Molecular evolutionary characterization of the mussel "Mytilus" histone multigene family: first record of a tandemly repeated unit of five histone genes containing an H1 subtype with orphon features

[Abstract] The present work represents the first characterization of a clustered histone repetitive unit containing an H1 gene in a bivalve mollusk. To complete the knowledge on the evolutionary history of the histone multigene family in invertebrates, we undertake its characterization in five mussel Mytilus species, as an extension of our previous work on the H1 gene family. We report the quintet H4–H2B–H2A–H3–H1 as the major organization unit in the genome of Mytilus galloprovincialis with two 5S rRNA genes with interspersed nontranscribed spacer segments linked to the unit, which is not justified by their cotranscription with histone genes. Surprisingly, 3′ UTR regions of histone genes show two different mRNA termination signals, a stem-loop and a polyadenylation signal, both related to the evolution of histone gene expression patterns throughout the cell cycle. The clustered H1 histones characterized share essential features with “orphon” H1 genes, suggesting a common evolutionary origin for both histone subtypes which is supported by the reconstructed phylogeny for H1 genes. The characterization of histone genes in four additional Mytilus species revealed the presence of strong purifying selection acting among the members of the family. The chromosomal location of most of the core histone genes studied was identified by FISH close to telomeric regions in M. galloprovincialis. Further analysis on nucleotide variation would be necessary to assess if H1 proteins evolve according to the birth-and-death model of evolution and if the effect of the strong purifying selection maintaining protein homogeneity could account for the homologies detected between clustered and “orphon” variants.Xunta de Galicia; 10PX110304P

Common evolutionary origin and birth-and-death process in the replication-independent histone H1 isoforms from vertebrate and invertebrate genomes

[Abstract]The H1 histone multigene family shows the greatest diversity of isoforms among the five histone gene families, including replication-dependent (RD) and replication-independent (RI) genes, according to their expression patterns along the cell cycle and their genomic organization. Although the molecular characterization of the RI isoforms has been well documented in vertebrates, similar information is lacking in invertebrates. In this work we provide evidence for a polyadenylation signature in the Mytilus “orphon” H1 genes similar to the polyadenylation characteristic of RI H1 genes. These mussel genes, together with the sea urchin H1δ genes, are part of a lineage of invertebrate “orphon” H1 genes that share several control elements with vertebrate RI H1 genes. These control elements include the UCE element, H1-box and H4-box. We provide evidence for a functional evolution of vertebrate and invertebrate RI H1 genes, which exhibit a clustering pattern by type instead of by species, with a marked difference from the somatic variants. In addition, these genes display an extensive silent divergence at the nucleotide level which is always significantly larger than the nonsilent. It thus appears that RI and RD H1 isoforms display similar long-term evolutionary patterns, best described by the birth-and-death model of evolution. Notably, this observation is in contrast with the theoretical belief that clustered RD H1 genes evolve in a concerted manner. The split of the RI group from the main RD group must therefore have occurred before the divergence between vertebrates and invertebrates about 815 million years ago. This was the result of the transposition of H1 genes to solitary locations in the genome.Xunta de Galicia; 10PX110304Canadá. Canadian Institutes of Health Research; MOP-5771

Effect of the Inoculation Site of Bovine and Avian Purified Protein Derivatives (PPDs) on the Performance of the Intradermal Tuberculin Test in Goats From Tuberculosis-Free and Infected Herds

The single and comparative intradermal tuberculin (SIT and CIT) tests are used for the ante-mortem diagnosis of caprine tuberculosis (TB). The tuberculin injection site has been associated with a different performance of the test in cattle. In contrast to that required in cattle in Europe (cervical injection), it can be carried out in the scapular region in goats. Nevertheless, there are no previous data concerning the effect of the injection site on the performance of the test in goats. The aim of the present study was to evaluate the effect of two different inoculation sites (cervical and scapular) on the performance of the SIT/CIT tests. This was done by intradermally inoculating 309 goats from two infected herds and one TB-free herd with both avian and bovine PPDs in the mid-cervical and scapular regions. None of the animals from the TB-free herd had positive reactions, and the number of reactors was not significantly higher, regardless of the inoculation site, in the high and low prevalence herds. However, significantly higher increases in skin fold thickness were observed on the cervical site when compared to the scapular site after the avian and bovine PPD inoculations in the TB-free herd (p < 0.001) and after the bovine PPD injection in the high prevalence herd (p = 0.003). The presence of clinical signs was also more evident on the cervical site when using avian and bovine PPDs in the high prevalence herd (p < 0.01). In contrast, increases in higher skin fold thickness were observed on the scapular site when compared to the cervical site after the bovine and avian PPD inoculations were employed in the low prevalence herd (p < 0.01). These results suggest that the cervical injection of PPDs may improve the sensitivity of the intradermal tuberculin test in high TB prevalence caprine herds, mainly owing to the increased presence of local clinical signs and a better performance of the CIT test. Moreover, specificity was not affected when using standard interpretations, although further analyses in a great number of herds are required in order to confirm these findings.This study was funded by the Herramientas para alcanzar la erradicación de la tuberculosis caprina (GoaTBfree) project (PID2019-105155RB-C31) and the Spanish Government's Ministerio de Agricultura, Pesca y Alimentación. JO was supported by an FPU (Formación de Profesorado Universitario) contract-fellowship provided by the Spanish Ministerio de Ciencia, Innovación y Universidades (FPU18/05197).S

La argumentación a favor del trabajo sexual y sus implicaciones éticas

Cómo deben actuar los Estados democráticos modernos ante la práctica de la prostitución constituye actualmente una cuestión polémica. Dentro del movimiento feminista la forma de resolver este problema ha generado una brecha que parece difícil de resolver. Las partidarias de que los gobiernos regularicen la prostitución como una relación laboral más justifican su postura con argumentos que consideran sólidos jurídicamente y neutrales desde el punto de vista ético.Afirman que las razones dadas para prohibir la prostitución y para no considerarla una actividad laboral son razones morales. A su vez, sostienen que los Estados democráticos de derecho no tienen como función el imponer creencias éticas a sus ciudadanos sino salvaguardar los derechos de los mismos, en especial elderecho a la libertad individual. En el trabajo recojo los argumentos esgrimidos a favor y en contra de que la prostitución deba regularizarse como un trabajo y muestro cómo el razonamiento de las representantes del feminismo a favor del trabajo sexual está construido sobre una teoría ética que se presupone comoválida y que, por lo tanto, no es objeto de discusión. Sostengo que la forma más adecuada de llegar a un consenso sobre este tema sería plantear abiertamente y de forma previa al debate político y jurídico, una reflexión ética sobre qué postulados y que concepción moral de la sexualidad nos parecen más valiosos para tratar este complejo problema

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file

Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Objective Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. Methods Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. Results Four clusters were identified and validated. Three were pathologic, representing “inflammatory,” “lymphoid,” and “interferon” patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse–remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. Conclusion Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe