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"Russell, Josh"
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Science Educational Outreach Programs That Benefit Students and Scientists
Both scientists and the public would benefit from improved communication of basic scientific research and from integrating scientists into education outreach, but opportunities to support these efforts are limited. We have developed two low-cost programs--\"Present Your PhD Thesis to a 12-Year-Old\" and \"Shadow a Scientist\"--that combine training in science communication with outreach to area middle schools. We assessed the outcomes of these programs and found a 2-fold benefit: scientists improve their communication skills by explaining basic science research to a general audience, and students' enthusiasm for science and their scientific knowledge are increased. Here we present details about both programs, along with our assessment of them, and discuss the feasibility of exporting these programs to other universities.
Journal Article
Peroxisome Proliferator–activated Receptor-γ Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model
We established a murine model of multiwall carbon nanotube (MWCNT)-elicited chronic granulomatous disease that bears similarities to human sarcoidosis pathology, including alveolar macrophage deficiency of peroxisome proliferator-activated receptor γ (PPARγ). Because lymphocyte reactivity to mycobacterial antigens has been reported in sarcoidosis, we hypothesized that addition of mycobacterial ESAT-6 (early secreted antigenic target protein 6) to MWCNT might exacerbate pulmonary granulomatous pathology. MWCNTs with or without ESAT-6 peptide 14 were instilled by the oropharyngeal route into macrophage-specific PPARγ-knockout (KO) or wild-type mice. Control animals received PBS or ESAT-6. Lung tissues, BAL cells, and BAL fluid were evaluated 60 days after instillation. PPARγ-KO mice receiving MWCNT + ESAT-6 had increased granulomas and significantly elevated fibrosis (trichrome staining) compared with wild-type mice or PPARγ-KO mice that received only MWCNT. Immunostaining of lung tissues revealed elevated fibronectin and Siglec F expression on CD11c
infiltrating alveolar macrophages in the presence of MWCNT + ESAT-6 compared with MWCNT alone. Analyses of BAL fluid proteins indicated increased levels of transforming growth factor (TGF)-β and the TGF-β pathway mediator IL-13 in PPARγ-KO mice that received MWCNT + ESAT-6 compared with wild-type or PPARγ-KO mice that received MWCNT. Similarly, mRNA levels of matrix metalloproteinase 9, another requisite factor for TGF-β production, was elevated in PPARγ-KO mice by MWCNT + ESAT-6. Analysis of ESAT-6 in lung tissues by mass spectrometry revealed ESAT-6 retention in lung tissues of PPARγ-KO but not wild-type mice. These data indicate that PPARγ deficiency promotes pulmonary ESAT-6 retention, exacerbates macrophage responses to MWCNT + ESAT-6, and intensifies pulmonary fibrosis. The present findings suggest that the model may facilitate understanding of the effects of environmental factors on sarcoidosis-associated pulmonary fibrosis.
Journal Article
Science Educational Outreach Programs That Benefit Students and Scientists
Both scientists and the public would benefit from improved communication of basic scientific research and from integrating scientists into education outreach, but opportunities to support these efforts are limited. We have developed two low-cost programs--\"Present Your PhD Thesis to a 12-Year-Old\" and \"Shadow a Scientist\"--that combine training in science communication with outreach to area middle schools. We assessed the outcomes of these programs and found a 2-fold benefit: scientists improve their communication skills by explaining basic science research to a general audience, and students' enthusiasm for science and their scientific knowledge are increased. Here we present details about both programs, along with our assessment of them, and discuss the feasibility of exporting these programs to other universities.
Journal Article
Principled Feature Attribution for Unsupervised Gene Expression Analysis
As interest in unsupervised deep learning models for the analysis of gene expression data has grown, an increasing number of methods have been developed to make these deep learning models more interpretable. These methods can be separated into two groups: (1) post hoc analyses of black box models through feature attribution methods and (2) approaches to build inherently interpretable models through biologically-constrained architectures. In this work, we argue that these approaches are not mutually exclusive, but can in fact be usefully combined. We propose a novel unsupervised pathway attribution method, which better identifies major sources of transcriptomic variation than prior methods when combined with biologically-constrained neural network models. We demonstrate how principled feature attributions aid in the analysis of a variety of single cell datasets. Finally, we apply our approach to a large dataset of post-mortem brain samples from patients with Alzheimer's disease, and show that it identifies Mitochondrial Respiratory Complex I as an important factor in this disease. Competing Interest Statement The authors have declared no competing interest.
Paper
DECODER: A probabilistic approach to integrate big data reveals mitochondrial Complex I as a potential therapeutic target for Alzheimer's disease
Identifying gene expression markers for Alzheimer's disease (AD) neuropathology through meta-analysis is a complex undertaking because available data are often from different studies and/or brain regions involving study-specific confounders and/or region-specific biological processes. Here, we developed a probabilistic model-based framework, DECODER, leveraging these discrepancies to identify robust biomarkers for complex phenotypes. Our experiments present: (1) DECODER's potential as a general meta-analysis framework widely applicable to various diseases (e.g., AD and cancer) and phenotypes (e.g., Amyloid-beta (Abeta) pathology, tau pathology, and survival), (2) our results from a meta-analysis using 1,746 human brain tissue samples from nine brain regions in three studies -- the largest expression meta-analysis for AD, to our knowledge --, and (3) in vivo validation of identified modifiers of Abeta toxicity in a transgenic Caenorhabditis elegans model expressing AD-associated Abeta, which pinpoints mitochondrial Complex I as a critical mediator of proteostasis and a promising pharmacological avenue toward treating AD.
Paper
Diversification of large-effect loci in a duplicated genomic region leads to complex phenotypes
Whole genome duplication provides evolutionary opportunities to increase biological complexity and phenotypic diversity by selective retention of duplicated genes. We identify a small genomic region associated with complex phenotypic variation on duplicate copies of the same ancestral chromosome in salmon (Salmonidae). Across six species, three large-effect loci involved in migration timing, reproduction, and maturation are located in this genomic region. Life history and whole genome resequencing data support lineage-specific evolution of polymorphism related to early- and late-migrating phenotypes. The high frequency of transcription factors and lack of non-synonymous mutations suggests this region influences gene expression rather than modifying gene function. Repeated evolution of large-effect loci in multiple salmon species provides evidence of adaptive evolution facilitated by the salmonid specific whole genome duplication.
Paper