MMsPred: a bioactivity and toxicology predictive system

In the last decade, the development and use of new methods in combinatorial chemistry and high-throughput screening has dramatically increased the number of known biologically active compounds. Paradoxically, the number of drugs reaching the market has not followed the same trend, often because many of the candidate drugs present poor qualities in absorption, distribution, metabolism, excretion, and toxicological properties (ADME-Tox). The ability to recognize and discard bad candidates early in the drug discovery steps would save lost investments in time and money. Machine learning techniques could provide solutions to this problem.
The goal of my research is to develop classifiers that accurately discriminate between active and inactive molecules for a specific target. To this end, I am comparing the effectiveness of the application of different machine learning techniques to this problem.	As a source of data we have selected a set of PubChem's public BioAssays1. In addition, with the objective of realizing a real-time query service with our predictors, we aim to keep the features describing the chemical compounds relatively simple.
At the end of this process, we should better understand how to build statistical models that are able to recognize molecules active in a specific bioassay, including how to select the most appropriate classification technique, and how to describe compounds in such a way that is not excessively resource-consuming to generate, yet contains sufficient information for the classification. We see immediate applications of such technology to recognize compounds with high-risk of toxicity, and also to suggest likely metabolic pathways that would process it

Union after multiple anterior cervical fusion 21 cases followed for 1-6 years

With a mean follow-up of 3 (1-6) years, we report on 21 patients who underwent multiple level cervical fusion, using autologous iliac crest grafts. Dissectomies were performed in 14 patients and corpectomies in another 7. Instrumentation was used in all patients with corpectomies and in 2 patients who underwent 2-level and 3-level dissectomies. Non-union occurred in 1 patient at 1 level. Graft displacement requiring reoperation was observed in 2 patients with massive corpectomies, in 1 of them as a consequence of trauma. In both patients complete bony fusion was obtained after reoperation and no other complications were observed. We conclude that the success rate with multiple-level fusion is comparable to that of single-level fusion when adequate fixation is achieve

Mania as Debut of Cushing's Syndrome

This is a case of a patient affected by Cushing syndrome that was admitted at the hospital due to hormonal problems. He had presented psychiatric symptoms that were mistakenly considered not directly connected to the pathology causing the clinical condition, but a mere psychological reaction to it

X-box binding protein 1 (XBP1): A key protein for renal osmotic adaptation: Its role in lipogenic program regulation

In renal cells, hyperosmolarity can induce cellular stress or differentiation. Both processes require active endoplasmic reticulum (ER)-associated protein synthesis. Lipid biosynthesis also occurs at ER surface. We showed that hyperosmolarity upregulates glycerophospholipid (GP) and triacylglycerol (GL-TG) de novo synthesis. Considering that massive synthesis of proteins and/or lipids may drive to ER stress, herein we evaluated whether hyperosmolar environment induces ER stress and the participation of inositol-requiring enzyme 1α (IRE1α)-XBP1 in hyperosmotic-induced lipid synthesis. Treatment of Madin-Darby canine kidney (MDCK) cells with hyperosmolar medium triggered ER stress-associated unfolded protein response (UPR). Hyperosmolarity significantly increased xbp1 mRNA and protein as function of time; 24 h of treatment raised the spliced form of XBP1 protein (XBP1s) and induced its translocation to nuclear compartment where it can act as a transcription factor. XBP1 silencing or IRE1α ribonuclease (RNAse) inhibition impeded the expression of lipin1, lipin2 and diacylglycerol acyl transferase-1 (DGAT1) enzymes which yielded decreased GL-TG synthesis. The lack of XBP1s also decreased sterol regulatory element binding protein (SREBP) 1 and 2. Together our data demonstrate that hyperosmolarity induces IRE1α → XBP1s activation; XBP1s drives the expression of SREBP1 and SREBP2 which in turn regulates the expression of the lipogenic enzymes lipin1 (LPIN1) and 2 (LPIN2) and DGAT1. We also demonstrated for the first time that tonicity-responsive enhancer binding protein (TonEBP), the master regulator of osmoprotective response, regulates XBP1 expression. Thus, XBP1 acts as an osmoprotective protein since it is activated by high osmolarity and upregulates lipid metabolism, membranes generation and the restoration of ER homeostasis.Fil: Casali, Cecilia Irene. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Biología Celular y Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Malvicini, Ricardo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Biología Celular y Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Erjavec, Luciana Cecilia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Biología Celular y Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Parra, Leandro Gastón. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Biología Celular y Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Artuch, Ayelen. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Biología Celular y Molecular; ArgentinaFil: Fernández Tome, María C.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Biología Celular y Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

