Publications by authors named "Elena Moreno"

48 Publications

Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture.

Cell Rep 2021 05 27;35(7):109133. Epub 2021 Apr 27.

Department of Chemistry and Chemical Biology, and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA. Electronic address:

Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS-CoV-2 main protease (M) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the M substrate-binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 M protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their M inhibiting activities did not correlate with their antiviral activities. This conundrum is resolved by demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PL). HCV drugs that inhibit PL synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir's antiviral activity as much as 10-fold, while those that only inhibit M do not synergize with remdesivir.
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http://dx.doi.org/10.1016/j.celrep.2021.109133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075848PMC
May 2021

Population Disequilibrium as Promoter of Adaptive Explorations in Hepatitis C Virus.

Viruses 2021 04 3;13(4). Epub 2021 Apr 3.

Centro de Biología Molecular "Severo Ochoa" (CBMSO) (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain.

Replication of RNA viruses is characterized by exploration of sequence space which facilitates their adaptation to changing environments. It is generally accepted that such exploration takes place mainly in response to positive selection, and that further diversification is boosted by modifications of virus population size, particularly bottleneck events. Our recent results with hepatitis C virus (HCV) have shown that the expansion in sequence space of a viral clone continues despite prolonged replication in a stable cell culture environment. Diagnosis of the expansion was based on the quantification of diversity indices, the occurrence of intra-population mutational waves (variations in mutant frequencies), and greater individual residue variations in mutant spectra than those anticipated from sequence alignments in data banks. In the present report, we review our previous results, and show additionally that mutational waves in amplicons from the NS5A-NS5B-coding region are equally prominent during HCV passage in the absence or presence of the mutagenic nucleotide analogues favipiravir or ribavirin. In addition, by extending our previous analysis to amplicons of the NS3- and NS5A-coding region, we provide further evidence of the incongruence between amino acid conservation scores in mutant spectra from infected patients and in the Los Alamos National Laboratory HCV data banks. We hypothesize that these observations have as a common origin a permanent state of HCV population disequilibrium even upon extensive viral replication in the absence of external selective constraints or changes in population size. Such a persistent disequilibrium-revealed by the changing composition of the mutant spectrum-may facilitate finding alternative mutational pathways for HCV antiviral resistance. The possible significance of our model for other genetically variable viruses is discussed.
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http://dx.doi.org/10.3390/v13040616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067247PMC
April 2021

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.

Front Pharmacol 2021 23;12:633680. Epub 2021 Mar 23.

MIT Lincoln Laboratory, Lexington, MA, United States.

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.
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http://dx.doi.org/10.3389/fphar.2021.633680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021898PMC
March 2021

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.

Front Pharmacol 2021 23;12:633680. Epub 2021 Mar 23.

MIT Lincoln Laboratory, Lexington, MA, United States.

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.
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http://dx.doi.org/10.3389/fphar.2021.633680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021898PMC
March 2021

Study of Probiotic Effects of subsp. BB-12 and 299v Strains on Biochemical and Morphometric Parameters of Rabbits after Obesity Induction.

Biology (Basel) 2021 Feb 7;10(2). Epub 2021 Feb 7.

Food Quality and Sensory Science Department, Teagasc Food Research Centre, Ashtown, 15 Dublin, Ireland.

This study aimed first to develop an experimental model of obesity and metabolic syndrome over 14 weeks using a diet called "cafeteria", which is a high-fat diet, to evaluate its consequences on the biochemical and morphometric parameters in ITELV2006 strain rabbits. Second, the trial aimed to evaluate the effect of two strains of probiotics, these being subsp. BB-12 and 299v, on the obesity and MetS induced during the first experiment. Overall, the results of the "cafeteria" diet demonstrated significant changes in numerous biochemical and morphometric parameters, reproducing obesity and the main clinical manifestations of the metabolic syndrome in humans. The administration of the two probiotic strains demonstrated an impact on certain parameters of obesity and induced MetS. This study makes it possible to conclude that probiotics could be useful in the treatment of obesity and metabolic syndrome of rabbits, but in a dependent manner. Furthermore, this study evidenced the importance of selecting specific probiotic strains and dosages to achieve desirable results on rabbits or other species.
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http://dx.doi.org/10.3390/biology10020131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915171PMC
February 2021

Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A.

Science 2021 02 25;371(6532):926-931. Epub 2021 Jan 25.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.
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http://dx.doi.org/10.1126/science.abf4058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963220PMC
February 2021

SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling.

Proc Natl Acad Sci U S A 2020 11 23;117(45):28344-28354. Epub 2020 Oct 23.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that is a serious global health problem. Evasion of IFN-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of IFN-stimulated genes (ISGs). Our results demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. We found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) and directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor (karyopherin/importin) complex and disrupt nuclear import. In addition, we show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together our data unravel a mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.
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http://dx.doi.org/10.1073/pnas.2016650117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668094PMC
November 2020

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

Science 2020 12 15;370(6521). Epub 2020 Oct 15.

