37 results on '"Scherler K"'
Search Results
2. Besprechungen
- Author
-
Schubert, M., Kolb, M., Höfer, A., and Scherler, K.
- Published
- 1995
- Full Text
- View/download PDF
3. Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder
- Author
-
Dean, K. R., Hammamieh, R., Mellon, S. H., Abu-Amara, D., Flory, J. D., Guffanti, G., Wang, K., Daigle, B. J., Gautam, A., Lee, I., Yang, R., Almli, L. M., Bersani, F. S., Chakraborty, N., Donohue, D., Kerley, K., Kim, T. -K., Laska, E., Young Lee, M., Lindqvist, D., Lori, A., Lu, L., Misganaw, B., Muhie, S., Newman, J., Price, N. D., Qin, S., Reus, V. I., Siegel, C., Somvanshi, P. R., Thakur, G. S., Zhou, Y., Baxter, D., Bierer, L., Blessing, E., Cho, J. H., Coy, M., Desarnaud, F., Fossati, S., Hoke, A., Kumar, R., Li, M., Makotkine, I., Miller, S. -A., Petzold, L., Price, L., Qian, M., Scherler, K., Srinivasan, S., Suessbrick, A., Tang, L., Wu, X., Wu, G., Wu, C., Hood, L., Ressler, K. J., Wolkowitz, O. M., Yehuda, R., Jett, M., Doyle, F. J., and Marmar, C.
- Subjects
0301 basic medicine ,Biomarker identification ,Oncology ,Male ,medicine.medical_specialty ,post-traumatic ,stress ,disorder ,MEDLINE ,Disease ,Stress Disorders, Post-Traumatic ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Internal medicine ,Diagnostic biomarker ,Medicine ,Humans ,Molecular Biology ,Veterans ,business.industry ,Traumatic stress ,Brain ,Integrated approach ,Omics ,Psychiatry and Mental health ,030104 developmental biology ,Military Personnel ,Cohort ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.
- Published
- 2018
4. Besprechungen
- Author
-
Hermanns, A., Kleine, D., and Scherler, K.
- Published
- 1994
- Full Text
- View/download PDF
5. Besprechungen
- Author
-
Meinberg, E., Balz, E., Baur, J., Bachleitner, R., and Scherler, K. -H.
- Published
- 1988
- Full Text
- View/download PDF
6. Besprechungen
- Author
-
Eichberg, H., Scherler, K., Leciejewski, K., Kaschuba, W., and Güldenpfennig, S.
- Published
- 1989
- Full Text
- View/download PDF
7. EL MEDIO AMBIENTE COMO ESPACIO PARA EL MOVIMIENTO
- Author
-
Scherler, K., primary
- Published
- 2015
- Full Text
- View/download PDF
8. Kinder lernen Sport
- Author
-
Scherler, K.
- Published
- 1976
- Full Text
- View/download PDF
9. Besprechungen
- Author
-
Scherler, K., primary and Wieland, H., additional
- Published
- 1995
- Full Text
- View/download PDF
10. Besprechungen
- Author
-
Schubert, M., primary, Kolb, M., additional, Höfer, A., additional, and Scherler, K., additional
- Published
- 1995
- Full Text
- View/download PDF
11. Besprechungen
- Author
-
Hermanns, A., primary, Kleine, D., additional, and Scherler, K., additional
- Published
- 1994
- Full Text
- View/download PDF
12. Kinder lernen Sport
- Author
-
Scherler, K., primary
- Published
- 1976
- Full Text
- View/download PDF
13. Besprechungen
- Author
-
Eichberg, H., primary, Scherler, K., additional, Leciejewski, K., additional, Kaschuba, W., additional, and Güldenpfennig, S., additional
- Published
- 1989
- Full Text
- View/download PDF
14. Besprechungen
- Author
-
Meinberg, E., primary, Balz, E., additional, Baur, J., additional, Bachleitner, R., additional, and Scherler, K. -H., additional
- Published
- 1988
- Full Text
- View/download PDF
15. Integrated Antigenic and Nucleic Acid Detection in Single Virions and Extracellular Vesicles with Viral Content.
- Author
-
Nguyen KT, Rima XY, Nguyen LTH, Wang X, Kwak KJ, Yoon MJ, Li H, Chiang CL, Doon-Ralls J, Scherler K, Fallen S, Godfrey SL, Wallick JA, Magaña SM, Palmer AF, Lee I, Nunn CC, Reeves KM, Kaplan HG, Goldman JD, Heath JR, Wang K, Pancholi P, Lee LJ, and Reátegui E
- Abstract
Virion-mediated outbreaks are imminent and despite rapid responses, continue to cause adverse symptoms and death. Therefore, tunable, sensitive, high-throughput assays are needed to help diagnose future virion-mediated outbreaks. Herein, it is developed a tunable in situ assay to selectively enrich virions and extracellular vesicles (EVs) and simultaneously detect antigens and nucleic acids at a single-particle resolution. The Biochip Antigen and RNA Assay (BARA) enhanced sensitivities compared to quantitative reverse-transcription polymerase chain reaction (qRT-PCR), enabling the detection of virions in asymptomatic patients, genetic mutations in single virions, and enabling the continued long-term expression of viral RNA in the EV-enriched subpopulation in the plasma of patients with post-acute sequelae of the coronavirus disease of 2019 (COVID-19). BARA revealed highly accurate diagnoses of COVID-19 by simultaneously detecting the spike glycoprotein and nucleocapsid-encoding RNA in saliva and nasopharyngeal swab samples. Altogether, the single-particle detection of antigens and viral RNA provides a tunable framework for the diagnosis, monitoring, and mutation screening of current and future outbreaks., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)
- Published
- 2024
- Full Text
- View/download PDF
16. Engineering a tunable micropattern-array assay to sort single extracellular vesicles and particles to detect RNA and protein in situ.
