The effect of the neutral cytidine protonated analogue pseudoisocytidine on the stability of i-motif structures

Incorporation of pseudoisocytidine (psC), a neutral analogue of protonated cytidine, in i-motifs has been studied by spectroscopic methods. Our results show that neutral psC:C base pairs can stabilize i-motifs at neutral pH, but the stabilization only occurs when psC:C base pairs are located at the ends of intercalated C:C+ stacks. When psC occupies central positions, the resulting i-motifs are only observed at low pH and psC:C+ or psC:psC+ hemiprotonated base pairs are formed instead of their neutral analogs. Overall, our results suggest that positively charged base pairs are necessary to stabilize this non-canonical DNA structure

Virus satellites drive viral evolution and ecology

Virus satellites are widespread subcellular entities, present both in eukaryotic and in prokaryotic cells. Their modus vivendi involves parasitism of the life cycle of their inducing helper viruses, which assures their transmission to a new host. However, the evolutionary and ecological implications of satellites on helper viruses remain unclear. Here, using staphylococcal pathogenicity islands (SaPIs) as a model of virus satellites, we experimentally show that helper viruses rapidly evolve resistance to their virus satellites, preventing SaPI proliferation, and SaPIs in turn can readily evolve to overcome phage resistance. Genomic analyses of both these experimentally evolved strains as well as naturally occurring bacteriophages suggest that the SaPIs drive the coexistence of multiple alleles of the phage-coded SaPI inducing genes, as well as sometimes selecting for the absence of the SaPI depressing genes. We report similar (accidental) evolution of resistance to SaPIs in laboratory phages used for Staphylococcus aureus typing and also obtain the same qualitative results in both experimental evolution and phylogenetic studies of Enterococcus faecalis phages and their satellites viruses. In summary, our results suggest that helper and satellite viruses undergo rapid coevolution, which is likely to play a key role in the evolution and ecology of the viruses as well as their prokaryotic hosts

Estudio del juego como recurso para trabajar la probabilidad en Educación Primaria

El presente trabajo tiene como objetivo principal el estudio del uso de los juegos matemáticos como recurso para la enseñanza de las matemáticas en Educación Primaria, concretamente, de la probabilidad. Por ello, el marco teórico trata desde el concepto global de juego, hasta conceptos más específicos como son la relación entre los juegos matemáticos y la enseñanza. A su vez, también trata nociones básicas sobre la probabilidad que aparecerán posteriormente en los juegos propuestos. A continuación, se presentan tres juegos de conocimiento y una actividad experimental en los que se concretan cuáles son los objetivos de cada uno de ellos en la adquisición de conocimientos sobre la probabilidad. El objetivo que se persigue en los siguientes juegos y actividades es partir trabajando, mediante la experimentación, el significado intuitivo de la probabilidad, hasta llegar al significado frecuencial, pasando por el significado clásico. Después, se contextualiza tanto el CEIP Juan XXIII, como el aula y se comenta y se explica tanto la implementación, como el análisis de los resultados de los juegos. Finalmente, el trabajo concluye con las conclusiones sobre los resultados obtenidos.<br /

Resistencias en femenino. La oposición de las mujeres al primer franquismo (1939-1952).

Terminada la Guerra Civil comenzó un periodo de represión que vino acompañado también por las primeras muestras de protesta contra el nuevo régimen. En el caso de las mujeres, tanto la represión como la oposición tuvieron un carácter especial derivado del hecho de ser mujeres en una sociedad que pretendía borrar los logros adquiridos en materia de derechos durante la II República. Estas formas de oposición formaron un amplio abanico que engloba desde las resistencias cotidianas hasta la labor desempeñada por el PCE en la clandestinidad, pasando por la movilización de las mujeres de presos para conseguir la amnistía, las actividades que llevaron a cabo las mujeres que estaban presas dentro de los propios muros de las cárceles y el apoyo a la lucha armada que representaba el maquis. Sin embargo, pese a que la oposición al franquismo tuvo un claro carácter político, la mayoría de las mujeres que protagonizaron estas acciones no tenían una conciencia política previa, sino que la adquirieron en el proceso.<br /

