Héctor Moreno

Ribavirin Can Be Mutagenic for Arenaviruses

ABSTRACT Arenaviruses include several important human pathogens, and there are very limited options of preventive or therapeutic interventions to combat these viruses. An off-label use of the purine nucleoside analogue ribavirin (1-β-d-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) is the only antiviral treatment currently available for arenavirus infections. However, the ribavirin antiviral mechanism action against arenaviruses remains unknown. Here we document that ribavirin is mutagenic for the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) in cell culture. The mutagenic activity of ribavirin on LCMV was observed under single- and multiple-passage regimes and could not be accounted for by a decrease of the intracellular GTP pool promoted by ribavirin-mediated inhibition of inosine monophosphate dehydrogenase (IMPDH). Our findings suggest that the antiviral activity of ribavirin on arenaviruses might be exerted, at least partially, by lethal mutagenesis. Implications for antiarenavirus therapy are discussed.

ROAD: domestic assistant and rehabilitation robot

This study introduces the concept design and analysis of a robotic system for the assistance and rehabilitation of disabled people. Based on the statistical data of the most common types of disabilities in Spain and other industrialized countries, the different tasks that the device must be able to perform have been determined. In this study, different robots for rehabilitation and assistance previously introduced have been reviewed. This survey is focused on those robots that assist with gait, balance and standing up. The structure of the ROAD robot presents various advantages over these robots, we discuss some of them. The performance of the proposed architecture is analyzed when it performs the sit to stand activity.

Arenaviruses and Lethal Mutagenesis. Prospects for New Ribavirin-based Interventions

Lymphocytic choriomeningitis virus (LCMV) has contributed to unveil some of the molecular mechanisms of lethal mutagenesis, or loss of virus infectivity due to increased mutation rates. Here we review these developments, and provide additional evidence that ribavirin displays a dual mutagenic and inhibitory activity on LCMV that can be relevant to treatment designs. Using 5-fluorouracil as mutagenic agent and ribavirin either as inhibitor or mutagen, we document an advantage of a sequential inhibitor-mutagen administration over the corresponding combination treatment to achieve a low LCMV load in cell culture. This advantage is accentuated in the concentration range in which ribavirin acts mainly as an inhibitor, rather than as mutagen. This observation reinforces previous theoretical and experimental studies in supporting a sequential inhibitor-mutagen administration as a possible antiviral design. Given recent progress in the development of new inhibitors of arenavirus replication, our results suggest new options of ribavirin-based anti-arenavirus treatments.

Vaccination with Recombinant Adenoviruses Expressing the Peste des Petits Ruminants Virus F or H Proteins Overcomes Viral Immunosuppression and Induces Protective Immunity against PPRV Challenge in Sheep

Peste des petits ruminants (PPR) is a highly contagious disease of small ruminants caused by the Morbillivirus peste des petits ruminants virus (PPRV). Two recombinant replication-defective human adenoviruses serotype 5 (Ad5) expressing either the highly immunogenic fusion protein (F) or hemagglutinin protein (H) from PPRV were used to vaccinate sheep by intramuscular inoculation. Both recombinant adenovirus vaccines elicited PPRV-specific B- and T-cell responses. Thus, neutralizing antibodies were detected in sera from immunized sheep. In addition, we detected a significant antigen specific T-cell response in vaccinated sheep against two different PPRV strains, indicating that the vaccine induced heterologous T cell responses. Importantly, no clinical signs and undetectable virus shedding were observed after virulent PPRV challenge in vaccinated sheep. These vaccines also overcame the T cell immunosuppression induced by PPRV in control animals. The results indicate that these adenovirus constructs could be a promising alternative to current vaccine strategies for the development of PPRV DIVA vaccines.

