Human PXR Forms a Tryptophan Zipper-Mediated Homodimer †

The human nuclear receptor pregnane X receptor (PXR) responds to a wide variety of potentially harmful chemicals and coordinates the expression of genes central to xenobiotic and endobiotic metabolism. Structural studies reveal that the PXR ligand binding domain (LBD) uses a novel sequence insert to form a homodimer unique to the nuclear receptor superfamily. Terminal β-strands from each monomeric LBD interact in an ideal antiparallel fashion to bury potentially exposed surface β-strands, generating a ten-stranded intermolecular β-sheet. Conserved tryptophan and tyrosine residues lock across the dimer interface and provide the first tryptophan-zipper (Trp-Zip) interaction observed in a native protein. We show using analytical ultracentrifugation that the PXR LBD forms a homodimer in solution. We further find that removal of the interlocking aromatic residues eliminates dimer formation but does not affect PXR's ability to interact with DNA, RXRα, or ligands. Disruption of the homodimer significantly reduces receptor activity in transient transfection experiments, however, and effectively eliminates the receptor's recruitment of the transcriptional coactivator SRC-1 both in vitro and in vivo. Taken together, these results suggest that the unique Trp-Zip-mediated PXR homodimer plays a role in the function of this nuclear xenobiotic receptor

Winter territory prospecting is associated with life-history stage but not activity in a passerine

Finding a high quality territory is essential for many animals to reproduce successfully. Despite its importance for fitness, we know little about the process of territory prospecting in wild birds, and whether individual traits and behaviours, such as personality, co-vary with territory prospecting. Here, we use long-term data from a wild, insular house sparrow Passer domesticus population to test three hypotheses about territory fidelity and prospecting: (1) House sparrows show high territory fidelity between years and also during winter. (2) Individuals will prospect for a breeding territory during their first winter whereas older, more experienced individuals will keep a territory from previous years and will, therefore, show no or reduced winter territory prospecting. (3) More active behavioural types will prospect more than less active behavioural types. We use data from four winters from automatically, daily recorded nest-box visits of 188 birds of known age. The number of nest-boxes that each individual visited within each winter was used as a proxy of winter territory prospecting. We show that house sparrows visit multiple nest-boxes during their first winter, whereas older individuals keep territories year-round and, potentially because of this, indeed show reduced winter territory prospecting. Activity was not associated with the number of nest-boxes visited. Further research is needed to investigate whether time of territory and mate acquisition differs among individuals and the possible effect on lifetime fitness

Sequential Release of Nanoparticle Payloads from Ultrasonically Burstable Capsules

In many biomedical contexts ranging from chemotherapy to tissue engineering, it is beneficial to sequentially present bioactive payloads. Explicit control over the timing and dose of these presentations is highly desirable. Here, we present a capsule-based delivery system capable of rapidly releasing multiple payloads in response to ultrasonic signals. In vitro, these alginate capsules exhibited excellent payload retention for up to 1 week when unstimulated and delivered their entire payloads when ultrasonically stimulated for 10–100 s. Shorter exposures (10 s) were required to trigger delivery from capsules embedded in hydrogels placed in a tissue model and did not result in tissue heating or death of encapsulated cells. Different types of capsules were tuned to rupture in response to different ultrasonic stimuli, thus permitting the sequential, on-demand delivery of nanoparticle payloads. As a proof of concept, gold nanoparticles were decorated with bone morphogenetic protein-2 to demonstrate the potential bioactivity of nanoparticle payloads. These nanoparticles were not cytotoxic and induced an osteogenic response in mouse mesenchymal stem cells. This system may enable researchers and physicians to remotely regulate the timing, dose, and sequence of drug delivery on-demand, with a wide range of clinical applications ranging from tissue engineering to cancer treatment

Automated deep-phenotyping of the vertebrate brain

Here, we describe an automated platform suitable for large-scale deep-phenotyping of zebrafish mutant lines, which uses optical projection tomography to rapidly image brain-specific gene expression patterns in 3D at cellular resolution. Registration algorithms and correlation analysis are then used to compare 3D expression patterns, to automatically detect all statistically significant alterations in mutants, and to map them onto a brain atlas. Automated deep-phenotyping of a mutation in the master transcriptional regulator fezf2 not only detects all known phenotypes but also uncovers important novel neural deficits that were overlooked in previous studies. In the telencephalon, we show for the first time that fezf2 mutant zebrafish have significant patterning deficits, particularly in glutamatergic populations. Our findings reveal unexpected parallels between fezf2 function in zebrafish and mice, where mutations cause deficits in glutamatergic neurons of the telencephalon-derived neocortex.National Institutes of Health (U.S.) (Director’s Pioneer Award DP1-NS082101)David & Lucile Packard Foundation. Award in Science and EngineeringBroad Institute of MIT and Harvard (SPARC Award)Epilepsy Foundation of America (Postdoctoral Fellowship

Options for Producing a Warm-Water Fish in the UK: limits to "Green-Growth"?

This paper explores the development of a sustainable production system for tilapia and the research implications involved with ensuring commercial viability of such a system for UK farmers. The tilapia is a warm water fish with firm texture, white flesh and mild taste quite similar to a cod or haddock. Whilst tropical in origin it is thought to be highly suitable for low cost aquaculture in temperate zones with the potential to be a more sustainable source of food with fewer environmental impacts than other substitutes. Drawing on a literature review and findings from technical trials the paper will review and compare two production systems - novel Activated Suspension Technology (AST) and conventional Recirculating Aquaculture Systems (RAS) - considering their feasibility in terms of potential and financial viability for scaling up to commercial production of tilapia and their environmental and sustainability benefits. The review concludes that AST based only on microbial floc is currently uncompetitive with RAS in a UK context although the approach has benefits that might be incorporated in a new generation of mixed systems. Refinement of such systems needs to occur with potential adopters and could be part of diversification of mixed farms. Such development might further enhance the ethical values of fish produced in small-scale, modular RAS

Galactic Gradients, Postbiological Evolution and the Apparent Failure of SETI

Motivated by recent developments impacting our view of Fermi's paradox (absence of extraterrestrials and their manifestations from our past light cone), we suggest a reassessment of the problem itself, as well as of strategies employed by SETI projects so far. The need for such reevaluation is fueled not only by the failure of searches thus far, but also by great advances recently made in astrophysics, astrobiology, computer science and future studies, which have remained largely ignored in SETI practice. As an example of the new approach, we consider the effects of the observed metallicity and temperature gradients in the Milky Way on the spatial distribution of hypothetical advanced extraterrestrial intelligent communities. While, obviously, properties of such communities and their sociological and technological preferences are entirely unknown, we assume that (1) they operate in agreement with the known laws of physics, and (2) that at some point they typically become motivated by a meta-principle embodying the central role of information-processing; a prototype of the latter is the recently suggested Intelligence Principle of Steven J. Dick. There are specific conclusions of practical interest to be drawn from coupling of these reasonable assumptions with the astrophysical and astrochemical structure of the Galaxy. In particular, we suggest that the outer regions of the Galactic disk are most likely locations for advanced SETI targets, and that intelligent communities will tend to migrate outward through the Galaxy as their capacities of information-processing increase, for both thermodynamical and astrochemical reasons. This can also be regarded as a possible generalization of the Galactic Habitable Zone, concept currently much investigated in astrobiology.Comment: 30 pages, 2 figure

Pheromone-sensing neurons regulate peripheral lipid metabolism in <i>Caenorhabditis elegans</i>

It is now established that the central nervous system plays an important role in regulating whole body metabolism and energy balance. However, the extent to which sensory systems relay environmental information to modulate metabolic events in peripheral tissues has remained poorly understood. In addition, it has been challenging to map the molecular mechanisms underlying discrete sensory modalities with respect to their role in lipid metabolism. In previous work our lab has identified instructive roles for serotonin signaling as a surrogate for food availability, as well as oxygen sensing, in the control of whole body metabolism. In this study, we now identify a role for a pair of pheromone-sensing neurons in regulating fat metabolism in C. elegans, which has emerged as a tractable and highly informative model to study the neurobiology of metabolism. A genetic screen revealed that GPA-3, a member of the Gα family of G proteins, regulates body fat content in the intestine, the major metabolic organ for C. elegans. Genetic and reconstitution studies revealed that the potent body fat phenotype of gpa-3 null mutants is controlled from a pair of neurons called ADL(L/R). We show that cAMP functions as the second messenger in the ADL neurons, and regulates body fat stores via the neurotransmitter acetylcholine, from downstream neurons. We find that the pheromone ascr#3, which is detected by the ADL neurons, regulates body fat stores in a GPA-3-dependent manner. We define here a third sensory modality, pheromone sensing, as a major regulator of body fat metabolism. The pheromone ascr#3 is an indicator of population density, thus we hypothesize that pheromone sensing provides a salient 'denominator' to evaluate the amount of food available within a population and to accordingly adjust metabolic rate and body fat levels

Radiolabelled peptides for oncological diagnosis

Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The 111In-labelled somatostatin analogue octreotide (OctreoScan™) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours

Environmental impacts of the deep-water oil and gas industry: a review to guide management strategies

The industrialization of the deep sea is expanding worldwide. Increasing oil and gas exploration activities in the absence of sufficient baseline data in deep-sea ecosystems has made environmental management challenging. Here, we review the types of activities that are associated with global offshore oil and gas development in water depths over 200 m, the typical impacts of these activities, some of the more extreme impacts of accidental oil and gas releases, and the current state of management in the major regions of offshore industrial activity including 18 exclusive economic zones. Direct impacts of infrastructure installation, including sediment resuspension and burial by seafloor anchors and pipelines, are typically restricted to a radius of ~100 m on from the installation on the seafloor. Discharges of water-based and low-toxicity oil-based drilling muds and produced water can extend over 2 km, while the ecological impacts at the population and community levels on the seafloor are most commonly on the order of 200–300 m from their source. These impacts may persist in the deep sea for many years and likely longer for its more fragile ecosystems, such as cold-water corals. This synthesis of information provides the basis for a series of recommendations for the management of offshore oil and gas development. An effective management strategy, aimed at minimizing risk of significant environmental harm, will typically encompass regulations of the activity itself (e.g., discharge practices, materials used), combined with spatial (e.g., avoidance rules and marine protected areas), and temporal measures (e.g., restricted activities during peak reproductive periods). Spatial management measures that encompass representatives of all of the regional deep-sea community types is important in this context. Implementation of these management strategies should consider minimum buffer zones to displace industrial activity beyond the range of typical impacts: at least 2 km from any discharge points and surface infrastructure and 200 m from seafloor infrastructure with no expected discharges. Although managing natural resources is, arguably, more challenging in deep-water environments, inclusion of these proven conservation tools contributes to robust environmental management strategies for oil and gas extraction in the deep sea.Copyright © 2016 Cordes, Jones, Schlacher, Amon, Bernardino, Brooke, Carney, DeLeo, Dunlop, Escobar-Briones, Gates, Génio, Gobin, Henry, Herrera, Hoyt, Joye, Kark, Mestre, Metaxas, Pfeifer, Sink, Sweetman and Witte. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms