Emerging organic contaminants in aquatic environments: state-of-the-art and recent scientific contributions

Els contaminants emergents són contaminants prèviament desconeguts o no reconeguts com a tals, la presència dels quals en el medi ambient no és necessàriament nova, però sí la preocupació pels possibles efectes perillosos sobre la salut humana i la dels ecosistemes. A causa de llur recent descobriment o reconeixement com a contaminants, la informació que se'n disposa sobre la presència, el destí i la toxicitat en ambients aquàtics, i sobre els mètodes analítics per a detectar- los en diverses matrius ambientals és escassa. En els darrers anys, el grup liderat pel professor d'investigació Damià Barceló Cullerès ha participat intensament en l'estudi de nombroses classes de contaminants emergents (estrògens, fàrmacs, drogues, nanopartícules, plaguicides polars, etc.). Aquest article repassa les contribucions més recents fetes pel grup en aquest camp dels contaminants emergents en les línies de desenvolupament de mètodes analítics, programes de vigilància ambiental i estudis de biodisponibilitat, degradació i toxicitat.Emerging contaminants are previously unknown or unrecognized contaminants whose presence in the environment is not necessarily new but which raise concern due to their potentially dangerous effects on the ecosystem and on human health. Due to their recent discovery or recognition as contaminants, information about the occurrence, fate, and toxicity of these compounds in the aquatic environment, as well as analytical methods for their detection in various environmental matrices, is scarce. We have intensively studied many of these classes of emerging contaminants (estrogens, pharmaceuticals, illicit drugs, nanoparticles, polar pesticides, etc.). This article reviews the most recent contributions made by our group to the field of emerging contaminants with respect to the development of analytical methods, monitoring studies, and bioavailability, degradation, and toxicity studies

Peptide-mediated Interference of TIR Domain Dimerization in MyD88 Inhibits Interleukin-1-dependent Activation of NF-κB *

Myeloid differentiation factor 88 (MyD88) plays a crucial role in the signaling pathways triggered by interleukin (IL)-1 and Toll-like receptors in several steps of innate host defense. A crucial event in this signaling pathway is represented by dimerization of MyD88, which allows the recruitment of downstream kinases like IRAK-1 and IRAK-4. Herein, we have investigated the function of the Toll/IL-1 receptor (TIR) domain in MyD88 homodimerization in cell-free and in vitro experimental settings by using epta-peptides that mimic the BB-loop region of the conserved TIR domain of different proteins. By using a pull-down assay with purified glutathione S-transferase-MyD88 TIR or co-immunoprecipitation experiments, we found that epta-peptides derived from the TIR domain of MyD88 and IL-18R are the most effective in inhibiting homodimerization with either the isolated TIR or full-length MyD88. Moreover, we demonstrated that a cell permeable analog of MyD88 epta-peptide inhibits homodimerization of MyD88 TIR domains in an in vitro cell system and significantly reduces IL-1 signaling, as assayed by activation of the downstream transcription factor NF-kappaB. Our results indicate that the BB-loop in TIR domain of MyD88 is a good target for specific inhibition of MyD88-mediated signaling in vivo

HDV can constrain HBV genetic evolution in hbsag: Implications for the identification of innovative pharmacological targets

Chronic HBV + HDV infection is associated with greater risk of liver fibrosis, earlier hepatic decompensation, and liver cirrhosis hepatocellular carcinoma compared to HBV mono-infection. However, to-date no direct anti-HDV drugs are available in clinical practice. Here, we identified conserved and variable regions in HBsAg and HDAg domains in HBV + HDV infection, a critical finding for the design of innovative therapeutic agents. The extent of amino-acid variability was measured by Shannon-Entropy (Sn) in HBsAg genotype-D sequences from 31 HBV + HDV infected and 62 HBV mono-infected patients (comparable for demographics and virological-parameters), and in 47 HDAg genotype-1 sequences. Positions with Sn = 0 were defined as conserved. The percentage of conserved HBsAg-positions was significantly higher in HBV + HDV infection than HBV mono-infection (p = 0.001). Results were confirmed after stratification for HBeAg-status and patients’ age. A Sn = 0 at specific positions in the C-terminus HBsAg were correlated with higher HDV-RNA, suggesting that conservation of these positions can preserve HDV-fitness. Conversely, HDAg was characterized by a lower percentage of conserved-residues than HBsAg (p < 0.001), indicating higher functional plasticity. Furthermore, specific HDAg-mutations were significantly correlated with higher HDV-RNA, suggesting a role in conferring HDV replicative-advantage. Among HDAg-domains, only the virus-assembly signal exhibited a high genetic conservation (75% of conserved-residues). In conclusion, HDV can constrain HBsAg genetic evolution to preserve its fitness. The identification of conserved regions in HDAg poses the basis for designing innovative targets against HDV-infection

The atypical kinase RIOK1 promotes tumor growth and invasive behavior

Despite being overexpressed in different tumor entities, RIO kinases are hardly characterized in mammalian cells. We investigated the role of these atypical kinases in different cancer cells. Using isogenic colon-, breast- and lung cancer cell lines, we demonstrate that knockdown of RIOK1, but not of RIOK2 or RIOK3, strongly impairs proliferation and invasiveness in conventional and 3D culture systems. Interestingly, these effects were mainly observed in RAS mutant cancer cells. In contrast, growth of RAS wildtype Caco-2 and Bcr-Abl-driven K562 cells is not affected by RIOK1 knockdown, suggesting a specific requirement for RIOK1 in the context of oncogenic RAS signaling. Furthermore, we show that RIOK1 activates NF-κB signaling and promotes cell cycle progression. Using proteomics, we identified the pro-invasive proteins Metadherin and Stathmin1 to be regulated by RIOK1. Additionally, we demonstrate that RIOK1 promotes lung colonization in vivo and that RIOK1 is overexpressed in different subtypes of human lung- and breast cancer. Altogether, our data suggest RIOK1 as a potential therapeutic target, especially in RAS-driven cancers

Transcriptomic, biochemical and individual markers in transplanted Daphnia magna to characterize impacts in the field.

Daphnia magna individuals were transplanted across 12 sites from three Spanish river basins (Llobregat, Ebro, Jucar) showing different sources of pollution. Gene transcription, feeding and biochemical responses in the field were assessed and compared with those obtained in re-constituted water treatments spiked with organic eluates obtained from water samples collected at the same locations and sampling periods. Up to 166 trace contaminants were detected in water and classified by their mode of action into 45 groups that included metals, pharmaceuticals, pesticides, illicit drugs, and other industrial compounds. Physicochemical water parameters differentiated the three river basins with Llobregat having the highest levels of conductivity, metals and pharmaceuticals, followed by Ebro, whereas the Jucar river had the greatest levels of illicit drugs. D. magna grazing rates and cholinesterase activity responded similarly than the diversity of riparian benthic communities. Transcription patterns of 13 different genes encoding for general stress, metabolism and energy processes, molting and xenobiotic transporters corroborate phenotypic responses differentiated sites within and across river basins. Principal Component Analysis and Partial Least Square Projections to Latent Structures regression analyses indicated that measured in situ responses of most genes and biomarkers and that of benthic macroinvertebrate diversity indexes were affected by distinct environmental factors. Conductivity, suspended solids and fungicides were negatively related with the diversity of macroinvertebrates cholinesterase, and feeding responses. Gene transcripts of heat shock protein and metallothionein were positively related with 11 classes of organic contaminants and 6 metals. Gene transcripts related with signaling paths of molting and reproduction, sugar, protein and xenobiotic metabolism responded similarly in field and lab exposures and were related with high residue concentrations of analgesics, diuretics, psychiatric drugs, β blockers, illicit drugs, trizoles, bisphenol A, caffeine and pesticides. These results indicate that application of omic technologies in the field is a promising subject in water management

Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Enterobacterales Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study)

Background. Few data are reported in the literature about the outcome of patients with severe extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) infections treated with ceftolozane/tazobactam (C/T), in empiric or definitive therapy.Methods. A multicenter retrospective study was performed in Italy (June 2016-June 2019). Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to ESBL-E infection and lack of microbiological evidence of infection. The primary end point was to identify predictors of clinical failure of C/T therapy.Results. C/T treatment was documented in 153 patients: pneumonia was the most common diagnosis (n = 46, 30%), followed by 34 cases of complicated urinary tract infections (22.2%). Septic shock was observed in 42 (27.5%) patients. C/T was used as empiric therapy in 46 (30%) patients and as monotherapy in 127 (83%) patients. Favorable clinical outcome was observed in 128 (83.7%) patients; 25 patients were considered to have failed C/T therapy. Overall, 30-day mortality was reported for 15 (9.8%) patients. At multivariate analysis, Charlson comorbidity index &gt;4 (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-3.5; P = .02), septic shock (OR, 6.2; 95% CI, 3.8-7.9; P &lt; .001), and continuous renal replacement therapy (OR, 3.1; 95% CI, 1.9-5.3; P = .001) were independently associated with clinical failure, whereas empiric therapy displaying in vitro activity (OR, 0.12; 95% CI, 0.01-0.34; P &lt; .001) and adequate source control of infection (OR, 0.42; 95% CI, 0.14-0.55; P &lt; .001) were associated with clinical success.Conclusions. Data show that C/T could be a valid option in empiric and/or targeted therapy in patients with severe infections caused by ESBL-producing Enterobacterales. Clinicians should be aware of the risk of clinical failure with standard-dose C/T therapy in septic patients receiving CRRT

