Breeding for grapevine downy mildew resistance via gene editing

Downy mildew (DM) caused by the oomycete Plasmopara viticola ranks in the top diseases affecting grapevine (Vitis vinifera L.) cultivation and its control requires every year a large use of fungicides. The Farm to Fork strategy newly promoted by the EU aims to accelerate the transition to a sustainable food system and has set very ambitious targets including the reduction by 50% of the use and risk of pesticides by 2030. The introduction of disease-tolerant grapevine varieties or clones clearly represents a step forward to reach this goal. The recent advent of new breeding tools such as genome editing and cis-genesis offers a great opportunity to obtain resistant plants with higher precision and speed than by conventional breeding, either by knocking down susceptibility genes or by introducing known resistance-genes in commercial cultivars. Based on reports in other crops, the family of Downy Mildew Resistant 6 (DMR6) and DMR6-like oxygenases (DLOs) are candidate susceptibility genes for the control of DM resistance in V. vinifera. Deep-sequencing the putative susceptibility genes in 190 genetically diverse grapevine genotypes identified several Single Nucleotide Polymorphisms then screened for their impact on protein structure/function and association with DM resistant genotypes. Gene expression and gene network analysis suggested that grapevine DMR6 and DLO genes have distinct functions, and that VviDMR6-1 is co-regulated with several Pathogenesis-related genes. Based on this evidence, we generated a large collection of DMR6-1 and DMR6-2 single and double knock-out mutants in multiple grapevine cultivars and evaluated their resistance to DM. Phenotypic resistance data upon artificial infection are being collected and will be presented here. In parallel, we also developed a new DNA-free gene editing methodology and obtained non-transgenic and non-chimeric edited grapevine plants regenerated from a single cell

Approaches to mixture risk assessment of PFASs in the European population based on human hazard and biomonitoring data

Per- and polyfluoroalkyl substances (PFASs) are a highly persistent, mobile, and bioaccumulative class of chemicals, of which emissions into the environment result in long-lasting contamination with high probability for causing adverse effects to human health and the environment. Within the European Biomonitoring Initiative HBM4EU, samples and data were collected in a harmonized way from human biomonitoring (HBM) studies in Europe to derive current exposure data across a geographic spread. We performed mixture risk assessments based on recent internal exposure data of PFASs in European teenagers generated in the HBM4EU Aligned Studies (dataset with N = 1957, sampling years 2014-2021). Mixture risk assessments were performed based on three hazard-based approaches: the Hazard Index (HI) approach, the sum value approach as used by the European Food Safety Authority (EFSA) and the Relative Potency Factor (RPF) approach. The HI approach resulted in the highest risk estimates, followed by the RPF approach and the sum value approach. The assessments indicate that PFAS exposure may result in a health risk in a considerable fraction of individuals in the HBM4EU teenager study sample, thereby confirming the conclusion drawn in the recent EFSA scientific opinion. This study underlines that HBM data are of added value in assessing the health risks of aggregate and cumulative exposure to PFASs, as such data are able to reflect exposure from different sources and via different routes.This work was supported by the European Union’s Horizon 2020 research and innovation programme under Grant agreement No 733032 HBM4EU (www.HBM4EU.eu), and received co-funding from the au thors’ organizations. The Norwegian Institute of Public Health (NIPH) has contributed to funding of the Norwegian Environmental Biobank (NEB), and the laboratory measurements have partly been funded by the Research Council of Norway through research projects (275903 and 268465). The PCB cohort (follow-up) received additional funding from the Ministry of Health of the Slovak Republic (program 07B0103).S

Approaches to mixture risk assessment of PFASs in the European population based on human hazard and biomonitoring data

publishedVersio

Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial

Pharmacolog

Intravenous morphine versus intravenous paracetamol after cardiac surgery in neonates and infants

Background: Morphine is worldwide the analgesic of first choice after cardiac surgery in children. Morphine has unwanted hemodynamic and respiratory side effects. Therefore, post-cardiac surgery patients may potentially benefit from a non-opioid drug for pain relief. A previous study has shown that intravenous (IV) paracetamol is effective and opioid-sparing in children after major non-cardiac surgery. The aim of the study is to test the hypothesis that intermittent IV paracetamol administration in children after cardiac surgery will result in a reduction of at least 30% of the cumulative morphine requirement. Methods: This is a prospective, multi-center, randomized controlled trial at four level-3 pediatric intensive care units (ICUs) in the Netherlands and Belgium. Children who are 0-36months old will be randomly assigned to receive either intermittent IV paracetamol or continuous IV morphine up to 48h post-operatively. Morphine will be available as rescue medication for both groups. Validated pain and sedation assessment tools will be used to monitor patients. The sample size (n=208, 104 per arm) was calculated in order to detect a 30% reduction in morphine dose; two-sided significance level was 5% and power was 95%. Discussion: This study will focus on the reduction, or replacement, of morphine by IV paracetamol in children (0-36months old) after cardiac surgery. The results of this study will form the basis of a new pain management algorithm and will be implemented at the participating ICUs, resulting in an evidence-based guideline on post-operative pain after cardiac surgery in infants who are 0-36months old