Peering Into the Black Box: An Examination of Community-Based Therapists' Intentions for Treating Youth.

M.A. Thesis. University of Hawaiʻi at Mānoa 2017

Most probable transition paths in piecewise-smooth stochastic differential equations

We develop a path integral framework for determining most probable paths in a class of systems of stochastic differential equations with piecewise-smooth drift and additive noise. This approach extends the Freidlin-Wentzell theory of large deviations to cases where the system is piecewise-smooth and may be non-autonomous. In particular, we consider an $n-$dimensional system with a switching manifold in the drift that forms an $(n-1)-$dimensional hyperplane and investigate noise-induced transitions between metastable states on either side of the switching manifold. To do this, we mollify the drift and use $\Gamma-$convergence to derive an appropriate rate functional for the system in the piecewise-smooth limit. The resulting functional consists of the standard Freidlin-Wentzell rate functional, with an additional contribution due to times when the most probable path slides in a crossing region of the switching manifold. We explore implications of the derived functional through two case studies, which exhibit notable phenomena such as non-unique most probable paths and noise-induced sliding in a crossing region.Comment: 38 pages, 9 figure

The stability of present-day Antarctic grounding lines – Part 2: Onset of irreversible retreat of Amundsen Sea glaciers under current climate on centennial timescales cannot be excluded

Observations of ocean-driven grounding-line retreat in the Amundsen Sea Embayment in Antarctica raise the question of an imminent collapse of the West Antarctic Ice Sheet. Here we analyse the committed evolution of Antarctic grounding lines under the present-day climate. To this aim, we first calibrate a sub-shelf melt parameterization, which is derived from an ocean box model, with observed and modelled melt sensitivities to ocean temperature changes, making it suitable for present-day simulations and future sea level projections. Using the new calibration, we run an ensemble of historical simulations from 1850 to 2015 with a state-of-the-art ice sheet model to create model instances of possible present-day ice sheet configurations. Then, we extend the simulations for another 10 000 years to investigate their evolution under constant present-day climate forcing and bathymetry. We test for reversibility of grounding-line movement in the case that large-scale retreat occurs. In the Amundsen Sea Embayment we find irreversible retreat of the Thwaites Glacier for all our parameter combinations and irreversible retreat of the Pine Island Glacier for some admissible parameter combinations. Importantly, an irreversible collapse in the Amundsen Sea Embayment sector is initiated at the earliest between 300 and 500 years in our simulations and is not inevitable yet – as also shown in our companion paper (Part 1, Hill et al., 2023). In other words, the region has not tipped yet. With the assumption of constant present-day climate, the collapse evolves on millennial timescales, with a maximum rate of 0.9 mm a−1 sea-level-equivalent ice volume loss. The contribution to sea level by 2300 is limited to 8 cm with a maximum rate of 0.4 mm a−1 sea-level-equivalent ice volume loss. Furthermore, when allowing ice shelves to regrow to their present geometry, we find that large-scale grounding-line retreat into marine basins upstream of the Filchner–Ronne Ice Shelf and the western Siple Coast is reversible. Other grounding lines remain close to their current positions in all configurations under present-day climate

Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes

Copyright: © 2010 Stimpson et al.Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extrachromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment.This work was supported by the Tumorzentrum Heidelberg/Mannheim grant (D.10026941)and by March of Dimes Research Foundation grant #1-FY06-377 and NIH R01 GM069514

Highly Pathogenic Avian Influenza A(H5N1) Virus Outbreak in New England Seals, United States

We report the spillover of highly pathogenic avian influenza A(H5N1) into marine mammals in the northeastern United States, coincident with H5N1 in sympatric wild birds. Our data indicate monitoring both wild coastal birds and marine mammals will be critical to determine pandemic potential of influenza A viruses

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes

Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages