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- Re‐evaluation of butane (E 943a), isobutane (E 943b) and propane (E 944) as food additivesPublication . EFSA Panel on Food Additives and Flavourings; Castle, Laurence; Andreassen, Monica; Aquilina, Gabriele; Bastos, Maria; Boon, Polly; Fallico, Biagio; Fitzgerald, Reginald; Frutos-Fernandez, Maria Jose; Grasl‐Kraupp, Bettina; Gundert‐Remy, Ursula; Gürtler, Rainer; Houdeau, Eric; Kurek, Marcin; Louro, Henriqueta; Morales, Patricia; Passamonti, Sabina; Gagliardi, Gabriele; Multari, Salvatore; Rasinger, Josef Daniel; Rincon, Ana Maria; Smeraldi, CamillaThe Panel on Food Additives and Flavourings (FAF) provides a scientific opinion re‐evaluating the safety of butane (E 943a), isobutane (E 943b) and propane (E 944) as food additives. Butane, isobutane and propane are short‐chain (C3–C4) alkanes, which are in gaseous state at room temperature. Their currently permitted use in food is in vegetable oil pan spray (for professional use only) and water‐based emulsion spray as propellants at quantum satis. They can also be used in food colour preparations with a maximum residual limit of 1 mg/kg in food. Two interested business operators (IBOs) provided information in response to the call for data published by EFSA reporting typical and maximum use levels. The toxicological hazards of the three gases via inhalation are known, however this route of exposure is not considered relevant for their safety assessment as food additives. Existing EU specifications for the three food additives already contain limits for the toxic impurity 1,3‐butadiene (1,3‐BD), however due to a lack of information on the manufacturing processes used, uncertainties do remain regarding the potential presence of other impurities not listed in the current EU specifications for food additives. Based on their physicochemical properties, the three gases are considered by the Panel to be of low toxicological concern when used as food additives and their dietary exposure very low. The Panel concluded that the use of butane (E 943a), isobutane (E 943b) and propane (E 944) as food additives at the currently permitted uses and use levels does not raise a safety concern. The Panel made some recommendations for amending existing EU specifications for butane (E 943a), isobutane (E 943b) and propane (E 944).
- Flavouring group evaluation 418 (FGE. 418): 3‐[3‐(2‐isopropyl‐5‐methyl‐cyclohexyl)‐ureido]‐butyric acid ethyl esterPublication . EFSA Panel on Food Additives and Flavourings (FAF); Castle, Laurence; Andreassen, Monica; Aquilina, Gabriele; Bastos, Maria; Boon, Polly; Fallico, Biagio; FitzGerald, Reginald; Frutos-Fernandez, Maria Jose; Grasl-Kraupp, Bettina; Gundert-Remy, Ursula; Gürtler, Rainer; Houdeau, Eric; Kurek, Marcin; Louro, Henriqueta; Morales, Patricia; Passamonti, Sabina; Benigni, Romualdo; Chipman, Kevin; Cordelli, Eugenia; Degen, Gisela; Engel, Karl-Heinz; Fowler, Paul; Carfí, Maria; Gagliardi, Gabriele; Mech, Agnieszka; Multari, Salvatore; Martino, CarlaThe EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of 3‐[3‐(2‐isopropyl‐5‐methyl‐cyclohexyl)‐ureido]‐butyric acid ethyl ester [FL‐no: 16.136] as a new flavouring substance, in accordance with Regulation (EC) No 1331/2008. The substance has not been reported to occur naturally and it is chemically synthesised. The information provided on the manufacturing process, the composition and the stability of [FL‐no: 16.136] was considered sufficient. The chronic dietary exposure to [FL‐no: 16.136] estimated using the added portions exposure technique (APET) is calculated to be 860 μg/person per day for a 60‐kg adult and 540 μg/person per day for a 15‐kg 3‐year‐old child. [FL‐no: 16.136] did not show genotoxic effects in bacterial mutagenicity and mammalian cell micronucleus assays in vitro. No ADME studies on [FL‐no: 16.136] were provided. In a prenatal developmental toxicity study, no maternal or fetal toxicity was observed in rats dosed up to 1000 mg/kg body weight (bw) per day. In a 90‐day toxicity study in rats, no adverse effects were observed. In this study, the Panel considered that the NOAEL is 777 and 923 mg/kg bw per day (the highest dose tested) for male and female rats, respectively. Considering the lowest NOAEL of 777 mg/kg bw per day, as a reference point, adequate margins of exposure of 55 × 103 and 21 × 103 were calculated for adults and children, respectively, when considering the chronic APET dietary exposure estimates. The Panel concluded that the use of 3‐[3‐(2‐isopropyl‐5‐methylcyclohexyl)‐ureido]‐butyric acid ethyl ester [FL‐no: 16.136] as a flavouring substance under the proposed conditions of use does not raise a safety concern at the dietary exposure estimates calculated using the APET approach.
- mRNA Degradation as a Therapeutic Solution for Mucopolysaccharidosis Type IIIC: Use of Antisense Oligonucleotides to Promote Downregulation of Heparan Sulfate SynthesisPublication . Santos, Juliana I.; Gonçalves, Mariana; Almeida, Matilde B.; Rocha, Hugo; Duarte, Ana J.; Matos, Liliana; Moreira, Luciana V.; Encarnação, Marisa; Gaspar, Paulo; Prata, Maria J.; Coutinho, Maria F.; Alves, SandraMucopolysaccharidosis type IIIC is a neurodegenerative lysosomal storage disorder (LSD) characterized by the accumulation of undegraded heparan sulfate (HS) due to the lack of an enzyme responsible for its degradation: acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT). Classical treatments are ineffective. Here, we attempt a new approach in genetic medicine, genetic substrate reduction therapy (gSRT), to counteract this neurological disorder. Briefly, we used synthetic oligonucleotides, particularly gapmer antisense oligonucleotides (ASOs), to target the synthesis of the accumulated compounds at the molecular level, downregulating a specific gene involved in the first step of HS biosynthesis, XYLT1. Our goal was to reduce HS production and, consequently, its accumulation. Initially, five gapmer ASOs were designed and their potential to decrease XYLT1 mRNA levels were tested in patient-derived fibroblasts. Subsequent analyses focused on the two best performing molecules alone. The results showed a high inhibition of the XYLT1 gene mRNA (around 90%), a decrease in xylosyltransferase I (XT-I) protein levels and a reduction in HS storage 6 and 10 days after transfection (up to 21% and 32%, respectively). Overall, our results are highly promising and may represent the initial step towards the development of a potential therapeutic option not only for MPS IIIC, but virtually for every other MPS III form. Ultimately, the same principle may also apply to other neuropathic MPS.
- Prediction of Genes Associated With Autism Spectrum Disorder Using Sequence and Graph Embedding MethodsPublication . Inácio, João Pedro da Silva; Martiniano, Hugo; Vicente, AstridNeurodevelopmental disorders impose a significant social and economic burden on individuals with these conditions and their families. Given that all neurodevelopmental disorders have a genetic component, identifying the risk genes for these disorders enhances our understanding of their etiology and can aid in the development of future screening methods and targeted therapies. Autism Spectrum Disorder (ASD) is a prototypical complex neurodevelopmental disorder characterized by high heritability and a heterogeneous genetic architecture and phenotypic presentation. This thesis presents a Machine Learning (ML) approach that improves upon state-of-the-art methods for ASD risk gene prediction, this thesis presents a Machine Learning (ML) approach capable of improving state-of-the-art methods for ASD risk gene prediction. To achieve this goal, a novel approach is created using publicly available ASD-associated genes and graph and sequence gene embeddings with supervised ML classifiers. Using a 5-fold nested stratified cross-validation, the pipeline achieved an AUC of 0.90, F1 of 0.82, and MCC of 0.77. Additionally, the top decile of the ranked list of predicted risk genes generated by the model was significantly enriched for ASD phenotypes but not other brain-specific disorders. The proposed pipeline improved state-of-the-art approaches in predicting genes targeted by LOF mutations in the MSSNG and SCC studies. A functional network characterization of the top decile identified four distinct communities significantly enriched for biological pathways associated with ASD. Of the 50 top predicted genes by the pipeline, 37 were already present in ASD risk gene databases, while 13 were not yet linked to ASD. The 13 genes were significantly enriched in the cerebral cortex, and the telencephalon cell migration processes critical for brain development and linked to neurodevelopmental disorders. This thesis provides an accurate comparison of embedding methods for risk gene discovery and improves existing ASD risk gene predictions, taking a step closer to a better understanding of this complex genetic disorder.
- Impact of non-pharmacological interventions on the first wave of COVID-19 in Portugal 2020Publication . Loyens, Dinis B.; Caetano, Constantino; Matias-Dias, CarlosIntroduction: The COVID-19 pandemic caused over 7 million global deaths. Without vaccines during the first wave, governments implemented nonpharmacological interventions (NPIs) such as lockdowns, school closures, and travel restrictions. This study quantifies the impact of NPIs on COVID-19 transmission in Portugal between 24th February and 1st May. Methods: A compartmental SEIR (Susceptible, Exposed, Infectious, Removed) model was employed to simulate the first COVID-19 wave in Portugal, using a Bayesian approach and symptom-onset incidence data. The effect of the lockdown, which began on March 22, 2020, on the effective reproductive number, R t was measured. A counterfactual scenario was created to ascertain the number of cases prevented by the NPIs during the first 15 days after the implementation of NPI. Results: The lockdown reduced overall transmission by 68·6 % (95%Credible Interval (95%CrI): 59·2 %; 77·5 %), almost immediately. This corresponds to a reduction in the effective reproductive number from 2·56 (95%CrI: 2·08; 3·40) to 0·80 (95%CrI: 0·76; 0·84). The counterfactual scenario estimated that the lockdown prevented 118052 (95%CrI: 99464; 145605) cases between 24th February and 6th April. Discussion: The lockdown significantly reduced COVID-19 transmission in Portugal, bringing Rt below 1, meaning each person infected fewer than one individual. While costly, lockdowns effectively control disease spread in the absence of vaccines. Conclusion: Our findings suggest NPIs curbed epidemic transmission, reducing Rt below 1 and easing hospital loads and deaths. This research will help inform future pandemic decision-making and infectious disease modeling worldwide.