A permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains

Resistance to antibiotics poses a major global threat according to the World Health Organization. Restoring the activity of existing drugs is an attractive alternative to address this challenge. One of the most efficient mechanisms of bacterial resistance involves the expression of efflux pump systems capable of expelling antibiotics from the cell. Although there are efflux pump inhibitors (EPIs) available, these molecules are toxic for humans. We hypothesized that permeability-increasing antimicrobial peptides (AMPs) could lower the amount of EPI necessary to sensitize bacteria to antibiotics that are efflux substrates. To test this hypothesis, we measured the ability of polymyxin B nonapeptide (PMBN), to synergize with antibiotics in the presence of EPIs. Assays were performed using planktonic and biofilm-forming cells of Pseudomonas aeruginosa strains overexpressing the MexAB-OprM efflux system. Synergy between PMBN and EPIs boosted azithromycin activity by a factor of 2,133 and sensitized P. aeruginosa to all tested antibiotics. This reduced several orders of magnitude the amount of inhibitor needed for antibiotic sensitization. The selected antibiotic-EPI-PMBN combination caused a 10 million-fold reduction in the viability of biofilm forming cells. We proved that AMPs can synergize with EPIs and that this phenomenon can be exploited to sensitize bacteria to antibiotics

Limitations of a commercial assay as diagnostic test of autoimmune encephalitis

Detection of neuronal surface antibodies (NSAb) is important for the diagnosis of autoimmune encephalitis (AE). Although most clinical laboratories use a commercial diagnostic kit (Euroimmun, Lübeck, Germany) based on indirect immunofluorescence on transfected cells (IIFA), clinical experience suggests diagnostic limitations. Here, we assessed the performance of the commercial IIFA in serum and CSF samples of patients with suspected AE previously examined by rat brain immunohistochemistry (Cohort A). Of 6213 samples, 404 (6.5%) showed brain immunostaining suggestive of NSAb: 163 (40%) were positive by commercial IIFA and 241 (60%) were negative. When these 241 samples were re-assessed with in-house IIFA, 42 (18%) were positive: 21 (9%) had NSAb against antigens not included in the commercial IIFA and the other 21 (9%) had NSAb against antigens included in the commercial kit (false negative results). False negative results occurred more frequently with CSF (29% vs 10% in serum) and predominantly affected GABABR (39%), LGI1 (17%) and AMPAR (11%) antibodies. Results were reproduced in a separate cohort (B) of 54 AE patients with LGI1, GABABR or AMPAR antibodies in CSF which were missed in 30% by commercial IIFA. Patients with discordant GABABR antibody results (positive in-house but negative commercial IIFA) were less likely to develop full-blown clinical syndrome; no significant clinical differences were noted for the other antibodies. Overall, NSAb testing by commercial IIFA led to false negative results in a substantial number of patients, mainly those affected by anti-LG1, GABABR or AMPAR encephalitis. If these disorders are suspected and commercial IIFA is negative, more comprehensive antibody studies are recommende

Niveles plasmáticos de calcio, magnesio y fósforo en rodeos lecheros del Valle de Lerma, Salta, Argentina

La cuenca lechera del Valle de Lerma representa una de las economías regionales más relevantes para la provincia de Salta. Si bien es conocida la importancia que tienen macrominerales como calcio (Ca), fósforo (P) y magnesio (Mg) sobre la producción y la salud de los rodeos lecheros, se desconoce la prevalencia de sus desequilibrios. Con el propósito de conocer estos datos se muestrearon 584 vacas de 4 tambos del Valle de Lerma, en 4 oportunidades y a intervalos de 3 a 4 meses entre sí. En cada visita se sangraron por punción yugular entre 9 y 10 animales de cada categoría: preparto, vaca fresca, 2.º tercio de lactancia y 3.º tercio de lactancia. Se determinaron los valores de Ca y Mg sérico por espectrofotometría de absorción atómica y P por espectrofotometría UV-visible. Para los análisis estadísticos los valores de referencia para considerar hipocalcemia clínica y subclínica fueron 6,18 mg/dl respectivamente. Las asociaciones entre variables fueron analizadas mediante correlación lineal (Pearson) y regresión lineal simple, además de analizar la probabilidad de ocurrencia de hipocalcemia mediante odds ratio. Las diferencias entre variables y periodos de lactancia se examinaron mediante los análisis de varianza y test de Tukey y de chi cuadrado usando el test de Fisher. La media del Ca sérico fue de 8,85 mg/dl, sin hallarse diferencias entre periodos de lactancia. La prevalencia media de hipocalcemia fue del 46,2% en todos los periodos productivos. La media del Mg sérico fue de 2,26%, con una prevalencia de hipomagnesemia del 10,6% y una mayor proporción de vacas hipomagnesémicas al preparto. Los animales con hipomagnesemia presentaron una probabilidad 3,5 veces mayores de sufrir hipocalcemia respecto a aquellos con valores normales. La prevalencia de animales con valores anormales de P fue elevada (48,3%), y si bien no se asociaron con los niveles de hipocalcemia, demostraron que el excesivo aporte dietario representa un riesgo sanitario y también medioambiental. En virtud a los resultados obtenidos en el presente trabajo se advierte de los riesgos potenciales de desequilibrios de Ca, Mg y P en los rodeos lecheros del Valle de Lerma.The dairy production of the Lerma Valley is one of the most relevant regional economies of the province of Salta. In order to known imbalances prevalence of calcium (Ca), phosphorus (P) and magnesium (Mg), 584 dairy cows of 4 farms of basin Lerma Valley were sampled in 4 opportunities. At each visit were bled from the jugular vein of 9/10 animals in each category: prepartum, fresh cow, 2nd and 3rd third of lactation. Values Ca and Mg serum were obtained by atomic absorption spectrophotometry and P values by UV-visible spectrophotometry. Associations between variables were analyzed using linear correlation and linear regression, in addition to analyzing the probability of occurrence of hypocalcemia by odds ratio. Differences between variables and moment of lactation were examined by analysis of variance and Tukey’s test and Chi square using Fisher’s test. The mean serum Ca was 8.85 mg / dl, with no differences found all over the periods. The average prevalence of hypocalcemia was 46.2% in all production periods. The mean serum Mg was 2.26%, with a prevalence of 10.6% hypomagnesemia. Animals with hypomagnesemic had a 3.5 times greater chance of having hypocalcemia compared to those with normal values. The prevalence of animals with abnormal values of P was high (48.3%), without association with hypocalcemia levels. Pursuant to the results obtained in this study are warned of the potential risks of imbalances Ca, Mg and P in the dairy herds Lerma Valley.EEA SaltaFil: Martinez,Gabriela Marcela. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Salta; ArgentinaFil: Micheloud, Juan Francisco. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Animal Chaco Semiarido. Grupo de Patología, Epidemiología e Investigación Diagnóstica-Área de Sanidad Animal; ArgentinaFil: Suarez, Victor Humberto. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Animal Chaco Semiarido. Grupo de Patología, Epidemiología e Investigación Diagnóstica-Área de Sanidad Animal; ArgentinaFil: Rosa, D.E. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Laboratorio de Nutrición Mineral; ArgentinaFil: Ventura, M.V. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Laboratorio de Nutrición Mineral; ArgentinaFil: Ortega, Adriana Elina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Salta; ArgentinaFil: Sánchez, C. Universidad Nacional de Salta. Facultad de Ciencias Naturales; ArgentinaFil: Mattioli, Guillermo Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Laboratorio de Nutrición Mineral; Argentin

Extra Virgin Olive Oil Contains a Phenolic Inhibitor of the Histone Demethylase LSD1/KDM1A

The lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a central epigenetic regulator of metabolic reprogramming in obesity-associated diseases, neurological disorders, and cancer. Here, we evaluated the ability of oleacein, a biophenol secoiridoid naturally present in extra virgin olive oil (EVOO), to target LSD1. Molecular docking and dynamic simulation approaches revealed that oleacein could target the binding site of the LSD1 cofactor flavin adenosine dinucleotide with high affinity and at low concentrations. At higher concentrations, oleacein was predicted to target the interaction of LSD1 with histone H3 and the LSD1 co-repressor (RCOR1/CoREST), likely disturbing the anchorage of LSD1 to chromatin. AlphaScreen-based in vitro assays confirmed the ability of oleacein to act as a direct inhibitor of recombinant LSD1, with an IC50 as low as 2.5 umol/L. Further, oleacein fully suppressed the expression of the transcription factor SOX2 (SEX determining Region Y-box 2) in cancer stem-like and induced pluripotent stem (iPS) cells, which specifically occurs under the control of an LSD1-targeted distal enhancer. Conversely, oleacein failed to modify ectopic SOX2 overexpression driven by a constitutive promoter. Overall, our findings provide the first evidence that EVOO contains a naturally occurring phenolic inhibitor of LSD1, and support the use of oleacein as a template to design new secoiridoid-based LSD1 inhibitors.Work in the Menendez laboratory is supported by the Spanish Ministry of Science and Innovation (Grant SAF2016-80639-P, Plan Nacional de l+D+I, founded by the European Regional Development Fund, Spain) and by an unrestricted research grant from the Fundació Oncolliga Girona (Lliga catalana d’ajuda al malalt de càncer, Girona). The Spanish Ministry of Economy and Competitiveness (MINECO, Project RTI2018-096724-B-C21) and the Generalitat Valenciana (PROMETEO/2016/006) supports work in the Encinar laborator

Machine learning methods applied to combined Raman and LIBS spectra: Implications for mineral discrimination in planetary missions

Producción CientíficaThe combined analysis of geological targets by complementary spectroscopic techniques could enhance the characterization of the mineral phases found on Mars. This is indeed the case with the SuperCam instrument onboard the Perseverance rover. In this framework, the present study seeks to evaluate and compare multiple machine learning techniques for the characterization of carbonate minerals based on Raman-LIBS (Laser-Induced Breakdown Spectroscopy) spectroscopic data. To do so, a Ca-Mg prediction curve was created by mixing hydromagnesite and calcite at different concentration ratios. After their characterization by Raman and LIBS spectroscopy, different multivariable machine learning (Gaussian process regression, support vector machines, ensembles of trees, and artificial neural networks) were used to predict the concentration ratio of each sample from their respective datasets. The results obtained by separately analyzing Raman and LIBS data were then compared to those obtained by combining them. By comparing their performance, this work demonstrates that mineral discrimination based on Gaussian and ensemble methods optimized the combine of Raman-LIBS dataset outperformed those ensured by Raman and LIBS data alone. This demonstrated that the fusion of data combination and machine learning is a promising approach to optimize the analysis of spectroscopic data returned from Mars.Agencia Estatal de Investigación, grant (PID2022-142490OB-C32)Ministerio de Economía y Competitividad (MINECO),Grant/Award Number (RDE2018-102600-T

Estudio para la implantación de Programas en Inglés en los títulos de grado de la ETSI Agrónomos de la Universidad Politécnica de Madrid

Universities are offering more and more courses and programmes in an additional language. At HEPCLIL, therefore, we would like to debate the methodological im - plications of these changes, giving voice to practical classroom experiences and initiatives. We would also like to act as a platform for cutting-edge research on CLIL in higher education. What impact does teaching in an additional language have on content or language learning? What are the effects on teachers and stu - dents in higher education

