633 results on '"Brown, James B"'
Search Results
2. Detention operations, behavior modification, and counterinsurgency
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Brown, James B., Col, and others
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PRISONERS AND PRISONS - Study and Teaching ,COUNTERINSURGENCY - Methodology ,IRAQ WAR, 2003 - Prisoners of War ,BEHAVIORISM (PSYCHOLOGY) - Abstract
illus bibliog
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- 2009
3. Radiological events in the homeland
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Brown, James B., Col, and others
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NUCLEAR WEAPONS - Protection - United States ,RADIOACTIVE FALLOUT ,CIVIL DEFENSE - United States ,PREPAREDNESS - Abstract
illus map bibliog
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- 2008
4. Learning from learning machines: a new generation of AI technology to meet the needs of science
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Pion-Tonachini, Luca, Bouchard, Kristofer, Martin, Hector Garcia, Peisert, Sean, Holtz, W. Bradley, Aswani, Anil, Dwivedi, Dipankar, Wainwright, Haruko, Pilania, Ghanshyam, Nachman, Benjamin, Marrone, Babetta L., Falco, Nicola, Prabhat, Arnold, Daniel, Wolf-Yadlin, Alejandro, Powers, Sarah, Climer, Sharlee, Jackson, Quinn, Carlson, Ty, Sohn, Michael, Zwart, Petrus, Kumar, Neeraj, Justice, Amy, Tomlin, Claire, Jacobson, Daniel, Micklem, Gos, Gkoutos, Georgios V., Bickel, Peter J., Cazier, Jean-Baptiste, Müller, Juliane, Webb-Robertson, Bobbie-Jo, Stevens, Rick, Anderson, Mark, Kreutz-Delgado, Ken, Mahoney, Michael W., and Brown, James B.
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Computer Science - Machine Learning ,Computer Science - Artificial Intelligence - Abstract
We outline emerging opportunities and challenges to enhance the utility of AI for scientific discovery. The distinct goals of AI for industry versus the goals of AI for science create tension between identifying patterns in data versus discovering patterns in the world from data. If we address the fundamental challenges associated with "bridging the gap" between domain-driven scientific models and data-driven AI learning machines, then we expect that these AI models can transform hypothesis generation, scientific discovery, and the scientific process itself.
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- 2021
5. In search of synergy: Joint amphibious/air assault operations
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Brown, James B., Maj
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AMPHIBIOUS OPERATIONS ,AIR ASSAULT CONCEPT - Abstract
illus bibliog
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- 1999
6. Estimating geographic variation of infection fatality ratios during epidemics
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Ladau, Joshua, Brodie, Eoin L., Falco, Nicola, Bansal, Ishan, Hoffman, Elijah B., Joachimiak, Marcin P., Mora, Ana M., Walker, Angelica M., Wainwright, Haruko M., Wu, Yulun, Pavicic, Mirko, Jacobson, Daniel, Hess, Matthias, Brown, James B., and Abuabara, Katrina
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- 2024
- Full Text
- View/download PDF
7. Effects of spatial variability in vegetation phenology, climate, landcover, biodiversity, topography, and soil property on soil respiration across a coastal ecosystem
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He, Yinan, Bond-Lamberty, Ben, Myers-Pigg, Allison N., Newcomer, Michelle E., Ladau, Joshua, Holmquist, James R., Brown, James B., and Falco, Nicola
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- 2024
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8. Downscaled hyper-resolution (400 m) gridded datasets of daily precipitation and temperature (2008–2019) for East Taylor subbasin (western United States)
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Mital, Utkarsh, Dwivedi, Dipankar, Brown, James B, and Steefel, Carl I
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Climate Action - Abstract
Abstract. High resolution gridded datasets of meteorological variables are needed in order to resolve fine-scale hydrological gradients in complex mountainous terrain. Across the United States, the highest available spatial resolution of gridded datasets of daily meteorological records is approximately 800 m. This work presents gridded datasets of daily precipitation and mean temperature for the East-Taylor subbasin (in western United States) covering a 12-year period (2008–2019) at a high spatial resolution (400 m). The datasets are generated using a downscaling framework that uses data-driven models to learn relationships between climate variables and topography. We observe that downscaled datasets of precipitation and mean temperature exhibit smoother spatial gradients compared to their coarser counterparts. Additionally, we also observe that when downscaled datasets are reaggregated to the original resolution (800 m), the mean residual error is almost zero, ensuring spatial consistency with the original data. Furthermore, the downscaled datasets are observed to be linearly related to elevation, which is consistent with the methodology underlying the original 800 m product. Finally, we validate the spatial patterns exhibited by downscaled datasets via an example use case that models lidar-derived estimates of snowpack. The presented dataset constitutes a valuable resource to resolve fine-sale hydrological gradients in the mountainous terrain of the East-Taylor subbasin, which is an important study area in the context of water security for southwestern United States and Mexico. The dataset is publicly available at https://doi.org/10.15485/1822259 (Mital et al., 2021).
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- 2022
9. Spatial Graph Attention and Curiosity-driven Policy for Antiviral Drug Discovery
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Wu, Yulun, Cashman, Mikaela, Choma, Nicholas, Prates, Érica T., Vergara, Verónica G. Melesse, Shah, Manesh, Chen, Andrew, Clyde, Austin, Brettin, Thomas S., de Jong, Wibe A., Kumar, Neeraj, Head, Martha S., Stevens, Rick L., Nugent, Peter, Jacobson, Daniel A., and Brown, James B.
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Computer Science - Machine Learning ,Computer Science - Artificial Intelligence ,Quantitative Biology - Biomolecules - Abstract
We developed Distilled Graph Attention Policy Network (DGAPN), a reinforcement learning model to generate novel graph-structured chemical representations that optimize user-defined objectives by efficiently navigating a physically constrained domain. The framework is examined on the task of generating molecules that are designed to bind, noncovalently, to functional sites of SARS-CoV-2 proteins. We present a spatial Graph Attention (sGAT) mechanism that leverages self-attention over both node and edge attributes as well as encoding the spatial structure -- this capability is of considerable interest in synthetic biology and drug discovery. An attentional policy network is introduced to learn the decision rules for a dynamic, fragment-based chemical environment, and state-of-the-art policy gradient techniques are employed to train the network with stability. Exploration is driven by the stochasticity of the action space design and the innovation reward bonuses learned and proposed by random network distillation. In experiments, our framework achieved outstanding results compared to state-of-the-art algorithms, while reducing the complexity of paths to chemical synthesis.
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- 2021
10. Downscaled hyper-resolution (400 m) gridded datasets of daily precipitation and temperature (2008–2019) for the East–Taylor subbasin (western United States)
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Mital, Utkarsh, Dwivedi, Dipankar, Brown, James B, and Steefel, Carl I
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Earth Sciences ,Atmospheric Sciences ,Bioengineering ,Climate Action ,Geochemistry ,Physical Geography and Environmental Geoscience ,Atmospheric sciences ,Geoinformatics ,Physical geography and environmental geoscience - Abstract
High-resolution gridded datasets of meteorological variables are needed in order to resolve fine-scale hydrological gradients in complex mountainous terrain. Across the United States, the highest available spatial resolution of gridded datasets of daily meteorological records is approximately 800 m. This work presents gridded datasets of daily precipitation and mean temperature for the East-Taylor subbasin (in the western United States) covering a 12-year period (2008-2019) at a high spatial resolution (400 m). The datasets are generated using a downscaling framework that uses data-driven models to learn relationships between climate variables and topography. We observe that downscaled datasets of precipitation and mean temperature exhibit smoother spatial gradients (while preserving the spatial variability) when compared to their coarser counterparts. Additionally, we also observe that when downscaled datasets are upscaled to the original resolution (800 m), the mean residual error is almost zero, ensuring no bias when compared with the original data. Furthermore, the downscaled datasets are observed to be linearly related to elevation, which is consistent with the methodology underlying the original 800 m product. Finally, we validate the spatial patterns exhibited by downscaled datasets via an example use case that models lidar-derived estimates of snowpack. The presented dataset constitutes a valuable resource to resolve fine-scale hydrological gradients in the mountainous terrain of the East-Taylor subbasin, which is an important study area in the context of water security for the southwestern United States and Mexico.
