) and 9.8% (95% CI 6.3%-13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer ≥80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million. CONCLUSION: We observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti-vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans

Plant phenomics, from sensors to knowledge

Major improvements in crop yield are needed to keep pace with population growth and climate change. While plant breeding efforts have greatly benefited from advances in genomics, profiling the crop phenome (i.e., the structure and function of plants) associated with allelic variants and environments remains a major technical bottleneck. Here, we review the conceptual and technical challenges facing plant phenomics. We first discuss how, given plants’ high levels of morphological plasticity, crop phenomics presents distinct challenges compared with studies in animals. Next, we present strategies for multi-scale phenomics, and describe how major improvements in imaging, sensor technologies and data analysis are now making high-throughput root, shoot, whole-plant and canopy phenomic studies possible. We then suggest that research in this area is entering a new stage of development, in which phenomic pipelines can help researchers transform large numbers of images and sensor data into knowledge, necessitating novel methods of data handling and modelling. Collectively, these innovations are helping accelerate the selection of the next generation of crops more sustainable and resilient to climate change, and whose benefits promise to scale from physiology to breeding and to deliver real world impact for ongoing global food security efforts