40 results on '"Alsop E"'
Search Results
2. M2 macrophage exosomes regulate hematopoiesis & resolve inflammation in atherosclerosis via microrna cargo
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Bouchareychas, L., primary, Duong, P., additional, Covarrubias, S., additional, Alsop, E., additional, Q Phu, T.A., additional, Chung, A., additional, Gomes, M., additional, Wong, D., additional, Meechoovet, B., additional, Capili, A., additional, Yamamoto, R., additional, Nakauchi, H., additional, Mcmanus, M., additional, Carpenter, S., additional, Van Keuren-Jensen, K., additional, and Raffai, R.L., additional
- Published
- 2020
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3. Long term follow-up of very low birthweight infants from a neonatal volume versus pressure mechanical ventilation trial
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Singh, J, Sinha, S K, Alsop, E, Gupta, S, Mishra, A, and Donn, S M
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- 2009
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4. The use of transabdominal ultrasonography in the diagnosis and management of splenic lesions in three horses
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Alsop, E. J., Marr, C., Barrelet, A. B., and Mcgladdery, A. J.
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- 2007
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5. 'The Mercurial Quality of Being': Sudden Moves in Beau Travail and Billy Budd
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Alsop, E., primary
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- 2014
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6. The use of transabdominal ultrasonography in the diagnosis and management of splenic lesions in three horses
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Alsop, E. J., primary, Marr, C., additional, Barrelet, A. B., additional, and McGladdery, A. J., additional
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- 2010
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7. Going Down: Changing Trends in Preterm Neonatal Oxygen Saturation Monitoring in the UK
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Alsop, E., primary, Walker, S., additional, Tin, W., additional, and Sinha, S.K., additional
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- 2008
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8. Optimized electrostatic surfaces parallel increased thermostability: a structural bioinformatic analysis
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Alsop, E., primary, Silver, M., additional, and Livesay, D. R., additional
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- 2003
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9. NASAL INJURIES IN PRETERM INFANTS ASSOCIATED WITH CONTINUOUS POSITIVE-AIRWAYS PRESSURE.
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Alsop, E. A., Cooke, J., and Gupta, S.
- Published
- 2008
10. Divergent Multiomic Acute Exercise Responses Reveal the Impact of Sex as a Biological Variable.
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Lavin KM, O'Bryan SM, Pathak KV, Garcia-Mansfield K, Graham ZA, McAdam JS, Drummer DJ, Bell MB, Kelley CJ, Lixandrão ME, Peoples B, Seay RS, Torres AR, Reiman R, Alsop E, Hutchins E, Bonfitto A, Antone J, Palade J, Van Keuren-Jensen K, Huentelman MJ, Pirrotte P, Broderick T, and Bamman MM
- Abstract
The majority of exercise physiology research has been conducted in males, resulting in a skewed biological representation of how exercise impacts the physiological system. Extrapolating male-centric physiological findings to females is not universally appropriate and may even be detrimental. Thus, addressing this imbalance and taking into consideration sex as a biological variable is mandatory for optimization of precision exercise interventions and/or regimens. Our present analysis focused on establishing multiomic profiles in young, exercise-naïve males (n=23) and females (n=17) at rest and following acute exercise. Sex differences were characterized at baseline and following exercise using skeletal muscle and extracellular vesicle transcriptomics, whole blood methylomics, and serum metabolomics. Sex-by-time analysis of the acute exercise response revealed notable overlap, as well as divergent molecular responses between males and females. An exploratory comparison of two combined exercise regimens (high-intensity: HITT and traditional: TRAD) was then performed using singular value decomposition, revealing latent data structures that suggest a complex dose-by-sex interaction response to exercise. These findings lay the groundwork for an understanding of key differences in responses to acute exercise exposure between sexes. This may be leveraged in designing optimal training strategies, understanding common and divergent molecular interplay guiding exercise responses, and elucidating the role of sex hormones and/or other sex-specific attributes in responses to acute and chronic exercise.
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- 2025
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11. Characterization of RNA cargo from extracellular vesicles obtained from cerebrospinal fluid and plasma samples in schizophrenia participants and healthy volunteers.
- Author
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Gallego JA, Palade J, Alsop E, Hutchins E, Hsieh M, Logerman A, Bilagody C, Reiman R, Meechoovet B, Terraf P, Beecroft B, Janss A, Gallaso F, Whitsett TG, Blanco EA, Lencz T, Keuren-Jensen KV, and Malhotra AK
- Abstract
Biomarkers that are clinically useful for the diagnosis and treatment of schizophrenia are lacking. Biomarkers are critical tools that reduce the incidence of misdiagnosis, identify subgroups of patients, assist in the proper characterization of patient phenotypes, predict response to treatment or the development of side effects, and can serve as targets for novel therapeutic interventions. In this study, we evaluated small (< 200 nucleotide) and long (> 200 nucleotide) RNAs found in extracellular vesicles (EVs) isolated from the cerebrospinal fluid (CSF) and plasma of individuals with schizophrenia spectrum disorders (SSD) and healthy volunteers (HV). As EVs carry cargo from all tissues in the body, they act as a potential proxy for the tissue of origin, including cells from the brain. We compared the transcriptomic features of EVs from these two biofluids and examined their ability to discriminate between SSD and HV participants, identifying a total of 141 differentially expressed genes, some of which have been previously associated with SSD. Next, we evaluated the potential cell-types that give rise to the SSD-associated CSF RNA cargo, and found the majority were predominantly expressed in excitatory neurons. Our results highlight the potential of EVs as both a source of schizophrenia relevant biomarkers, and molecular insight into disease mechanisms.
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- 2025
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12. Alzheimer's disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain.
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Readhead BP, Mastroeni DF, Wang Q, Sierra MA, de Ávila C, Jimoh TO, Haure-Mirande JV, Atanasoff KE, Nolz J, Suazo C, Barton NJ, Orszulak AR, Chigas SM, Tran K, Mirza A, Ryon K, Proszynski J, Najjar D, Dudley JT, Liu STH, Gandy S, Ehrlich ME, Alsop E, Antone J, Reiman R, Funk C, Best RL, Jhatro M, Kamath K, Shon J, Kowalik TF, Bennett DA, Liang WS, Serrano GE, Beach TG, Van Keuren-Jensen K, Mason CE, Chan Y, Lim ET, Tortorella D, and Reiman EM
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- Humans, Immunoglobulins, Male, Female, Organoids pathology, Organoids immunology, Cytomegalovirus Infections immunology, Cytomegalovirus Infections complications, Cytomegalovirus Infections pathology, Aged, Gastrointestinal Tract pathology, Alzheimer Disease pathology, Alzheimer Disease immunology, Microglia immunology, Microglia pathology, Immunoglobulin G, Cytomegalovirus immunology, CD83 Antigen, Brain pathology, Vagus Nerve pathology, Membrane Glycoproteins, Antigens, CD metabolism
- Abstract
Introduction: While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC)., Methods: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association., Results: CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti-HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV-infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau-212) and neuronal death., Discussion: Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+) microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+) microglia., Highlights: Cross-tissue interaction between HCMV and the adaptive immune response in a subset of persons with AD. Presence of CD83(+) microglial associated with IgG4 and HCMV in the gut. CD83(+) microglia are also associated presence of HCMV and IgG4 in the cortex and vagal nerve. Replication of key association in an independent cohort of AD subjects. HCMV infection of cerebral organoids accelerates the production of AD neuropathological features., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2025
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13. A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.
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Perry AS, Hadad N, Chatterjee E, Jimenez-Ramos M, Farber-Eger E, Roshani R, Stolze LK, Betti MJ, Zhao S, Huang S, Martens L, Kendall TJ, Thone T, Amancherla K, Bailin S, Gabriel CL, Koethe J, Carr JJ, Terry JG, Vaitinadin NS, Freedman JE, Tanriverdi K, Alsop E, Van Keuren-Jensen K, Sauld JFK, Mahajan G, Khan SS, Colangelo L, Nayor M, Fisher-Hoch S, McCormick JB, North KE, Below JE, Wells QS, Abel ED, Kalhan R, Scott C, Guilliams M, Gamazon ER, Fallowfield JA, Banovich NE, Das S, and Shah R
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- Humans, Prognosis, Proteomics methods, Transcriptome genetics, Male, Female, Middle Aged, Gene Expression Profiling, Liver pathology, Liver metabolism, Fatty Liver genetics, Fatty Liver pathology, Fatty Liver metabolism, Biomarkers metabolism
- Abstract
Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver. These transcripts are differentially expressed across areas of steatosis in spatial transcriptomics, and several are dynamic during stages of steatosis. Circulating multi-protein signatures of steatosis strongly associate with fatty liver disease and multi-system metabolic outcomes. Using a humanized "liver-on-a-chip" model, we induce hepatic steatosis, confirming cell-specific expression of prioritized targets. These results underscore the utility of this approach to identify a prognostic, functional, dynamic "liquid biopsy" of human liver, relevant to biomarker discovery and mechanistic research applications., Competing Interests: Declaration of interests R.S., J.E.B., and A.S.P. have filed for a patent relevant to the findings in this manuscript. R.S. is supported in part by grants from the National Institutes of Health (NIH) and the American Heart Association (AHA). R.S. has equity ownership in Thryv Therapeutics and has served as a consultant for Amgen and Cytokinetics. R.S. is a co-inventor on a patent for ex-RNA signatures of cardiac remodeling (not relevant to the current work), and other patents on proteomic signatures of fitness and lung disease. A.S.P. and E.C. are supported by the AHA Strategically Focused Research Network in Cardiometabolic Disease. J.F.K.S. and G.M. are employees of Emulate, Inc. (a maker of the liver-on-a-chip) and may hold equity interest in Emulate, Inc. S.D. holds a research grant from Bristol Myers Squibb, is a founder and holds equity in Switch Therapeutics, and is a founder and consultant and holds equity for Thryv Therapeutics. J.K. has served as a consultant to Gilead, Merck, ViiV Healthcare, and Janssen and also received research support from Gilead Sciences and Merck. R.K. is supported in part by grants from the NIH; has received grants from AstraZeneca, PneumRx/BTG, and Spiration; has received consulting fees from CVS Caremark, AstraZeneca, GlaxoSmithKline, and CSA Medical; and has received speaking fees from GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim. K.A. is supported by an AHA Career Development Award (#929347). J.A.F. serves as a consultant or advisory board member for Kynos Therapeutics, Resolution Therapeutics, Ipsen, River 2 Renal Corp., Stimuliver, Global Clinical Trial Partners, and Guidepoint and has received speaker’s fees from HistoIndex and research grant funding from GlaxoSmithKline, Intercept Pharmaceuticals, and Genentech. T.J.K. undertakes consultancy work for Perspectum, Clinnovate Health, Kynos Therapeutics, Fibrofind, HistoIndex, Concept Life Sciences, and Resolution Therapeutics and has received speaker’s fees from Incyte Corporation and Servier Laboratories. K.V.K.-J. is a member of the scientific advisory board at Dyrnamix. J.J.C. receives project funding from GE Healthcare, Siemens Healthineers, TheraTech, and the NIH. M.N. has received speaking honoraria from Cytokinetics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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14. Decreased SNCA Expression in Whole-Blood RNA Analysis of Parkinson's Disease Adjusting for Lymphocytes.
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Xu K, Violich I, Hutchins E, Alsop E, Nalls MA, Blauwendraat C, Gibbs JR, Cookson MR, Moore A, Van Keuren-Jensen K, and Craig DW
- Abstract
Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinson's Disease (PD) progression and may provide mechanistic insights into the systemic biological processes underlying its pathogenesis beyond the well-defined neurodegenerative features. Previous studies have indicated an age-dependent increase in neutrophil-enriched gene expression, alongside a reduction in lymphocyte counts, in individuals with PD. These immune cell changes can obscure disease-relevant transcriptomic signals. In this study, we performed differential expression (DE) analysis of whole-blood RNA sequencing data from PD cohorts, incorporating a correction for immune cell-enriched gene expression, particularly neutrophil-related pathways, to improve the resolution of PD-associated molecular changes. Using 1,254 Parkinson's Progression Markers Initiative (PPMI) samples with complete blood count (CBC) data, we developed a predictive model to estimate neutrophil percentages in a 6,987 PPMI and Parkinson's Disease Biomarkers Program (PDBP) samples. We mitigated the confounding effects of immune cell-enriched gene expression by integrating predicted neutrophil percentages as a covariate in DE analysis. This approach revealed a consistent and significant downregulation of SNCA across all PD cohorts, a finding previously obscured by immune cell signatures. Lowered SNCA expression was found in individuals with known predisposition genes (e.g., SNCA, GBA, LRRK2) and in non-genetic PD cohorts lacking known pathogenic mutations, suggesting it may represent a key transcriptomic hallmark of the disease., Competing Interests: Competing Interests. All authors declare no financial or non-financial competing interests.
- Published
- 2024
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15. Muscle-derived microRNAs correlated with thigh lean mass gains during progressive resistance training in older adults.
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O'Bryan SM, Lavin KM, Graham ZA, Drummer DJ, Tuggle SC, Van Keuren-Jensen K, Reiman R, Alsop E, Kadakia MP, Craig MP, Zhang J, and Bamman MM
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- Humans, Male, Aged, Female, Aging physiology, Aging genetics, Exosomes metabolism, Middle Aged, Body Composition physiology, Resistance Training methods, MicroRNAs genetics, MicroRNAs metabolism, Muscle, Skeletal metabolism, Muscle, Skeletal physiology, Thigh
- Abstract
Resistance training (RT) remains the most effective treatment for age-related declines in muscle mass. However, many older adults experience attenuated muscle hypertrophy in response to RT when compared with younger adults. This may be attributed to underlying molecular processes that are dysregulated by aging and exacerbated by improperly prescribed RT weekly volume, intensity, and/or frequency doses. MicroRNAs (miRNAs) are key epigenetic regulators that impact signaling pathways and protein expression within cells, are dynamic and responsive to exercise stimuli, and are often dysregulated in diseases. In this study, we used untargeted miRNA-seq to examine miRNA in skeletal muscle and serum-derived exosomes of older adults ( n = 18, 11 M/7 F, 66 ± 1 yr) who underwent three times per wk RT for 30 wk [e.g., high intensity three times/wk (HHH, n = 9) or alternating high-low-high (HLH) intensity ( n = 9)], after a standardized 4-wk washin. Within each tissue, miRNAs were clustered into modules based on pairwise correlation using weighted gene correlation network analysis (WGCNA). Modules were tested for association with the magnitude of RT-induced thigh lean mass (TLM) change [as measured by dual-energy X-ray absorptiometry (DXA)]. Although no modules were unique to training dose, we identified miRNA modules in skeletal muscle associated with TLM gains irrespective of exercise dose. Using miRNA-target interactions, we analyzed key miRNAs in significant modules for their potential regulatory involvement in biological pathways. Findings point toward potential miRNAs that may be informative biomarkers and could also be evaluated as potential therapeutic targets as an adjuvant to RT to maximize skeletal muscle mass accrual in older adults. NEW & NOTEWORTHY In this work, we identified a set of microRNAs correlated with thigh lean mass gains in a group of older adults. To our knowledge, this is the first time these microRNAs have been identified as novel predictive biomarkers correlating with lean mass gains in aging adults. As biomarkers, these may help interventionalists identify older individuals that are positively responding to an exercise intervention.
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- 2024
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16. Single cell transcriptomes and multiscale networks from persons with and without Alzheimer's disease.
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Wang Q, Antone J, Alsop E, Reiman R, Funk C, Bendl J, Dudley JT, Liang WS, Karr TL, Roussos P, Bennett DA, De Jager PL, Serrano GE, Beach TG, Van Keuren-Jensen K, Mastroeni D, Reiman EM, and Readhead BP
- Subjects
- Humans, Male, Female, Aged, Microglia metabolism, Aged, 80 and over, Oligodendroglia metabolism, Middle Aged, Immunoglobulin G metabolism, Gene Regulatory Networks, Sequence Analysis, RNA, Brain metabolism, Brain pathology, Gene Expression Profiling, Alzheimer Disease genetics, Alzheimer Disease metabolism, Transcriptome, Single-Cell Analysis
- Abstract
The emergence of single nucleus RNA sequencing (snRNA-seq) offers to revolutionize the study of Alzheimer's disease (AD). Integration with complementary multiomics data such as genetics, proteomics and clinical data provides powerful opportunities to link cell subpopulations and molecular networks with a broader disease-relevant context. We report snRNA-seq profiles from superior frontal gyrus samples from 101 well characterized subjects from the Banner Brain and Body Donation Program in combination with whole genome sequences. We report findings that link common AD risk variants with CR1 expression in oligodendrocytes as well as alterations in hematological parameters. We observed an AD-associated CD83(+) microglial subtype with unique molecular networks and which is associated with immunoglobulin IgG4 production in the transverse colon. Our major observations were replicated in two additional, independent snRNA-seq data sets. These findings illustrate the power of multi-tissue molecular profiling to contextualize snRNA-seq brain transcriptomics and reveal disease biology., (© 2024. The Author(s).)
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- 2024
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17. Cryopreservation of cerebrospinal fluid cells preserves the transcriptional landscape for single-cell analysis.
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Kodali MC, Antone J, Alsop E, Jayakumar R, Parikh K, Chiot A, Sanchez-Molina P, Ajami B, Arnold SE, Jensen K, Das S, and Weinberg MS
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- Humans, Cells, Cultured, Cryopreservation methods, Single-Cell Analysis, Cell Survival, Dimethyl Sulfoxide pharmacology, Cryoprotective Agents pharmacology
- Abstract
Cerebrospinal fluid (CSF) matrix biomarkers have become increasingly valuable surrogate markers of neuropsychiatric diseases in research and clinical practice. In contrast, CSF cells have been rarely investigated due to their relative scarcity and fragility, and lack of common collection and cryopreservation protocols, with limited exceptions for neurooncology and primary immune-based diseases like multiple sclerosis. the advent of a microfluidics-based multi-omics approach to studying individual cells has allowed for the study of cellular phenotyping, intracellular dynamics, and intercellular relationships that provide multidimensionality unable to be obtained through acellular fluid-phase analyses. challenges to cell-based research include site-to-site differences in handling, storage, and thawing methods, which can lead to inaccuracy and inter-assay variability. In the present study, we performed single-cell RNA sequencing (10x Genomics) on fresh or previously cryopreserved human CSF samples from three alternative cryopreservation methods: Fetal Bovine Serum with Dimethyl sulfoxide (FBS/DMSO), FBS/DMSO after a DNase step (a step often included in epigenetic studies), and cryopreservation using commercially available Recovery© media. In comparing relative differences between fresh and cryopreserved samples, we found little effect of the cryopreservation method on being able to resolve donor-linked cell type proportions, markers of cellular stress, and overall gene expression at the single-cell level, whereas donor-specific differences were readily discernable. We further demonstrate the compatibility of fresh and cryopreserved CSF immune cell sequencing using biologically relevant sexually dimorphic gene expression differences by donor. Our findings support the utility and interchangeability of FBS/DMSO and Recovery cryopreservation with fresh sample analysis, providing a methodological grounding that will enable researchers to further expand our understanding of the CSF immune cell contributions to neurological and psychiatric disease., (© 2024. The Author(s).)
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- 2024
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18. Biological basis of extensive pleiotropy between blood traits and cancer risk.
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Pardo-Cea MA, Farré X, Esteve A, Palade J, Espín R, Mateo F, Alsop E, Alorda M, Blay N, Baiges A, Shabbir A, Comellas F, Gómez A, Arnan M, Teulé A, Salinas M, Berrocal L, Brunet J, Rofes P, Lázaro C, Conesa M, Rojas JJ, Velten L, Fendler W, Smyczynska U, Chowdhury D, Zeng Y, He HH, Li R, Van Keuren-Jensen K, de Cid R, and Pujana MA
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- Humans, Female, Phenotype, Quantitative Trait Loci, Genetic Pleiotropy, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Genome-Wide Association Study, Neoplasms genetics
- Abstract
Background: The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations., Methods: Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis., Results: The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis., Conclusions: This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk., (© 2024. The Author(s).)
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- 2024
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19. Small RNA Changes in Plasma Have Potential for Early Diagnosis of Alzheimer's Disease before Symptom Onset.
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Palade J, Alsop E, Courtright-Lim A, Hsieh M, Whitsett TG, Galasko D, and Van Keuren-Jensen K
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- Humans, Brain pathology, Early Diagnosis, Biomarkers, Alzheimer Disease diagnosis, Alzheimer Disease genetics, Alzheimer Disease pathology, Extracellular Vesicles pathology
- Abstract
Alzheimer's disease (AD), due to its multifactorial nature and complex etiology, poses challenges for research, diagnosis, and treatment, and impacts millions worldwide. To address the need for minimally invasive, repeatable measures that aid in AD diagnosis and progression monitoring, studies leveraging RNAs associated with extracellular vesicles (EVs) in human biofluids have revealed AD-associated changes. However, the validation of AD biomarkers has suffered from the collection of samples from differing points in the disease time course or a lack of confirmed AD diagnoses. Here, we integrate clinical diagnosis and postmortem pathology data to form more accurate experimental groups and use small RNA sequencing to show that EVs from plasma can serve as a potential source of RNAs that reflect disease-related changes. Importantly, we demonstrated that these changes are identifiable in the EVs of preclinical patients, years before symptom manifestation, and that machine learning models based on differentially expressed RNAs can help predict disease conversion or progression. This research offers critical insight into early disease biomarkers and underscores the significance of accounting for disease progression and pathology in human AD studies.
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- 2024
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20. A public resource of single cell transcriptomes and multiscale networks from persons with and without Alzheimer's disease.
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Wang Q, Antone J, Alsop E, Reiman R, Funk C, Bendl J, Dudley JT, Liang WS, Karr TL, Roussos P, Bennett DA, De Jager PL, Serrano GE, Beach TG, Keuren-Jensen KV, Mastroeni D, Reiman EM, and Readhead BP
- Abstract
The emergence of technologies that can support high-throughput profiling of single cell transcriptomes offers to revolutionize the study of brain tissue from persons with and without Alzheimer's disease (AD). Integration of these data with additional complementary multiomics data such as genetics, proteomics and clinical data provides powerful opportunities to link observed cell subpopulations and molecular network features within a broader disease-relevant context. We report here single nucleus RNA sequencing (snRNA-seq) profiles generated from superior frontal gyrus cortical tissue samples from 101 exceptionally well characterized, aged subjects from the Banner Brain and Body Donation Program in combination with whole genome sequences. We report findings that link common AD risk variants with CR1 expression in oligodendrocytes as well as alterations in peripheral hematological lab parameters, with these observations replicated in an independent, prospective cohort study of ageing and dementia. We also observed an AD-associated CD83(+) microglial subtype with unique molecular networks that encompass many known regulators of AD-relevant microglial biology, and which are associated with immunoglobulin IgG4 production in the transverse colon. These findings illustrate the power of multi-tissue molecular profiling to contextualize snRNA-seq brain transcriptomics and reveal novel disease biology. The transcriptomic, genetic, phenotypic, and network data resources described within this study are available for access and utilization by the scientific community.
- Published
- 2023
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21. Modelling TDP-43 proteinopathy in Drosophila uncovers shared and neuron-specific targets across ALS and FTD relevant circuits.
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Godfrey RK, Alsop E, Bjork RT, Chauhan BS, Ruvalcaba HC, Antone J, Gittings LM, Michael AF, Williams C, Hala'ufia G, Blythe AD, Hall M, Sattler R, Van Keuren-Jensen K, and Zarnescu DC
- Subjects
- Animals, Humans, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Drosophila metabolism, Motor Neurons metabolism, RNA, Messenger, Amyotrophic Lateral Sclerosis pathology, Frontotemporal Dementia genetics, Frontotemporal Dementia pathology, Pick Disease of the Brain pathology, TDP-43 Proteinopathies pathology
- Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 inclusions that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous work in motor neurons, here we report a novel model of TDP-43 proteinopathy based on overexpression of TDP-43 in a subset of Drosophila Kenyon cells of the mushroom body (MB), a circuit with structural characteristics reminiscent of vertebrate cortical networks. This model recapitulates several aspects of dementia-relevant pathological features including age-dependent neuronal loss, nuclear depletion and cytoplasmic accumulation of TDP-43, and behavioral deficits in working memory and sleep that occur prior to axonal degeneration. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit and others that are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), which exhibits significant TDP-43 associated reduction in expression during aging. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits, conistent with Dlp acting as a mediator of TDP-43 toxicity. Substantiating our findings in the fly model, we find that the expression of GPC6 mRNA, a human ortholog of dlp, is specifically altered in neurons exhibiting the molecular signature of TDP-43 pathology in FTD patient brains. These findings suggest that circuit-specific Drosophila models provide a platform for uncovering shared or disease-specific molecular mechanisms and vulnerabilities across the spectrum of TDP-43 proteinopathies., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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22. Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features.
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Lorenzini I, Alsop E, Levy J, Gittings LM, Lall D, Rabichow BE, Moore S, Pevey R, Bustos LM, Burciu C, Bhatia D, Singer M, Saul J, McQuade A, Tzioras M, Mota TA, Logemann A, Rose J, Almeida S, Gao FB, Marks M, Donnelly CJ, Hutchins E, Hung ST, Ichida J, Bowser R, Spires-Jones T, Blurton-Jones M, Gendron TF, Baloh RH, Van Keuren-Jensen K, and Sattler R
- Abstract
While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G
4 C2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lorenzini, Alsop, Levy, Gittings, Lall, Rabichow, Moore, Pevey, Bustos, Burciu, Bhatia, Singer, Saul, McQuade, Tzioras, Mota, Logemann, Rose, Almeida, Gao, Marks, Donnelly, Hutchins, Hung, Ichida, Bowser, Spires-Jones, Blurton-Jones, Gendron, Baloh, Van Keuren-Jensen and Sattler.)- Published
- 2023
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23. exRNA-eCLIP intersection analysis reveals a map of extracellular RNA binding proteins and associated RNAs across major human biofluids and carriers.
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LaPlante EL, Stürchler A, Fullem R, Chen D, Starner AC, Esquivel E, Alsop E, Jackson AR, Ghiran I, Pereira G, Rozowsky J, Chang J, Gerstein MB, Alexander RP, Roth ME, Franklin JL, Coffey RJ, Raffai RL, Mansuy IM, Stavrakis S, deMello AJ, Laurent LC, Wang YT, Tsai CF, Liu T, Jones J, Van Keuren-Jensen K, Van Nostrand E, Mateescu B, and Milosavljevic A
- Abstract
Although the role of RNA binding proteins (RBPs) in extracellular RNA (exRNA) biology is well established, their exRNA cargo and distribution across biofluids are largely unknown. To address this gap, we extend the exRNA Atlas resource by mapping exRNAs carried by extracellular RBPs (exRBPs). This map was developed through an integrative analysis of ENCODE enhanced crosslinking and immunoprecipitation (eCLIP) data (150 RBPs) and human exRNA profiles (6,930 samples). Computational analysis and experimental validation identified exRBPs in plasma, serum, saliva, urine, cerebrospinal fluid, and cell-culture-conditioned medium. exRBPs carry exRNA transcripts from small non-coding RNA biotypes, including microRNA (miRNA), piRNA, tRNA, small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), Y RNA, and lncRNA, as well as protein-coding mRNA fragments. Computational deconvolution of exRBP RNA cargo reveals associations of exRBPs with extracellular vesicles, lipoproteins, and ribonucleoproteins across human biofluids. Overall, we mapped the distribution of exRBPs across human biofluids, presenting a resource for the community., Competing Interests: E.V.N. is co-founder, member of the Board of Directors, on the SAB, equity holder, and paid consultant for Eclipse BioInnovations. E.V.N.’s interests have been reviewed and approved by the Baylor College of Medicine in accordance with its conflict of interest policies., (© 2023 The Authors.)
- Published
- 2023
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24. Dynamic transcriptomic responses to divergent acute exercise stimuli in young adults.
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Lavin KM, Graham ZA, McAdam JS, O'Bryan SM, Drummer D, Bell MB, Kelley CJ, Lixandrão ME, Peoples B, Tuggle SC, Seay RS, Van Keuren-Jensen K, Huentelman MJ, Pirrotte P, Reiman R, Alsop E, Hutchins E, Antone J, Bonfitto A, Meechoovet B, Palade J, Talboom JS, Sullivan A, Aban I, Peri K, Broderick TJ, and Bamman MM
- Subjects
- Humans, Young Adult, Exercise physiology, Gene Expression Profiling, Muscle, Skeletal metabolism, Transcriptome genetics, Resistance Training
- Abstract
Acute exercise elicits dynamic transcriptional changes that, when repeated, form the fundamental basis of health, resilience, and performance adaptations. While moderate-intensity endurance training combined with conventional resistance training (traditional, TRAD) is often prescribed and recommended by public health guidance, high-intensity training combining maximal-effort intervals with intensive, limited-rest resistance training is a time-efficient alternative that may be used tactically (HITT) to confer similar benefits. Mechanisms of action of these distinct stimuli are incompletely characterized and have not been directly compared. We assessed transcriptome-wide responses in skeletal muscle and circulating extracellular vesicles (EVs) to a single exercise bout in young adults randomized to TRAD ( n = 21, 12 M/9 F, 22 ± 3 yr) or HITT ( n = 19, 11 M/8 F, 22 ± 2 yr). Next-generation sequencing captured small, long, and circular RNA in muscle and EVs. Analysis identified differentially expressed transcripts (|log
2 FC|>1, FDR ≤ 0.05) immediately (h0, EVs only), h3, and h24 postexercise within and between exercise protocols. In aaddition, all apparently responsive transcripts (FDR < 0.2) underwent singular value decomposition to summarize data structures into latent variables (LVs) to deconvolve molecular expression circuits and interregulatory relationships. LVs were compared across time and exercise protocol. TRAD, a longer but less intense stimulus, generally elicited a stronger transcriptional response than HITT, but considerable overlap and key differences existed. Findings reveal shared and unique molecular responses to the exercise stimuli and lay groundwork toward establishing relationships between protein-coding genes and lesser-understood transcripts that serve regulatory roles following exercise. Future work should advance the understanding of these circuits and whether they repeat in other populations or following other types of exercise/stress. NEW & NOTEWORTHY We examined small and long transcriptomics in skeletal muscle and serum-derived extracellular vesicles before and after a single exposure to traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found more consistent protein-coding gene responses to TRAD, whereas HITT elicited differential expression of microRNA enriched in brain regions. Follow-up analysis revealed relationships and temporal dynamics across transcript networks, highlighting potential avenues for research into mechanisms of exercise response and adaptation.- Published
- 2023
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25. The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism.
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Bressan E, Reed X, Bansal V, Hutchins E, Cobb MM, Webb MG, Alsop E, Grenn FP, Illarionova A, Savytska N, Violich I, Broeer S, Fernandes N, Sivakumar R, Beilina A, Billingsley KJ, Berghausen J, Pantazis CB, Pitz V, Patel D, Daida K, Meechoovet B, Reiman R, Courtright-Lim A, Logemann A, Antone J, Barch M, Kitchen R, Li Y, Dalgard CL, Rizzu P, Hernandez DG, Hjelm BE, Nalls M, Gibbs JR, Finkbeiner S, Cookson MR, Van Keuren-Jensen K, Craig DW, Singleton AB, Heutink P, and Blauwendraat C
- Abstract
The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.
- Published
- 2023
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26. Phase 2 of extracellular RNA communication consortium charts next-generation approaches for extracellular RNA research.
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Mateescu B, Jones JC, Alexander RP, Alsop E, An JY, Asghari M, Boomgarden A, Bouchareychas L, Cayota A, Chang HC, Charest A, Chiu DT, Coffey RJ, Das S, De Hoff P, deMello A, D'Souza-Schorey C, Elashoff D, Eliato KR, Franklin JL, Galas DJ, Gerstein MB, Ghiran IH, Go DB, Gould S, Grogan TR, Higginbotham JN, Hladik F, Huang TJ, Huo X, Hutchins E, Jeppesen DK, Jovanovic-Talisman T, Kim BYS, Kim S, Kim KM, Kim Y, Kitchen RR, Knouse V, LaPlante EL, Lebrilla CB, Lee LJ, Lennon KM, Li G, Li F, Li T, Liu T, Liu Z, Maddox AL, McCarthy K, Meechoovet B, Maniya N, Meng Y, Milosavljevic A, Min BH, Morey A, Ng M, Nolan J, De Oliveira Junior GP, Paulaitis ME, Phu TA, Raffai RL, Reátegui E, Roth ME, Routenberg DA, Rozowsky J, Rufo J, Senapati S, Shachar S, Sharma H, Sood AK, Stavrakis S, Stürchler A, Tewari M, Tosar JP, Tucker-Schwartz AK, Turchinovich A, Valkov N, Van Keuren-Jensen K, Vickers KC, Vojtech L, Vreeland WN, Wang C, Wang K, Wang Z, Welsh JA, Witwer KW, Wong DTW, Xia J, Xie YH, Yang K, Zaborowski MP, Zhang C, Zhang Q, Zivkovic AM, and Laurent LC
- Abstract
The extracellular RNA communication consortium (ERCC) is an NIH-funded program aiming to promote the development of new technologies, resources, and knowledge about exRNAs and their carriers. After Phase 1 (2013-2018), Phase 2 of the program (ERCC2, 2019-2023) aims to fill critical gaps in knowledge and technology to enable rigorous and reproducible methods for separation and characterization of both bulk populations of exRNA carriers and single EVs. ERCC2 investigators are also developing new bioinformatic pipelines to promote data integration through the exRNA atlas database. ERCC2 has established several Working Groups (Resource Sharing, Reagent Development, Data Analysis and Coordination, Technology Development, nomenclature, and Scientific Outreach) to promote collaboration between ERCC2 members and the broader scientific community. We expect that ERCC2's current and future achievements will significantly improve our understanding of exRNA biology and the development of accurate and efficient exRNA-based diagnostic, prognostic, and theranostic biomarker assays., Competing Interests: Crislyn D’Souza-Schorey, Satyajyoti Senapati and Hsueh-Chia Chang hold equity in AgenDx Biosciences. Hsueh-Chia Chang is a cofounder of Aopia Biosciences and holds equity. Daniel T. Chiu has financial interest and is a scientific founder and/or board member of the following companies and their respective affiliates: Micareo, Inc, Lamprogen, Inc, Cellectricon AB, and Fluicell AB. Saumya Das is a founding member of Dyrnamix Inc. that did not play any role in this study. Kendal Van Keuren-Jensen is a board member of Dyrnamix Inc. and HTG that did not play any role in this study. Aleksandar Milosavljevic is a founder of IP Genesis, Inc. that did not play any role in this study. Louise C. Laurent has stock in Illumina, Inc. Anil K. Sood has the following disclosures: Consultant (Merck, Kiyatec), shareholder (BioPath), research funding (MTrap). John Nolan holds equity in Cellarcus Biosciences Inc. L. James Lee holds equity at Spot Biosystems. David A. Routenberg, Sigal Shachar and Alexander K. Tucker-Schwartz are employees of Meso Scale Diagnostics, LLC. Andrey Turchinovich is founder of SciBerg e.Kfm, Mannheim, Germany. Angela M. Zivkovic is cofounder and board member at Innate Biology, Inc., (© 2022 The Author(s).)
- Published
- 2022
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27. A Novel Tissue Atlas and Online Tool for the Interrogation of Small RNA Expression in Human Tissues and Biofluids.
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Alsop E, Meechoovet B, Kitchen R, Sweeney T, Beach TG, Serrano GE, Hutchins E, Ghiran I, Reiman R, Syring M, Hsieh M, Courtright-Lim A, Valkov N, Whitsett TG, Rakela J, Pockros P, Rozowsky J, Gallego J, Huentelman MJ, Shah R, Nakaji P, Kalani MYS, Laurent L, Das S, and Van Keuren-Jensen K
- Abstract
One promising goal for utilizing the molecular information circulating in biofluids is the discovery of clinically useful biomarkers. Extracellular RNAs (exRNAs) are one of the most diverse classes of molecular cargo, easily assayed by sequencing and with expressions that rapidly change in response to subject status. Despite diverse exRNA cargo, most evaluations from biofluids have focused on small RNA sequencing and analysis, specifically on microRNAs (miRNAs). Another goal of characterizing circulating molecular information, is to correlate expression to injuries associated with specific tissues of origin. Biomarker candidates are often described as being specific, enriched in a particular tissue or associated with a disease process. Likewise, miRNA data is often reported to be specific, enriched for a tissue, without rigorous testing to support the claim. Here we provide a tissue atlas of small RNAs from 30 different tissues and three different blood cell types. We analyzed the tissues for enrichment of small RNA sequences and assessed their expression in biofluids: plasma, cerebrospinal fluid, urine, and saliva. We employed published data sets representing physiological (resting vs. acute exercise) and pathologic states (early- vs. late-stage liver fibrosis, and differential subtypes of stroke) to determine differential tissue-enriched small RNAs. We also developed an online tool that provides information about exRNA sequences found in different biofluids and tissues. The data can be used to better understand the various types of small RNA sequences in different tissues as well as their potential release into biofluids, which should help in the validation or design of biomarker studies., Competing Interests: KV and SD are members of the scientific advisory board at Dyrnamix. Their involvement in this company had no bearing on the work performed in this manuscript. KV is on the scientific advisory board of HTG. Her involvement has no bearing on this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alsop, Meechoovet, Kitchen, Sweeney, Beach, Serrano, Hutchins, Ghiran, Reiman, Syring, Hsieh, Courtright-Lim, Valkov, Whitsett, Rakela, Pockros, Rozowsky, Gallego, Huentelman, Shah, Nakaji, Kalani, Laurent, Das and Van Keuren-Jensen.)
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- 2022
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28. RNA sequencing of whole blood reveals early alterations in immune cells and gene expression in Parkinson's disease.
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Craig DW, Hutchins E, Violich I, Alsop E, Gibbs JR, Levy S, Robison M, Prasad N, Foroud T, Crawford KL, Toga AW, Whitsett TG, Kim S, Casey B, Reimer A, Hutten SJ, Frasier M, Kern F, Fehlman T, Keller A, Cookson MR, and Van Keuren-Jensen K
- Subjects
- Humans, Disease Progression, Biomarkers, Transcriptome genetics, Sequence Analysis, RNA, RNA, Parkinson Disease genetics
- Abstract
Changes in the blood-based RNA transcriptome have the potential to inform biomarkers of Parkinson's disease (PD) progression. Here we sequenced a discovery set of whole-blood RNA species in 4,871 longitudinally collected samples from 1,570 clinically phenotyped individuals from the Parkinson's Progression Marker Initiative (PPMI) cohort. Samples were sequenced to an average of 100 million read pairs to create a high-quality transcriptome. Participants with PD in the PPMI had significantly altered RNA expression (>2,000 differentially expressed genes), including an early and persistent increase in neutrophil gene expression, with a concomitant decrease in lymphocyte cell counts. This was validated in a cohort from the Parkinson's Disease Biomarkers Program (PDBP) consisting of 1,599 participants and by alterations in immune cell subtypes. This publicly available transcriptomic dataset, coupled with available detailed clinical data, provides new insights into PD biological processes impacting whole blood and new paths for developing diagnostic and prognostic PD biomarkers., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2021
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29. High glucose macrophage exosomes enhance atherosclerosis by driving cellular proliferation & hematopoiesis.
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Bouchareychas L, Duong P, Phu TA, Alsop E, Meechoovet B, Reiman R, Ng M, Yamamoto R, Nakauchi H, Gasper WJ, Van Keuren-Jensen K, and Raffai RL
- Abstract
We investigated whether extracellular vesicles (EVs) produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis. We did so by treating Apoe
-/- mice with exosomes produced by bone marrow-derived macrophages (BMDM) exposed to high glucose (BMDM-HG-exo) or control. Infusions of BMDM-HG-exo increased hematopoiesis, circulating myeloid cell numbers, and atherosclerotic lesions with an accumulation of macrophage foam and apoptotic cells. Transcriptome-wide analysis of cultured macrophages treated with BMDM-HG-exo or plasma EVs isolated from subjects with type II diabetes revealed a reduced inflammatory state and increased metabolic activity. Furthermore, BMDM-HG-exo induced cell proliferation and reprogrammed energy metabolism by increasing glycolytic activity. Lastly, profiling microRNA in BMDM-HG-exo and plasma EVs from diabetic subjects with advanced atherosclerosis converged on miR-486-5p as commonly enriched and recognized in dysregulated hematopoiesis and Abca1 control. Together, our findings show that EVs serve to communicate detrimental properties of hyperglycemia to accelerate atherosclerosis in diabetes., Competing Interests: The authors declare no competing interests.- Published
- 2021
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30. TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6.
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Lehmkuhl EM, Loganathan S, Alsop E, Blythe AD, Kovalik T, Mortimore NP, Barrameda D, Kueth C, Eck RJ, Siddegowda BB, Joardar A, Ball H, Macias ME, Bowser R, Van Keuren-Jensen K, and Zarnescu DC
- Subjects
- Amyotrophic Lateral Sclerosis pathology, Animals, Drosophila, Humans, Motor Neurons metabolism, Motor Neurons pathology, Nerve Degeneration metabolism, Nerve Degeneration pathology, RNA, Messenger metabolism, Spinal Cord metabolism, TDP-43 Proteinopathies pathology, Adaptor Proteins, Signal Transducing metabolism, Amyotrophic Lateral Sclerosis metabolism, Glypicans metabolism, Nuclear Proteins metabolism, Ribosomes metabolism, TDP-43 Proteinopathies metabolism
- Abstract
Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy.
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- 2021
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31. Deep sequencing of sncRNAs reveals hallmarks and regulatory modules of the transcriptome during Parkinson's disease progression.
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Kern F, Fehlmann T, Violich I, Alsop E, Hutchins E, Kahraman M, Grammes NL, Guimarães P, Backes C, Poston KL, Casey B, Balling R, Geffers L, Krüger R, Galasko D, Mollenhauer B, Meese E, Wyss-Coray T, Craig DW, Van Keuren-Jensen K, and Keller A
- Subjects
- Humans, Transcriptome genetics, High-Throughput Nucleotide Sequencing, Disease Progression, RNA, Small Untranslated genetics, Parkinson Disease diagnosis, MicroRNAs genetics
- Abstract
Noncoding RNAs have diagnostic and prognostic importance in Parkinson's disease (PD). We studied circulating small noncoding RNAs (sncRNAs) in two large-scale longitudinal PD cohorts (Parkinson's Progression Markers Initiative (PPMI) and Luxembourg Parkinson's Study (NCER-PD)) and modeled their impact on the transcriptome. Sequencing of sncRNAs in 5,450 blood samples of 1,614 individuals in PPMI yielded 323 billion reads, most of which mapped to microRNAs but covered also other RNA classes such as piwi-interacting RNAs, ribosomal RNAs and small nucleolar RNAs. Dysregulated microRNAs associated with disease and disease progression occur in two distinct waves in the third and seventh decade of life. Originating predominantly from immune cells, they resemble a systemic inflammation response and mitochondrial dysfunction, two hallmarks of PD. Profiling 1,553 samples from 1,024 individuals in the NCER-PD cohort validated biomarkers and main findings by an independent technology. Finally, network analysis of sncRNA and transcriptome sequencing from PPMI identified regulatory modules emerging in patients with progressing PD., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature.)
- Published
- 2021
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32. Mir-30d Regulates Cardiac Remodeling by Intracellular and Paracrine Signaling.
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Li J, Salvador AM, Li G, Valkov N, Ziegler O, Yeri A, Yang Xiao C, Meechoovet B, Alsop E, Rodosthenous RS, Kundu P, Huan T, Levy D, Tigges J, Pico AR, Ghiran I, Silverman MG, Meng X, Kitchen R, Xu J, Van Keuren-Jensen K, Shah R, Xiao J, and Das S
- Subjects
- Animals, Apoptosis, Cells, Cultured, Disease Models, Animal, Extracellular Vesicles genetics, Extracellular Vesicles metabolism, Extracellular Vesicles pathology, Fibroblasts metabolism, Fibroblasts pathology, Fibrosis, Gene Expression Regulation, Male, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs genetics, Myocardial Infarction genetics, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardium pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Rats, Sprague-Dawley, Rats, Transgenic, Signal Transduction, NF-kappaB-Inducing Kinase, Mice, Rats, MicroRNAs metabolism, Myocardial Infarction metabolism, Myocardium metabolism, Paracrine Communication, Ventricular Function, Left, Ventricular Remodeling
- Abstract
Rationale: Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular remodeling and clinical outcome in heart failure (HF) patients, although precise mechanisms remain obscure., Objective: To investigate the mechanism of miR-30d-mediated cardioprotection in HF., Methods and Results: In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus, or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid-based knock-down of miR-30d expression potentiates pathological left ventricular remodeling, with increased dysfunction, fibrosis, and cardiomyocyte death. RNA sequencing of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in cardiomyocytes, induced by hypoxic stress and is acutely protective, targeting MAP4K4 (mitogen-associate protein kinase 4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by cardiomyocytes and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma extracellular vesicles is associated with adverse remodeling in rodent models and human subjects and is linked to whole-blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems., Conclusions: These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of extracellular vesicle-contained miRNAs (microRNAs) to transregulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.
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- 2021
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33. Macrophage Exosomes Resolve Atherosclerosis by Regulating Hematopoiesis and Inflammation via MicroRNA Cargo.
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Bouchareychas L, Duong P, Covarrubias S, Alsop E, Phu TA, Chung A, Gomes M, Wong D, Meechoovet B, Capili A, Yamamoto R, Nakauchi H, McManus MT, Carpenter S, Van Keuren-Jensen K, and Raffai RL
- Subjects
- Animals, Apolipoproteins E deficiency, Apolipoproteins E metabolism, Cell Polarity, Exosomes ultrastructure, Gene Editing, Humans, Interleukin-4 metabolism, Macrophages ultrastructure, Mice, Inbred C57BL, MicroRNAs genetics, Myeloid Cells metabolism, NF-kappa B metabolism, Signal Transduction, Tissue Distribution, Tumor Necrosis Factor-alpha metabolism, Atherosclerosis genetics, Atherosclerosis pathology, Exosomes metabolism, Hematopoiesis genetics, Inflammation genetics, Inflammation pathology, Macrophages metabolism, MicroRNAs metabolism
- Abstract
Developing strategies that promote the resolution of vascular inflammation and atherosclerosis remains a major therapeutic challenge. Here, we show that exosomes produced by naive bone marrow-derived macrophages (BMDM-exo) contain anti-inflammatory microRNA-99a/146b/378a that are further increased in exosomes produced by BMDM polarized with IL-4 (BMDM-IL-4-exo). These exosomal microRNAs suppress inflammation by targeting NF-κB and TNF-α signaling and foster M2 polarization in recipient macrophages. Repeated infusions of BMDM-IL-4-exo into Apoe
-/- mice fed a Western diet reduce excessive hematopoiesis in the bone marrow and thereby the number of myeloid cells in the circulation and macrophages in aortic root lesions. This also leads to a reduction in necrotic lesion areas that collectively stabilize atheroma. Thus, BMDM-IL-4-exo may represent a useful therapeutic approach for atherosclerosis and other inflammatory disorders by targeting NF-κB and TNF-α via microRNA cargo delivery., Competing Interests: Declaration of Interests L.B. and R.L.R. have filed an invention disclosure related to some aspects of this work with the Department of Veterans Affairs., (Published by Elsevier Inc.)- Published
- 2020
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34. Extracellular microRNAs in blood differentiate between ischaemic and haemorrhagic stroke subtypes.
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Kalani MYS, Alsop E, Meechoovet B, Beecroft T, Agrawal K, Whitsett TG, Huentelman MJ, Spetzler RF, Nakaji P, Kim S, and Van Keuren-Jensen K
- Abstract
Rapid identification of patients suffering from cerebral ischaemia, while excluding intracerebral haemorrhage, can assist with patient triage and expand patient access to chemical and mechanical revascularization. We sought to identify blood-based, extracellular microRNAs 15 (ex-miRNAs) derived from extracellular vesicles associated with major stroke subtypes using clinical samples from subjects with spontaneous intraparenchymal haemorrhage (IPH), aneurysmal subarachnoid haemorrhage (SAH) and ischaemic stroke due to cerebral vessel occlusion. We collected blood from patients presenting with IPH (n = 19), SAH (n = 17) and ischaemic stroke (n = 21). We isolated extracellular vesicles from plasma, extracted RNA cargo, 20 sequenced the small RNAs and performed bioinformatic analyses to identify ex-miRNA biomarkers predictive of the stroke subtypes. Sixty-seven miRNAs were significantly variant across the stroke subtypes. A subset of exmiRNAs differed between haemorrhagic and ischaemic strokes, and LASSO analysis could distinguish SAH from the other subtypes with an accuracy of 0.972 ± 0.002. Further analyses predicted 25 miRNA classifiers that stratify IPH from ischaemic stroke with an accuracy of 0.811 ± 0.004 and distinguish haemorrhagic from ischaemic stroke with an accuracy of 0.813 ± 0.003. Blood-based, ex-miRNAs have predictive value, and could be capable of distinguishing between major stroke subtypes with refinement and validation. Such a biomarker could one day aid in the triage of patients to expand the pool eligible for effective treatment., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.)
- Published
- 2020
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35. Correction to: ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD.
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Moore S, Alsop E, Lorenzini I, Starr A, Rabichow BE, Mendez E, Levy JL, Burciu C, Reiman R, Chew J, Belzil VV, Dickson D, Robertson J, Staats KA, Ichida JK, Petrucelli L, Van Keuren-Jensen K, and Sattler R
- Abstract
The original article was published erroneously without mentioning the support of the U.S.
- Published
- 2019
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36. ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD.
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Moore S, Alsop E, Lorenzini I, Starr A, Rabichow BE, Mendez E, Levy JL, Burciu C, Reiman R, Chew J, Belzil VV, W Dickson D, Robertson J, Staats KA, Ichida JK, Petrucelli L, Van Keuren-Jensen K, and Sattler R
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Animals, DNA Repeat Expansion genetics, Frontotemporal Dementia genetics, Humans, Induced Pluripotent Stem Cells metabolism, Mice, Transgenic, Pick Disease of the Brain genetics, Adenosine Deaminase genetics, C9orf72 Protein genetics, RNA Editing genetics, RNA-Binding Proteins genetics
- Abstract
The hexanucleotide repeat expansion GGGGCC (G
4 C2 )n in the C9orf72 gene is the most common genetic abnormality associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent findings suggest that dysfunction of nuclear-cytoplasmic trafficking could affect the transport of RNA binding proteins in C9orf72 ALS/FTD. Here, we provide evidence that the RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is mislocalized in C9orf72 repeat expansion mediated ALS/FTD. ADAR2 is responsible for adenosine (A) to inosine (I) editing of double-stranded RNA, and its function has been shown to be essential for survival. Here we show the mislocalization of ADAR2 in human induced pluripotent stem cell-derived motor neurons (hiPSC-MNs) from C9orf72 patients, in mice expressing (G4 C2 )149 , and in C9orf72 ALS/FTD patient postmortem tissue. As a consequence of this mislocalization we observe alterations in RNA editing in our model systems and across multiple brain regions. Analysis of editing at 408,580 known RNA editing sites indicates that there are vast RNA A to I editing aberrations in C9orf72-mediated ALS/FTD. These RNA editing aberrations are found in many cellular pathways, such as the ALS pathway and the crucial EIF2 signaling pathway. Our findings suggest that the mislocalization of ADAR2 in C9orf72 mediated ALS/FTD is responsible for the alteration of RNA processing events that may impact vast cellular functions, including the integrated stress response (ISR) and protein translation.- Published
- 2019
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37. Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role.
- Author
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Bowers JR, Valentine M, Harrison V, Fofanov VY, Gillece J, Delisle J, Patton B, Schupp J, Sheridan K, Lemmer D, Ostdiek S, Bains HK, Heim J, Sylvester T, Prasai S, Kretschmer M, Fowle N, Komatsu K, Brady S, Robinson S, Fitzpatrick K, Ostovar GA, Alsop E, Hutchins E, Jensen K, Keim P, and Engelthaler DM
- Subjects
- Arizona epidemiology, Cerebrospinal Fluid virology, Enterovirus D, Human genetics, Humans, Molecular Epidemiology, Nasopharynx virology, RNA, Viral genetics, RNA, Viral isolation & purification, Real-Time Polymerase Chain Reaction, Sequence Analysis, DNA, Central Nervous System Viral Diseases epidemiology, Central Nervous System Viral Diseases virology, Cluster Analysis, Enterovirus D, Human classification, Enterovirus D, Human isolation & purification, Myelitis epidemiology, Myelitis virology, Neuromuscular Diseases epidemiology, Neuromuscular Diseases virology, Phylogeny
- Abstract
Enteroviruses are a common cause of respiratory and gastrointestinal illness, and multiple subtypes, including poliovirus, can cause neurologic disease. In recent years, enterovirus D68 (EV-D68) has been associated with serious neurologic illnesses, including acute flaccid myelitis (AFM), frequently preceded by respiratory disease. A cluster of 11 suspect cases of pediatric AFM was identified in September 2016 in Phoenix, AZ. To determine if these cases were associated with EV-D68, we performed multiple genomic analyses of nasopharyngeal (NP) swabs and cerebrospinal fluid (CSF) material from the patients, including real-time PCR and amplicon sequencing targeting the EV-D68 VP1 gene and unbiased microbiome and metagenomic sequencing. Four of the 11 patients were classified as confirmed cases of AFM, and an additional case was classified as probable AFM. Real-time PCR and amplicon sequencing detected EV-D68 virus RNA in the three AFM patients from which NP swabs were collected, as well as in a fourth patient diagnosed with acute disseminated encephalomyelitis, a disease that commonly follows bacterial or viral infections, including enterovirus. No other obvious etiological causes for AFM were identified by 16S or RNA and DNA metagenomic sequencing in these cases, strengthening the likelihood that EV-D68 is an etiological factor. Herpes simplex viral DNA was detected in the CSF of the fourth case of AFM and in one additional suspect case from the cluster. Multiple genomic techniques, such as those described here, can be used to diagnose patients with suspected EV-D68 respiratory illness, to aid in AFM diagnosis, and for future EV-D68 surveillance and epidemiology. IMPORTANCE Enteroviruses frequently result in respiratory and gastrointestinal illness; however, multiple subtypes, including poliovirus, can cause severe neurologic disease. Recent biennial increases (i.e., 2014, 2016, and 2018) in cases of non-polio acute flaccid paralysis have led to speculations that other enteroviruses, specifically enterovirus D68 (EV-D68), are emerging to fill the niche that was left from poliovirus eradication. A cluster of 11 suspect cases of pediatric acute flaccid myelitis (AFM) was identified in 2016 in Phoenix, AZ. Multiple genomic analyses identified the presence of EV-D68 in the majority of clinical AFM cases. Beyond limited detection of herpesvirus, no other likely etiologies were found in the cluster. These findings strengthen the likelihood that EV-D68 is a cause of AFM and show that the rapid molecular assays developed for this study are useful for investigations of AFM and EV-D68., (Copyright © 2019 Bowers et al.)
- Published
- 2019
- Full Text
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38. Beyond the tip of the iceberg; a new view of the diversity of sulfite- and sulfate-reducing microorganisms.
- Author
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Vigneron A, Cruaud P, Alsop E, de Rezende JR, Head IM, and Tsesmetzis N
- Subjects
- Bacteria classification, Bacteria genetics, Ecosystem, Oxidation-Reduction, Phylogeny, Bacteria isolation & purification, Bacteria metabolism, Biodiversity, Fresh Water microbiology, Seawater chemistry, Sulfates metabolism, Sulfites metabolism
- Abstract
Sulfite-reducing and sulfate-reducing microorganisms (SRM) play important roles in anoxic environments, linking the sulfur and carbon cycles. With climate warming, the distribution of anoxic habitats conductive to dissimilatory SRM is expanding. Consequently, we hypothesize that novel SRM are likely to emerge from the rare biosphere triggered by environmental changes. Using the dsrB gene as a molecular marker of sulfite-reducers and sulfate-reducers, we analyzed the diversity, community composition, and abundance of SRM in 200 samples representing 14 different ecosystems, including marine and freshwater environments, oil reservoirs, and engineered infrastructure. Up to 167,397 species-level OTUs affiliated with 47 different families were identified. Up to 96% of these can be considered as "rare biosphere SRM". One third of the dsrB genes identified belonged to uncharacterized lineages. The dsrB sequences exhibited a strong pattern of selection in different ecosystems. These results expand our knowledge of the biodiversity and distribution of SRM, with implications for carbon and sulfur cycling in anoxic ecosystems.
- Published
- 2018
- Full Text
- View/download PDF
39. Evaluation of commercially available small RNASeq library preparation kits using low input RNA.
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Yeri A, Courtright A, Danielson K, Hutchins E, Alsop E, Carlson E, Hsieh M, Ziegler O, Das A, Shah RV, Rozowsky J, Das S, and Van Keuren-Jensen K
- Subjects
- Brain metabolism, Female, High-Throughput Nucleotide Sequencing, Humans, Liver metabolism, MicroRNAs analysis, MicroRNAs chemistry, Placenta metabolism, Pregnancy, Principal Component Analysis, RNA chemistry, Reagent Kits, Diagnostic, Sequence Analysis, RNA, Gene Library, RNA metabolism
- Abstract
Background: Evolving interest in comprehensively profiling the full range of small RNAs present in small tissue biopsies and in circulating biofluids, and how the profile differs with disease, has launched small RNA sequencing (RNASeq) into more frequent use. However, known biases associated with small RNASeq, compounded by low RNA inputs, have been both a significant concern and a hurdle to widespread adoption. As RNASeq is becoming a viable choice for the discovery of small RNAs in low input samples and more labs are employing it, there should be benchmark datasets to test and evaluate the performance of new sequencing protocols and operators. In a recent publication from the National Institute of Standards and Technology, Pine et al., 2018, the investigators used a commercially available set of three tissues and tested performance across labs and platforms., Results: In this paper, we further tested the performance of low RNA input in three commonly used and commercially available RNASeq library preparation kits; NEB Next, NEXTFlex, and TruSeq small RNA library preparation. We evaluated the performance of the kits at two different sites, using three different tissues (brain, liver, and placenta) with high (1 μg) and low RNA (10 ng) input from tissue samples, or 5.0, 3.0, 2.0, 1.0, 0.5, and 0.2 ml starting volumes of plasma. As there has been a lack of robust validation platforms for differentially expressed miRNAs, we also compared low input RNASeq data with their expression profiles on three different platforms (Abcam Fireplex, HTG EdgeSeq, and Qiagen miRNome)., Conclusions: The concordance of RNASeq results on these three platforms was dependent on the RNA expression level; the higher the expression, the better the reproducibility. The results provide an extensive analysis of small RNASeq kit performance using low RNA input, and replication of these data on three downstream technologies.
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- 2018
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40. Contextual Effects on the Perception of Duration.
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Kingston J, Kawahara S, Chambless D, Mash D, and Brenner-Alsop E
- Abstract
In the experiments reported here, listeners categorized and discriminated speech and non-speech analogue stimuli in which the durations of a vowel and a following consonant or their analogues were varied orthogonally. The listeners' native languages differed in how these durations covary in speakers' productions of such sequences. Because auditorist and autonomous models of speech perception hypothesize that the auditory qualities evoked by both kinds of stimuli determine their initial perceptual evaluation, they both predict that listeners from all the languages will respond similarly to non-speech analogues as they do to speech in both tasks. Because neither direct realist nor interactive models hypothesize such a processing stage, they predict instead that in the way in which vowel and consonant duration covary in the listeners' native languages will determine how they categorize and discriminate the speech stimuli, and that all listeners will categorize and discriminate the non-speech differently from the speech stimuli. Listeners' categorization of the speech stimuli did differ as a function of how these durations covary in their native languages, but all listeners discriminated the speech stimuli in the same way, and they all categorized and discriminated the non-speech stimuli in the same way, too. These similarities could arise from listeners adding the durations of the vowel and consonant intervals (or their analogues) in these tasks with these stimuli; they do so when linguistic experience does not influence them to perceive these durations otherwise. These results support an autonomous rather than interactive model in which listeners either add or apply their linguistic experience at a post-perceptual stage of processing. They do not however support an auditorist over a direct realist model because they provide no evidence that the signal's acoustic properties are transformed during the hypothesized prior perceptual stage.
- Published
- 2009
- Full Text
- View/download PDF
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