The development of the radicular and vegetative systems of almond trees with different rootstocks following the application of biostimulants

[EN] Aim of study: Recently, the development of almond crops on a global scale has increased their area under cultivation. The demand for both plants and products that stimulate the growth of almond trees has therefore become increasingly necessary. Accordingly, in this project we have studied the response in the vegetative and root systems of almond trees with different rootstocks to varying inputs of several root stimulants. Area of study: Valencia (Spain) Material and methods: Several different organic biostimulants were studied in isolation, i.e. not combined with synthetic chemical fertilizers, in order to ascertain if chemical fertilizers could be at least partially replaced. Main results: Good results were obtained by applying a biostimulant composed of organic matter rich in saccharides and carboxylates. Using an approach that enabled a distinguishing between them, plant radicular systems were shown to respond differently according to the biostimulant applied and the rootstock tested. The best results were obtained with a biostimulant composed of organic matter from corn hydrolysis and containing free amino acids and extracts from algae, as well as 0.07% zeaxanthins. Research highlights: Although biostimulants are promoters of young almond tree growth, they should be applied to only partially replace chemical fertilizers. The present paper shows the importance of using an organic-origin biostimulant, as a complement to chemical nutritionMondragón-Valero, A.; Malheiro, R.; Salazar Hernández, DM.; Martinez-Tome, J.; Pereira, JA.; López- Cortés, I. (2020). The development of the radicular and vegetative systems of almond trees with different rootstocks following the application of biostimulants. Spanish Journal of Agricultural Research (Online). 18(4):1-11. https://doi.org/10.5424/sjar/2020184-14787S111184Apone F, Tito A, Carola A, Arciello S, Tortora A, Filippini L, 2010. A mixture of peptides and sugars derived from plant cell walls increases plant defense responses to stress and attenuates ageing-associated molecular changes in cultured skin cells. J Biotech 145: 367-376.Basak A, 2008. Effect of preharvest treatment with seaweed products, Kelpak® and Goëmar BM 86®, on fruit quality in apple. Inter J Fruit Sci 8: 1-14.Battacharyya D, Babgohari MZ, Rathor P, Prithiviraj B, 2015. Seaweed extracts as biostimulants in horticulture. Sci Hortic 196: 39-48.Bernhard R, Grasselly C, 1981. Les pêchers x amandiers. Arb Fruit 328: 37-42.Bi G, Scagel C, Cheng L, Dong S, Fuchigami L, 2003. Spring growth of almond nursery trees depends upon nitrogen from both plant reserves and spring fertilizer application. J Hortic Sci Biotech 78: 853-858.Burns AM, Zitt MA, Rowe CC, Langkamp-Henken B, Mai V, Nieves C, et al., 2016. Diet quality improves for parents and children when almonds are incorporated into their daily diet: a randomized, crossover