Reverse Trojan-horse effect decreased wastewater toxicity in the presence of inorganic nanoparticles

We studied the toxicological interaction of 46 micropollutants from a biologically treated wastewater effluent in mixtures with silica, amine-modified silica, titanium dioxide and magnetite nanoparticles. The pollutants tracked in this work were polar pharmaceuticals belonging to different therapeutic groups, some of their metabolites and artificial sweeteners, the concentrations of which were mostly in the tens to hundreds of ng L-1 range. The results showed particularly high adsorption for furosemide, gemfibrozil and the aminopyrine metabolite 4FAA. There was preferential adsorption of the less polar compounds on the less polar nanoparticles. The total amounts of compounds adsorbed and quantified were 13.4, 4.8, 10.8 and 7.1 μg g-1 for SiO2, SiO2-NH2, TiO2 and Fe3O4, respectively. The toxicity of wastewater-nanoparticle mixtures was assessed using the bioluminescent cyanobacterium Anabaena sp. PCC 7120 CPB4337. The interactions were quantified by means of the combination index (CI)-isobologram method. The binary mixtures of wastewater with SiO2, SiO2-NH2 and TiO2 displayed antagonism for the lower affected fractions, which corresponded to the lower concentrations. For higher effects and for the Fe3O4 nanoparticles over the whole tested range, the mixtures were additive leading to synergism for the higher affected fractions. No internalization was observed. The results showed that the reduced toxicant bioavailability due to the interaction with nanoparticles is relevant for micropollutants at environmental concentrations. The amount of anthropogenic pollutants retained by metal oxide nanoparticles has significant toxicological effectsFinancial support was provided by FP7-ERA-Net Susfood, 2014/00153/001, the Spanish Ministry of Economy, CTM2013-45775-C2-1-R and CTM2013-45775-C2-2-R and the Dirección General de Universidades e Investigación de la Comunidad de Madrid, Network S2013/MAE-271

Case report: A novel case of parental mosaicism in SMC1A gene causes inherited Cornelia de Lange syndrome

Ultimate advances in genetic technologies have permitted the detection of transmitted cases of congenital diseases due to parental gonadosomatic mosaicism. Regarding Cornelia de Lange syndrome (CdLS), up to date, only a few cases are known to follow this inheritance pattern. However, the high prevalence of somatic mosaicism recently reported in this syndrome (∼13%), together with the disparity observed in tissue distribution of the causal variant, suggests that its prevalence in this disorder could be underestimated. Here, we report a new case of parental gonadosomatic mosaicism in SMC1A gene that causes inherited CdLS, in which the mother of the patient carries the causative variant in very low allele frequencies in buccal swab and blood. While the affected child presents with typical CdLS phenotype, his mother does not show any clinical manifestations. As regards SMC1A, the difficulty of clinical identification of carrier females has been already recognized, as well as the gender differences observed in CdLS expressivity when the causal variant is found in this gene. Currently, the use of DNA deep-sequencing techniques is highly recommended when it comes to molecular diagnosis of patients, as well as in co-segregation studies. These enable us to uncover gonadosomatic mosaic events in asymptomatic or oligosymptomatic parents that had been overlooked so far, which might have great implications regarding genetic counseling for recurrence risk