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- 2022
11. Machine-Learning Functional Zonation Approach for Characterizing Terrestrial–Aquatic Interfaces: Application to Lake Erie
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Enguehard, Léa, Falco, Nicola, Schmutz, Myriam, Newcomer, Michelle E, Ladau, Joshua, Brown, James B, Bourgeau-Chavez, Laura, and Wainwright, Haruko M
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Earth Sciences ,Physical Geography and Environmental Geoscience ,Atmospheric Sciences ,Machine Learning and Artificial Intelligence ,Life Below Water ,coastal wetlands ,plant productivity ,Great Lakes Region ,machine learning ,functional zonation ,remote sensing ,Classical Physics ,Geomatic Engineering ,Atmospheric sciences ,Physical geography and environmental geoscience ,Geomatic engineering - Abstract
Ecosystems at coastal terrestrial–aquatic interfaces play a significant role in global biogeo-chemical cycles. In this study, we aimed to characterize coastal wetlands with particular focus on the co-variability between plant dynamics, topography, soil, and other environmental factors. We proposed a functional zonation approach based on machine learning clustering to identify the spatial regions, i.e., zones that capture these co-varied properties. This approach was applied to publicly available datasets along Lake Erie, in the Great Lakes Region. We investigated the heterogeneity of coastal ecosystem structures as a function of along-shore distance and transverse distance, based on the spatial data layers, including topography, wetland vegetation cover, and the time series of Land-sat’s enhanced vegetation index (EVI) between 1990 and 2020. Results showed that the topographic metrics (elevation and slope), soil texture, and plant productivity influence the spatial distribution of wetland land-covers (emergent and phragmites). These results highlight a natural organization along the transverse axis, where the elevation and the EVI increase further away from the coastline. In addition, the clustering analysis allowed us to identify regions with distinct environmental characteristics, as well as the ones that are more sensitive to interannual lake-level variations.
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- 2022
12. Media access to the battlefield
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Brown, James B., Capt
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MASS MEDIA - Abstract
illus bibliog
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- 1992
13. General Practice Education: Context and Trends
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Wearne, Susan M., Brown, James B., Nestel, Debra, editor, Reedy, Gabriel, editor, McKenna, Lisa, editor, and Gough, Suzanne, editor
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- 2023
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14. A novel random forest approach to revealing interactions and controls on chlorophyll concentration and bacterial communities during coastal phytoplankton blooms.
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Cheng, Yiwei, Bhoot, Ved N, Kumbier, Karl, Sison-Mangus, Marilou P, Brown, James B, Kudela, Raphael, and Newcomer, Michelle E
- Abstract
Increasing occurrence of harmful algal blooms across the land-water interface poses significant risks to coastal ecosystem structure and human health. Defining significant drivers and their interactive impacts on blooms allows for more effective analysis and identification of specific conditions supporting phytoplankton growth. A novel iterative Random Forests (iRF) machine-learning model was developed and applied to two example cases along the California coast to identify key stable interactions: (1) phytoplankton abundance in response to various drivers due to coastal conditions and land-sea nutrient fluxes, (2) microbial community structure during algal blooms. In Example 1, watershed derived nutrients were identified as the least significant interacting variable associated with Monterey Bay phytoplankton abundance. In Example 2, through iRF analysis of field-based 16S OTU bacterial community and algae datasets, we independently found stable interactions of prokaryote abundance patterns associated with phytoplankton abundance that have been previously identified in laboratory-based studies. Our study represents the first iRF application to marine algal blooms that helps to identify ocean, microbial, and terrestrial conditions that are considered dominant causal factors on bloom dynamics.
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- 2021
15. An infrared spectral biomarker accurately predicts neurodegenerative disease class in the absence of overt symptoms.
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Lovergne, Lila, Ghosh, Dhruba, Schuck, Renaud, Polyzos, Aris A, Chen, Andrew D, Martin, Michael C, Barnard, Edward S, Brown, James B, and McMurray, Cynthia T
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Neurodegenerative ,Neurosciences - Abstract
Although some neurodegenerative diseases can be identified by behavioral characteristics relatively late in disease progression, we currently lack methods to predict who has developed disease before the onset of symptoms, when onset will occur, or the outcome of therapeutics. New biomarkers are needed. Here we describe spectral phenotyping, a new kind of biomarker that makes disease predictions based on chemical rather than biological endpoints in cells. Spectral phenotyping uses Fourier Transform Infrared (FTIR) spectromicroscopy to produce an absorbance signature as a rapid physiological indicator of disease state. FTIR spectromicroscopy has over the past been used in differential diagnoses of manifest disease. Here, we report that the unique FTIR chemical signature accurately predicts disease class in mouse with high probability in the absence of brain pathology. In human cells, the FTIR biomarker accurately predicts neurodegenerative disease class using fibroblasts as surrogate cells.
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- 2021
16. Molecular and functional characterization of the Drosophila melanogaster conserved smORFome
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Bosch, Justin A., Keith, Nathan, Escobedo, Felipe, Fisher, William W., LaGraff, James Thai, Rabasco, Jorden, Wan, Kenneth H., Weiszmann, Richard, Wu, Yulun, Hu, Yanhui, Kondo, Shu, Brown, James B., Perrimon, Norbert, and Celniker, Susan E.
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- 2023
- Full Text
- View/download PDF
17. Selective time-dependent changes in activity and cell-specific gene expression in human postmortem brain.
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Dachet, Fabien, Brown, James B, Valyi-Nagy, Tibor, Narayan, Kunwar D, Serafini, Anna, Boley, Nathan, Gingeras, Thomas R, Celniker, Susan E, Mohapatra, Gayatry, and Loeb, Jeffrey A
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As a means to understand human neuropsychiatric disorders from human brain samples, we compared the transcription patterns and histological features of postmortem brain to fresh human neocortex isolated immediately following surgical removal. Compared to a number of neuropsychiatric disease-associated postmortem transcriptomes, the fresh human brain transcriptome had an entirely unique transcriptional pattern. To understand this difference, we measured genome-wide transcription as a function of time after fresh tissue removal to mimic the postmortem interval. Within a few hours, a selective reduction in the number of neuronal activity-dependent transcripts occurred with relative preservation of housekeeping genes commonly used as a reference for RNA normalization. Gene clustering indicated a rapid reduction in neuronal gene expression with a reciprocal time-dependent increase in astroglial and microglial gene expression that continued to increase for at least 24 h after tissue resection. Predicted transcriptional changes were confirmed histologically on the same tissue demonstrating that while neurons were degenerating, glial cells underwent an outgrowth of their processes. The rapid loss of neuronal genes and reciprocal expression of glial genes highlights highly dynamic transcriptional and cellular changes that occur during the postmortem interval. Understanding these time-dependent changes in gene expression in post mortem brain samples is critical for the interpretation of research studies on human brain disorders.
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- 2021
18. An integrated host-microbiome response to atrazine exposure mediates toxicity in Drosophila
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Brown, James B, Langley, Sasha A, Snijders, Antoine M, Wan, Kenneth H, Morris, Siti Nur Sarah, Booth, Benjamin W, Fisher, William W, Hammonds, Ann S, Park, Soo, Weiszmann, Richard, Yu, Charles, Kirwan, Jennifer A, Weber, Ralf JM, Viant, Mark R, Mao, Jian-Hua, and Celniker, Susan E
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Microbiology ,Biological Sciences ,Biomedical and Clinical Sciences ,Medical Biochemistry and Metabolomics ,Genetics ,Microbiome ,Human Genome ,Prevention ,Nutrition ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Aetiology ,Acetobacter ,Animals ,Atrazine ,Drosophila melanogaster ,Female ,Gastrointestinal Microbiome ,Host Microbial Interactions ,Inactivation ,Metabolic ,Insecticides ,Male ,Biological sciences ,Biomedical and clinical sciences - Abstract
The gut microbiome produces vitamins, nutrients, and neurotransmitters, and helps to modulate the host immune system-and also plays a major role in the metabolism of many exogenous compounds, including drugs and chemical toxicants. However, the extent to which specific microbial species or communities modulate hazard upon exposure to chemicals remains largely opaque. Focusing on the effects of collateral dietary exposure to the widely used herbicide atrazine, we applied integrated omics and phenotypic screening to assess the role of the gut microbiome in modulating host resilience in Drosophila melanogaster. Transcriptional and metabolic responses to these compounds are sex-specific and depend strongly on the presence of the commensal microbiome. Sequencing the genomes of all abundant microbes in the fly gut revealed an enzymatic pathway responsible for atrazine detoxification unique to Acetobacter tropicalis. We find that Acetobacter tropicalis alone, in gnotobiotic animals, is sufficient to rescue increased atrazine toxicity to wild-type, conventionally reared levels. This work points toward the derivation of biotic strategies to improve host resilience to environmental chemical exposures, and illustrates the power of integrative omics to identify pathways responsible for adverse health outcomes.
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- 2021
19. Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models.
