Autonomic arousal and attentional orienting to visual threat are predicted by awareness

The rapid detection and evaluation of threat is of fundamental importance for survival. Theories suggest that this evolutionary pressure has driven functional adaptations in a specialized visual pathway that evaluates threat independently of conscious awareness. This is supported by evidence that threat-relevant stimuli rendered invisible by backward masking can induce physiological fear responses and modulate spatial attention. The validity of these findings has since been questioned by research using stringent, objective measures of awareness. Here, we use a modified continuous flash suppression paradigm to ask whether threatening images induce adaptive changes in autonomic arousal, attention, or perception when presented outside of awareness. In trials where stimuli broke suppression to become visible, threatening stimuli induced a significantly larger skin conductance response than nonthreatening stimuli and attracted spatial attention over scrambled images. However, these effects were eliminated in trials where observers were unaware of the stimuli. In addition, concurrent behavioral data provided no evidence that threatening images gained prioritized access to awareness. Taken together, our data suggest that the evaluation and spatial detection of visual threat are predicted by awareness

Fearful faces have a sensory advantage in the competition for awareness

Only a subset of visual signals give rise to a conscious percept. Threat signals, such as fearful faces, are particularly salient to human vision. Research suggests that fearful faces are evaluated without awareness and preferentially promoted to conscious perception. This agrees with evolutionary theories that posit a dedicated pathway specialized in processing threat-relevant signals. We propose an alternative explanation for this "fear advantage." Using psychophysical data from continuous flash suppression (CFS) and masking experiments, we demonstrate that awareness of facial expressions is predicted by effective contrast: the relationship between their Fourier spectrum and the contrast sensitivity function. Fearful faces have higher effective contrast than neutral expressions and this, not threat content, predicts their enhanced access to awareness. Importantly, our findings do not support the existence of a specialized mechanism that promotes threatening stimuli to awareness. Rather, our data suggest that evolutionary or learned adaptations have molded the fearful expression to exploit our general-purpose sensory mechanisms

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles.IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve \u3e 95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets

Redefining the "carrier" state for foot-and-mouth disease from the dynamics of virus persistence in endemically affected cattle populations

The foot-and-mouth disease virus (FMDV) “carrier” state was defined by van Bekkum in 1959. It was based on the recovery of infectious virus 28 days or more post infection and has been a useful construct for experimental studies. Using historic data from 1,107 cattle, collected as part of a population based study of endemic FMD in 2000, we developed a mixed effects logistic regression model to predict the probability of recovering viable FMDV by probang and culture, conditional on the animal’s age and time since last reported outbreak. We constructed a second set of models to predict the probability of an animal being probang positive given its antibody response in three common non-structural protein (NSP) ELISAs and its age. We argue that, in natural ecological settings, the current definition of a ”carrier” fails to capture the dynamics of either persistence of the virus (as measured by recovery using probangs) or the uncertainty in transmission from such animals that the term implies. In these respects it is not particularly useful. We therefore propose the first predictive statistical models for identifying persistently infected cattle in an endemic setting that captures some of the dynamics of the probability of persistence. Furthermore, we provide a set of predictive tools to use alongside NSP ELISAs to help target persistently infected cattle

‘Triple wins’ or ‘triple faults’? Analysing the equity implications of policy discourses on climate-smart agriculture (CSA)

This paper analyses contrasting discourses of ‘climate-smart agriculture’ (CSA) for their implications on control over and access to changing resources in agriculture. One of the principal areas of contestation around CSA relates to equity, including who wins and who loses, who is able to participate, and whose knowledge and perspectives count in the process. Yet to date, the equity implications of CSA remain an under-researched area. We apply an equity framework centred on procedure, distribution and recognition, to four different discourses. Depending on which discourses are mobilised, the analysis helps to illuminate: (1) how CSA may transfer the burden of responsibility for climate change mitigation to marginalised producers and resource managers (distributive equity); (2) how CSA discourses generally fail to confront entrenched power relations that may constrain or block the emergence of more ‘pro-poor’ forms of agricultural development, adaptation to climate change, or carbon sequestration and storage (procedural equity); (3) how CSA discourses can have tangible implications for the bargaining power of the poorest and most vulnerable groups (recognition). The paper contributes to work showing the need for deeper acknowledgement of the political nature of the transformations necessary to address the challenges caused by a changing climate for the agricultural sector

Lack of privileged access to awareness for rewarding social scenes in Autism Spectrum Disorder

Reduced social motivation is hypothesised to underlie social behavioural symptoms of Autism Spectrum Disorder (ASD). The extent to which rewarding social stimuli are granted privileged access to awareness in ASD is currently unknown. We use continuous flash suppression to investigate whether individuals with and without ASD show privileged access to awareness for social over nonsocial rewarding scenes that are closely matched for stimulus features. Strong evidence for a privileged access to awareness for rewarding social over nonsocial scenes was observed in neurotypical adults. No such privileged access was seen in ASD individuals, and moderate support for the null model was noted. These results suggest that the purported deficits in social motivation in ASD may extend to early processing mechanisms

Antiviral responses of human Leydig cells to mumps virus infection or poly I:C stimulation

International audienceBACKGROUND: The immuno-privileged status of the testis is essential to the maintenance of its functions, and innate immunity is likely to play a key role in limiting harmful viral infections, as demonstrated in the rat. In men mumps virus infects Leydig cells and has deleterious effects on testosterone production and spermatogenesis. The aim of this study was to test whether mumps virus infection of isolated human Leydig cells was associated with an inhibition of their innate antiviral defences. METHODS: Leydig cell production of mRNA and protein for interferons (IFNs) and of three antiviral proteins-2'5' oligoadenylate synthetase (2'5'OAS), double-stranded RNA-activated protein kinase (PKR) and MxA-was investigated, in the absence or presence of mumps virus or viral stimuli including poly I:C, a mimetic of RNA viruses replication product. RESULTS: Stimulated or not, human Leydig cells appeared unable to produce routinely detectable IFNs alpha, beta and gamma. Although the level of PKR remained unchanged after stimulation, the expression of 2'5'OAS and MxA was enhanced following either mumps virus or poly I:C exposure (P < 0.05 versus control). CONCLUSIONS: Overall, our results demonstrate that mumps virus replication in human Leydig cells is not associated with a specific inhibition of IFNs or 2'5'OAS, MxA and PKR production and that these cells display relatively weak endogenous antiviral abilities, as opposed to their rat counterparts

Spinal Cord Injury Causes Sustained Disruption of the Blood-Testis Barrier in the Rat

There is a high incidence of infertility in males following traumatic spinal cord injury (SCI). Quality of semen is frequently poor in these patients, but the pathophysiological mechanism(s) causing this are not known. Blood-testis barrier (BTB) integrity following SCI has not previously been examined. The objective of this study was to characterize the effects of spinal contusion injury on the BTB in the rat. 63 adult, male Sprague Dawley rats received SCI (n = 28), laminectomy only (n = 7) or served as uninjured, age-matched controls (n = 28). Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), BTB permeability to the vascular contrast agent gadopentate dimeglumine (Gd) was assessed at either 72 hours-, or 10 months post-SCI. DCE-MRI data revealed that BTB permeability to Gd was greater than controls at both 72 h and 10 mo post-SCI. Histological evaluation of testis tissue showed increased BTB permeability to immunoglobulin G at both 72 hours- and 10 months post-SCI, compared to age-matched sham-operated and uninjured controls. Tight junctional integrity within the seminiferous epithelium was assessed; at 72 hours post-SCI, decreased expression of the tight junction protein occludin was observed. Presence of inflammation in the testes was also examined. High expression of the proinflammatory cytokine interleukin-1 beta was detected in testis tissue. CD68+ immune cell infiltrate and mast cells were also detected within the seminiferous epithelium of both acute and chronic SCI groups but not in controls. In addition, extensive germ cell apoptosis was observed at 72 h post-SCI. Based on these results, we conclude that SCI is followed by compromised BTB integrity by as early as 72 hours post-injury in rats and is accompanied by a substantial immune response within the testis. Furthermore, our results indicate that the BTB remains compromised and testis immune cell infiltration persists for months after the initial injury

Identifying and tracking key climate adaptation actors in the UK

To understand how climate adaptation planning and decision-making will progress, a better understanding is needed as to which organisations are expected to take on key responsibilities. Methodological challenges have impeded efforts to identify and track adaptation actors beyond the coarse scale of nation states. Yet, for effective adaptation to succeed, who do national governments need to engage, support and encourage? Using the UK as a case study, we conducted a systematic review of official government documents on climate adaptation, between 2006 and 2015, to understand which organisations are identified as key to future adaptation efforts and tracked the extent to which these organisations changed over time. Our unique longitudinal dataset found a very large number of organisations (n = 568). These organisations varied in size (small-medium enterprises to large multinationals), type (public, private and not-for-profit), sector (e.g. water, energy, transport and health), scale (local, national and international), and roles and responsibilities (policymaking, decision-making, knowledge production, retail). Importantly, our findings reveal a mismatch between official government policies that repeatedly call on private organisations to drive adaptation, on the one hand, and a clear dominance of the public sector on the other hand. Yet, the capacity of organisations to fulfil the roles and responsibilities assigned to them, particularly in the public sector, is diminishing. Unless addressed, climate adaptation actions could be assigned to those either unable, or unwilling, to implement them