- Author
-
Zhang J, Rima XY, Wang X, Nguyen LTH, Huntoon K, Ma Y, Palacio PL, Nguyen KT, Albert K, Duong-Thi MD, Walters N, Kwak KJ, Yoon MJ, Li H, Doon-Ralls J, Hisey CL, Lee D, Wang Y, Ha J, Scherler K, Fallen S, Lee I, Palmer AF, Jiang W, Magaña SM, Wang K, Kim BYS, Lee LJ, and Reátegui E
- Subjects
- Humans, Lipopolysaccharides, RNA, Messenger, Lipoproteins, Extracellular Vesicles genetics, Extracellular Vesicles metabolism, MicroRNAs genetics, MicroRNAs metabolism, Glioblastoma diagnosis, Glioblastoma genetics
- Abstract
The molecular heterogeneity of extracellular vesicles (EVs) and the co-isolation of physically similar particles, such as lipoproteins (LPs), confounds and limits the sensitivity of EV bulk biomarker characterization. Herein, we present a single-EV and particle (siEVP) protein and RNA assay (
siEVP PRA) to simultaneously detect mRNAs, miRNAs, and proteins in subpopulations of EVs and LPs. ThesiEVP PRA immobilizes and sorts particles via positive immunoselection onto micropatterns and focuses biomolecular signals in situ. By detecting EVPs at a single-particle resolution, thesiEVP PRA outperformed the sensitivities of bulk-analysis benchmark assays for RNA and protein. To assess the specificity of RNA detection in complex biofluids, EVs from various glioma cell lines were processed with small RNA sequencing, whereby two mRNAs and two miRNAs associated with glioblastoma multiforme (GBM) were chosen for cross-validation. Despite the presence of single-EV-LP co-isolates in serum, thesiEVP PRA detected GBM-associated vesicular RNA profiles in GBM patient siEVPs. ThesiEVP PRA effectively examines intravesicular, intervesicular, and interparticle heterogeneity with diagnostic promise., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)- Published
- 2023
- Full Text
- View/download PDF
17. Organ-specific immunity: A tissue analysis framework for investigating local immune responses to SARS-CoV-2.
- Author
-
Ng AHC, Hu H, Wang K, Scherler K, Warren SE, Zollinger DR, McKay-Fleisch J, Sorg K, Beechem JM, Ragaglia E, Lacy JM, Smith KD, Marshall DA, Bundesmann MM, López de Castilla D, Corwin D, Yarid N, Knudsen BS, Lu Y, Goldman JD, and Heath JR
- Subjects
- Humans, Post-Acute COVID-19 Syndrome, Inflammation, Immunity, SARS-CoV-2, COVID-19
- Abstract
Local immune activation at mucosal surfaces, mediated by mucosal lymphoid tissues, is vital for effective immune responses against pathogens. While pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread to multiple organs, patients with coronavirus disease 2019 (COVID-19) primarily experience inflammation and damage in their lungs. To investigate this apparent organ-specific immune response, we develop an analytical framework that recognizes the significance of mucosal lymphoid tissues. This framework combines histology, immunofluorescence, spatial transcript profiling, and mathematical modeling to identify cellular and gene expression differences between the lymphoid tissues of the lung and the gut and predict the determinants of those differences. Our findings indicate that mucosal lymphoid tissues are pivotal in organ-specific immune response to SARS-CoV-2, mediating local inflammation and tissue damage and contributing to immune dysfunction. The framework developed here has potential utility in the study of long COVID and may streamline biomarker discovery and treatment design for diseases with differential pathologies at the organ level., Competing Interests: Declaration of interests S.E.W., D.R.Z., J.M.-F., K. Sorg, and J.M.B. are employees of NanoString Technologies (NSTG). J.R.H. is on the scientific advisory board of NSTG., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
18. An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets.
- Author
-
Park J, Fong Legaspi SL, Schwartzman LM, Gygli SM, Sheng ZM, Freeman AD, Matthews LM, Xiao Y, Ramuta MD, Batchenkova NA, Qi L, Rosas LA, Williams SL, Scherler K, Gouzoulis M, Bellayr I, Morens DM, Walters KA, Memoli MJ, Kash JC, and Taubenberger JK
- Subjects
- Animals, Antibodies, Viral, Ferrets, Horses, Humans, Influenza A Virus, H7N3 Subtype, Mice, Swine, Influenza A Virus, H1N1 Subtype, Influenza A Virus, H3N8 Subtype, Influenza A Virus, H5N1 Subtype, Influenza A Virus, H7N9 Subtype, Influenza Vaccines, Orthomyxoviridae Infections
- Abstract
Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics and pandemics and from viruses adapted to a variety of animals including poultry, pigs, and horses. Vaccines that broadly protect against all such IAVs, so-called "universal" influenza vaccines, do not currently exist but are urgently needed. Here, we demonstrated that an inactivated, multivalent whole-virus vaccine, delivered intramuscularly or intranasally, was broadly protective against challenges with multiple IAV hemagglutinin and neuraminidase subtypes in both mice and ferrets. The vaccine is composed of four β-propiolactone-inactivated low-pathogenicity avian IAV subtypes of H1N9, H3N8, H5N1, and H7N3. Vaccinated mice and ferrets demonstrated substantial protection against a variety of IAVs, including the 1918 H1N1 strain, the highly pathogenic avian H5N8 strain, and H7N9. We also observed protection against challenge with antigenically variable and heterosubtypic avian, swine, and human viruses. Compared to control animals, vaccinated mice and ferrets demonstrated marked reductions in viral titers, lung pathology, and host inflammatory responses. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development.
