Chiral Distorted Hexa-peri-hexabenzocoronenes Bearing a Nonagon-Embedded Carbohelicene

We acknowledge the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC-2015-STG-677023), the Ministerio de Ciencia, Innovacion y Universidades (MICIU/FEDER/AEI, Spain, PGC2018-101181-B-I00), the Universidad de Granada (UGR) (Plan Propio - Intensificacion de la Investigacion PP2017-PRI.I-02) and the Swiss National Science Foundation (Spark 2019 Grant CRSK-2_190365) for financial support. We thank the CSIRC-Alhambra, the Service and Support for Science IT (S3IT) of the University of Zurich and Prof.Dr. Michal Juriek for supercomputing facilities. Funding for open access charge: Universidad de Granada/CBUA.A new family of chiral saddle-helix hybrid nanographenes is reported. The first hexa-peri-hexabenzocoronene (HBC) analogues bearing a nine-membered carbocycle are presented. Furthermore, for the first time, pi-extended carbo[n]helicenes containing a nine-membered ring as part of the helical moiety have been synthesized. The combination of a [5]helicene moiety and a nonagon ring in a single chiral motif induces a tremendous distortion from planarity into the nanographenic structures compared to other saddle-helix hybrids such as heptagon- and octagon-containing pi-extended carbo[5]helicenes. In fact, the interplanar angle of the two terminal rings reaches the largest angle (134.8 degrees) of a carbohelicene reported to date, thus being by far the most twisted helicene yet prepared. Photophysical properties evaluation showed improved absorption dissymmetry factors (|g(abs)|=4.2x10(-3)) in the new family of nonagon-containing pi-extended carbo[5]helicenes.European Research Council (ERC) ERC-2015-STG-677023Ministerio de Ciencia, Innovacion y Universidades (MICIU/FEDER/AEI, Spain) PGC2018-101181-B-I00Universidad de Granada (UGR) (Plan Propio - Intensificacion de la Investigacion) PP2017-PRI.I-02Swiss National Science Foundation (SNSF) European Commission CRSK-2_190365Universidad de Granada/CBU

Copy number variation analysis in the great apes reveals species-specific patterns of structural variation

Gazave, Elodie et al.Copy number variants (CNVs) are increasingly acknowledged as an important source of evolutionary novelties in the human lineage. However, our understanding of their significance is still hindered by the lack of primate CNV data. We performed intraspecific comparative genomic hybridizations to identify loci harboring copy number variants in each of the four great apes: bonobos, chimpanzees, gorillas, and orangutans. For the first time, we could analyze differences in CNV location and frequency in these four species, and compare them with human CNVs and primate segmental duplication (SD) maps. In addition, for bonobo and gorilla, patterns of CNV and nucleotide diversity were studied in the same individuals. We show that CNVs have been subject to different selective pressures in different lineages.Evidence for purifying selection is stronger in gorilla CNVs overlapping genes, while positive selection appears to have driven the fixation of structural variants in the orangutan lineage. In contrast, chimpanzees and bonobos present high levels of common structural polymorphism, which is indicative of relaxed purifying selection together with the higher mutation rates induced by the known burst of segmental duplication in the ancestor of the African apes. Indeed, the impact of the duplication burst is noticeable by the fact that bonobo and chimpanzee share more CNVs with gorilla than expected. Finally, we identified a number of interesting genomic regions that present high-frequency CNVs in all great apes, while containing only very rare or even pathogenic structural variants in humans.Financial support was provided by a Beatriu de Pinos postdoctoral Grant to E.G., the Spanish Ministry of Science and Innovation (Grant BFU2009-13409-02-02toA.N.),and the Spanish National Institute for Bioinformatics (INB, www.inab.org).Peer reviewe

Recent human evolution has shaped geographical differences in susceptibility to disease

Background: Searching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.Results: We report three main findings. First, contrary to previous results, genes associated to complex diseases present lower degrees of genetic differentiation among human populations than average genome-wide levels. Second, also contrary to previous results, the differences in replicability of disease associated-loci between Europeans and East Asians are highly correlated with genetic differentiation between these populations. Finally, highly replicated genes present increased levels of high-frequency derived alleles in European and Asian populations when compared to African populations.Conclusions: Our findings highlight the heterogeneous nature of the genetic etiology of complex disease, confirm the importance of the recent evolutionary history of our species in current patterns of disease susceptibility and could cast doubts on the status as false positives of some associations that have failed to replicate across populations

Decay of linkage disequilibrium within genes across HGDP-CEPH human samples: most population isolates do not show increased LD

9 pages, 2 figures, 4 additional files.[Background] It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, particularly in isolated populations where it is assumed to be higher. Here, we explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing particularly on the populations defined as isolates. Within each gene region and population we use r2 between all possible single nucleotide polymorphism (SNP) pairs as a measure of linkage disequilibrium and focus on the proportion of SNP pairs with r2 greater than 0.8.[Results] Although the average r2 was found to be significantly different both between and within continental regions, a much higher proportion of r2 variance could be attributed to differences between continental regions (2.8% vs. 0.5%, respectively). Similarly, while the proportion of SNP pairs with r2 > 0.8 was significantly different across continents for all distance classes, it was generally much more homogenous within continents, except in the case of Africa and the Americas. The only isolated populations with consistently higher LD in all distance classes with respect to their continent are the Kalash (Central South Asia) and the Surui (America). Moreover, isolated populations showed only slightly higher proportions of SNP pairs with r2 > 0.8 per gene region than non-isolated populations in the same continent. Thus, the number of SNPs in isolated populations that need to be genotyped may be only slightly less than in non-isolates.[Conclusion] The "isolated population" label by itself does not guarantee a greater genotyping efficiency in association studies, and properties other than increased linkage disequilibrium may make these populations interesting in genetic epidemiology.This research was supported by "Fundación Genoma España" (proyectos piloto CEGEN 2004–2005), Dirección General de Investigación, Ministerio de Educación y Ciencia of Spain (grants BFU2005-00243, BFU2006-01235, BFU2006-15413-CO2-01, SEJ2006-13537) and Direcció General de Recerca, Generalitat de Catalunya (2005SGR00608). SNP genotyping services were provided by the Spanish "Centro Nacional de Genotipado"Peer reviewe

Desarrollar una propuesta de enseñanza aprendizaje de Matemáticas y su Didáctica para la formación de Docentes considerando la diversidad funcional asociada a la discapacidad intelectual, mediante la intervención en el Proyecto Liceo

Depto. de Didáctica de las Ciencias Experimentales , Sociales y MatemáticasFac. de EducaciónFALSEsubmitte

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Analysis of genetic polymorphisms for statistical genomics: tools and applications

New approaches are needed to manage and analyze the enormous quantity of biological data generated by modern technologies. Existing solutions are often fragmented and uncoordinated and, thus, they require considerable bioinformatics skills from users. Three applications have been developed illustrating different strategies to help users without extensive IT knowledge to take maximum profit from their data. SNPator is an easy-to-use suite that integrates all the usual tools for genetic association studies: from initial quality control procedures to final statistical analysis. CHAVA is an interactive visual application for CNV calling from aCGH data. It presents data in a visual way that helps assessing the quality of the calling and assists in the process of optimization. Haplotype Association Pattern Analysis visually presents data from exhaustive genomic haplotype associations, so that users can recognize patterns of possible associations that cannot be detected by single-SNP tests.Calen noves aproximacions per la gestió i anàlisi de les enormes quantitats de dades biològiques generades per les tecnologies modernes. Les solucions existents, sovint fragmentaries i descoordinades, requereixen elevats nivells de formació bioinformàtica. Hem desenvolupat tres aplicacions que il•lustren diferents estratègies per ajudar als usuaris no experts en informàtica a aprofitar al màxim les seves dades. SNPator és un paquet de fàcil us que integra les eines usades habitualment en estudis de associació genètica: des del control de qualitat fins les anàlisi estadístiques. CHAVA és una aplicació visual interactiva per a la determinació de CNVs a partir de dades aCGH. Presenta les dades visualment per ajudar a valorar la qualitat de les CNV predites i ajudar a optimitzar-la. Haplotype Pattern Analysis presenta dades d’anàlisi d’associació haplotípica de forma visual per tal que els usuaris puguin reconèixer patrons de associacions que no es possible detectar amb tests de SNPs individuals

Chitinase 3-like 1 plasma levels are increased in patients with progressive forms of multiple sclerosis

Cantó, E. et al.[Background] Chitinase 3-like 1 (CHI3L1) is upregulated in a wide variety of inflammatory conditions. Recent studies have pointed to a role of CHI3L1 in multiple sclerosis (MS) pathogenesis.[Objective] The objective of this study was to investigate the role of plasma CHI3L1 in MS clinical course and disease activity and to evaluate the effect of interferon-beta (IFNβ) treatment on protein levels.[Methods] Plasma CHI3L1 levels were determined by ELISA in 57 healthy controls (HC), 220 untreated MS patients [66 primary progressive MS patients (PPMS), 30 secondary progressive MS patients (SPMS), and 124 relapsing-remitting MS patients (RRMS), 94 during clinical remission and 30 during relapse], and 32 MS patients receiving IFNβ treatment. A polymorphism of the CHI3L1 gene, rs4950928, was genotyped in 3274 MS patients and 3483 HC.[Results] Plasma CHI3L1 levels were significantly increased in patients with progressive forms of MS compared with RRMS patients and HC. CHI3L1 levels were similar between RRMS patients in relapse and remission. A trend towards decreased CHI3L1 levels was observed in IFNβ-treated patients. Allele C of rs4950928 was significantly associated with PPMS patients and with higher plasma CHI3L1 levels.[Conclusions] These findings point to a role of CHI3L1 in patients with progressive forms of MS, particularly in those with PPMS. © The Author(s) 2012.This work was supported by grants from the ‘Fondo de Investigación Sanitaria’ (FIS; grant numbers PI09/00788 and CP10/00526), Ministry of Science and Innovation, Spain. EC is supported by a contract from the FIS (contract number FI 09/00705), Ministry of Science and Innovation, Spain. The authors thank the ‘Red Española de Esclerosis Múltiple (REEM)’ sponsored by the ‘Fondo de Investigación Sanitaria’ (FIS), Ministry of Science and Innovation, Spain, and the ‘Ajuts per donar Suport als Grups de Recerca de Catalunya’ (SGR 2005-1081), sponsored by the ‘Agència de Gestió d’Ajuts Universitaris i de Recerca’ (AGAUR), Generalitat de Catalunya, Spain.Peer Reviewe

IL28B polymorphisms are not associated with the response to interferon-beta in multiple sclerosis

Malhotra, Sunny et al.Recent studies have revealed an association between interleukin 28B (IL28B) and response to IFN-alpha treatment in hepatitis C patients. Here we investigated the influence of IL28B polymorphisms in the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. We genotyped two SNPs of the IL28B gene (rs8099917 and rs12979860) in 588 MS patients classified into responders (n = 281) and non-responders (n = 307) to IFNβ. Combined analysis of the study cohorts showed no significant associations between SNPs rs8099917 and rs12979860 and the response to treatment. These findings do not support a role of IL28B polymorphisms in the response to IFNβ in MS patients. © 2011 Elsevier B.V.This study was supported by a grant from the DANA Foundation's Neuroimmunology program. SM is early stage researcher funded by the European Community's Seventh Framework Program ([FP7/2007–2013]) under grant agreement no. 212877 (UEPHA*MS). The authors thank the “Red Española de Esclerosis Múltiple (REEM)” sponsored by the “Fondo de Investigación Sanitaria” (FIS), Ministry of Science and Innovation, Spain, and the “Ajuts per donar Suport als Grups de Recerca de Catalunya (SGR 2005–1081)”, sponsored by the “Agència de Gestió d'Ajuts Universitaris i de Recerca” (AGAUR), Generalitat de Catalunya, Spain. J Drulovic has received research grant support from the Ministry of Education and Science, Republic of Serbia (project no. 175031).Peer Reviewe