Using Chemical Modeling to Asses Water Quality in the Raigón Aquifer System in Southern Uruguay

The Raigón aquifer is an important groundwater system in southern Uruguay. The increasing use of groundwater resources in the last decades has provoked changes in the concentration of many elements which are strongly related to anthropogenic pollution sources. Concentration levels are useful to detect changes in reservoir status but it is also necessary to analyze their chemical significance in order to make an accurate assessment of the sources of contamination and the causes of changes. In this work we use the available thermodynamic data to calculate chemical speciation on these groundwater samples. Trace elements present as anions, in particular Se and Mo, are especially focused to show the chemical modeling possibilities. Both elements form anionic species, predominantly MoO42- and SeO42-. Results show that these anions interact in solution and are greatly influenced by the concentration of the abundant calcium ion. Localized changes in pH can strongly affect the situation. The same is observed with the pE parameter, but only in the case of Se. Chemical speciation of trace elements is in general highly dependent on pH, pE and concentration of major elements. In consequence, for a fixed analytical total concentration, these parameters can markedly change the situation, affecting the mobility, the bioavailability and environmental fate of these elements. The strategy employed in this work can also be extended to the study of many other environmental water scenarios.The authors are grateful to CSIC (Programa de Apoyo a Grupos) and ANII (Project FCE_2011_6491), Uruguayan organizations, for financial support.Peer Reviewe

Using Chemical Modeling to Asses Water Quality in the Raigón Aquifer System in Southern Uruguay

The Raigón aquifer is an important groundwater system in southern Uruguay. The increasing use of groundwater resources in the last decades has provoked changes in the concentration of many elements which are strongly related to anthropogenic pollution sources. Concentration levels are useful to detect changes in reservoir status but it is also necessary to analyze their chemical significance in order to make an accurate assessment of the sources of contamination and the causes of changes. In this work we use the available thermodynamic data to calculate chemical speciation on these groundwater samples. Trace elements present as anions, in particular Se and Mo, are especially focused to show the chemical modeling possibilities. Both elements form anionic species, predominantly MoO42- and SeO42-. Results show that these anions interact in solution and are greatly influenced by the concentration of the abundant calcium ion. Localized changes in pH can strongly affect the situation. The same is observed with the pE parameter, but only in the case of Se. Chemical speciation of trace elements is in general highly dependent on pH, pE and concentration of major elements. In consequence, for a fixed analytical total concentration, these parameters can markedly change the situation, affecting the mobility, the bioavailability and environmental fate of these elements. The strategy employed in this work can also be extended to the study of many other environmental water scenarios

A novel nonsense mutation of EXT1 gene in an Argentinian patient with Multiple Hereditary Exostoses

Multiple hereditary exostoses (MHE), also known as multiple osteochondromatosis, is an autosomal-dominant O-linked glycosylation disorder recently classified as EXT1/EXT2-CDG in the congenital disorder of glycosylation (CDG)nomenclature. MHE is characterized by the presence of multiple cartilage-capped tumors,called “osteochondromas,” which usually develop in the juxta-epiphyseal regions of the long bones. The prevalence of MHE is estimated at 1:50,000 in the general population1,2. The Online Mendelian Inheritance in Man (OMIM) database classified it as either 133700 or 133701, according to whether the mutations occurred in the EXT1 or the EXT2 gene. These genes are located at 8q24 and 11p11-11p12, respectively, and they encode the copolymerases responsible for heparan sulfate biosynthesis. EXT1 and EXT2 are tumor suppressor genes of the EXT gene family. The EXT1 gene contains eleven exons with a coding region of 2238 base pairs (bp), and the EXT2 gene contains sixteen exons with a coding region of 2154 bp3-6. These genes encode two glycosyltransferases involved in heparan sulphate biosynthesis, exostosin-1 (EXT1) (EC2.4.1.224)and exostosin-2 (EXT2) (EC2.4.1.225), whose impairment leads to the formation of exostoses4,7-9. Inactivating mutations (nonsense, frameshift, and splice site mutations) in EXT1 and EXT2 genes represent the majority of mutations that cause MHE. An overview of the reported variants is provided by the online Multiple Osteochondroma Mutation Database10. The most important complication of MHE is the malignant transformation of osteochondroma to chondrosarcoma, which is estimated to occur in 0.5% to 5% of patients6. Chondrosarcomas arise de novo (primary) or as a result of a preexistingcartilage lesion (secondary). The biological aggressiveness of chondrosarcomas can be predicted by means of a histological grading system (grade I to grade III), based on three parameters: cellularity, degree of nuclear atypia, and mitotic activity11,12.In our case report, we investigated the clinical, radiographic, and genetic aspects of a patient with MHE with a severe phenotype and malignant transformation to chondrosarcoma.Fil: Delgado, María Andrea. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; ArgentinaFil: Sarrión, Patricia. Universidad de Barcelona; EspañaFil: Azar, Nydia Beatríz. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; ArgentinaFil: Zecchini, Lorena del Valle. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; ArgentinaFil: Robledo, Hector Hugo. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; ArgentinaFil: Segura, Florencio Vicente. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; ArgentinaFil: Balcells, Susana. Universidad de Barcelona; EspañaFil: Grinberg Vaisman, Daniel Raúl. Universidad de Barcelona; EspañaFil: Dodelson de Kremer, Raquel. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; ArgentinaFil: Asteggiano, Carla Gabriela. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba; Argentina. Universidad Católica de Córdoba; Argentin

