First-Episode Psychotic Patients Showed Longitudinal Brain Changes Using fMRI With an Emotional Auditory Paradigm

Most previous longitudinal studies of functional magnetic resonance imaging (fMRI) in first-episode psychosis (FEP) using cognitive paradigm task found an increased activation after antipsychotic medications. We designed an emotional auditory paradigm to explore brain activation during emotional and nonemotional word processing. This study aimed to analyze if longitudinal changes in brain fMRI BOLD activation is present in patients vs. healthy controls. A group of FEP patients (n = 34) received clinical assessment and had a fMRI scan at baseline and follow-up (average, 25-month interval). During the fMRI scan, both emotional and nonemotional words were presented as a block design. Results were compared with a pair of healthy control group (n = 13). Patients showed a decreased activation at follow-up fMRI in amygdala (F = 4.69; p = 0.04) and hippocampus (F = 5.03; p = 0.03) compared with controls. Middle frontal gyrus was the only area that showed a substantial increased activation in patients (F = 4.53; p = 0.04). A great heterogeneity in individual activation patterns was also found. These results support the relevance of the type of paradigm in neuroimaging for psychosis. This is, as far as we know, the first longitudinal study with an emotional auditory paradigm in FEP. Our results suggested that the amygdala and hippocampus play a key role in psychotic disease. More studies are needed to understand the heterogeneity of response at individual level

FOXP2 expression and gray matter density in the male brains of patients with schizophrenia

Common genetic variants of FOXP2 may contribute to schizophrenia vulnerability, but controversial results have been reported for this proposal. Here we evaluated the potential impact of the common FOXP2 rs2396753 polymorphism in schizophrenia. It was previously reported to be part of a risk haplotype for this disease and to have significant effects on gray matter concentration in the patients. We undertook the first examination into whether rs2396753 affects the brain expression of FOXP2 and a replication study of earlier neuroimaging findings of the influence of this genetic variant on brain structure. FOXP2 expression levels were measured in postmortem prefrontal cortex samples of 84 male subjects (48 patients and 36 controls) from the CIBERSAM Brain and the Stanley Foundation Array Collections. High-resolution anatomical magnetic resonance imaging was performed on 79 male subjects (61 patients, 18 controls) using optimized voxel-based morphometry. We found differences in FOXP2 expression and brain morphometry depending on the rs2396753, relating low FOXP2 mRNA levels with reduction of gray matter density. We detected an interaction between rs2396753 and the clinical groups, showing that heterozygous patients for this polymorphism have gray matter density decrease and low FOXP2 expression comparing with the heterozygous controls.This study shows the importance of independent replication of neuroimaging genetic studies of FOXP2 as a candidate gene in schizophrenia. Furthermore, our results suggest that the FOXP2 rs2396753 affects mRNA levels, thus providing new knowledge about its significance as a potential susceptibility polymorphism in schizophrenia

Variation in RNA Virus Mutation Rates across Host Cells

It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10−6 to 10−4 substitutions per nucleotide per round of copying (s/n/r) and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on the rate of spontaneous mutation of the vesicular stomatitis virus (VSV), which has a broad host range and cell tropism. Luria-Delbrück fluctuation tests and sequencing showed that VSV mutated similarly in baby hamster kidney, murine embryonic fibroblasts, colon cancer, and neuroblastoma cells (approx. 10−5 s/n/r). Cell immortalization through p53 inactivation and oxygen levels (1–21%) did not have a significant impact on viral replication fidelity. This shows that previously published mutation rates can be considered reliable despite being based on a narrow and artificial set of laboratory conditions. Interestingly, we also found that VSV mutated approximately four times more slowly in various insect cells compared with mammalian cells. This may contribute to explaining the relatively slow evolution of VSV and other arthropod-borne viruses in nature

Does Mutational Robustness Inhibit Extinction by Lethal Mutagenesis in Viral Populations?

Lethal mutagenesis is a promising new antiviral therapy that kills a virus by raising its mutation rate. One potential shortcoming of lethal mutagenesis is that viruses may resist the treatment by evolving genomes with increased robustness to mutations. Here, we investigate to what extent mutational robustness can inhibit extinction by lethal mutagenesis in viruses, using both simple toy models and more biophysically realistic models based on RNA secondary-structure folding. We show that although the evolution of greater robustness may be promoted by increasing the mutation rate of a viral population, such evolution is unlikely to greatly increase the mutation rate required for certain extinction. Using an analytic multi-type branching process model, we investigate whether the evolution of robustness can be relevant on the time scales on which extinction takes place. We find that the evolution of robustness matters only when initial viral population sizes are small and deleterious mutation rates are only slightly above the level at which extinction can occur. The stochastic calculations are in good agreement with simulations of self-replicating RNA sequences that have to fold into a specific secondary structure to reproduce. We conclude that the evolution of mutational robustness is in most cases unlikely to prevent the extinction of viruses by lethal mutagenesis

Prevalence of Epistasis in the Evolution of Influenza A Surface Proteins

The surface proteins of human influenza A viruses experience positive selection to escape both human immunity and, more recently, antiviral drug treatments. In bacteria and viruses, immune-escape and drug-resistant phenotypes often appear through a combination of several mutations that have epistatic effects on pathogen fitness. However, the extent and structure of epistasis in influenza viral proteins have not been systematically investigated. Here, we develop a novel statistical method to detect positive epistasis between pairs of sites in a protein, based on the observed temporal patterns of sequence evolution. The method rests on the simple idea that a substitution at one site should rapidly follow a substitution at another site if the sites are positively epistatic. We apply this method to the surface proteins hemagglutinin and neuraminidase of influenza A virus subtypes H3N2 and H1N1. Compared to a non-epistatic null distribution, we detect substantial amounts of epistasis and determine the identities of putatively epistatic pairs of sites. In particular, using sequence data alone, our method identifies epistatic interactions between specific sites in neuraminidase that have recently been demonstrated, in vitro, to confer resistance to the drug oseltamivir; these epistatic interactions are responsible for widespread drug resistance among H1N1 viruses circulating today. This experimental validation demonstrates the predictive power of our method to identify epistatic sites of importance for viral adaptation and public health. We conclude that epistasis plays a large role in shaping the molecular evolution of influenza viruses. In particular, sites with , which would normally not be identified as positively selected, can facilitate viral adaptation through epistatic interactions with their partner sites. The knowledge of specific interactions among sites in influenza proteins may help us to predict the course of antigenic evolution and, consequently, to select more appropriate vaccines and drugs

Administración de documentos y archivos. Textos fundamentales

Prólogo / Aurelio Tanodi .- Introducción / José Ramón Cruz Mundet .- 1. Principios, términos y conceptos fundamentales / José Ramón Cruz Mundet .- 2. Normativa de referencia / Alejandro Delgado Gómez .- 3. Funciones, procesos y requisitos / Alicia Barnard Amozorrutia .- 4. El sistema de administración de documentos. 4.1 La identificación / Ramón Aguilera Murguía .- 4.2 La clasificación / Ana M. Herrero Montero y Alfonso Díaz Rodríguez .- 4.3 Descripción / Lucília Runa .- 4.4 Valoración, selección y eliminación / Lluís Cermeno Martorell y Elena Rivas Palá .- 4.5 Captura y transferencia / Claudia C. M. Lacombe Rocha .- 5. Funciones de administración del sistema. 5.1 Formación de usuarios / Maria J. Pires de Lima y António A.Sousa .- 5.2 Gestión de recursos / José Antonio Sáinz Varela .- 5.3 Gestión de accesos y consultas / Virginia Chacón Arias .- 5.4 Elaboración de disposiciones normativas / Aída Luz Mendoza Navarro .- 5.5 Manual de buenas prácticas / Joaquim Llansó Sanjuán .- 5.6 Difusión y acción cultural / Ramon Alberch i Fuguera