Occurrence of pharmaceutical, recreational and psychotropic drug residues in surface water on the northern Antarctic Peninsula region

Human presence in the Antarctic is increasing due to research activities and the rise in tourism. These activities contribute a number of potentially hazardous substances. The aim of this study is to conduct the first characterisation of the pharmaceuticals and recreational drugs present in the northern Antarctic Peninsula region, and to assess the potential environmental risk they pose to the environment. The study consisted of a single sampling of ten water samples from different sources, including streams, ponds, glacier drains, and a wastewater discharge into the sea. Twenty-five selected pharmaceuticals and 21 recreational drugs were analysed. The highest concentrations were found for the analgesics acetaminophen (48.74 μg L−1), diclofenac (15.09 μg L−1) and ibuprofen (10.05 μg L−1), and for the stimulant caffeine (71.33 μg L−1). All these substances were detected in waters that were discharged directly into the ocean without any prior purification processes. The hazard quotient (HQ) values for ibuprofen, diclofenac and acetaminophen were far in excess of 10 at several sampling points. The concentrations of each substance measured and used as measured environmental concentration values for the HQ calculations are based on a one-time sampling. The Toxic Unit values indicate that analgesics and anti-inflammatories are the therapeutic group responsible for the highest toxic burden. This study is the first to analyse a wide range of substances and to determine the presence of pharmaceuticals and psychotropic drugs in the Antarctic Peninsula region. We believe it can serve as a starting point to focus attention on the need for continued environmental monitoring of these substances in the water cycle, especially in protected regions such as the Antarctic. This will determine whether pharmaceuticals and recreational drugs are hazardous to the environment and, if so, can be used as the basis for risk-assessment studies to prioritise the exposure to risk.Research Group and Teaching in Environmental Toxicology and Risk Assessment, Universidad Rey Juan Carlos, EspañaInstituto Geológico y Minero de España, EspañaWater and Soil Quality Research Group, Instituto de Diagnóstico Ambiental y Estudios del Agua, EspañaWater and Soil Quality Research Group, Consejo Superior de Investigaciones Científicas, EspañaInstitut Català de Recerca de l'Aigua, Parc Científic i Tecnològic de la Universitat de Girona, EspañaDepartamento de Geología y Geoquímica, Universidad Autónoma de Madrid, EspañaInstituto Nacional de Agua, ArgentinaDepartamento de Biología y Geología, Universidad Rey Juan Carlos, EspañaDepartamento de Medicina y Cirugía, Psicología, Medicina Preventiva y Salud Pública y Microbiología e Inmunología Médica, Universidad Rey Juan Carlos, Españ

Efficacy and safety of reparixin in patients with severe covid-19 Pneumonia. A phase 3, randomized, double-blind placebo-controlled study

Introduction: Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia. Methods: In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200&nbsp;mg three times daily or placebo for up to 21&nbsp;days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28. Results: Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment. Conclusions: This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated. Trial registration: ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51

Comparative measurement and quantitative risk assessment of alcohol consumption through wastewater-based epidemiology: An international study in 20 cities

Quantitative measurement of drug consumption biomarkers in wastewater can provide objective information on community drug use patterns and trends. This study presents the measurement of alcohol consumption in 20 cities across 11 countries through the use of wastewater-based epidemiology (WBE), and reports the application of these data for the risk assessment of alcohol on a population scale using the margin of exposure (MOE) approach. Raw 24-h composite wastewater samples were collected over a one-week period from 20 cities following a common protocol. For each sample a specific and stable alcohol consumption biomarker, ethyl sulfate (EtS) was determined by liquid chromatography coupled to tandem mass spectrometry. The EtS concentrations were used for estimation of per capita alcohol consumption in each city, which was further compared with international reports and applied for risk assessment by MOE. The average per capita consumption in 20 cities ranged between 6.4 and 44.3. L/day/1000 inhabitants. An increase in alcohol consumption during the weekend occurred in all cities, however the level of this increase was found to differ. In contrast to conventional data (sales statistics and interviews), WBE revealed geographical differences in the level and pattern of actual alcohol consumption at an inter-city level. All the sampled cities were in the "high risk" category (MOE

Preliminary Assessment of Radiolysis for the Cooling Water System in the Rotating Target of {SORGENTINA}-{RF}

The SORGENTINA-RF project aims at developing a 14 MeV fusion neutron source featuring an emission rate in the order of 5-7 x 10(13) s(-1). The plant relies on a metallic water-cooled rotating target and a deuterium (50%) and tritium (50%) ion beam. Beyond the main focus of medical radioisotope production, the source may represent a multi-purpose neutron facility by implementing a series of neutron-based techniques. Among the different engineering and technological issues to be addressed, the production of incondensable gases and corrosion product into the rotating target deserves a dedicated investigation. In this study, a preliminary analysis is carried out, considering the general layout of the target and the present choice of the target material