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Abstract We have studied the recombination rate behaviour of a set of 140 genes which were investigated for their potential importance in inflammatory disease. Each gene was extensively sequenced in 24 individuals of African descent and 23 individuals of European descent, and the recombination process was studied separately in the two population samples. The results obtained from the two populations were highly correlated, suggesting that demographic bias does not affect our population genetic estimation procedure. We found evidence that levels of recombination correlate with levels of nucleotide diversity. High marker density allowed us to study recombination rate variation on a very fine spatial scale. We found that about 40 per cent of genes showed evidence of uniform recombination, while approximately 12 per cent of genes carried distinct signatures of recombination hotspots. On studying the locations of these hotspots, we found that they are not always confined to introns but can also stretch across exons. An investigation of the protein products of these genes suggested that recombination hotspots can sometimes separate exons belonging to different protein domains; however, this occurs much less frequently than might be expected based on evolutionary studies into the origins of recombination. This suggests that evolutionary analysis of the recombination process is greatly aided by considering nucleotide sequences and protein products jointly.

Birds use their visual systems for important tasks, such as foraging and predator detection, that require them to resolve an image. However, visual acuity (the ability to perceive spatial detail) varies by two orders of magnitude across birds. Prior studies indicate that eye size and aspects of a species' ecology may drive variation in acuity, but these studies have been restricted to small numbers of species. We used a literature review to gather data on acuity measured either behaviorally or anatomically for 94 species from 38 families. We then examined how acuity varies in relation to (1) eye size, (2) habitat spatial complexity, (3) habitat light level, (4) diet composition, (5) prey mobility and (6) foraging mode. A phylogenetically controlled model including all of the above factors as predictors indicated that eye size and foraging mode are significant predictors of acuity. Examining each ecological variable in turn revealed that acuity is higher in species whose diet comprises vertebrates or scavenged food and whose foraging modes require resolving prey from farther away. Additionally, species that live in spatially complex, vegetative habitats have lower acuity than expected for their eye sizes. Together, our results suggest that the need to detect important objects from far away - such as predators for species that live in open habitats, and food items for species that forage on vertebrate and scavenged prey - has likely been a key driver of higher acuity in some species, helping us to elucidate how visual capabilities may be adapted to an animal's visual needs., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Bullough et al. introduce Weber's Law and proportional processing during perception., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Many animals use shading to infer the three-dimensional (3D) shape of objects, and mimicking natural shading patterns can produce the illusion of 3D form on a flat surface. Over 150 years ago, Charles Darwin noted that the ocelli (eyespots) on the feathers of the great argus Argusianus argus , when held vertically during courtship displays to females, were perfectly shaded to resemble 3D hemispheres to human viewers. We tested whether these ocelli appear 3D to birds by training chickens Gallus gallus domesticus to select images of either convex or concave shapes using shading cues, and then presenting them with images of great argus ocelli. Chickens successfully learned how to discriminate between convex and concave shapes, and treated the great argus pheasant ocelli in the same way as convex training stimuli. Our findings are consistent with previous studies that birds can perceive 3D shape from shading cues in a similar manner to humans. The perception of great argus ocelli as consistent with 3D shape by avian viewers suggests that shape illusions can play a role in male courtship.

Camouflage is a fundamental way for animals to avoid detection and recognition. While depth information is critical for object detection and recognition, little is known about how camouflage patterns might interfere with the mechanisms of depth perception. We reveal how many common camouflage strategies could exploit 3D visual processing mechanisms., Competing Interests: Declaration of interests The authors have no interests to declare., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Wild animals encounter humans on a regular basis, but humans vary widely in their behaviour: whereas many people ignore wild animals, some people present a threat, while others encourage animals' presence through feeding. Humans thus send mixed messages to which animals must respond appropriately to be successful. Some species appear to circumvent this problem by discriminating among and/or socially learning about humans, but it is not clear whether such learning strategies are actually beneficial in most cases. Using an individual-based model, we consider how learning rate, individual recognition (IR) of humans, and social learning (SL) affect wild animals' ability to reach an optimal avoidance strategy when foraging in areas frequented by humans. We show that 'true' IR of humans could be costly. We also find that a fast learning rate, while useful when human populations are homogeneous or highly dangerous, can cause unwarranted avoidance in other scenarios if animals generalize. SL reduces this problem by allowing conspecifics to observe benign interactions with humans. SL and a fast learning rate also improve the viability of IR. These results provide an insight into how wild animals may be affected by, and how they may cope with, contrasting human behaviour., Competing Interests: The authors have no competing interests., (© 2022 The Authors.)

Among fishes in the family Poeciliidae, signals such as colour patterns, ornaments and courtship displays play important roles in mate choice and male-male competition. Despite this, visual capabilities in poeciliids are understudied, in particular, visual acuity, the ability to resolve detail. We used three methods to quantify visual acuity in male and female green swordtails (Xiphophorus helleri), a species in which body size and the length of the male's extended caudal fin ('sword') serve as assessment signals during mate choice and agonistic encounters. Topographic distribution of retinal ganglion cells (RGCs) was similar in all individuals and was characterized by areas of high cell densities located centro-temporally and nasally, as well as a weak horizontal streak. Based on the peak density of RGCs in the centro-temporal area, anatomical acuity was estimated to be approximately 3 cycles per degree (cpd) in both sexes. However, a behavioural optomotor assay found significantly lower mean acuity in males (0.8 cpd) than females (3.0 cpd), which was not explained by differences in eye size between males and females. An additional behavioural assay, in which we trained individuals to discriminate striped gratings from grey stimuli of the same mean luminance, also showed lower acuity in males (1-2 cpd) than females (2-3 cpd). Thus, although retinal anatomy predicts identical acuity in males and females, two behavioural assays found higher acuity in females than males, a sexual dimorphism that is rare outside of invertebrates. Overall, our results have implications for understanding how poeciliids perceive visual signals during mate choice and agonistic encounters., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

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.

Humans have a profound effect on the planet's ecosystems, and unprecedented rates of human population growth and urbanization have brought wild animals into increasing contact with people. For many species, appropriate responses toward humans are likely to be critical to survival and reproductive success. Although numerous studies have investigated the impacts of human activity on biodiversity and species distributions, relatively few have examined the effects of humans on the behavioral responses of animals during human-wildlife encounters, and the cognitive processes underpinning those responses. Furthermore, while humans often present a significant threat to animals, the presence or behavior of people may be also associated with benefits, such as food rewards. In scenarios where humans vary in their behavior, wild animals would be expected to benefit from the ability to discriminate between dangerous, neutral and rewarding people. Additionally, individual differences in cognitive and behavioral phenotypes and past experiences with humans may affect animals' ability to exploit human-dominated environments and respond appropriately to human cues. In this review, we examine the cues that wild animals use to modulate their behavioral responses toward humans, such as human facial features and gaze direction. We discuss when wild animals are expected to attend to certain cues, how information is used, and the cognitive mechanisms involved. We consider how the cognitive abilities of wild animals are likely to be under selection by humans and therefore influence population and community composition. We conclude by highlighting the need for long-term studies on free-living, wild animals to fully understand the causes and ecological consequences of variation in responses to human cues. The effects of humans on wildlife behavior are likely to be substantial, and a detailed understanding of these effects is key to implementing effective conservation strategies and managing human-wildlife conflict., (Copyright © 2020 Goumas, Lee, Boogert, Kelley and Thornton.)

Substantial progress has been made in the past 15 years regarding how prey use a variety of visual camouflage types to exploit both predator visual processing and cognition, including background matching, disruptive coloration, countershading and masquerade. By contrast, much less attention has been paid to how predators might overcome these defences. Such strategies include the evolution of more acute senses, the co-opting of other senses not targeted by camouflage, changes in cognition such as forming search images, and using behaviours that change the relationship between the cryptic individual and the environment or disturb prey and cause movement. Here, we evaluate the methods through which visual camouflage prevents detection and recognition, and discuss if and how predators might evolve, develop or learn counter-adaptations to overcome these. This article is part of the theme issue 'Signal detection theory in recognition systems: from evolving models to experimental tests'.

While many animals are negatively affected by urbanization, some species appear to thrive in urban environments. Herring gulls ( Larus argentatus ) are commonly found in urban areas and often scavenge food discarded by humans. Despite increasing interactions between humans and gulls, little is known about the cognitive underpinnings of urban gull behaviour and to what extent they use human behavioural cues when making foraging decisions. We investigated whether gulls are more attracted to anthropogenic items when they have been handled by a human. We first presented free-living gulls with two identical food objects, one of which was handled, and found that gulls preferentially pecked at the handled food object. We then tested whether gulls' attraction to human-handled objects generalizes to non-food items by presenting a new sample of gulls with two non-food objects, where, again, only one was handled. While similar numbers of gulls approached food and non-food objects in both experiments, they did not peck at handled non-food objects above chance levels. These results suggest that urban gulls generally show low levels of neophobia, but that they use human handling as a cue specifically in the context of food. These behaviours may contribute to gulls' successful exploitation of urban environments., Competing Interests: We declare that we have no competing interests., (© 2020 The Authors.)

Genome3D (https://www.genome3d.eu) is a freely available resource that provides consensus structural annotations for representative protein sequences taken from a selection of model organisms. Since the last NAR update in 2015, the method of data submission has been overhauled, with annotations now being 'pushed' to the database via an API. As a result, contributing groups are now able to manage their own structural annotations, making the resource more flexible and maintainable. The new submission protocol brings a number of additional benefits including: providing instant validation of data and avoiding the requirement to synchronise releases between resources. It also makes it possible to implement the submission of these structural annotations as an automated part of existing internal workflows. In turn, these improvements facilitate Genome3D being opened up to new prediction algorithms and groups. For the latest release of Genome3D (v2.1), the underlying dataset of sequences used as prediction targets has been updated using the latest reference proteomes available in UniProtKB. A number of new reference proteomes have also been added of particular interest to the wider scientific community: cow, pig, wheat and mycobacterium tuberculosis. These additions, along with improvements to the underlying predictions from contributing resources, has ensured that the number of annotations in Genome3D has nearly doubled since the last NAR update article. The new API has also been used to facilitate the dissemination of Genome3D data into InterPro, thereby widening the visibility of both the annotation data and annotation algorithms., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Instructor Talk-noncontent language used by instructors in classrooms-is a recently defined and promising variable for better understanding classroom dynamics. Having previously characterized the Instructor Talk framework within the context of a single course, we present here our results surrounding the applicability of the Instructor Talk framework to noncontent language used by instructors in novel course contexts. We analyzed Instructor Talk in eight additional biology courses in their entirety and in 61 biology courses using an emergent sampling strategy. We observed widespread use of Instructor Talk with variation in the amount and category type used. The vast majority of Instructor Talk could be characterized using the originally published Instructor Talk framework, suggesting the robustness of this framework. Additionally, a new form of Instructor Talk-Negatively Phrased Instructor Talk, language that may discourage students or distract from the learning process-was detected in these novel course contexts. Finally, the emergent sampling strategy described here may allow investigation of Instructor Talk in even larger numbers of courses across institutions and disciplines. Given its widespread use, potential influence on students in learning environments, and ability to be sampled, Instructor Talk may be a key variable to consider in future research on teaching and learning in higher education.

Human-wildlife conflict is one of the greatest threats to species populations worldwide. One species facing national declines in the UK is the herring gull (Larus argentatus), despite an increase in numbers in urban areas. Gulls in urban areas are often considered a nuisance owing to behaviours such as food-snatching. Whether urban gull feeding behaviour is influenced by human behavioural cues, such as gaze direction, remains unknown. We therefore measured the approach times of herring gulls to a food source placed in close proximity to an experimenter who either looked directly at the gull or looked away. We found that only 26% of targeted gulls would touch the food, suggesting that food-snatching is likely to be conducted by a minority of individuals. When gulls did touch the food, they took significantly longer to approach when the experimenter's gaze was directed towards them compared with directed away. However, inter-individual behaviour varied greatly, with some gulls approaching similarly quickly in both treatments, while others approached much more slowly when the experimenter was looking at them. These results indicate that reducing human-herring gull conflict may be possible through small changes in human behaviour, but will require consideration of behavioural differences between individual gulls.

PhyreRisk is an open-access, publicly accessible web application for interactively bridging genomic, proteomic and structural data facilitating the mapping of human variants onto protein structures. A major advance over other tools for sequence-structure variant mapping is that PhyreRisk provides information on 20,214 human canonical proteins and an additional 22,271 alternative protein sequences (isoforms). Specifically, PhyreRisk provides structural coverage (partial or complete) for 70% (14,035 of 20,214 canonical proteins) of the human proteome, by storing 18,874 experimental structures and 84,818 pre-built models of canonical proteins and their isoforms generated using our in house Phyre2. PhyreRisk reports 55,732 experimentally, multi-validated protein interactions from IntAct and 24,260 experimental structures of protein complexes. Another major feature of PhyreRisk is that, rather than presenting a limited set of precomputed variant-structure mapping of known genetic variants, it allows the user to explore novel variants using, as input, genomic coordinates formats (Ensembl, VCF, reference SNP ID and HGVS notations) and Human Build GRCh37 and GRCh38. PhyreRisk also supports mapping variants using amino acid coordinates and searching for genes or proteins of interest. PhyreRisk is designed to empower researchers to translate genetic data into protein structural information, thereby providing a more comprehensive appreciation of the functional impact of variants. PhyreRisk is freely available at http://phyrerisk.bc.ic.ac.uk., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Many efforts to improve science teaching in higher education focus on a few faculty members at an institution at a time, with limited published evidence on attempts to engage faculty across entire departments. We created a long-term, department-wide collaborative professional development program, Biology Faculty Explorations in Scientific Teaching (Biology FEST). Across 3 years of Biology FEST, 89% of the department's faculty completed a weeklong scientific teaching institute, and 83% of eligible instructors participated in additional semester-long follow-up programs. A semester after institute completion, the majority of Biology FEST alumni reported adding active learning to their courses. These instructor self-reports were corroborated by audio analysis of classroom noise and surveys of students in biology courses on the frequency of active-learning techniques used in classes taught by Biology FEST alumni and nonalumni. Three years after Biology FEST launched, faculty participants overwhelmingly reported that their teaching was positively affected. Unexpectedly, most respondents also believed that they had improved relationships with departmental colleagues and felt a greater sense of belonging to the department. Overall, our results indicate that biology department-wide collaborative efforts to develop scientific teaching skills can indeed attract large numbers of faculty, spark widespread change in teaching practices, and improve departmental relations., (© 2018 M. T. Owens et al. CBE—Life Sciences Education © 2018 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

Autotransporters (ATs) belong to a family of modular proteins secreted by the Type V, subtype a, secretion system (T5aSS) and considered as an important source of virulence factors in lipopolysaccharidic diderm bacteria (archetypical Gram-negative bacteria). While exported by the Sec pathway, the ATs are further secreted across the outer membrane via their own C-terminal translocator forming a β-barrel, through which the rest of the protein, namely the passenger, can pass. In several ATs, an autochaperone domain (AC) present at the C-terminal region of the passenger and upstream of the translocator was demonstrated as strictly required for proper secretion and folding. However, considering it was functionally characterised and identified only in a handful of ATs, wariness recently fells on the commonality and conservation of this structural element in the T5aSS. To circumvent the issue of sequence divergence and taking advantage of the resolved three-dimensional structure of some ACs, identification of this domain was performed following structural alignment among all AT passengers experimentally resolved by crystallography before searching in a dataset of 1523 ATs. While demonstrating that the AC is indeed a conserved structure found in numerous ATs, phylogenetic analysis further revealed a distribution into deeply rooted branches, from which emerge 20 main clusters. Sequence analysis revealed that an AC could be identified in the large majority of SAATs (self-associating ATs) but not in any LEATs (lipase/esterase ATs) nor in some PATs (protease autotransporters) and PHATs (phosphatase/hydrolase ATs). Structural analysis indicated that an AC was present in passengers exhibiting single-stranded right-handed parallel β-helix, whatever the type of β-solenoid, but not with α-helical globular fold. From this investigation, the AC of type 1 appears as a prevalent and conserved structural element exclusively associated to β-helical AT passenger and should promote further studies about the protein secretion and folding via the T5aSS, especially toward α-helical AT passengers.

A big challenge in current systems biology research arises when different types of data must be accessed from separate sources and visualized using separate tools. The high cognitive load required to navigate such a workflow is detrimental to hypothesis generation. Accordingly, there is a need for a robust research platform that incorporates all data and provides integrated search, analysis, and visualization features through a single portal. Here, we present ePlant (http://bar.utoronto.ca/eplant), a visual analytic tool for exploring multiple levels of Arabidopsis thaliana data through a zoomable user interface. ePlant connects to several publicly available web services to download genome, proteome, interactome, transcriptome, and 3D molecular structure data for one or more genes or gene products of interest. Data are displayed with a set of visualization tools that are presented using a conceptual hierarchy from big to small, and many of the tools combine information from more than one data type. We describe the development of ePlant in this article and present several examples illustrating its integrative features for hypothesis generation. We also describe the process of deploying ePlant as an "app" on Araport. Building on readily available web services, the code for ePlant is freely available for any other biological species research., (© 2017 American Society of Plant Biologists. All rights reserved.)

Some animals hide food to consume later; however, these caches are susceptible to theft by conspecifics and heterospecifics. Caching animals can use protective strategies to minimize sensory cues available to potential pilferers, such as caching in shaded areas and in quiet substrate. Background matching (where object patterning matches the visual background) is commonly seen in prey animals to reduce conspicuousness, and caching animals may also use this tactic to hide caches, for example, by hiding coloured food in a similar coloured substrate. We tested whether California scrub-jays ( Aphelocoma californica ) camouflage their food in this way by offering them caching substrates that either matched or did not match the colour of food available for caching. We also determined whether this caching behaviour was sensitive to social context by allowing the birds to cache when a conspecific potential pilferer could be both heard and seen (acoustic and visual cues present), or unseen (acoustic cues only). When caching events could be both heard and seen by a potential pilferer, birds cached randomly in matching and non-matching substrates. However, they preferentially hid food in the substrate that matched the food colour when only acoustic cues were present. This is a novel cache protection strategy that also appears to be sensitive to social context. We conclude that studies of cache protection strategies should consider the perceptual capabilities of the cacher and potential pilferers., (© 2017 The Author(s).)

Active-learning pedagogies have been repeatedly demonstrated to produce superior learning gains with large effect sizes compared with lecture-based pedagogies. Shifting large numbers of college science, technology, engineering, and mathematics (STEM) faculty to include any active learning in their teaching may retain and more effectively educate far more students than having a few faculty completely transform their teaching, but the extent to which STEM faculty are changing their teaching methods is unclear. Here, we describe the development and application of the machine-learning-derived algorithm Decibel Analysis for Research in Teaching (DART), which can analyze thousands of hours of STEM course audio recordings quickly, with minimal costs, and without need for human observers. DART analyzes the volume and variance of classroom recordings to predict the quantity of time spent on single voice (e.g., lecture), multiple voice (e.g., pair discussion), and no voice (e.g., clicker question thinking) activities. Applying DART to 1,486 recordings of class sessions from 67 courses, a total of 1,720 h of audio, revealed varied patterns of lecture (single voice) and nonlecture activity (multiple and no voice) use. We also found that there was significantly more use of multiple and no voice strategies in courses for STEM majors compared with courses for non-STEM majors, indicating that DART can be used to compare teaching strategies in different types of courses. Therefore, DART has the potential to systematically inventory the presence of active learning with ∼90% accuracy across thousands of courses in diverse settings with minimal effort.

Many animals build structures to provide shelter, avoid predation, attract mates or house offspring, but the behaviour and potential cognitive processes involved during building are poorly understood. Great bowerbird ( Ptilinorhynchus nuchalis ) males build and maintain display courts by placing tens to hundreds of objects in a positive size-distance gradient. The visual angles created by the gradient create a forced perspective illusion that females can use to choose a mate. Although the quality of illusion is consistent within males, it varies among males, which may reflect differences in how individuals reconstruct their courts. We moved all objects off display courts to determine how males reconstructed the visual illusion. We found that all individuals rapidly created the positive size-distance gradient required for forced perspective within the first 10 objects placed. Males began court reconstruction by placing objects in the centre of the court and then placing objects further out, a technique commonly used when humans lay mosaics. The number of objects present after 72 h was not related to mating success or the quality of the illusion, indicating that male skill at arranging objects rather than absolute number of objects appears to be important. We conclude that differences arise in the quality of forced perspective illusions despite males using the same technique to reconstruct their courts.

The identification of structurally similar proteins can provide a range of biological insights, and accordingly, the alignment of a query protein to a database of experimentally determined protein structures is a technique commonly used in the fields of structural and evolutionary biology. The PhyreStorm Web server has been designed to provide comprehensive, up-to-date and rapid structural comparisons against the Protein Data Bank (PDB) combined with a rich and intuitive user interface. It is intended that this facility will enable biologists inexpert in bioinformatics access to a powerful tool for exploring protein structure relationships beyond what can be achieved by sequence analysis alone. By partitioning the PDB into similar structures, PhyreStorm is able to quickly discard the majority of structures that cannot possibly align well to a query protein, reducing the number of alignments required by an order of magnitude. PhyreStorm is capable of finding 93±2% of all highly similar (TM-score>0.7) structures in the PDB for each query structure, usually in less than 60s. PhyreStorm is available at http://www.sbg.bio.ic.ac.uk/phyrestorm/., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Phyre2 is a suite of tools available on the web to predict and analyze protein structure, function and mutations. The focus of Phyre2 is to provide biologists with a simple and intuitive interface to state-of-the-art protein bioinformatics tools. Phyre2 replaces Phyre, the original version of the server for which we previously published a paper in Nature Protocols. In this updated protocol, we describe Phyre2, which uses advanced remote homology detection methods to build 3D models, predict ligand binding sites and analyze the effect of amino acid variants (e.g., nonsynonymous SNPs (nsSNPs)) for a user's protein sequence. Users are guided through results by a simple interface at a level of detail they determine. This protocol will guide users from submitting a protein sequence to interpreting the secondary and tertiary structure of their models, their domain composition and model quality. A range of additional available tools is described to find a protein structure in a genome, to submit large number of sequences at once and to automatically run weekly searches for proteins that are difficult to model. The server is available at http://www.sbg.bio.ic.ac.uk/phyre2. A typical structure prediction will be returned between 30 min and 2 h after submission., Competing Interests: MJES is a Director and shareholder in Equinox Pharma Ltd which uses bioinformatics and chemoinformatics in drug discovery research and services.

Protein domains are generally thought to correspond to units of evolution. New research raises questions about how such domains are defined with bioinformatics tools and sheds light on how evolution has enabled partial domains to be viable.

Genome3D (http://www.genome3d.eu) is a collaborative resource that provides predicted domain annotations and structural models for key sequences. Since introducing Genome3D in a previous NAR paper, we have substantially extended and improved the resource. We have annotated representatives from Pfam families to improve coverage of diverse sequences and added a fast sequence search to the website to allow users to find Genome3D-annotated sequences similar to their own. We have improved and extended the Genome3D data, enlarging the source data set from three model organisms to 10, and adding VIVACE, a resource new to Genome3D. We have analysed and updated Genome3D's SCOP/CATH mapping. Finally, we have improved the superposition tools, which now give users a more powerful interface for investigating similarities and differences between structural models., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Inhibitor development complicates haemophilia treatment and may impact caregiver burden. Compare overall burden of caregivers of children with/without inhibitors in the United States using a novel disease-specific questionnaire and the previously validated CarerQol. An on-line questionnaire with six burden domains (i.e. emotional stress, personal sacrifice, financial burden, medical management, child's pain, and transportation) and three visual analogue scales (VAS) was developed based upon a targeted literature review and previous survey findings. The study sample consisted of caregivers of children with haemophilia. The total burden score was calculated by summing the six individual burden domain scores. Higher scores represented greater burden. Descriptive statistics was performed to examine the sample characteristics. The Wilcoxon rank-sum test was performed to compare burden by inhibitor status. All variables were considered significant at P < 0.001. A total of 310 caregivers completed the survey; 30 of them reported caring for a child with an inhibitor. A majority of caregivers of children with inhibitors were mothers (80.0%) and between 35 and 44 years of age (56.7%). Caregivers of children with inhibitors reported significantly higher median total burden scores (99.0 vs. 76.5, P < 0.0001) and median burden-VAS scores (5.5 vs. 3.0, P < 0.0001), as compared to those caring for children without inhibitors. A similar trend was seen across all the six burden domains, with greatest difference in the median burden scores observed in the 'personal sacrifice' (3.2 vs. 2.0) and 'transportation' (3.3 vs. 2.3) domains. Burden of caregivers should be considered when assessing the psychosocial aspects of managing patients with inhibitors., (© 2014 John Wiley & Sons Ltd.)

Whole-genome and exome sequencing studies reveal many genetic variants between individuals, some of which are linked to disease. Many of these variants lead to single amino acid variants (SAVs), and accurate prediction of their phenotypic impact is important. Incorporating sequence conservation and network-level features, we have developed a method, SuSPect (Disease-Susceptibility-based SAV Phenotype Prediction), for predicting how likely SAVs are to be associated with disease. SuSPect performs significantly better than other available batch methods on the VariBench benchmarking dataset, with a balanced accuracy of 82%. SuSPect is available at www.sbg.bio.ic.ac.uk/suspect. The Web site has been implemented in Perl and SQLite and is compatible with modern browsers. An SQLite database of possible missense variants in the human proteome is available to download at www.sbg.bio.ic.ac.uk/suspect/download.html., (Copyright © 2014. Published by Elsevier Ltd.)

Congenital haemophilia is an inherited bleeding disorder typically diagnosed at birth or shortly thereafter. Haemophilia imposes a significant burden on patients and their caregivers. The aim of the study was to quantify the overall burden of haemophilia on caregivers in the USA using a novel disease-specific questionnaire and the previously validated CarerQol. Targeted literature review and a previous survey conducted by the authors was used to develop an online questionnaire with six burden domains of interest to caregivers (emotional stress, financial, sacrifice, medical management, child's pain and transportation) and several visual analogue scales (VAS). Content validity of the questionnaire was confirmed by three haemophilia caregivers. The study sample consisted of caregivers of children with haemophilia identified via a previously developed opt-in research database. Descriptive statistics were employed for demographic and clinical characteristics; a generalized linear model (GLM) was used to identify factors influencing caregiver burden. A total of 310 caregivers completed the survey (45.5% response rate). Most of the participating caregivers were mothers of a child with haemophilia (88%), between 35 and 44 years of age (48%), and with a college education or a postgraduate degree (63%). 'Child's pain' was identified as the most burdensome domain to caregivers (median score = 3.50 out of 5), followed by 'emotional stress' (2.67), 'financial' (2.40), 'transportation' (2.33), 'sacrifice' (2.17) and 'medical management' (2.00) domains. Although higher income exhibited a protective effect, episodes of bleeds, current presence of an inhibitor and lower caregiver productivity in the past month negatively affected caregiver burden per GLM results. Training and educational programs should potentially be developed to address caregiver burden., (© 2014 John Wiley & Sons Ltd.)

It is often assumed that the primary purpose of a male's sexual display is to provide information about quality, or to strongly stimulate prospective mates, but other functions of courtship displays have been relatively neglected. Male great bowerbirds (Ptilonorhynchus nuchalis) construct bowers that exploit the female's predictable field of view (FOV) during courtship displays by creating forced perspective illusions, and the quality of illusion is a good predictor of mating success. Here, we present and discuss two additional components of male courtship displays that use the female's predetermined viewpoint: (i) the rapid and diverse flashing of coloured objects within her FOV and (ii) chromatic adaptation of the female's eyes that alters her perception of the colour of the displayed objects. Neither is directly related to mating success, but both are likely to increase signal efficacy, and may also be associated with attracting and holding the female's attention. Signal efficacy is constrained by trade-offs between the signal components; there are both positive and negative interactions within multicomponent signals. Important signal components may have a threshold effect on fitness rather than the often assumed linear relationship.

Coarse-grained protein structure models offer increased efficiency in structural modeling, but these must be coupled with fast and accurate methods to revert to a full-atom structure. Here, we present a novel algorithm to reconstruct mainchain models from C traces. This has been parameterized by fitting Gaussian mixture models (GMMs) to short backbone fragments centered on idealized peptide bonds. The method we have developed is statistically significantly more accurate than several competing methods, both in terms of RMSD values and dihedral angle differences. The method produced Ramachandran dihedral angle distributions that are closer to that observed in real proteins and better Phaser molecular replacement log-likelihood gains. Amino acid residue sidechain reconstruction accuracy using SCWRL4 was found to be statistically significantly correlated to backbone reconstruction accuracy. Finally, the PD2 method was found to produce significantly lower energy full-atom models using Rosetta which has implications for multiscale protein modeling using coarse-grained models. A webserver and C++ source code is freely available for noncommercial use from: http://www.sbg.bio.ic.ac.uk/phyre2/PD2&#95;ca2main/., (Copyright © 2013 Wiley Periodicals, Inc.)

Coarse-grained (CG) methods for sampling protein conformational space have the potential to increase computational efficiency by reducing the degrees of freedom. The gain in computational efficiency of CG methods often comes at the expense of non-protein like local conformational features. This could cause problems when transitioning to full atom models in a hierarchical framework. Here, a CG potential energy function was validated by applying it to the problem of loop prediction. A novel method to sample the conformational space of backbone atoms was benchmarked using a standard test set consisting of 351 distinct loops. This method used a sequence-independent CG potential energy function representing the protein using [Formula: see text]-carbon positions only and sampling conformations with a Monte Carlo simulated annealing based protocol. Backbone atoms were added using a method previously described and then gradient minimised in the Rosetta force field. Despite the CG potential energy function being sequence-independent, the method performed similarly to methods that explicitly use either fragments of known protein backbones with similar sequences or residue-specific [Formula: see text]/[Formula: see text]-maps to restrict the search space. The method was also able to predict with sub-Angstrom accuracy two out of seven loops from recently solved crystal structures of proteins with low sequence and structure similarity to previously deposited structures in the PDB. The ability to sample realistic loop conformations directly from a potential energy function enables the incorporation of additional geometric restraints and the use of more advanced sampling methods in a way that is not possible to do easily with fragment replacement methods and also enable multi-scale simulations for protein design and protein structure prediction. These restraints could be derived from experimental data or could be design restraints in the case of computational protein design. C++ source code is available for download from http://www.sbg.bio.ic.ac.uk/phyre2/PD2/.

Hundreds of putative enzymes from Mycobacterium tuberculosis as well as other mycobacteria remain categorized as "conserved hypothetical proteins" or "hypothetical proteins", offering little or no information on their functional role in pathogenic and non-pathogenic processes. In this study we have predicted the fold and 3-D structure of more than 99% of all proteins encoded in the genome of M. tuberculosis H37Rv. Fold-recognition, database search, 3-D modelling was performed using Protein Homology/analogy Recognition Engine V 2.0 (Phyre2). These results are used to tentatively assign potential function for unannotated enzymes and proteins. In summary, fold-recognition and structural homology might be used as a complementary tool in genome annotation efforts and furthermore, it can deliver primary sequence-independent information regarding structure, ligands and even substrate specificity for enzymes that display low primary sequence identity with potential homologues in other species., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Genome3D, available at http://www.genome3d.eu, is a new collaborative project that integrates UK-based structural resources to provide a unique perspective on sequence-structure-function relationships. Leading structure prediction resources (DomSerf, FUGUE, Gene3D, pDomTHREADER, Phyre and SUPERFAMILY) provide annotations for UniProt sequences to indicate the locations of structural domains (structural annotations) and their 3D structures (structural models). Structural annotations and 3D model predictions are currently available for three model genomes (Homo sapiens, E. coli and baker's yeast), and the project will extend to other genomes in the near future. As these resources exploit different strategies for predicting structures, the main aim of Genome3D is to enable comparisons between all the resources so that biologists can see where predictions agree and are therefore more trusted. Furthermore, as these methods differ in whether they build their predictions using CATH or SCOP, Genome3D also contains the first official mapping between these two databases. This has identified pairs of similar superfamilies from the two resources at various degrees of consensus (532 bronze pairs, 527 silver pairs and 370 gold pairs).