Quantitative Biosciences Institute (QBI) COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.
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http://dx.doi.org/10.1126/science.abe9403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808408PMC
December 2020

The Global Phosphorylation Landscape of SARS-CoV-2 Infection.

Cell 2020 08 28;182(3):685-712.e19. Epub 2020 Jun 28.

Institute for Clinical and Experimental Pharmacology and Toxicology, University of Freiburg, Freiburg 79104, Germany.

The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.
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http://dx.doi.org/10.1016/j.cell.2020.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321036PMC
August 2020

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

Nature 2020 07 30;583(7816):459-468. Epub 2020 Apr 30.

QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
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http://dx.doi.org/10.1038/s41586-020-2286-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431030PMC
July 2020

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

Nature 2020 07 30;583(7816):459-468. Epub 2020 Apr 30.

QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
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http://dx.doi.org/10.1038/s41586-020-2286-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431030PMC
July 2020

Synergistic lethal mutagenesis of hepatitis C virus.

Antimicrob Agents Chemother 2019 Sep 30. Epub 2019 Sep 30.

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049, Madrid, Spain

Lethal mutagenesis is an antiviral approach that consists in extinguishing a virus by an excess of mutations acquired during replication in the presence of a mutagenic agent, often a nucleotide analogue. One of its advantages is its broad spectrum nature that renders the strategy potentially effective against emergent RNA viral infections. Here we describe synergistic lethal mutagenesis of hepatitis C virus (HCV) by a combination of favipiravir (T-705) and ribavirin. Synergy has been documented over a broad range of analogue concentrations using the Chou-Talalay method as implemented in the CompuSyn graphics, with average dose reduction index (DRI) above 1 (68.02±101.6 for favipiravir, and 5.83±6.07 for ribavirin), and average combination indices (CI) below 1 (0.52±0.28). Furthermore, analogue concentrations that individually did not extinguish high fitness HCV in ten serial infections, when used in combination they extinguished high fitness HCV in one to two passages. Although both analogues display a preference for G→A and C→U transitions, deep sequencing analysis of mutant spectra indicated a different preference of the two analogues for the mutation sites, thus unveiling a new possible synergy mechanism in lethal mutagenesis. Prospects of synergy among mutagenic nucleotides as a strategy to confront emerging viral infections are discussed.
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http://dx.doi.org/10.1128/AAC.01653-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879252PMC
September 2019

Comparison of Perfectionism Dimensions in Adolescents with Anorexia Nervosa or Obsessive-Compulsive Disorder.

J Can Acad Child Adolesc Psychiatry 2019 Aug 1;28(2):45-54. Epub 2019 Aug 1.

Department of Child and Adolescent Psychiatry and Psychology, 2017SGR881, Institute of Clinical Neurosciences, Hospital Clinic, Barcelona, Spain.

Objective: The aim of the study was to compare two dimensions of perfectionism, namely self-oriented perfectionism (SOP) and socially prescribed perfectionism (SPP), in adolescents with anorexia nervosa (AN) or obsessive-compulsive disorder (OCD) and in healthy controls. A further objective was to investigate the influence of perfectionism dimensions on obsessive-compulsive, depressive, and eating symptomatology.

Methods: A total of 79 adolescents with AN, 32 with OCD, and 74 healthy controls were recruited. The Child and Adolescent Perfectionism Scale (CAPS) was used to assess SOP and SPP. Measures of depression, obsessive-compulsive and eating symptomatology were administered.

Results: The AN group scored higher on SOP than did both the OCD group (p < 0.001) and controls (p < 0.001). In the AN group, SOP accounted for significant variance in scores on the obsessive (p < 0.001), depressive (p < 0.001), and eating symptomatology (p = 0.001), and the interaction between group and SOP was statistically significant when compared with the controls. Mean SPP total score among controls was similar to that in the AN group and higher than that in the OCD group (p = 0.003). Only in the control group did SPP account for significant variance in scores on the measures of obsessive-compulsive (p = 0.002), depression (p = 0.011), and eating symptomatology (p = 0.006).

Conclusions: Self-oriented perfectionism seemed more specific to AN than to OCD or controls. It predicted obsessive-compulsive, depressive, and eating symptoms in the AN group. In healthy controls, SPP was related to obsessive-compulsive, depressive, and eating symptomatology.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691799PMC
August 2019

Comparison of Perfectionism Dimensions in Adolescents with Anorexia Nervosa or Obsessive-Compulsive Disorder.

J Can Acad Child Adolesc Psychiatry 2019 Aug 1;28(2):45-54. Epub 2019 Aug 1.

Department of Child and Adolescent Psychiatry and Psychology, 2017SGR881, Institute of Clinical Neurosciences, Hospital Clinic, Barcelona, Spain.

