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Hand, Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination

Saki Takahashi, Qiaohong Liao, Thomas P. Van Boeckel, Weijia Xing, Junling Sun, Victor Y. Hsiao, C. Jessica E. Metcalf, Zhaorui Chang, Fengfeng Liu, Jing Zhang, Joseph T. Wu, Benjamin J. Cowling (+6 others)
2016 PLoS Medicine  
Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials
more » ... wed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus. were used to fit multi-serotype time series susceptibleinfected-recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of PLOS Medicine | province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R 0 , weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16. Conclusions The ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden.
doi:10.1371/journal.pmed.1001958 pmid:26882540 pmcid:PMC4755668 fatcat:3nf5qonmqfcdzhoffmfzear4s4

Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc) in PericytesNovelty and Significance

Florian C. Bischoff, Astrid Werner, David John, Jes-Niels Boeckel, Maria-Theodora Melissari, Phillip Grote, Simone F. Glaser, Shemsi Demolli, Shizuka Uchida, Katharina M. Michalik, Benjamin Meder, Hugo A. Katus (+7 others)
2017 Circulation Research  
Rationale: Pericytes are essential for vessel maturation and endothelial barrier function. Long noncoding RNAs regulate many cellular functions, but their role in pericyte biology remains unexplored. Objective: Here, we investigate the effect of hypoxia-induced endoplasmic reticulum stress regulating long noncoding RNAs (HypERlnc, also known as ENSG00000262454) on pericyte function in vitro and its regulation in human heart failure and idiopathic pulmonary arterial hypertension. Methods and
more » ... lts : RNA sequencing in human primary pericytes identified hypoxia-regulated long noncoding RNAs, including HypERlnc. Silencing of HypERlnc decreased cell viability and proliferation and resulted in pericyte dedifferentiation, which went along with increased endothelial permeability in cocultures consisting of human primary pericyte and human coronary microvascular endothelial cells. Consistently, Cas9-based transcriptional activation of HypERlnc was associated with increased expression of pericyte marker genes. Moreover, HypERlnc knockdown reduced endothelial-pericyte recruitment in Matrigel assays (P<0.05). Mechanistically, transcription factor reporter arrays demonstrated that endoplasmic reticulum stress-related transcription factors were prominently activated by HypERlnc knockdown, which was confirmed via immunoblotting for the endoplasmic reticulum stress markers IRE1α (P<0.001), ATF6 (P<0.01), and soluble BiP (P<0.001). Kyoto encyclopedia of genes and gene ontology pathway analyses of RNA sequencing experiments after HypERlnc knockdown indicate a role in cardiovascular disease states. Indeed, HypERlnc expression was significantly reduced in human cardiac tissue from patients with heart failure (P<0.05; n=19) compared with controls. In addition, HypERlnc expression significantly correlated with pericyte markers in human lungs derived from patients diagnosed with idiopathic pulmonary arterial hypertension and from donor lungs (n=14). Conclusions: Here, we show that HypERlnc regulates human pericyte function and the endoplasmic reticulum stress response. In addition, RNA sequencing analyses in conjunction with reduced expression of HypERlnc in heart failure and correlation with pericyte markers in idiopathic pulmonary arterial hypertension indicate a role of HypERlnc in human cardiopulmonary disease. (Circ Res. 2017;121:368-375.
doi:10.1161/circresaha.116.310531 pmid:28611075 fatcat:lbvmaaco4vakpkaui7u422fdwi

Genomic structural variations lead to dysregulation of important coding and non‐coding RNA species in dilated cardiomyopathy

Jan Haas, Stefan Mester, Alan Lai, Karen S Frese, Farbod Sedaghat‐Hamedani, Elham Kayvanpour, Tobias Rausch, Rouven Nietsch, Jes‐Niels Boeckel, Avisha Carstensen, Mirko Völkers, Carsten Dietrich (+16 others)
2017 EMBO Molecular Medicine  
The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as noncoding RNAs. Besides this dynamic regulation, a large part of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome-wide structural genomic variants (SVs) and their association with gene expression in the human heart. We detected 3,898 individual SVs affecting all
more » ... classes of gene transcripts (e.g., mRNA, miRNA, lncRNA) and regulatory genomic regions (e.g., enhancer or TFBS). In a cohort of patients (n = 50) with dilated cardiomyopathy (DCM), 80,635 non-protein-coding elements of the genome are deleted or duplicated by SVs, containing 3,758 long non-coding RNAs and 1,756 proteincoding transcripts. 65.3% of the SV-eQTLs do not harbor a significant SNV-eQTL, and for the regions with both classes of association, we find similar effect sizes. In case of deleted protein-coding exons, we find downregulation of the associated transcripts, duplication events, however, do not show significant changes over all events. In summary, we are first to describe the genomic variability associated with SVs in heart failure due to DCM and dissect their impact on the transcriptome. Overall, SVs explain up to 7.5% of the variation of cardiac gene expression, underlining the importance to study human myocardial gene expression in the context of the individual genome. This has immediate implications for studies on basic mechanisms of cardiac maladaptation, biomarkers, and (gene) therapeutic studies alike.
doi:10.15252/emmm.201707838 pmid:29138229 pmcid:PMC5760848 fatcat:p2ipwsf7cjaupmj7akcvshqjse

Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice

Elliot D. Mock, Mohammed Mustafa, Ozge Gunduz-Cinar, Resat Cinar, Gavin N. Petrie, Vasudev Kantae, Xinyu Di, Daisuke Ogasawara, Zoltan V. Varga, Janos Paloczi, Cristina Miliano, Giulia Donvito (+27 others)
2020 Nature Chemical Biology  
N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as a CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD)
more » ... r. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus-pituitary-adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB1 receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.
doi:10.1038/s41589-020-0528-7 pmid:32393901 fatcat:2hmriodjknaafcp2b4yzbtsgqm

Ominous projections for global antibiotic use in food-animal production

Lance B. Price, Benjamin J. Koch, Bruce A. Hungate
2015 Proceedings of the National Academy of Sciences of the United States of America  
According to Van Boeckel et al.  ...  According to the findings of Van Boeckel et al. (2) in PNAS, the proliferation of ignorance is only poised to increase.  ... 
doi:10.1073/pnas.1505312112 pmid:25922534 pmcid:PMC4426449 fatcat:2mfq6gjhn5dfleelqqxojs5sum

Page 152 of English Journal Vol. 24, Issue 2 [page]

1935 English Journal  
Boeckel, ‘““Teaching Students To Read Newspapers Intelligently”’ Frank K.  ...  Marckwardt, ‘“The High-School Teacher and the Standard of Usage”’ Alain Locke, ‘Creative Expression and Suppressed Personalities” Benjamin J. R.  ... 

Page 179 of The Quarterly Journal of Economics Vol. 38, Issue 1 [page]

1923 The Quarterly Journal of Economics  
BOOKS RECEIVED Andrews, Benjamin R. Economics of the Household. Its Administra- tion and Finance. New York: Macmillan. 1923. pp. 623. Boeckel, Richard. Labor’s Money.  ... 

Page 954 of American Journal of Sociology Vol. 34, Issue 5 [page]

1929 American Journal of Sociology  
Boeckel, Florence Brewer. Between War and Peace: A Handbook for Peace Workers. New York: MacMillan. Pp. xi+so1. $2.50. Clapp, Mary A., and Strong, Mabel A.  ...  Goldstein, Benjamin F. Marketing: A Farmer’s Problem. New York: Mac- millan. Pp. xiv+ 330. $3.50. Gollock, G. A. Lives of Eminent Afri- cans. New York: Longmans, Green. Pp. viii+152. $1.25.  ... 

Page 11 of Reedy's Mirror Vol. 11, Issue 11 [page]

1901 Reedy's Mirror  
Henry Boeckeler were quietly married at the residence of Mr. and Mrs. Benjamin W. Clark, of Portland place. Only a very limited number of guests were present, and these were almost all relations.  ...  Boeckeler had for his best man, Mr. Henry Lackland, and as groomsmen, Messrs, Claude Kennerly, Hamilton Gamble, William Colladay and Charles Scudder.  ... 

Page 518 of American Journal of Sociology Vol. 29, Issue 4 [page]

1924 American Journal of Sociology  
Andrews, Benjamin Richard. Economics of the Household; Its Administration and Finance. New York: Macmillan. Pp. 623. $3.25. Angell, Norman. The Press and the Organization of Society.  ...  Boeckel, Richard. Labor’s Money. New York: Harcourt, Brace. Pp. 181. $1.50. Béhm-Bawerk, Eugene V. The Positive Theory of Capital. Translated with a Preface and Analysis by William Smart.  ... 

Page 389 of Annals of the American Academy of Political and Social Science Vol. 143, Issue [page]

1929 Annals of the American Academy of Political and Social Science  
Home Woman as Buyer AND CONTROLLER OF Consumption, Tue, Benjamin R. Andrews, 41-8. Home Workers, 53, 54; paid, 54. Home, American, 51, 52. Household Aid Company, 55.  ...  INTERNATIONAL Arrarrs, WoMEN IN, Florence Brewer Boeckel, 230-48. International Alliance of Women for Suffrage and Equal Citizenship, 245. International Arbitration Treaties, 211.  ... 

Page 195 of New Outlook Vol. 135, Issue [page]

1923 New Outlook  
By Benjamin A. Morton. G. P. Putnam’s Sons, New York. $2.50. HISTORY AND POLITICAL ECONOMY LABOR’S MONEY. By Richard Boeckel. Har- court, Brace & Co., New York. $1.50.  ... 

Page 436 of Medical News Vol. 43, Issue 16 [page]

1883 Medical News  
In 1783, one hundred years ago, John Warren, Benjamin Waterhouse, and Aaron Dexter founded the Medical School of Harvard University.  ...  Fischer, Boeckel, Nicaise, Dussutour, Tillaux, the elder and younger Gross, Agnew, Ashhurst, Lidell, and Markoe, should be abolished from practice as a dangerous expedient.  ... 

Page 2249 of JAMA: The Journal of the American Medical Association Vol. 57, Issue 27 [page]

1911 JAMA: The Journal of the American Medical Association  
., (99) 1643 Benjamin A, E., *1891 Blayney, A., (23) 344 Bowers, C. E., (99) 47 Brown, A., (21) 170, (13) 1323 Benjamin, E., (112) 435, (190) 1332 Bledsoe, E. P., 156 Gowers, L.  ...  N., (77) 1798 Bettmann, M., (103) 52, (78) 172 Boeckel, A., (54) 1167, (51) 2029 Braun, J (133) 598 Bryan, R. C., (5) 168, 1556 Betts, A. J.  ... 

Page 402 of Journal of the Louisiana State Medical Society Vol. 85, Issue 6 [page]

1932 Journal of the Louisiana State Medical Society  
Boeckel, J.: focant; guérrson por premiére intention, Mem. Soc. de mréd. de Stresb., (1879-80 17:129-132, 1881. 17. Mikulicz, J.: Beitrag zur Operation des Kropfes, Wein. med.  ...  Bell, Benjamin: Bell’s System of Surgery, Penniman and Co., Troy, N. Y., 1804. 10. Billroth, Th.: Enfalrungen, Chirur- gische Klinik Zurich, Pages 167-180, August Hirschwald, Berlin, 1869. 11.  ... 
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