Males often produce elaborate displays that increase their attractiveness to females, and some species extend their displays to include structures or objects that are not part of their body. Such "extended phenotypes" may communicate information that cannot be transmitted by bodily signals or may provide a more reliable signal than bodily signals. However, it is unclear whether these signals are individually distinct and whether they are consistent over long periods of time. Male bowerbirds construct and decorate bowers that function in mate choice. Bower display courts constructed by male great bowerbirds (Ptilonorhynchus nuchalis) induce a visual illusion known as forced perspective for the female viewing the male's display over the court, and the quality of illusion is associated with mating success. We improved the quality of the forced perspective to determine whether males maintained it at the new higher level, decreased the perspective quality back to its original value, or allowed it to decay at random over time. We found that the original perspective quality was actively recovered to individual original values within 3 d. We measured forced perspective over the course of one breeding season and compared the forced perspective of individual males between two successive breeding seasons. We found that differences in the quality of visual illusion among males were consistent within and between two breeding seasons. This suggests that forced perspective is actively and strongly maintained at a different level by each individual male.

The acid-labile subunit (ALS) is the main regulator of IGF1 and IGF2 bioavailability. ALS deficiency caused by mutations in the ALS (IGFALS) gene often results in mild short stature in adulthood. Little is known about the ALS structure-function relationship. A structural model built in 1999 suggested a doughnut shape, which has never been observed in the leucine-rich repeat (LRR) superfamily, to which ALS belongs. In this study, we built a new ALS structural model, analysed its glycosylation and charge distribution and studied mechanisms by which missense mutations affect protein structure. We used three structure prediction servers and integrated their results with information derived from ALS experimental studies. The ALS model was built at high confidence using Toll-like receptor protein templates and resembled a horseshoe with an extensively negatively charged concave surface. Enrichment in prolines and disulphide bonds was found at the ALS N- and C-termini. Moreover, seven N-glycosylation sites were identified and mapped. ALS mutations were predicted to affect protein structure by causing loss of hydrophobic interactions (p.Leu134Gln), alteration of the amino acid backbone (p.Leu241Pro, p.Leu172Phe and p.Leu244Phe), loss of disulphide bridges (p.Cys60Ser and p.Cys540Arg), change in structural constrains (p.Pro73Leu), creation of novel glycosylation sites (p.Asp440Asn) or alteration of LRRs (p.Asn276Ser). In conclusion, our ALS structural model was identified as a highly confident prediction by three independent methods and disagrees with the previously published ALS model. The new model allowed us to analyse the ALS core and its caps and to interpret the potential structural effects of ALS mutations.

Sexual selection studies normally compare signal strengths, but signal components and sensory processing may interact to create misleading or attention-capturing illusions. Visual illusions can be produced by altering object and scene geometry in ways that trick the viewer when seen from a particular direction. Male great bowerbirds actively maintain size-distance gradients of objects on their bower courts that create forced-perspective illusions for females viewing their displays from within the bower avenue. We show a significant relationship between mating success and the female's view of the gradient; this view explains substantially more variance in mating success than the strength of the gradients. Illusions may be widespread in other animals because males of most species display to females with characteristic orientation and distance, providing excellent conditions for illusions.

ATRX is a member of the Snf2 family of chromatin-remodelling proteins and is mutated in an X-linked mental retardation syndrome associated with alpha-thalassaemia (ATR-X syndrome). We have carried out an analysis of 21 disease-causing mutations within the Snf2 domain of ATRX by quantifying the expression of the ATRX protein and placing all missense mutations in their structural context by homology modelling. While demonstrating the importance of protein dosage to the development of ATR-X syndrome, we also identified three mutations which primarily affect function rather than protein structure. We show that all three of these mutant proteins are defective in translocating along DNA while one mutant, uniquely for a human disease-causing mutation, partially uncouples adenosine triphosphate (ATP) hydrolysis from DNA binding. Our results highlight important mechanistic aspects in the development of ATR-X syndrome and identify crucial functional residues within the Snf2 domain of ATRX. These findings are important for furthering our understanding of how ATP hydrolysis is harnessed as useful work in chromatin remodelling proteins and the wider family of nucleic acid translocating motors.

Although vocal mimicry in songbirds is well documented, little is known about the function of such mimicry. One possibility is that the mimic produces the vocalisations of predatory or aggressive species to deter potential predators or competitors. Alternatively, these sounds may be learned in error as a result of their acoustic properties such as structural simplicity. We determined the mimetic repertoires of a population of male spotted bowerbirds Ptilonorhynchus maculatus, a species that mimics predatory and aggressive species. Although male mimetic repertoires contained an overabundance of vocalisations produced by species that were generally aggressive, there was also a marked prevalence of mimicry of sounds that are associated with alarm such as predator calls, alarm calls and mobbing calls, irrespective of whether the species being mimicked was aggressive or not. We propose that it may be the alarming context in which these sounds are first heard that may lead both to their acquisition and to their later reproduction. We suggest that enhanced learning capability during acute stress may explain vocal mimicry in many species that mimic sounds associated with alarm.

Motivation: Databases of sequenced genomes are widely used to characterize the structure, function and evolutionary relationships of proteins. The ability to discern such relationships is widely expected to grow as sequencing projects provide novel information, bridging gaps in our map of the protein universe., Results: We have plotted our progress in protein sequencing over the last two decades and found that the rate of novel sequence discovery is in a sustained period of decline. Consequently, PSI-BLAST, the most widely used method to detect remote evolutionary relationships, which relies upon the accumulation of novel sequence data, is now showing a plateau in performance. We interpret this trend as signalling our approach to a representative map of the protein universe and discuss its implications.

Vocal mimicry is one of the more striking aspects of avian vocalization and is widespread across songbirds. However, little is known about how mimics acquire heterospecific and environmental sounds. We investigated geographical and individual variation in the mimetic repertoires of males of a proficient mimic, the spotted bowerbird Ptilonorhynchus maculatus. Male bower owners shared more of their mimetic repertoires with neighbouring bower owners than with more distant males. However, interbower distance did not explain variation in the highly repeatable renditions given by bower owners of two commonly mimicked species. From the similarity between model and mimic vocalizations and the patterns of repertoire sharing among males, we suggest that the bowerbirds are learning their mimetic repertoire from heterospecifics and not from each other.

Transforming growth factor-beta (TGF-β), a multifunctional cytokine regulating several immunologic processes, is expressed by virtually all cells as a biologically inactive molecule termed latent TGF-β (LTGF-β). We have previously shown that TGF-β activity increases during influenza virus infection in mice and suggested that the neuraminidase (NA) protein mediates this activation. In the current study, we determined the mechanism of activation of LTGF-β by NA from the influenza virus A/Gray Teal/Australia/2/1979 by mobility shift and enzyme inhibition assays. We also investigated whether exogenous TGF-β administered via a replication-deficient adenovirus vector provides protection from H5N1 influenza pathogenesis and whether depletion of TGF-β during virus infection increases morbidity in mice. We found that both the influenza and bacterial NA activate LTGF-β by removing sialic acid motifs from LTGF-β, each NA being specific for the sialic acid linkages cleaved. Further, NA likely activates LTGF-β primarily via its enzymatic activity, but proteases might also play a role in this process. Several influenza A virus subtypes (H1N1, H1N2, H3N2, H5N9, H6N1, and H7N3) except the highly pathogenic H5N1 strains activated LTGF-β in vitro and in vivo. Addition of exogenous TGF-β to H5N1 influenza virus-infected mice delayed mortality and reduced viral titers whereas neutralization of TGF-β during H5N1 and pandemic 2009 H1N1 infection increased morbidity. Together, these data show that microbe-associated NAs can directly activate LTGF-β and that TGF-β plays a pivotal role protecting the host from influenza pathogenesis.

3DLigandSite is a web server for the prediction of ligand-binding sites. It is based upon successful manual methods used in the eighth round of the Critical Assessment of techniques for protein Structure Prediction (CASP8). 3DLigandSite utilizes protein-structure prediction to provide structural models for proteins that have not been solved. Ligands bound to structures similar to the query are superimposed onto the model and used to predict the binding site. In benchmarking against the CASP8 targets 3DLigandSite obtains a Matthew's correlation co-efficient (MCC) of 0.64, and coverage and accuracy of 71 and 60%, respectively, similar results to our manual performance in CASP8. In further benchmarking using a large set of protein structures, 3DLigandSite obtains an MCC of 0.68. The web server enables users to submit either a query sequence or structure. Predictions are visually displayed via an interactive Jmol applet. 3DLigandSite is available for use at http://www.sbg.bio.ic.ac.uk/3dligandsite.

Macromolecular crowding has a profound effect upon biochemical processes in the cell. We have computationally studied the effect of crowding upon protein folding for 12 small domains in a simulated cell using a coarse-grained protein model, which is based upon Langevin dynamics, designed to unify the often disjoint goals of protein folding simulation and structure prediction. The model can make predictions of native conformation with accuracy comparable with that of the best current template-free models. It is fast enough to enable a more extensive analysis of crowding than previously attempted, studying several proteins at many crowding levels and further random repetitions designed to more closely approximate the ensemble of conformations. We found that when crowding approaches 40% excluded volume, the maximum level found in the cell, proteins fold to fewer native-like states. Notably, when crowding is increased beyond this level, there is a sudden failure of protein folding: proteins fix upon a structure more quickly and become trapped in extended conformations. These results suggest that the ability of small protein domains to fold without the help of chaperones may be an important factor in limiting the degree of macromolecular crowding in the cell. Here, we discuss the possible implications regarding the relationship between protein expression level, protein size, chaperone activity and aggregation., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Structural genomics initiatives are rapidly generating vast numbers of protein structures. Comparative modelling is also capable of producing accurate structural models for many protein sequences. However, for many of the known structures, functions are not yet determined, and in many modelling tasks, an accurate structural model does not necessarily tell us about function. Thus, there is a pressing need for high-throughput methods for determining function from structure. The spatial arrangement of key amino acids in a folded protein, on the surface or buried in clefts, is often the determinants of its biological function. A central aim of molecular biology is to understand the relationship between such substructures or surfaces and biological function, leading both to function prediction and to function design. We present a new general method for discovering the features of binding pockets that confer specificity for particular ligands. Using a recently developed machine-learning technique which couples the rule-discovery approach of inductive logic programming with the statistical learning power of support vector machines, we are able to discriminate, with high precision (90%) and recall (86%) between pockets that bind FAD and those that bind NAD on a large benchmark set given only the geometry and composition of the backbone of the binding pocket without the use of docking. In addition, we learn rules governing this specificity which can feed into protein functional design protocols. An analysis of the rules found suggests that key features of the binding pocket may be tied to conformational freedom in the ligand. The representation is sufficiently general to be applicable to any discriminatory binding problem. All programs and data sets are freely available to non-commercial users at http://www.sbg.bio.ic.ac.uk/svilp&#95;ligand/.

Sara Shettleworth has played a defining role in the development of animal cognition and its integration into other parts of biology, especially behavioural ecology. Here we chart some of that progress in understanding the causes and importance of variation in cognitive ability and highlight how Tinbergen's levels of explanation provide a useful framework for this field. We also review how experimental design is crucial in investigating cognition and stress the need for naturalistic experiments and field studies. We focus particularly on the example of the relationship among food hoarding, spatial cognition and hippocampal structure, and review the conflicting evidence for sex differences in spatial cognition. We finish with speculation that a combination of Tinbergen and Shettleworth-style approaches would be the way to grapple with the as-yet unanswered questions of why birds mimic heterospecifics.