Multi-state Models for Natural History of Disease

Longitudinal studies are a useful tool for investigating the course of chronic diseases. Many chronic diseases can be characterized by a set of health states. We can improve our understanding of the natural history of the disease by modeling the sequence of visited health states and the duration in each state. However, in most applications, subjects are observed only intermittently. This observation scheme creates a major modeling challenge: the transition times are not known exactly, and in some cases the path through the health states is not known. In this manuscript we review existing approaches for modeling multi-state longitudinal data. We introduce Bayesian estimation methods and illustrate their use in two longitudinal studies of chronic disease

The evening complex is central to the difference between the circadian clocks of Arabidopsis thaliana shoots and roots

The circadian clock regulates the timing of many aspects of plant physiology, and this requires entrainment of the clock to the prevailing day:night cycle. Different plant cells and tissues can oscillate with different free‐running periods, so coordination of timing across the plant is crucial. Previous work showed that a major difference between the clock in mature shoots and roots involves light inputs. The objective of this work was to define, in Arabidopsis thaliana , the operation of the root clock in more detail, and in particular how it responds to light quality. Luciferase imaging was used to study the shoot and root clocks in several null mutants of clock components and in lines with aberrant expression of phytochromes. Mutations in each of the components of the evening complex (EARLY FLOWERING 3 and 4, and LUX ARRHYTHMO) were found to have specific effects on roots, by affecting either rhythmicity or period and its response to light quality. The data suggest that the evening complex is a key part of the light input mechanism that differs between shoots and roots and show that roots sense red light via phytochrome B

Discrete and continuous time simulations of spatial ecological processes predict different final population sizes and interspecific competition outcomes

Cellular automata (CAs) are commonly used to simulate spatial processes in ecology. Although appropriate for modelling events that occur at discrete time points, they are also routinely used to model biological processes that take place continuously. We report on a study comparing predictions of discrete time CA models to those of their continuous time counterpart. Specifically, we investigate how the decision to model time discretely or continuously affects predictions regarding long-run population sizes, the probability of extinction and interspecific competition. We show effects on predicted ecological outcomes, finding quantitative differences in all cases and in the case of interspecific competition, additional qualitative differences in predictions regarding species dominance. Our findings demonstrate that qualitative conclusions drawn from spatial simulations can be critically dependent on the decision to model time discretely or continuously. Contrary to our expectations, simulating in continuous time did not incur a heavy computational penalty. We also raise ecological questions on the relative benefits of reproductive strategies that take place in discrete and continuous time

The Demographics and Atmospheres of Giant Planets with the ELTs

Gas giants are the most readily detectable exoplanets but fundamental questions about their system architectures, formation, migration, and atmospheres have been unanswerable with the current generation of ground- and space-based facilities. The dominant techniques to detect and characterize giant planets $-$ radial velocities, transits, direct imaging, microlensing, and astrometry $-$ are each isolated to a limited range of planet masses, separations, ages, and temperatures. These windows into the arrangement and physical properties of giant planets have spawned new questions about the timescale and location of their assembly; the distributions of planet mass and orbital separation at young and old ages; the composition and structure of their atmospheres; and their orbital and rotational angular momentum architectures. The ELTs will address these questions by building bridges between these islands of mass, orbital distance, and age. The angular resolution, collecting area, all-sky coverage, and novel instrumentation suite of these facilities are needed to provide a complete map of the orbits and atmospheric evolution of gas giant planets (0.3$-$10 $M_\mathrm{Jup}$) across space (0.1$-$100 AU) and time (1 Myr to 10 Gyr). This white paper highlights the scientific potential of the GMT and TMT to address these outstanding questions, with a particular focus on the role of direct imaging and spectroscopy of large samples of giant planets that will soon be made available with $Gaia$.Comment: White paper for the Astro2020 decadal surve

Direct Imaging in Reflected Light: Characterization of Older, Temperate Exoplanets With 30-m Telescopes

Direct detection, also known as direct imaging, is a method for discovering and characterizing the atmospheres of planets at intermediate and wide separations. It is the only means of obtaining spectra of non-transiting exoplanets. Characterizing the atmospheres of planets in the <5 AU regime, where RV surveys have revealed an abundance of other worlds, requires a 30-m-class aperture in combination with an advanced adaptive optics system, coronagraph, and suite of spectrometers and imagers - this concept underlies planned instruments for both TMT (the Planetary Systems Imager, or PSI) and the GMT (GMagAO-X). These instruments could provide astrometry, photometry, and spectroscopy of an unprecedented sample of rocky planets, ice giants, and gas giants. For the first time habitable zone exoplanets will become accessible to direct imaging, and these instruments have the potential to detect and characterize the innermost regions of nearby M-dwarf planetary systems in reflected light. High-resolution spectroscopy will not only illuminate the physics and chemistry of exo-atmospheres, but may also probe rocky, temperate worlds for signs of life in the form of atmospheric biomarkers (combinations of water, oxygen and other molecular species). By completing the census of non-transiting worlds at a range of separations from their host stars, these instruments will provide the final pieces to the puzzle of planetary demographics. This whitepaper explores the science goals of direct imaging on 30-m telescopes and the technology development needed to achieve them.Comment: (March 2018) Submitted to the Exoplanet Science Strategy committee of the NA

Neural response to monetary loss among youth with disruptive behavior disorders and callous-unemotional traits in the ABCD study

Etiological models highlight reduced punishment sensitivity as a core risk factor for disruptive behavior disorders (DBD) and callous-unemotional (CU) traits. The current study examined neural sensitivity to the anticipation and receipt of loss, one key aspect of punishment sensitivity, among youth with DBD, comparing those with and without CU traits. Data were obtained from the Adolescent Brain and Cognitive Development (ABCD)SM Study (N = 11,874; Mage = 9.51; 48% female). Loss-related fMRI activity during the monetary incentive delay task was examined across 16 empirically-derived a priori brain regions (e.g., striatum, amygdala, insula, anterior cingulate cortex, medial prefrontal cortex) and compared across the following groups: (1) typically developing (n = 693); (2) DBD (n = 995), subdivided into those (3) with CU traits (DBD + CU, n = 198), and (4) without CU traits (DBD-only, n = 276). Latent variable modeling was also employed to examine network-level activity. There were no significant between-group differences in brain activity to loss anticipation or receipt. Null findings were confirmed with and without covariates, using alternative grouping approaches, and in dimensional models. Network-level analyses also demonstrated comparable activity across groups during loss anticipation and receipt. Findings suggest that differences in punishment sensitivity among youth with DBD are unrelated to loss anticipation or receipt. More precise characterizations of other aspects punishment sensitivity are needed to understand risk for DBD and CU traits

The Gift:Transforming Lives through Organ Donation

It is my great pleasure to introduce this comic. Our project originated from an honest conversation with my friend and colleague Prof Chris Murray: how to communicate complex issues surrounding the issue of organ donation? Over the last seven years I have had the honour of being an ambassador for the Organ Donation campaign by telling my son, Andrew’s, story.Through my role as an Organ Donation ambassador I meet courageous and selfless people. Some are in desperate need of hope, some are in the position to provide hope, and those who, through their professionalism and dedication, transform lives.Our sincere thanks for the support of the following organisations: University of Dundee; the NHS Blood and Transplant Specialist Nurses in Organ Donation; Dundee Comics Creative Space; Good Life, Good Death, Good Grief, and the Organ Donation Comics team. it is only through their support that this projectcame to fruition.In the following pages we share heartfelt stories and life experiences related to organ donation. By doing so we hope to bring awareness to a wider audience and prompt honest conversations about organ donation.Finally, I would like thank my sons Andrew and Stuart for warming my heart. Through tears and laughter we present to you… The Gift

A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis

Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αβ based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαβ induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage-TCRαβ expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR Vβ repertoires. In vivo, TCRαβ bearing macrophages abundantly accumulate at the inner host-pathogen contact zone of caseous granulomas from patients with lung tuberculosis. In chimeric mouse models, deletion of the variable macrophage-TCRαβ or TNF is associated with structurally compromised granulomas of pulmonary tuberculosis even in the presence of intact T cells. These results uncover a TNF-regulated recombinatorial immune receptor in monocytes/macrophages and demonstrate its implication in granuloma formation in tuberculosis