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OBJECTIVES/GOALS: HIV-specific CD8+ T-cells play a critical role in partially controlling viral replication in infected-individuals, but ultimately fail to eliminate infection. Enhancing these T-cell responses through lymphocyte engineering approaches has the potential as a novel therapy capable of achieving durable control or eradication of infection. METHODS/STUDY POPULATION: IL-15 Superagonist (IL-15SA) potently supports the in vivo persistence and antiviral activity of adoptively transferred CD8+ T-cells. The Deep-PrimingTM technology platform, developed by Torque, allows for loading of immunomodulators onto the surface of T-cells via electrostatic ‘nanogels’, which slowly release to deliver sustained autocrine immune stimulation without the harmful effects of systemic exposure. Here, we investigate the impact of IL-15SA Deep-Priming on HIV-specific CD8+ T-cells in a humanized mouse model of HIV infection. Humanized mice were generated by engrafting NOD-scid-IL2Rgnull mice with memory CD4+ T-cells isolated from an ARV-suppressed HIV+ donor. An autologous HIV-specific Cytotoxic T-Lymphocyte (CTL) clone was isolated, and killing potential confirmed. Four weeks post humanization, mice were infected with HIV and received an infusion of unmodified HIV-Specific CTLs, or IL-15SA Deep-Primed HIV-specific CTLs (CTL-DP). T-cell numbers and plasma viral loads were quantified weekly by flow cytometry and qRT-PCR. RESULTS/ANTICIPATED RESULTS: Mice receiving unmodified CTLs trended toward reduced viral loads compared to the No Treatment condition, while mice receiving CTL-DP saw significant, 2-Log10 reductions in VL (p < 0.01). At 41 days post-infection 100% (5/5) of the No Treatment, 66.7% (4/6) of the CTL treatment, and 16.7% (1/6) of CTL-DP treatment mice had detectable viremia. IL-15SA Deep-Priming increased CTL expansion and persistence in peripheral blood which correlated with improved CD4+T-cell preservation. DISCUSSION/SIGNIFICANCE OF IMPACT: Here we demonstrate the first in vivo analysis of IL-15SA Deep-Priming of HIV-Specific CTLs. These data suggest that Deep-Priming of patient T-cells can enhance in vivo function and persistence, leading to improved viral suppression; a significant advancement in the field of HIV cure research. CONFLICT OF INTEREST DESCRIPTION: Austin Boesch, Thomas Andresen, and Douglas Jones are employees of Torque. Darrell Irvine is a co-founder of Torque and Chairman of Torque’s Scientific Advisory Board.
Analysis of food webs is important for defining functional components of ecosystems, but dietary data are often difficult to obtain and coarsely characterised. We compared three methods of rainbow trout (Oncorhynchus mykiss (Walbaum); Salmoniformes: Salmonidae) and prickly sculpin (Cottus asper Richardson; Scorpaeniformes: Cottidae) gut content analysis: traditional morphological taxonomy of prey items, genetic sequencing of individual prey items, and next-generation sequencing of homogenised gut contents. Prey analysis of invertebrates by morphological identification allowed order-level classifications and produced ecologically important count and mass data. Sequencing individual specimens provided greater taxonomic resolution, while next-generation sequencing of stomach contents revealed more prey diversity in the diets of both fish species as it was possible to detect prey that were degraded beyond visual recognition. Both fish species exhibited generalist feeding characteristics; however, terrestrial Insecta were a large diet component for rainbow trout. This study demonstrates an efficient approach for prey analysis using molecular techniques that complement traditional taxonomy.
As the worldwide standard for radiocarbon (14C) dating over the past ca. 50,000 years, the International Calibration Curve (IntCal) is continuously improving towards higher resolution and replication. Tree-ring-based 14C measurements provide absolute dating throughout most of the Holocene, although high-precision data are limited for the Younger Dryas interval and farther back in time. Here, we describe the dendrochronological characteristics of 1448 new 14C dates, between ~11,950 and 13,160 cal BP, from 13 pines that were growing in Switzerland. Significantly enhancing the ongoing IntCal update (IntCal20), this Late Glacial (LG) compilation contains more annually precise 14C dates than any other contribution during any other period of time. Thus, our results now provide unique geochronological dating into the Younger Dryas, a pivotal period of climate and environmental change at the transition from LG into Early Holocene conditions.
Single-molecule localization microscopy (SMLM) is a family of super-resolution microscopy techniques based on localizing clusters of detected photons that are emitted by single molecules. The localization procedure is based on careful statistical analysis of long image sequences to derive the nanometer positions of the molecules. By introducing additional optics, such as cylindrical lenses in the optical system, SMLM techniques have been extended to 3D super-resolution imaging. This adds a calibration step, thereby further complicating the data analysis. Here we present Huygens Localizer, a well-supported user-friendly package that carries out these tasks quickly by offloading carefully designed 2D and 3D analysis and visualization procedures to massively parallel graphical processors (GPUs).
