OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis

Sixteen ovarian tumor (OTU) family deubiquitinases (DUBs) exist in humans, and most members regulate cell-signaling cascades. Several OTU DUBs were reported to be ubiquitin (Ub) chain linkage specific, but comprehensive analyses are missing, and the underlying mechanisms of linkage specificity are unclear. Using Ub chains of all eight linkage types, we reveal that most human OTU enzymes are linkage specific, preferring one, two, or a defined subset of linkage types, including unstudied atypical Ub chains. Biochemical analysis and five crystal structures of OTU DUBs with or without Ub substrates reveal four mechanisms of linkage specificity. Additional Ub-binding domains, the ubiquitinated sequence in the substrate, and defined S1’ and S2 Ub-binding sites on the OTU domain enable OTU DUBs to distinguish linkage types. We introduce Ub chain restriction analysis, in which OTU DUBs are used as restriction enzymes to reveal linkage type and the relative abundance of Ub chains on substrates

Agent swarms: cooperation and coordination under stringent communications constraint

Here we consider the communications tactics appropriate for a group of agents that need to ``swarm'' together in a highly adversarial environment. Specifically, whilst they need to exchange information with each other about their location and their plans; at the same time they also need to keep such communications to an absolute minimum. This might be due to a need for stealth, or otherwise be relevant to situations where communications are significantly restricted. Complicating this process is that we assume each agent has (a) no means of passively locating others, (b) it must rely on being updated by reception of appropriate messages; and if no such update messages arrive, (c) then their own beliefs about other agents will gradually become out of date and increasingly inaccurate. Here we use a geometry-free multi-agent model that is capable of allowing for message-based information transfer between agents with different intrinsic connectivities, as would be present in a spatial arrangement of agents. We present agent-centric performance metrics that require only minimal assumptions, and show how simulated outcome distributions, risks, and connectivities depend on the ratio of information gain to loss. We also show that checking for too-long round-trip-times can be an effective minimal-information filter for determining which agents to no longer target with messages.Comment: 11 pager, 7 figure

Do dance floor force reduction and static stiffness represent dynamic floor stiffness during dance landings?

Dance training on floors that are not \u27sprung\u27 are assumed to have direct implications for injury. Standards for dance floor manufacture in Europe and North America quantify floor force reduction by measuring the impact forces of drop masses. In addition, many studies of human mechanical adaptations to varied surfaces, have quantified test surfaces using measures of static stiffness. It is unclear whether these methods for the measurement of floor mechanical properties actually reflect dancer requirements or floor behaviour under dancer loading. The aim of this study was to compare the force reduction, static stiffness and dynamic stiffness of a range of dance floors. Dynamic stiffness was measured during dancers performing drop landings. Force reduction highly correlated (p= 0.086) with floors of moderate dynamic stiffness, but was less accurate for high and low stiffness floors. Static stiffness underestimated the dynamic stiffness of the floors. Measurement of floor force reduction using European sports surface standards may provide an accurate representation of dynamic floor stiffness when under load from dancers performing drop landings. The discrepancy between static and dynamic stiffness may be explained by the inertial characteristics of the floor and the rapid loading of the floors during dancer landings. The development of portable systems for measuring floor behaviour under human loads using modern motion capture technologies may be beneficial for improving the quantification of dance floor mechanical properties

Detection of Planetary and Stellar Companions to Neighboring Stars via a Combination of Radial Velocity and Direct Imaging Techniques

13 pages, 6 figures, 4 tables, accepted for publication in the Astronomical Journal (submitted 25 Feb 2019; accepted 28 April 2019). Machine readable tables and Posteriors from the RadVel fits are available here: http://stephenkane.net/rvfits.tarThe sensitivities of radial velocity (RV) surveys for exoplanet detection are extending to increasingly longer orbital periods, where companions with periods of several years are now being regularly discovered. Companions with orbital periods that exceed the duration of the survey manifest in the data as an incomplete orbit or linear trend, a feature that can either present as the sole detectable companion to the host star, or as an additional signal overlain on the signatures of previously discovered companion(s). A diagnostic that can confirm or constrain scenarios in which the trend is caused by an unseen stellar rather than planetary companion is the use of high-contrast imaging observations. Here, we present RV data from the Anglo-Australian Planet Search (AAPS) for 20 stars that show evidence of orbiting companions. Of these, six companions have resolved orbits, with three that lie in the planetary regime. Two of these (HD 92987b and HD 221420b) are new discoveries. Follow-up observations using the Differential Speckle Survey Instrument (DSSI) on the Gemini South telescope revealed that 5 of the 20 monitored companions are likely stellar in nature. We use the sensitivity of the AAPS and DSSI data to place constraints on the mass of the companions for the remaining systems. Our analysis shows that a planetary-mass companion provides the most likely self-consistent explanation of the data for many of the remaining systems.Peer reviewedFinal Accepted Versio

Photochemistry of [Ru(pytz)(btz)2]2+and Characterization of a κ1-btz Ligand-Loss Intermediate

We report the synthesis, characterisation and photochemical reactivity of the triazole-containing complex [Ru(pytz)(btz)2]2+ (1, pytz = 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole, btz = 1,1’-dibenzyl-4,4’-bi-1,2,3-triazolyl). The UV-visible absorption spectrum of 1 exhibits pytz- and btz-centred 1MLCT bands at 365 and 300 nm respectively. Upon photo-excitation, acetonitrile solutions of 1 undergo conversion to the ligand loss intermediate, trans-[Ru(pytz)(2-btz)(1-btz)(NCMe)]2+ (2, 363 = 0.013) and ultimately to the ligand loss product trans-[Ru(pytz)(btz)(NCMe)2]2+ (3), both of which are observed and characterised by 1H NMR spectroscopy. Time-dependent density functional theory calculations reveal that the S1 state of the complex has primarily HOMOLUMO pytz-based 1MLCT character. Data show that the 3MLCT and 3MC states are in close energetic proximity ( 0.11 eV to 2 d.p.) and that the T1 state from a single point triplet state calculation at the S0 geometry suggests 3MC character. Optimisation of the T1 state of the complex starting from the ground state geometry leads to elongation of the two Ru-N(btz) bonds cis to the pytz ligand to 2.539 and 2.544 Å leading to a psuedo 4-coordinate 3MC state rather than the 3MLCT state. The work therefore provides additional insights into the photophysical and photochemical properties of ruthenium triazole-containing complexes and their excited state dynamics

Bridging the gap between policy and science in assessing the health status of marine ecosystems

Human activities, both established and emerging, increasingly affect the provision of marine ecosystem services that deliver societal and economic benefits. Monitoring the status of marine ecosystems and determining how human activities change their capacity to sustain benefits for society requires an evidence-based Integrated Ecosystem Assessment approach that incorporates knowledge of ecosystem functioning and services). Although, there are diverse methods to assess the status of individual ecosystem components, none assesses the health of marine ecosystems holistically, integrating information from multiple ecosystem components. Similarly, while acknowledging the availability of several methods to measure single pressures and assess their impacts, evaluation of cumulative effects of multiple pressures remains scarce. Therefore, an integrative assessment requires us to first understand the response of marine ecosystems to human activities and their pressures and then develop innovative, cost-effective monitoring tools that enable collection of data to assess the health status of large marine areas. Conceptually, combining this knowledge of effective monitoring methods with cost-benefit analyses will help identify appropriate management measures to improve environmental status economically and efficiently. The European project DEVOTES (DEVelopment Of innovative Tools for understanding marine biodiversity and assessing good Environmental Status) specifically addressed t hese topics in order to support policy makers and managers in implementing the European Marine Strategy Framework Directive. Here, we synthesize our main innovative findings, placing these within the context of recent wider research, and identifying gaps and the major future challenges

Miniaturized data loggers and computer programming improve seabird risk and damage assessments for marine oil spills in Atlantic Canada

Obtaining useful information on marine birds that can aid in oil spill (and other hydrocarbon release) risk and damage assessments in offshore environments is challenging. Technological innovations in miniaturization have allowed archival data loggers to be deployed successfully on marine birds vulnerable to hydrocarbons on water. A number of species, including murres (both Common, Uria aalge, and Thick-billed, U. lomvia) have been tracked using geolocation devices in eastern Canada, increasing our knowledge of the seasonality and colony-specific nature of their susceptibility to oil on water in offshore hydrocarbon production areas and major shipping lanes. Archival data tags are starting to resolve questions around behaviour of vulnerable seabirds at small spatial scales relevant to oil spill impact modelling, specifically to determine the duration and frequency at which birds fly at sea. Advances in data capture methods using voice activated software have eased the burden on seabird observers who are collecting increasingly more detailed information on seabirds during ship-board and aerial transects. Computer programs that integrate seabird density and bird behaviour have been constructed, all with a goal of creating more credible seabird oil spill risk and damage assessments. In this paper, we discuss how each of these technological and computing innovations can help define critical inputs into seabird risk and damage assessments, and when combined, can provide a more realistic understanding of the impacts to seabirds from any hydrocarbon release

Hyperbaric pressure of 51 atmospheres is without effect on the depression of oxygen uptake in kidney tissue culture produced by halothane

Although anesthetized animals are awakened when subjected to increased pressure, compression does not result in antagonism of all phenomena associated with these drugs. It has recently been demonstrated that halothane's inhibition of respiration of isolated rat liver mitochondria is not reversed by hydraulic compression to 51 atmospheres. In order to determine whether this phenomenon can be extrapolated to the whole cell, we have investigated the effect of hydraulic compression of intact renal cells equilibrated with halothane, and conclude that pressure does not overcome the inhibitory effect of this anesthetic.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25565/1/0000107.pd

Discovery of a compact companion to a nearby star

Radial velocity (RV) searches for exoplanets have surveyed many of the nearest and brightest stars for long-term velocity variations indicative of a companion body. Such surveys often detect high-amplitude velocity signatures of objects that lie outside the planetary mass regime, most commonly those of a low-mass star. Such stellar companions are frequently discarded as false-alarms to the main science goals of the survey, but high-resolution imaging techniques can be employed to either directly detect or place significant constraints on the nature of the companion object. Here, we present the discovery of a compact companion to the nearby star HD 118475. Our Anglo-Australian Telescope RV data allow the extraction of the full Keplerian orbit of the companion, which is found to have a minimum mass of 0.445 M⊙. Follow-up speckle imaging observations at the predicted time of maximum angular separation rule out a main-sequence star as the source of the RV signature at the 3.3σ significance level, implying that the companion must be a low-luminosity compact object, most likely a white dwarf. We provide an isochrone analysis combined with our data that constrain the possible inclinations of the binary orbit. We discuss the eccentric orbit of the companion in the context of tidal circularization timescales and show that non-circular orbit was likely inherited from the progenitor. Finally, we emphasize the need for utilizing such an observation method to further understand the demographics of white dwarf companions around nearby stars

The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity.

Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.This work was supported by the Medical Research Council (U105192732 and U105178805), the European Research Council (309756), the Lister Institute for Preventive Medicine, and the EMBO Young Investigator Program (to D.K.); a Marie-Sklodowska Curie Individual Fellowship from the European Commission (MC-IF-654019) and a Research Fellowship from Corpus Christi College Cambridge (to R.B.D.); and Wellcome Trust (to N.V.M., E.R.M., and A.N.J.M [100963/Z/13/Z]), WellChild (to N.V.M. and E.R.M.), and UCB (to H.L.T., D.M. and E.R.M.).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.cell.2016.07.01