Prevalent sequences in the Human Genome Can Form Mini i-Motif Structures at Physiological pH

We report here the solution structure of several repetitive DNA sequences containing d(TCGTTCCGT) and related repeats. At physiological pH, these sequences fold into i-motif like quadruplexes in which every two repeats a globular structure is stabilized by two hemiprotonated C:C+ base pairs, flanked by two minor groove tetrads resulting from the association of G:C or G:T base pairs. The interaction between the minor groove tetrads and the nearby C:C+ base pairs affords a strong stabilization, which results in effective pHT values above 7.5. Longer sequences with more than two repeats are able to fold in tandem, forming a rosary bead-like structure. Bioinformatics analysis shows that these sequences are prevalent in the human genome, and are present in development-related genes

Cost-effectiveness analysis of second-line pharmacological treatment of acromegaly in Spain

[Abstract] Objective: To estimate the cost-effectiveness of second-line pharmacological treatments in patients with acromegaly resistant to first-generation somatostatin analogues (FG SSA) from the Spanish National Health System (NHS) perspective. Methods: A Markov model was developed to analyze the cost-effectiveness of pegvisomant and pasireotide in FG SSA-resistant acromegaly, simulating a cohort of patients from the treatment beginning to death. Treatment with pegvisomant or pasireotide was compared to FG SSA retreatment. Efficacy data were obtained from clinical trials and utilities from the literature. Direct health costs were obtained from Spanish sources (€2018). Results: The Incremental Cost Effectiveness Ratio (ICER) of pegvisomant vs. FG SSA was €85,869/ Quality-adjusted life years (QALY). The ICER of pasireotide vs. FG SSA was €551,405/QALY. The ICER was mainly driven by the incremental efficacy (4.41 QALY for pegvisomant vs. FG SSA and 0.71 QALY for pasireotide vs. FG SSA), with a slightly lower increase in costs with pegvisomant (€378,597 vs. FG SSA) than with pasireotide (€393,151 vs. FG SSA). Conclusion: The ICER of pasireotide compared to FG SSA was six times higher than the ICER of pegvisomant vs. FG SSA. Pegvisomant is a more cost-effective alternative for the treatment of acromegaly in FG SSA-resistant patients in the Spanish NHS

Treatment adherence to pegvisomant (somavert®) in Spain: PEGASO study

This is a pre-copyedited, author-produced version of an article accepted for publication in Endocrine Reviews following peer review. The version of record is avaliable online at Oxford University web page

Treatment adherence to pegvisomant in patients with acromegaly in Spain: PEGASO study

The final publication is avaliable at Springer Link[Abstract] PURPOSE: The burden of chronic daily subcutaneous administration of pegvisomant on adherence has not been previously studied. This study was aimed to determine the adherence to pegvisomant treatment in acromegaly patients in the real-world clinical practice setting in Spain. METHODS: Multicenter, observational, descriptive, cross-sectional study in patients with acromegaly treated with pegvisomant for at least 12 months. Patient adherence was indirectly determined by Batalla and Haynes-Sackett questionnaires and directly by prescription record review. Additionally, treatment satisfaction was assessed by the Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) and treatment convenience by an ad-hoc Pegvisomant questionnaire. Errors in reconstitution and administration process were determined by direct observation. RESULTS: 108 patients were included in the analysis. Rates of adherence varied from 60.7 to 92.1% and did not correlate with disease control. Older patient age and alternative schedules other than daily pegvisomant dosing were associated with lower adherence. Treatment satisfaction and convenience was high, with a mean (SD) total SATMED-Q score of 74.6 ± 15.4 over 100 and a total ad-hoc Pegvisomant questionnaire score of 71.2 ± 15.2 over 100. 34.3% of patients made mistakes during the reconstitution /administration process. CONCLUSIONS: Patient adherence to pegvisomant was high (60.7-92.1%), but more than a third of the patients in the study made mistakes during the administration process, with a potential impact on disease control. Besides dosing compliance, correct administration of medication should be carefully assessed in these patients