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Garvin, Michael R, T Prates, Erica, Pavicic, Mirko, Jones, Piet, Amos, B Kirtley, Geiger, Armin, Shah, Manesh B, Streich, Jared, Felipe Machado Gazolla, Joao Gabriel, Kainer, David, Cliff, Ashley, Romero, Jonathon, Keith, Nathan, Brown, James B, and Jacobson, Daniel
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Viral Proteins ,Adaptation ,Biological ,Evolution ,Molecular ,Haplotypes ,Mutation ,Genome ,Viral ,Models ,Genetic ,Artificial Intelligence ,Selection ,Genetic ,SARS-CoV-2 ,Adaptive mutation ,COVID-19 ,Coronavirus ,Local adaptation ,Molecular evolution ,Infectious Diseases ,Prevention ,Lung ,Emerging Infectious Diseases ,Biodefense ,Genetics ,Vaccine Related ,2.2 Factors relating to the physical environment ,Infection ,Bioinformatics ,Environmental Sciences ,Biological Sciences ,Information and Computing Sciences - Abstract
BackgroundA mechanistic understanding of the spread of SARS-CoV-2 and diligent tracking of ongoing mutagenesis are of key importance to plan robust strategies for confining its transmission. Large numbers of available sequences and their dates of transmission provide an unprecedented opportunity to analyze evolutionary adaptation in novel ways. Addition of high-resolution structural information can reveal the functional basis of these processes at the molecular level. Integrated systems biology-directed analyses of these data layers afford valuable insights to build a global understanding of the COVID-19 pandemic.ResultsHere we identify globally distributed haplotypes from 15,789 SARS-CoV-2 genomes and model their success based on their duration, dispersal, and frequency in the host population. Our models identify mutations that are likely compensatory adaptive changes that allowed for rapid expansion of the virus. Functional predictions from structural analyses indicate that, contrary to previous reports, the Asp614Gly mutation in the spike glycoprotein (S) likely reduced transmission and the subsequent Pro323Leu mutation in the RNA-dependent RNA polymerase led to the precipitous spread of the virus. Our model also suggests that two mutations in the nsp13 helicase allowed for the adaptation of the virus to the Pacific Northwest of the USA. Finally, our explainable artificial intelligence algorithm identified a mutational hotspot in the sequence of S that also displays a signature of positive selection and may have implications for tissue or cell-specific expression of the virus.ConclusionsThese results provide valuable insights for the development of drugs and surveillance strategies to combat the current and future pandemics.
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- 2020
20. Roundup causes embryonic development failure and alters metabolic pathways and gut microbiota functionality in non-target species.
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Suppa, Antonio, Kvist, Jouni, Li, Xiaojing, Dhandapani, Vignesh, Almulla, Hanan, Tian, Antoine Y, Kissane, Stephen, Zhou, Jiarui, Perotti, Alessio, Mangelson, Hayley, Langford, Kyle, Rossi, Valeria, Brown, James B, and Orsini, Luisa
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Animals ,Daphnia ,Glycine ,Embryonic Development ,Metabolic Networks and Pathways ,Gastrointestinal Microbiome ,Digestive Diseases ,Human Genome ,Genetics ,Oral and gastrointestinal ,Ecology ,Microbiology ,Medical Microbiology - Abstract
BackgroundResearch around the weedkiller Roundup is among the most contentious of the twenty-first century. Scientists have provided inconclusive evidence that the weedkiller causes cancer and other life-threatening diseases, while industry-paid research reports that the weedkiller has no adverse effect on humans or animals. Much of the controversial evidence on Roundup is rooted in the approach used to determine safe use of chemicals, defined by outdated toxicity tests. We apply a system biology approach to the biomedical and ecological model species Daphnia to quantify the impact of glyphosate and of its commercial formula, Roundup, on fitness, genome-wide transcription and gut microbiota, taking full advantage of clonal reproduction in Daphnia. We then apply machine learning-based statistical analysis to identify and prioritize correlations between genome-wide transcriptional and microbiota changes.ResultsWe demonstrate that chronic exposure to ecologically relevant concentrations of glyphosate and Roundup at the approved regulatory threshold for drinking water in the US induce embryonic developmental failure, induce significant DNA damage (genotoxicity), and interfere with signaling. Furthermore, chronic exposure to the weedkiller alters the gut microbiota functionality and composition interfering with carbon and fat metabolism, as well as homeostasis. Using the "Reactome," we identify conserved pathways across the Tree of Life, which are potential targets for Roundup in other species, including liver metabolism, inflammation pathways, and collagen degradation, responsible for the repair of wounds and tissue remodeling.ConclusionsOur results show that chronic exposure to concentrations of Roundup and glyphosate at the approved regulatory threshold for drinking water causes embryonic development failure and alteration of key metabolic functions via direct effect on the host molecular processes and indirect effect on the gut microbiota. The ecological model species Daphnia occupies a central position in the food web of aquatic ecosystems, being the preferred food of small vertebrates and invertebrates as well as a grazer of algae and bacteria. The impact of the weedkiller on this keystone species has cascading effects on aquatic food webs, affecting their ability to deliver critical ecosystem services. Video Abstract.
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- 2020
21. A comprehensive epigenomic analysis of phenotypically distinguishable, genetically identical female and male Daphnia pulex
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Kvist, Jouni, Athanàsio, Camila Gonçalves, Pfrender, Michael E, Brown, James B, Colbourne, John K, and Mirbahai, Leda
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Biological Sciences ,Genetics ,Human Genome ,Generic health relevance ,Animals ,DNA Methylation ,Daphnia ,Epigenesis ,Genetic ,Epigenomics ,Female ,Gene Expression ,Histones ,Lysine ,Male ,Methylation ,Phenotype ,Promoter Regions ,Genetic ,Sex Factors ,Epigenetics ,Evolution ,Gene expression ,Non-conventional model organisms ,Information and Computing Sciences ,Medical and Health Sciences ,Bioinformatics ,Biological sciences ,Biomedical and clinical sciences - Abstract
BackgroundDaphnia species reproduce by cyclic parthenogenesis involving both sexual and asexual reproduction. The sex of the offspring is environmentally determined and mediated via endocrine signalling by the mother. Interestingly, male and female Daphnia can be genetically identical, yet display large differences in behaviour, morphology, lifespan and metabolic activity. Our goal was to integrate multiple omics datasets, including gene expression, splicing, histone modification and DNA methylation data generated from genetically identical female and male Daphnia pulex under controlled laboratory settings with the aim of achieving a better understanding of the underlying epigenetic factors that may contribute to the phenotypic differences observed between the two genders.ResultsIn this study we demonstrate that gene expression level is positively correlated with increased DNA methylation, and histone H3 trimethylation at lysine 4 (H3K4me3) at predicted promoter regions. Conversely, elevated histone H3 trimethylation at lysine 27 (H3K27me3), distributed across the entire transcript length, is negatively correlated with gene expression level. Interestingly, male Daphnia are dominated with epigenetic modifications that globally promote elevated gene expression, while female Daphnia are dominated with epigenetic modifications that reduce gene expression globally. For examples, CpG methylation (positively correlated with gene expression level) is significantly higher in almost all differentially methylated sites in male compared to female Daphnia. Furthermore, H3K4me3 modifications are higher in male compared to female Daphnia in more than 3/4 of the differentially regulated promoters. On the other hand, H3K27me3 is higher in female compared to male Daphnia in more than 5/6 of differentially modified sites. However, both sexes demonstrate roughly equal number of genes that are up-regulated in one gender compared to the other sex. Since, gene expression analyses typically assume that most genes are expressed at equal level among samples and different conditions, and thus cannot detect global changes affecting most genes.ConclusionsThe epigenetic differences between male and female in Daphnia pulex are vast and dominated by changes that promote elevated gene expression in male Daphnia. Furthermore, the differences observed in both gene expression changes and epigenetic modifications between the genders relate to pathways that are physiologically relevant to the observed phenotypic differences.
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- 2020
22. Sparse Canonical Correlation Analysis via Concave Minimization
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Solari, Omid S., Brown, James B., and Bickel, Peter J.