- Published
- 2022
- Full Text
- View/download PDF
19. Multiple early factors anticipate post-acute COVID-19 sequelae.
- Author
-
Su Y, Yuan D, Chen DG, Ng RH, Wang K, Choi J, Li S, Hong S, Zhang R, Xie J, Kornilov SA, Scherler K, Pavlovitch-Bedzyk AJ, Dong S, Lausted C, Lee I, Fallen S, Dai CL, Baloni P, Smith B, Duvvuri VR, Anderson KG, Li J, Yang F, Duncombe CJ, McCulloch DJ, Rostomily C, Troisch P, Zhou J, Mackay S, DeGottardi Q, May DH, Taniguchi R, Gittelman RM, Klinger M, Snyder TM, Roper R, Wojciechowska G, Murray K, Edmark R, Evans S, Jones L, Zhou Y, Rowen L, Liu R, Chour W, Algren HA, Berrington WR, Wallick JA, Cochran RA, Micikas ME, Wrin T, Petropoulos CJ, Cole HR, Fischer TD, Wei W, Hoon DSB, Price ND, Subramanian N, Hill JA, Hadlock J, Magis AT, Ribas A, Lanier LL, Boyd SD, Bluestone JA, Chu H, Hood L, Gottardo R, Greenberg PD, Davis MM, Goldman JD, and Heath JR
- Subjects
- Adaptive Immunity genetics, Adolescent, Adult, Aged, Aged, 80 and over, Autoantibodies blood, Biomarkers metabolism, Blood Proteins metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, COVID-19 immunology, COVID-19 pathology, COVID-19 virology, Disease Progression, Female, Humans, Immunity, Innate genetics, Longitudinal Studies, Male, Middle Aged, Risk Factors, SARS-CoV-2 isolation & purification, Transcriptome, Young Adult, Post-Acute COVID-19 Syndrome, COVID-19 complications, COVID-19 diagnosis, Convalescence
- Abstract
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8
+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies., Competing Interests: Declaration of interests J.R.H. and A.R. are founders and board members of PACT Pharma. J.R.H. is a board member of Isoplexis, and A.R. is the scientific advisor to Isoplexis. M.M.D. is a member of the Scientific Advisory Board of PACT Pharma. J.A.B. is a member of the Scientific Advisory Boards of Arcus, Solid, and VIR. J.A.B. is a member of the Board of Directors of Gilead and Provention. J.A.B. is the CEO of Sonoma Biotherapeutics. L.L.L. is on the scientific advisory boards of Alector, Atreca, Dragonfly, DrenBio, Nkarta, Obsidian Therapeutics, and SBI Biotech. R.G. has received consulting income from Juno Therapeutics, Takeda, Infotech Soft, Celgene, and Merck, has received research support from Janssen Pharmaceuticals and Juno Therapeutics, and declares ownership in CellSpace Biosciences. P.D.G. is on the Scientific Advisory Board of Celsius, Earli, Elpiscience, Immunoscape, Rapt, and Nextech, was a scientific founder of Juno Therapeutics, and receives research support from Lonza. J.D.G. declared contracted research with Gilead, Lilly, and Regeneron. J.A.H. received consulting fees or honoraria from Gilead Sciences, Amplyx, Allovir, Allogene therapeutics, CRISPR therapeutics, CSL Behring, OptumHealth, Octapharma, and Takeda and research funding from Takeda, Allovir, Karius, and Gilead Sciences. Q.D., D.H.M., R.T., R.M.G., M.K., and T.M.S. have employment and equity ownership with Adaptive Biotechnologies. The remaining authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
20. Sex Differences in Influenza: The Challenge Study Experience.
- Author
-
Giurgea LT, Cervantes-Medina A, Walters KA, Scherler K, Han A, Czajkowski LM, Baus HA, Hunsberger S, Klein SL, Kash JC, Taubenberger JK, and Memoli MJ
- Subjects
- Animals, Antibodies, Viral, Female, Hemagglutination Inhibition Tests, Humans, Male, Neuraminidase, Prospective Studies, Retrospective Studies, Sex Characteristics, Influenza A Virus, H1N1 Subtype, Influenza Vaccines, Influenza, Human epidemiology
- Abstract
Background: Preclinical animal studies and retrospective human studies suggest that adult females have worse outcomes from influenza than males. Prospective studies in humans are missing., Methods: Data from 164 healthy volunteers who underwent influenza A/California/04/2009/H1N1 challenge were compiled to compare differences between sexes. Baseline characteristics, including hormone levels, hemagglutination inhibition (HAI) titers, neuraminidase inhibition (NAI) titers, and outcomes after challenge were compared. Linear and logistic regression models were built to determine significant predictor variables with respect to outcomes of interest., Results: HAI titers were similar between the sexes, but NAI titers were higher in males than females at 4 weeks and 8 weeks postchallenge. Females were more likely to have symptoms (mean, 0.96 vs 0.80; P = .003) and to have a higher number of symptoms (median, 3 vs 4; P = .011) than males. Linear and logistic regression models showed that prechallenge NAI titers, but not HAI titers or sex hormone levels, were predictive of all shedding and symptom outcomes of interest., Conclusions: Females in our cohorts were more likely to be symptomatic and to have a higher number of symptoms than males. NAI titers predicted all outcomes of interest and may explain differential outcomes between the sexes., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)
- Published
- 2022
- Full Text
- View/download PDF
21. Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19.
- Author
-
D'Agnillo F, Walters KA, Xiao Y, Sheng ZM, Scherler K, Park J, Gygli S, Rosas LA, Sadtler K, Kalish H, Blatti CA 3rd, Zhu R, Gatzke L, Bushell C, Memoli MJ, O'Day SJ, Fischer TD, Hammond TC, Lee RC, Cash JC, Powers ME, O'Keefe GE, Butnor KJ, Rapkiewicz AV, Travis WD, Layne SP, Kash JC, and Taubenberger JK
- Subjects
- Cellular Senescence, Fibrinolysis, Humans, Lung, SARS-CoV-2, COVID-19
- Abstract
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.
- Published
- 2021
- Full Text
- View/download PDF
22. The effect of calcium and magnesium on activity, immunogenicity, and efficacy of a recombinant N1/N2 neuraminidase vaccine.
