Search

Specificity of the ubiquitin-proteasome system depends on E3 ligase-substrate interactions. Many such pairings depend on E3 ligases binding to peptide-like sequences - termed N- or C-degrons - at the termini of substrates. However, our knowledge of structural features distinguishing closely related C-degron substrate-E3 pairings is limited. Here, by systematically comparing ubiquitylation activities towards a suite of common model substrates, and defining interactions by biochemistry, crystallography, and cryo-EM, we reveal principles of C-degron recognition across the KLHDCX family of Cullin-RING ligases (CRLs). First, a motif common across these E3 ligases anchors a substrate's C-terminus. However, distinct locations of this C-terminus anchor motif in different blades of the KLHDC2, KLHDC3, and KLHDC10 β-propellers establishes distinct relative positioning and molecular environments for substrate C-termini. Second, our structural data show KLHDC3 has a pre-formed pocket establishing preference for an Arg or Gln preceding a C-terminal Gly, whereas conformational malleability contributes to KLHDC10's recognition of varying features adjacent to substrate C-termini. Finally, additional non-consensus interactions, mediated by C-degron binding grooves and/or by distal propeller surfaces and substrate globular domains, can substantially impact substrate binding and ubiquitylatability. Overall, the data reveal combinatorial mechanisms determining specificity and plasticity of substrate recognition by KLDCX-family C-degron E3 ligases. Kelch-domain KLHDCX E3 ligases bind substrate C-terminal glycines. This study reveals substrate selectivity by E3s with similar structures; C-degrons are perceived by a "C-terminus anchor motif", whose display on different Kelch propeller blades along with distal interactions establish specificity. [ABSTRACT FROM AUTHOR]

We introduce the notion of porous invariants for multipath affine loops over the integers. These are invariants definable in (fragments of) Presburger arithmetic and, as such, lack certain tame geometrical properties, such a convexity and connectedness. Nevertheless, we show that in many cases such invariants can be automatically synthesised, and moreover can be used to settle reachability questions for various non-trivial classes of affine loops and target sets. For the class of Z -linear invariants (those defined as conjunctions of linear equations with integer coefficients), we show that a strongest such invariant can be computed in polynomial time. For the more general class of N -semi-linear invariants (those defined as Boolean combinations of linear inequalities with integer coefficients), such a strongest invariant need not exist. Here we show that for point targets the existence of a separating invariant is undecidable in general. However we show that such separating invariants can be computed either by restricting the number of program variables or by restricting from multipath to single-path loops. Additionally, we consider porous targets, represented as Z -semi-linear sets (those defined as Boolean combinations of equations with integer coefficients). We show that an invariant can be computed providing the target spans the whole space. We present our tool porous, which computes porous invariants. [ABSTRACT FROM AUTHOR]

A contemporary challenge for the scalability of quantum networks is developing quantum nodes with simultaneous high photonic efficiency and long-lived qubits. Here we present a fibre-packaged nanophotonic diamond waveguide hosting a tin-vacancy centre with a spin-1/2 117Sn nucleus. The interaction between the electronic and nuclear spins results in a signature 452(7) MHz hyperfine splitting. This exceeds the natural optical linewidth by a factor of 16, enabling direct optical nuclear spin initialization with 98.6(3)% fidelity and single-shot readout with 80.0(1)% fidelity. The waveguide-to-fibre extraction efficiency of our device of 57(6)% enables the practical detection of five-photon events. Combining the photonic performance with the optically initialized nuclear spin, we demonstrate a spin-gated single-photon nonlinearity with 11(1)% contrast in the absence of an external magnetic field. These capabilities position our nanophotonic interface as a versatile quantum node in the pursuit of scalable quantum networks. By implanting 117Sn, a fibre-packaged nanophotonic diamond waveguide with optically addressable hyperfine transitions separated by 452 MHz is demonstrated. This enables the formation of a spin-gated optical switch and achieving a waveguide-to-fibre extraction efficiency of 57%. [ABSTRACT FROM AUTHOR]