study. Nutr Res 36: 80-89.Bussi C, Huguet J, Besset J, Girard T, 1995. Rootstock effects on the growth and fruit yield of peach. Eur J Agron 4: 387-393.Chen SK, Edwards CA, Subler S, 2003. The influence of two agricultural biostimulants on nitrogen transformations, microbial activity, and plant growth in soil microcosms. Soil Biol Biochem 35: 9-19.Chouliaras V, Tasioula M, Chatzissavvidis C, Therios I, Tsabolatidou E, 2009. The effects of a seaweed extract in addition to nitrogen and boron fertilization on productivity, fruit maturation, leaf nutritional status and oil quality of the olive (Olea europaea L.) cultivar Koroneiki. J Sci Food Agric 89: 984-988.Deliopoulos T, Kettlewell P, Hare M, 2010. Fungal disease suppression by inorganic salts. A review. Crop Prot 29: 1059-1075.Enz M, Dachler CH, 1997. Compendium of growth stage identification keys for mono- and dicotyledonous plants. Extended BBCH scale. A joint publication of BBA, BSA, IGZ, IVA, AgrEvo, BASF, Bayer, Novartis. 94 pp.Ertani A, Cavani L, Pizzeghello D, Brandellero E, Altissimo A, Ciavatta C, Nardi S, 2009. Biostimulant activity of two protein hydrolyzates in the growth and nitrogen metabolism of maize seedlings. J Plant Nutr Soil Sci 172: 237-244.Espada J, Romero J, Cmuñas F, Alonso J, 2013. Nuevos patrones para el melocotonero: mejora de la eficiencia y calidad del fruto. Gobierno de Aragón, Zaragoza, Spain.European Biostimulants Industry Council, 2018. Economic overview of biostimulants sector in Europe. http://www.biostimulants.eu/.Felipe A, 2009. Felinem, Garnem and Monegro almond x peach hybrid rootstocks. HortScience 44: 196-197.Forcada C, Gogorcena Y, Moreno M, 2012. Agronomical and fruit quality traits of two peach cultivars on peach-almond hybrid rootstocks growing on Mediterranean conditions. Sci Hortic 140: 157-163.Gómez-Aparisi J, Carrera M, Felipe A, Socias I Company R, 2001. Garnem, Monegro y Felinem: Nuevos patrones híbridos almendro x melocotonero, resistentes a nematodos y de hoja roja para frutales de hueso. Inf Téc Econ Agrar 97: 282-288.Goss M, Miller M, Bailey L, Grant C, 1993. Root growth and distribution in relation to nutrient availability and uptake. Eur J Agron 2: 57-67.INC, 2019. Global statistical review 2017-2018. International Nut and Dried Fruit Council, Reus, Spain.Khan W, Rayirath UP, Subramanian S, Jithesh MN, Rayorath P, Hodges DM, et al., 2009. Seaweed extracts as biostimulants of plant growth and development. J Plant Growth Reg 28: 386-399.Lopus SE, Santibañez MP, Beede RH, Duncan RA, Edstrom J, Niederholzer FJA, et al., 2010. Survey examines the adoption of perceived best management practices for almond nutrition. Calif Agric 64: 149-154.Mondragón-Valero A, Lopéz-Cortés I, Salazar DM, Córdova PF, 2017. Physical mechanisms produced in the development of nursery almond trees (Prunus dulcis Miller) as a response to the plant adaptation to different substrates. Rhizosphere 3: 44-49.Moreno M, Gogorcena Y, Pinochet J, 2008. Mejora y selección de patrones de