The European antibody network's practical guide to finding and validating suitable antibodies for research

[EN]Antibodies are widely exploited as research/diagnostic tools and therapeutics. Despite providing exciting research opportunities, the multitude of available antibodies also offers a bewildering array of choice. Importantly, not all companies comply with the highest standards, and thus many reagents fail basic validation tests. The responsibility for antibodies being fit for purpose rests, surprisingly, with their user. This paper condenses the extensive experience of the European Monoclonal Antibody Network to help researchers identify antibodies specific for their target antigen. A stepwise strategy is provided for prioritising antibodies and making informed decisions regarding further essential validation requirements. Web-based antibody validation guides provide practical approaches for testing antibody activity and specificity. We aim to enable researchers with little or no prior experience of antibody characterization to understand how to determine the suitability of their antibody for its intended purpose, enabling both time and cost effective generation of high quality antibody-based data fit for publication.SIOur research has been supported by funding from Cancer Research UK (Program A10702 to A.H.B) and Bloodwise (Program 13047 to A.H.B). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Center based at Oxford University Hospitals NHS Trust and University of Oxford. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Grant No 310/6 from the Deutsche Forschungsgemeinschaft to F.K.-N. Grants from the Instituto de Salud Carlos III (PI14/00703, PN de I+D+I 2013-2016) and the CSIC (201320E109 and 201420E109) to L.K. laboratory. Grants of the Spanish Ministry of Health (Fondo de Investigaciones Sanitarias, PI10/01039), Department of Education of Castilla and León Regional Government (Grant# LE007A10–2) and Mutua Madrileña Foundation (Basic research grants 2012) to J.I.R.B. This work was supported by a grant from the Dutch government to the Netherlands Institute for Regenerative Medicine (NIRM, grant No. FES0908)

Llama-Derived Single Domain Antibodies to Build Multivalent, Superpotent and Broadened Neutralizing Anti-Viral Molecules

For efficient prevention of viral infections and cross protection, simultaneous targeting of multiple viral epitopes is a powerful strategy. Llama heavy chain antibody fragments (VHH) against the trimeric envelope proteins of Respiratory Syncytial Virus (Fusion protein), Rabies virus (Glycoprotein) and H5N1 Influenza (Hemagglutinin 5) were selected from llama derived immune libraries by phage display. Neutralizing VHH recognizing different epitopes in the receptor binding sites on the spikes with affinities in the low nanomolar range were identified for all the three viruses by viral neutralization assays. By fusion of VHH with variable linker lengths, multimeric constructs were made that improved neutralization potencies up to 4,000-fold for RSV, 1,500-fold for Rabies virus and 75-fold for Influenza H5N1. The potencies of the VHH constructs were similar or better than best performing monoclonal antibodies. The cross protection capacity against different viral strains was also improved for all three viruses, both by multivalent (two or three identical VHH) and biparatopic (two different VHH) constructs. By combining a VHH neutralizing RSV subtype A, but not subtype B with a poorly neutralizing VHH with high affinity for subtype B, a biparatopic construct was made with low nanomolar neutralizing potency against both subtypes. Trivalent anti-H5N1 VHH neutralized both Influenza H5N1 clade1 and 2 in a pseudotype assay and was very potent in neutralizing the NIBRG-14 Influenza H5N1 strain with IC50 of 9 picomolar. Bivalent and biparatopic constructs against Rabies virus cross neutralized both 10 different Genotype 1 strains and Genotype 5. The results show that multimerization of VHH fragments targeting multiple epitopes on a viral trimeric spike protein is a powerful tool for anti-viral therapy to achieve "best-in-class" and broader neutralization capacity

Preventing Phosphorylation of Sterol Regulatory Element-Binding Protein 1a by MAP-Kinases Protects Mice from Fatty Liver and Visceral Obesity

The transcription factor sterol regulatory element binding protein (SREBP)-1a plays a pivotal role in lipid metabolism. Using the SREBP-1a expressing human hepatoma cell line HepG2 we have shown previously that human SREBP-1a is phosphorylated at serine 117 by ERK-mitogen-activated protein kinases (MAPK). Using a combination of cell biology and protein chemistry approach we show that SREBP-1a is also target of other MAPK-families, i.e. c-JUN N-terminal protein kinases (JNK) or p38 stress activated MAP kinases. Serine 117 is also the major phosphorylation site in SREBP-1a for JNK. In contrast to that the major phosphorylation sites of p38 MAPK family are serine 63 and threonine 426. Functional analyses reveal that phosphorylation of SREBP-1a does not alter protein/DNA interaction. The identified phosphorylation sites are specific for both kinase families also in cellular context. To provide direct evidence that phosphorylation of SREBP-1a is a regulatory principle of biological and clinical relevance, we generated transgenic mice expressing mature transcriptionally active N-terminal domain of human SREBP–1a variant lacking all identified phosphorylaton sites designed as alb-SREBP-1aΔP and wild type SREBP-1a designed as alb-SREBP-1a liver specific under control of the albumin promoter and a liver specific enhancer. In contrast to alb-SREBP–1a mice the phosphorylation–deficient mice develop no enlarged fatty livers under normocaloric conditions. Phenotypical examination reveales a massive accumulation of adipose tissue in alb-SREBP-1a but not in the phosphorylation deficient alb-SREBP-1aΔP mice. Moreover, preventing phosphorylation of SREBP-1a protects mice also from dyslipidemia. In conclusion, phosphorylation of SREBP-1a by ERK, JNK and p38 MAPK-families resembles a biological principle and plays a significant role, in vivo

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Why Are Teachers Absent? Probing Service Delivery in Peruvian Primary Schools

A high rate of absence of teachers from their posts is a serious obstacle to delivery of education in many developing countries, but hard evidence on the problem has been scarce. This study, carried out as part of a new multi-country survey project, is the first systematic investigation in Peru into the extent and causes of teachers’ absence from schools. Data from our nationally representative survey of public primary schools, based on unannounced visits and direct observation of teachers, reveals that public school teachers in Peru are absent from their posts 11 percent of the time. While this overall absence rate is low compared with those of other survey countries, the absence rates in Peru’s poorest and remotest communities are much higher—16 and 21 percent, respectively. In our multivariate analysis of the causes of public school teacher absence, we identify several important variables that are associated with increased absence: poor working conditions, such as poorer communities and infrastructure; teachers with fewer ties to the school’s community; contract teaching; and, perhaps, an absence of private competition. By contrast, proxies for more vigorous top-down and bottom-up monitoring are not associated with lower absence. These results, together with the relatively high overall public school teacher attendance rates in an environment where financial incentives for performance are weak, suggest that non-pecuniary incentives are important determinants of teacher performance

Using Chemical Modeling to Asses Water Quality in the Raigón Aquifer System in Southern Uruguay

The Raigón aquifer is an important groundwater system in southern Uruguay. The increasing use of groundwater resources in the last decades has provoked changes in the concentration of many elements which are strongly related to anthropogenic pollution sources. Concentration levels are useful to detect changes in reservoir status but it is also necessary to analyze their chemical significance in order to make an accurate assessment of the sources of contamination and the causes of changes. In this work we use the available thermodynamic data to calculate chemical speciation on these groundwater samples. Trace elements present as anions, in particular Se and Mo, are especially focused to show the chemical modeling possibilities. Both elements form anionic species, predominantly MoO42- and SeO42-. Results show that these anions interact in solution and are greatly influenced by the concentration of the abundant calcium ion. Localized changes in pH can strongly affect the situation. The same is observed with the pE parameter, but only in the case of Se. Chemical speciation of trace elements is in general highly dependent on pH, pE and concentration of major elements. In consequence, for a fixed analytical total concentration, these parameters can markedly change the situation, affecting the mobility, the bioavailability and environmental fate of these elements. The strategy employed in this work can also be extended to the study of many other environmental water scenarios