UK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential.
Describe the development, implementation and results of this questionnaire.
An expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use.
A total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.
The UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.
We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.
In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).
AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
Scholars and policy makers need systematic assessments of the validity of the measures produced by V-Dem. In Chapter 6, we present our approach to comparative data validation – the set of steps we take to evaluate the precision, accuracy, and reliability of our measures, both in isolation and compared to extant measures of the same concepts. Our approach assesses the degree to which measures align with shared concepts (content validation), shared rules of translation (data generation assessment), and shared realities (convergent validation). Within convergent validity, we execute two convergent validity tests. First, we examine convergent validity as it is typically conceived – examining convergence between V-Dem measures and extant measures. Second, we evaluate the level of convergence across coders, considering the individual coder and country traits that predict coder convergence. Throughout the chapter, we focus on three indices included in the V-Dem data set: polyarchy, corruption, and core civil society. These three concepts collectively provide a “hard test” for the validity of our data, representing a range of existing measurement approaches, challenges, and solutions.
This chapter sets forth the conceptual scheme for the V–Dem project. We begin by discussing the concept of democracy. Next, we lay out seven principles by which this key concept may be understood – electoral, liberal, majoritarian, consensual, participatory, deliberative, and egalitarian. Each defines a “variety“ of democracy, and together they offer a fairly comprehensive accounting of the concept as used in the world today. Next, we show how this seven-part framework fits into our overall thinking about democracy, including multiple levels of disaggregation – to components, subcomponents, and indicators. The final section of the chapter discusses several important caveats and clarifications pertaining to this ambitious taxonomic exercise.
This chapter recounts how a project of this scale came together and why it has succeeded. Five main factors were responsible for V–Dem’s success: timing, inclusion, deliberation, administrative centralization, and fund–raising. First, planning for V-Dem began at a time when both social scientists and practitioners were realizing that they needed better democracy measures. This made it possible to recruit collaborators and find funding. Second, the leaders of the project were always eager to expand the team to acquire whatever expertise they lacked and share credit with everyone who contributed. Third, the project leaders practiced an intensely deliberative decision–making style to ensure that all points of view were consulted and only decisions that won wide acceptance were adopted. Fourth, centralizing the execution of the agreed–upon tasks helped tremendously by streamlining processes and promoting standardization, documentation, professionalization, and coordination of a large number of intricate steps. Finally, successful fund–raising from a mix of both research foundations and bilateral and multilateral organizations has been critical.
In this chapter we focus on the measurement of five key principles of democracy – electoral, liberal, participatory, deliberative, and egalitarian. For each principle, we discuss (1) the theoretical rationale for the selected indicators, (2) whether these indicators are correlated strongly enough to warrant being collapsed into an index, and (3) the justification of aggregation rules for moving from indicators to components and from components to higher–level indices. In each section we also (4) highlight the top– and bottom–five countries on each principle of democracy in early (1812 or 1912) and late (2012) years of our sample period, as well as the aggregate trend over the whole time period 1789–2017 (where applicable). Finally, we (5) look at how the different principles are intercorrelated in order to assess the trade–offs involved between the conceptual parsimony achieved by aggregating to a few general concepts and the retention of useful variation permitted by aggregating less.
Four characteristics of V-Dem data present distinct opportunities and challenges for explanatory analysis: (1) the large number of democracy indicators (i.e., variables), (2) the measurement of concepts by multiple coders filtered through the V-Dem measurement model, (3) the large number of years in the data set, and 4) the ex ante potential for dependence across countries (generically referred to as spatial dependence). This chapter discusses 3 challenges and 10 opportunities that are implied by these characteristics. At the end of this chapter, we also discuss three assumptions that are implicit in most analyses of observational indicators of macro-features at the national level, which aim to draw conclusions about causal relationships.
Varieties of Democracy is the essential user's guide to The Varieties of Democracy project (V-Dem), one of the most ambitious data collection efforts in comparative politics. This global research collaboration sparked a dramatic change in how we study the nature, causes, and consequences of democracy. This book is ambitious in scope: more than a reference guide, it raises standards for causal inferences in democratization research and introduces new, measurable, concepts of democracy and many political institutions. Varieties of Democracy enables anyone interested in democracy - teachers, students, journalists, activists, researchers and others - to analyze V-Dem data in new and exciting ways. This book creates opportunities for V-Dem data to be used in education, research, news analysis, advocacy, policy work, and elsewhere. V-Dem is rapidly becoming the preferred source for democracy data.