Browsing by Issue Date, starting with "2022-08"
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- How Hydroxyurea Alters the Gut Microbiome: A Longitudinal Study Involving Angolan Children with Sickle Cell AnemiaPublication . Delgadinho, Mariana; Ginete, Catarina; Santos, Brígida; Fernandes, Carolina; Silva, Carina; Miranda, Armandina; Vasconcelos, Jocelyne Neto de; Brito, MiguelSickle cell anemia (SCA) is an inherited hematological disorder and a serious global health problem, especially in Sub-Saharan Africa. Although hydroxyurea (HU) is the leading treatment for patients with SCA, its effects on the gut microbiome have not yet been explored. In this context, the aim of this study was to investigate this association by characterizing the gut microbiome of an Angolan SCA pediatric population before and after 6 months of HU treatment. A total of 66 stool samples were obtained and sequenced for the 16S rRNA gene (V3-V4 regions). Significant associations were observed in alpha and beta-diversity, with higher values of species richness for the children naïve for HU. We also noticed that children after HU had higher proportions of several beneficial bacteria, mostly short-chain fatty acids (SCFAs) producing species, such as Blautia luti, Roseburia inulinivorans, Eubacterium halli, Faecalibacterium, Ruminococcus, Lactobacillus rogosae, among others. In addition, before HU there was a higher abundance of Clostridium_g24, which includes C. bolteae and C. clostridioforme, both considered pathogenic. This study provides the first evidence of the HU effect on the gut microbiome and unravels several microorganisms that could be considered candidate biomarkers for disease severity and HU efficacy.
- Functional profiling of LDLR variants: Important evidence for variant classification: Functional profiling of LDLR variantsPublication . Graça, Rafael; Alves, Ana Catarina; Zimon, Magdalena; Pepperkok, Rainer; Bourbon, MafaldaBackground: Familial Hypercholesterolemia (FH) is a semidominant disorder of the lipid metabolism associated with premature atherosclerosis and coronary heart disease. So far, about 3,000 unique LDLR variants have been described, most of which lack functional evidence proving their effect on LDLR function, despite the important role that functional studies play in variant classification. Objective: In this work, we aimed to functionally characterize 13 rare missense variants, identified worldwide and in Portugal, in clinical FH patients. Methods: LDLR-deficient CHO-ldlA7 cells were transfected with plasmids carrying different LDLR variants generated by site-directed mutagenesis. LDLR activity and expression were assessed by FACS. Results: 11/13 variants affect LDLR function (p.Cys109Phe; p.Cys143Arg; p.Glu267Lys; p.Cys352Ser; p.Ile451Thr; p.His485Gln; p.Asp492Asn; p.Val500Ala; p.Gly529Arg; p.Phe614Ile; p.Glu626Lys) and 2/13 are inconclusive (p.Arg81Cys; p.Gly98Arg;). Conclusion: Of the 13 variants studied, 8 were classified as VUS by ACMG criteria, but for 7 of these 8, our functional studies were able to reassign them as Likely pathogenic or Pathogenic. For an accurate diagnosis, an effort must be made to improve functional characterization of putative disease-causing variants.
- Interlaboratory exercise for the analysis of carotenoids and related compounds in dried mango fruit (Mangifera indica L.)Publication . Villacís-Chiriboga, José; Jacobs, Griet; Van Camp, John; Elst, Kathy; Ruales, Jenny; Marcillo-Parra, Verónica; Volker, Böhmg; Bunea, Andrea; Cirlini, Martina; Craft, Neal; De Meulenaer, Bruno; Graça Dias, M.; Lazzarino, Giacomo; Meléndez-Martínez, Antonio J.; Versloot, Pieter; Mercadante, Adriana Z.; Olmedilla-Alonso, Begoña; Ortiz-Ulloa, Johana; Stinco, lCarla M.; Voorspoels, StefanAn interlaboratory comparison was done for the analysis of carotenoids in freeze-dried mango. The study was performed from July to September 2018. Mango fruit was freeze-dried, homogenized, and packaged under vacuum conditions in portions of 6 g (test sample). Two test samples were sent to the participating laboratories for analysis. Laboratory results were rated using Z-scores in accordance with ISO 13528 and ISO 17043. The standard deviation for proficiency assessment (also called target standard deviation) was determined using a modified Horwitz function and varied between 10% and 25%, depending on the analyte. Out of 14 laboratories from 10 different countries, 9 laboratories (64%) obtained a satisfactory performance (Z ≤ 2) for the analysis of β-carotene. While for 7 laboratories that analyzed α-carotene, (9Z)-β-carotene, β-cryptoxanthin, and zeaxanthin, 4 laboratories (57%) obtained a satisfactory performance. However, only 2 laboratories out of 7 (29%) obtained a satisfactory performance for lutein. Based on the comparability of the analytical results, this study concludes that freeze-dried mango pulp can be used as a reference material for the analysis of α and β-carotene, (9Z)-β-carotene, β-cryptoxanthin, and zeaxanthin by applying different analytical procedures for their extraction and quantification.
- Phylogenomic characterization and signs of microevolution in the 2022 multi-country outbreak of monkeypox virusPublication . Isidro, Joana; Borges, Vítor; Pinto, Miguel; Sobral, Daniel; Santos, João Dourado; Nunes, Alexandra; Mixão, Verónica; Ferreira, Rita; Santos, Daniela; Duarte, Silvia; Vieira, Luís; Borrego, Maria José; Núncio, Sofia; de Carvalho, Isabel Lopes; Pelerito, Ana; Cordeiro, Rita; Gomes, João PauloThe largest monkeypox virus (MPXV) outbreak described so far in non-endemic countries was identified in May 2022 (refs. 1-6). In this study, shotgun metagenomics allowed the rapid reconstruction and phylogenomic characterization of the first MPXV outbreak genome sequences, showing that this MPXV belongs to clade 3 and that the outbreak most likely has a single origin. Although 2022 MPXV (lineage B.1) clustered with 2018-2019 cases linked to an endemic country, it segregates in a divergent phylogenetic branch, likely reflecting continuous accelerated evolution. An in-depth mutational analysis suggests the action of host APOBEC3 in viral evolution as well as signs of potential MPXV human adaptation in ongoing microevolution. Our findings also indicate that genome sequencing may provide resolution to track the spread and transmission of this presumably slow-evolving double-stranded DNA virus.
- Mono and multilayer active films containing green tea to extend food shelf lifePublication . Vieira, Dalila M.; Andrade, Mariana; Vilarinho, Fernanda; Sanches Silva, Ana; Rodrigues, Pedro; Castro, M. Cidália; Machado, Ana VeraAn active packaging film made of one and two-layers structure based on low-density polyethylene (LDPE) was produced with the incorporation of green tea extract (GTE) at different amounts by blown film extrusion. Film structure, optical, mechanical, antioxidant and barrier properties were characterized. The films revealed homogeneous film surface, the presence of GTE increases the tensile properties, improves friction coefficient and reduces LDPE films transparency. Moreover, the antioxidant capacity and barrier properties (water and oxygen) were enhanced, even at low concentrations. This study demonstrates the benefits of GTE incorporation into LDPE matrix, mainly in coextruded films, and its potential to develop an active and sustainable food packaging film at industrial scale.
- Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy DevelopmentPublication . Marques, Rita; Lacerda, Rafaela; Romão, LuísaMany conditions can benefit from RNA-based therapies, namely, those targeting internal ribosome entry sites (IRESs) and their regulatory proteins, the IRES trans-acting factors (ITAFs). IRES-mediated translation is an alternative mechanism of translation initiation, known for maintaining protein synthesis when canonical translation is impaired. During a stress response, it contributes to cell reprogramming and adaptation to the new environment. The relationship between IRESs and ITAFs with tumorigenesis and resistance to therapy has been studied in recent years, proposing new therapeutic targets and treatments. In addition, IRES-dependent translation initiation dysregulation is also related to neurological and cardiovascular diseases, muscular atrophies, or other syndromes. The participation of these structures in the development of such pathologies has been studied, yet to a far lesser extent than in cancer. Strategies involving the disruption of IRES-ITAF interactions or the modification of ITAF expression levels may be used with great impact in the development of new therapeutics. In this review, we aim to comprehend the current data on groups of human pathologies associated with IRES and/or ITAF dysregulation and their application in the designing of new therapeutic approaches using them as targets or tools. Thus, we wish to summarise the evidence in the field hoping to open new promising lines of investigation toward personalised treatments.
- Trends of Exposure to Acrylamide as Measured by Urinary Biomarkers Levels within the HBM4EU Biomonitoring Aligned Studies (2000–2021)Publication . Poteser, Michael; Laguzzi, Federica; Schettgen, Thomas; Vogel, Nina; Weber, Till; Murawski, Aline; Schmidt, Phillipp; Rüther, Maria; Kolossa-Gehring, Marike; Namorado, Sónia; Van Nieuwenhuyse, An; Appenzeller, Brice; Dufthaksdóttir, Edda; Olafsdottir, Kristin; Haug, Line Småstuen; Thomsen, Cathrine; Barbone, Fabio; Rosolen, Valentina; RAMBAUD, Loic; RIOU, Margaux; Göen, Thomas; Nübler, Stefanie; Schäfer, Moritz; Zarrabi, Karin H.A.; Gilles, Liese; Rodriguez Martin, Laura; Schoeters, Greta; Sepai, Ovnair; Govarts, Eva; Moshammer, HannsAcrylamide, a substance potentially carcinogenic in humans, represents a very prevalent contaminant in food and is also contained in tobacco smoke. Occupational exposure to higher concentrations of acrylamide was shown to induce neurotoxicity in humans. To minimize related risks for public health, it is vital to obtain data on the actual level of exposure in differently affected segments of the population. To achieve this aim, acrylamide has been added to the list of substances of concern to be investigated in the HBM4EU project, a European initiative to obtain biomonitoring data for a number of pollutants highly relevant for public health. This report summarizes the results obtained for acrylamide, with a focus on time-trends and recent exposure levels, obtained by HBM4EU as well as by associated studies in a total of seven European countries. Mean biomarker levels were compared by sampling year and time-trends were analyzed using linear regression models and an adequate statistical test. An increasing trend of acrylamide biomarker concentrations was found in children for the years 2014–2017, while in adults an overall increase in exposure was found to be not significant for the time period of observation (2000–2021). For smokers, represented by two studies and sampling for, over a total three years, no clear tendency was observed. In conclusion, samples from European countries indicate that average acrylamide exposure still exceeds suggested benchmark levels and may be of specific concern in children. More research is required to confirm trends of declining values observed in most recent years.
- A Tiered Approach for Assessing Individual and Combined Risk of Pyrethroids Using Human Biomonitoring DataPublication . Tarazona, Jose; Cattaneo, Irene; Niemann, Lars; Pedraza-Diaz, Susana; González-Caballero, MCarmen; Alba-Gonzalez, Mercedes de; Cañas, Ana; Domínguez-Morueco, Noelia; Esteban, Marta; Castano, Argelia; Borges, Teresa; Katsonouri, Andromachi; Makris, Konstantinos C.; Ottenbros, Ilse; Mol, Hans; De Decker, Annelies; Morrens, Bert; Berman, Tamar; Barnett-Itzhaki, Zohar; Probst-Hensch, Nicole; Fuhrimann, Samuel; Snoj Tratnik, Janja; Horvat, Milena; RAMBAUD, Loic; RIOU, Margaux; Schoeters, Greta; Govarts, Eva; Kolossa-Gehring, Marike; Weber, Till; Apel, Petra; Namorado, Sónia; Santonen, TiinaPyrethroids are a major insecticide class, suitable for biomonitoring in humans. Due to similarities in structure and metabolic pathways, urinary metabolites are common to various active substances. A tiered approach is proposed for risk assessment. Tier I was a conservative screening for overall pyrethroid exposure, based on phenoxybenzoic acid metabolites. Subsequently, probabilistic approaches and more specific metabolites were used for refining the risk estimates. Exposure was based on 95th percentiles from HBM4EU aligned studies (2014–2021) covering children in Belgium, Cyprus, France, Israel, Slovenia, and The Netherlands and adults in France, Germany, Israel, and Switzerland. In all children populations, the 95th percentiles for 3-phenoxybenzoic acid (3-PBA) exceeded the screening value. The probabilistic refinement quantified the risk level of the most exposed population (Belgium) at 2% or between 1–0.1% depending on the assumptions. In the substance specific assessments, the 95th percentiles of urinary concentrations in the aligned studies were well below the respective human biomonitoring guidance values (HBM-GVs). Both information sets were combined for refining the combined risk. Overall, the HBM data suggest a low health concern, at population level, related to pyrethroid exposure for the populations covered by the studies, even though a potential risk for highly exposed children cannot be completely excluded. The proposed tiered approach, including a screening step and several refinement options, seems to be a promising tool of scientific and regulatory value in future.
- Climatic and Physiographic Variables to Evaluate Culex pipiens s.l. Risk and HabitatPublication . Proença, M. da Conceição; Alves, Maria João; Rebelo, M.T.Using a geographic information system (GIS), the relations between a georeferenced data set of Culex pipiens s.l . collected in Portugal mainland during seven years (2006-2012) and meteorological and physiographic parameters are evaluated. This work is one of the results of a long-term surveillance program of pernicious insects that act as vectors of various diseases; its focus is on the possibility of prevention that can be achieved with abundance data. The focus on Culex pipiens is justified by its abundance and its competence as a vector for numerous health issues. The cumulative distribution of monthly captures by each meteorological parameter allows to compute thresholds corresponding to mosquito massive presence related to 90% of the captures. Using the weather parameters measured in the network of weather stations across the country, a monthly average of each parameter of interest (temperature, humidity, etc.) is computed and an interpolation of the results is made to produce raster maps corresponding to each month. The previously obtained thresholds are applied to each map, producing spatial masks with the relevant zones for each parameter. The intersection of the various masks for each month shows the most densely populated area of Culex, and the ensemble allows us to observe the evolution of mosquito presence through the critical season, which is from May to October at these latitudes. In parallel, mosquito abundance data are related to physiographic parameters. The relative distribution of female mosquitoes across land cover types in each month allows identifying which classes and seasons are most relevant. Orthometric altitude related to the presence of 90% of the catches shows the limits reached by mosquitoes in each month. The results are applied to the previously obtained climate envelopes, delimiting critical areas where the level of risk of transmission of the pathogens for which Culex pipiens is a competent vector is high and countermeasures should be concentrated, allowing its planning, and targeting on a monthly basis. The described procedure can be used with other relevant vectors in any region of the world, whenever abundance data is available.
- Vaccines against Neisseria meningitidis serogroup B strains – What does genomics reveal on the Portuguese strain’s coveragePublication . Bettencourt, Célia; Nogueira, Paulo; Gomes, João Paulo; Simões, Maria JoãoIn Portugal, Neisseria meningitidis serogroup B (MenB) is the most common serogroup causing invasive meningococcal disease. To protect against MenB disease two protein based MenB vaccines are available in Portugal, the 4CMenB that was licenced in 2014 and included in the routine immunization program in October 2020, and the bivalent rLP2086 vaccine licensed in 2017. The aim of this study was to predict the coverage of the 4CMenB and rLP2086 vaccines against Portuguese isolates of Neisseria meningitidis sampled between 2012 and 2019 and to evaluate the diversity of vaccine antigens based on genomic analysis. Whole-genome sequence data from 324 Portuguese Neisseria meningitidis isolates were analysed. To predict strain coverage by 4CMenB and rLP2086, vaccine antigen reactivity was assessed using the MenDeVar index available on the PubMLST Neisseria website. This study included 235 (75.6%) MenB isolates of all invasive MenB strains reported between 2012 and 2019. Moreover, 89 non MenB isolates sampled in the same period, enrolling 68 from invasive disease and 21 from healthy carriers, were also studied. The predicted strain coverage of MenB isolates was 73.5% (95% CI: 64.8%-81.2%) for 4CMenB and 100% for rLP2086. Predicted strain coverage by 4CMenB in the age group from 0 to 4 years old, was 73.9%. Most of MenB isolates were covered by a single antigen (85.4%), namely fHbp (30.3%), P1.4 (29.2%), and NHBA (24.7%). In Portugal, the most prevalent peptides in MenB isolates were: P1.4 (16.2%), NHBA peptide 2 (14.0%), and fHbp peptide 14 (7.2%), from 4CMenB and fHbp peptide 19 (10.6%) from rLP2086. No significant temporal trends were observed concerning the distribution and diversity of vaccine antigen variants. 4CMenB and rLP2086 vaccines showed potential coverage for isolates regardless serogroup. The use of both vaccines should be considered to control possible outbreaks caused by serogroups with no vaccine available.
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