CSVS, a crowdsourcing database of the Spanish population genetic variability

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variabilityworldwide. CSVS is also part of the GA4GH Beacon network.Spanish Ministry of Economy and Competitiveness SAF2017-88908-R PT17/0009/0006 PI19/00321 CIBERER ACCI-06/07/0036 PI14-948 PI171659Regional Government of Madrid, RAREGenomicsCM B2017/BMD3721 B2017/BMD-3721European Union (EU)European Union (EU) 676559University Chair UAM-IIS-FJD of Genomic MedicineRamon Areces Foundatio

Incidence, clinical characteristics, risk factors and outcomes of meningoencephalitis in patients with COVID-19

We investigated the incidence, clinical characteristics, risk factors, and outcome of meningoencephalitis (ME) in patients with COVID-19 attending emergency departments (ED), before hospitalization. We retrospectively reviewed all COVID patients diagnosed with ME in 61 Spanish EDs (20% of Spanish EDs, COVID-ME) during the COVID pandemic. We formed two control groups: non-COVID patients with ME (non-COVID-ME) and COVID patients without ME (COVID-non-ME). Unadjusted comparisons between cases and controls were performed regarding 57 baseline and clinical characteristics and 4 outcomes. Cerebrospinal fluid (CSF) biochemical and serologic findings of COVID-ME and non-COVID-ME were also investigated. We identified 29 ME in 71,904 patients with COVID-19 attending EDs (0.40‰, 95%CI=0.27-0.58). This incidence was higher than that observed in non-COVID patients (150/1,358,134, 0.11‰, 95%CI=0.09-0.13; OR=3.65, 95%CI=2.45-5.44). With respect to non-COVID-ME, COVID-ME more frequently had dyspnea and chest X-ray abnormalities, and neck stiffness was less frequent (OR=0.3, 95%CI=0.1-0.9). In 69.0% of COVID-ME, CSF cells were predominantly lymphocytes, and SARS-CoV-2 antigen was detected by RT-PCR in 1 patient. The clinical characteristics associated with a higher risk of presenting ME in COVID patients were vomiting (OR=3.7, 95%CI=1.4-10.2), headache (OR=24.7, 95%CI=10.2-60.1), and altered mental status (OR=12.9, 95%CI=6.6-25.0). COVID-ME patients had a higher in-hospital mortality than non-COVID-ME patients (OR=2.26; 95%CI=1.04-4.48), and a higher need for hospitalization (OR=8.02; 95%CI=1.19-66.7) and intensive care admission (OR=5.89; 95%CI=3.12-11.14) than COVID-non-ME patients. ME is an unusual form of COVID presentation (<0.5‰ cases), but is more than 4-fold more frequent than in non-COVID patients attending the ED. As the majority of these MEs had lymphocytic predominance and in one patient SARS-CoV-2 antigen was detected in CSF, SARS-CoV-2 could be the cause of most of the cases observed. COVID-ME patients had a higher unadjusted in-hospital mortality than non-COVID-ME patients

Resource recovery from sulphate-rich sewage through an innovative anaerobic-based water resource recovery facility (WRRF)

[EN] This research work proposes an innovative water resource recovery facility (WRRF) for the recovery of energy, nutrients and reclaimed water from sewage, which represents a promising approach towards enhanced circular economy scenarios. To this aim, anaerobic technology, microalgae cultivation, and membrane technology were combined in a dedicated platform. The proposed platform produces a high-quality solid- and coliform-free effluent that can be directly discharged to receiving water bodies identified as sensitive areas. Specifically, the content of organic matter, nitrogen and phosphorus in the effluent was 45 mg COD.L-1 , 14.9 mg N.L-1 and 0.5 mg P.L-1 , respectively. Harvested solar energy and carbon dioxide biofixation in the form of microalgae biomass allowed remarkable methane yields (399 STP L CH 4.kg(-1) CODinf ) to be achieved, equivalent to theoretical electricity productions of around 0.52 kWh per m 3 of wastewater entering the WRRF. Furthermore, 26.6% of total nitrogen influent load was recovered as ammonium sulphate, while nitrogen and phosphorus were recovered in the biosolids produced (650 +/- 77 mg N.L-1 and 121.0 +/- 7.2 mg P.L-1).This research was supported by the Spanish Ministry of Economy and Competitiveness (MINECO, Projects CTM2014-54980-C2-1-R and CTM2014-54980-C2-2-R) jointly with the European Regional Development Fund (ERDF), which are gratefully acknowledged. This research was also supported by the Spanish Ministry of Education, Culture and Sport via two pre-doctoral FPU fellowships (FPU14/05082 and FPU15/02595) and by the Spanish Ministry of Economy and Competitiveness via two pre-doctoral FPI fellowships (BES-2015-071884, BES-2015-073403) and one Juan de la Cierva contract (FJCI-2014-21616). The authors would also like to acknowledge the support received from Generalitat Valenciana via two VALithornd post-doctoral grants (APOSTD/2014/049 and APOSTD/2016/104) and via the fellowships APOTI/2016/059 and CPI-16-155, as well as the financial aid received from the European Climate KIC association for the 'MAB 2.0' Project (APIN0057_ 2015-3.6-230_ P066-05) and Universitat Politecnica de Valencia via a pre-doctoral FPI fellowship to the seventh author.Seco Torrecillas, A.; Aparicio Antón, SE.; Gonzalez-Camejo, J.; Jiménez Benítez, AL.; Mateo-Llosa, O.; Mora-Sánchez, JF.; Noriega-Hevia, G.... (2018). Resource recovery from sulphate-rich sewage through an innovative anaerobic-based water resource recovery facility (WRRF). Water Science & Technology. 78(9):1925-1936. https://doi.org/10.2166/wst.2018.492S19251936789Bair, R. A., Ozcan, O. O., Calabria, J. L., Dick, G. H., & Yeh, D. H. (2015). 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Bioresource Technology, 102(19), 8799-8806. doi:10.1016/j.biortech.2011.07.014Giménez, J. B., Martí, N., Ferrer, J., & Seco, A. (2012). Methane recovery efficiency in a submerged anaerobic membrane bioreactor (SAnMBR) treating sulphate-rich urban wastewater: Evaluation of methane losses with the effluent. Bioresource Technology, 118, 67-72. doi:10.1016/j.biortech.2012.05.019Giménez, J. B., Bouzas, A., Carrere, H., Steyer, J.-P., Ferrer, J., & Seco, A. (2018). Assessment of cross-flow filtration as microalgae harvesting technique prior to anaerobic digestion: Evaluation of biomass integrity and energy demand. Bioresource Technology, 269, 188-194. doi:10.1016/j.biortech.2018.08.052González-Camejo, J., Serna-García, R., Viruela, A., Pachés, M., Durán, F., Robles, A., … Seco, A. (2017). Short and long-term experiments on the effect of sulphide on microalgae cultivation in tertiary sewage treatment. 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Designing an AnMBR-based WWTP for energy recovery from urban wastewater: The role of primary settling and anaerobic digestion. Separation and Purification Technology, 156, 132-139. doi:10.1016/j.seppur.2015.09.047Pretel, R., Robles, A., Ruano, M. V., Seco, A., & Ferrer, J. (2016). Economic and environmental sustainability of submerged anaerobic MBR-based (AnMBR-based) technology as compared to aerobic-based technologies for moderate-/high-loaded urban wastewater treatment. Journal of Environmental Management, 166, 45-54. doi:10.1016/j.jenvman.2015.10.004Sharma, B., Sarkar, A., Singh, P., & Singh, R. P. (2017). Agricultural utilization of biosolids: A review on potential effects on soil and plant grown. Waste Management, 64, 117-132. doi:10.1016/j.wasman.2017.03.002Sialve, B., Bernet, N., & Bernard, O. (2009). Anaerobic digestion of microalgae as a necessary step to make microalgal biodiesel sustainable. 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