Broad Spectrum Antiviral Activity of Favipiravir (T-705): Protection from Highly Lethal Inhalational Rift Valley Fever

Background:Development of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705), which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV). RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route.Methodology/Principal Findings:Wistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92%) survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease.Conclusions/Significance:Currently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug. © 2014 Caroline et al

Caretaker Brca1: keeping the genome in the straight and narrow

Inheritance of germline BRCA1 mutations is associated with a high risk of breast and ovarian cancers. A multitude of cellular functions has been ascribed to BRCA1, including transcription activation and various aspects of DNA repair. So far, indirect evidence has indicated a role for BRCA1 in the repair of double-strand breaks. Recently, an elegant gene targeting design was used to provide definitive evidence that BRCA1 promotes homologous recombination and limits nonhomologous mutagenic repair processes. This reaffirms the role of BRCA1 as caretaker in preserving genomic integrity

Motor contagion: the contribution of trajectory and end-points

Increased involuntary arm movement deviation when observing an incongruent human arm movement has been interpreted as a strong indicator of motor contagion. Here, we examined the contribution of trajectory and end-point information on motor contagion by altering congruence between the stimulus and arm movement. Participants performed cyclical horizontal arm movements whilst simultaneously observing a stimulus representing human arm movement. The stimuli comprised congruent horizontal movements or vertical movements featuring incongruent trajectory and end-points. A novel, third, stimulus comprised curvilinear movements featuring congruent end-points, but an incongruent trajectory. In Experiment 1, our dependent variables indicated increased motor contagion when observing the vertical compared to horizontal movement stimulus. There was even greater motor contagion in the curvilinear stimulus condition indicating an additive effect of an incongruent trajectory comprising congruent end-points. In Experiment 2, this additive effect was also present when facing perpendicular to the display, and thus with end-points represented as a product of the movement rather than an external spatial reference. Together, these findings support the theory of event coding (Hommel et al., Behav Brain Sci 24:849–878, 2001), and the prediction that increased motor contagion takes place when observed and executed actions share common features (i.e., movement end-points)

Atypical Social Modulation of Imitation in Autism Spectrum Conditions.

Appropriate modulation of imitation according to social context is important for successful social interaction. In the present study we subliminally primed high-functioning adults with ASC and age- and IQ-matched controls with either a pro- or non- social attitude. Following priming, an automatic imitation paradigm was used to acquire an index of imitation. Whereas imitation levels were higher for pro-socially primed relative to non-socially primed control participants, there was no difference between pro- and non- socially primed individuals with ASC. We conclude that high-functioning adults with ASC demonstrate atypical social modulation of imitation. Given the importance of imitation in social interaction we speculate that difficulties with the modulation of imitation may contribute to the social problems characteristic of ASC

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Subtle oculomotor difficulties and their relation to motor skill in children with autism spectrum disorder

Objectives Sensorimotor difficulties are often reported in autism spectrum disorders (ASD). Visual and motor skills are linked in that the processing of visual information can help in guiding motor movements. The present study investigated oculomotor skill and its relation to general motor skill in ASD by providing a comprehensive assessment of oculomotor control. Methods Fifty children (25 ASD; 25 typically developing [TD]), aged 7–10 years, completed a motor assessment (comprising fine and gross motor tasks) and oculomotor battery (comprising fixation, smooth pursuit, prosaccade and antisaccade tasks). Results No group differences were found for antisaccade errors, nor saccade latencies in prosaccade and antisaccade tasks, but increased saccade amplitude variability was observed in children with ASD, suggesting a reduced consistency in saccade accuracy. Children with ASD also demonstrated poorer fixation stability than their peers and spent less time in pursuit of a moving target. Motor skill was not correlated with saccade amplitude variability. However, regression analyses revealed that motor skill (and not diagnosis) accounted for variance in fixation performance and fast smooth pursuit. Conclusions The findings highlight the importance of considering oculomotor paradigms to inform the functional impact of neuropathologies in ASD and also assessing the presentation of co-occurring difficulties to further our understanding of ASD. Avenues for future research are suggested

Moving Just Like You: Motor Interference Depends on Similar Motility of Agent and Observer

Recent findings in neuroscience suggest an overlap between brain regions involved in the execution of movement and perception of another’s movement. This so-called “action-perception coupling” is supposed to serve our ability to automatically infer the goals and intentions of others by internal simulation of their actions. A consequence of this coupling is motor interference (MI), the effect of movement observation on the trajectory of one’s own movement. Previous studies emphasized that various features of the observed agent determine the degree of MI, but could not clarify how human-like an agent has to be for its movements to elicit MI and, more importantly, what ‘human-like’ means in the context of MI. Thus, we investigated in several experiments how different aspects of appearance and motility of the observed agent influence motor interference (MI). Participants performed arm movements in horizontal and vertical directions while observing videos of a human, a humanoid robot, or an industrial robot arm with either artificial (industrial) or human-like joint configurations. Our results show that, given a human-like joint configuration, MI was elicited by observing arm movements of both humanoid and industrial robots. However, if the joint configuration of the robot did not resemble that of the human arm, MI could longer be demonstrated. Our findings present evidence for the importance of human-like joint configuration rather than other human-like features for perception-action coupling when observing inanimate agents

Geophysical and geochemical survey of a large marine pockmark on the Malin Shelf, Ireland

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 13 (2012): Q01011, doi:10.1029/2011GC003787.Marine pockmarks are a specific type of seabed geological setting resembling craters or pits and are considered seabed surface expressions of fluid flow in the subsurface. A large composite pockmark on the Malin Shelf, off the northern coast of Ireland was surveyed and ground truthed to assess its activity and investigate fluid related processes in the subsurface. Geophysical (including acoustic and electromagnetic) data confirmed the subsurface presence of signatures typical of fluids within the sediment. Shallow seismic profiling revealed a large shallow gas pocket and typical gas related indicators such as acoustic blanking and enhanced reflectors present underneath and around the large pockmark. Sulphate profiles indicate that gas from the shallow reservoir has been migrating upwards, at least recently. However, there are no chimney structures observed in the sub-bottom data and the migration pathways are not apparent. Electromagnetic data show slightly elevated electrical conductivity on the edges of the pockmarks and a drop below regional levels within the confines of the pockmark, suggesting changes in physical properties of the sediment. Nuclear Magnetic Resonance (NMR) experiments were employed to characterize the organic component of sediments from selected depths. Very strong microbial signatures were evident in all NMR spectra but microbes outside the pockmark appear to be much more active than inside. These observations coincide with spikes in conductivity and the lateral gas bearing body suggesting that there is an increase in microbial activity and biomass when gas is present.We wish to thank the Geological Survey of Ireland, the INtegrated Mapping FOr the Sustainable Development of Ireland’s MArine Resource (INFOMAR) program, the Irish Environmental Protection Agency, Science Foundation of Ireland, QUESTOR (Queens University Belfast) and the Irish Council for Science, engineering and technology for funding this research. AJS thanks NSERC, (Strategic and Discovery Programs), the Canada Foundation for Innovation (CFI), and the Ministry of Research and Innovation (MRI) for providing Canadian funding. The survey data utilized in the research has been co‐funded by the Geological Survey of Ireland and the Offshore Irish Petroleum Infrastructure Programme (PIP; Ref. No: IS05/16 Malin Basin EM).2012-07-1