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The zymogen protease plasminogen and its active form plasmin perform key roles in blood clot dissolution, tissue remodeling, cell migration, and bacterial pathogenesis. Dysregulation of the plasminogen/plasmin system results in life-threatening hemorrhagic disorders or thrombotic vascular occlusion. Accordingly, inhibitors of this system are clinically important. Currently, tranexamic acid (TXA), a molecule that prevents plasminogen activation through blocking recruitment to target substrates, is the most widely used inhibitor for the plasminogen/plasmin system in therapeutics. However, TXA lacks efficacy on the active form of plasmin. Thus, there is a need to develop specific inhibitors that target the protease active site. Here we report the crystal structures of plasmin in complex with the novel YO (trans-4-aminomethylcyclohexanecarbonyl-l-tyrosine-n-octylamide) class of small molecule inhibitors. We found that these inhibitors form key interactions with the S1 and S3' subsites of the catalytic cleft. Here, the TXA moiety of the YO compounds inserts into the primary (S1) specificity pocket, suggesting that TXA itself may function as a weak plasmin inhibitor, a hypothesis supported by subsequent biochemical and biophysical analyses. Mutational studies reveal that F587 of the S' subsite plays a key role in mediating the inhibitor interaction. Taken together, these data provide a foundation for the future development of small molecule inhibitors to specifically regulate plasmin function in a range of diseases and disorders.

Aim We present a novel quantitative framework that combines information on phylogeny and the spatial distributions of related species to enhance the single-species distributional models commonly used in ecology. Innovation While species distribution models (SDMs) are becoming increasingly sophisticated, they rarely take into consideration the shared evolutionary histories of species. Species are not independent entities, and phylogenies may capture how species have configured their spatial distributions as a response to their ecological similarities and interactions in space and through evolutionary time. Our framework provides a flexible approach to include phylogenies as a surrogate for missing trait data within SDMs, and may be particularly valuable for disentangling current and historical drivers of species distributions and modelling data-poor species when their close relatives are better sampled. Main conclusions Using both simulations and empirical examples, we demonstrate how the inclusion of phylogenetic information can significantly improve the fit of species distribution models by up to 30% for certain species. We show that the potential of phylogenies to improve model fit directly relates to the phylogenetic structure of species distributions and suggest that our framework has the potential to reconcile the apparent conflict between current and historical drivers of biodiversity patterns.

Objectives: To investigate the effects of nutraceuticals on key processes associated with atherosclerosis in vitro and in vivo. Background: Atherosclerosis is an inflammatory disease of the vasculature in which macrophages play key roles at all stages and represent promising therapeutic targets. Unfortunately, current therapies against atherosclerosis are not fully effective and associated with other issues such as adverse side effects. In addition, there have been many failures on pharmaceutical agents identified from drug discovery programs. Nutraceuticals represent promising alternatives in the prevention and treatment of atherosclerosis but requires a thorough understanding of their actions together with the underlying mechanisms. The purpose of this study was to address this with emphasis on key macrophage processes associated with atherosclerosis. Methods: A combination of macrophage cell lines and primary cultures were used with gene expression analysed by atherosclerosis profiler arrays and real time quantitative PCR. Foam cell formation was investigated by following the uptake of fluorescently labeled modified LDL, intracellular lipid profiling and cholesterol efflux assays. Inflammasome activation was evaluated by following the release of interleukin (IL)-1beta using an ELISA and ROS production using a kit from Abcam. The effects in vivo were analysed in C57BL/6 mice fed a high fat diet. Results: The studies focused on polyphenols, flavanols and omega-6 polyunsaturated fatty acids. These either inhibited or had no effect on several key macrophage processes associated with atherosclerosis such as pro-inflammatory gene expression, the uptake of modified LDL, macropinocytosis, ROS production and the activation of the inflammasome. In addition, where analysed, the nutraceutical inhibited several atherosclerosis-associated markers in mice fed a high fat diet. The mechanisms underlying such actions will be presented. Conclusions: The studies provide new insights into the beneficial actions of nutraceuticals in atherosclerosis.

As high-throughput sequencing technologies advance, standardized methods for high quality tissue acquisition and preservation allow for the extension of these methods to non-model organisms. A series of protocols to optimize tissue collection from bats has been developed for a series of high-throughput sequencing approaches. Outlined here are protocols for the capture of bats, desired demographics to be collected for each bat, and optimized methods to minimize stress on a bat during tissue collection. Specifically outlined are methods for collecting and treating tissue to obtain (i) DNA for high molecular weight genomic analyses, (ii) RNA for tissue-specific transcriptomes, and (iii) proteins for proteomic-level analyses. Lastly, also outlined is a method to avoid lethal sampling by creating viable primary cell cultures from wing clips. A central motivation of these methods is to maximize the amount of potential molecular and morphological data for each bat and suggest optimal ways to preserve tissues so they retain their value as new methods develop in the future. This standardization has become particularly important as initiatives to sequence chromosome-level, error-free genomes of species across the world have emerged, in which multiple scientific parties are spearheading the sequencing of different taxonomic groups. The protocols outlined herein define the ideal tissue collection and tissue preservation methods for Bat1K, the consortium that is sequencing the genomes of every species of bat.

Predator–prey interactions play a key role in the evolution of species traits through antagonistic coevolutionary arms races. The evolution of beak morphology in the Darwin's finches in response to competition for seed resources is a classic example of evolution by natural selection. The seeds of Tribulus cistoides are an important food source for the largest ground finch species (Geospiza fortis, G. magnirostris, and G. conirostris) in dry months, and the hard spiny morphology of the fruits is a potent agent of selection that drives contemporary evolutionary change in finch beak morphology. Although the effects of these interactions on finches are well known, how seed predation affects the ecology and evolution of the plants is poorly understood. Here we examine whether seed predation by Darwin's finches affects the ecology and evolution of T. cistoides. We ask whether the intensity of seed predation and the strength of natural selection by finches on fruit defense traits vary among populations, islands, years, or with varying finch community composition (i.e., the presence/absence of the largest beaked species, which feed on T. cistoides most easily). We then further test whether T. cistoides fruit defenses have diverged among islands in response to spatial variation in finch communities. We addressed these questions by examining seed predation by finches in 30 populations of T. cistoides over 3 yr. Our study reveals three key results. First, Darwin's finches strongly influence T. cistoides seed survival, whereby seed predation varies with differences in finch community composition among islands and in response to interannual fluctuations in precipitation. Second, finches impose phenotypic selection on T. cistoides fruit morphology, whereby smaller and harder fruits with longer or more spines exhibited higher seed survival. Variation in finch community composition and precipitation also explains variation in phenotypic selection on fruit defense traits. Third, variation in the number of spines on fruits among islands is consistent with divergent phenotypic selection imposed by variation in finch community composition among islands. These results suggest that Darwin's finches and T. cistoides are experiencing an ongoing coevolutionary arms race, and that the strength of this coevolution varies in space and time.

Predicting the B_{s}^{0}-B[over ¯]_{s}^{0} width difference ΔΓ_{s} relies on the heavy quark expansion and on hadronic matrix elements of ΔB=2 operators. We present the first lattice QCD results for matrix elements of the dimension-7 operators R_{2,3} and linear combinations R[over ˜]_{2,3} using nonrelativistic QCD for the bottom quark and a highly improved staggered quark (HISQ) action for the strange quark. Computations use MILC Collaboration ensembles of gauge field configurations with 2+1+1 flavors of sea quarks with the HISQ discretization, including lattices with physically light up or down quark masses. We discuss features unique to calculating matrix elements of these operators and analyze uncertainties from series truncation, discretization, and quark mass dependence. Finally we report the first standard model determination of ΔΓ_{s} using lattice QCD results for all hadronic matrix elements through O(1/m_{b}). The main result of our calculations yields the 1/m_{b} contribution ΔΓ_{1/m_{b}}=-0.022(10) ps^{-1}. Adding this to the leading order contribution, the standard model prediction is ΔΓ_{s}=0.092(14) ps^{-1}.

Objective: Our overall research goal is to use electroencephalography (EEG) to identify recognition of faces by patients with dementia to improve reminiscence therapy. The objective of this paper was to evaluate the performance of a g.tec EEG system using a facial recognition event related potential (ERP) task. Previous work has used the Emotiv off-the-shelf system which resulted in lack of classification. For this work, we sought to use a g.tec system with the same electrode placement as the Emotiv Insight to evaluate whether a reduced electrode set would provide sufficient classification accuracy. Methods: EEG was recorded with the same electrode montage as the Insight while obscure and famous facial stimuli were presented; participants confirmed recognition with a button press and oral confirmation. ERPs were averaged across five presentations of each facial stimuli to improve the signal to noise ratio. Classifiers were trained on one session, tested on another session. Results: Using the same electrode montage as the Insight, the g.tec achieved an average accuracy of 80%. Conclusion and Significance: A new research quality system with only the Pz electrode may provide sufficient classification to develop a system for reminiscence therapy.

Objective: Our overall research goal is to use electroencephalography (EEG) to identify recognition of faces by patients with dementia to improve reminiscence therapy. The objective of this paper was to evaluate the performance of the consumer grade Emotiv Insight using a facial recognition event related potential (ERP) task. Good classification accuracy would enable the use of commercial systems such as the Insight to be used for reminiscence therapy. Methods: EEG was recorded with the Insight while obscure and famous facial stimuli were presented; participants confirmed recognition with a button press and oral confirmation. ERPs were averaged across five presentations of each facial stimuli to improve the signal to noise ratio. Classifiers were trained on one session, tested on another session, and the accuracy of each system was compared. Results: The Insight did produce ERPs typical of recognition memory however, it did not perform much better than chance. Event integration and artefacts were a significant problem. Conclusion: The Insight has practical advantages; however, the recording quality is not high enough to achieve adequate classification accuracy.

Plasminogen (Plg)-binding M protein (PAM) is a group A streptococcal cell surface receptor that is crucial for bacterial virulence. Previous studies revealed that, by binding to the kringle 2 (KR2) domain of host Plg, the pathogen attains a proteolytic microenvironment on the cell surface that facilitates its dissemination from the primary infection site. Each of the PAM molecules in their dimeric assembly consists of two Plg binding motifs (called the a1 and a2 repeats). To date, the molecular interactions between the a1 repeat and KR2 have been structurally characterized, whereas the role of the a2 repeat is less well defined. Here, we report the 1.7-A x-ray crystal structure of KR2 in complex with a monomeric PAM peptide that contains both the a1 and a2 motifs. The structure reveals how the PAM peptide forms key interactions simultaneously with two KR2 via the high-affinity lysine isosteres within the a1a2 motifs. Further studies, through combined mutagenesis and functional characterization, show that a2 is a stronger KR2 binder than a1, suggesting that these two motifs may play discrete roles in mediating the final PAM-Plg assembly.

Aim Community phylogenetic studies use information about the evolutionary relationships of species to understand the ecological processes of community assembly. A central premise of the field is that the evolution of species maps onto ecological patterns, and phylogeny reveals something more than species traits alone about the ecological mechanisms structuring communities, such as environmental filtering, competition, and facilitation. We argue, therefore, that there is a need for better understanding and modelling of the interaction of phylogeny with species traits and community composition. Innovation We outline a new approach that identifies clades that are ecophylogenetically clustered or overdispersed and assesses whether those clades have different rates of trait evolution. Ecophylogenetic theory would predict that the traits of clustered or overdispersed clades might have evolved differently, in terms of either tempo (fast or slow) or mode (e.g., under constraint or neutrally). We suggest that modelling the evolution of independent trait data in these clades represents a strong test of whether there is an association between the ecological co‐occurrence patterns of a species and its evolutionary history. Main conclusions Using an empirical dataset of mammals from around the world, we identify two clades of rodents whose species tend not to co‐occur in the same local assemblages (are phylogenetically overdispersed) and find independent evidence of slower rates of body mass evolution in these clades. Our approach, which assumes nothing about the mode of species trait evolution but instead seeks to explain it using ecological information, presents a new way to examine ecophylogenetic structure.

Color-coded duplex sonography (CCDS) remains the primary angiological method for most clinical cerebrovascular problems. The application of ultrasound is a non-invasive, cost-effective and arbitrarily repeatable examination technique. Simultaneous acquisition of morphologic B‑mode images and hemodynamic parameters with high temporal and spatial resolution is unequalled by any other neurovascular imaging modality. The correct and reproducible use of CCDS requires knowledge of technical details and adequate examination techniques. Its multiparametric approach uses main and additional criteria to detect and precisely quantify clinically highly relevant stenosis of the proximal internal carotid artery. Quantification of vertebral artery stenosis is performed semiquantitatively due to the generally less reliable sonographic approach. The use of CCDS plays an essential role in supporting endovascular and operative procedures as well as in monitoring hemodynamically relevant dissections.

Multigene families evolve from single-copy ancestral genes via duplication, and typically encode proteins critical to key biological processes. Molecular analyses of these gene families require high-confidence sequences, but the high sequence similarity of the members can create challenges for sequencing and downstream analyses. Focusing on the common vampire bat, Desmodus rotundus, we evaluated how different sequencing approaches performed in recovering the largest mammalian protein-coding multigene family: olfactory receptors (OR). Using the genome as a reference, we determined the proportion of intact protein-coding receptors recovered by: (a) amplicons from degenerate primers sequenced via Sanger technology, (b) RNA-Seq of the main olfactory epithelium, and (c) those genes captured with probes designed from transcriptomes of closely-related species. Our initial re-annotation of the high-quality vampire bat genome resulted in400 intact OR genes, more than doubling the original estimate. Sanger-sequenced amplicons performed the poorest among the three approaches, detecting33% of receptors in the genome. In contrast, the transcriptome reliably recovered50% of the annotated genomic ORs, and targeted sequence capture recovered nearly 75% of annotated genes. Each sequencing approach assembled high-quality sequences, even if it did not recover all receptors in the genome. While some variation may be due to limitations of the study design (e.g., different individuals), variation among approaches was mostly caused by low coverage of some receptors rather than high rates of assembly error. Given this variability, we caution against using the counts of intact receptors per species to model the birth-death process of multigene families. Instead, our results support the use of orthologous sequences to explore and model the evolutionary processes shaping these genes.