Objective: The aim of the study was to compare two dimensions of perfectionism, namely self-oriented perfectionism (SOP) and socially prescribed perfectionism (SPP), in adolescents with anorexia nervosa (AN) or obsessive-compulsive disorder (OCD) and in healthy controls. A further objective was to investigate the influence of perfectionism dimensions on obsessive-compulsive, depressive, and eating symptomatology.

Methods: A total of 79 adolescents with AN, 32 with OCD, and 74 healthy controls were recruited. The Child and Adolescent Perfectionism Scale (CAPS) was used to assess SOP and SPP. Measures of depression, obsessive-compulsive and eating symptomatology were administered.

Results: The AN group scored higher on SOP than did both the OCD group (p < 0.001) and controls (p < 0.001). In the AN group, SOP accounted for significant variance in scores on the obsessive (p < 0.001), depressive (p < 0.001), and eating symptomatology (p = 0.001), and the interaction between group and SOP was statistically significant when compared with the controls. Mean SPP total score among controls was similar to that in the AN group and higher than that in the OCD group (p = 0.003). Only in the control group did SPP account for significant variance in scores on the measures of obsessive-compulsive (p = 0.002), depression (p = 0.011), and eating symptomatology (p = 0.006).

Conclusions: Self-oriented perfectionism seemed more specific to AN than to OCD or controls. It predicted obsessive-compulsive, depressive, and eating symptoms in the AN group. In healthy controls, SPP was related to obsessive-compulsive, depressive, and eating symptomatology.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691799PMC
August 2019

Functional MRI with a set-shifting task in adolescent anorexia nervosa: A cross-sectional and follow-up study.

Neuropsychologia 2019 08 28;131:1-8. Epub 2019 May 28.

Magnetic Resonance Image Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Villarroel, 170, Barcelona, 08036, Spain; Image Diagnostic Center, Hospital Clínic of Barcelona, Villarroel, 170, Barcelona, 08036, Spain.

Studies of set-shifting in adolescent AN present conflicting results, since not all have found differences with regard to controls. To date, no functional Magnetic Resonance Imaging (fMRI) studies have been carried out in adolescent patients, nor have patients been assessed after weight recovery. In this study, 30 female AN patients aged 12-17 and 16 matched control subjects were assessed both at baseline and after six months and renutrition using a structured diagnostic interview, clinical and neurocognitive scales, and fMRI during a set-shifting task. Adolescent AN patients presented similar performance on different neurocognitive tests and also on a set-shifting task during fMRI, but they showed a lower activation in the inferior and middle occipital and lingual gyri, fusiform gyri and cerebellum during the set-shifting task. No correlations were found between decreased activation and clinical variables such as body mass index, eating or depressive symptoms. After six months of treatment and renutrition in AN patients, there were no differences between patients and controls. These results show that adolescent AN patients have lower activation in relevant brain areas during a set-shifting task, and support the use of fMRI with set-shifting paradigms as a biomarker in future studies.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.05.019DOI Listing
August 2019

Genetic variability in the serotoninergic system and age of onset in anorexia nervosa and obsessive-compulsive disorder.

Psychiatry Res 2019 01 6;271:554-558. Epub 2018 Dec 6.

Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, C/ Villarroel 170, E-08036 Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain; The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Spain. Electronic address:

The age of onset of some psychiatric disorders may have etiopathogenic and clinical effects and may influence outcome. Following on from previous work by our group where we showed that early onset anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) shared a common genetic background, the aim of the present study is to assess genetic pleiotropy related to the serotonergic system (SLC6A4, 5HTR2A, 5HTR2C, TPH2, SLC18A1), in a common phenotype such as very-early age of onset. One hundred and sixteen adolescents diagnosed with AN and 74 adolescents diagnosed with OCD participated in the present study. We confirmed the existence of a genetic overlap between OCD and AN. Specifically, we described genetic pleiotropy for age at onset across these disorders, associating two SNPs (rs6311, rs4942587) of the HTR2A with the very-early onset phenotype.
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http://dx.doi.org/10.1016/j.psychres.2018.12.019DOI Listing
January 2019

Prevalence of sarcopenia and associated factors in institutionalised older adult patients.

Clin Nutr ESPEN 2018 10 2;27:113-119. Epub 2018 Jun 2.

Center Management and Elderly Program Department, Generalitat Valenciana, Valencia, Spain.

Background & Aims: Sarcopenia is a syndrome characterised by a progressive and generalised loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death. The main aim of the present study was to establish the prevalence of sarcopenia using EWGSOP-defined criteria in institutionalised older adult patients in long-term care institutions. A secondary purpose was to identify the risk factors that develop Sarcopenia in this population.

Methods: A Multicentre cross-sectional study was conducted in 334 institutionalised older adult patients, where the prevalence of sarcopenia and its relation with certain risk factors were measured. Physical performance was measured by gait speed, muscle strength measured by a handheld dynamometer and skeletal muscle mass measured using bioimpedance analysis. Different variables were collected: body mass index (BMI), diseases documented in the clinical record, the numbers of falls, the level of activity and functional ability.