Mutagenesis-Mediated Virus Extinction: Virus-Dependent Effect of Viral Load on Sensitivity to Lethal Defection

Background Lethal mutagenesis is a transition towards virus extinction mediated by enhanced mutation rates during viral genome replication, and it is currently under investigation as a potential new antiviral strategy. Viral load and virus fitness are known to influence virus extinction. Here we examine the effect or the multiplicity of infection (MOI) on progeny production of several RNA viruses under enhanced mutagenesis. Results The effect of the mutagenic base analogue 5-fluorouracil (FU) on the replication of the arenavirus lymphocytic choriomeningitis virus (LCMV) can result either in inhibition of progeny production and virus extinction in infections carried out at low multiplicity of infection (MOI), or in a moderate titer decrease without extinction at high MOI. The effect of the MOI is similar for LCMV and vesicular stomatitis virus (VSV), but minimal or absent for the picornaviruses foot-and-mouth disease virus (FMDV) and encephalomyocarditis virus (EMCV). The increase in mutation frequency and Shannon entropy (mutant spectrum complexity) as a result of virus passage in the presence of FU was more accentuated at low MOI for LCMV and VSV, and at high MOI for FMDV and EMCV. We present an extension of the lethal defection model that agrees with the experimental results. Conclusions (i) Low infecting load favoured the extinction of negative strand viruses, LCMV or VSV, with an increase of mutant spectrum complexity. (ii) This behaviour is not observed in RNA positive strand viruses, FMDV or EMCV. (iii) The accumulation of defector genomes may underlie the MOI-dependent behaviour. (iv) LCMV coinfections are allowed but superinfection is strongly restricted in BHK-21 cells. (v) The dissimilar effects of the MOI on the efficiency of mutagenic-based extinction of different RNA viruses can have implications for the design of antiviral protocols based on lethal mutagenesis, presently under development.

Two replication-defective adenoviral vaccine vectors for the induction of immune responses to PPRV

Peste des petits ruminants is a highly contagious disease of small ruminants caused by a Morbillivirus, peste des petits ruminants virus (PPRV). Two recombinant replication-defective human adenovirus serotype 5 (Ad5) containing the highly immunogenic fusion protein (F) and hemaglutinine protein (H) genes from PPRV were constructed. HEK293A cells infected with either virus (Ad5-PPRV-F or -H) express F and H proteins respectively. These viruses were used to vaccinate mice by intramuscular inoculation. Both viruses elicited PPRV-specific B- and T-cell responses. Thus, after two immunizations, sera from immunized mice elicited neutralizing antibody response, indicating that this approach has the potential to confer protective immunity. In addition, we detected a significant antigen specific CD4(+) and CD8(+) T-cell response in mice vaccinated with either virus. These results indicate that these adenovirus constructs offer a promising alternative to current vaccine strategies for the development of PPRV DIVA vaccines.

Neural Networks for FDI on the First Actuator of a Two-Link Planar Manipulator

This paper shows an approach to use a Neural Network trained by the classic backpropagation algorithm for solving the problem of fault detection and isolation (FDI) of simple mechanisms subject to failures in actuators. The approach taken was to reserve the term of the projection of the tuning algorithm used for keeping bounded the weight, and use it at the time of the fault. Works like Vemuri et.al. [12], where faults are focused in the inertia matrix and the isolation technique does not show clearly the results it aims, were the inspiration for this research. Here the fault is modelled as a torque suddenly bounded at first actuator and a neural network of two layers is used with an adaptive law whose projection operation is a reserved degree of freedom for keeping the system under control.

Dynamic Analysis of the ROAD Robot During the Sit to Stand Task

There is a large part of the population that needs technical assistance to accomplish with activities of daily living, among them are the elderly and those with a physical disability. We found that a technical assistance that is commonly needed by those users is to help to stand up or sit down. This work presents the dynamic analysis of a robotic device that helps with this task. The analysis presented here can be useful for simulation, design, path planning and control of the mechanism.

2 DOF Mechanism for a Variable Geometry Hybrid Wheel

The design of a 2 degree of freedom (DOF) mechanism for a variable geometry hybrid wheel is presented in this paper. The mechanism allows transforming a circular wheel in a hybrid one with multiple limbs. It is actuated by both rotational and a linear motors mounted on the vehicle chassis. The former rotates the wheel and the linear motor makes that the legs be extended or contracted. The highlights of the mechanism are discussed in the paper.

Multibody Dynamics Model of a Human Hand for Haptics Interaction

In this paper we propose a strategy for modelling a human hand for Haptics interaction.The strategy consists in a parallel computing architecture that calculates the dynamics of a hand, this is accomplished by computing the dynamics of each finger in a parallel manner. In this approach multiple threads (e.g. haptics thread, graphics thread, collision detection thread, etc.) run concurrently and therefore we developed a synchronization mechanism for data exchange. We describe in detail the elements of the developed software.