Multigene families evolve from single-copy ancestral genes via duplication, and typically encode proteins critical to key biological processes. Molecular analyses of these gene families require high-confidence sequences, but the high sequence similarity of the members can create challenges for both sequencing and downstream analyses. Focusing on the common vampire bat,Desmodus rotundus, we evaluated how different sequencing approaches performed in recovering the largest mammalian protein-coding multigene family:olfactory receptors(OR). Using the common vampire bat genome as a reference, we determined the proportion of putatively protein-coding receptors recovered by: 1) amplicons from degenerate primers sequenced via Sanger technology, 2) RNA-Seq of the main olfactory epithelium, and 3) those genes “captured” with probes designed from transcriptomes of closely-related species. Our initial re-annotation of the high-quality vampire bat genome resulted in >400 intactORgenes, more than double the number based on original estimates. Sanger-sequenced amplicons performed the poorest among the three approaches, detecting 50% of the annotated genomicORs, and targeted sequence capture recovered nearly 75% of annotated genes. Each sequencing approach assembled high-quality sequences, even if it did not recover all putative receptors in the genome. Therefore, variation among assemblies was caused by low coverage of some receptors, rather than high rates of assembly error. Given this variability, we caution against using the counts of number of intact receptors per species to model the birth-death process of multigene families. Instead, our results support the use of orthologous sequences to explore and model the evolutionary processes shaping these genes.

The horse has evolved to gallop economically at high speed. Limb force increases with speed but direct measures of limb ground reaction forces (GRFs) at gallop are sparse. This study reports GRFs for multiple limbs, using force plates, across seven Thoroughbred racehorses during ridden galloping. The results show peak vertical GRF values of 13.6 N kg−1 (non-lead hindlimb), 12.3 N kg−1 (lead hindlimb), 14.0 N kg−1 (non-lead forelimb) and 13.6 N kg−1 (lead forelimb) at 11.4 m s−1 and recorded values are consistent with those predicted from duty factor. The distribution of body weight between the forelimbs and hindlimbs is approximated to 50:50, and is variable with speed, unlike the 60:40 commonly stated for cursorial quadrupeds in the literature. An even distribution of load on all limbs may help minimise accumulation of fatigue and assist in injury avoidance. Cranio-caudal force data concur with the observation that horses apply a net accelerative impulse with the hindlimbs and a net decelerative impulse with the forelimbs. Capturing GRFs enhances our knowledge on the mechanics of galloping in fast-moving species and provides insight into injury risk and factors limiting athletic performance.

Additional figures and further notes on methodology.

International audience; A sixth great mass extinction is ongoing due to the direct and indirect effects of human pressures. However, not all lineages are affected equally. From an anthropocentric perspective, it is often purported that humans hold a unique place on Earth. Here, we show that our current impacts on the natural world risk realizing that expectation. We simulated species loss on the mammalian phylogenetic tree, informed by species current extinction risks. We explored how Homo sapiens could become isolated in the tree if species currently threatened with extinction disappeared. We analyzed correlates of mammal extinctions risks that may drive this isolation pattern. We show that, within mammals, and more particularly within primates, extinction risks increase with the number of known threat types, and decrease with geographic range size. Extinctions increase with species body mass, trophic level, and the median longitudinal extent of each species range in mammals but not within primates. The risks of extinction are frequently high among H. sapiens close relatives. Pruning threatened primates, including apes (Hominidae, Hylobatidae), from the tree of life will lead to our species being among those with the fewest close relatives. If no action is taken, we will thus not only lose crucial biodiversity for the preservation of Earth ecosystems, but also a key living reference to what makes us human.

Neurodegeneration has been linked to changes in the gut microbiota and this study compares the neuroprotective capability of two bacterial consortia, known as Lab4 and Lab4b, using the established SH-SY5Y neuronal cell model. Firstly, varying total antioxidant capacities (TAC) were identified in the intact cells from each consortia and their secreted metabolites, referred to as conditioned media (CM). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Crystal Violet (CV) assays of cell viability revealed that Lab4 CM and Lab4b CM could induce similar levels of proliferation in SH-SY5Y cells and, despite divergent TAC, possessed a comparable ability to protect undifferentiated and retinoic acid-differentiated cells from the cytotoxic actions of rotenone and undifferentiated cells from the cytotoxic actions of 1-methyl-4-phenylpyridinium iodide (MPP+). Lab4 CM and Lab4b CM also had the ability to attenuate rotenone-induced apoptosis and necrosis with Lab4b inducing the greater effect. Both consortia showed an analogous ability to attenuate intracellular reactive oxygen species accumulation in SH-SY5Y cells although the differential upregulation of genes encoding glutathione reductase and superoxide dismutase by Lab4 CM and Lab4b CM, respectively, implicates the involvement of consortia-specific antioxidative mechanisms of action. This study implicates Lab4 and Lab4b as potential neuroprotective agents and justifies their inclusion in further in vivo studies.

A streamlined pipeline for structure determination is described that applies in cellulo X-ray diffraction analysis to crystal-containing cells isolated by flow cytometry. Application of this pipeline to in vivo-grown crystals of the recombinant CPV1 polyhedrin shows that in cellulo analysis is more efficient, is compatible with experimental phasing and does not compromise the quality of the final model., While structure determination from micrometre-sized crystals used to represent a challenge, serial X-ray crystallography on microfocus beamlines at synchrotron and free-electron laser facilities greatly facilitates this process today for microcrystals and nanocrystals. In addition to typical microcrystals of purified recombinant protein, these advances have enabled the analysis of microcrystals produced inside living cells. Here, a pipeline where crystals are grown in insect cells, sorted by flow cytometry and directly analysed by X-ray diffraction is presented and applied to in vivo-grown crystals of the recombinant CPV1 polyhedrin. When compared with the analysis of purified crystals, in cellulo diffraction produces data of better quality and a gain of ∼0.35 Å in resolution for comparable beamtime usage. Importantly, crystals within cells are readily derivatized with gold and iodine compounds through the cellular membrane. Using the multiple isomorphous replacement method, a near-complete model was autobuilt from 2.7 Å resolution data. Thus, in favourable cases, an in cellulo pipeline can replace the complete workflow of structure determination without compromising the quality of the resulting model. In addition to its efficiency, this approach maintains the protein in a cellular context throughout the analysis, which reduces the risk of disrupting transient or labile interactions in protein–protein or protein–ligand complexes.

The use of phylogenies in ecology is increasingly common and has broadened our understanding of biological diversity. Ecological sub-disciplines, particularly conservation, community ecology and macroecology, all recognize the value of evolutionary relationships but the resulting development of phylogenetic approaches has led to a proliferation of phylogenetic diversity metrics. The use of many metrics across the sub-disciplines hampers potential meta-analyses, syntheses, and generalizations of existing results. Further, there is no guide for selecting the appropriate metric for a given question, and different metrics are frequently used to address similar questions. To improve the choice, application, and interpretation of phylo-diversity metrics, we organize existing metrics by expanding on a unifying framework for phylogenetic information. Generally, questions about phylogenetic relationships within or between assemblages tend to ask three types of question: how much; how different; or how regular? We show that these questions reflect three dimensions of a phylogenetic tree: richness, divergence, and regularity. We classify 70 existing phylo-diversity metrics based on their mathematical form within these three dimensions and identify ‘anchor’ representatives: for α-diversity metrics these are PD (Faith's phylogenetic diversity), MPD (mean pairwise distance), and VPD (variation of pairwise distances). By analysing mathematical formulae and using simulations, we use this framework to identify metrics that mix dimensions, and we provide a guide to choosing and using the most appropriate metrics. We show that metric choice requires connecting the research question with the correct dimension of the framework and that there are logical approaches to selecting and interpreting metrics. The guide outlined herein will help researchers navigate the current jungle of indices.

As a megadiverse country with three global biodiversity hotspots, a growing human population, and a rapidly developing economy, South Africa exemplifies the challenges facing modern conservation biology. South Africa has established a protected areas network which encompasses 1527 National Parks, nature reserves, wilderness areas, mountain catchment areas, and World Heritage sites. However, the contribution of South Africa's protected areas to biodiversity conservation remains poorly known as many currently protected areas were selected based on the affordability of land or simply situated on sites that were unsuitable for commercial activities, rather than on the biological diversity within them. Here, we model the distribution of >10,000 species, representing South Africa's endemic flora, to evaluate the conservation effectiveness of the current protected areas network. We show that the flora within protected areas has been better sampled than sites outside of protected areas. However, the current protected areas network fails to adequately encompass threatened taxa, many of which are found in threatened ecosystems. We identify locations that represent important conservation gaps, and we suggest that these areas should be included in future conservation planning.

Human activity is accelerating rates of extinction around the world, and there is therefore an urgent need to understand the potential consequences of species loss on functional diversity and ecosystem functioning. It is frequently assumed that the extinction of threatened species, which are usually rare species, may have limited effects on ecosystem functioning, especially within highly diverse regions, given the low abundance of individuals of each species and the potentially high functional redundancy among them. However, these rare species may contribute unique and irreplaceable functional roles, and therefore their extinction could have disproportionate impacts on ecosystems. We assess the functional importance of highly threatened anurans (frogs and toads) and then explore how the loss of these threatened species would impact spatial patterns of β-diversity in Ecuador, a hotspot of anuran biodiversity and endemism. We found that highly threatened species are, on average, more functionally distinct at an assemblage level than are less threatened anurans. We then show that the potential extinction of these highly endangered species would drive the taxonomic, phylogenetic, and, especially, functional homogenization of anuran assemblages across the Ecuadorian Andes. We suggest this could lead to profound alterations in the stability of local ecosystem functioning. Finally, we highlight the limited scope of the existing network of protected areas in Ecuador to effectively cover anuran assemblages predicted to become increasingly functionally homogenous. Our study underscores the potential losses of functional diversity that accompany species extinctions and the importance of considering the many facets of biodiversity in conservation decision-making.

Part 1 Scene setting: is health care a business? an analysis of health care, and its considerations as a business, John L. Deffenbaugh managing the design of health care services, Moira Fischbacher and Arthur Francis. Part 2 Quality in health care: towards critical quality, Mike Walsh whose quality? different interest groups' perspectives on health care quality, Juan I. Baeza and Michael Calnan the quantification of patient satisfaction, Mike Hart managing clinical audit - diagnozing the problems and designing solutions, Gail Johnston et al improving child dental health in Scotland - an audit in primary care, Chris Southwick et al human resource management audits - contributions to quality, Sandra Nutley. Part 3 Using performance indicators: what are we counting with hospital episode statistics (HES)?, Richard Wilson clinical outcomes indicators in Scotland - lessons and prospects, Steve Kendrick et al what do managers and physicians prefer as indicators of clinical outcome?, Regis Blais et al performance indicators - a patient-centred approach, Anne Ludbrook and Colin Gordon is indicator use for quality improvement and performance measurement compatible?, Joanne Lally and Richard Thomson published health outcomes - guiding lights or wreckers' lanterns?, Huw T.O. Davies et al.

The loss of previously adaptive traits is typically linked to relaxation in selection, yet the molecular steps leading to such repeated losses are rarely known. Molecular studies of loss have tended to focus on gene sequences alone, but overlooking other aspects of protein expression might underestimate phenotypic diversity. Insights based almost solely on opsin gene evolution, for instance, have made mammalian color vision a textbook example of phenotypic loss. We address this gap by investigating retention and loss of opsin genes, transcripts, and proteins across ecologically diverse noctilionoid bats. We find multiple, independent losses of short-wave-sensitive opsins. Mismatches between putatively functional DNA sequences, mRNA transcripts, and proteins implicate transcriptional and post-transcriptional processes in the ongoing loss of S-opsins in some noctilionoid bats. Our results provide a snapshot of evolution in progress during phenotypic trait loss, and suggest vertebrate visual phenotypes cannot always be predicted from genotypes alone., eLife digest Bats are famous for using their hearing to explore their environments, yet fewer people are aware that these flying mammals have both good night and daylight vision. Some bats can even see in color thanks to two light-sensitive proteins at the back of their eyes: S-opsin which detects blue and ultraviolet light and L-opsin which detects green and red light. Many species of bat, however, are missing one of these proteins and cannot distinguish any colors; in other words, they are completely color-blind. Some bat species found in Central and South America have independently lost their ability to see blue-ultraviolet light and have thus also lost their color vision. These bats have diverse diets – ranging from insects to fruits and even blood – and being able to distinguish color may offer an advantage in many of their activities, including hunting or foraging. The vision genes in these bats, therefore, give scientists an opportunity to explore how a seemingly important trait can be lost at the molecular level. Sadier, Davies et al. now report that S-opsin has been lost more than a dozen times during the evolutionary history of these Central and South American bats. The analysis used samples from 55 species, including animals caught from the wild and specimens from museums. As with other proteins, the instructions encoded in the gene sequence for S opsin need to be copied into a molecule of RNA before they can be translated into protein. As expected, S-opsin was lost several times because of changes in the gene sequence that disrupted the formation of the protein. However, at several points in these bats’ evolutionary history, additional changes have taken place that affected the production of the RNA or the protein, without an obvious change to the gene itself. This finding suggests that other studies that rely purely on DNA to understand evolution may underestimate how often traits may be lost. By capturing ‘evolution in action’, these results also provide a more complete picture of the molecular targets of evolution in a diverse set of bats.

Global change has become a central focus of modern biology. Yet, our knowledge of how anthropogenic drivers affect biodiversity and natural resources is limited by a lack of biological data spanning the Anthropocene. We propose that the hundreds of millions of plant, fungal and animal specimens deposited in natural history museums have the potential to transform the field of global change biology. We suggest that museum specimens are underused, particularly in ecological studies, given their capacity to reveal patterns that are not observable from other data sources. Increasingly, museum specimens are becoming mobilized online, providing unparalleled access to physiological, ecological and evolutionary data spanning decades and sometimes centuries. Here, we describe the diversity of collections data archived in museums and provide an overview of the diverse uses and applications of these data as discussed in the accompanying collection of papers within this theme issue. As these unparalleled resources are under threat owing to budget cuts and other institutional pressures, we aim to shed light on the unique discoveries that are possible in museums and, thus, the singular value of natural history collections in a period of rapid change. This article is part of the theme issue ‘Biological collections for understanding biodiversity in the Anthropocene’.

From butterflies to elephants, the rapidly developing science of movement ecology is providing increasingly detailed spatio-temporal data on a wide array of mobile animals. Thus, this discipline also holds great promise for improving the conservation of wildlife. To measure progress towards this promise, we investigated the degree to which movement ecology research is connected to conservation goals as well as the proportion of studies that were incorporated into federal and international status assessments for mobile species at risk. We examined 13,349 “movement ecology” papers published between 1990 and 2014 and found that explicit connections to conservation and management were made in 35% (n = 4, 672) of these papers, with the number of connections increasing over time. We then measured the uptake of movement ecology research into species status assessment and recovery plans (n = 72 documents) produced by three different governance agencies for 12 endangered mobile species. We found that on average 60 % of available movement ecology research was used in the status assessment process, demonstrating that when movement ecology research is available, it is generally being utilized in conservation planning. However, for 25% of these species, there was little movement research available to be used, highlighting that knowledge gaps remain for some at-risk species despite the general growth of movement ecology research. We outline opportunities for movement ecology to promote more effective conservation of taxa that move.

Lysine binding sites (LBSs) of plasminogen (Plg) are essential for maintaining a closed conformation in circulation and binding to fibrin and cell surface receptors.1,2 Upon binding to the targets, Plg is activated to plasmin (Plm) by the fibrin-bound tissue plasminogen activator (tPA) or the cell receptor–bound urokinase plasminogen activator (uPA). Tranexamic acid (TXA) is a lysine analog that binds to the LBSs of Plg with 1 high-affinity (1.1 μM) and 3 medium-affinity (∼0.75 mM) binding sites.1-3 Accordingly, TXA at submicromolar concentrations significantly attenuates in situ Plm formation4 and is used frequently as an antifibrinolytic agent in trauma, as well as in major surgeries, including cardiac, orthopedic, and hepatic surgeries.5 The CRASH-26 and MATTERs7 clinical studies revealed that, when TXA is administered within 3 hours after injury, mortality is reduced by up to 20%.8 Recent reanalysis of the clinical data further showed that the survival benefit of TXA decreased by 10% for every 15 minutes of delayed administration, with no benefit obtained after 3 hours.9 This lack of efficacy outside of the “3-hour window” has been associated with the upregulation of plasma uPA postinjury.6,10,11 We have previously observed that a very high concentration (∼25 mM) of TXA inhibits Plm activity via binding to the primary catalytic (S1) pocket of the enzyme.12 However, because of the low affinity of TXA for Plm, we do not anticipate that TXA functions as a Plm inhibitor during clinical use.12 However, given these findings, we investigated whether TXA may have an inhibitory effect on other proteases in the Plg-activation system. Unexpectedly, our results revealed that TXA attenuates uPA activity with an inhibitory constant (Ki) of 2 mM. In contrast, similar efficacy is not observed in the presence of e-aminocaproic acid (EACA; an alternative drug to TXA).

Decline in balance control is an issue for older adults as it leads to an increased risk of falling which may result in serious injury. Mitigating this risk may be achieved through balance training and exercise, but lack of adherence to an exercise program often occurs. Improvement in balance control may be difficult to quantify in an unbiased manner given the therapist providing the treatment also assesses the patient. We developed a gamified system using an off-the-shelf technology through an iterative feedback with therapists and clients to evaluate a response time during stepping as a measure of balance control. The game was designed using serious game strategies to increase participant engagement. This game included two Nintendo Wii balance boards between which the individual was required to step while the times were recorded. To provide evidence that the system could be used in a clinical environment, we conducted a cross-sectional study collecting data for five minutes at the beginning of a physiotherapy assessment. One hundred and four individuals older than 50 years of age were recruited who were able to step forward with or without an aid. The response time for a step using the system was negatively correlated to the Berg balance score.

Complement component 9 (C9) functions as the pore-forming component of the Membrane Attack Complex (MAC). During MAC assembly, multiple copies of C9 are sequentially recruited to membrane associated C5b8 to form a pore. Here we determined the 2.2 Å crystal structure of monomeric murine C9 and the 3.9 Å resolution cryo EM structure of C9 in a polymeric assembly. Comparison with other MAC proteins reveals that the first transmembrane region (TMH1) in monomeric C9 is uniquely positioned and functions to inhibit its self-assembly in the absence of C5b8. We further show that following C9 recruitment to C5b8, a conformational change in TMH1 permits unidirectional and sequential binding of additional C9 monomers to the growing MAC. This mechanism of pore formation contrasts with related proteins, such as perforin and the cholesterol dependent cytolysins, where it is believed that pre-pore assembly occurs prior to the simultaneous release of the transmembrane regions., The Complement component 9 (C9) is the pore-forming component of the Membrane Attack Complex which targets pathogens. Here authors use structural biology to compare monomeric C9 to C9 within the polymeric assembly and identify the element which inhibits C9 self-assembly in the absence of the target membrane.

Mounting evidence shows that species interactions may mediate how individual species respond to climate change. However, long-term anthropogenic effects on species interactions are poorly characterized owing to a lack of data. Insect herbivory is a major ecological process that represents the interaction between insect herbivores and their host plants, but historical data on insect damage to plants is particularly sparse. Here, we suggest that museum collections of insects and plants can fill key gaps in our knowledge on changing trophic interactions, including proximate mechanisms and the net outcomes of multiple global change drivers across diverse insect herbivore–plant associations. We outline theory on how global change may affect herbivores and their host plants and highlight the unique data that could be extracted from museum specimens to explore their shifting interactions. We aim to provide a framework for using museum specimens to explore how some of the most diverse co-evolved relationships are responding to climate and land use change. This article is part of the theme issue ‘Biological collections for understanding biodiversity in the Anthropocene’.

Current conservation templates prioritize biogeographic regions with high intensity ecosystem values, such as exceptional species richness or threat. Intensity-based targets are an important consideration in global efforts, but they do not capture all available opportunities to conserve ecosystem values, including those that accrue in low intensity over large areas. We assess six globally-significant ecosystem values-intact wilderness, freshwater availability, productive marine environments, breeding habitat for migratory wildlife, soil carbon storage, and latitudinal potential for range shift in the face of climate change-to highlight opportunities for high-impact broadly-distributed contributions to global conservation. Nations can serve as a cohesive block of policy that can profoundly influence conservation outcomes. Contributions to global ecosystem values that exceed what is predicted by a nation's area alone, can give rise to countries with the capacity to act as 'conservation superpowers', such as Canada and Russia. For these conservation superpowers, a relatively small number of national policies can have environmental repercussions for the rest of the world.

The objective of this research was to develop a “paper-based” prototype design of a device that will eventually be developed to teach braille in a co-design process that involved end-user input throughout the process. Questionnaires aimed to explore the use of assistive technologies to help learn or teach braille. Features of existing assistive technologies were identified by the participants. Taking these features into consideration, seven conceptual design solutions were developed by six designers. A weighted evaluation matrix (WEM) ranked potential designs. A weighting for each design feature was calculated using the frequency of that feature. The responses from each participant group were weighted equally. Two semi-structured interviews were conducted with braille teachers. The design preferred by both the teachers was ranked fifth in the weighted evaluation matrix. Designs that were ranked poorly according to the WEM, were actually ranked highly by the end-users. The co-design process was essential in identifying these differences.

Microbiomes impact a variety of processes including a host’s ability to access nutrients and maintain health. While host species differences in microbiomes have been described across ecosystems, little is known about how microbiomes assemble, particularly in the ecological and social contexts in which they evolved. We examined gut microbiome composition in nine sympatric wild non-human primate (NHP) species. Despite sharing an environment and interspecific interactions, individuals harbored unique and persistent microbiomes influenced by host species, social group, and parentage, but surprisingly not by social relationships among members of a social group. We found a branching order of host-species networks constructed using the composition of their microbiomes as characters, which was incongruent with known NHP phylogenetic relationships, with chimpanzees (Pan troglodytes verus) sister to colobines, upon which they regularly prey. In contrast to phylogenetic clustering found in all monkey microbiomes, chimpanzee microbiomes were unique in that they exhibited patterns of phylogenetic overdispersion. This reflects unique ecological processes impacting microbiome composition in chimpanzees and future studies will elucidate the aspects of chimpanzee ecology, life history, and physiology that explain their unique microbiome community structure. Our study of contemporaneous microbiomes of all sympatric diurnal NHP in an ecosystem highlights the diverse dispersal routes shaping these complex communities.

In a recent publication (Pearse et al. 2018b), we explored the macroevolution and macroecology of passerine song using a large citizen science database of bird songs and powerful machine learning tools. Mikula et al. (2018) examine a small subset (

Rising global temperatures are causing a poleward shift in species distribution. Range shift velocities are higher in the marine environment, with observed rates of 30–130 km per decade. Both protected and exploited species will be at risk if marine species management policies are not structured to anticipate these range shifts. The 2017 mass mortality event of the North Atlantic right whale showcases the detrimental impact of unanticipated climate-mediated behavior in a species protected by geographically and seasonally fixed policies. Based on the results of a demographic capture-​recapture model, right whales may face extinction in fewer than 30 years unless protective policies are expanded to cover their shifting distribution. Increased support of long-term monitoring programs paired with environmental modeling research is critical to developing more proactive conservation management strategies and preventing further ecological crises.

Large‐scale environmental gradients have been invaluable for unraveling the processes shaping the evolution and maintenance of biodiversity. Environmental gradients provide a natural setting to test theories about species diversity and distributions within a landscape with changing biotic and abiotic interactions. Elevational gradients are particularly useful because they often encompass a large climatic range within a small geographical extent. Here, we analyzed tree communities in plots located throughout Arunachal Pradesh, a province in northeast India located on the southern face of the Eastern Himalayas, representing one of the largest elevational gradients in the world. Using indices of species and phylogenetic diversity, we described shifts in community structure across the landscape and explored the putative biotic and abiotic forces influencing species assembly. As expected, species richness and phylogenetic diversity decreased with increasing elevation; however, contrary to predictions of environmental filtering, species relatedness did not show any clear trend. Nonetheless, patterns of beta diversity (both taxonomic and phylogenetic) strongly suggest lineage filtering along the elevational gradient. Our results may be explained if filtering is driving the assembly of species from distinct evolutionary lineages. New metrics exploring community contributions to regional taxonomic and phylogenetic beta diversity provided additional evidence for the persistence of unique communities at high elevations. We suggest that these patterns may be consistent with filtering on glacial relicts, part of once more diverse clades with convergent traits suited to climates at the last glacial maximum, resulting in random or over‐dispersed community assemblages at high elevations. We propose that these high‐elevation sites with evolutionarily distinct species represent possible regions for conservation priority that may provide refugia for species threatened by current warming trends.

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Objective: The objective of this study was to identify the immunomodulatory potential of two consortia of lactic acid bacteria, “Lab4” and “Lab4b”, using human macrophages as an in vitro model system. Methods: THP-1 monocyte-derived macrophages were exposed to metabolites of Lab4 or Lab4b. RT-qPCR was performed on macrophages to determine the expression of M1 pro-inflammatory (IL-1β, IL-18 and CD80) or M2 anti-inflammatory (CD206) marker mRNA in addition to IL-1β protein and inflammasome (NLRP3, Caspase-1, NLRP1, NLRC4 and AIM2) mRNA expression. Bacterial (LPS and ATP) and viral (Poly I:C) challenge were stimulated to determine the potential of these consortia to regulate IL-1β protein, inflammasome mRNA expression, and antiviral IL-12 mRNA expression and protein under inflammatory conditions. The ability of these consortia to modulate macrophage phagocytosis of E. coliwas also assessed. Results:Results: Lab4 and Lab4b metabolites promoted an M1 phenotype in macrophages in vitro by increasing mRNA expression of IL-1β, IL-18, and CD80 and reducing mRNA expression of CD206. Induction of IL-1β protein suggested involvement of the inflammasome. mRNA expression of NLRP3, Caspase-1, NLRP1 and AIM2 was induced by Lab4 and mRNA expression of NLRP3 and Caspase-1 was induced by Lab4b suggesting different potential modes of action of the two consortia. Lab4 and Lab4b metabolites, in combination with this LPS and ATP challenge, enhanced IL-1β mRNA and protein expression further, accompanied by different mRNA expression profiles of inflammasome genes by the two consortia. Lab4 and Lab4b also induced expression of mRNA and protein of the antiviral response gene, IL-12. In combination with Poly I:C challenge, Lab4 induced IL-12 protein further, while Lab4b induced IL-12p25/IL-12p40 mRNA further highlighting potential differences. Both consortia were also able to induce phagocytosis of E. coli particles. Conclusion: Data generated from this study suggest the potential for organism-dependent control of the immunoregulatory response seen in human macrophages.

Using a commercial electroencephalography (EEG)-based brain-computer interface (BCI), the training and testing protocol for six individuals with spastic quadriplegic cerebral palsy (GMFCS and MACS IV and V) was evaluated.A customised, gamified training paradigm was employed. Over three weeks, the participants spent two sessions exploring the system, and up to six sessions playing the game which focussed on EEG feedback of left and right arm motor imagery.The participants showed variable inconclusive results in the ability to produce two distinct EEG patterns. Participant performance was influenced by physical illness, motivation, fatigue and concentration.The results from this case study highlight the infancy of BCIs as a form of assistive technology for people with cerebral palsy. Existing commercial BCIs are not designed according to the needs of end-users. Implications for Rehabilitation Mood, fatigue, physical illness and motivation influence the usability of a brain-computer interface. Commercial brain-computer interfaces are not designed for practical assistive technology use for people with cerebral palsy. Practical brain-computer interface assistive technologies may need to be flexible to suit individual needs.

Summary The polar desert biome of the Canadian high Arctic Archipelago is currently experiencing some of the greatest mean annual air temperature increases on the planet, threatening the stability of ecosystems residing above temperature-sensitive permafrost. Ice wedges are the most widespread form of ground ice, occurring in up to 25% of the world's terrestrial near-surface, and their melting (thermokarst) may catalyse a suite of biotic and ecological changes, facilitating major ecosystem shifts. These unknown ecosystem shifts raise serious questions as to how permafrost stability, vegetation diversity and edaphic conditions will change with a warming high Arctic. Ecosystem and thermokarst processes tend to be examined independently, limiting our understanding of a coupled system whereby the effect of climate change on one will affect the outcome of the other. Using in-depth, comprehensive field observations and a space-for-time approach, we investigate the highly structured landscape that has emerged due to the thermokarst-induced partitioning of microhabitats. We examine differences in vegetation diversity, community composition and soil conditions on the Fosheim Peninsula, Ellesmere Island, Nunavut. We hypothesize that (i) greater ice wedge subsidence results in increased vegetation cover due to elevated soil moisture, thereby decreasing the seasonal depth of thaw and restricting groundwater outflow; (ii) thermokarst processes result in altered vegetation richness, turnover and dispersion, with greater microhabitat diversity at the landscape scale; and (iii) shifts in hydrology and plant community structure alter soil chemistry. We found that the disturbance caused by melting ice wedges catalysed a suite of environmental and biotic effects: topographical changes, a new hydrological balance, significant species richness and turnover changes, and distinct soil chemistries. Thermokarst areas favour a subset of species unique from the polar desert and are characterized by greater species turnover (β-diversity) across the landscape. Synthesis. Our findings suggest that projected increases of thermokarst in the polar desert will lead to the increased partitioning of microhabitats, creating a more heterogeneous high arctic landscape through diverging vegetation communities and edaphic conditions, resulting in a wetland-like biome in the high Arctic that could replace much of the ice-rich polar desert.

Question Community phylogenetic approaches can provide information on the ecological forces structuring plant community composition. For example, assuming evolutionary conservatism of ecological traits, environmental filtering has been suggested to result in phylogenetic clustering, whereas competition has been suggested to lead to phylogenetic over-dispersion. However, current approaches report aggregate community-wide metrics and typically assume that all lineages respond similarly. Here, we question this assumption and evaluate evidence for lineage-specific patterns of co-occurrence. Location Eastern Canadian subarctic. Methods We use a novel individual-based, neighbourhood approach to evaluate lineage-specific co-occurrence patterns among 35 focal species of Cyperaceae (sedges). Cyperaceae is a species-rich clade, with many species sharing similar niche preferences and environmental tolerances, making this a model clade for evaluating interspecific interaction strengths. Results We reveal striking differences in co-occurrence patterns between clades. Within the Cyperaceae, the two species of the genus Trichophorum tended to cluster with each other, whereas species within Eriophorum co-occurred more often with less closely related neighbours. These contrasting patterns repeated themselves within Carex, with species in the Core Carex clade more often co-occurring with close relatives, while phylogenetic over-dispersion was more prominent in the Vignea clade. As a consequence of these opposing lineage-specific relationships, the overall phylogenetic structure of sedge communities appears random. Conclusions We show opposing lineage-specific patterns in phylogenetic structure that are obscured when species are aggregated into larger clades. Our results reveal cryptic complexities in plant community assembly across taxonomic scales, and indicate that different plant lineages may vary in their response to community-level processes. We suggest that the processes underlying community composition can be better understood by using alternative sampling and analytical approaches combined with thoughtfully-created null models.

Oceanographic surveys were conducted in Roseway Basin, western Scotian Shelf, during late-summer from 2007 through 2009 to measure the magnitude of interannual variation in the spatial distribution of diapausing copepods Calanus finmarchicus and C. hyperboreus and associated water mass characteristics. Calanus spp. abundance, energy density and hydrography were measured at depths > 50 m along transects using a Towed Underwater Biological Sampling System equipped with an Optical Plankton Counter (OPC) and a conductivity-temperature-depth (CTD) sensor, as well as at fixed stations using a Biological Net and Environmental Sampling System equipped with nets, OPC and CTD. Water mass density and in some cases salinity explained variation in the deep copepod layer across both time and space, whereas temperature did not. Water mass density, copepod energy density and thickness of the copepod layer were statistically lower during 2008 than 2007 or 2009. The copepod layer was absent from the western Basin margin during 2008 where low density continental water resided that year, whereas during 2007 and 2009 higher density continental slope water and copepods were each present along the western margin. Our results suggest that water mass density is an important characteristic defining the spatial and interannual ecology of the deep copepod layer in Roseway Basin. The 26 σ t isopycnal may be a lower density limit to diapausing Calanus spp. habitat on continental shelves with shallow bathymetry, that helps the animals maintain neutral buoyancy during diapause.

The Earth's evolutionary history is threatened by species loss in the current sixth mass extinction event in Earth's history. Such extinction events not only eliminate species but also their unique evolutionary histories. Here we review the expected loss of Earth's evolutionary history quantified by phylogenetic diversity (PD) and evolutionary distinctiveness (ED) at risk. Due to the general paucity of data, global evolutionary history losses have been predicted for only a few groups, such as mammals, birds, amphibians, plants, corals and fishes. Among these groups, there is now empirical support that extinction threats are clustered on the phylogeny; however this is not always a sufficient condition to cause higher loss of phylogenetic diversity in comparison to a scenario of random extinctions. Extinctions of the most evolutionarily distinct species and the shape of phylogenetic trees are additional factors that can elevate losses of evolutionary history. Consequently, impacts of species extinctions differ among groups and regions, and even if global losses are low within large groups, losses can be high among subgroups or within some regions. Further, we show that PD and ED are poorly protected by current conservation practices. While evolutionary history can be indirectly protected by current conservation schemes, optimizing its preservation requires integrating phylogenetic indices with those that capture rarity and extinction risk. Measures based on PD and ED could bring solutions to conservation issues, however they are still rarely used in practice, probably because the reasons to protect evolutionary history are not clear for practitioners or due to a lack of data. However, important advances have been made in the availability of phylogenetic trees and methods for their construction, as well as assessments of extinction risk. Some challenges remain, and looking forward, research should prioritize the assessment of expected PD and ED loss for more taxonomic groups and test the assumption that preserving ED and PD also protects rare species and ecosystem services. Such research will be useful to inform and guide the conservation of Earth's biodiversity and the services it provides.

The Roseway and Grand Manan basins on the Canadian Atlantic coast are neighboring late-summer critical feeding habitats for endangered North Atlantic right whales. Although in late summer these habitats regularly contain thick aggregations of right whale food – the copepod Calanus spp. – right whales periodically abandon one or both habitats in the same year. The causes of abandonments, their relationship to food supply, and the locations of whales during abandonment periods are unclear. The goals of this study were to explain variation in right whale abundance indices from a habitat perspective, and to determine whether or not oceanographic variation in the habitats influences occupancy. Four indices of whale abundance and habitat occupancy, including sightings per unit effort (SPUE), photographic sightings of known individuals, population size and habitat transition probabilities, were analyzed in relation to unique datasets of Calanus concentration and water mass characteristics in each basin over the period 1987 through 2009. Calanus concentration, water mass sources and various hydrographic properties each varied coherently between basins. Calanus concentration showed an increasing trend over time in each habitat, although a short-lived reduction in Calanus may have caused right whales to abandon Roseway Basin during the mid-1990s. Food supply explained variation in right whale sightings and population size in Roseway Basin, but not in Grand Manan Basin, suggesting that the Grand Manan Basin has important habitat characteristics in addition to food supply. Changes in the distribution of whale abundance indices during years when oceanographic conditions were associated with reduced food supply in the Scotia-Fundy region suggest that other suitable feeding habitats may not have existed during such years and resulted in negative effects on whale health and reproduction.

Government of Canada through Genome Canada and the Ontario Genomics Institute (2008-OGI-ICI-03), the International Development Research Centre (IDRC) Canada, the University of Johannesburg and the South African National Research Foundation (NRF).

Summary 1. Phylogenetic tools have increasingly been used in community ecology to describe the evolutionary relationships among co-occurring species. In studies of succession, such tools may allow us to identify the evolutionary lineages most suited for particular stages of succession and habitat rehabilitation. However, to date, these two applications have been largely separate. Here, we suggest that information on phylogenetic community structure might help to inform community restoration strategies following major disturbance. 2. Our study examined phylogenetic patterns of succession based on a chronosequence of three abandoned subarctic mine spoil heaps (waste piles) dating from the early 1970s, mid-1970s and early 1980s. The vegetation at each mine site was compared to the surrounding vegetation, and community structure on mines was explored assuming species pools at nested spatial scales. 3. We found that the adjacent vegetation was more phylogenetically clustered than the vegetation on the mines, with mines demonstrating weaker phylogenetic community structure. Using simulation models, we showed that phylogenetic dissimilarity between mine sites did not depart from null expectations. However, we found evidence for species sorting along abiotic gradients (slope and aspect) on the mine sites that had been abandoned for the longest. 4. Synthesis and applications. Understanding the trajectory of succession is critical for restoration efforts. Our results suggest that early colonizers represent a phylogenetically random subset of species from the local species pool. Over time, there appears to be selection for particular lineages that come to be filtered across space and environment. The species most appropriate for mine site restoration might, therefore, depend on the successional stage of the community and the local species composition. For example, in later succession, it could be more beneficial to facilitate establishment of more distant relatives. Our findings can improve management practices by providing relatedness information for known successful colonizers and by informing seeding decisions with knowledge of the surrounding and regional species pools. The application of phylogenetics to restoration ecology and succession is relatively new, but it has the potential to provide novel insight into the dynamics of changing community structures during succession.

An accurate assessment of ankle ligament kinematics is crucial in understanding the injury mechanisms and can help to improve the treatment of an injured ankle, especially when used in conjunction with robot-assisted therapy. A number of computational models have been developed and validated for assessing the kinematics of ankle ligaments. However, few of them can do real-time assessment to allow for an input into robotic rehabilitation programs.An ankle computational model was proposed and validated to quantify the kinematics of ankle ligaments as the foot moves in real-time. This model consists of three bone segments with three rotational degrees of freedom (DOFs) and 12 ankle ligaments. This model uses inputs for three position variables that can be measured from sensors in many ankle robotic devices that detect postures within the foot-ankle environment and outputs the kinematics of ankle ligaments. Validation of this model in terms of ligament length and strain was conducted by comparing it with published data on cadaver anatomy and magnetic resonance imaging.The model based on ligament lengths and strains is in concurrence with those from the published studies but is sensitive to ligament attachment positions.This ankle computational model has the potential to be used in robot-assisted therapy for real-time assessment of ligament kinematics. The results provide information regarding the quantification of kinematics associated with ankle ligaments related to the disability level and can be used for optimizing the robotic training trajectory.

The transcription of the ATP-binding cassette transporter A1 (ABCA1) gene, which plays a key anti-atherogenic role, is known to be induced by agonists of liver X receptors (LXRs). LXRs form obligate heterodimers with retinoid X receptors (RXRs) and interact with their recognition sequences in the regulatory regions of key genes implicated in the control of cholesterol, fatty acid and glucose homeostasis. We have previously shown a novel role for c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K) in the LXRs-mediated induction of macrophage gene expression. Protein kinase C (PKC) is often found to regulate the action of nuclear receptors and cross talk between this kinase family and JNK and/or PI3K has been shown in several settings. We have, therefore, investigated a potential role for PKC in the action of LXR/RXR agonist 22-(R)-hydroxycholesterol (22-(R)-HC)/9-cis-retinoic acid (9cRA) in THP-1 macrophages, including the induction of ABCA1 expression. The pan PKC inhibitor bisindoylmaleimide was found to attenuate the induction of ABCA1 protein expression, the activation of the JNK signaling pathway and the stimulation of activator protein-1 (AP-1) DNA binding activity in macrophages treated with 22-(R)-HC and 9cRA. The role of PKC in the action of these ligands was confirmed further by the use of more isotype-specific inhibitors. These studies, therefore, reveal a potentially important role for PKC in the action of 22-(R)-HC and 9cRA in human macrophages.