prunus tolerantes a estreses abióticos. In: La adaptación al ambiente y los estreses abióticos en la mejora vegetal, pp. 451-475. Junta de Andalucía, Dirección General de Planificación y Análisis de Mercados, Servicio de Publicaciones y Divulgación, Sevilla.Muhammad S, Luedeling E, Brown P, 2009. A nutrient budget approach to nutrient management in almond. XVI Proc Int Plant Nutr Col, California (USA), pp: 1-9.Nardi S, Pizzeghello D, Schiavon M, Ertani A, 2016. Plant biostimulants: physiological responses induced by protein hydrolyzed-based products and humic substances in plant metabolism. Sci Agric 73: 18-23.Olivares FL, Busato JG, Paula AM, Lima LS, Aguiar NO, Canellas LP, 2017. Plant growth promoting bacteria and humic substances: crop promotion and mechanisms of action. Chem Biol Tech Agric 4: 30.Pinochet J, 2010. 'Replantpac' (Rootpac R), a plum-almond hybrid rootstock for replant situations. HortScience 45: 299-301.Pinochet J, Bordas M, Torrents J, 2011. ROOTPAC R: un nuevo portainjerto de Prunus para situaciones de replante. Revista de Fruticultura 15: 4-10.Pizzeghello D, Francioso O, Ertani A, Muscolo A, Nardi S, 2013. Isopentenyladenosine and cytokinin-like activity of different humic substances. J Geochem Expl 129: 70-75.Rayorath P, Jithesh M. Farid A, Khan W, Palanisamy R, 2008. Rapid bioassays to evaluate the plant growth promoting activity of Ascophyllum nodosum (L.) Le Jol. using a model plant, Arabidopsis thaliana (L.) Heynh. J Appl Phycol 20: 423-429.Rouphael Y, Cardarelli M, Bonini P, Colla G, 2017. Synergistic action of a microbial-based biostimulant and a plant derived-protein hydrolysate enhances lettuce tolerance to alkalinity and salinity. Front Plant Sci 8: 131.Salazar D, Melgarejo P, 2002. El cultivo del almendro. Mundi-Prensa, Madrid, Spain. 307 pp.Scaglia B, Pognani M, Adani F, 2017. The anaerobic digestion process capability to produce biostimulant: the case study of the dissolved organic matter (DOM) vs. auxin-like property. Sci Total Environ 589: 36-45.Sotomayor C, Castro J, Bustos E, 2008. Nuevos portainjertos para Chile. Rev Agron For UC 35: 22-26.Vargas F, Romero M, Altea N, 1985. Porte-greffe d'amandier: Aspects importants des programmes de Centre Agropecuari Mas Bové. GREMPA, colloque 1985. CIHEAM, Paris. Opt Mediterr Sér Etudes 1985-I: 61-68. http://om.ciheam.org/om/pdf/s09/CI010822.pdfVernieri P, Borghesi E, Ferrante A, Magnani G, 2005. Application of biostimulants in floating system for improving rocket quality. J Food Agric Environ 3: 86-88.Wells C, Labranche A, Mccarty L, Skipper H, 2003. Biostimulants encourage strong root growth. Turfgrass Trend 59: 56-59.Williams L, Smith R, 1991. The effect of rootstocck on the partitioning of dry weight, nitrogen and potassium and root distribution of cabernet sauvignon grapevines. Am J Enol Vitic 42: 118-112.Zhang X, Ervin E, 2004. Cytokinin-containing seaweed and humic acid extracts associated with creeping bentgrass leaf cytokinins and drought resistance. J Appl Phycol 44: 1737-1745

Lumbosacral arthrodesis using pedicular screws and ringed rods

Sixty-one patients who had lumbar instability and chronic low back pain or deformity from nontraumatic lumbar pathologies were studied. In all of them a posterior lumbosacral fusion with CUN (Clinic of the University of Navarre) pedicle rod fixation was used. The mean follow-up period was 36 months (range 26-46 months). The consolidation rate was evaluated according to plain and functional radiographs, and a clinical evaluation was made using an analogue pain scale. The rate of fusion was 93.5%. Neurological complications occurred in 3.3%. The incidence of screw failure was 2.3% of all the screws. No other implant failure occurred. The patients rated their clinical results as 'excellent' in 33.8% of the cases, 'good' in 42.2%, 'fair' in 16.9% and 'poor' in 6.7%. CUN instrumentation is a versatile internal fixation system that has been shown to provide satisfactory stability. Furthermore, the clinical results are comparable to those reported in studies in which the most common hardwares were used

Muon Array with RPCs for Tagging Air showers (MARTA)

We discuss the concept of an array with Resistive Plate Chambers (RPC) for muon detection in ultra-high energy cosmic ray (UHECR) experiments. RPC have been used in particle physics experiments due to their fast timing properties and spatial resolution. The operation of a ground array detector poses challenging demands, as the RPC must operate remotely under extreme en- vironments, with limited power and minimal maintenance. In its baseline configuration, each MARTA unit includes one 1.5x1.2 m 2 RPC, with 64 pickup electrodes (pads). The DAQ sys- tem is based on an ASIC, allowing one to read out the high number of channels with low power consumption. Data are recorded using a dual technique: single particle counting with a simple threshold on the signal from each pad and charge integration for high occupancy. The RPC, DAQ, High Voltage and monitoring systems are enclosed in an aluminum-sealed case, providing a com- pact and robust unit suited for outdoor environments, which can be easily deployed and connected. The RPCs developed at LIP-Coimbra are able to operate using very low gas flux, which allows running them for few years with a small gas reservoir. Several full-scale units are already installed and taking data in several locations and with different configurations, proving the viability of the MARTA concept. By shielding the detector units with enough slant mass to absorb the electro- magnetic component in the air showers, a clean measurement of the muon content is allowed, a concept to be implemented in a next generation of UHECR experiments. The specificities of a MARTA unit are presented, which include particle counting with high efficiency, time resolu- tion and spatial segmentation. The potential of the MARTA concept for muon measurements in air showers is assessed, as well as tentative methods for calibration and cross-calibrations with existing detectors.Peer Reviewe

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Dynamical and statistical downscaling of a global seasonal hindcast in eastern Africa

Within the FP7 EUPORIAS project we have assessed the utility of dynamical and statistical downscaling to provide seasonal forecast for impact modelling in eastern Africa. An ensemble of seasonal hindcasts was generated by the global climate model (GCM) EC-EARTH and then downscaled by four regional climate models and by two statistical methods over eastern Africa with focus on Ethiopia. The five-month hindcast includes 15 members, initialised on May 1?st covering 1991?2012. There are two sub-regions where the global hindcast has some skill in predicting June?September rainfall (northern Ethiopia ? northeast Sudan and southern Sudan - northern Uganda). The regional models are able to reproduce the predictive signal evident in the driving EC-EARTH hindcast over Ethiopia in June?September showing about the same performance as their driving GCM. Statistical downscaling, in general, loses a part of the EC-EARTH signal at grid box scale but shows some improvement after spatial aggregation. At the same time there are no clear evidences that the dynamical and statistical downscaling provide added value compared to the driving EC-EARTH if we define the added value as a higher forecast skill in the downscaled hindcast, although there is a tendency of improved reliability through the downscaling. The use of the global and downscaled hindcasts as input for the Livelihoods, Early Assessment and Protection (LEAP) platform of the World Food Programme in Ethiopia shows that the performance of the LEAP platform in predicting humanitarian needs at the national and sub-national levels is not improved by using downscaled seasonal forecasts.This work was done in the EUPORIAS project that received funding from the European Union Seventh Framework Programme (FP7) for Research, under grant agreement 308291. The authors thank the European Centre for Medium-Range Weather Forecasts (ECMWF), the Global Precipitation Climatology Centre (GPCC), the British Atmospheric Data Centre (BADC), the University of East Anglia (UEA), the University of Delaware, the University of Reading, the University of California, the Climate Prediction Center (CPC), the US Agency for International Development’s Famine Early Warning Network (FEWS NET) and the WATCH project for providing data. For the WRF simulations, the UCAN group acknowledges Santander Supercomputacion support group at the University of Cantabria, who provided access to the Altamira Supercomputer at the Institute of Physics of Cantabria (IFCA-CSIC), member of the Spanish Supercomputing Network. DWD wants to thank ECMWF for the support during the CCLM4 simulations which have been carried out at the ECMWF computing system. The SMHI RCA4 simulations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at National Supercomputer Centre (NSC) and the PDC Center for High Performance Computing (PDC-HPC)