Results: Two hundred eighty five individuals were included. According the EWGSOP algorithm and the cut-off points proposed by Masanes et al. for the Spanish population, 118 (41.4%) participants presented sarcopenia, of which 32 patients (27%) suffered from moderate sarcopenia, 78 patients (66%) were identified as severe sarcopenia patients and only 8 (7%) were classified as sarcopenic obesity. More female residents (96 females (81.4%) vs. 22 males (18.6%), p < 0.0001) tended to be sarcopenic. Patients diagnosed with sarcopenia tended to be more functionally impaired and had a more unfavourable BMI than those who were not sarcopenic (Barthel score 40.93 vs, 49.22, p = 0.0034 and BMI 23.57 vs, 27.61, p < 0.0001). Results from regression analysis indicated that those older than 85 years old (OR 2.495, 95% CI 1.401-4.441), the female gender, (OR 3.215, 95%CI 1.635-6.324) and whose BMI was lower than 22 (OR 5.973, 95% CI 2.932-12.165) appeared to be associated with sarcopenia, whereas the Barthel Index and other factors were not.

Conclusion: The present study suggests that sarcopenia is highly prevalent in patients living in long-term care institutions, especially in female patients. Our findings support that the muscle mass was negatively associated with poor nutritional status and poor capacity to develop basic activities of daily living that indicates high dependency of these patients and high necessity of care.
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http://dx.doi.org/10.1016/j.clnesp.2018.05.008DOI Listing
October 2018

Contribution of a Multifunctional Polymerase Region of Foot-and-Mouth Disease Virus to Lethal Mutagenesis.

J Virol 2018 10 26;92(20). Epub 2018 Sep 26.

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Cantoblanco, Madrid, Spain

Viral RNA-dependent RNA polymerases (RdRps) are major determinants of high mutation rates and generation of mutant spectra that mediate RNA virus adaptability. The RdRp of the picornavirus foot-and-mouth disease virus (FMDV), termed 3D, is a multifunctional protein that includes a nuclear localization signal (NLS) in its N-terminal region. Previous studies documented that some amino acid substitutions within the NLS altered nucleotide recognition and enhanced the incorporation of the mutagenic purine analogue ribavirin in viral RNA, but the mutants tested were not viable and their response to lethal mutagenesis could not be studied. Here we demonstrate that NLS amino acid substitution M16A of FMDV serotype C does not affect infectious virus production but accelerates ribavirin-mediated virus extinction. The mutant 3D displays polymerase activity, RNA binding, and copying processivity that are similar to those of the wild-type enzyme but shows increased ribavirin-triphosphate incorporation. Crystal structures of the mutant 3D in the apo and RNA-bound forms reveal an expansion of the template entry channel due to the replacement of the bulky Met by Ala. This is a major difference with other 3D mutants with altered nucleotide analogue recognition. Remarkably, two distinct loop β9-α11 conformations distinguish 3Ds that exhibit higher or lower ribavirin incorporation than the wild-type enzyme. This difference identifies a specific molecular determinant of ribavirin sensitivity of FMDV. Comparison of several polymerase mutants indicates that different domains of the molecule can modify nucleotide recognition and response to lethal mutagenesis. The connection of this observation with current views on quasispecies adaptability is discussed. The nuclear localization signal (NLS) of the foot-and-mouth disease virus (FMDV) polymerase includes residues that modulate the sensitivity to mutagenic agents. Here we have described a viable NLS mutant with an amino acid replacement that facilitates virus extinction by ribavirin. The corresponding polymerase shows increased incorporation of ribavirin triphosphate and local structural modifications that implicate the template entry channel. Specifically, comparison of the structures of ribavirin-sensitive and ribavirin-resistant FMDV polymerases has identified loop β9-α11 conformation as a determinant of sensitivity to ribavirin mutagenesis.
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http://dx.doi.org/10.1128/JVI.01119-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158410PMC
October 2018

Comparison of urinary iodine levels in women of childbearing age during and after pregnancy.

Eur J Nutr 2018 Aug 29;57(5):1807-1816. Epub 2017 Apr 29.

Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Purpose: Median urinary iodine concentration (UIC) is used to describe the iodine status of a population. However, the link between UIC and iodine intake may vary during pregnancy. The aim of this study was to compare UIC during and after pregnancy, adjusting for factors that affect iodine intake.

Methods: Two repeated measures of UIC and data on maternal iodine intake estimated through questionnaires were collected during pregnancy and 1-4 years after pregnancy in a subsample of women (n = 598) from a mother and child cohort study in Spain. Random-effects interval regression was used to assess the changes in UIC according to pregnancy status.

Results: Median UIC was similar during (133 μg/L) and after pregnancy (139 μg/L). After adjusting for iodised salt, iodine supplement consumption, and socio-demographic related variables, UIC was 24.0% (95% CI 11.3, 38.2) higher after than during pregnancy. This difference was maintained in a subsample of women with exhaustive information on diet (n = 291): 26.2%, 95% CI 10.3, 44.4.

Conclusions: In an iodine sufficient area for the general population, iodine excretion was lower during than after pregnancy when factors affecting iodine intake were controlled for. Current recommendations of median UIC during pregnancy are based on the equivalence between iodine intake and UIC estimated from studies in non-pregnant populations, which might lead to overestimation of iodine deficiency during gestation. Further studies should evaluate the equivalence between iodine intake and its urinary excretion during pregnancy.
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http://dx.doi.org/10.1007/s00394-017-1465-4DOI Listing
August 2018

Favipiravir can evoke lethal mutagenesis and extinction of foot-and-mouth disease virus.

Virus Res 2017 04 18;233:105-112. Epub 2017 Mar 18.

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, E-28049, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. Electronic address:

Antiviral agents are increasingly considered an option for veterinary medicine. An understanding of their mechanism of activity is important to plan their administration either as monotherapy or in combination with other agents. Previous studies have shown that the broad spectrum antiviral agent favipiravir (T-705) and its derivatives T-1105 and T-1106 are efficient inhibitors of foot-and-mouth disease virus (FMDV) replication in cell culture and in vivo. However, no mechanism for their activity against FMDV has been proposed. In the present study we show that favipiravir (T-705) can act as a lethal mutagen for FMDV in cell culture. Evidence includes virus extinction associated with increase in mutation frequency in the mutant spectrum of 860 residues of the 3D (polymerase)-coding region, and a decrease of specific infectivity while the consensus nucleotide sequence of the region analyzed remained invariant. The mutational spectrum evoked by favipiravir differs from that observed with other viruses in that no predominant transition type is observed, indicating that a movement towards A,U- or G,C-rich regions of sequence space is not a prerequisite for virus extinction. We discuss prospects for the use of favipiravir to assist in the control of FMDV, and its possible broader use in veterinary medicine as an extension of its current status as antiviral agent for human influenza virus.
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http://dx.doi.org/10.1016/j.virusres.2017.03.014DOI Listing
April 2017

Internal Disequilibria and Phenotypic Diversification during Replication of Hepatitis C Virus in a Noncoevolving Cellular Environment.

J Virol 2017 05 28;91(10). Epub 2017 Apr 28.

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain

Viral quasispecies evolution upon long-term virus replication in a noncoevolving cellular environment raises relevant general issues, such as the attainment of population equilibrium, compliance with the molecular-clock hypothesis, or stability of the phenotypic profile. Here, we evaluate the adaptation, mutant spectrum dynamics, and phenotypic diversification of hepatitis C virus (HCV) in the course of 200 passages in human hepatoma cells in an experimental design that precluded coevolution of the cells with the virus. Adaptation to the cells was evidenced by increase in progeny production. The rate of accumulation of mutations in the genomic consensus sequence deviated slightly from linearity, and mutant spectrum analyses revealed a complex dynamic of mutational waves, which was sustained beyond passage 100. The virus underwent several phenotypic changes, some of which impacted the virus-host relationship, such as enhanced cell killing, a shift toward higher virion density, and increased shutoff of host cell protein synthesis. Fluctuations in progeny production and failure to reach population equilibrium at the genomic level suggest internal instabilities that anticipate an unpredictable HCV evolution in the complex liver environment. Long-term virus evolution in an unperturbed cellular environment can reveal features of virus evolution that cannot be explained by comparing natural viral isolates. In the present study, we investigate genetic and phenotypic changes that occur upon prolonged passage of hepatitis C virus (HCV) in human hepatoma cells in an experimental design in which host cell evolutionary change is prevented. Despite replication in a noncoevolving cellular environment, the virus exhibited internal population disequilibria that did not decline with increased adaptation to the host cells. The diversification of phenotypic traits suggests that disequilibria inherent to viral populations may provide a selective advantage to viruses that can be fully exploited in changing environments.
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http://dx.doi.org/10.1128/JVI.02505-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411618PMC
May 2017

Off-label use of rilpivirine in combination with emtricitabine and tenofovir in HIV-1-infected pediatric patients: A multicenter study.

Medicine (Baltimore) 2016 Jun;95(24):e3842

Unidad de Enfermedades Infecciosas e Inmunopatologias, Hospital Infantil Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal Sección de Enfermedades Infecciosas, Servicio de Pediatría, Hospital General Universitario Gregorio Marañón, Madrid Unitat de Patologia Infecciosa i Immunodeficiències de Pediatria, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona Servicio de Infecciosas Pediátricas, Hospital Universitario Doce de Octubre Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM); Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid Unitat d'Infectologia, Servei de Pediatria; Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain Servicio de Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Madrid Unidad de Enfermedades Infecciosas e Inmunodeficiencias, Sección Urgencias de Pediatría, Hospital Universitario Virgen de las Nieves, Granada Enfermedades Infecciosas, Microbiología y Medicina Preventiva. Instituto de Biomedicina de Sevilla/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, Madrid, Spain.

To assess the safety and efficacy of rilpivirine in combination with emtricitabine and tenofovir (RPV/FTC/TDF) as a once-daily single-tablet regimen (STR) in HIV-1-infected children and adolescents we performed a multicenter case series study of HIV-1-infected patients. Inclusion criteria were initiation of therapy with RPV/FTC/TDF before the age of 18. Patients were divided into undetectable viral load (uVL) group, HIV-1 RNA < 20 copies/mL on stable combined antiretroviral therapy (cART), and detectable viral load (dVL) group, HIV-1 RNA ≥ 20 copies/mL at RPV/FTC/TDF initiation. Patients were monitored from the date of RPV/FTC/TDF initiation until June 30, 2015, RPV/FTC/TDF discontinuation or failure to follow-up. Seventeen patients (8 in uVL and 9 in dVL group) with age between 11.6 and 17.6 were included. Reasons for switching were toxicity (n = 4) and simplification (n = 4) in uVL; viral failure (n = 8) and cART initiation (n = 1) in the dVL group. After a median follow-up of 90 (uVL) and 40 weeks (dVL), 7/8 (86%) patients maintained and 8/9 (89%) achieved and maintained HIV-1 suppression. Median CD4 count increased from 542 to 780/μL (uVL, P = 0.069) and 480 to 830/μL (dVL, P = 0.051). Five patients (2 in uVL and 3 in dVL) improved their immunological status from moderate to no immunosuppression. Serum lipid profiles improved in both groups; cholesterol dropped significantly in the dVL group (P = 0.008). Grade 1 laboratory adverse events (AEs) were observed in 3 patients. No clinical AEs occurred. Adherence was complete in 9 patients (5 in uVL and 4 in dVL); 1 adolescent interrupted treatment. Once-daily STR with RPV/FTC/TDF may be a safe and effective choice in selected HIV-1-infected adolescents and children.
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http://dx.doi.org/10.1097/MD.0000000000003842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998448PMC
June 2016

Factor Structure, Reliability, and Validity of the Spanish Version of the Children's Florida Obsessive Compulsive Inventory (C-FOCI).

Child Psychiatry Hum Dev 2017 02;48(1):166-179

University of South Florida, Tampa, FL, USA.

The Children's Florida Obsessive Compulsive Inventory (C-FOCI) is a promising self-report measure of the presence and severity of obsessive-compulsive symptoms in children and adolescents. Although initial research showed it to have adequate psychometric properties, only one study has been published to date, which dealt exclusively with children. The aim of this report was to examine the psychometric properties of the C-FOCI across clinical and community samples of children and adolescents. The sample consisted of 94 Spanish-speaking patients with obsessive-compulsive disorder (OCD) and 1068 healthy community controls, aged 8-19 years. Factor analysis supported two single and independent factors (severity and symptoms), as well as metric invariance across groups for the symptom checklist and the Severity Scale. Results also indicated good reliability in terms of internal consistency and temporal stability, significant and high correlations with other OCD measures, and acceptable sensitivity and specificity for detect OCD. In summary, the C-FOCI is a promising, brief measure of 22 items for screening OCD symptoms and severity in children and adolescents.
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http://dx.doi.org/10.1007/s10578-016-0661-4DOI Listing
February 2017

Evaluation of Adult Acute Scrotum in the Emergency Room: Clinical Characteristics, Diagnosis, Management, and Costs.

Urology 2016 Aug 19;94:36-41. Epub 2016 May 19.

Department of Urology, University and Polytechnic Hospital La Fe, Valencia, Spain.

Objective: To evaluate the clinic characteristics, diagnosis, management, and costs of the adult acute scrotum in the emergency room (ER). Acute scrotum is a syndrome characterized by intense, acute scrotal pain that may be accompanied by other symptoms. It is usual in children and commonly found as well in adults, with different causal pathologies between these groups.

Methods: Between November 2013 and September 2014, 669 cases of adult acute scrotum who presented to our ER were prospectively analyzed. Patients under 15 years of age were excluded. Patient age, reason for consultation, investigations performed, final diagnosis, management, and costs were evaluated. For the statistical analysis, the Mann-Whitney, Kruskal-Wallis U, and chi-square tests were used.

Results: A total of 669 cases of acute scrotum were analyzed. The mean age at presentation was 40.2 ± 17.3 years. The most presented diagnoses were orchiepididymitis (28.7%), epididymitis (28.4%), symptoms of uncertain etiology (25.1%), and orchitis (10.3%). Diagnostic tests were carried out in 57.8% of cases. Most cases were treated as outpatients (94.2%), with 5.83% admitted and 1% undergoing surgical treatment. Overall, 13.3% of patients represented to the ER. Abnormal results in blood and urine tests were more common among older patients and infectious pathologies. The average cost generated by an acute scrotum ER consult was 195.03€.

Conclusion: Infectious pathologies are the most common causes of acute scrotum at ER. Abnormal blood and urine tests are unusual and are more common in older patients and infectious pathologies.
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http://dx.doi.org/10.1016/j.urology.2016.05.018DOI Listing
August 2016

Distance effects during polyprotein processing in the complementation between defective FMDV RNAs.

J Gen Virol 2016 07 12;97(7):1575-1583. Epub 2016 Apr 12.

Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d´Hebron, (VHIR-HUVH), Universitat Autònoma de Barcelona, Barcelona, Spain.

Passage of foot-and-mouth disease virus (FMDV) in BHK-21 cells resulted in the segmentation of the viral genome into two defective RNAs lacking part of either the L- or the capsid-coding region. The two RNAs are infectious by complementation. Electroporation of L-defective RNA in BHK-21 cells resulted in the accumulation of the precursor P3 located away from the deleted sequence. Expression of L in trans led to the processing of P3, indicating that there is a connection between L protease activity and the secondary cleavages carried out by 3C protease within P3. These results suggest that the complementation mechanism between defective RNAs is not restricted to supplying the L and capsid proteins but that distance effects on polyprotein processing events are also implicated.
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http://dx.doi.org/10.1099/jgv.0.000480DOI Listing
July 2016

Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus.

Antimicrob Agents Chemother 2016 06 23;60(6):3786-93. Epub 2016 May 23.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

Sofosbuvir displays a high phenotypic barrier to resistance, and it is a component of several combination therapies for hepatitis C virus (HCV) infections. HCV fitness can be a determinant of decreased sensitivity to direct-acting antiviral agents such as telaprevir or daclatasvir, but fitness-dependent decreased drug sensitivity has not been established for drugs with a high phenotypic barrier to resistance. Low- and high-fitness HCV populations and biological clones derived from them were used to infect Huh-7.5 hepatoma cells. Sofosbuvir efficacy was analyzed by measuring virus progeny production during several passages and by selection of possible sofosbuvir resistance mutations determined by sequencing the NS5B-coding region of the resulting populations. Sofosbuvir exhibited reduced efficacy against high-fitness HCV populations, without the acquisition of sofosbuvir-specific resistance mutations. A reduced sofosbuvir efficacy, similar to that observed with the parental populations, was seen for high-fitness individual biological clones. In independently derived high-fitness HCV populations or clones passaged in the presence of sofosbuvir, M289L was selected as the only substitution in the viral polymerase NS5B. In no case was the sofosbuvir-specific resistance substitution S282T observed. High HCV fitness can lead to decreased sensitivity to sofosbuvir, without the acquisition of specific sofosbuvir resistance mutations. Thus, fitness-dependent drug sensitivity can operate with HCV inhibitors that display a high barrier to resistance. This mechanism may underlie treatment failures not associated with selection of sofosbuvir-specific resistance mutations, linked to in vivo fitness of pretreatment viral populations.
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http://dx.doi.org/10.1128/AAC.00581-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879421PMC
June 2016

Clonality and intracellular polyploidy in virus evolution and pathogenesis.

Proc Natl Acad Sci U S A 2015 Jul 20;112(29):8887-92. Epub 2015 Jul 20.

Centro de Biologia Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, E-28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; and

In the present article we examine clonality in virus evolution. Most viruses retain an active recombination machinery as a potential means to initiate new levels of genetic exploration that go beyond those attainable solely by point mutations. However, despite abundant recombination that may be linked to molecular events essential for genome replication, herein we provide evidence that generation of recombinants with altered biological properties is not essential for the completion of the replication cycles of viruses, and that viral lineages (near-clades) can be defined. We distinguish mechanistically active but inconsequential recombination from evolutionarily relevant recombination, illustrated by episodes in the field and during experimental evolution. In the field, recombination has been at the origin of new viral pathogens, and has conferred fitness advantages to some viruses once the parental viruses have attained a sufficient degree of diversification by point mutations. In the laboratory, recombination mediated a salient genome segmentation of foot-and-mouth disease virus, an important animal pathogen whose genome in nature has always been characterized as unsegmented. We propose a model of continuous mutation and recombination, with punctuated, biologically relevant recombination events for the survival of viruses, both as disease agents and as promoters of cellular evolution. Thus, clonality is the standard evolutionary mode for viruses because recombination is largely inconsequential, since the decisive events for virus replication and survival are not dependent on the exchange of genetic material and formation of recombinant (mosaic) genomes.
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http://dx.doi.org/10.1073/pnas.1501715112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517279PMC
July 2015

Validation of the Short Obsessive-Compulsive Disorder Screener (SOCS) in children and adolescents.

BJPsych Open 2015 Jun 10;1(1):21-26. Epub 2015 Jul 10.

, PhD, Universidad de Málaga, Málaga, Spain.

Background: The Short Obsessive-Compulsive Disorder Screener (SOCS) is recommended by the National Institute for Health and Care Excellence as a suitable and validated screening tool for 11- to 15-year olds. Despite its excellent sensitivity and specificity in detecting obsessive-compulsive disorder (OCD), it has limitations.

Aims: To empirically examine whether the SOCS is suitable for assessing OCD symptoms across a wide age range of children and adolescents and to provide new data about its psychometric properties.

Method: Participants were 94 patients (9-19 years) with OCD, and 880 healthy controls.

Results: The results supported the SOCS' unidimensional factor structure and metric invariance across samples. It showed good reliability in terms of internal consistency and temporal stability. Furthermore, it had significantly high correlations with other OCD measures and an acceptable sensitivity and specificity for detecting OCD.

Conclusions: The SOCS is a brief screening tool suitable for detecting OCD in children and adolescents.

Declaration Of Interest: None.

Copyright And Usage: © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.
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http://dx.doi.org/10.1192/bjpo.bp.115.000695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998931PMC
June 2015

Multifunctionality of a picornavirus polymerase domain: nuclear localization signal and nucleotide recognition.

J Virol 2015 Jul 22;89(13):6848-59. Epub 2015 Apr 22.

Institut de Biologia Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Barcelona, Spain

Unlabelled: The N-terminal region of the foot-and-mouth disease virus (FMDV) 3D polymerase contains the sequence MRKTKLAPT (residues 16 to 24) that acts as a nuclear localization signal. A previous study showed that substitutions K18E and K20E diminished the transport to the nucleus of 3D and 3CD and severely impaired virus infectivity. These residues have also been implicated in template binding, as seen in the crystal structures of different 3D-RNA elongation complexes. Here, we report the biochemical and structural characterization of different mutant polymerases harboring substitutions at residues 18 and 20, in particular, K18E, K18A, K20E, K20A, and the double mutant K18A K20A (KAKA). All mutant enzymes exhibit low RNA binding activity, low processivity, and alterations in nucleotide recognition, including increased incorporation of ribavirin monophosphate (RMP) relative to the incorporation of cognate nucleotides compared with the wild-type enzyme. The structural analysis shows an unprecedented flexibility of the 3D mutant polymerases, including both global rearrangements of the closed-hand architecture and local conformational changes at loop β9-α11 (within the polymerase motif B) and at the template-binding channel. Specifically, in 3D bound to RNA, both K18E and K20E induced the opening of new pockets in the template channel where the downstream templating nucleotide at position +2 binds. The comparisons of free and RNA-bound enzymes suggest that the structural rearrangements may occur in a concerted mode to regulate RNA replication, processivity, and fidelity. Thus, the N-terminal region of FMDV 3D that acts as a nuclear localization signal (NLS) and in template binding is also involved in nucleotide recognition and can affect the incorporation of nucleotide analogues.

Importance: The study documents multifunctionality of a nuclear localization signal (NLS) located at the N-terminal region of the foot-and-mouth disease viral polymerase (3D). Amino acid substitutions at this polymerase region can impair the transport of 3D to the nucleus, reduce 3D binding to RNA, and alter the relative incorporation of standard nucleoside monophosphate versus ribavirin monophosphate. Structural data reveal that the conformational changes in this region, forming part of the template channel entry, would be involved in nucleotide discrimination. The results have implications for the understanding of viral polymerase function and for lethal mutagenesis mechanisms.
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http://dx.doi.org/10.1128/JVI.03283-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468482PMC
July 2015

Microstructural brain abnormalities and symptom dimensions in child and adolescent patients with obsessive-compulsive disorder: a diffusion tensor imaging study.

Depress Anxiety 2014 Dec 28;31(12):1007-17. Epub 2014 Nov 28.

Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clínic Universitari, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en red de Salud Mental (CIBERSAM), Spain.

Background: The aims of this study were to determine white matter (WM) microstructure abnormalities in obsessive-compulsive disorder (OCD) using diffusion tensor imaging, and to investigate whether these abnormalities differ according to OCD symptom dimensions.

Methods: Sixty-three child and adolescent OCD patients (11-18 years old) and 37 healthy subjects matched for gender, age, and estimated intelligence quotient were assessed by means of psychopathology scales and diffusion tensor magnetic resonance imaging.

Results: Compared with healthy controls OCD patients showed a significant decrease (t = 3.79, P = .049 FDR-corrected) in fractional anisotropy (FA) in the anterior region of the corpus callosum (CC). In addition, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were significantly increased in OCD compared with controls in the CC and in several WM regions of the cingulate, frontal and occipital lobes, basal ganglia, cerebellum, and pons. Compared with healthy controls, OCD patients presenting the harm/checking dimension showed decreased FA in the CC and in the left anterior cingulate gyrus and caudate nucleus, whereas patients with a predominant contamination/washing symptom dimension presented significantly decreased FA in the left midbrain, lentiform nucleus, insula, and thalamus, and increased MD, AD, and RD in both the anterior lobes of cerebellum and in the pons.

Conclusions: The findings suggest WM abnormalities at the microstructural level in the pathogenesis of OCD. Moreover, WM abnormalities in OCD may vary according to the specific OCD symptom dimensions, thus indicating the clinical heterogeneity of the condition.
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http://dx.doi.org/10.1002/da.22330DOI Listing
December 2014