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"Concannon, Amy"
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The Imagination Set Ablaze
The Tate Britain in London, England, is rehanging its collection of British art in 2013. Among the collection is J. M. W. Turner's watercolor sketchings of the 1834 burning of the Houses of Parliament. His technique and his ability to capture the historical moment are considered.
Magazine Article
Facilitating stakeholder engagement in early stage translational research
Stakeholder engagement can play an important role in increasing public trust and the understanding of scientific research and its impact. Frameworks for stakeholder identification exist, but these frameworks may not apply well to basic science and early stage translational research.
Four Clinical and Translational Science Award (CTSA) hubs led six focus groups and two semi-structured interviews using a semi-structured discussion guide to learn from basic science researchers about stakeholder engagement in their work. The 24 participants represented fourteen clinical and academic disciplines.
Early stage translational researchers reported engagement with a broad array of stakeholders. Those whose research has a clinical focus reported working with a more diverse range of stakeholders than those whose work did not. Common barriers to stakeholder engagement were grouped into three major themes: a poor definition of concepts, absence of guidance, and limited resources.
The National Center for Advancing Translational Sciences (NCATS), the consortium of CTSAs, and the individual CTSA \"hubs\" are three actors that can help early stage translational researchers develop shared terms of reference, build the necessary skills, and assemble the appropriate resources for engaging stakeholders in Clinical and Translational Research. Getting this right will involve a coordinated push by all three entities.
Journal Article
Optimizing the Cell Painting assay for image-based profiling
In image-based profiling, software extracts thousands of morphological features of cells from multi-channel fluorescence microscopy images, yielding single-cell profiles that can be used for basic research and drug discovery. Powerful applications have been proven, including clustering chemical and genetic perturbations on the basis of their similar morphological impact, identifying disease phenotypes by observing differences in profiles between healthy and diseased cells and predicting assay outcomes by using machine learning, among many others. Here, we provide an updated protocol for the most popular assay for image-based profiling, Cell Painting. Introduced in 2013, it uses six stains imaged in five channels and labels eight diverse components of the cell: DNA, cytoplasmic RNA, nucleoli, actin, Golgi apparatus, plasma membrane, endoplasmic reticulum and mitochondria. The original protocol was updated in 2016 on the basis of several years’ experience running it at two sites, after optimizing it by visual stain quality. Here, we describe the work of the Joint Undertaking for Morphological Profiling Cell Painting Consortium, to improve upon the assay via quantitative optimization by measuring the assay’s ability to detect morphological phenotypes and group similar perturbations together. The assay gives very robust outputs despite various changes to the protocol, and two vendors’ dyes work equivalently well. We present Cell Painting version 3, in which some steps are simplified and several stain concentrations can be reduced, saving costs. Cell culture and image acquisition take 1–2 weeks for typically sized batches of ≤20 plates; feature extraction and data analysis take an additional 1–2 weeks.
This protocol is an update to
Nat. Protoc
. 11, 1757–1774 (2016):
https://doi.org/10.1038/nprot.2016.105
We provide an updated protocol for image-based profiling with Cell Painting. A detailed procedure, with standardized conditions for the assay, is presented, along with a comprehensive description of parameters to be considered when optimizing the assay.
Journal Article
“I’m not gonna be able to do anything about it, then what’s the point?”: A broad group of stakeholders identify barriers and facilitators to HCV testing in a Massachusetts jail
Despite national guidelines promoting hepatitis C virus (HCV) testing in prisons, there is substantial heterogeneity on the implementation of HCV testing in jails. We sought to better understand barriers and opportunities for HCV testing by interviewing a broad group of stakeholders involved in HCV testing and treatment policies and procedures in Massachusetts jails. We conducted semi-structured interviews with people incarcerated in Middlesex County Jail (North Billerica, MA), clinicians working in jail and community settings, corrections administrators, and representatives from public health, government, and industry between November 2018-April 2019. 51/120 (42%) of people agreed to be interviewed including 21 incarcerated men (mean age 32 [IQR 25, 39], 60% non-White). Themes that emerged from these interviews included gaps in knowledge about HCV testing and treatment opportunities in jail, the impact of captivity and transience, and interest in improving linkage to HCV care after release. Many stakeholders discussed stigma around HCV infection as a factor in reluctance to provide HCV testing or treatment in the jail setting. Some stakeholders expressed that stigma often led decisionmakers to estimate a lower \"worth\" of incarcerated individuals living with HCV and therefore to decide against paying for HCV testing.\". All stakeholders agreed that HCV in the jail setting is a public health issue that needs to be addressed. Exploring stakeholders' many ideas about how HCV testing and treatment can be approached is the first step in developing feasible and acceptable strategies.
Journal Article
Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes
We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (
P
< 5 × 10
−8
) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4
+
effector T cells. Using chromatin-accessibility profiling of CD4
+
T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in
BACH2
as a candidate causal T1D variant leading to decreased enhancer accessibility and
BACH2
expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein–protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
A large-scale genetic analysis of type 1 diabetes identifies new susceptibility variants, highlights potential regulatory mechanisms and provides genetic support for therapeutic targets for immune intervention.
Journal Article
A review of reported stakeholder engagement in early-stage translational research
We conducted a scoping review of peer-reviewed literature to describe the nature and extent of reporting on the involvement of stakeholders in early-stage translational research.
We conducted two literature searches in six databases, screened records and full-text articles, and abstracted and analyzed data from included publications. The literature searches yielded unduplicated 2,894 records. After screening, 13 articles were included.
Our review of the literature yielded rare reports of engagement in early-stage translational research. Half of included articles reported on engagement with patients, clinicians, and researchers while fewer that one in three reported on engagement with policymakers, industry, and insurers. One in four reported engagement in the publication's acknowledgments but not in the main text. More than half drew unmeasured conclusions about the outcomes of engagement.
Our definition of early-stage translation pointed to a specific set of peer-reviewed research; our findings indicate a reporting gap and not necessarily a gap in practice. By addressing four themes-developing a shared language, identifying frameworks and principles, creating a repository of resources, and establishing a research agenda, research leaders can develop new insights about how to engage communities in early-stage translational research.
Journal Article
The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity
Single-nucleotide polymorphisms in the gene encoding the cytosolic viral sensor IFIH1 are linked to a variety of autoimmune diseases. Rawlings and colleagues demonstrate that one such common polymorphism results in IFIH1 with more-potent activation and can act synergistically with other genetic backgrounds to manifest autoimmune disease.
The single-nucleotide polymorphism rs1990760 in the gene encoding the cytosolic viral sensor IFIH1 results in an amino-acid change (A946T; IFIH1
T946
) that is associated with multiple autoimmune diseases. The effect of this polymorphism on both viral sensing and autoimmune pathogenesis remains poorly understood. Here we found that human peripheral blood mononuclear cells (PBMCs) and cell lines expressing the risk variant IFIH1
T946
exhibited heightened basal and ligand-triggered production of type I interferons. Consistent with those findings, mice with a knock-in mutation encoding IFIH1
T946
displayed enhanced basal expression of type I interferons, survived a lethal viral challenge and exhibited increased penetrance in autoimmune models, including a combinatorial effect with other risk variants. Furthermore, IFIH1
T946
mice manifested an embryonic survival defect consistent with enhanced responsiveness to RNA self ligands. Together our data support a model wherein the production of type I interferons driven by an autoimmune risk variant and triggered by ligand functions to protect against viral challenge, which probably accounts for its selection within human populations but provides this advantage at the cost of modestly promoting the risk of autoimmunity.
Journal Article