- Author
-
Giurgea LT, Park JK, Walters KA, Scherler K, Cervantes-Medina A, Freeman A, Rosas LA, Kash JC, Taubenberger JK, and Memoli MJ
- Abstract
Despite the importance of immunity against neuraminidase (NA), NA content and immunogenicity are neglected in current influenza vaccines. To address this, a recombinant N1/N2 NA vaccine (NAV) was developed. Stability assays were used to determine optimal temperature and buffer conditions for vaccine storage. The effect of divalent cation-related enhancement of NA stability and activity on N1 and N2 immunogenicity and efficacy against viral challenge was assessed. Differences in activity between N1 and N2 and cation-related activity enhancement did not translate into differences in immunogenicity or efficacy. NAV-vaccinated mice showed robust antibody titers against N1 and N2, and after challenge with influenza A (H1N1) virus, decreased viral titers and decreased antiviral and inflammatory responses by transcriptomic analysis. These findings provide guidance for optimal storage and assessment of NA-based vaccines and confirm the importance of NA in influenza vaccination strategies in attenuating viral replication and limiting inflammatory responses necessary to clear infection.
- Published
- 2021
- Full Text
- View/download PDF
23. Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.
- Author
-
Su Y, Chen D, Yuan D, Lausted C, Choi J, Dai CL, Voillet V, Duvvuri VR, Scherler K, Troisch P, Baloni P, Qin G, Smith B, Kornilov SA, Rostomily C, Xu A, Li J, Dong S, Rothchild A, Zhou J, Murray K, Edmark R, Hong S, Heath JE, Earls J, Zhang R, Xie J, Li S, Roper R, Jones L, Zhou Y, Rowen L, Liu R, Mackay S, O'Mahony DS, Dale CR, Wallick JA, Algren HA, Zager MA, Wei W, Price ND, Huang S, Subramanian N, Wang K, Magis AT, Hadlock JJ, Hood L, Aderem A, Bluestone JA, Lanier LL, Greenberg PD, Gottardo R, Davis MM, Goldman JD, and Heath JR
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Severity of Illness Index, COVID-19 blood, COVID-19 immunology, Genomics, RNA-Seq, SARS-CoV-2 immunology, SARS-CoV-2 metabolism, Single-Cell Analysis
- Abstract
We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention., Competing Interests: Declaration of Interests J.R.H. is founder and board member of Isoplexis and PACT Pharma. M.M.D. is a member of the Scientific Advisory Board of PACT Pharma. J.A.B. is a member of the Scientific Advisory Boards of Arcus, Celsius, and VIR. J.A.B. is a member of the Board of Directors of Rheos and Provention. J.A.B. has recently joined Sonoma Biotherapeutics as President and CEO. Sonoma Biotherapeutics is involved in developing novel Treg-based cell therapies for the treatment of autoimmune diseases. R.G. has received consulting income from Juno Therapeutics, Takeda, Infotech Soft, Celgene, Merck and has received research support from Janssen Pharmaceuticals and Juno Therapeutics, and declares ownership in CellSpace Biosciences. P.D.G is on the Scientific Advisory Board of Celsius, Earli, Elpiscience, Immunoscape, Rapt, and Nextech, was a scientific founder of Juno Therapeutics, and receives research support from Lonza. J.D.G. declared contracted research with Gilead, Lilly, and Regeneron. The remaining authors declare no competing interests., (Published by Elsevier Inc.)
- Published
- 2020
- Full Text
- View/download PDF
24. Pre-existing immunity to influenza virus hemagglutinin stalk might drive selection for antibody-escape mutant viruses in a human challenge model.
- Author
-
Park JK, Xiao Y, Ramuta MD, Rosas LA, Fong S, Matthews AM, Freeman AD, Gouzoulis MA, Batchenkova NA, Yang X, Scherler K, Qi L, Reed S, Athota R, Czajkowski L, Han A, Morens DM, Walters KA, Memoli MJ, Kash JC, and Taubenberger JK
- Subjects
- Animals, Antibodies, Neutralizing genetics, Antibodies, Neutralizing immunology, Antibodies, Neutralizing pharmacology, Antibodies, Viral genetics, Antibodies, Viral immunology, Antibodies, Viral pharmacology, Conserved Sequence genetics, Cross Reactions immunology, Hemagglutinin Glycoproteins, Influenza Virus immunology, Humans, Influenza A Virus, H1N1 Subtype immunology, Influenza A Virus, H1N1 Subtype pathogenicity, Influenza Vaccines genetics, Influenza Vaccines immunology, Influenza, Human immunology, Influenza, Human prevention & control, Influenza, Human virology, Mice, Selection, Genetic immunology, Hemagglutinin Glycoproteins, Influenza Virus genetics, Influenza A Virus, H1N1 Subtype genetics, Influenza, Human genetics, Selection, Genetic genetics
- Abstract
The conserved region of influenza hemagglutinin (HA) stalk (or stem) has gained attention as a potent target for universal influenza vaccines
1-5 . Although the HA stalk region is relatively well conserved, the evolutionarily dynamic nature of influenza viruses6 raises concerns about the possible emergence of viruses carrying stalk escape mutation(s) under sufficient immune pressure. Here we show that immune pressure on the HA stalk can lead to expansion of escape mutant viruses in study participants challenged with a 2009 H1N1 pandemic influenza virus inoculum containing an A388V polymorphism in the HA stalk (45% wild type and 55% mutant). High level of stalk antibody titers was associated with the selection of the mutant virus both in humans and in vitro. Although the mutant virus showed slightly decreased replication in mice, it was not observed in cell culture, ferrets or human challenge participants. The A388V mutation conferred resistance to some of the potent HA stalk broadly neutralizing monoclonal antibodies (bNAbs). Co-culture of wild-type and mutant viruses in the presence of either a bNAb or human serum resulted in rapid expansion of the mutant. These data shed light on a potential obstacle for the success of HA-stalk-targeting universal influenza vaccines-viral escape from vaccine-induced stalk immunity.- Published
- 2020
- Full Text
- View/download PDF
25. Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories.