Nutrición enteral domiciliaria en España: registro Nadya del año 2011-2012

Objective: To describe the results of the home enteral nutrition (HEN) registry of the NADYA-SENPE group in 2011 and 2012. Material and methods: We retrieved the data of the patients recorded from January 1st 2011 to December 31st 2012. Results: There were 3021 patients in the registry during the period from 29 hospitals, which gives 65.39 per million inhabitants. 97.95% were adults, 51.4% male. Mean age was 67.64 ± 19.1, median age was 72 years for adults and 7 months for children. Median duration with HEN was 351 days and for 97.5% was their first event with HEN. Most patients had HEN because of neurological disease (57.8%). Access route was nasogastric tube for 43.5% and gastrostomy for 33.5%. Most patients had limited activity level and, concerning autonomy, 54.8% needed total help. Nutritional formula was supplied from chemist’s office to 73.8% of patients and disposables, when necessary, was supplied from hospitals to 53.8% of patients. HEN was finished for 1,031 patients (34.1%) during the period of study, 56.6% due to decease and 22.2% due to recovery of oral intake. Conclusions: Data from NADYA-SENPE registry must be explained cautiously because it is a non-compulsory registry. In spite of the change in the methodology of the registry in 2010, tendencies regarding HEN have been maintained, other than oral routeObjetivos: Describir los resultados del registro de nutrición enteral domiciliaria (NED) del grupo NADYASENPE de los años 2011 y 12. Material y métodos: Se recopilaron los datos introducidos en el registro desde el 1 de enero de 2011 al 31 de diciembre de 2012. Resultados: Hubo 3021 pacientes en el registro durante el periodo, procedentes de 29 hospitales, lo que da una prevalencia de 65,39 casos por millón de habitantes. 97.95% fueron adultos, 51,4% varones. La edad media fue 67,64 ± 19,1 años y la mediana 72 años para los adultos y 7 meses para los niños. La duración media de la NED fue 351 días y para el 97,5% fue el primer episodio con NED. La mayoría de pacientes tenían NED por una enfermedad neurológica (57,8%). La vía de acceso fue sonda nasogástrica para el 43,5% y gastrostomía para el 33,5%. La mayoría de pacientes tuvieron un nivel de actividad física limitado y, respecto a la autonomía, 54,8% necesitaba ayuda total. La fórmula de nutrición se suministró desde las oficinas de farmacia para el 73,8% y los fungibles, cuando fueron necesarios, desde los hospitales para el 53,8%. La NED se suspendió en 1.031 pacientes (34,1%) durante el periodo de estudio, 56,6% debido a fallecimiento y 22,2% debido a recuperación de la vía oral. Conclusiones: Los datos del registro NADYA-SENPE deben ser interpretados con precaución ya que se trata de un registro voluntario. A pesar del cambio de metodología del registro en 2010, las tendencias en NED se han mantenido, salvo la importancia cuantitativa de la vía ora

A Multitrait Genetic Study of Hemostatic Factors and Hemorrhagic Transformation after Stroke Treatment

BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient\u27s prognosis. OBJECTIVES: to investigate the association between genetically determined natural hemostatic factors\u27 levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10 CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed

Demographic History of Indigenous Populations in Mesoamerica Based on mtDNA Sequence Data

The genetic characterization of Native American groups provides insights into their history and demographic events. We sequenced the mitochondrial D-loop region (control region) of 520 samples from eight Mexican indigenous groups. In addition to an analysis of the genetic diversity, structure and genetic relationship between 28 Native American populations, we applied Bayesian skyline methodology for a deeper insight into the history of Mesoamerica. AMOVA tests applying cultural, linguistic and geographic criteria were performed. MDS plots showed a central cluster of Oaxaca and Maya populations, whereas those from the North and West were located on the periphery. Demographic reconstruction indicates higher values of the effective number of breeding females (Nef) in Central Mesoamerica during the Preclassic period, whereas this pattern moves toward the Classic period for groups in the North and West. Conversely, Nef minimum values are distributed either in the Lithic period (i.e. founder effects) or in recent periods (i.e. population declines). The Mesomerican regions showed differences in population fluctuation as indicated by the maximum Inter-Generational Rate (IGRmax): i) Center-South from the lithic period until the Preclassic; ii) West from the beginning of the Preclassic period until early Classic; iii) North characterized by a wide range of temporal variation from the Lithic to the Preclassic. Our findings are consistent with the genetic variations observed between central, South and Southeast Mesoamerica and the North-West region that are related to differences in genetic drift, structure, and temporal survival strategies (agriculture versus hunter-gathering, respectively). Interestingly, although the European contact had a major negative demographic impact, we detect a previous decline in Mesoamerica that had begun a few hundred years before

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

[Background] Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient’s prognosis.[Objectives] To investigate the association between genetically determined natural hemostatic factors’ levels and increased risk of HT after r-tPA treatment.[Methods] Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT.[Results] Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10−11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10−10; rs1421067 (CHD9), P = 1.81 × 10−14; and rs34780449, near ROBO1 gene, P = 1.64 × 10−8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10−14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [−0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05).[Conclusion] We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.This study is supported in part by the National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141291. G.T.-S. is supported by the Pla Estratègic de Recerca i Innovació en Salut grant from the Catalan Department of Health for junior research personnel (SLT017/20/000100). M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. E.M. is supported by a Río Hortega Contract (CM18/00198) from the ISCIII. J.C.-M. is supported by an Agència de Gestió d’Ajuts Universitaris i de Recerca Contract (FI_DGR 2020, grant number 2020FI_B1 00157) cofinanced by the European Social Fund. C.G.-F. is supported by a Sara Borrell Contract (CD20/00043) from ISCIII and Fondo Europeo de Desarrollo Regional (ISCIII- FEDER). M.L. is supported by a Contratos Predoctorales de Formación en Investigación en Salud Contract from the ISCIII (FI19/00309).Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas