Different modes of interaction by TIAR and HuR with target RNA and DNA

TIAR and HuR are mRNA-binding proteins that play important roles in the regulation of translation. They both possess three RNA recognition motifs (RRMs) and bind to AU-rich elements (AREs), with seemingly overlapping specificity. Here we show using SPR that TIAR and HuR bind to both U-rich and AU-rich RNA in the nanomolar range, with higher overall affinity for U-rich RNA. However, the higher affinity for U–rich sequences is mainly due to faster association with U-rich RNA, which we propose is a reflection of the higher probability of association. Differences between TIAR and HuR are observed in their modes of binding to RNA. TIAR is able to bind deoxy-oligonucleotides with nanomolar affinity, whereas HuR affinity is reduced to a micromolar level. Studies with U-rich DNA reveal that TIAR binding depends less on the 2′-hydroxyl group of RNA than HuR binding. Finally we show that SAXS data, recorded for the first two domains of TIAR in complex with RNA, are more consistent with a flexible, elongated shape and not the compact shape that the first two domains of Hu proteins adopt upon binding to RNA. We thus propose that these triple-RRM proteins, which compete for the same binding sites in cells, interact with their targets in fundamentally different ways

Discovery and functional characterization of neuropeptides in crinoid echinoderms.

Neuropeptides are one of the largest and most diverse families of signaling molecules in animals and, accordingly, they regulate many physiological processes and behaviors. Genome and transcriptome sequencing has enabled the identification of genes encoding neuropeptide precursor proteins in species from a growing variety of taxa, including bilaterian and non-bilaterian animals. Of particular interest are deuterostome invertebrates such as the phylum Echinodermata, which occupies a phylogenetic position that has facilitated reconstruction of the evolution of neuropeptide signaling systems in Bilateria. However, our knowledge of neuropeptide signaling in echinoderms is largely based on bioinformatic and experimental analysis of eleutherozoans-Asterozoa (starfish and brittle stars) and Echinozoa (sea urchins and sea cucumbers). Little is known about neuropeptide signaling in crinoids (feather stars and sea lilies), which are a sister clade to the Eleutherozoa. Therefore, we have analyzed transcriptome/genome sequence data from three feather star species, Anneissia japonica, Antedon mediterranea, and Florometra serratissima, to produce the first comprehensive identification of neuropeptide precursors in crinoids. These include representatives of bilaterian neuropeptide precursor families and several predicted crinoid neuropeptide precursors. Using A. mediterranea as an experimental model, we have investigated the expression of selected neuropeptides in larvae (doliolaria), post-metamorphic pentacrinoids and adults, providing new insights into the cellular architecture of crinoid nervous systems. Thus, using mRNA in situ hybridization F-type SALMFamide precursor transcripts were revealed in a previously undescribed population of peptidergic cells located dorso-laterally in doliolaria. Furthermore, using immunohistochemistry a calcitonin-type neuropeptide was revealed in the aboral nerve center, circumoral nerve ring and oral tube feet in pentacrinoids and in the ectoneural and entoneural compartments of the nervous system in adults. Moreover, functional analysis of a vasopressin/oxytocin-type neuropeptide (crinotocin), which is expressed in the brachial nerve of the arms in A. mediterranea, revealed that this peptide causes a dose-dependent change in the mechanical behavior of arm preparations in vitro-the first reported biological action of a neuropeptide in a crinoid. In conclusion, our findings provide new perspectives on neuropeptide signaling in echinoderms and the foundations for further exploration of neuropeptide expression/function in crinoids as a sister clade to eleutherozoan echinoderms

Freedom and need: The evolution of public strategy for biomedical and health research in England

The optimal support of health-related research and development with public money is a complex challenge. Over the last century, policy makers in England have conceived and implemented a variety of models, ranging from independent, curiosity driven research to needs-based state commissions, and promoting different bodies to oversee scientific work. This paper traces these approaches, identifies the principles that drove them, and discusses their role in shaping policy for publicly funded health research, up to the recent launch of a new research strategy by the Department of Health

Global Diversity of Brittle Stars (Echinodermata: Ophiuroidea)

This review presents a comprehensive overview of the current status regarding the global diversity of the echinoderm class Ophiuroidea, focussing on taxonomy and distribution patterns, with brief introduction to their anatomy, biology, phylogeny, and palaeontological history. A glossary of terms is provided. Species names and taxonomic decisions have been extracted from the literature and compiled in The World Ophiuroidea Database, part of the World Register of Marine Species (WoRMS). Ophiuroidea, with 2064 known species, are the largest class of Echinodermata. A table presents 16 families with numbers of genera and species. The largest are Amphiuridae (467), Ophiuridae (344 species) and Ophiacanthidae (319 species). A biogeographic analysis for all world oceans and all accepted species was performed, based on published distribution records. Approximately similar numbers of species were recorded from the shelf (n = 1313) and bathyal depth strata (1297). The Indo-Pacific region had the highest species richness overall (825 species) and at all depths. Adjacent regions were also relatively species rich, including the North Pacific (398), South Pacific (355) and Indian (316) due to the presence of many Indo-Pacific species that partially extended into these regions. A secondary region of enhanced species richness was found in the West Atlantic (335). Regions of relatively low species richness include the Arctic (73 species), East Atlantic (118), South America (124) and Antarctic (126)

Extent, intensity and drivers of mammal defaunation:a continental-scale analysis across the Neotropics

Neotropical mammal diversity is currently threatened by several chronic human-induced pressures. We compiled 1,029 contemporary mammal assemblages surveyed across the Neotropics to quantify the continental-scale extent and intensity of defaunation and understand their determinants based on environmental covariates. We calculated a local defaunation index for all assemblages—adjusted by a false-absence ratio—which was examined using structural equation models. We propose a hunting index based on socioenvironmental co-variables that either intensify or inhibit hunting, which we used as an additional predictor of defaunation. Mammal defaunation intensity across the Neotropics on average erased 56.5% of the local source fauna, with ungulates comprising the most ubiquitous losses. The extent of defaunation is widespread, but more incipient in hitherto relatively intact major biomes that are rapidly succumbing to encroaching deforestation frontiers. Assemblage-wide mammal body mass distribution was greatly reduced from a historical 95th-percentile of ~ 14 kg to only ~ 4 kg in modern assemblages. Defaunation and depletion of large-bodied species were primarily driven by hunting pressure and remaining habitat area. Our findings can inform guidelines to design transnational conservation policies to safeguard native vertebrates, and ensure that the “empty ecosystem” syndrome will be deterred from reaching much of the New World tropics

Habit and the Politics of Social Change: A comparison of nudge theory and pragmatist philosophy

Rethinking the political workings of habit and habituation, this paper suggests, is vital to understanding the logics and possibilities of social change today. Any endeavour to explore habit’s affirmative potential, however, must confront its legacies as a colonialist, imperialist and capitalist technology. As a means to explore what it is that differentiates contemporary neoliberal modes of governing through habit from more critical approaches, this article compares contemporary ‘nudge’ theory and policy, as espoused by the behavioural economist Richard Thaler and the legal scholar Cass Sunstein, with the pragmatist philosophies of habit offered by John Dewey, William James and Shannon Sullivan. While nudge advocates focus on how policymakers and corporate leaders can intervene in the ‘choice architectures’ that surround us to outsmart or bypass problematic human tendencies, I argue, pragmatist philosophers appreciate the necessity of collective efforts to develop new and flexible forms of habituation in order to engender more enduring and democratic forms of social transformation

Scientific drilling projects in ancient lakes: integrating geological and biological histories

Sedimentary sequences in ancient or long-lived lakes can reach several thousands of meters in thickness and often provide an unrivalled perspective of the lake's regional climatic, environmental, and biological history. Over the last few years, deep drilling projects in ancient lakes became increasingly multi- and interdisciplinary, as, among others, seismological, sedimentological, biogeochemical, climatic, environmental, paleontological, and evolutionary information can be obtained from sediment cores. However, these multi- and interdisciplinary projects pose several challenges. The scientists involved typically approach problems from different scientific perspectives and backgrounds, and setting up the program requires clear communication and the alignment of interests. One of the most challenging tasks, besides the actual drilling operation, is to link diverse datasets with varying resolution, data quality, and age uncertainties to answer interdisciplinary questions synthetically and coherently. These problems are especially relevant when secondary data, i.e., datasets obtained independently of the drilling operation, are incorporated in analyses. Nonetheless, the inclusion of secondary information, such as isotopic data from fossils found in outcrops or genetic data from extant species, may help to achieve synthetic answers. Recent technological and methodological advances in paleolimnology are likely to increase the possibilities of integrating secondary information, e.g., through molecular dating of molecular phylogenies. Some of the new approaches have started to revolutionize scientific drilling in ancient lakes, but at the same time, they also add a new layer of complexity to the generation and analysis of sediment core data. The enhanced opportunities presented by new scientific approaches to study the paleolimnological history of these lakes, therefore, come at the expense of higher logistic, communication, and analytical efforts. Here we review types of data that can be obtained in ancient lake drilling projects and the analytical approaches that can be applied to empirically and statistically link diverse datasets for creating an integrative perspective on geological and biological data. In doing so, we highlight strengths and potential weaknesses of new methods and analyses, and provide recommendations for future interdisciplinary deep drilling projects

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

The order of entry as an explanatory factor in a brand's performance

The majority of research into the order of entry advantage has been focused on the benefits that it creates for the pioneer brand. This has led to a limited application of the order of entry advantage to situations where it may also help to explain the performance of all other brands. Through consideration of how the order of entry advantage is driven by consumer learning, the objective of this thesis is to use the order of entry advantage to explain the performance of different brand strategies and to apply the order of entry advantage to situations where the consumers’ learnings may be determinants on their purchase decision. The objective of the thesis is therefore broad in firstly aiming to explain the performance of five different brand strategies for late entrants (low price strategy, innovation through enhanced attributes, innovation through unique product attributes, non-innovation and a strategy based on having the highest number of products within a category). The thesis further explains the performance of a low price strategy, innovation through enhanced attributes and innovation through unique product attributes by applying the order of entry advantage to two specific situations. First, it applies the order of entry advantage to a segment of low price brands. Second, it is used to examine the effect of enhanced and unique product attributes within a brand’s range. The thesis is a thesis by publication, consisting of five papers that allow for the objective to be separated into components. All five papers used consumer scan data from a range of brands within either Over—The—Counter medicines or vitamin health supplement categories. Each paper analysed this consumer scan data through different variations of a multiplicative market share model, each of which explains a brand or product’s market share as a function of its entry position and marketing mix variables. The results from these multiplicative market share models demonstrate that an order of entry advantage was a significant explanatory factor in the performance of all brands. The papers take the perspectives of pioneer brands protecting their market share from late entrants as well as late entrants aiming to overcome the disadvantage of their entry position. In addition to the specific results from each paper, the thesis concludes with a summary of the findings which identifies three central themes that provide contributions to several streams of literature. The first theme is the impact of attribute and attitude—based information on a consumer’s purchase decision. This thesis has addressed how a late entrant can create either type of information through its product development strategies. It compares the effectiveness of attitude and attribute—based information derived from these product development strategies and provides an understanding as to which type of information brands should seek to create. It also provides additional support for the process by which pioneer brands benefit from both attribute and attitude—based information. The second theme of the research is the effectiveness of product innovation in helping brands overcome a late entry position. The thesis considered the importance of enhanced and unique product attributes in two situations, the differentiation of a brand within a category and as a line extension within a brand’s product range. The results provided a contribution to the literature through demonstrating that the performance of these types of attributes is affected by several category factors and the product’s fit with existing brand knowledge. These findings change the academic debate as to which type of product attribute is more effective. The debate has previously focused on what the consumer will learn about the new product attribute, but these findings highlight the need to include the existing product and brand information the consumer will use to evaluate the new product. The third theme was the effectiveness of low price brands. This thesis challenges the insights from the current literature through demonstrating why a low price strategy is an effective strategy for a late entrant. It has provided insights into how low price brands impact category dynamics, segment the market, and in addition offered suggestions regarding the optimal strategies which pioneer and innovative brands should use when faced with this competitive threat. In addition to the three themes, the thesis extended the application of the order entry advantage by demonstrating that it also exists in two different situations where consumers categorise brand information. The order of entry advantage was demonstrated to exist within a low price segment of brands and within a brand’s product range. The finding that an order of entry advantage exists in these two situations provides an important contribution to the literature in that it reinforces the consumer learning theories that underpin it. From a managerial perspective, the thesis has provided a greater understanding of how a brand’s entry position and product development strategy will impact its performance. However a manager needs to consider more than just these two factors. This thesis highlighted the importance of consumer learning and the types of information which consumers use to form brand judgements. Through also considering the importance of consumer learning in changing consumer preferences, a manager’s perspective will change from how the brand’s entry position will impact their performance, to how it can overcome the disadvantage of their entry position. Overall, this thesis achieved its objective of extending the concept of the order of entry advantage by using it to explain the performance of different brand strategies and applying it to situations where the consumers’ learnings may be determinants on their purchase decision. By achieving this objective, it provided academic contributions to several streams of literature as well as offering managers valuable insights for practice

The Impact of low-price brands on the order of entry advantage

The objectives of this research are to investigate (1) if a later entrant can reduce an order of entry effect by positioning itself as a low-price brand; and (2) if the type of low-price brand impacts the effectiveness of this strategy. The impact of a low-price strategy on the order of entry effect has been modelled using three categories of over-the-counter medicines. The results indicate that, in a majority of categories and dependent on the type of low-price brand, a low-price strategy can reduce the market share penalty for being a later entrant. In addition, the results provide evidence that leveraging an existing store brand name does not provide a strategic advantage over establishing a new brand name. The implications for managers is that a low-price brand provides a motivating point of difference for consumers, which shifts brand preferences and market share away from the pioneer brand