- Author
-
Su Y, Chen D, Lausted C, Yuan D, Choi J, Dai C, Voillet V, Scherler K, Troisch P, Duvvuri VR, Baloni P, Qin G, Smith B, Kornilov S, Rostomily C, Xu A, Li J, Dong S, Rothchild A, Zhou J, Murray K, Edmark R, Hong S, Jones L, Zhou Y, Roper R, Mackay S, O'Mahony DS, Dale CR, Wallick JA, Algren HA, Michael ZA, Magis A, Wei W, Price ND, Huang S, Subramanian N, Wang K, Hadlock J, Hood L, Aderem A, Bluestone JA, Lanier LL, Greenberg P, Gottardo R, Davis MM, Goldman JD, and Heath JR
- Abstract
Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8
+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.- Published
- 2020
- Full Text
- View/download PDF
26. Alterations in Plasma microRNA and Protein Levels in War Veterans with Chronic Mild Traumatic Brain Injury.
- Author
-
Ghai V, Fallen S, Baxter D, Scherler K, Kim TK, Zhou Y, Meabon JS, Logsdon AF, Banks WA, Schindler AG, Cook DG, Peskind ER, Lee I, and Wang K
- Subjects
- Afghan Campaign 2001-, Biomarkers blood, Blast Injuries diagnosis, Blast Injuries psychology, Brain Concussion diagnosis, Brain Concussion psychology, Chronic Disease, Humans, Iraq War, 2003-2011, Retrospective Studies, Blast Injuries blood, Blood Proteins metabolism, Brain Concussion blood, MicroRNAs blood, Veterans psychology
- Abstract
Blast-related mild traumatic brain injury (mTBI) is considered the "signature" injury of the wars in Iraq and Afghanistan. Identifying biomarkers that could aid in diagnosis and assessment of chronic mTBI are urgently needed, as little progress has been made toward identifying blood-based biomarkers of repetitive mTBI in the chronic state. Addressing this knowledge gap is especially important in the population of military veterans who are receiving assessment and care often years after their last exposure. Circulating microRNAs (miRNAs), especially those encapsulated in extracellular vesicles (EVs), have gained interest as a source of biomarkers for neurological conditions. To identify biomarkers for chronic mTBI, we used next generation sequencing (NGS) to analyze miRNAs in plasma and plasma-derived EVs from 27 Iraq and Afghanistan war veterans with blast-related chronic mTBI, 11 deployed veteran non-TBI controls, and 31 civilian controls. We identified 32 miRNAs in plasma and 45 miRNAs in EVs that significantly changed in the chronic mTBI cohort compared with control groups. These miRNAs were predominantly associated with pathways involved in neuronal function, vascular remodeling, blood-brain barrier integrity, and neuroinflammation. In addition, the plasma proteome was analyzed and showed that the concentrations of C-reactive protein (CRP) and membrane metalloendopeptidase (MME) were elevated in chronic mTBI samples. These plasma miRNAs and proteins could potentially be used as biomarkers and provide insights into the molecular processes associated with the long-term health outcomes associated with blast-related chronic mTBI.
- Published
- 2020
- Full Text
- View/download PDF
27. The Impact of Moyamoya Disease and RNF213 Mutations on the Spectrum of Plasma Protein and MicroRNA.
- Author
-
Lee MJ, Fallen S, Zhou Y, Baxter D, Scherler K, Kuo MF, and Wang K
- Abstract
Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by occlusion of bilateral internal carotid and intracerebral arteries with the compensatory growth of fragile small vessels. MMD patients develop recurrent infarctions in the basal ganglia and subcortical regions. Symptoms include transient ischemic attack or stroke, seizures, and headaches, which may occur suddenly or in a stepwise progression. Mutations in Ring Finger Protein 213 ( RNF213 ), a Zinc ring finger protein, have been identified in some MMD patients but the etiology of MMD is still largely unknown. To gain insight into the pathophysiology of MMD, we characterized the impact of the RNF213 mutations on plasma protein and RNA profiles. Isobaric tags for relative and absolute quantitation and proximity extension assay were used to characterize the plasma proteome. Next generation sequencing-based small RNAseq was used to analyze the cell-free small RNAs in whole plasma and RNA encapsulated in extracellular vesicles. The changes of miRNAs and proteins identified are associated with signaling processes including angiogenesis and immune activities which may reflect the pathology and progression of MMD.
- Published
- 2019
- Full Text
- View/download PDF
28. Distinct Profiles of Cell-Free MicroRNAs in Plasma of Veterans with Post-Traumatic Stress Disorder.
- Author
-
Lee MY, Baxter D, Scherler K, Kim TK, Wu X, Abu-Amara D, Flory J, Yehuda R, Marmar C, Jett M, Lee I, Wang K, and Hood L
- Abstract
Dysregulation of circulating microRNAs (miRNAs) in body fluids has been reported in psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, and post-traumatic stress disorder (PTSD). Recent studies of various diseases showed that extracellular vesicles (EV) in body fluids can provide different spectra of circulating miRNAs and disease-associated signatures from whole fluid or EV-depleted fraction. However, the association of miRNAs in EVs to PTSD has not been studied. In this study, we performed a comprehensive profiling of miRNAs in whole plasma, extracellular vesicles (EV) and EV-depleted plasma (EVD) samples collected from combat veterans with PTSD and matched controls by utilizing a next-generation sequencing (NGS) platform. In total, 520 circulating miRNAs were quantified from 24 male Iraq and Afghanistan combat veterans with ( n = 12) and without ( n = 12) PTSD. The overall miRNA profiles in whole plasma, EV and EVD fractions were different and miRNAs affected by PTSD were also distinct in each sample type. The concentration changes of miR-203a-3p in EV and miR-339-5p in EVD were confirmed in an independent validation cohort that consisted of 20 veterans (10 with and 10 without PTSD) using qPCR. The target genes of these two miRNAs were involved in signaling pathways and comorbid conditions associated with PTSD (e.g., neurotransmitter systems such as dopaminergic and serotonergic signaling, inflammatory response, and cardiovascular diseases). Our findings suggest that PTSD may have different impacts on miRNAs encapsulated in vesicles and outside of vesicles. Further studies using larger samples are needed to evaluate the utility of these miRNAs as diagnostic biomarkers for PTSD.
- Published
- 2019
- Full Text
- View/download PDF
29. Differential Effects of Influenza Virus NA, HA Head, and HA Stalk Antibodies on Peripheral Blood Leukocyte Gene Expression during Human Infection.
- Author
-
Walters KA, Zhu R, Welge M, Scherler K, Park JK, Rahil Z, Wang H, Auvil L, Bushell C, Lee MY, Baxter D, Bristol T, Rosas LA, Cervantes-Medina A, Czajkowski L, Han A, Memoli MJ, Taubenberger JK, and Kash JC
- Subjects
- Acute Disease, Adolescent, Adult, Convalescence, Cross Protection, Female, Gene Expression Profiling, Healthy Volunteers, Hemagglutination Inhibition Tests, Human Experimentation, Humans, Influenza A Virus, H1N1 Subtype, Influenza, Human blood, Male, Middle Aged, Virus Shedding, Young Adult, Antibodies, Viral blood, Hemagglutinin Glycoproteins, Influenza Virus immunology, Influenza, Human immunology, Leukocytes immunology, Neuraminidase immunology
- Abstract
In this study, we examined the relationships between anti-influenza virus serum antibody titers, clinical disease, and peripheral blood leukocyte (PBL) global gene expression during presymptomatic, acute, and convalescent illness in 83 participants infected with 2009 pandemic H1N1 virus in a human influenza challenge model. Using traditional statistical and logistic regression modeling approaches, profiles of differentially expressed genes that correlated with active viral shedding, predicted length of viral shedding, and predicted illness severity were identified. These analyses further demonstrated that challenge participants fell into three peripheral blood leukocyte gene expression phenotypes that significantly correlated with different clinical outcomes and prechallenge serum titers of antibodies specific for the viral neuraminidase, hemagglutinin head, and hemagglutinin stalk. Higher prechallenge serum antibody titers were inversely correlated with leukocyte responsiveness in participants with active disease and could mask expression of peripheral blood markers of clinical disease in some participants, including viral shedding and symptom severity. Consequently, preexisting anti-influenza antibodies may modulate PBL gene expression, and this must be taken into consideration in the development and interpretation of peripheral blood diagnostic and prognostic assays of influenza infection. IMPORTANCE Influenza A viruses are significant human pathogens that caused 83,000 deaths in the United States during 2017 to 2018, and there is need to understand the molecular correlates of illness and to identify prognostic markers of viral infection, symptom severity, and disease course. Preexisting antibodies against viral neuraminidase (NA) and hemagglutinin (HA) proteins play a critical role in lessening disease severity. We performed global gene expression profiling of peripheral blood leukocytes collected during acute and convalescent phases from a large cohort of people infected with A/H1N1pdm virus. Using statistical and machine-learning approaches, populations of genes were identified early in infection that correlated with active viral shedding, predicted length of shedding, or disease severity. Finally, these gene expression responses were differentially affected by increased levels of preexisting influenza antibodies, which could mask detection of these markers of contagiousness and disease severity in people with active clinical disease.
- Published
- 2019
- Full Text
- View/download PDF
30. Extracellular vesicle RNAs reflect placenta dysfunction and are a biomarker source for preterm labour.
- Author
-
Fallen S, Baxter D, Wu X, Kim TK, Shynlova O, Lee MY, Scherler K, Lye S, Hood L, and Wang K
- Subjects
- Chromosomes, Human genetics, Female, Gene Regulatory Networks, Humans, MicroRNAs blood, Obstetric Labor, Premature blood, Pregnancy, Reproducibility of Results, Sequence Analysis, RNA, Biomarkers metabolism, Extracellular Vesicles genetics, Obstetric Labor, Premature genetics, Placenta metabolism, Placenta physiopathology, RNA metabolism
- Abstract
Preterm birth (PTB) can lead to lifelong complications and challenges. Identifying and monitoring molecular signals in easily accessible biological samples that can diagnose or predict the risk of preterm labour (PTL) in pregnant women will reduce or prevent PTBs. A number of studies identified putative biomarkers for PTL including protein, miRNA and hormones from various body fluids. However, biomarkers identified from these studies usually lack consistency and reproducibility. Extracellular vesicles (EVs) in circulation have gained significant interest in recent years as these vesicles may be involved in cell-cell communication. We have used an improved small RNA library construction protocol and a newly developed size exclusion chromatography (SEC)-based EV purification method to gain a comprehensive view of circulating RNA in plasma and its distribution by analysing RNAs in whole plasma and EV-associated and EV-depleted plasma. We identified a number of miRNAs in EVs that can be used as biomarkers for PTL, and these miRNAs may reflect the pathological changes of the placenta during the development of PTL. To our knowledge, this is the first study to report a comprehensive picture of circulating RNA, including RNA in whole plasma, EV and EV-depleted plasma, in PTL and reveal the usefulness of EV-associated RNAs in disease diagnosis., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Published
- 2018
- Full Text
- View/download PDF
31. sRNAnalyzer-a flexible and customizable small RNA sequencing data analysis pipeline.
- Author
-
Wu X, Kim TK, Baxter D, Scherler K, Gordon A, Fong O, Etheridge A, Galas DJ, and Wang K
- Subjects
- Escherichia coli genetics, Gene Expression Profiling, Humans, MicroRNAs blood, MicroRNAs metabolism, Oligonucleotide Array Sequence Analysis, RNA, Bacterial chemistry, RNA, Bacterial metabolism, RNA, Small Untranslated chemistry, RNA, Small Untranslated metabolism, Real-Time Polymerase Chain Reaction, Software, High-Throughput Nucleotide Sequencing methods, MicroRNAs chemistry, Sequence Analysis, RNA methods
- Abstract
Although many tools have been developed to analyze small RNA sequencing (sRNA-Seq) data, it remains challenging to accurately analyze the small RNA population, mainly due to multiple sequence ID assignment caused by short read length. Additional issues in small RNA analysis include low consistency of microRNA (miRNA) measurement results across different platforms, miRNA mapping associated with miRNA sequence variation (isomiR) and RNA editing, and the origin of those unmapped reads after screening against all endogenous reference sequence databases. To address these issues, we built a comprehensive and customizable sRNA-Seq data analysis pipeline-sRNAnalyzer, which enables: (i) comprehensive miRNA profiling strategies to better handle isomiRs and summarization based on each nucleotide position to detect potential SNPs in miRNAs, (ii) different sequence mapping result assignment approaches to simulate results from microarray/qRT-PCR platforms and a local probabilistic model to assign mapping results to the most-likely IDs, (iii) comprehensive ribosomal RNA filtering for accurate mapping of exogenous RNAs and summarization based on taxonomy annotation. We evaluated our pipeline on both artificial samples (including synthetic miRNA and Escherichia coli cultures) and biological samples (human tissue and plasma). sRNAnalyzer is implemented in Perl and available at: http://srnanalyzer.systemsbiology.net/., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2017
- Full Text
- View/download PDF
32. The Importance of Standardization on Analyzing Circulating RNA.
- Author
-
Lee I, Baxter D, Lee MY, Scherler K, and Wang K
- Subjects
- Biomarkers, Tumor genetics, Blood Platelets, Cell-Free Nucleic Acids isolation & purification, Diet, Exercise, Female, High-Throughput Nucleotide Sequencing methods, Humans, Male, MicroRNAs genetics, Polymerase Chain Reaction methods, Polymerase Chain Reaction standards, Specimen Handling standards, Time Factors, Cell-Free Nucleic Acids analysis, Genetic Markers, High-Throughput Nucleotide Sequencing standards
- Abstract
Circulating RNAs, especially microRNAs (miRNAs), have recently emerged as non-invasive disease biomarkers. Despite enthusiasm and numerous reports on disease-associated circulating miRNAs, currently there is no circulating miRNA-based diagnostic in use. In addition, there are many contradictory reports on the concentration changes of specific miRNA in circulation. Here we review the impact of various technical and non-technical factors related to circulating miRNA measurement and elucidate the importance of having a general guideline for sample preparation and concentration measurement in studying circulating RNA.
- Published
- 2017
- Full Text
- View/download PDF
33. Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease.
- Author
-
Kash JC, Walters KA, Kindrachuk J, Baxter D, Scherler K, Janosko KB, Adams RD, Herbert AS, James RM, Stonier SW, Memoli MJ, Dye JM, Davey RT Jr, Chertow DS, and Taubenberger JK
- Subjects
- Disease Outbreaks, Hemorrhagic Fever, Ebola blood, Humans, Longitudinal Studies, RNA, Viral blood, RNA, Viral genetics, Virus Replication physiology, Ebolavirus pathogenicity, Hemorrhagic Fever, Ebola virology, Leukocytes metabolism
- Abstract
The 2013-2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration-approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily peripheral blood samples collected from a patient with severe Ebola virus disease. This individual was provided with supportive care without experimental therapies at the National Institutes of Health Clinical Center from before onset of critical illness to recovery. Pearson analysis of daily gene expression signatures revealed marked gene expression changes in peripheral blood leukocytes that correlated with changes in serum and peripheral blood leukocytes, viral load, antibody responses, coagulopathy, multiple organ dysfunction, and then recovery. This study revealed marked shifts in immune and antiviral responses that preceded changes in medical condition, indicating that clearance of replicating Ebola virus from peripheral blood leukocytes is likely important for systemic viral clearance., (Copyright © 2017, American Association for the Advancement of Science.)
- Published
- 2017
- Full Text
- View/download PDF
34. High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington's disease CAG knock-in mice across multiple genetic backgrounds.
- Author
-
Ament SA, Pearl JR, Grindeland A, St Claire J, Earls JC, Kovalenko M, Gillis T, Mysore J, Gusella JF, Lee JM, Kwak S, Howland D, Lee MY, Baxter D, Scherler K, Wang K, Geman D, Carroll JB, MacDonald ME, Carlson G, Wheeler VC, Price ND, and Hood LE
- Subjects
- Animals, Corpus Striatum pathology, Disease Models, Animal, Gene Expression Regulation, Developmental, Gene Knock-In Techniques, Genetic Background, Genomic Instability genetics, Humans, Huntingtin Protein biosynthesis, Huntington Disease pathology, Mice, Mutation genetics, Neurons metabolism, Neurons pathology, Phenotype, Transcriptome genetics, Corpus Striatum metabolism, Huntingtin Protein genetics, Huntington Disease genetics, Trinucleotide Repeat Expansion genetics
- Abstract
Huntington's disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+ mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
- Full Text
- View/download PDF
35. Circulating MicroRNAs and Life Expectancy Among Identical Twins.
- Author
-
Wu S, Kim TK, Wu X, Scherler K, Baxter D, Wang K, Krasnow RE, Reed T, and Dai J
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers blood, Humans, Male, MicroRNAs genetics, Middle Aged, Mortality, Life Expectancy, MicroRNAs blood, Twins, Monozygotic genetics
- Abstract
Human life expectancy is influenced not only by longevity assurance mechanisms and disease susceptibility loci but also by the environment, gene-environment interactions, and chance. MicroRNAs (miRNAs) are a class of small noncoding RNAs closely related to genes. Circulating miRNAs have been shown as promising noninvasive biomarkers in the development of many pathophysiological conditions. However, the concentration of miRNA in the circulation may also be affected by environmental factors. We used a next-generation sequencing platform to assess the association of circulating miRNA with life expectancy, for which deaths are due to all causes independent of genes. In addition, we showed that miRNAs are present in 41-year archived plasma samples, which may be useful for both life expectancy and all-cause mortality risk assessment. Plasma miRNAs from nine identical male twins were profiled using next-generation sequencing. The average absolute difference in the minimum life expectancy was 9.68 years. Intraclass correlation coefficients were above 0.4 for 50% of miRNAs. Comparing deceased twins with their alive co-twin brothers, the concentrations were increased for 34 but decreased for 30 miRNAs. Identical twins discordant in life expectancy were dissimilar in the majority of miRNAs, suggesting that environmental factors are pivotal in miRNAs related to life expectancy., (© 2016 John Wiley & Sons Ltd/University College London.)
- Published
- 2016
- Full Text
- View/download PDF
36. Contemporary avian influenza A virus subtype H1, H6, H7, H10, and H15 hemagglutinin genes encode a mammalian virulence factor similar to the 1918 pandemic virus H1 hemagglutinin.
- Author
-
Qi L, Pujanauski LM, Davis AS, Schwartzman LM, Chertow DS, Baxter D, Scherler K, Hartshorn KL, Slemons RD, Walters KA, Kash JC, and Taubenberger JK
- Subjects
- Animals, Birds, Cytopathogenic Effect, Viral, Disease Models, Animal, Epithelial Cells virology, Hemagglutinin Glycoproteins, Influenza Virus genetics, Humans, Influenza A virus genetics, Influenza A virus pathogenicity, Lung immunology, Lung pathology, Macrophages immunology, Mammals, Mice, Neutrophils immunology, Orthomyxoviridae Infections pathology, Orthomyxoviridae Infections virology, Reassortant Viruses genetics, Reassortant Viruses growth & development, Reassortant Viruses pathogenicity, Reverse Genetics, Virulence Factors genetics, Hemagglutinin Glycoproteins, Influenza Virus metabolism, Influenza A virus growth & development, Influenza in Birds virology, Virulence Factors metabolism
- Abstract
Unlabelled: Zoonotic avian influenza virus infections may lead to epidemics or pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its H1 hemagglutinin was identified as a key mammalian virulence factor. A chimeric 1918 virus expressing a contemporary avian H1 hemagglutinin, however, displayed murine pathogenicity indistinguishable from that of the 1918 virus. Here, isogenic chimeric avian influenza viruses were constructed on an avian influenza virus backbone, differing only by hemagglutinin subtype expressed. Viruses expressing the avian H1, H6, H7, H10, and H15 subtypes were pathogenic in mice and cytopathic in normal human bronchial epithelial cells, in contrast to H2-, H3-, H5-, H9-, H11-, H13-, H14-, and H16-expressing viruses. Mouse pathogenicity was associated with pulmonary macrophage and neutrophil recruitment. These data suggest that avian influenza virus hemagglutinins H1, H6, H7, H10, and H15 contain inherent mammalian virulence factors and likely share a key virulence property of the 1918 virus. Consequently, zoonotic infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals., Importance: Influenza viruses from birds can cause outbreaks in humans and may contribute to the development of pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its main surface protein, an H1 subtype hemagglutinin, was identified as a key mammalian virulence factor. In a previous study, a 1918 virus expressing an avian H1 gene was as virulent in mice as the reconstructed 1918 virus. Here, a set of avian influenza viruses was constructed, differing only by hemagglutinin subtype. Viruses with the avian H1, H6, H7, H10, and H15 subtypes caused severe disease in mice and damaged human lung cells. Consequently, infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals, and therefore surveillance for human infections with these subtypes may be important in controlling future outbreaks., (Copyright © 2014 Qi et al.)
- Published
- 2014
- Full Text
- View/download PDF
37. Molecular evidence of stress-induced acute heart injury in a mouse model simulating posttraumatic stress disorder.
- Author
-
Cho JH, Lee I, Hammamieh R, Wang K, Baxter D, Scherler K, Etheridge A, Kulchenko A, Gautam A, Muhie S, Chakraborty N, Galas DJ, Jett M, and Hood L
- Subjects
- Animals, Cell Line, Cell Proliferation, Epithelial-Mesenchymal Transition physiology, Extracellular Matrix physiology, Gene Expression Profiling, Humans, Longitudinal Studies, Mice, MicroRNAs genetics, MicroRNAs metabolism, Microarray Analysis, Stress Disorders, Post-Traumatic etiology, Stress, Psychological immunology, Systems Biology, Gene Expression Regulation physiology, Myocarditis etiology, Myocarditis metabolism, Stress Disorders, Post-Traumatic physiopathology, Stress, Psychological complications, Transcriptome physiology
- Abstract
Posttraumatic stress disorder (PTSD) is a common condition induced by life-threatening stress, such as that experienced by soldiers under battlefield conditions. Other than the commonly recognized behavioral and psychological dysfunction, epidemiological studies have also revealed that PTSD patients have a higher risk of other diseases, such as cardiovascular disorders. Using a PTSD mouse model, we investigated the longitudinal transcriptomic changes in heart tissues after the exposure to stress through intimidation. Our results revealed acute heart injury associated with the traumatic experience, reflecting the underlying biological injury processes of the immune response, extracellular matrix remodeling, epithelial-to-mesenchymal cell transitions, and cell proliferation. Whether this type of injury has any long-term effects on heart function is yet to be determined. The differing responses to stress leading to acute heart injury in different inbred strains of mice also suggest that this response has a genetic as well as an environmental component. Accordingly, the results from this study suggest a molecular basis for the observed higher risk of cardiovascular disorders in PTSD patients, which raises the likelihood of cardiac dysfunction induced by long-term stress exposures.
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.