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Statistics - Machine Learning ,Computer Science - Machine Learning - Abstract
A new approach to the sparse Canonical Correlation Analysis (sCCA)is proposed with the aim of discovering interpretable associations in very high-dimensional multi-view, i.e.observations of multiple sets of variables on the same subjects, problems. Inspired by the sparse PCA approach of Journee et al. (2010), we also show that the sparse CCA formulation, while non-convex, is equivalent to a maximization program of a convex objective over a compact set for which we propose a first-order gradient method. This result helps us reduce the search space drastically to the boundaries of the set. Consequently, we propose a two-step algorithm, where we first infer the sparsity pattern of the canonical directions using our fast algorithm, then we shrink each view, i.e. observations of a set of covariates, to contain observations on the sets of covariates selected in the previous step, and compute their canonical directions via any CCA algorithm. We also introduceDirected Sparse CCA, which is able to find associations which are aligned with a specified experiment design, andMulti-View sCCA which is used to discover associations between multiple sets of covariates. Our simulations establish the superior convergence properties and computational efficiency of our algorithm as well as accuracy in terms of the canonical correlation and its ability to recover the supports of the canonical directions. We study the associations between metabolomics, trasncriptomics and microbiomics in a multi-omic study usingMuLe, which is an R-package that implements our approach, in order to form hypotheses on mechanisms of adaptations of Drosophila Melanogaster to high doses of environmental toxicants, specifically Atrazine, which is a commonly used chemical fertilizer., Comment: 45 Pages
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- 2019
23. BLOCCS: Block Sparse Canonical Correlation Analysis With Application To Interpretable Omics Integration
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Solari, Omid Shams, Safavi, Rojin, and Brown, James B.
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Statistics - Machine Learning ,Computer Science - Machine Learning - Abstract
We introduce Block Sparse Canonical Correlation Analysis which estimates multiple pairs of canonical directions (together a "block") at once, resulting in significantly improved orthogonality of the sparse directions which, we demonstrate, translates to more interpretable solutions. Our approach builds on the sparse CCA method of (Solari, Brown, and Bickel 2019) in that we also express the bi-convex objective of our block formulation as a concave minimization problem over an orthogonal k-frame in a unit Euclidean ball, which in turn, due to concavity of the objective, is shrunk to a Stiefel manifold, which is optimized via gradient descent algorithm. Our simulations show that our method outperforms existing sCCA algorithms and implementations in terms of computational cost and stability, mainly due to the drastic shrinkage of our search space, and the correlation within and orthogonality between pairs of estimated canonical covariates. Finally, we apply our method, available as an R-package called BLOCCS, to multi-omic data on Lung Squamous Cell Carcinoma(LUSC) obtained via The Cancer Genome Atlas, and demonstrate its capability in capturing meaningful biological associations relevant to the hypothesis under study rather than spurious dominant variations., Comment: 8 pages
- Published
- 2019
24. Sequential Imputation of Missing Spatio-Temporal Precipitation Data Using Random Forests
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Mital, Utkarsh, Dwivedi, Dipankar, Brown, James B, Faybishenko, Boris, Painter, Scott L, and Steefel, Carl I
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- 2020
25. *-DCC: A platform to collect, annotate, and explore a large variety of sequencing experiments.
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Hörtenhuber, Matthias, Mukarram, Abdul K, Stoiber, Marcus H, Brown, James B, and Daub, Carsten O
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Sequence Analysis ,Software ,Molecular Sequence Annotation ,databases ,sample annotation ,sequencing data annotation ,sequencing experiments ,Generic health relevance - Abstract
BackgroundOver the past few years the variety of experimental designs and protocols for sequencing experiments increased greatly. To ensure the wide usability of the produced data beyond an individual project, rich and systematic annotation of the underlying experiments is crucial.FindingsWe first developed an annotation structure that captures the overall experimental design as well as the relevant details of the steps from the biological sample to the library preparation, the sequencing procedure, and the sequencing and processed files. Through various design features, such as controlled vocabularies and different field requirements, we ensured a high annotation quality, comparability, and ease of annotation. The structure can be easily adapted to a large variety of species. We then implemented the annotation strategy in a user-hosted web platform with data import, query, and export functionality.ConclusionsWe present here an annotation structure and user-hosted platform for sequencing experiment data, suitable for lab-internal documentation, collaborations, and large-scale annotation efforts.
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- 2020
26. Can exascale computing and explainable artificial intelligence applied to plant biology deliver on the United Nations sustainable development goals?
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Streich, Jared, Romero, Jonathon, Gazolla, João Gabriel Felipe Machado, Kainer, David, Cliff, Ashley, Prates, Erica Teixeira, Brown, James B, Khoury, Sacha, Tuskan, Gerald A, Garvin, Michael, Jacobson, Daniel, and Harfouche, Antoine L
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Humans ,Goals ,Agriculture ,Artificial Intelligence ,United Nations ,Sustainable Development ,Biological Sciences ,Engineering ,Technology ,Biotechnology - Abstract
Human population growth and accelerated climate change necessitate agricultural improvements using designer crop ideotypes (idealized plants that can grow in niche environments). Diverse and highly skilled research groups must integrate efforts to bridge the gaps needed to achieve international goals toward sustainable agriculture. Given the scale of global agricultural needs and the breadth of multiple types of omics data needed to optimize these efforts, explainable artificial intelligence (AI with a decipherable decision making process that provides a meaningful explanation to humans) and exascale computing (computers that can perform 1018 floating-point operations per second, or exaflops) are crucial. Accurate phenotyping and daily-resolution climatype associations are equally important for refining ideotype production to specific environments at various levels of granularity. We review advances toward tackling technological hurdles to solve multiple United Nations Sustainable Development Goals and discuss a vision to overcome gaps between research and policy.
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- 2020
27. Vision of a near future: Bridging the human health–environment divide. Toward an integrated strategy to understand mechanisms across species for chemical safety assessment
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Rivetti, Claudia, Allen, Timothy EH, Brown, James B, Butler, Emma, Carmichael, Paul L, Colbourne, John K, Dent, Matthew, Falciani, Francesco, Gunnarsson, Lina, Gutsell, Steve, Harrill, Joshua A, Hodges, Geoff, Jennings, Paul, Judson, Richard, Kienzler, Aude, Margiotta-Casaluci, Luigi, Muller, Iris, Owen, Stewart F, Rendal, Cecilie, Russell, Paul J, Scott, Sharon, Sewell, Fiona, Shah, Imran, Sorrel, Ian, Viant, Mark R, Westmoreland, Carl, White, Andrew, and Campos, Bruno
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Generic health relevance ,Animals ,Chemical Safety ,Environment ,Environmental Health ,Humans ,Risk Assessment ,Species Specificity ,Toxicology ,Risk assessment ,Human health ,Cross-species extrapolation ,Mechanism of action ,Pharmacology and pharmaceutical sciences - Abstract
There is a growing recognition that application of mechanistic approaches to understand cross-species shared molecular targets and pathway conservation in the context of hazard characterization, provide significant opportunities in risk assessment (RA) for both human health and environmental safety. Specifically, it has been recognized that a more comprehensive and reliable understanding of similarities and differences in biological pathways across a variety of species will better enable cross-species extrapolation of potential adverse toxicological effects. Ultimately, this would also advance the generation and use of mechanistic data for both human health and environmental RA. A workshop brought together representatives from industry, academia and government to discuss how to improve the use of existing data, and to generate new NAMs data to derive better mechanistic understanding between humans and environmentally-relevant species, ultimately resulting in holistic chemical safety decisions. Thanks to a thorough dialogue among all participants, key challenges, current gaps and research needs were identified, and potential solutions proposed. This discussion highlighted the common objective to progress toward more predictive, mechanistically based, data-driven and animal-free chemical safety assessments. Overall, the participants recognized that there is no single approach which would provide all the answers for bridging the gap between mechanism-based human health and environmental RA, but acknowledged we now have the incentive, tools and data availability to address this concept, maximizing the potential for improvements in both human health and environmental RA.
- Published
- 2020
28. Iron Supplementation Eliminates Antagonistic Interactions Between Root-Associated Bacteria.
- Author
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Eng, Thomas, Herbert, Robin A, Martinez, Uriel, Wang, Brenda, Chen, Joseph C, Brown, James B, Deutschbauer, Adam M, Bissell, Mina J, Mortimer, Jenny C, and Mukhopadhyay, Aindrila
- Subjects
Acinetobacter ,Pseudomonas putida ,RB-TnSeq ,composition and function ,iron depletion ,microbe-macroorganism interaction ,rhizobiota ,Environmental Science and Management ,Soil Sciences ,Microbiology - Abstract
The rhizosphere microbiome (rhizobiome) plays a critical role in plant health and development. However, the processes by which the constituent microbes interact to form and maintain a community are not well understood. To investigate these molecular processes, we examined pairwise interactions between 11 different microbial isolates under select nutrient-rich and nutrient-limited conditions. We observed that when grown with media supplemented with 56 mM glucose, two microbial isolates were able to inhibit the growth of six other microbes. The interaction between microbes persisted even after the antagonistic microbe was removed, upon exposure to spent media. To probe the genetic basis for these antagonistic interactions, we used a barcoded transposon library in a proxy bacterium, Pseudomonas putida, to identify genes which showed enhanced sensitivity to the antagonistic factor(s) secreted by Acinetobacter sp. 02. Iron metabolism-related gene clusters in P. putida were implicated by this systems-level analysis. The supplementation of iron prevented the antagonistic interaction in the original microbial pair, supporting the hypothesis that iron limitation drives antagonistic microbial interactions between rhizobionts. We conclude that rhizobiome community composition is influenced by competition for limiting nutrients, with implications for growth and development of the plant.