In this paper, inhomogeneous chemical kinetics are simulated by describing the concentrations of interacting chemical species by a linear expansion of basis functions in such a manner that the coupled reaction and diffusion processes are propagated through time efficiently by tailor-made numerical methods. The approach is illustrated through modelling α - and γ -radiolysis in thin layers of water and at their solid interfaces from the start of the chemical phase until equilibrium was established. The method's efficiency is such that hundreds of such systems can be modelled in a few hours using a single core of a typical laptop, allowing the investigation of the effects of the underlying parameter space. Illustrative calculations showing the effects of changing dose-rate and water-layer thickness are presented. Other simulations are presented which show the approach's capability to solve problems with spherical symmetry (an approximation to an isolated radiolytic spur), where the hollowing out of an initial Gaussian distribution is observed, in line with previous calculations. These illustrative simulations show the generality and the computational efficiency of this approach to solving reaction-diffusion problems. Furthermore, these example simulations illustrate the method's suitability for simulating solid-fluid interfaces, which have received a lot of experimental attention in contrast to the lack of computational studies. [ABSTRACT FROM AUTHOR]

Seamounts are isolated underwater mountains stretching > 1000 m above the seafloor. They are identified as biodiversity hotspots of marine life, and host benthic assemblages that may vary on regional (among seamounts) and local (within seamounts) scales. Here, we collected seafloor imagery of three seamounts at the Langseth Ridge in the central Arctic Ocean to assess habitats and megabenthos community composition at the Central Mount (CM), the Karasik Seamount (KS), and the Northern Mount (NM). The majority of seafloor across these seamounts comprised bare rock, covered with a mixed layer of sponge spicule mats intermixed with detrital debris composed of polychaete tubes, and sand, gravel, and/or rocks. The megabenthos assemblages consisted of in total 15 invertebrate epibenthos taxa and 4 fish taxa, contributing to mean megabenthos densities of 55,745 ind. ha−1 at CM, 110,442 ind. ha−1 at KS, and 65,849 ind. ha−1 at NM. The faunal assemblages at all three seamounts were dominated by habitat-forming Tetractinellida sponges that contributed between 66% (KS) and 85% (CM) to all megabenthos. Interestingly, taxa richness did not differ at regional and local scale, whereas the megabenthos community composition did. Abiotic and biogenic factors shaping distinct habitat types played a major role in structuring of benthic communities in high-Arctic seamounts. [ABSTRACT FROM AUTHOR]

The Aurora hydrothermal system, Arctic Ocean, hosts active submarine venting within an extensive field of relict mineral deposits. Here we show the site is associated with a neovolcanic mound located within the Gakkel Ridge rift-valley floor, but deep-tow camera and sidescan surveys reveal the site to be ≥100 m across—unusually large for a volcanically hosted vent on a slow-spreading ridge and more comparable to tectonically hosted systems that require large time-integrated heat-fluxes to form. The hydrothermal plume emanating from Aurora exhibits much higher dissolved CH4/Mn values than typical basalt-hosted hydrothermal systems and, instead, closely resembles those of high-temperature ultramafic-influenced vents at slow-spreading ridges. We hypothesize that deep-penetrating fluid circulation may have sustained the prolonged venting evident at the Aurora hydrothermal field with a hydrothermal convection cell that can access ultramafic lithologies underlying anomalously thin ocean crust at this ultraslow spreading ridge setting. Our findings have implications for ultra-slow ridge cooling, global marine mineral distributions, and the diversity of geologic settings that can host abiotic organic synthesis - pertinent to the search for life beyond Earth. The Aurora hydrothermal field (Arctic Ocean) is hosted in volcanic rocks but also shows evidence of mantle rock influence in the shallow sub-surface. Our discovery is pertinent to disciplines from marine mining to the search for life beyond Earth. [ABSTRACT FROM AUTHOR]

Monoterpenes (C10H16) are emitted in large quantities by vegetation to the atmosphere (>100 TgC year−1), where they readily react with hydroxyl radicals and ozone to form new particles and, hence, clouds, affecting the Earth’s radiative budget and, thereby, climate change1–3. Although most monoterpenes exist in two chiral mirror-image forms termed enantiomers, these (+) and (−) forms are rarely distinguished in measurement or modelling studies4–6. Therefore, the individual formation pathways of monoterpene enantiomers in plants and their ecological functions are poorly understood. Here we present enantiomerically separated atmospheric monoterpene and isoprene data from an enclosed tropical rainforest ecosystem in the absence of ultraviolet light and atmospheric oxidation chemistry, during a four-month controlled drought and rewetting experiment7. Surprisingly, the emitted enantiomers showed distinct diel emission peaks, which responded differently to progressive drying. Isotopic labelling established that vegetation emitted mainly de novo-synthesized (−)-α-pinene, whereas (+)-α-pinene was emitted from storage pools. As drought progressed, the source of (−)-α-pinene emissions shifted to storage pools, favouring cloud formation. Pre-drought mixing ratios of both α-pinene enantiomers correlated better with other monoterpenes than with each other, indicating different enzymatic controls. These results show that enantiomeric distribution is key to understanding the underlying processes driving monoterpene emissions from forest ecosystems and predicting atmospheric feedbacks in response to climate change.Analysis of atmospheric data on two enantiomerically separated forms of monoterpene from a controlled drought and rewetting experiment in an enclosed tropical rainforest ecosystem showed distinct diel emission peaks, regulated by different production pathways. [ABSTRACT FROM AUTHOR]

Underwater images are used to explore and monitor ocean habitats, generating huge datasets with unusual data characteristics that preclude traditional data management strategies. Due to the lack of universally adopted data standards, image data collected from the marine environment are increasing in heterogeneity, preventing objective comparison. The extraction of actionable information thus remains challenging, particularly for researchers not directly involved with the image data collection. Standardized formats and procedures are needed to enable sustainable image analysis and processing tools, as are solutions for image publication in long-term repositories to ascertain reuse of data. The FAIR principles (Findable, Accessible, Interoperable, Reusable) provide a framework for such data management goals. We propose the use of image FAIR Digital Objects (iFDOs) and present an infrastructure environment to create and exploit such FAIR digital objects. We show how these iFDOs can be created, validated, managed and stored, and which data associated with imagery should be curated. The goal is to reduce image management overheads while simultaneously creating visibility for image acquisition and publication efforts. [ABSTRACT FROM AUTHOR]

The Central Arctic Ocean is one of the most oligotrophic oceans on Earth because of its sea-ice cover and short productive season. Nonetheless, across the peaks of extinct volcanic seamounts of the Langseth Ridge (87°N, 61°E), we observe a surprisingly dense benthic biomass. Bacteriosponges are the most abundant fauna within this community, with a mass of 460 g C m−2 and an estimated carbon demand of around 110 g C m−2 yr−1, despite export fluxes from regional primary productivity only sufficient to provide <1% of this required carbon. Observed sponge distribution, bulk and compound-specific isotope data of fatty acids suggest that the sponge microbiome taps into refractory dissolved and particulate organic matter, including remnants of an extinct seep community. The metabolic profile of bacteriosponge fatty acids and expressed genes indicate that autotrophic symbionts contribute significantly to carbon assimilation. We suggest that this hotspot ecosystem is unique to the Central Arctic and associated with extinct seep biota, once fueled by degassing of the volcanic mounts. This study reports the discovery of dense sponge gardens across the peaks of permanently ice-covered, extinct volcanic seamounts of the Langseth Ridge and on the remnants of a now extinct seep ecosystem. Using approaches to sample and infer food and energy sources to this ice-covered community, the authors suggest that the sponges use refractory organic matter trapped in the extinct seep community on which they sit. [ABSTRACT FROM AUTHOR]

The ocean moderates the world's climate through absorption of heat and carbon, but how much carbon the ocean will continue to absorb remains unknown. The North Atlantic Ocean west (Baffin Bay/Labrador Sea) and east (Fram Strait/Greenland Sea) of Greenland features the most intense absorption of anthropogenic carbon globally; the biological carbon pump (BCP) contributes substantially. As Arctic sea-ice melts, the BCP changes, impacting global climate and other critical ocean attributes (e.g. biodiversity). Full understanding requires year-round observations across a range of ice conditions. Here we present such observations: autonomously collected Eulerian continuous 24-month time-series in Fram Strait. We show that, compared to ice-unaffected conditions, sea-ice derived meltwater stratification slows the BCP by 4 months, a shift from an export to a retention system, with measurable impacts on benthic communities. This has implications for ecosystem dynamics in the future warmer Arctic where the seasonal ice zone is expected to expand. The North Atlantic biological pump has the most intense absorption of C globally, but how this will fare in light of climate changes (especially sea-ice melting) is poorly understood. Here the authors present a 24-month continuous time series of physical, chemical, and biological observations in the Fram Strait. [ABSTRACT FROM AUTHOR]

Since the late 1980s, various experiments have been conducted in polymetallic nodule fields of the Pacific Ocean to assess the potential environmental impacts of future mining, specifically in two areas: the Peru Basin and the Clarion-Clipperton Fracture Zone (CCZ). Two expeditions, SO242/2 in 2015 (Peru Basin) and SO268/1 + 2 in 2019 (CCZ), deployed a towed camera system to collect imagery from both areas. These expeditions aimed to assess recovery of fauna in the short (few weeks) and long term (several years) following physical seafloor disturbance actions designed to mimic potential mining, by ploughs, dredges and epibenthic sleds. Within the collected image data, several strikingly hexagonal hole patterns were observed and identified as Paleodictyon nodosum, and an irregular form of Paleodictyon traces, both on undisturbed and disturbed areas of seafloor. Recent forms occur abundantly in various deep-sea regions, but their origin, and how they represent the mode of life of the forming organism, remains unknown. In this study, the imaged occurrences of Paleodictyon traces on disturbed seafloor sheds light on the lifecycle of the forming organism, demonstrating that they can recolonize disturbed habitat and produce the trace network in a few weeks. Nevertheless, the density of these patterns on disturbed substrates was lower than observed on undisturbed substrates in both nodule regions. We therefore hypothesize that, along with other benthic deep-sea fauna, these structures and the forming organism are impacted by physical seafloor disturbance, and even 26 years after disturbance, densities on disturbed sediments have not recovered to undisturbed levels. [ABSTRACT FROM AUTHOR]

Interlayer excitons in layered materials constitute a novel platform to study many-body phenomena arising from long-range interactions between quantum particles. Long-lived excitons are required to achieve high particle densities, to mediate thermalisation, and to allow for spatially and temporally correlated phases. Additionally, the ability to confine them in periodic arrays is key to building a solid-state analogue to atoms in optical lattices. Here, we demonstrate interlayer excitons with lifetime approaching 0.2 ms in a layered-material heterostructure made from WS2 and WSe2 monolayers. We show that interlayer excitons can be localised in an array using a nano-patterned substrate. These confined excitons exhibit microsecond-lifetime, enhanced emission rate, and optical selection rules inherited from the host material. The combination of a permanent dipole, deterministic spatial confinement and long lifetime places interlayer excitons in a regime that satisfies one of the requirements for simulating quantum Ising models in optically resolvable lattices. Excitons are quasiparticles consisting of an electron-hole pair and can be used to study many-body phenomenon. Here, the authors demonstrate on-demand quantum confinement of long-lived interlayer excitons in WS2/WSe2 heterostructures deposited on nanopatterned substrates. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is associated with coagulation activation and high incidence of venous thromboembolism (VTE) in severe patients despite routine thromboprophylaxis. Conflicting results exist regarding the epidemiology of VTE for unselected anticoagulated COVID-19 patients hospitalized in general wards. The aim of this study was to evaluate the prevalence of asymptomatic deep venous thrombosis (DVT) in unselected patients with COVID-19 recently hospitalized in general wards. We performed a systematic complete doppler ultrasound (CDU) at a median 4 days after admission in 42 consecutive COVID-19 patients hospitalized in general wards of our university hospital, irrespective of D-Dimer level, and retrospectively collected clinical, biological and outcome data from electronic charts. Thromboprophylaxis was systematically applied following a French national proposal. In our population, the prevalence of asymptomatic DVT was 19% (8/42 patients), with distal thrombosis in 7/8 cases and bilateral DVT in 4/8 cases. Symptomatic pulmonary embolism was detected in 4 (9.5%) patients, associated to DVT in one case. Compared to patients without DVT, patients with DVT were older and experienced poorer outcomes. In conclusion, prevalence of asymptomatic DVT is high in the first days of hospitalization of unselected COVID-19 patients in general wards and may be related to poor prognosis. Individualized assessment of thromboprophylaxis and early systematic screening for DVT is warranted in this context. [ABSTRACT FROM AUTHOR]

The embodied creative practice of dance facilitates a particular kind of awareness or attunement which can inform both the therapeutic and the intellectual work of the Health Humanities. This paper therefore considers dance as a way of 'doing' Health Humanities in two interlinked ways: dance as a way of healing and dance as a way of knowing. In bringing together carnal and the creative dimensions of human experience, dance offers us a way of making sense of our place in the world that provides us both with much needed existential security (tethering) and much needed epistemological freedom (untethering). [ABSTRACT FROM AUTHOR]

Place/transition Petri nets are a standard model for a class of distributed systems whose reachability spaces might be infinite. One of well-studied topics is verification of safety and liveness properties in this model; despite an extensive research effort, some basic problems remain open, which is exemplified by the complexity status of the reachability problem that is still not fully clarified. The liveness problems are known to be closely related to the reachability problem, and various structural properties of nets that are related to liveness have been studied. Somewhat surprisingly, the decidability status of the problem of determining whether a net is structurally live, i.e. whether there is an initial marking for which it is live, remained open for some time; e.g. Best and Esparza (Inf Process Lett 116(6):423–427, 2016. 10.1016/j.ipl.2016.01.011) emphasize this open question. Here we show that the structural liveness problem for Petri nets is ExpSpace-hard and decidable. In particular, given a net N and a semilinear set S, it is decidable whether there is an initial marking of N for which the reachability set is included in S; this is based on results by Leroux (28th annual ACM/IEEE symposium on logic in computer science, LICS 2013, New Orleans, LA, USA, June 25–28, 2013, IEEE Computer Society, pp 23–32, 2013. 10.1109/LICS.2013.7). [ABSTRACT FROM AUTHOR]

As a contribution to the burgeoning field of health humanities, this paper seeks to explore the power of dance to mitigate human suffering and reacquaint us with what it means to be human through bringing the embodied practice of dance into dialogue with the work of the French philosopher Maurice Merleau-Ponty. Merleau-Ponty's conceptualisation of subjectivity as embodied and of intersubjectivity as intercorporeality frees us from many of the constraints of Cartesian thinking and opens up a new way of thinking about how dance functions as a healing art through its ability to ground and reconnect us with self, world, and others--with our humanity. It is argued that through a Merleau-Pontian framework, we can come to appreciate the true potential of dance as a positive and deeply humanising experience, demonstrating how expressive arts practice understood through the lens of philosophical theory can open up new dimensions of understanding and experience in relation to well-being and self- (and other-) care. [ABSTRACT FROM AUTHOR]

Introduction: The objective was to estimate, from the perspective of a managed care organization in the United States, the budget impact and effect on health outcomes of expanded use of vagus nerve stimulation [VNS (VNS Therapy®)] among patients aged ≥ 12 years with drug-resistant epilepsy (DRE) with partial-onset seizures.Methods: An Excel model was developed to compare the costs of continued anti-epileptic drug (AED) treatment with the costs of VNS plus AED treatment. The number of people eligible for VNS was estimated using published prevalence data and an estimate of the percentage of eligible patients currently without VNS. Costs included VNS device, placement, programming, and battery changes; adverse events associated with VNS (cough, voice alteration, device removal resulting from surgical site infection); AEDs; and seizure-related costs affected by seizure frequency, which affects resource utilization (i.e., hospitalizations, emergency department visits, neurologist visits). To estimate the potential savings with VNS due to a reduction in seizure frequency, the budget impact model uses the results of an underlying Markov model to estimate seizure-related costs by seizure frequency. Transitions occurred among four health states, defined by number of seizures per month (i.e., seizure-free, ≤ 1, > 1 to < 10, ≥ 10) on a 3-month cycle based on published clinical trials and registry data.Results: VNS resulted in an estimated net cost savings, on average, over 5 years, due to the expected reduction in seizure frequency. The initial cost of the VNS device, placement, and programming was estimated to be offset 1.7 years after VNS device placement. Reductions in hospitalizations were the main contributor to the cost savings with VNS.Conclusions: VNS is a proven intervention that offers a long-term solution for patients with DRE by reducing seizure frequency, which leads to lower resource utilization and lower costs.Funding: LivaNova PLC. [ABSTRACT FROM AUTHOR]

Job readiness programs are a propitious site for investigating the literal making of the US working class. With the imposition of workfarist policies, these programs have become a mainstay of social service provision to, and paternalist management of, the poor. We draw upon ethnographic fieldwork carried out in two different job readiness programs to illustrate variations in the ideological frameworks for this project of working class formation. Our first case, a prominent faith-based program targeted to the homeless, draws upon scripture to produce what we call “disciples” who treat work as a biblical mandate and way of serving the Lord. Our second case, a local nonprofit program serving welfare recipients and other poor job seekers, draws upon motivational discourse and practices to produce “dreamers” who cling to the promise that work delivers both upward mobility and personal fulfillment. Despite their differing languages and logics, both programs aim to accommodate participants to the world of low-wage work, instill within them the moral value of labor, and develop worker subjectivities premised on the obfuscation of class and the optimization of employability. [ABSTRACT FROM AUTHOR]

The original version of this Article contained an error in reference 70, which incorrectly read 'Effects of drought and recovery on volatile organic compound soil fluxes in an experimental rainforest'. The correct version replaces this title with 'Effects of drought and recovery on soil volatile organic compound fluxes in an experimental rainforest'. [Extracted from the article]

The 1996 passage of welfare reform radically reshaped the principles and practices of poverty management in the U.S. On the one hand, it brought about an end to welfare as an entitlement and imposed rigid time limits, work requirements, and a programmatic supply-sided focus on 'job-readiness.' On the other hand, it permitted and promoted the expansion of faith-based organizations in the provision of social services. This ethnographic case study of a prominent faith-based job-readiness program--Jobs for Life--is situated at the underexplored nexus of these two trends. Drawing upon participant observation in a Jobs for Life class, in-depth interviews with class instructors and participants, and content analysis of organizational materials, this article documents the program's use of biblical principles and teachings to expound on the moral irreproachability of work and to fabricate 'employable' subjects who submit themselves to both God and the employer. At play is a project that we call the 'righteous responsibilization' of the poor, a responsibilization achieved through religious salvation. The case of Jobs for Life, we argue, not only extends our understanding of 'religious neoliberalism' (Hackworth 2012), revealing how it shapes the process of subjectification and practices of poverty management. It also remediates a tension at the heart of neoliberal ideology between its emphasis on individualistic entrepreneurialism and its demand for submission to the abstract, alien decrees of the market. In the religious neoliberal framework exemplified by Jobs for Life, deference to capital is recast as the first step toward the entrepreneurial achievement of individual salvation. [ABSTRACT FROM AUTHOR]

Is it acceptable and moral to sacrifice a few people's lives to save many others? Research on moral dilemmas in psychology, experimental philosophy, and neuropsychology has shown that respondents judge utilitarian personal moral actions (footbridge dilemma) as less appropriate than equivalent utilitarian impersonal moral actions (trolley dilemma). Accordingly, theorists (e.g., Greene et al., 2001) have argued that judgments of appropriateness in personal moral dilemmas are more emotionally salient and cognitively demanding (taking more time to be rational) than impersonal moral dilemmas. Our novel findings show an effect of psychological accessibility (driven by partial contextual information; Kahneman, 2003) on utilitarian moral behavior and response time for rational choices. Enhanced accessibility of utilitarian outcomes through comprehensive information about moral actions and consequences boosted utility maximization in moral choices, with rational choices taking less time. Moreover, our result suggests that previous results indicating emotional interference, with rational choices taking more time to make, may have been artifacts of presenting partial information. [ABSTRACT FROM AUTHOR]

There are two types of behaviour by which an animal can use spatial memory in order to exploit food availability: win-stay (lose-shift) and win-shift (lose-stay). This study aimed to determine which strategy was used by rainbow trout fish. To test whether fish were using win-shift or win-stay, the fish were given three consecutive morning feedings or afternoon feedings only. The behaviour of fish during this trial was a win-stay strategy. The experiment suggests that rainbow trout engage in 'win stay' behaviour. This finding may help us to understand the spatial memory regarding win-stay in rainbow trout. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to estimate the cost effectiveness of ofatumumab plus chlorambucil (OChl) versus chlorambucil in patients with chronic lymphocytic leukaemia for whom fludarabine-based therapies are considered inappropriate from the perspective of the publicly funded healthcare system in Canada.Methods: A semi-Markov model (3-month cycle length) used survival curves to govern progression-free survival (PFS) and overall survival (OS). Efficacy and safety data and health-state utility values were estimated from the COMPLEMENT-1 trial. Post-progression treatment patterns were based on clinical guidelines, Canadian treatment practices and published literature. Total and incremental expected lifetime costs (in Canadian dollars [$Can], year 2013 values), life-years and quality-adjusted life-years (QALYs) were computed. Uncertainty was assessed via deterministic and probabilistic sensitivity analyses.Results: The discounted lifetime health and economic outcomes estimated by the model showed that, compared with chlorambucil, first-line treatment with OChl led to an increase in QALYs (0.41) and total costs ($Can27,866) and to an incremental cost-effectiveness ratio (ICER) of $Can68,647 per QALY gained. In deterministic sensitivity analyses, the ICER was most sensitive to the modelling time horizon and to the extrapolation of OS treatment effects beyond the trial duration. In probabilistic sensitivity analysis, the probability of cost effectiveness at a willingness-to-pay threshold of $Can100,000 per QALY gained was 59 %.Conclusions: Base-case results indicated that improved overall response and PFS for OChl compared with chlorambucil translated to improved quality-adjusted life expectancy. Sensitivity analysis suggested that OChl is likely to be cost effective subject to uncertainty associated with the presence of any long-term OS benefit and the model time horizon. [ABSTRACT FROM AUTHOR]

Background: Individuals with Down syndrome (DS) and individuals with Williams syndrome (WS) have poor navigation skills, which impact their potential to become independent. Two aspects of navigation were investigated in these groups, using virtual environments (VE): route knowledge (the ability to learn the way from A to B by following a fixed sequence of turns) and configural knowledge (knowledge of the spatial relationships between places within an environment). Methods: Typically developing (TD) children aged 5 to 11 years ( N = 93), individuals with DS ( N = 29) and individuals with WS ( N = 20) were presented with a sparse and a rich VE grid maze. Within each maze, participants were asked to learn a route from A to B and a route from A to C before being asked to find a novel shortcut from B to C. Results: Performance was broadly similar across sparse and rich mazes. The majority of participants were able to learn novel routes, with poorest performance in the DS group, but the ability to find a shortcut, our measure of configural knowledge, was limited for all three groups. That is, 59 % TD participants successfully found a shortcut, compared to 10 % participants with DS and 35 % participants with WS. Differences in the underlying mechanisms associated with route knowledge and configural knowledge and in the developmental trajectories of performance across groups were observed. Only the TD participants walked a shorter distance in the last shortcut trial compared to the first, indicative of increased configural knowledge across trials. The DS group often used an alternative strategy to get from B to C, summing the two taught routes together. Conclusions: Our findings demonstrate impaired configural knowledge in DS and in WS, with the strongest deficit in DS. This suggests that these groups rely on a rigid route knowledge based method for navigating and as a result are likely to get lost easily. Route knowledge was also impaired in both DS and WS groups and was related to different underlying processes across all three groups. These are discussed with reference to limitations in attention and/or visuo-spatial processing in the atypical groups. [ABSTRACT FROM AUTHOR]

The inclusion of behavioral components in the analysis of a community can be of paramount importance in marine ecology. Diel (i.e., 24-h based), seasonal activity rhythms, or longer durational in behavioral responses can result in shifts in populations, and therefore on measurable abundances. Here, we review the value of developing cabled video observatory technology for the remote, long-term, and high-frequency monitoring of fish and their environments in coastal temperate areas. We provide details on the methodological requirements and constraints for the appropriate measurement of fish behavior over various seasonal scales (24 h, seasonal, annual) with camera systems mounted at fixed observatory locations. We highlight the importance of using marine sensors to simultaneously collect relevant environmental data in parallel to image data acquisition. Here we present multiparametric video, oceanographic, and meteorological data collected from the Mediterranean observatory platform, OBSEA (; 20 m water depth). These data are reviewed in relation to ongoing and future developments of cabled observatory science. Two key approaches for the future improvement of cabled observatory technology are: (1) the application of Artificial Intelligence to aid in the analysis of increasingly large, complex, and highly interrelated biological and environmental data sets, and (2) the development of geographical observational networks to enable the reliable spatial analysis of observed populations over extended distances. [ABSTRACT FROM AUTHOR]