Embodied perspective-taking indicated by selective disruption from aberrant self motion

Spatial perspective-taking that involves imagined changes in one’s spatial orientation is facilitated by vestibular stimulation inducing a congruent sensation of self-motion. We examined further the role of vestibular resources in perspective-taking by evaluating whether aberrant and conflicting vestibular stimulation impaired perspective-taking performance. Participants (N = 39) undertook either an “own body transformation” (OBT)task, requiring speeded spatial judgments made from the perspective of a schematic figure, or a control task requiring reconfiguration of spatial mappings from one’s own visuo-spatial perspective. These tasks were performed both without and with vestibular stimulation by whole-body Coriolis motion, according to a repeated measures design, balanced for order. Vestibular stimulation was found to impair performance during the first minute post stimulus relative to the stationary condition. This disruption was task-specific, affecting only the OBT task and not the control task, and dissipated by the second minute post-stimulus. Our experiment thus demonstrates selective temporary impairment of perspective-taking from aberrant vestibular stimulation, implying that uncompromised vestibular resources are necessary for efficient perspective-taking. This finding provides evidence for an embodied mechanism for perspective-taking whereby vestibular input contributes to multisensory processing underlying bodily and social cognition. Ultimately, this knowledge may contribute to the design of interventions that help patients suffering sudden vertigo adapt to the cognitive difficulties caused by aberrant vestibular stimulation

A diagnosis of the plasma waves responsible for the explosive energy release of substorm onset

During geomagnetic substorms, stored magnetic and plasma thermal energies are explosively converted into plasma kinetic energy. This rapid reconfiguration of Earth’s nightside magnetosphere is manifest in the ionosphere as an auroral display that fills the sky. Progress in understanding of how substorms are initiated is hindered by a lack of quantitative analysis of the single consistent feature of onset; the rapid brightening and structuring of the most equatorward arc in the ionosphere. Here, we exploit state-of-the-art auroral measurements to construct an observational dispersion relation of waves during substorm onset. Further, we use kinetic theory of high-beta plasma to demonstrate that the shear Alfven wave dispersion relation bears remarkable similarity to the auroral dispersion relation. In contrast to prevailing theories of substorm initiation, we demonstrate that auroral beads seen during the majority of substorm onsets are likely the signature of kinetic Alfven waves driven unstable in the high-beta magnetotail

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

Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation

The second extracellular loop (EL2) of rhodopsin forms a cap over the binding site of its photoreactive 11-cis retinylidene chromophore. A crucial question has been whether EL2 forms a reversible gate that opens upon activation or acts as a rigid barrier. Distance measurements using solid-state 13C NMR spectroscopy between the retinal chromophore and the β4 strand of EL2 show that the loop is displaced from the retinal binding site upon activation, and there is a rearrangement in the hydrogen-bonding networks connecting EL2 with the extracellular ends of transmembrane helices H4, H5 and H6. NMR measurements further reveal that structural changes in EL2 are coupled to the motion of helix H5 and breaking of the ionic lock that regulates activation. These results provide a comprehensive view of how retinal isomerization triggers helix motion and activation in this prototypical G protein-coupled receptor. © 2009 Nature America, Inc. All rights reserved

A new framework for cortico-striatal plasticity: behavioural theory meets In vitro data at the reinforcement-action interface

Operant learning requires that reinforcement signals interact with action representations at a suitable neural interface. Much evidence suggests that this occurs when phasic dopamine, acting as a reinforcement prediction error, gates plasticity at cortico-striatal synapses, and thereby changes the future likelihood of selecting the action(s) coded by striatal neurons. But this hypothesis faces serious challenges. First, cortico-striatal plasticity is inexplicably complex, depending on spike timing, dopamine level, and dopamine receptor type. Second, there is a credit assignment problem—action selection signals occur long before the consequent dopamine reinforcement signal. Third, the two types of striatal output neuron have apparently opposite effects on action selection. Whether these factors rule out the interface hypothesis and how they interact to produce reinforcement learning is unknown. We present a computational framework that addresses these challenges. We first predict the expected activity changes over an operant task for both types of action-coding striatal neuron, and show they co-operate to promote action selection in learning and compete to promote action suppression in extinction. Separately, we derive a complete model of dopamine and spike-timing dependent cortico-striatal plasticity from in vitro data. We then show this model produces the predicted activity changes necessary for learning and extinction in an operant task, a remarkable convergence of a bottom-up data-driven plasticity model with the top-down behavioural requirements of learning theory. Moreover, we show the complex dependencies of cortico-striatal plasticity are not only sufficient but necessary for learning and extinction. Validating the model, we show it can account for behavioural data describing extinction, renewal, and reacquisition, and replicate in vitro experimental data on cortico-striatal plasticity. By bridging the levels between the single synapse and behaviour, our model shows how striatum acts as the action-reinforcement interface

A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis

During angiogenesis, Rho GTPases influence endothelial cell migration and cell-cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that recapitulates distinct stages of VEGF-dependent angiogenesis, we show that lumen formation requires early cytoskeletal remodelling and lateral cell-cell contacts, mediated through the RAC1 guanine nucleotide exchange factor (GEF) DOCK4. DOCK4 signalling is necessary for lateral filopodial protrusions and tubule remodelling prior to lumen formation, whereas proximal, tip filopodia persist in the absence of DOCK4. VEGF-dependent Rac activation via DOCK4 is necessary for CDC42 activation to signal filopodia formation and depends on the activation of RHOG through the RHOG GEF, SGEF. VEGF promotes interaction of DOCK4 with the CDC42 GEF DOCK9. These studies identify a novel Rho-family GTPase activation cascade for the formation of endothelial cell filopodial protrusions necessary for tubule remodelling, thereby influencing subsequent stages of lumen morphogenesis

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity

Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1

Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag−/− mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.National Institutes of Health (U.S.) (NIH grant R01-CA075576)National Institutes of Health (U.S.) (NIH grant R01-CA055042)National Institutes of Health (U.S.) (NIH grant R01-CA149261)National Institutes of Health (U.S.) (NIH grant P30-ES00002)National Institutes of Health (U.S.) (NIH grant P30-ES02109)National Center for Research Resources (U.S.) (grant number M01RR-01066)National Center for Research Resources (U.S.) (grant number UL1 RR025758, Harvard Clinical and Translational Science Center

Atypical Neurophysiology Underlying Episodic and Semantic Memory in Adults with Autism Spectrum Disorder

Individuals with autism spectrum disorder (ASD) show atypicalities in episodic memory (Boucher et al. in Psychological Bulletin, 138 (3), 458-496, 2012). We asked participants to recall the colours of a set of studied line drawings (episodic judgement), or to recognize line drawings alone (semantic judgement). Cycowicz et al. (Journal of Experimental Child Psychology, 65, 171-237, 2001) found early (300 ms onset) posterior old-new event-related potential effects for semantic judgements in typically developing (TD) individuals, and occipitally focused negativity (800 ms onset) for episodic judgements. Our results replicated findings in TD individuals and demonstrate attenuated early old-new effects in ASD. Late posterior negativity was present in the ASD group, but was not specific to this time window. This non-specificity may contribute to the atypical episodic memory judgements characteristic of individuals with ASD