In Vivo Evidence for ATPase-Dependent DNA Translocation by the Bacillus subtilis SMC Condensin Complex.

Structural maintenance of chromosomes (SMC) complexes shape the genomes of virtually all organisms, but how they function remains incompletely understood. Recent studies in bacteria and eukaryotes have led to a unifying model in which these ring-shaped ATPases act along contiguous DNA segments, processively enlarging DNA loops. In support of this model, single-molecule imaging experiments indicate that Saccharomyces cerevisiae condensin complexes can extrude DNA loops in an ATP-hydrolysis-dependent manner in vitro. Here, using time-resolved high-throughput chromosome conformation capture (Hi-C), we investigate the interplay between ATPase activity of the Bacillus subtilis SMC complex and loop formation in vivo. We show that point mutants in the SMC nucleotide-binding domain that impair but do not eliminate ATPase activity not only exhibit delays in de novo loop formation but also have reduced rates of processive loop enlargement. These data provide in vivo evidence that SMC complexes function as loop extruders.

A novel Shiga toxin 2a neutralizing antibody therapeutic with low immunogenicity and high efficacy.

Shiga toxin-producing Escherichia coli infections are difficult to treat due to the risk of antibiotic-induced stress upregulating the production of toxins, medical treatment is consequently limited to supportive care to prevent the development of hemolytic uremic syndrome (HUS). Here, we introduce a potentially therapeutic humanized mouse monoclonal antibody (Hu-mAb 2-5) targeting Stx2a, the most common Shiga toxin subtype identified from outbreaks. We demonstrate that Hu-mAb 2-5 has low immunogenicity in healthy adults ex vivo and high neutralizing efficacy in vivo, protecting mice from mortality and HUS-related tissue damage.

Correction: Foraging as sampling without replacement: A Bayesian statistical model for estimating biases in target selection.

[This corrects the article DOI: 10.1371/journal.pcbi.1009813.].

Foraging as sampling without replacement: A Bayesian statistical model for estimating biases in target selection.

Foraging entails finding multiple targets sequentially. In humans and other animals, a key observation has been a tendency to forage in 'runs' of the same target type. This tendency is context-sensitive, and in humans, it is strongest when the targets are difficult to distinguish from the distractors. Many important questions have yet to be addressed about this and other tendencies in human foraging, and a key limitation is a lack of precise measures of foraging behaviour. The standard measures tend to be run statistics, such as the maximum run length and the number of runs. But these measures are not only interdependent, they are also constrained by the number and distribution of targets, making it difficult to make inferences about the effects of these aspects of the environment on foraging. Moreover, run statistics are underspecified about the underlying cognitive processes determining foraging behaviour. We present an alternative approach: modelling foraging as a procedure of generative sampling without replacement, implemented in a Bayesian multilevel model. This allows us to break behaviour down into a number of biases that influence target selection, such as the proximity of targets and a bias for selecting targets in runs, in a way that is not dependent on the number of targets present. Our method thereby facilitates direct comparison of specific foraging tendencies between search environments that differ in theoretically important dimensions. We demonstrate the use of our model with simulation examples and re-analysis of existing data. We believe our model will provide deeper insights into visual foraging and provide a foundation for further modelling work in this area.

AccessLab: Workshops to broaden access to scientific research.

AccessLabs are workshops with two simultaneous motivations, achieved through direct citizen-scientist pairings: (1) to decentralise research skills so that a broader range of people are able to access/use scientific research, and (2) to expose science researchers to the difficulties of using their research as an outsider, creating new open access advocates. Five trial AccessLabs have taken place for policy makers, media/journalists, marine sector participants, community groups, and artists. The act of pairing science academics with local community members helps build understanding and trust between groups at a time when this relationship appears to be under increasing threat from different political and economic currents in society. Here, we outline the workshop motivations, format, and evaluation, with the aim that others can build on the methods developed.

Nest sanitation as an effective defence against brood parasitism.

Egg rejection is a crucial defence strategy against brood parasitism that requires the host to correctly recognise the foreign egg. Rejection behaviour has, thus, evolved in many hosts, facilitated by the visual differences between the parasitic and host eggs, and driving hosts to rely on colour and pattern cues. On the other hand, the need to recognise non-egg-shaped objects to carry out nest sanitation led birds to evolve the ability to discriminate and eject objects using mainly shape cues. However, little is known regarding the evolutionary significance of rejection behaviour in general and the cognitive processes underlying it. Here, we investigated the response of the barn swallow (Hirundo rustica) during pre-laying and laying stages to four objects types that differed in shape (eggs vs stars) and colour/pattern (mimetic vs non-mimetic) to investigate (1) what cognitive mechanisms are involved in object discrimination and (2) whether egg rejection is a direct defence against brood parasitism, or simply a product of nest sanitation. We found that swallows ejected stars more often than eggs in both stages, indicating that swallows possess a template for the shape of their eggs. Since the effect of colour/pattern on ejection decisions was minor, we suggest that barn swallows have not evolved a direct defence against brood parasitism but instead, egg ejection might be a product of their well-developed nest sanitation behaviour. Nonetheless, the fact that mimetic eggs were ejected especially in the pre-laying stage shows that nest sanitation could be an effective defence against poorly timed brood parasitism.

The evolution of patterning during movement in a large-scale citizen science game.

The motion dazzle hypothesis posits that high contrast geometric patterns can cause difficulties in tracking a moving target and has been argued to explain the patterning of animals such as zebras. Research to date has only tested a small number of patterns, offering equivocal support for the hypothesis. Here, we take a genetic programming approach to allow patterns to evolve based on their fitness (time taken to capture) and thus find the optimal strategy for providing protection when moving. Our 'Dazzle Bug' citizen science game tested over 1.5 million targets in a touch screen game at a popular visitor attraction. Surprisingly, we found that targets lost pattern elements during evolution and became closely background matching. Modelling results suggested that targets with lower motion energy were harder to catch. Our results indicate that low contrast, featureless targets offer the greatest protection against capture when in motion, challenging the motion dazzle hypothesis.

Neuropathology of Mowat-Wilson Syndrome.

Mowat-Wilson syndrome (MWS) is a syndromic form of Hirschsprung disease that is characterized by variable degrees of intellectual disability, characteristic facial dysmorphism, and a diverse set of other congenital malformations due to haploinsufficiency of ZEB2. A variety of brain malformations have been described in neuroimaging studies of MWS patients, and the role of ZEB2 in the brain has been studied in a multitude of genetically engineered mouse models that are now available. However, a paucity of autopsy information limits our ability to correlate data from neuroimaging studies and animal models with actual MWS patient tissues. Here, we report the autopsy neuropathology of a 19-year-old male patient with MWS. Autopsy neuropathology findings correlated well with the reported MWS neuroimaging data and are in keeping with data from genetically engineered MWS mouse models. This autopsy enhances our understanding of ZEB2 function in human brain development and demonstrates the reliability of MWS murine models.

Population receptive field estimates for motion-defined stimuli.

The processing of motion changes throughout the visual hierarchy, from spatially restricted 'local motion' in early visual cortex to more complex large-field 'global motion' at later stages. Here we used functional magnetic resonance imaging (fMRI) to examine spatially selective responses in these areas related to the processing of random-dot stimuli defined by differences in motion. We used population receptive field (pRF) analyses to map retinotopic cortex using bar stimuli comprising coherently moving dots. In the first experiment, we used three separate background conditions: no background dots (dot-defined bar-only), dots moving coherently in the opposite direction to the bar (kinetic boundary) and dots moving incoherently in random directions (global motion). Clear retinotopic maps were obtained for the bar-only and kinetic-boundary conditions across visual areas V1-V3 and in higher dorsal areas. For the global-motion condition, retinotopic maps were much weaker in early areas and became clear only in higher areas, consistent with the emergence of global-motion processing throughout the visual hierarchy. However, in a second experiment we demonstrate that this pattern is not specific to motion-defined stimuli, with very similar results for a transparent-motion stimulus and a bar defined by a static low-level property (dot size) that should have driven responses particularly in V1. We further exclude explanations based on stimulus visibility by demonstrating that the observed differences in pRF properties do not follow the ability of observers to localise or attend to these bar elements. Rather, our findings indicate that dorsal extrastriate retinotopic maps may primarily be determined by the visibility of the neural responses to the bar relative to the background response (i.e. neural signal-to-noise ratios) and suggests that claims about stimulus selectivity from pRF experiments must be interpreted with caution.

Imperfect camouflage: how to hide in a variable world?

Camouflage is an important anti-predator strategy for many animals and is traditionally thought of as being tightly linked to a specific visual background. While much work focuses on optimizing camouflage against one background, this may not be relevant for many species and contexts, as animals may encounter many different habitats throughout their lives due to temporal and spatial variation in their environment. How should camouflage be optimized when an animal or object is seen against multiple visual backgrounds? Various solutions may exist, including colour change to match new environments or use of behaviour to maintain crypsis by choosing appropriate substrates. Here, we focus on a selection of approaches under a third alternative strategy: animals may adopt (over evolution) camouflage appearances that represent an optimal solution against multiple visual scenes. One approach may include a generalist or compromise strategy, where coloration matches several backgrounds to some extent, but none closely. A range of other camouflage types, including disruptive camouflage, may also provide protection in multiple environments. Despite detailed theoretical work determining the plausibility of compromise camouflage and elucidating the conditions under which it might evolve, there is currently mixed experimental evidence supporting its value and little evidence of it in natural systems. In addition, there remain many questions including how camouflage strategies should be defined and optimized, and how they might interact with other types of crypsis and defensive markings. Overall, we provide a critical overview of our current knowledge about how camouflage can enable matching to multiple backgrounds, discuss important challenges of working on this question and make recommendations for future research.

The C-Terminal Region of Bacillus subtilis SwrA Is Required for Activity and Adaptor-Dependent LonA Proteolysis.

SwrA is the master activator of flagellar biosynthesis in Bacillus subtilis, and SwrA activity is restricted by regulatory proteolysis in liquid environments. SwrA is proteolyzed by the LonA protease but requires a proteolytic adaptor protein, SmiA. Here, we show that SwrA and SmiA interact directly. To better understand SwrA activity, SwrA was randomly mutagenized and loss-of-function and gain-of-function mutants were localized primarily to the predicted unstructured C-terminal region. The loss-of-function mutations impaired swarming motility and activation from the Pfla-che promoter. The gain-of-function mutations increased protein stability but did not abolish SmiA binding, suggesting that SmiA association was a precursor to, but not sufficient for, LonA-dependent proteolysis. Finally, one allele abolished simultaneously SwrA activity and regulatory proteolysis, suggesting that the two functions may be in steric competition.IMPORTANCE SwrA is the master activator of flagellar biosynthesis in Bacillus subtilis, and its mechanism of activation is poorly understood. Moreover, SwrA levels are restricted by SmiA, the first adaptor protein reported for the Lon family of proteases. Here, we show that the C-terminal region of SwrA is important for both transcriptional activation and regulatory proteolysis. Competition between the two processes at this region may be critical for responding to cell contact with a solid surface and the initiation of swarming motility.

Dissociation between perception and smooth pursuit eye movements in speed judgments of moving Gabor targets.

The relationship between eye movements and subjective perception is still relatively poorly understood. In this study, participants tracked the movement of a Gabor patch and made perceptual judgments of its speed using a two-interval forced choice task. The Gabor patch could either have a static carrier or a carrier moving in the same or opposite direction as the overall envelope motion. We found that smooth pursuit speed was strongly affected by the internal motion of the Gabor carrier, with faster smooth pursuit being made to targets with internal motion in the same direction as overall motion compared to targets with internal motion in the opposite direction. However, we found that there were only small and highly variable differences in the perceptual speed judgments made simultaneously, and that these perceptual and smooth pursuit measures did not significantly correlate with each other. This contrasts with the number of catch-up saccades (saccades made in the direction of overall target motion), which was significantly correlated with the simultaneous perceptual judgments. There was also a significant correlation between perceptual judgments and the difference between the target and eye position immediately before a saccade. These results suggest that it is possible to see dissociations between vision and action in this task, and that the specific type of visual action studied may determine the relationship with perception.

Diverted by dazzle: perceived movement direction is biased by target pattern orientation.

'Motion dazzle' is the hypothesis that predators may misjudge the speed or direction of moving prey which have high-contrast patterning, such as stripes. However, there is currently little experimental evidence that such patterns cause visual illusions. Here, observers binocularly tracked a Gabor target, moving with a linear trajectory randomly chosen within 18° of the horizontal. This target then became occluded, and observers were asked to judge where they thought it would later cross a vertical line to the side. We found that internal motion of the stripes within the Gabor biased judgements as expected: Gabors with upwards internal stripe motion relative to the overall direction of motion were perceived to be crossing above Gabors with downwards internal stripe movement. However, surprisingly, we found a much stronger effect of the rigid pattern orientation. Patches with oblique stripes pointing upwards relative to the direction of motion were perceived to cross above patches with downward-pointing stripes. This effect occurred only at high speeds, suggesting that it may reflect an orientation-dependent effect in which spatial signals are used in direction judgements. These findings have implications for our understanding of motion dazzle mechanisms and how human motion and form processing interact.

Quantifying peripheral and foveal perceived differences in natural image patches to predict visual search performance.

Duncan and Humphreys (1989) identified two key factors that affected performance in a visual search task for a target among distractors. The first was the similarity of the target to distractors (TD), and the second was the similarity of distractors to each other (DD). Here we investigate if it is the perceived similarity in foveal or peripheral vision that determines performance. We studied search using stimuli made from patches cut from colored images of natural objects; differences between targets and their modified distractors were estimated using a ratings task peripherally and foveally. We used search conditions in which the targets and distractors were easy to distinguish both foveally and peripherally ("high" stimuli), in which they were difficult to distinguish both foveally and peripherally ("low"), and in which they were easy to distinguish foveally but difficult to distinguish peripherally ("metamers"). In the critical metameric condition, search slopes (change of search time with number of distractors) were similar to the "low" condition, indicating a key role for peripheral information in visual search as both conditions have low perceived similarity peripherally. Furthermore, in all conditions, search slope was well described quantitatively from peripheral TD and DD but not foveal. However, some features of search, such as error rates, do indicate roles for foveal vision too.

The role of stripe orientation in target capture success.

INTRODUCTION: 'Motion dazzle' refers to the hypothesis that high contrast patterns such as stripes and zigzags may have evolved in a wide range of animals as they make it difficult to judge the trajectory of an animal in motion. Despite recent research into this idea, it is still unclear to what extent stripes interfere with motion judgement and if effects are seen, what visual processes might underlie them. We use human participants performing a touch screen task in which they attempt to 'catch' moving targets in order to determine whether stripe orientation affects capture success, as previous research has suggested that different stripe orientations may be processed differently by the visual system. We also ask whether increasing the number of targets presented in a trial can affect capture success, as previous research has suggested that motion dazzle effects may be larger in groups. RESULTS: When single targets were presented sequentially within each trial, we find that perpendicular and oblique striped targets are captured at a similar rate to uniform grey targets, but parallel striped targets are significantly easier to capture. However, when multiple targets are present simultaneously during a trial we find that striped targets are captured in fewer attempts and more quickly than grey targets. CONCLUSIONS: Our results suggest that there may be differences in capture success based on target pattern orientation, perhaps suggesting that different visual mechanisms are involved in processing of parallel stripes compared to perpendicular/oblique stripes. However, these results do not seem to generalise to trials with multiple targets, and contrary to previous predictions, striped targets appear to be easier to capture when multiple targets are present compared to being presented individually. These results suggest that the different orientations of stripes seen on animals in nature (such as in fish and snakes) may serve different purposes, and that it is unclear whether motion dazzle effects may have greater benefits for animals living in groups.

Motion dazzle and the effects of target patterning on capture success.

BACKGROUND: Stripes and other high contrast patterns found on animals have been hypothesised to cause "motion dazzle", a type of defensive coloration that operates when in motion, causing predators to misjudge the speed and direction of object movement. Several recent studies have found some support for this idea, but little is currently understood about the mechanisms underlying this effect. Using humans as model 'predators' in a touch screen experiment we investigated further the effectiveness of striped targets in preventing capture, and considered how stripes compare to other types of patterning in order to understand what aspects of target patterning are important in making a target difficult to capture. RESULTS: We find that striped targets are among the most difficult to capture, but that other patterning types are also highly effective at preventing capture in this task. Several target types, including background sampled targets and targets with a 'spot' on were significantly easier to capture than striped targets. We also show differences in capture attempt rates between different target types, but we find no differences in learning rates between target types. CONCLUSIONS: We conclude that striped targets are effective in preventing capture, but are not uniquely difficult to catch, with luminance matched grey targets also showing a similar capture rate. We show that key factors in making capture easier are a lack of average background luminance matching and having trackable 'features' on the target body. We also find that striped patterns are attempted relatively quickly, despite being difficult to catch. We discuss these findings in relation to the motion dazzle hypothesis and how capture rates may be affected more generally by pattern type.

A Functional Magnetic Resonance Imaging Meta-Analysis of Childhood Trauma.

BACKGROUND: Traumatic experiences during childhood significantly impact the developing brain and contribute to the development of numerous physical and mental health problems. To date, however, a comprehensive understanding of the functional impairments within the brain associated with childhood trauma histories does not exist. Previous functional magnetic resonance imaging (fMRI) meta-analytical tools required homogeneity of task types and the clinical populations studied, thus preventing the comprehensive pooling of brain-based deficits present in children who have trauma histories. We hypothesized that the use of the novel, data-driven Bayesian author-topic model approach to fMRI meta-analyses would reveal deficits in brain networks that span fMRI task types in children with trauma histories. METHODS: To our knowledge, this is the first study to use the Bayesian author-topic model approach to fMRI meta-analyses within a clinical population. Using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we present data-driven results obtained by combining activation patterns across heterogeneous tasks from 1428 initially screened studies and combining data from 14 studies that met study criteria (285 children with trauma histories, 297 healthy control children). RESULTS: Altered brain activity was revealed within 2 clusters in children with trauma histories compared to control children: the default mode/affective network/posterior insula and the central executive network. Our identified clusters were associated with tasks pertaining to cognitive processing, emotional/social stress, self-referential thought, memory, unexpected stimuli, and avoidance behaviors in youths who have experienced childhood trauma. CONCLUSIONS: Our results reveal disturbances in children with trauma histories within the modulation of the default mode and central executive networks-but not the salience network-regardless of whether children also presented with posttraumatic stress symptoms.

Bayesian multi-level modelling for predicting single and double feature visual search.

Performance in visual search tasks is frequently summarised by "search slopes" - the additional cost in reaction time for each additional distractor. While search tasks with a shallow search slopes are termed efficient (pop-out, parallel, feature), there is no clear dichotomy between efficient and inefficient (serial, conjunction) search. Indeed, a range of search slopes are observed in empirical data. The Target Contrast Signal (TCS) Theory is a rare example of quantitative model that attempts to predict search slopes for efficient visual search. One study using the TCS framework has shown that the search slope in a double-feature search (where the target differs in both colour and shape from the distractors) can be estimated from the slopes of the associated single-feature searches. This estimation is done using a contrast combination model, and a collinear contrast integration model was shown to outperform other options. In our work, we extend TCS to a Bayesian multi-level framework. We investigate modelling using normal and shifted-lognormal distributions, and show that the latter allows for a better fit to previously published data. We run a new fully within-subjects experiment to attempt to replicate the key original findings, and show that overall, TCS does a good job of predicting the data. However, we do not replicate the finding that the collinear combination model outperforms the other contrast combination models, instead finding that it may be difficult to conclusively distinguish between them.

SwrA-mediated Multimerization of DegU and an Upstream Activation Sequence Enhance Flagellar Gene Expression in Bacillus subtilis.

The earliest genes in bacterial flagellar assembly are activated by narrowly-conserved proteins called master regulators that often act as heteromeric complexes. A complex of SwrA and the response-regulator transcription factor DegU is thought to form the master flagellar regulator in Bacillus subtilis but how the two proteins co-operate to activate gene expression is poorly-understood. Here we find using ChIP-Seq that SwrA interacts with a subset of DegU binding sites in the chromosome and does so in a DegU-dependent manner. Using this information, we identify a DegU-specific inverted repeat DNA sequence in the Pflache promoter region and show that SwrA synergizes with DegU phosphorylation to increase binding affinity. We further demonstrate that the SwrA/DegU footprint extends from the DegU binding site towards the promoter, likely through SwrA-induced DegU multimerization. The location of the DegU inverted repeat was critical and moving the binding site closer to the promoter impaired transcription by disrupting a previously-unrecognized upstream activation sequence (UAS). Thus, the SwrA-DegU heteromeric complex likely enables both remote binding and interaction between the activator and RNA polymerase. Small co-activator proteins like SwrA may allow selective activation of subsets of genes where activator multimerization is needed. Why some promoters require activator multimerization and some require UAS sequences is unknown.