Search

Horizontal gene transfer (HGT) is pervasive in viruses and thought to be a key mechanism in their evolution. On the other hand, strong selective constraints against increasing genome size are an impediment for HGT, rapidly purging horizontally transferred sequences and thereby potentially hindering evolutionary innovation. Here, we explore experimentally the evolutionary fate of viruses with simulated HGT events, using the plant RNA virus Tobacco etch virus (TEV), by separately introducing two functional, exogenous sequences to its genome. One of the events simulates the acquisition of a new function though HGT of a conserved AlkB domain, responsible for the repair of alkylation or methylation damage in many organisms. The other event simulates the acquisition of a sequence that duplicates an existing function, through HGT of the 2b RNA silencing suppressor from Cucumber mosaic virus. We then evolved these two viruses, tracked the maintenance of the horizontally transferred sequences over time, and for the final virus populations, sequenced their genome and measured viral fitness. We found that the AlkB domain was rapidly purged from the TEV genome, restoring fitness to wild-type levels. Conversely, the 2b gene was stably maintained and did not have a major impact on viral fitness. Moreover, we found that 2b is functional in TEV, as it provides a replicative advantage when the RNA silencing suppression domain of HC-Pro is mutated. These observations suggest a potentially interesting role for HGT of short functional sequences in ameliorating evolutionary constraints on viruses, through the duplication of functions.

Horizontal gene transfer (HGT) is pervasive in viruses and thought to be a key mechanism in their evolution. On the other hand, strong selective constraints against increasing genome size are an impediment for HGT, rapidly purging horizontally transferred sequences and thereby potentially hindering evolutionary innovation. Here, we explore experimentally the evolutionary fate of viruses with simulated HGT events, using the plant RNA virus Tobacco etch virus (TEV), by separately introducing two functional, exogenous sequences to its genome. One of the events simulates the acquisition of a new function though HGT of a conserved AlkB domain, responsible for the repair of alkylation or methylation damage in many organisms. The other event simulates the acquisition of a sequence that duplicates an existing function, through HGT of the 2b RNA silencing suppressor from Cucumber mosaic virus. We then evolved these two viruses, tracked the maintenance of the horizontally transferred sequences over time, and for the final virus populations, sequenced their genome and measured viral fitness. We found that the AlkB domain was rapidly purged from the TEV genome, restoring fitness to wild-type levels. Conversely, the 2b gene was stably maintained and did not have a major impact on viral fitness. Moreover, we found that 2b is functional in TEV, as it provides a replicative advantage when the RNA silencing suppression domain of HC-Pro is mutated. These observations suggest a potentially interesting role for HGT of short functional sequences in ameliorating evolutionary constraints on viruses, through the duplication of functions.

Follow-up studies revealed that subjects with borderline personality disorder (BPD) present high rates of clinical remission, although psychosocial functioning often remains impaired. The aim of this study is to evaluate the efficacy of a cognitive rehabilitation intervention versus a psychoeducational program on psychosocial functioning in subjects with BPD. A multicenter, randomized, and positive-controlled clinical trial was conducted. Seventy outpatients with BPD were randomized to cognitive rehabilitation or psychoeducational group interventions. Participants were evaluated after completion of the intervention period (16 weeks) and after the follow-up period (6 months). Psychosocial functioning, clinical and neuropsychological outcomes were evaluated. No main effects of group or group x time were observed on functionality but a significant effect of time was found. Post-hoc analyses showed that only cognitive rehabilitation increased psychosocial functioning significantly at endpoint. Psychoeducation showed a significant enhancement of depressive symptoms. Cognitive rehabilitation and psychoeducational interventions appeared to show good efficacy in improving disabilities in daily life in subjects with BPD. These interventions are easily implemented in mental health settings and have the advantage of improving general functioning and clinical symptoms. Clinicaltrials.gov:. Registered 9 January 2014 The online version of this article (doi:10.1186/s12888-015-0640-5) contains supplementary material, which is available to authorized users.

Miguel A Ruiz,1 Enrique Álvarez,2 Jose L Carrasco,3 José M Olivares,4 María Pérez,5 Javier Rejas6 1Department of Methodology, School of Psychology, Universidad Autónoma de Madrid, Madrid, 2Department of Psychiatry, Hospital de la Santa Creu i San Pau, Barcelona, 3Department of Psychiatry, Hospital Clínico San Carlos, Madrid, 4Department of Psychiatry, Hospital Meixoeiro, Complejo Hospitalario Universitario, Vigo, 5Medical Department, Pfizer, S.L.U., Alcobendas, Madrid, 6Health Economics and Outcomes Research Department, Pfizer, S.L.U., Alcobendas, Madrid, Spain Background: Anxiety disorders are among the most common psychiatric illnesses, with generalized anxiety disorder (GAD) being one of the most common. Sleep disturbances are highly prevalent in GAD patients. While treatment with pregabalin has been found to be associated with significant improvement in GAD-related sleep disturbance across many controlled clinical trials, mediational analysis has suggested that a substantial portion of this effect could be the result of a direct effect of pregabalin. Thus, the objective of this study was to model the longitudinal latent effect of pregabalin or usual care (UC) therapies on changes in sleep in outpatients with GAD under routine clinical practice. Methods: Male and female GAD outpatients, aged 18 years or above, from a 6-month prospective noninterventional trial were analyzed. Direct and indirect effects of either pregabalin or UC changes in anxiety symptoms (assessed with Hamilton Anxiety Scale) and sleep disturbances (assessed with Medical Outcomes Study-Sleep Scale [MOS-S]) were estimated by a conditional latent curve model applying structural equation modeling. Results: A total of 1,546 pregabalin-naïve patients were analyzed, 984 receiving pregabalin and 562 UC. Both symptoms of anxiety and sleep disturbances were significantly improved in both groups, with higher mean (95% con

Marina De Salas-Cansado,1 José M Olivares,2 Enrique Álvarez,3 Jose L Carrasco,4 Andoni Barrueta,5 Javier Rejas,51Trial Form Support Spain, Madrid; 2Department of Psychiatry, Hospital Meixoeiro, Complejo Hospitalario Universitario, Vigo; 3Department of Psychiatry, Hospital de la Santa Creu i San Pau, Barcelona; 4Department of Psychiatry, Hospital Clínico San Carlos, Madrid; 5Health Outcomes Research Department, Medical Unit, Pfizer Spain, Alcobendas, Madrid, SpainBackground: Generalized anxiety disorder (GAD) is a prevalent health condition which seriously affects both patient quality of life and the National Health System. The aim of this research was to carry out a post hoc cost-effectiveness analysis of the effect of pregabalin versus selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) in treated benzodiazepine-refractory outpatients with GAD.Methods: This post hoc cost-effectiveness analysis used secondary data extracted from the 6-month cohort, prospective, noninterventional ADAN study, which was conducted to ascertain the cost of illness in GAD subjects diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Benzodiazepine-refractory subjects were those who claimed persistent symptoms of anxiety and showed a suboptimal response (Hamilton Anxiety Rating Scale ≥16) to benzodiazepines, alone or in combination, over 6 months. Patients could switch to pregabalin (as monotherapy or addon) or to an SSRI or SNRI, alone or in combination. Effectiveness was expressed as quality-adjusted life years gained, and the perspective was that of the National Health System in the year 2008. A sensitivity analysis was performed using bootstrapping techniques (10,000 resamples were obtained) in order to obtain a cost-effectiveness plane and a corresponding acceptability curve.Results: A total of 282 subjects (mean Hamilton Anxiety Rating Scale score