- Published
- 2020
29. Reagent-free Hyperspectral Diagnosis of SARS-CoV-2 Infection in saliva samples
- Author
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Saint-John, Brandon, primary, Wolf-Yadlin, Alejandro, additional, Jacobsen, Daniel E., additional, Inman, Jamie L., additional, Gart, Serge, additional, Keener, Matt, additional, McMurray, Cynthia, additional, Snijders, Antoine M., additional, Mukundan, Harshini, additional, Kubicek-Sutherland, Jessica Z., additional, and Brown, James B., additional
- Published
- 2024
- Full Text
- View/download PDF
30. Signed iterative random forests to identify enhancer-associated transcription factor binding
- Author
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Kumbier, Karl, Basu, Sumanta, Frise, Erwin, Celniker, Susan E., Brown, James B., Celniker, Susan, and Yu, Bin
- Subjects
Statistics - Machine Learning ,Computer Science - Machine Learning - Abstract
Standard ChIP-seq peak calling pipelines seek to differentiate biochemically reproducible signals of individual genomic elements from background noise. However, reproducibility alone does not imply functional regulation (e.g., enhancer activation, alternative splicing). Here we present a general-purpose, interpretable machine learning method: signed iterative random forests (siRF), which we use to infer regulatory interactions among transcription factors and functional binding signatures surrounding enhancer elements in Drosophila melanogaster.
- Published
- 2018
31. Complete Genome Sequence of Agrobacterium sp. Strain 33MFTa1.1, Isolated from Thlaspi arvense Roots
- Author
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Langley, Sasha, Eng, Thomas, Wan, Kenneth H, Herbert, Robin A, Klein, Andrew P, Yoshikuni, Yasuo, Tringe, Susannah G, Brown, James B, Celniker, Susan E, Mortimer, Jenny C, and Mukhopadhyay, Aindrila
- Subjects
Microbiology ,Biological Sciences ,Genetics ,Human Genome - Abstract
Agrobacterium sp. strain 33MFTa1.1 was isolated for functional host-microbe interaction studies from the Thlaspi arvense root-associated microbiome. The complete genome is comprised of a circular chromosome of 2,771,937 bp, a linear chromosome of 2,068,443 bp, and a plasmid of 496,948 bp, with G+C contents of 59%, 59%, and 58%, respectively.
- Published
- 2019
32. Rhizobacteria Mediate the Phytotoxicity of a Range of Biorefinery‐Relevant Compounds
- Author
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Herbert, Robin A, Eng, Thomas, Martinez, Uriel, Wang, Brenda, Langley, Sasha, Wan, Kenneth, Pidatala, Venkataramana, Hoffman, Elijah, Chen, Joseph C, Bissell, Mina J, Brown, James B, Mukhopadhyay, Aindrila, and Mortimer, Jenny C
- Subjects
Biological Sciences ,Industrial Biotechnology ,Climate Action ,Affordable and Clean Energy ,Responsible Consumption and Production ,Agriculture ,Arabidopsis ,Biofuels ,Biomass ,Ecotoxicology ,Plant Roots ,Rhizobium ,Soil Pollutants ,Sorghum ,Toxicology screening ,Microbiome ,Plants ,Ionic liquids ,Chemical Sciences ,Environmental Sciences ,Biological sciences ,Chemical sciences ,Environmental sciences - Abstract
Advances in engineering biology have expanded the list of renewable compounds that can be produced at scale via biological routes from plant biomass. In most cases, these chemical products have not been evaluated for effects on biological systems, defined in the present study as bioactivity, that may be relevant to their manufacture. For sustainable chemical and fuel production, the industry needs to transition from fossil to renewable carbon sources, resulting in unprecedented expansion in the production and environmental distribution of chemicals used in biomanufacturing. Further, although some chemicals have been assessed for mammalian toxicity, environmental and agricultural hazards are largely unknown. We assessed 6 compounds that are representative of the emerging biofuel and bioproduct manufacturing process for their effect on model plants (Arabidopsis thaliana, Sorghum bicolor) and show that several alter plant seedling physiology at submillimolar concentrations. However, these responses change in the presence of individual bacterial species from the A. thaliana root microbiome. We identified 2 individual microbes that change the effect of chemical treatment on root architecture and a pooled microbial community with different effects relative to its constituents individually. The present study indicates that screening industrial chemicals for bioactivity on model organisms in the presence of their microbiomes is important for biologically and ecologically relevant risk analyses. Environ Toxicol Chem 2019;38:1911-1922. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
- Published
- 2019
33. EcoFABs: advancing microbiome science through standardized fabricated ecosystems
- Author
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Zengler, Karsten, Hofmockel, Kirsten, Baliga, Nitin S, Behie, Scott W, Bernstein, Hans C, Brown, James B, Dinneny, José R, Floge, Sheri A, Forry, Samuel P, Hess, Matthias, Jackson, Scott A, Jansson, Christer, Lindemann, Stephen R, Pett-Ridge, Jennifer, Maranas, Costas, Venturelli, Ophelia S, Wallenstein, Matthew D, Shank, Elizabeth A, and Northen, Trent R
- Subjects
Microbiology ,Biological Sciences ,Genetics ,Human Genome ,Animals ,Ecosystem ,Host Microbial Interactions ,Humans ,Microbiota ,Reproducibility of Results ,Technology ,Medical and Health Sciences ,Developmental Biology ,Biological sciences - Abstract
Microbiomes play critical roles in ecosystems and human health, yet in most cases scientists lack standardized and reproducible model microbial communities. The development of fabricated microbial ecosystems, which we term EcoFABs, will provide such model systems for microbiome studies.
- Published
- 2019
34. Exploiting regulatory heterogeneity to systematically identify enhancers with high accuracy
- Author
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Arbel, Hamutal, Basu, Sumanta, Fisher, William W, Hammonds, Ann S, Wan, Kenneth H, Park, Soo, Weiszmann, Richard, Booth, Benjamin W, Keranen, Soile V, Henriquez, Clara, Shams Solari, Omid, Bickel, Peter J, Biggin, Mark D, Celniker, Susan E, and Brown, James B
- Subjects
Biological Sciences ,Genetics ,Human Genome ,1.1 Normal biological development and functioning ,Generic health relevance ,Animals ,Drosophila Proteins ,Drosophila melanogaster ,Embryo ,Nonmammalian ,Embryonic Development ,Enhancer Elements ,Genetic ,Genome-Wide Association Study ,Sequence Analysis ,DNA ,Transcription Factors ,enhancers ,embryo development ,machine learning ,random forests ,Drosophila - Abstract
Identifying functional enhancer elements in metazoan systems is a major challenge. Large-scale validation of enhancers predicted by ENCODE reveal false-positive rates of at least 70%. We used the pregrastrula-patterning network of Drosophila melanogaster to demonstrate that loss in accuracy in held-out data results from heterogeneity of functional signatures in enhancer elements. We show that at least two classes of enhancers are active during early Drosophila embryogenesis and that by focusing on a single, relatively homogeneous class of elements, greater than 98% prediction accuracy can be achieved in a balanced, completely held-out test set. The class of well-predicted elements is composed predominantly of enhancers driving multistage segmentation patterns, which we designate segmentation driving enhancers (SDE). Prediction is driven by the DNA occupancy of early developmental transcription factors, with almost no additional power derived from histone modifications. We further show that improved accuracy is not a property of a particular prediction method: after conditioning on the SDE set, naïve Bayes and logistic regression perform as well as more sophisticated tools. Applying this method to a genome-wide scan, we predict 1,640 SDEs that cover 1.6% of the genome. An analysis of 32 SDEs using whole-mount embryonic imaging of stably integrated reporter constructs chosen throughout our prediction rank-list showed >90% drove expression patterns. We achieved 86.7% precision on a genome-wide scan, with an estimated recall of at least 98%, indicating high accuracy and completeness in annotating this class of functional elements.
- Published
- 2019
35. Review of and Recommendations for Monitoring Contaminants and their Effects in the San Francisco Bay−Delta
- Author
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Connon, Richard E., Hasenbein, Simone, Brander, Susanne M., Poynton, Helen C., Holland, Erika B., Schlenk, Daniel, Orlando, James L., Hladik, Michelle L., Collier, Tracy K., Scholz, Nathaniel L., Incardona, John P., Denslow, Nancy D., Hamdoun, Amro, Nicklisch, Sascha C. E., Garcia–Reyero, Natàlia, Perkins, Edward J., Gallagher, Evan P., Deng, Xin, Wang, Dan, Fong, Stephanie, Breuer, Richard S., Hajibabaei, Mehrdad, Brown, James B., Colbourne, John K., Young, Thomas M., Cherr, Gary, Whitehead, Andrew, and Todgham, Anne E.
- Subjects
aquatic toxicology ,effect-based ,resistance ,pesticycle ,mixtures ,multiple stressors' omics ,metabarcoding - Abstract
Legacy and current-use contaminants enter into and accumulate throughout the San Francisco Bay−Delta (Bay−Delta), and are present at concentrations with known effects on species important to this diverse watershed. There remains major uncertainty and a lack of focused research able to address and provide understanding of effects across multiple biological scales, despite previous and ongoing emphasis on the need for it. These needs are challenging specifically because of the established regulatory programs that often monitor on a chemical-by-chemical basis, or in which decisions are grounded in lethality-based endpoints. To best address issues of contaminants in the Bay−Delta, monitoring efforts should consider effects of environmentally relevant mixtures and sub-lethal impacts that can affect ecosystem health. These efforts need to consider the complex environment in the Bay−Delta including variable abiotic (e.g., temperature, salinity) and biotic (e.g., pathogens) factors. This calls for controlled and focused research, and the development of a multi-disciplinary contaminant monitoring and assessment program that provides information across biological scales. Information gained in this manner will contribute toward evaluating parameters that could alleviate ecologically detrimental outcomes. This review is a result of a Special Symposium convened at the University of California−Davis (UCD) on January 31, 2017 to address critical information needed on how contaminants affect the Bay−Delta. The UCD Symposium focused on new tools and approaches for assessing multiple stressor effects to freshwater and estuarine systems. Our approach is similar to the recently proposed framework laid out by the U.S. Environmental Protection Agency (USEPA) that uses weight of evidence to scale toxicological responses to chemical contaminants in a laboratory, and to guide the conservation of priority species and habitats. As such, we also aimed to recommend multiple endpoints that could be used to promote a multi-disciplinary understanding of contaminant risks in Bay−Delta while supporting management needs.
- Published
- 2019
36. The Time Machine framework: monitoring and prediction of biodiversity loss
- Author
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Eastwood, Niamh, Stubbings, William A., Abou-Elwafa Abdallah, Mohamed A., Durance, Isabelle, Paavola, Jouni, Dallimer, Martin, Pantel, Jelena H., Johnson, Samuel, Zhou, Jiarui, Hosking, J. Scott, Brown, James B., Ullah, Sami, Krause, Stephan, Hannah, David M., Crawford, Sarah E., Widmann, Martin, and Orsini, Luisa
- Published
- 2022
- Full Text
- View/download PDF
37. Iterative Random Forests to detect predictive and stable high-order interactions
- Author
-
Basu, Sumanta, Kumbier, Karl, Brown, James B., and Yu, Bin
- Subjects
Statistics - Machine Learning ,Quantitative Biology - Genomics - Abstract
Genomics has revolutionized biology, enabling the interrogation of whole transcriptomes, genome-wide binding sites for proteins, and many other molecular processes. However, individual genomic assays measure elements that interact in vivo as components of larger molecular machines. Understanding how these high-order interactions drive gene expression presents a substantial statistical challenge. Building on Random Forests (RF), Random Intersection Trees (RITs), and through extensive, biologically inspired simulations, we developed the iterative Random Forest algorithm (iRF). iRF trains a feature-weighted ensemble of decision trees to detect stable, high-order interactions with same order of computational cost as RF. We demonstrate the utility of iRF for high-order interaction discovery in two prediction problems: enhancer activity in the early Drosophila embryo and alternative splicing of primary transcripts in human derived cell lines. In Drosophila, among the 20 pairwise transcription factor interactions iRF identifies as stable (returned in more than half of bootstrap replicates), 80% have been previously reported as physical interactions. Moreover, novel third-order interactions, e.g. between Zelda (Zld), Giant (Gt), and Twist (Twi), suggest high-order relationships that are candidates for follow-up experiments. In human-derived cells, iRF re-discovered a central role of H3K36me3 in chromatin-mediated splicing regulation, and identified novel 5th and 6th order interactions, indicative of multi-valent nucleosomes with specific roles in splicing regulation. By decoupling the order of interactions from the computational cost of identification, iRF opens new avenues of inquiry into the molecular mechanisms underlying genome biology.
- Published
- 2017
- Full Text
- View/download PDF
38. An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys
- Author
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Parra, Marilyn, Booth, Ben W, Weiszmann, Richard, Yee, Brian, Yeo, Gene W, Brown, James B, Celniker, Susan E, and Conboy, John G
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Human Genome ,1.1 Normal biological development and functioning ,Underpinning research ,Alternative Splicing ,Cell Differentiation ,Cells ,Cultured ,Erythroblasts ,Exons ,Humans ,Introns ,Nonsense Mediated mRNA Decay ,Protein Isoforms ,RNA Splice Sites ,RNA Splicing Factors ,Sequence Analysis ,RNA ,Splicing Factor U2AF ,SF3B1 ,alternative splicing ,intron retention ,Biochemistry and Cell Biology ,Developmental Biology ,Biochemistry and cell biology - Abstract
During terminal erythropoiesis, the splicing machinery in differentiating erythroblasts executes a robust intron retention (IR) program that impacts expression of hundreds of genes. We studied IR mechanisms in the SF3B1 splicing factor gene, which expresses ∼50% of its transcripts in late erythroblasts as a nuclear isoform that retains intron 4. RNA-seq analysis of nonsense-mediated decay (NMD)-inhibited cells revealed previously undescribed splice junctions, rare or not detected in normal cells, that connect constitutive exons 4 and 5 to highly conserved cryptic cassette exons within the intron. Minigene splicing reporter assays showed that these cassettes promote IR. Genome-wide analysis of splice junction reads demonstrated that cryptic noncoding cassettes are much more common in large (>1 kb) retained introns than they are in small retained introns or in nonretained introns. Functional assays showed that heterologous cassettes can promote retention of intron 4 in the SF3B1 splicing reporter. Although many of these cryptic exons were spliced inefficiently, they exhibited substantial binding of U2AF1 and U2AF2 adjacent to their splice acceptor sites. We propose that these exons function as decoys that engage the intron-terminal splice sites, thereby blocking cross-intron interactions required for excision. Developmental regulation of decoy function underlies a major component of the erythroblast IR program.
- Published
- 2018
39. Pattern of DNA methylation in Daphnia: Evolutionary perspective
- Author
-
Kvist, Jouni, Athanàsio, Camila Gonçalves, Solari, Omid Shams, Brown, James B, Colbourne, John K, Pfrender, Michael E, and Mirbahai, Leda
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Human Genome ,Generic health relevance ,Animals ,CpG Islands ,DNA Methylation ,Daphnia ,Evolution ,Molecular ,Gene Expression Regulation ,Genetic Variation ,Genotype ,Phylogeny ,Species Specificity ,epigenetics ,gene expression ,evolution ,non-conventional models ,Biochemistry and Cell Biology ,Evolutionary Biology ,Developmental Biology ,Biochemistry and cell biology ,Evolutionary biology - Abstract
DNA methylation is an evolutionary ancient epigenetic modification that is phylogenetically widespread. Comparative studies of the methylome across a diverse range of non-conventional and conventional model organisms is expected to help reveal how the landscape of DNA methylation and its functions have evolved. Here, we explore the DNA methylation profile of two species of the crustacean Daphnia using whole genome bisulfite sequencing. We then compare our data with the methylomes of two insects and two mammals to achieve a better understanding of the function of DNA methylation in Daphnia. Using RNA-sequencing data for all six species, we investigate the correlation between DNA methylation and gene expression. DNA methylation in Daphnia is mainly enriched within the coding regions of genes, with the highest methylation levels observed at exons 2-4. In contrast, vertebrate genomes are globally methylated, and increase towards the highest methylation levels observed at exon 2, and maintained across the rest of the gene body. Although DNA methylation patterns differ among all species, their methylation profiles share a bimodal distribution across the genomes. Genes with low levels of CpG methylation and gene expression are mainly enriched for species specific genes. In contrast, genes associated with high methylated CpG sites are highly transcribed and evolutionary conserved across all species. Finally, the positive correlation between internal exons and gene expression potentially points to an evolutionary conserved mechanism, whereas the negative regulation of gene expression via methylation of promoters and exon 1 is potentially a secondary mechanism that has been evolved in vertebrates.
- Published
- 2018
40. Iterative random forests to discover predictive and stable high-order interactions
- Author
-
Basu, Sumanta, Kumbier, Karl, Brown, James B, and Yu, Bin
- Subjects
Human Genome ,Genetics ,Biotechnology ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Algorithms ,Alternative Splicing ,Animals ,Computational Biology ,Drosophila ,Gene Expression Regulation ,Developmental ,Gene Regulatory Networks ,Genome-Wide Association Study ,Models ,Genetic ,high-order interaction ,random forests ,stability ,interpretable machine learning ,genomics - Abstract
Genomics has revolutionized biology, enabling the interrogation of whole transcriptomes, genome-wide binding sites for proteins, and many other molecular processes. However, individual genomic assays measure elements that interact in vivo as components of larger molecular machines. Understanding how these high-order interactions drive gene expression presents a substantial statistical challenge. Building on random forests (RFs) and random intersection trees (RITs) and through extensive, biologically inspired simulations, we developed the iterative random forest algorithm (iRF). iRF trains a feature-weighted ensemble of decision trees to detect stable, high-order interactions with the same order of computational cost as the RF. We demonstrate the utility of iRF for high-order interaction discovery in two prediction problems: enhancer activity in the early Drosophila embryo and alternative splicing of primary transcripts in human-derived cell lines. In Drosophila, among the 20 pairwise transcription factor interactions iRF identifies as stable (returned in more than half of bootstrap replicates), 80% have been previously reported as physical interactions. Moreover, third-order interactions, e.g., between Zelda (Zld), Giant (Gt), and Twist (Twi), suggest high-order relationships that are candidates for follow-up experiments. In human-derived cells, iRF rediscovered a central role of H3K36me3 in chromatin-mediated splicing regulation and identified interesting fifth- and sixth-order interactions, indicative of multivalent nucleosomes with specific roles in splicing regulation. By decoupling the order of interactions from the computational cost of identification, iRF opens additional avenues of inquiry into the molecular mechanisms underlying genome biology.
- Published
- 2018
41. Early transcriptional response pathways in Daphnia magna are coordinated in networks of crustacean‐specific genes
- Author
-
Orsini, Luisa, Brown, James B, Solari, Omid Shams, Li, Dong, He, Shan, Podicheti, Ram, Stoiber, Marcus H, Spanier, Katina I, Gilbert, Donald, Jansen, Mieke, Rusch, Douglas B, Pfrender, Michael E, Colbourne, John K, Frilander, Mikko J, Kvist, Jouni, Decaestecker, Ellen, De Schamphelaere, Karel AC, and De Meester, Luc
- Subjects
Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Underpinning research ,1.1 Normal biological development and functioning ,Animals ,Conserved Sequence ,Daphnia ,Gene Expression Regulation ,Gene Regulatory Networks ,Genome ,Genotype ,Multigene Family ,Transcription ,Genetic ,abiotic stressors ,biotic stressors ,differential co-expression networks ,differential gene expression ,ecological gene annotation ,ecoresponsive genes ,waterflea ,Biological Sciences ,Evolutionary Biology - Abstract
Natural habitats are exposed to an increasing number of environmental stressors that cause important ecological consequences. However, the multifarious nature of environmental change, the strength and the relative timing of each stressor largely limit our understanding of biological responses to environmental change. In particular, early response to unpredictable environmental change, critical to survival and fitness in later life stages, is largely uncharacterized. Here, we characterize the early transcriptional response of the keystone species Daphnia magna to twelve environmental perturbations, including biotic and abiotic stressors. We first perform a differential expression analysis aimed at identifying differential regulation of individual genes in response to stress. This preliminary analysis revealed that a few individual genes were responsive to environmental perturbations and they were modulated in a stressor and genotype-specific manner. Given the limited number of differentially regulated genes, we were unable to identify pathways involved in stress response. Hence, to gain a better understanding of the genetic and functional foundation of tolerance to multiple environmental stressors, we leveraged the correlative nature of networks and performed a weighted gene co-expression network analysis. We discovered that approximately one-third of the Daphnia genes, enriched for metabolism, cell signalling and general stress response, drives transcriptional early response to environmental stress and it is shared among genetic backgrounds. This initial response is followed by a genotype- and/or condition-specific transcriptional response with a strong genotype-by-environment interaction. Intriguingly, genotype- and condition-specific transcriptional response is found in genes not conserved beyond crustaceans, suggesting niche-specific adaptation.
- Published
- 2018
42. Molecular and functional characterization of the Drosophila melanogaster conserved smORFome
- Author
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Bosch, Justin A., primary, Keith, Nathan, additional, Escobedo, Felipe, additional, Fisher, William W., additional, LaGraff, James Thai, additional, Rabasco, Jorden, additional, Wan, Kenneth H., additional, Weiszmann, Richard, additional, Wu, Yulun, additional, Hu, Yanhui, additional, Kondo, Shu, additional, Brown, James B., additional, Perrimon, Norbert, additional, and Celniker, Susan E., additional
- Published
- 2024
- Full Text
- View/download PDF
43. MODA: MOdule Differential Analysis for weighted gene co-expression network
- Author
-
Li, Dong, Brown, James B., Orsini, Luisa, Pan, Zhisong, Hu, Guyu, and He, Shan
- Subjects
Quantitative Biology - Quantitative Methods ,Quantitative Biology - Molecular Networks - Abstract
Gene co-expression network differential analysis is designed to help biologists understand gene expression patterns under different condition. By comparing different gene co-expression networks we may find conserved part as well as condition specific set of genes. Taking the network as a collection as modules, we use a sample-saving method to construct condition-specific gene co-expression network, and identify differentially expressed subnetworks as conserved or condition specific modules which may be associated with biological processes. We have implemented the method as an R package which establishes a pipeline from expression profile to biological explanations. The usefulness of the method is also demonstrated by synthetic data as well as Daphnia magna gene expression data under different environmental stresses.
- Published
- 2016
44. Age-related gene expression in luminal epithelial cells is driven by a microenvironment made from myoepithelial cells
- Author
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Miyano, Masaru, Sayaman, Rosalyn W, Stoiber, Marcus H, Lin, Chun-Han, Stampfer, Martha R, Brown, James B, and LaBarge, Mark A
- Subjects
Biological Sciences ,Genetics ,Aging ,Women's Health ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Aetiology ,Underpinning research ,Breast ,Cell Lineage ,Cellular Microenvironment ,Coculture Techniques ,Epithelial Cells ,Female ,Humans ,Phenotype ,Transcriptome ,mammary epithelia ,breast cancer ,aging ,microenvironment ,epigenetic ,Biochemistry and Cell Biology ,Physiology ,Oncology and Carcinogenesis ,Developmental Biology - Abstract
Luminal epithelial cells in the breast gradually alter gene and protein expression with age, appearing to lose lineage-specificity by acquiring myoepithelial-like characteristics. We hypothesize that the luminal lineage is particularly sensitive to microenvironment changes, and age-related microenvironment changes cause altered luminal cell phenotypes. To evaluate the effects of different microenvironments on the fidelity of epigenetically regulated luminal and myoepithelial gene expression, we generated a set of lineage-specific probes for genes that are controlled through DNA methylation. Culturing primary luminal cells under conditions that favor myoepithelial propogation led to their reprogramming at the level of gene methylation, and to a more myoepithelial-like expression profile. Primary luminal cells' lineage-specific gene expression could be maintained when they were cultured as bilayers with primary myoepithelial cells. Isogenic stromal fibroblast co-cultures were unable to maintain the luminal phenotype. Mixed-age luminal-myoepithelial bilayers revealed that luminal cells adopt transcription and methylation patterns consistent with the chronological age of the myoepithelial cells. We provide evidence that the luminal epithelial phenotype is exquisitely sensitive to microenvironment conditions, and that states of aging are cell non-autonomously communicated through microenvironment cues over at least one cell diameter.
- Published
- 2017
45. Daphnia magna transcriptome by RNA-Seq across 12 environmental stressors.
- Author
-
Orsini, Luisa, Gilbert, Donald, Podicheti, Ram, Jansen, Mieke, Brown, James B, Solari, Omid Shams, Spanier, Katina I, Colbourne, John K, Rusch, Douglas B, Decaestecker, Ellen, Asselman, Jana, De Schamphelaere, Karel AC, Ebert, Dieter, Haag, Christoph R, Kvist, Jouni, Laforsch, Christian, Petrusek, Adam, Beckerman, Andrew P, Little, Tom J, Chaturvedi, Anurag, Pfrender, Michael E, De Meester, Luc, and Frilander, Mikko J
- Published
- 2017
46. Influence of early life exposure, host genetics and diet on the mouse gut microbiome and metabolome
- Author
-
Snijders, Antoine M, Langley, Sasha A, Kim, Young-Mo, Brislawn, Colin J, Noecker, Cecilia, Zink, Erika M, Fansler, Sarah J, Casey, Cameron P, Miller, Darla R, Huang, Yurong, Karpen, Gary H, Celniker, Susan E, Brown, James B, Borenstein, Elhanan, Jansson, Janet K, Metz, Thomas O, and Mao, Jian-Hua
- Subjects
Microbiology ,Biological Sciences ,Human Genome ,Genetics ,Arthritis ,Vaccine Related ,Prevention ,Nutrition ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Oral and gastrointestinal ,Animals ,Diet ,Gastrointestinal Microbiome ,Gastrointestinal Tract ,Life History Traits ,Metabolome ,Mice ,Quantitative Trait Loci ,Medical Microbiology - Abstract
Although the gut microbiome plays important roles in host physiology, health and disease1, we lack understanding of the complex interplay between host genetics and early life environment on the microbial and metabolic composition of the gut. We used the genetically diverse Collaborative Cross mouse system2 to discover that early life history impacts the microbiome composition, whereas dietary changes have only a moderate effect. By contrast, the gut metabolome was shaped mostly by diet, with specific non-dietary metabolites explained by microbial metabolism. Quantitative trait analysis identified mouse genetic trait loci (QTL) that impact the abundances of specific microbes. Human orthologues of genes in the mouse QTL are implicated in gastrointestinal cancer. Additionally, genes located in mouse QTL for Lactobacillales abundance are implicated in arthritis, rheumatic disease and diabetes. Furthermore, Lactobacillales abundance was predictive of higher host T-helper cell counts, suggesting an important link between Lactobacillales and host adaptive immunity.
- Published
- 2017
47. Erratum: Daphnia magna transcriptome by RNA-Seq across 12 environmental stressors
- Author
-
Orsini, Luisa, Gilbert, Donald, Podicheti, Ram, Jansen, Mieke, Brown, James B, Solari, Omid Shams, Spanier, Katina I, Colbourne, John K, Rusch, Douglas B, Decaestecker, Ellen, Asselman, Jana, De Schamphelaere, Karel AC, Ebert, Dieter, Haag, Christoph R, Kvist, Jouni, Laforsch, Christian, Petrusek, Adam, Beckerman, Andrew P, Little, Tom J, Chaturvedi, Anurag, Pfrender, Michael E, De Meester, Luc, and Frilander, Mikko J
- Subjects
Biological Sciences ,Genetics - Abstract
Scientific Data 3:160030 doi:10.1038/sdata.2016.30 (2016); Published 10 May 2016; Updated 31 Jan 2017 The original version of this Data Descriptor contained a typographical error in the spelling of the author Douglas B. Rusch, which was incorrectly given as Douglas Rush. This has now been corrected in the PDF and HTML versions of the Data Descriptor.
- Published
- 2017
48. Influence of early life exposure, host genetics and diet on the mouse gut microbiome and metabolome.
- Author
-
Snijders, Antoine M, Langley, Sasha A, Kim, Young-Mo, Brislawn, Colin J, Noecker, Cecilia, Zink, Erika M, Fansler, Sarah J, Casey, Cameron P, Miller, Darla R, Huang, Yurong, Karpen, Gary H, Celniker, Susan E, Brown, James B, Borenstein, Elhanan, Jansson, Janet K, Metz, Thomas O, and Mao, Jian-Hua
- Subjects
Gastrointestinal Tract ,Animals ,Mice ,Diet ,Quantitative Trait Loci ,Metabolome ,Gastrointestinal Microbiome ,Life History Traits ,Genetics ,Nutrition ,Prevention ,Arthritis ,Human Genome ,2.1 Biological and endogenous factors ,2.2 Factors relating to physical environment ,Inflammatory and Immune System ,Microbiology ,Medical Microbiology - Abstract
Although the gut microbiome plays important roles in host physiology, health and disease1, we lack understanding of the complex interplay between host genetics and early life environment on the microbial and metabolic composition of the gut. We used the genetically diverse Collaborative Cross mouse system2 to discover that early life history impacts the microbiome composition, whereas dietary changes have only a moderate effect. By contrast, the gut metabolome was shaped mostly by diet, with specific non-dietary metabolites explained by microbial metabolism. Quantitative trait analysis identified mouse genetic trait loci (QTL) that impact the abundances of specific microbes. Human orthologues of genes in the mouse QTL are implicated in gastrointestinal cancer. Additionally, genes located in mouse QTL for Lactobacillales abundance are implicated in arthritis, rheumatic disease and diabetes. Furthermore, Lactobacillales abundance was predictive of higher host T-helper cell counts, suggesting an important link between Lactobacillales and host adaptive immunity.
- Published
- 2016
49. Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy.
- Author
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Zhang, Weiguo, Mao, Jian-Hua, Zhu, Wei, Jain, Anshu K, Liu, Ke, Brown, James B, and Karpen, Gary H
- Subjects
Breast ,Lung ,Centromere ,Humans ,Breast Neoplasms ,Lung Neoplasms ,Chromosomal Instability ,Neoplasm Staging ,Prognosis ,Treatment Outcome ,Chemotherapy ,Adjuvant ,Radiotherapy ,Adjuvant ,Tissue Array Analysis ,Gene Expression Profiling ,Gene Expression Regulation ,Neoplastic ,Female ,Kaplan-Meier Estimate ,Datasets as Topic ,Chemotherapy ,Adjuvant ,Radiotherapy ,Gene Expression Regulation ,Neoplastic ,Human Genome ,Cancer ,Genetics ,2.1 Biological and endogenous factors - Abstract
Chromosomal instability (CIN) is a hallmark of cancer that contributes to tumour heterogeneity and other malignant properties. Aberrant centromere and kinetochore function causes CIN through chromosome missegregation, leading to aneuploidy, rearrangements and micronucleus formation. Here we develop a Centromere and kinetochore gene Expression Score (CES) signature that quantifies the centromere and kinetochore gene misexpression in cancers. High CES values correlate with increased levels of genomic instability and several specific adverse tumour properties, and prognosticate poor patient survival for breast and lung cancers, especially early-stage tumours. They also signify high levels of genomic instability that sensitize cancer cells to additional genotoxicity. Thus, the CES signature forecasts patient response to adjuvant chemotherapy or radiotherapy. Our results demonstrate the prognostic and predictive power of the CES, suggest a role for centromere misregulation in cancer progression, and support the idea that tumours with extremely high CIN are less tolerant to specific genotoxic therapies.
- Published
- 2016
50. Daphnia magna transcriptome by RNA-Seq across 12 environmental stressors.
- Author
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Orsini, Luisa, Gilbert, Donald, Podicheti, Ram, Jansen, Mieke, Brown, James B, Solari, Omid Shams, Spanier, Katina I, Colbourne, John K, Rusch, Douglas B, Decaestecker, Ellen, Asselman, Jana, De Schamphelaere, Karel AC, Ebert, Dieter, Haag, Christoph R, Kvist, Jouni, Laforsch, Christian, Petrusek, Adam, Beckerman, Andrew P, Little, Tom J, Chaturvedi, Anurag, Pfrender, Michael E, De Meester, Luc, and Frilander, Mikko J
- Subjects
Animals ,Daphnia ,RNA ,Base Sequence ,Genome ,Databases ,Genetic ,Gene-Environment Interaction ,Transcriptome ,Databases ,Genetic - Abstract
The full exploration of gene-environment interactions requires model organisms with well-characterized ecological interactions in their natural environment, manipulability in the laboratory and genomic tools. The waterflea Daphnia magna is an established ecological and toxicological model species, central to the food webs of freshwater lentic habitats and sentinel for water quality. Its tractability and cyclic parthenogenetic life-cycle are ideal to investigate links between genes and the environment. Capitalizing on this unique model system, the STRESSFLEA consortium generated a comprehensive RNA-Seq data set by exposing two inbred genotypes of D. magna and a recombinant cross of these genotypes to a range of environmental perturbations. Gene models were constructed from the transcriptome data and mapped onto the draft genome of D. magna using EvidentialGene. The transcriptome data generated here, together with the available draft genome sequence of D. magna and a high-density genetic map will be a key asset for future investigations in environmental genomics.
- Published
- 2016
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